Title of Invention

TETRAHYDROCARBAZOLE COMPOUNDS

Abstract The invention is concerned with novel tetrahydrocarbazole compounds of the formula (I) wherein R1, R2, R3, R4, R5, X1, X, X3, X4, n, and k are defined in the description and claims, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. The compounds are useful for in the treatment and prophylaxis of diseases which are modulated by LXRα and/or LXRß agonists, including increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as Alzheimer's disease or impaired/improvable cognitive function.
Full Text Liver-X-Receptors (LXRs) are members of the nuclear hormone receptor superfamily.
The LXRs are activated by endogenous oxysterols and regulate the transcription of
genes controlling multiple metabolic pathways. Two subtypes, LXRa and LXR|3, have
been described (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad
Sci USA.1994, 91:10809-13). LXRp is ubiquitously expressed, while LXRa is
predominantly expressed in cholesterol metabolizing tissues such as the liver, adipose,
intestine and macrophage. The LXRs modulate a variety of physiological responses
including regulation of cholesterol absorption, cholesterol elimination (bile acid
synthesis), and transport of cholesterol from peripheral tissues via plasma lipoproteins
to the liver. The LXRs are also involved in glucose metabolism, cholesterol metabolism
in the brain, cell differentiation, and inflammation.
At present, approximately half of all patients with coronary artery disease have low
concentrations of plasma high-density lipoprotein cholesterol (HDL-C). The
atheroprotective function of HDL was first highlighted almost 25 years ago and
stimulated exploration of the genetic and environmental factors that influence HDL-C
levels (Miller NE., Lipids 1978,13:914-9). The protective function of HDL derives
from its role in a process termed reverse cholesterol transport. HDL mediates the
removal of cholesterol from cells in peripheral tissues, including macrophage foam
cells in the atherosclerotic lesions of the arterial wall. HDL delivers its cholesterol to
the liver and sterol-metabolizing organs for conversion to bile and elimination in feces.
Studies have shown that HDL-C levels are predictive of coronary artery disease risk
independently of low-density lipoprotein cholesterol (LDL-C) levels (Gordon et al., Am
JMed. 1977, 62:707-14).
At present, the estimated age-adjusted prevalence among Americans age 20 and older
who have HDL-C of less than 35 mg/dl is 16% (males) and 5.7 % (females). A
substantial increase of HDL-C is currently achieved by treatment with niacin in various
formulations. However, the substantial unfavorable side-effects limit the therapeutic
potential of this approach.
It has been observed that as many as 90% of the 14 million diagnosed type 2 diabetic
patients in the United States are overweight or obese, and a high proportion of type 2
diabetic patients have abnormal concentrations of lipoproteins. Studies have shown
that the prevalence of total cholesterol > 240 mg/dl is 37% in diabetic men and 44% in
women. The rates for LDL-C > 160 mg/dl are 31% and 44%, and for HDL-C mg/dl are 28% and 11%, in diabetic men and women respectively. Diabetes is a disease
in which a patient's ability to control glucose levels in blood is decreased because of
partial impairment in response to the action of insulin. Type II diabetes (T2D) is also
called non-insulin dependent diabetes mellitus (NIDDM) and has been shown to afflict
80-90 % of all diabetic patients in developed countries. In T2D, the pancreatic Islets of
Langerhans continue to produce insulin. However, the target organs for insulin action,
mainly muscle, liver and adipose tissue, exhibit a profound resistance to insulin
stimulation. The body continues to compensate by producing unphysiologically high
levels of insulin, which ultimately decreases in the later stages of the disease, due to
exhaustion and failure of pancreatic insulin-producing capacity. Thus, T2D is a
cardiovascular-metabolic syndrome associated with multiple co-morbidities, including
insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and
inflammatory atherosclerosis.
The first line of treatment for dyslipidemia and diabetes at present generally involves a
low-fat and low-glucose diet, exercise and weight loss. However, compliance can be
moderate, and as the disease progresses, treatment of the various metabolic deficiencies
becomes necessary with lipid-modulating agents such as statins and fibrates for
dyslipidemia, and hypoglycemic drugs, e.g. sulfonylureas, metformin, or insulin
sensitizers of the thiazolidinedione (TZD) class of PPARy-agonists, for insulin
resistance. Recent studies provide evidence that modulators of LXRs would result in
compounds with enhanced therapeutic potential, and as such, modulators of LXRs
should improve the plasma lipid profile, and raise HDL-C levels (Lund et al.,
Arterioscler. Thromb. Vase. Biol. 2003, 23:1169-77). LXRs are also known to control
the efflux of cholesterol from the macrophage foam cell of the atherosclerotic lesion,
and agonists of LXRs have been shown to be atheroprotective (Joseph and Tontonoz,
Curr. Opin. Pharmacol. 2003, 3:192-7). Thus, modulators of LXRs would be effective
treatments for the atherosclerotic disease which underlies the cardiovascular morbidity
and mortality of stroke and heart disease. Recent observations also suggest that there is
an independent LXR mediated effect on insulin-sensitization in addition to its role in
atheroprotection (Cao et al., J Biol Chem. 2003, 278:1131-6). Thus LXR modulators
can also show superior therapeutic efficacy on HDL-raising and atheroprotection, with
additional effects on diabetes, compared to current therapies.
The present invention is concerned with novel liver-X-receptor modulators, their
manufacture and their use as medicaments. In particular, the invention relates to
compounds of the formula (I)
wherein
n is an integer selected from 0 to 3;
R1 is independently selected from the group consisting of halogen, -CN, -NO2,
-SO2Me, lower alkyl, trifluoromethoxy, -OR11, piperidinyl, pyrrolidinyl, and -
N(R11)(R11), wherein R" is independently selected from lower alkyl and H,
X1, X2, X3, and X4 are independently selected from nitrogen and carbon, provided
that no more than two of X1, X2, X3, and X4 can be nitrogen at one time, and
when two of X1, X2, X3, and X4 are nitrogen, n is 0, 1, or 2;
k is an integer from 0 to 1;
R3 is H, alkyl, or halogen;
R4 is aryl, heteroaryl, alkylaryl or alkylheteroaryl, all being optionally substituted
with from one to five substituents independently selected from the group
consisting of halogen, alkyl, -OR41, lower alkynyl, and NR42R43, wherein R41 is
lower alkyl or -H, R42 and R43 independently from each other are hydrogen or
alkyl, or NR42R43 is piperidinyl or pyrrolidinyl, or R4 is alkyl;
R" is selected from the group consisting of
(Figure Removed)
said aryl and heteroaryl being optionally substituted at one or more positions
with one or more susbtituents independently selected from the group consisting
of H, halogen, lower alkyl and (CH2)VR53, wherein
R51 is selected from the group consisting of H, alkyl, lower alkenyl and
alkylaryl, said alkylaryl being optionally substituted at one or more
positions with one or more of lower alkyl, -CN, halogen, -COOR54, and -
CH2OR54, wherein R54 is alkyl or -H;
R52 is lower alkyl or -H;
R53 is H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -
CONH2,
-CH2OR55 or -CONR55R56, wherein R55 is independently selected from the
group consisting of alkyl ,-H, -C(O)-aryl, -C(O)-alkyl, or -C(O)-heteroaryl,
and R56 is selected from the group consisting of H, alkyl, C(O)CF3, -C(O)-
aryl, -C(O)-alkyl,
-C(O)-heteroaryl, alkylaryl and alkylheteroaryl, and wherein said aryl,
heteroaryl, alkylaryl and alkyl-heteroaryl are optionally substituted at one or
more positions with one or more of alkyl, -CN, halogen, -COOR57, and -
CH2OR57, wherein R57 is lower alkyl or -H, or R5S and R56 together with
the atom to which they are attached form a ring;
or R53 is aryl which can optionally be substituted with benzyloxy, carboxy,
lower-alkoxy-carbonyl, hydroxy-lower-alkyl, halogen, carbamoyl, loweralkyl-
carbamoyl, di-lower-alkyl-carbamoyl,
m is an integer selected from 0 to 2;
v is an integer selected from 0 to 4;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters
thereof.
The novel compounds of the present invention have been found to bind to and
selectively activate LXRa or LXRp or coactivate LXRa and LXRp. Consequently,
cholesterol absorption is reduced, HDL cholesterol is increased, and inflammatory
atherosclerosis is reduced. Since multiple facets of combined dyslipidemia and
cholesterol homeostasis are addressed by LXR modulators, novel compounds of the
present invention have an enhanced therapeutic potential compared to the compounds
already known in the art. They can therefore be used in the treatment and prophylaxis of
diseases which are modulated by LXRa and/or LXRp agonists. Such diseases include
increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDLcholesterol,
atherosclerotic diseases, diabetes, particularly non-insulin dependent
diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and
inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, and
diseases that have an inflammatory component such as Alzheimer's disease or
impaired/improvable cognitive function. The novel compounds of the present can
further be used for treatment and prophylaxis of age-related macular degeneration.
The present invention also relates to pharmaceutical compositions comprising a
compound of formula I and a pharmaceutically acceptable carrier and/or adjuvant.
Furthermore, the present invention relates to the use of such compounds as therapeutic
active substances as well as their use for the preparation of medicaments for the
treatment or prophylaxis of diseases which are modulated by LXRa and/or LXRp
agonists. The invention further relates to processes for the preparation of the
compounds of formula I. In addition, the present invention relates to a method for the
prophylaxis or therapeutic treatment of diseases modulated by LXRa and/or LXRp
agonist, such as increased lipid and cholesterol levels, particularly low HDLcholesterol,
high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly noninsulin
dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's
disease, sepsis, and inflammatory diseases such as colitis, pancreatitis,
cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such
as Alzheimer's disease or impaired/improvable cognitive function, said method
comprising administering a compound of formula I to a human being or animal.
In more detail, the invention relates to compounds of the formula (I)
wherein
n is an integer selected from 0 to 3;
R1 is independently selected from the group consisting of halogen, -CN, -NO2,
-SO2Me, lower alkyl, trifluoromethoxy, -OR11, piperidinyl, pyrrolidinyl, and -
N(Rn)(Rn), wherein R11 is independently selected from lower alkyl and H,
X1, X2, X3, and X4 are independently selected from nitrogen and carbon, provided
that no more than two of X1, X2, X3, and X4 can be nitrogen at one time, and
when two of X1, X2, X3, and X4 are nitrogen, n is 0, 1, or 2;
k is an integer from 0 to 1;
R2 is H;
R3 is H, alkyl, or halogen;
R4 is aryl, heteroaryl, alkylaryl or alkylheteroaryl, all being optionally substituted
with from one to five substituents independently selected from the group
consisting of halogen, alkyl, -OR41, lower alkynyl, and NR42R43, wherein R41 is
)42 „ . r>43 lower alkyl or -H, R and R independently from each other are hydrogen or
alkyl, or NR42R43 is piperidinyl or pyrrolidinyl, or R4 is alkyl;
Rs is selected from the group consisting of
I (CH2)m COOR51 ; I (CH2)m OR51;
-CONR52R51. ) (CH2)m CN
(CH
2)m-aryl; and ) (CH2)m-heteroaryl;
said aryl and heteroaryl being optionally substituted at one or more positions
with one or more susbtituents independently selected from the group consisting
of H, halogen, lower alkyl and (CH2)VR53, wherein
R51 is selected from the group consisting of H, alkyl, lower alkenyl and
alkylaryl, said alkylaryl being optionally substituted at one or more
positions with one or more of lower alkyl, -CN, halogen, -COOR54, and -
CH2OR54, wherein R54 is alkyl or -H;
R52 is lower alkyl or -H;
R53 is H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -
CONH2,
-CH2OR55 or -CONRS5R56, wherein R55 is independently selected from the
group consisting of alkyl ,-H, -C(O)-aryl, -C(O)-alkyl, or -C(O)-heteroaryl,
and R56 is selected from the group consisting of H, alkyl, C(O)CF3, -C(O)-
aryl, -C(O)-alkyl,
-C(O)-heteroaryl, alkylaryl and alkylheteroaryl, and wherein said aryl,
heteroaryl, alkylaryl and alkyl-heteroaryl are optionally substituted at one or
more positions with one or more of alkyl, -CN, halogen, -COOR57, and -
CH2OR57, wherein R57 is lower alkyl or -H, or R55 and R56 together with
the atom to which they are attached form a ring;
or R53 is aryl which can optionally be substituted with benzyloxy, carboxy,
lower-alkoxy-carbonyl, hydroxy-lower-alkyl, halogen, carbamoyl, loweralkyl-
carbamoyl, di-lower-alkyl-carbamoyl,
m is an integer selected from 0 to 2;
v is an integer selected from 0 to 4;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters
thereof.
Preferred compounds of formula (I) as defined above are those, wherein
n is an integer selected from 0 to 3;
R1 is independently selected from the group consisting of halogen, -C"N, -NO2,
-SO2Me, lower alkyl, trifluoromethoxy, -OR11, and -N(RH)(Rn), wherein R11 is
independently selected from lower alkyl and H;
X1, X2, X3, and X4 are independently selected from nitrogen and carbon, provided that
no more than two of Xi, X2, Xs, and X4 can be nitrogen at one time, and when
two of Xi, X2, Xa, and X4 are nitrogen, n is 0, 1, or 2;
k is an integer from 0 to 1;
R2 is H;
R3 is H, alkyl, or halogen;
R4 is aryl, heteroaryl, alkylaryl or alkylheteroaryl, all being optionally substituted
with from one to five substituents independently selected from the group
consisting of halogen, alkyl and -OR41, wherein R41 is lower alkyl or -H, or R4
is alkyl;
R5 is selected from the group consisting of
(Figure Removed)
said aryl and heteroaryl being optionally substituted at one or more
positions with one or more susbtituents independently selected from the
group consisting of H, halogen, lower alkyl and (CH2)VR53, wherein
R51 is selected from the group consisting of H, alkyl, allyl and alkylaryl,
said alkylaryl being optionally substituted at one or more positions with one
or more of lower alkyl, -CN, halogen, -COOR54, and -CH2OR54, wherein
R54 is alkyl or-H;
R52 is lower alkyl or-H;
R53 is H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, -
CONH2, -CH2ORSS or -CONRS5R56, wherein R55 is independently selected
from the group consisting of alkyl ,-H, -C(O)-aryl, -C(O)-alkyl, or -C(O)-
heteroaryl, and R56 is selected from the group consisting of H, alkyl, -C(O)-
aryl, -C(O)-alkyl, -C(O)-heteroaryl, alkylaryl and alkylheteroaryl, and
wherein said aryl, heteroaryl, alkylaryl and alkyl-heteroaryl are optionally
substituted at one or more positions with one or more of alkyl, -CN,
halogen, -COOR57, and -CH2OR57, wherein R57 is lower alkyl or -H, or
R55 and R56 taken together with the atom to which they are attached form a
ring;
m is an integer selected from 0 to 2;
v is an integer selected from 0 to 4;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters
thereof.
Unless otherwise indicated, the following definitions are set forth to illustrate and
define the meaning and scope of the various terms used to describe the invention
herein.
The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine,
chlorine and bromine being preferred.
The term "alkyl", alone or in combination with other groups, refers to a branched or
straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty
carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten
carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups.
The term "lower alkyl", alone or in combination with other groups, refers to a branched
or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to
four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, npropyl,
isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term "lower alkenyl", alone or in combination, signifies a straight-chain or
branched hydrocarbon residue comprising an olefmic bond and 2 to 8, preferably 2 to 6,
particularly preferred 2 to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1 -
propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl
and isobutenyl.
The term "lower alkynyl", alone or in combination with other groups, stands for a
straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7,
preferably up to 4 carbon atoms, such as e.g. 2-propinyl or ethinyl.
The term "cycloalkyl" refers to a monovalent carbocyclic radical of 3 to 10 carbon
atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl.
The term "aryl" refers to either an aromatic monocyclic system containing six carbon
atoms or an aromatic bicyclic system containing 10 carbon atoms. For example, the
term aryl includes a phenyl or naphthyl ring system, preferably the phenyl group. The
term "alkylaryl" refers to an aryl group which is bound via an alkyl group, e.g. benzyl.
The term "heteroaryl" refers to an aromatic 5- or 6-membered ring which can comprise
1-4 heteroatoms selected from nitrogen, oxygen and/or sulphur, such as furyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or
pyrrolyl. The term "heteroaryl" also includes a heteroaryl as defined above fused to one
or more other cycle be it a heterocycle, aryl, or heteroaryl, for example benzothiazolyl.
The term "alkylheteroaryl" refers to a heteroaryl group which is bound via an alkyl
group.
The term "pharmaceutically acceptable salts" embraces salts of the compounds of
formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid,
nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic
acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, ptoluenesulphonic
acid and the like, which are non toxic to living organisms. Preferred
salts are phosphates, citrates, fumarates, formates, hydrochlorides, hydrobromides and
methanesulfonic acid salts.
The term "pharmaceutically acceptable esters" embraces esters of the compounds of
formula (I), in which hydroxy groups have been converted to the corresponding esters
with inorganic or organic acids such as, nitric acid, sulphuric acid, phosphoric acid,
citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid,
methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to
living organisms.
Preferred are compounds of formula (I) wherein each of X1, X2, X3, and X4 are carbon.
Also preferred are compounds of formula (I), wherein X1 is nitrogen and each of X2,
X3, and X4 is carbon.
In another embodiment, compounds of formula (I) are preferred wherein n is 1, X2 is
carbon and R1 is directly attached to the X2 carbon. Compounds wherein R1 is selected
from the group consisting of halogen, preferably Cl, cyano, nitro, SOaMe, lower alkyl,
and N(Me)2 are more particulary preferred. Another preferred embodiment relates to
compounds wherein R1 is selected from the group consisting of halogen, cyano, nitro,
SO2Me, lower alkyl, N(Me)2, NHMe and piperidinyl.
Also preferred are compounds according to formula (I), wherein R1 is halogen.
Particularly preferred are those compounds of formula (I), wherein R1 is Cl.
Further preferred compounds of formula (I) are those, wherein n is 2.
In another embodiment, compounds of formula (I) are preferred wherein n is 2, and
each R1 is halogen. More preferably, X2 is carbon, and one of the two R1 groups is
directly attached to the X2 carbon.
In yet another preferred embodiment, compounds of formula (I) are preferred wherein k
is 0 or 1, more preferably wherein k is 0. Compounds wherein k is 0 and wherein k is 1
individually constitute preferred embodiments.
In another preferred embodiment of the present invention, R3 of formula (I) is H,
halogen or methyl. Preferably, R3 is F or methyl. F and methyl individually constitute
preferred embodiments.
Another preferred embodiment relates to compounds as defined above, wherein R4 is
aryl or heteroaryl, all being optionally substituted with from one to five substituents
independently selected from the group consisting of halogen, alkyl, -OR41, lower
alkynyl, and NR42R43, wherein R41 is lower alkyl or -H, R42 and R43 independently
from each other are hydrogen or alkyl, or NR42R43 is piperidinyl or pyrrolidinyl, or R4 is
lower alkyl
Compounds as defined above, wherein R4 is selected from the group consisiting of
napthyl, pyridinyl, methyl, phenyl or mono-or di-substituted phenyl, wherein the phenyl
substituents are halogen, N(lower alkyl)2 or OR41, and wherein R41 is defined as above,
are also preferred.
Also preferred are those compounds of formula (I), wherein R4 is aryl, heteroaryl, or
lower alkyl.
Further preferred compounds of formula (I) are those, wherein R4 is selected from the
group consisiting of napthyl, pyridinyl, methyl, phenyl or mono-or di-substituted
phenyl, wherein the phenyl substituents are halo or OR41, and wherein R41 is lower
alkyl or hydrogen.
Further preferred compounds of the present invention are those wherein R4 is aryl or
heteroaryl which is optionally subsituted at one or more positions with lower alkyl.
More particularly, compounds wherein R4 is selected from the group consisiting of
phenyl; mono-or di-substituted phenyl wherein the one or more substituents are halo or
OR41; naphthyl; pyridinyl; or methyl are preferred. More particularly, compounds of
formula (I) are preferred wherein R4 is phenyl, or mono- or di-susbituted phenyl
wherein the one or more substituents is halogen, more preferably R4 is phenyl, 4-
chlorophenyl, 3-fluorophenyl, or 3,4-difluorophenyl. Another preferred embodiment of
the present invention relates to compounds as described above, wherein R4 is phenyl, 3-
bromophenyl or 3-dimethylaminophenyl.
In yet another preferred embodiment of compounds of formula (I) of the present
invention, R5 is selected from the group consisting of
(CH
2)m -COOR51 . - (CH2)m -OR51
\ (CH2)m CN ; j (CH2)_ CONR52R51 .
and ) (CH2)m-heteroaryl;
said heteroaryl being optionally substituted at one or more positions with one or
more susbtituents independently selected from the group consisting of H, halogen,
lower alkyl and (CH2)VR53, wherein R51 is selected from the group consisting of H,
alkyl, and alkylaryl, said alkylaryl being optionally substituted at one or more
positions with one or more of lower alkyl, -CN, halogen, -COOR54, and -CH2OR54,
wherein R54 is alkyl or -H; R52 is lower alkyl or -H; R53 is H, alkyl, cycloalkyl, -
COOR55, -N(R5S)(R56), -CH2OH, -CN, -CONH2, -CH2OR55 or -CONR5SR56,
wherein R55 is independently selected from the group consisting of alkyl ,-H, -
C(O)-aryl, -C(O)-alkyl, or -C(O)-heteroaryl, and R56 is selected from the group
consisting of H, alkyl, -C(O)-aryl, -C(O)-alkyl, -C(O)-heteroaryl, alkylaryl and
alkylheteroaryl, and wherein said aryl, heteroaryl, alkylaryl and alkyl-heteroaryl are
optionally substituted at one or more positions with one or more of alkyl, -CN,
halogen, -COOR57, and -CH2OR57, wherein R57 is lower alkyl or -H, or R5S and
R56 taken together with the atom to which they are attached form a ring; m is an
integer selected from 0 to 2; and v is an integer selected from 0 to 4. In a preferred
embodiment, m is 0.
In yet antother preferred embodiment of compounds of the present invention, R5 is
selected from the group consisting of
(Figure Removed)
wherein RS1 is selected from the group consisting of H; alkyl; alkylaryl optionally
mono- or di- substituted at with one or more of lower alkyl, -CN, halogen, or -COOR54
wherein R54 is alkyl or -H; and R52 is lower alkyl or H and, wherein m is defined as
before.
Alternatively, compounds of formula (I) wherein Rs is selected from the group
consisting of
(CH2)m-heteroaryl;
said heteroaryl being optionally substituted at one or more positions with one or more
substituents independently selected from the group consisting of H, halogen, lower
alkyl and (CH2)VR53 are also preferred, wherein m, v and R53 are defined as before.
More preferably, the heteroaryl is selected from the group consisting of
(Figure Removed)
wherein v and R53 are defined as before, R58 is independently selected from H,
halogen and lower alkyl, D1 is O or S, and D2 is O, S, or NR58, and wherein, when
said compound contains two (CH2)-R53 groups, said groups may be optionally
joined together along with the atoms to which they are attached to form a ring.
In an alternative preferred embodiment, preferred compounds of formula (1) are those
wherein Rs is selected from the group consisting of
(CH2)m-aryl;
wherein aryl is selected from the group consisting of:
(Figure Removed)
wherein R53 is described as before, and wherein Xs, X6, X7, X8 and X9 are selected from
carbon and nitrogen with the proviso that no more than two of Xs, X6, X7, X8 and X9
can be N at one time, and wherein m and v are defined as before. Preferably, m is 0.
Preferably, aryl is phenyl substituted with -(CH2)VR53, wherein R53 and v are as
described above.
Preferred compounds as defined above are those, wherein R5 is a heteroaryl selected
from the group consisting of oxadiazolyl, oxazolyl and benzothiazolyl, which heteroaryl
is optionally substituted with lower alkyl, lower alkoxy carbonyl or phenyl, which
phenyl is optionally substituted with carboxy, lower alkyl carbonyl, carbamoyl or di
(lower alkyl) carbamoyl. More preferred are those compounds, wherein R5 is 5-methyI-
(l,3,4)oxadiazol-2-yl, 5-(4-benzoic acid methyl ester)-(l,3,4)oxadiazol-2-yl, 5-(4-
benzoic acid)-(l,3,4)oxadiazol-2-yl, 5-(4-benzamide)-(l,3,4)oxadiazol-2-yl, 5-(4-
dimethylbenzamide)-(l,3,4)oxadiazol-2-yl, 4-(carboxylic acid methyl ester)-oxazo-2-yl
or benzothiazol-2-yl.
Preferred compounds of formula (I) are those of formula (la)
(la)
wherein R1, R2, R3, R4, R5, n, k, X1, X2, X3 and X4 are defined as before. Preferably, R3
is halogen or alkyl.
Further preferred compounds of formula (I) are those of formula (Ib)
wherein R1, R2, R3, R4, R5, n, k, X1, X2, X3 and X4 are defined as before. Preferably, R3
is halogen or alkyl.
Particular preferred are those compounds of formula (I), wherein m is zero.
Preferred compounds of general formula (I) are those selected from the group
consisting of
Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-17/-carbazol-2-yl)-acetic acid methyl
ester;
Benzenesulfonyl-(6-fluoro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-acetic acid methyl
ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-lHcarbazol-2-yl)-propionic
acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-fluoro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-propionic
acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-propionic
acid methyl ester;
RS,SR)-2-Benzenesulfonyl-2-(6-nitro-2,3,4,9-tetrahydro-l/H-carbazol-2-yl)-propionic
acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-cyano-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-propionic
acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)-
propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(2,3,4,9-tetrahydro-l/H/-carbazol-2-yl)-propionic acid
methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-methanesulfonyl-2,3,4,9-tetrahydro-lH-carbazol-2-
yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(8-fluoro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-propionic
acid methyl ester;
RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-acetic
acid methyl ester;
(RS,SR)-Benzenesulfonyl-fluoro-(6-methyl-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-acetic
acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-cyano-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-acetic
acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-bromo-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-acetic
acid methyl ester;
(RS,SR)-Benzenesulfonyl-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)-
fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-l/H/-carbazol-2-yl)-
fluoro-acetic acid methyl ester;
(RS,SR-Benzenesulfonyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro-l/Hcarbazol-2-yl)-
fluoro-acetic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-bromo-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-cyano- 1,2,3, 4-tetrahydro-cyclopenta[b]indol-2-yl)-
propionic acid methyl ester;
propionic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoroacetic
acid methyl ester;
(RS,SR-Benzenesulfonyl-(7-bromo-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoroacetic
acid methyl ester;
yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-bromo-6-fluoro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-bromo-8-fluoro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-acetic acid methyl ester;
propionic acid methyl ester;
propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-l/f-carbazol-2-yl)-2-(3,4-dichlorobenzenesulfonyl)-
propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-(toluene-3-sulfonyl)-
propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-(3-methoxybenzenesulfonyl)-
propionic acid methyl ester;
(RS,SR)-2-(2-Chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-
yl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-(2-methoxybenzenesulfonyl)-
propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-(4-fluorobenzenesulfonyl)-
propionic acid methyl ester;
(RS,SR)-2-(3-Chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-l/f-carbazol-2-
yl)-propionic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-(4-fluorobenzenesulfonyl)-
acetic acid methyl ester;
(RS,SR)-(3-Chloro-benzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-
fluoro-acetic acid methyl ester;
benzenesulfonyl)-acetic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-(3,4-difluorobenzenesulfonyl)-
fluoro-acetic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-lfl-carbazol-2-yl)-fluoro-(pyridine-3-sulfonyl)-
acetic acid methyl ester;
benzenesulfonyl)-acetic acid methyl ester;
yl)-fluoro-acetic acid methyl ester;
sulfonyl)-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-fluorobenzenesulfonyl)-
acetic acid methyl ester;
benzenesulfonyl)-fluoro-acetic acid methyl ester;
sulfonyl)-acetic acid methyl ester;
sulfonyl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionic
acid;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-acetic
acid;
l//-carbazole;
(RS,SR)-2-Benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionitrile;
RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionitrile;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoroacetonitrile;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-
N -methyl-acetam ide ;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-
fluoro-N-methyl-acetamide;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-lfl'-carbazol-2-yl)-2-fluoro-2-(3-fluorobenzenesulfonyl)-
N-methyl-acetamide;
(RS,SR)-2-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-2-(3-fluorobenzenesulfonyl)-
N-methyl-acetamide;
N,N-dimethyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-
fluoro-N,N-dimethyl-acetamide;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-2-(3-fluorobenzenesulfonyl)-
N,N-dimethyl-acetamide;
(RS,SR)-2-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-2-(3-fluorobenzenesulfonyl)-
N,N-dimethyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-N-(4-
cyano-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-N-(4-bromo-benzyl)-2-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-N-(3,5-
difluoro-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-4-({[2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-
fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid methyl ester;
(RS,SR)-3-({[2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-
fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-N-(2-
cyano-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-N-Allyl-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-N-(3-
cyano-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-3-({[2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-
fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-
N-(3-hydroxymethyl-benzyl)-N-methyl-acetamide;
l,2,3,4-tetrahydro-cyclopenta[b]indole;
(S)-2-[(R)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole;
(R)-2-[(S)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[l-Ben2enesulfonyl-l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-(Benzenesulfonyl-fluoro-[l,3,4]oxadiazol-2-yl-methyl)-7-chloro- 1,2,3,4-
tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[Benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[Benzenesulfonyl-(5-cyclopropyl-[l,3;4]oxadiazol-2-yl)-fluoro-methyl]-6-
chloro-2,3,4,9-tetrahydro-l//-carbazole;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-amine;
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-amine;
l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-5-[Benzenesulfonyl-(7-chloro- 1,2,3, 4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methanol;
fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid;
(RS,SR)-5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid amide;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yI)-
fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-amine;
yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole;
yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione;
fluoro-methyl]-[l,2,4]oxadiazol-3-yI}-methylamine;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-dimethyl-amine;
(RS,SRBenzenesulfonyl-CT-chloro-l^^^-tetrahydro-cyclopentafbJindol^-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-diethyl-amine;
(RS,SR)-{5-[Benzenesulfony[-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-diethyl-amine;
RS,SR-(Benzenesulfonyl-benzooxazol^-yl-fluoro-methyO-y-chloro-l^^^-
tetrahydro-cyclopenta[b]indole;
(RS,SR)-N-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-acetamide;
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-benzamide;
(RS,SR-2-Benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionic
acid methyl ester;
RS,SR)-2-Benzenesulfonyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionic acid methyl ester;
(6-Bromo-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-methanesulfonyl-acetic acid methyl
ester
(RS,SR)-2-(6-Bromo-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-methanesulfonyl-propionic
acid methyl ester;
(RS,SR)-2-(6-Dimethylamino-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-methanesulfonylpropionic
acid methyl ester;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters
thereof.
Other preferred compounds of general formula (I) are those selected from the group
consisting of
(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-acetic
acid methyl ester;
(RS, SR)-2-(3-bromo-benzenesulfonyl)-2-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-propionic acid methyl ester;
(RS, SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-(3-pyrrolidin-l-ylbenzenesulfonyl)-
propionic acid methyl ester;
(RS, SR) 2-[l-(3-bromo-benzenesulfonyl)-l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-
methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) 2-[(5-benzyl-[l,3,4]oxadiazol-2-yl)-(3-bromo-benzenesulfonyl)-fluoromethyl]-
7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) {3-[(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methanesulfonyl]-phenyl}-dimethyl-amine;
(RS, SR)-7-chloro-2-[(3-ethynyl-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-
yl)-methyl]-1,2,3,4-tetrahydro-cyclopenta[b] indole;
(RS, SR)-2-[5-(4-benzyloxy-benzyl)-[l,3,4]oxadiazol-2-yl-(3-bromo-benzenesulfonyl)-
fluoro-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR)-7-chloro-2-[(3-ethyl-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-
yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl
ester;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid;
(RS, SR) (4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-phenyl)-methanol;
(RS, SR) 2-{benzenesulfonyl-fluoro-[5-(4-iodo-benzyl)-[l ,3,4]oxadiazol-2-yl]-
methyl}-7-chloro-l,2,3,4-tetrahydro-cycIopenta[b]indole;
(RS, SR) 4-{5-[(benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-methyl]-[l ,3,4]oxadiazol-2-yl}-benzoic acid;
(RS, SR) 4-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,3,4]oxadiazol-2-ylmethyl}-benzoic acid;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzamide;
(RS, SR) 4- {5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-N-methyl-benzamide;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide;
(RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-
bromo-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-
piperidin-l-yl-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)- N-{2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-
l,2,3,4-tetrahydro-cyclopenta[b]indol-7-yi}-N-methyl-amine;
2-[benzenesulfonyl-fluoro-(5-trifluoromethyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-(l-benzenesulfonyl-2-methoxy-l-methyl-ethyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indole;
(RS,SR)-2-benzenesulfonyl-2-(-6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-fluoro-
N-methyl-N-(3-methyl-but-2-enyl)-acetamide;
(RS,SR)-5-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[ 1,2,4]oxadiazole-3-carbonitrile;
(RS,SR)-{5-[-benzenesulfonyl-(-6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoromethyl]-[
l,2,4]oxadiazol-3-yl}-dimethyl-amine;
(RS,SR)-4-[({5-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-methyl]-[l ,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl
ester;
(RS,SR)-3-[({5-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-methyl]-[l ,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl
ester;
(RS,SR)-{4-[({5-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-phenyl}-methanol;
(RS,SR)-2-(benzenesulfonyl-pyridin-2-yl-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indole;
(RS,SR)-N-{5-[(S)-benzenesulfonyl-((R)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-2,2,2-trifluoroacetamide
2-[benzenesulfonyl-fluoro-(3-phenyl-[l,2,4]oxadiazol-5-yl)-methyl]-7-chloro-1,2,3,4-
tetrahydro-cyclopenta[b] indo le;
(RS,SR)-2-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-oxazole-4-carboxylic acid methyl ester;
2-(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b] indole;
(RS,SR)-2-[-benzenesulfonyl-(4,5-dimethyl-oxazol-2-yl)-methyl]-7-chloro-l,2,3,4-
tetrahydro-cyclopenta[b]indole;
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Particularly preferred compounds of the general formula (I) are those selected from the
group consisting of
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionic
acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetic
acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
propionic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoroacetic
acid methyl ester;
RS,SR)-Benzenesulfonyl-(7-bromo-8-fluoro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fiuoro-acetic acid methyl ester;
(RS,SR)-(3-Chloro-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-fluorobenzenesulfonyl)-
acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-(3,4-difluorobenzenesulfonyl)-
fluoro-acetic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-2-(3-fluorobenzenesulfonyl)-
N,N-dimethyl-acetamide;
l,2,3,4-tetrahydro-cyclopenta[b]indole;
(S)-2-[(R)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole;
(R)-2-[(S)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[Benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-7-
chloro- 1 ,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,354]oxadiazol-2-yl}-dimethyl-amine;
1 ,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-amine;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters
thereof.
Other particularly preferred compounds of the general formula (I) are those selected
from the group consisting of
(RS, SR)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-
methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) {3-[(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methanesulfonyl]-phenyl}-dimethyl-amine;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl
ester;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzamide;
(RS, SR) 4- {5 -[(3 -bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide;
(RS,SR)-2-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-oxazole-4-carboxylic acid methyl ester;
2-(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indole;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters
thereof.
The compounds of formula (I) can contain several asymmetric centres and can be
present in the form of optically pure enantiomers, mixtures of enantiomers such as, for
example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers,
diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically
active forms can be obtained for example by resolution of the racemates, by asymmetric
synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or
eluent).
The compounds of formula (I), the pharmaceutically acceptable salts of the
compounds of formula (I) and the pharmaceutically acceptable esters of the compounds
of formula (I) individually constitute preferred embodiments of the present invention.
Particularly preferred are compounds of formula (I).
It will be appreciated that the compounds of the general formula (I) in this invention
may be derivatized at functional groups to provide derivatives which are capable of
conversion back to the parent compound in vivo.
The present invention also relates to a process for the manufacture of compounds of
formula (I) as described above, the process comprising reacting a compound of formula
(Figure Removed)
wherein R2, R3, R4, R5, and k have the significances given above, with a compound of
formula III
(Figure Removed)
wherein R1, n, X1, X2, X3, and X4 have the significances given above, and optionally
converting the compound of formula I to a pharmaceutically acceptable salt and/or a
pharmaceutically acceptable ester.
Reactions of a compound of formula (II) with a hydrazine of formula (III) can be
carried out by procedures known in the art and as described in Scheme 1 below. For
example, when reacting a substituted aryl hydrazine with a compound of formula (II),
pure acetic acid between RT and 40 °C when k is 1, and between RT and 75°C when k
is 0, can be employed in the modified Fischer-Indole synthesis. Alternatively, when
reacting a heteroaryl hydrazine, reaction can take place at 120 °C in a sealed tube.
In another embodiment, when compounds of formula (I) contain an R5 group that is a
tertiary amide, compounds of formula I can be carried out by procedures known in the
art and as described in Scheme 5 and Scheme 6 below.
The invention further relates to compounds of formula (I) as defined above, when
manufactured according to a process as defined above.
As described above, the compounds of formula (I) of the present invention can be used
as medicaments for the treatment and/or prevention of diseases which are modulated by
LXRa and/or LXRp agonists. Examples of such diseases are increased lipid and
cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol,
atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus,
metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, inflammatory diseases
such as colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an
inflammatory component such as Alzheimer's disease or impaired/improvable
cognitive function. The use of compounds of formula (I) for in the treatment of
atherosclerosis, low HDL cholesterol levels, non-insulin dependent diabetes mellitus,
and metabolic syndrome is preferred. The compounds of formula (I) can further be used
for treatment and prophylaxis of age-related macular degeneration.
The invention therefore also relates to pharmaceutical compositions comprising a
compound of formula (I) as defined above and a pharmaceutically acceptable carrier
and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutic
active substances, particularly as therapeutic active substances for the treatment and/or
prophylaxis of diseases which are modulated by LXRct and/or LXRP agonists.
Preferred examples of such diseases are atherosclerosis, increased lipid and cholesterol
levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent
diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and
inflammatory diseases.
In another embodiment, the invention relates to a method for the treatment and/or
prophylaxis of diseases which are modulated by LXRa and/or LXRP agonists, such as
e.g. atherosclerosis, increased lipid and cholesterol levels, particularly low HDLcholesterol,
high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic
syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases, the
method comprising administering a compound of formula (I) to a human or animal.
Further preferred is a method for the treatment and/or prophylaxis of diseases which are
modulated by LXRa and/or LXRP agonists, the method comprising administering a
compound as defined above to a human being or animal in particular, wherein said
disease is selected from the group consisiting of increased lipid and cholesterol levels,
particularly low HDL-cholesterol and/or high LDL-cholesterol, atherosclerotic diseases,
diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome,
dyslipidemia, sepsis, inflammatory diseases including colitis, pancreatitis,
cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such
as Alzheimer's disease or impaired/improvable cognitive function.
The invention further relates to the use of compounds as defined above for the
treatment and/or prophylaxis of diseases which are modulated by LXRa and/or LXRp
agonists such as atherosclerosis, increased lipid and cholesterol levels, particularly low
HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus,
metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory
diseases.
In addition, the invention relates to the use of compounds as defined above for the
preparation of medicaments for the treatment and/or prophylaxis of diseases which are
modulated by LXRa and/or LXRP agonists such as atherosclerosis, increased lipid and
cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin
dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease,
sepsis, and/or inflammatory diseases.
The compounds of formula (I) can be manufactured by the methods given below, by the
methods given in the examples or by analogous methods. Appropriate reaction
conditions for the individual reaction steps are known to the person skilled in the art.
Starting materials are either commercially available or can be prepared by methods
analogous to the methods given below or in the examples or by methods known in the
art. In case it is not otherwise indicated all substituents mentioned in Schemes 1, 2a, 2b,
3, 4, 5, and 6 are defined as before. Substituent R2 means hydrogen and is therefore not
always mentioned.
Compounds of formula I can be prepared by the following Reaction Scheme 1:
(Figure Removed)
wherein R1, R3, R4, R5, X, k, and n have the signifigances given above. R means
hydrogen and is therefore not mentioned in formula (I).
Michael addition of a sulfonyl derivative 2 to a cyclic 2-enone 1, at RT in MeOH
ontaining 10-20% of NaOMe or in THF or acetonitrile in the presence of bases such as
K/2COs or CS2CO3 , leads to the corresponding 3-substituted cyclic ketone 3 (step a).
The alkylation of 3 may be carried out with NaH in DMF at 0°C followed by the
addition of the electrophile R3-X (Mel, N-fluorobenzenesulfonimide for example) to
give 4 as a racemic mixture of diastereomers (step b). The two diastereomers (RS,SR)
and (RR,SS) may be separated by column chromatography on silica gel at this stage. A
modified Fischer-Indole synthesis is used to prepare compounds of formula (I).
Reaction of the ketone 3 or 4 with the aryl hydrazine (substituted aryl hydrazine) in
pure acetic acid between RT and 40°C for k=l, and between RT and 75°C for k= 0, and
at around 120°C in a sealed tube for heteroaryl hydrazines leads to compounds of
formula (1) (step c).
Functional groups present on R1 and R4 can be be transformed into other functional
groups at this stage of the synthesis using standard procedures commonly known to
those of the art. Typical examples are the replacement of an iodo- or bromo-substituent
by an amino group using Buchwald coupling conditions or replacement of a iodo- or
bromo-substituent by a 1-alkynylo-group using Sonogashira coupling conditions. These
alkynyl moieties can be further modified to alkyl residues by hydrogentation.
Functional groups present on R5 may be converted to other residues by formations
listed for R1 and R4 or by conversion of an alkoxycarbonyl group into a carboxyl group
by hydrolysis in presence of LiOH or NaOH, of a carboxyl group into a aminocarbonyl
group using a primary or secondary amine and a peptide coupling reagent such as e.g.
EDCI, of an alkoxycarbonyl group into a hydroxyalkyl residue by reduction with
LiAlH4, or of an hydroxyalkyl residue into an ether moiety by alkylation. If required the
nitrogen of the tetrahydrocarbazoles, l,2,3,3a,4,8b-tetrahydro-cyclopenta[b]indoles and
related heterocycles may be BOC- or Z-protected prior to these transformations.
For the preparation of the sulfonyl derivatives 2 needed for the Michael-Addition in
Scheme 1 the following 2 different synthetic routes may be used. Scheme 2a describes
the synthesis of the sulfonyl derivatives starting with the alkylation of thiols 1 with an
electrophile of formula 2 in the presence of a base to give the sulfides 3. The preferred
bases are either KaCOs using acetone as solvent or NaH in DMF (step a). The sulfides 3
are subsequently oxidized to the corresponding sulfonyl derivatives 4 with either oxone
(potassium peroxymonosulfate) in MeOH at RT over night, or with mCPBA. in CHCb
or CH2C12 at RT (step b).
An alternative route to the sulfon derivatives is depicted in scheme 2b. The sulfinic acid
sodium salt 5, either commercially available or prepared from the corresponding
sulfinic acid and a base, may be treated with the electrophile 6 to afford sulfon
derivatives 4 (e.g. Y.Nagao, S.Yamada, E. Fujita, Tet. Lett. 1983, 2291-2294).
If it is desired to produce compounds of formula I wherein the sulfonyl derivatives bear
a R5 substituted [l,3,4]-oxadiazole moiety, the process depicted in Scheme 3 may be
used. Addition of hydrazine hydrate to the ester 1 (prepared as described in Scheme 2a,
for R5 = X-CH2-(CH2)mCO2Me) in MeOH at RT leads to the hydrazide 2 (step a). The
hydrazide 2 is acylated with acetic anhydride in acetic acid to the intermediate of
formula 3 (step b), which is cyclised with POCb in acetonitrile to 4 (step c).
Alternatively, the oxadiazole 4 may be prepared by treatment of the hydrazide 2 in
POC13 in the presence of a carboxylic acid R53-(CH2)V-COOH at reflux (route d). An
additional mode of preparation of derivatives 4 is the treatment of the hydrazide 2 in
trimethyl orthoformate with POC13.
(Figure Removed)
The preparation of sulfonyl derivatives with a substituted [l,2,4]-oxadiazole moiety is
depicted in Scheme 4 below (compounds 5). Treatment of nitrile derivatives 1 with
hydroxylamine hydrochloride and NaOMe in MeOH at RT leads to aminohydroxyimino
derivatives 2 (step a), which are converted into the oxadiazoles 4 by
reaction with compound 3 using one of the following methods (step b):
Method A) After treatment of 2 with NaH in THF at RT, the ester 3 is added and the
reaction mixture is then stirred at 60°C for 2 hours.
Method B) Alternatively, 2 is treated at RT in THF with 3 (for X= Cl) for 2 hours. After
evaporation of the solvent, the mixture is refluxed in dioxane over night in the presence
of molecular sieves.
The resulting sulfides 4 are oxidized to the sulfonyl derivatives of formula 5 with
wCPBA at RT in CHC13 (step c).
(Figure Removed)
he preparation of compound of general formula (I) with R5 being a tertiary amide is
shown e.g. in Scheme 5. Esters of type 1 (prepared using the procedure described
above) are converted to secondary amides 2 by reaction with a primary amine and KCN
in a sealed tube (step a). Boc-protection using (BochO, DMAP, EtsN, CFbCb at RT
leads to compounds 3 (step b), which are alkylated via deprotonation with NaH in THF
and subsequent treatment with a range of electrophiles. TFA mediated deprotection in
CH2C12 leads to the final compounds 4 (step c).
Scheme 5
alkyl isprefereebly methyl or ethyl
The following tests were carried out in order to determine the activity of the compounds
of formula (I) and their salts.
Functional groups present on R4 or R53 can - if desired or required - be transformed
into other functional groups at a suitable stage of the synthesis using standard
procedures commonly known to those of the art. Typical examples are the
transformation of an alkoxycarbonyl group into a carboxyl group by hydrolysis in
presence of LiOH, of a carboxyl group into a aminocarbonyl group using a primary or
secondary amine and a peptide coupling reagent such as e.g. EDCI, replacement of a
iodo- or bromo-substituent by an amino group using Buchwald coupling conditions or
replacement of a iodo- or bromo-substituent by a 1-alkynylo-group using Sonogashira
coupling conditions. If required the nitrogen of the tetrahydrocarbazoles, l,2,3,3a,4,8btetrahydro-
cyclopenta[b]indoles and related heterocycles may be BOC- or Z-protected
prior to these transformations.
General Information
Background information on the performed assays can be found in: Nichols JS et al.
"Development of a scintillation proximity assay for peroxisome proliferator-activated
receptor gamma ligand binding domain", Anal Biochem. 1998, 257: 112-119.
Mammalian expression vectors were constructed to express full-length human LXRa
and LXRp. Bacterial expression vectors were constructed to produce glutathione-stransferase
(GST) fused to the ligand binding domains (LBD) of human LXRa (aa 164
to 447) and human LXRp (aa 155 to 460). To accomplish this, the portions of the
sequences encoding the LBDs were amplified from full-length clones by PCR and then
subcloned into the plasmid vectors. Final clones were verified by DNA sequence
analysis (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad Sc.i
USA.1994, 91:10809-13).
Induction, expression, and purification of GST-LBD fusion proteins were performed in
E. coli strain BL21(pLysS) cells by standard methods (Ref: Current Protocols in
Molecular Biology, Wiley Press, edited by Ausubel et al).
Radioligand Binding Assay
LXRa and LXRp receptor binding were assayed in buffer consisting of 50 mM HEPES,
pH 7.4, 10 mM NaCl, 5 mM MgCl2. For each 96-well reaction, 500 ng of GST-LXRa-
LBD or 700 ng of GST-LXRP-LBD fusion proteins were bound to 80 u.g or 40 ng SPA
beads (Pharmacia Amersham) respectively, in a final volume of 50 |j,l by shaking. The
resulting slurry was incubated for 1 h at RT and centrifuged for 2 min at 1300 X g. The
supernatant containing unbound protein was removed, and the semi-dry pellet
containing the receptor-coated beads was re-suspended in 50 ^1 of buffer. Radioligand
(eg. 100,000 dpm of (A^-(2,2,2-trifluoroethyl)-A^-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethylethyl)-
phenyl]-benzenesulfonamide)) was added, and the reaction
incubated at RT for 1 h in the presence of test compounds, and then scintillation
proximity counting was performed. All binding assays were performed in 96-well plates
and the amount of bound ligand was measured on a Packard TopCount using OptiPlates
(Packard). Dose response curves were performed within a range of concentration from
10-10Mto 10-4M- 4
Luciferase Transcriptional Reporter Gene Assays
Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium
containing 10% FBS at 37°C in a 95%O2:5%CO2 atmosphere. Cells were seeded in 6-
well plates at a density of 105 Cells/well and then batch-transfected with either the fulllength-
LXRa or full-length-LXRp expression plasmids plus a reporter plasmid
expressing luceriferase under the control of LXR response elements . Transfection was
accomplished with the Fugene 6 reagent (Roche Molecular Biochemicals) according to
the suggested protocol. Six hours following transfection, the cells were harvested by
trypsinization and seeded in 96-well plates at a density of 104 cells/well. After 24 hours
to allow attachment of cells, the medium was removed and replaced with 100 jal of
phenol red-free medium containing the test substances or control ligands (final DMSO
concentration: 0.1%). Following incubation of the cells for 24 hours with substances,
50 (al of the supernatant was discarded and then 50 ul of Luciferase Constant-Light
Reagent (Roche Molecular Biochemicals) was added to lyse the cells and initiate the
luciferase reaction. Luminescence, as a measure of luciferase activity, was detected in a
Packard TopCount. Transcriptional activation in the presence of a test substance was
expressed as fold-change in luminescence compared to that of cells incubated in the
absence of the substance. EC50 values were calculated using the XLfit program (ID
Business Solutions Ltd. UK).
The compounds according to formula (I) have an activity in at least one of the above
assays (EC50 or IC50) of 0.1 nM to 100 uM, preferably 0.1 nM to luM. (uM means
micromolar).
For example, the following compounds exhibited the following IC50 values in the
binding assay:
LXRalpha LXRbeta
Binding Binding
IC50 [umol/1] IC50 [umol/1]
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9- 1.600 0.270
etrahydro-1 H-carbazol-2-yl)-propionic acid
methyl ester
(RS,SR)-Benzenesulfonyl-(7-chloro-l, 2,3,4- 0.090 0.050
tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic
acid methyl ester
(RS, SR) (3-[(7-chloro-l,2,3,4-tetrahydro-0.043 0.006
cycIopenta[6]indol-2-yl)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methanesulfonyl]-phenyl}-
dimethyl-amine
The compounds of formula I and/or pharmaceutically-acceptable salts and/or
pharmaceutically-acceptable esters can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parenteral or topical administration. They can
be administered, for example, perorally, e.g. in the form of tablets, coated tablets,
dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally,
e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or
infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral
administration is preferred.
The production of the pharmaceutical preparations can be effected in a manner which
will be familiar to any person skilled in the art by bringing the described compounds of
ormula I and/or their pharmaceutical ly acceptable salts, optionally in combination with
other therapeutical ly valuable substances, into a galenical administration form together
with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier
materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic
carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc,
stearic acid or its salts can be used as carrier materials for tablets, coated tablets,
dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules
are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols
(depending on the nature of the active ingredient no carriers might, however, be
required in the case of soft gelatine capsules). Suitable carrier materials for the
production of solutions and syrups are, for example, water, polyols, sucrose, invert
sugar and the like. Suitable carrier materials for injection solutions are, for example,
water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for
suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or
liquid polyols. Suitable carrier materials for topical preparations are glycerides, semisynthetic
and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,
liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving
agents, flavour-improving agents, salts for varying the osmotic pressure, buffer
substances, solubilizers, colorants and masking agents and antioxidants come into
consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on
the disease to be controlled, the age and the individual condition of the patient and the
mode of administration, and will, of course, be fitted to the individual requirements in
each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially
about 1 to 100 mg, comes into consideration. Depending on severity of the disease and
the precise pharmacokinetic profile the compound could be administered with one or
several daily dosage units, e.g. in 1 to 3 dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-
100 mg, of a compound of formula I.
The present invention will be better understood from the following examples, which are
for purposes of illustration and are not intended to limit the invention defined in the
claims, which follow thereafter.
Examples
Abbreviations:
BOC = t-butyloxycarbonyl, CH2Cb = dichloromethane, CCU = tetrachloromethane,
mCPBA = m-chloroperbenzoic acid, Cul = copper iodide, DMAP = 4-
dimethylaminopyridine, DMF = dimethylformamide, EDCI = l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EtOAc = ethylacetate, EtOH
= ethanol, Et2O = diethylether, EtsN = triethylamine, eq = equivalent, Huenig's base =
iPr2NEt = N-ethyl diisopropylamine, LiAlHU = lithium aluminum hydride, MeOH =
methanol, NaH = sodium hydride, NaOtBu = sodium tert. butylate, NBS = Nbromosuccinimide,
RT = room temperature, THF = tetrahydrofuran, NaHCOs = sodium
bicarbonate, NH4C1 = ammonium chloride, TFA = trifluoroacetic acid, NaOH = sodium
hydroxide.
General remarks
All reactions were performed under argon.
Example 1
benzenesu!fonyl-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)- acetic acid methyl
ester
To a stirred solution of 9 g (0.042 mol) of methyl phenylsulfonylacetate in 90 mL of
MeOH at 0°C, 1.56 mL (0.008 mol, 0.2 eq) of a solution of sodium methoxide (5.4 M
in MeOH) were added. After 15 min, 4.04 g (0.02 mol) of 2-cyclohexen-l-one were
added. The reaction mixture was allowed to reach RT within 4 hours, diluted with
saturated aqueous NRtCl and extracted with EtOAc. The combined organic phases
were dried over Na2SCO4, filtered and evaporated. Column chromatography on silica gel
with heptane/EtOAc 1:1 yielded 11.50 g (88%) of benzenesulfonyl-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light yellow oil, MS:
1.2
To 5 g (0.016 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in
glacial acetic acid (30 mL), 3.17 g (0.018 mol, 1.1 eq) of 4-chlorophenylhydrazine
hydrochloride were added and the reaction mixture was stirred at 40°C for 2 hours. An
aqueous solution of NaHCOs was added until pH = 7 was reached, and the mixture was
extracted with EtOAc. The combined organic phases were dried over Na2SC>4, filtered
and evaporated. A column chromatography on silica gel followed by a trituration from
EtaO yielded 4.3 g (64%) of benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-
2-yl)-acetic acid methyl ester as a racemic mixture of diastereomers, light brown
crystals, MS: 418 (MH+).
Example 2
benzenesulfonyl-(6-fluoro-2,3,4,9-tetrahydro-l//-carbazoI-2-yl)-acetic acid methyl
ester
in analogy to example 1.2, from benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl
ester and (4-fluoro-phenyl)-hydrazine hydrochloride was prepared benzenesulfonyl-(6-
fluoro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-acetic acid methyl ester as a racemic
mixture of diastereomers, light yellow solid, MS: 402 (MH+).
Example 3
(J?5'yS'J?)-2-benzenesulfonyI-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazoI-2-yl)-
propionic acid methyl ester
3.1
To a stirred solution of 2 g (6.44 mmol) of benzenesulfonyl-(3-oxo-cyclohexyI)-acetic
acid methyl ester in 40 mL of DMF at 0°C, 283 mg (7.09 mmol, 1.1 eq) of NaH (60%)
were added. The reaction mixture was stirred at this temperature for one hour, and 1.37
g (9.66 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction
mixture was poured into water and extracted with EtOAc. The combined organic
phases were dried over NaaSO4 filtered and evaporated. The resulting two
diastereomers were separated by column chromatography on silica gel with
heptane/EtOAc 2:1, yielding 0.79 g (38%) of (RS,SR)- 2-benzenesulfonyl-2-(3-oxocyclohexyl)-
propionic acid methyl ester as a white solid, MS: 325 (MH+) and 0.71 g
(34%) of (RR,SS)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester
as a white solid, MS: 325 (MH+).
3.2
To 0.14 g (0.43 mmol) (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic
acid methyl ester in glacial acetic acid (3 mL), 88 mg (0.47 mmol, 1.1 eq) of (4-chlorophenyl)-
hydrazine hydrochloride were added and the reaction mixture was stirred at
40°C over night. An aqueous solution of NaHCOa was added until pH = 7 was reached,
and the mixture was extracted with EtOAc. The combined organic phases were dried
over Na2SO4, filtered and evaporated. A column chromatography on silica gel with
heptane/EtOAc 2:1 followed by a trituration with Et2O yielded 187 mg (65%) of
(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionic
acid methyl ester as a white solid, MS: 432 (MH+).
The enantiomers were separated by preparative chiral HPLC. Column: chiralpak AD,
solvent: 20%isopropanol/heptane
Example 4
propionic acid methyl ester
In analogy to example 3.2, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-
propionic acid methyl ester and (4-fluoro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(6-fluoro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionic acid methyl ester as a white solid, MS: 416 (MH+).
Example 5
propionic acid methyl ester
In analogy to example 3.2, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-
propionic acid methyl ester and (4-methyl-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionic acid methyl ester as a white solid, MS: 412 (MH+).
Example 6
propionic acid methyl ester
Analogously to example 3.2, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-
propionic acid methyl ester and (4-nitro-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-2-benzenesulfonyl-2-(6-nitro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionic
acid methyl ester as a light yellow solid, MS: 460 (MNH4+).
Example 7
(RS,SR)-2-benzenesulfonyl-2-(6-cyano-2,3,4,9-tetrahydro-l^-carbazol-2-yI)-
propionic acid methyl ester
Analogously to example 3.2, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-
propionic acid methyl ester and (4-cyano-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(6-cyano-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionic acid methyl ester as a light yellow solid, MS: 423 (MH+).
Example 8
(RS,SR)-2-benzenesulfonyl-2-(2-chloro-6,7,8,9-tetrahydro-5A-pyrido[3,2-b]indoI-
7-yI)-propionic acid methyl ester
8.1
To 0.5 g (3.9 mmol) of 6-chloro-pyridin-3-ylamine in 6 mL of 12M HC1 at-20°C were
added a solution of 0.36 g (5.2 mmol, 1.3 eq) of sodium nitrite dissolved in 2 mL of
KbO. The reaction mixture was stirred for 15 min, and 4.4 g (19.5 mmol, 5 eq) of tin
chloride dihydrate dissolved in 2 mL of 12M HC1 were added. The reaction mixture
was allowed to reach 0°C within 40 min, and the white precipitate was recovered by
filtration and washed with Et2O to yield 0.35 g (62%) of (6-chloro-pyridin-3-yl)-
hydrazine hydrochloride as a white solid, MS: 144 (MH+).
In a sealed tube, 50 mg (0.15 mmol) of (RS,SR)- 2-benzenesulfonyl-2-(3-oxocyclohexyl)-
propionic acid methyl ester in 4 mL of glacial acetic acid were treated with
27 mg (0.18 mmol, 1.2 eq) of (6-chloro-pyridin-3-yl)-hydrazine hydrochloride and
stirred at 115°C for 3 hours. An aqueous solution of NaHCOs was added until pH = 7
was reached, and the mixture was extracted with EtOAc. The combined organic phases
were dried over Na2SO4, filtered and evaporated. A column chromatography on silica
gel with heptane/EtOAc 1:1 followed by trituration with EtaO yielded 52 mg (76%) of
(RS,SR)- 2-benzenesulfonyl-2-(2-chloro-6,7,8,9-tetrahydro-5//-pyrido[3,2-b]indol-7-
yl)-propionic acid methyl ester as a white solid, MS: 433 (MH+).
Example 9
15.71 g (0.048 mol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours
at RT, the reaction mixture was poured into water and extracted with EtOAc. The
combined organic phases were dried over Na2SO4, filtered and evaporated. The
resulting two diastereomers were separated by column chromatography on silica gel
with heptane/EtOAc 2:1, yielding 3.06 g (27%) o f (RS,SR) - benzenesulfonyl-fluoro-(3-
oxo-cyclohexyl)-acetic acid methyl ester as a white solid, MS: 329 (MH+) and 3.2 g
(28%) of (RR,SS)- benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester
as a white solid, MS: 329 (MH+).
12.2
To 1.70 g (5.2 mmol) (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid
methyl ester in glacial acetic acid (20 mL), 1.05 g (5.72 mmol, 1.1 eq) of (4-chlorophenyl)-
hydrazine hydrochloride were added and the reaction mixture was stirred at
40°C over night. An aqueous solution of NaHCOs was added until pH = 7 was reached,
and the mixture was extracted with EtOAc. The combined organic phases were dried
over Na2SCO4, filtered and evaporated. A column chromatography on silica gel with
heptane/EtOAc 2:1 followed by a trituration from Et2O yielded 1.56 g (70%) of
(RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetic
acid methyl ester as a white solid, MS: 436 (MH+).
The enantiomers were separated by preparative chiral HPLC. Column: chiralpak AD,
solvent: 20%isopropanol/heptane
Example 13
(RS,SR)-benzenesulfonyl-fluoro-(6-methyl-2,3,4,9-tetrahydro-lflr-carbazol-2-yl)-
acetic acid methyl ester
In analogy to example 12.2, from (/?5',5'^)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetic acid methyl ester and (4-methyl-phenyl)-hydrazine hydrochloride was prepared
(RS,SR-benzenesulfonyl-fluoro-(6-methyl-2,3,4,9-tetrahydro-Hcarbazol-2-yl)-acetic
acid methyl ester as a light yellow solid, MS: 416 (MH+).
Example 14
15.71 g (0.048 mol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours
at RT, the reaction mixture was poured into water and extracted with EtOAc. The
combined organic phases were dried over Na2SCO4, filtered and evaporated. The
resulting two diastereomers were separated by column chromatography on silica gel
with heptane/EtOAc 2:1, yielding 3.06 g (27%) of(RS,SR)- benzenesulfonyl-fluoro-(3-
oxo-cyclohexyl)-acetic acid methyl ester as a white solid, MS: 329 (MH+) and 3.2 g
(28%) of (RR,SS)- benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester
as a white solid, MS: 329 (MH+).
To 1.70 g (5.2 mmol) RS,SR-benzenesulfonyl-fluoro-^-oxo-cyclohexyO-acetic acid
methyl ester in glacial acetic acid (20 mL), 1.05 g (5.72 mmol, 1.1 eq) of (4-chlorophenyl)-
hydrazine hydrochloride were added and the reaction mixture was stirred at
40°C over night. An aqueous solution of NaHCO3 was added until pH = 7 was reached,
and the mixture was extracted with EtOAc. The combined organic phases were dried
over Na2SCO4, filtered and evaporated. A column chromatography on silica gel with
heptane/EtOAc 2:1 followed by a trituration from Et2O yielded 1.56 g (70%) of
(RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-17/-carbazol-2-yl)-fluoro-acetic
acid methyl ester as a white solid, MS: 436 (MH+).
The enantiomers were separated by preparative chiral HPLC. Column: chiralpak AD,
solvent: 20%isopropanol/heptane
Example 13
acetic acid methyl ester
In analogy to example 12.2, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetic acid methyl ester and (4-methyl-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-benzenesulfonyl-fluoro-(6-methyl-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-acetic
acid methyl ester as a light yellow solid, MS: 416 (MH+).
Example 14
(RS,SR)-benzenesulfonyl-(6-cyano-2,3,4,9-tetrahydro-lHr-carbazoI-2-yl)-fluoroacetic
acid methyl ester
In analogy to example 12.2, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetic acid methyl ester and (4-cyano-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-benzenesulfonyl-(6-cyano-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetic
acid methyl ester as a light yellow solid, MS: 427 (MH+).
Example 15
acetic acid methyl ester
In analogy to example 12.2, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetic acid methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-benzenesulfonyl-(6-bromo-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetic
acid methyl ester as a white solid, MS: 480; 482 (MH+).
Example 16
fluoro-acetic acid methyl ester
In analogy to example 8.2, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetic acid methyl ester and (6-chloro-pyridin-3-yl)-hydrazine hydrochloride (example
8.1) was prepared (RS,SR)-benzenesulfonyl-(2-chloro-6,7,8,9-tetrahydro-5//-
pyrido[3,2-b]indol-7-yl)-fluoro-acetic acid methyl ester as a white solid, MS: 437
Example 17-18
(RS,SR)-benzenesulfonyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-l^-carbazol-2-yl)-
fluoro-acetic acid methyl ester
and
(RS,SR)-benzenesulfonyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro-lJy-carbazol-2-yl)-
fluoro-acctic acid methyl ester
In analogy to example 12.2, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetic acid methyl ester and (4-bromo-3-fluoro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-benzenesulfonyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-l//-carbazol-
2-yl)-fluoro-acetic acid methyl ester as a white solid, MS: 515; 517 (MNH4+); (example
1 7) and (RS,SR)-benzenesulfonyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro- l//-carbazol-2-
yl)-fluoro-acetic acid methyl ester as a white solid, MS: 515; 517 (MNH/); (example
18). The two regioisomers were obtained in a ratio of 1:1, and separated by column
chromatography on silica gel with Heptane/EtOAc 2:1 .
Example 19
(RS,SR)-2-benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-propionic acid methyl ester
To a stirred solution of 1.26 g (5.9 mmol) of methyl phenylsulfonylacetate in 20 mL of
MeOH at 0°C, 0.22 mL (1.17 mmol, 0.2 eq) of a solution of sodium methoxide (5.4 M
in MeOH) were added. After 15 min, 0.53 g (6.5 mmol, 1.1 eq) of cyclopent-2-enone
were added. The reaction mixture was allowed to reached RT within 4 hours, diluted
with saturated aqueous NH4C1 and extracted with EtOAc. The combined organic phases
were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel
with heptane/EtOAc 1 : 1 yielded 1 .34 g (77%) of benzenesulfonyl-(3-oxo-cyclopentyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 297
19.2
To a stirred solution of 2.4 g (8.1 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic
acid methyl ester in 15 mL of DMF at 0°C, 389 mg (8.9 mmol, 1.1 eq) of NaH (60%)
were added. The reaction mixture was stirred at this temperature for one hour, and 1.72
g (12.1 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction
mixture was poured into water and extracted with EtOAc. The combined organic
phases were dried over Na2SCO4, filtered and evaporated. The resulting two
diastereomers were separated by column chromatography on silica gel with
heptane/EtOAc (from 2:1 to 2:1) yielded 0.78 g (31%) of (RS,SR)- 2-benzenesulfonyl-
2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 3 1 1 (MH+) and
0.53 g (21%) of (RR,SS)- 2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid
methyl ester as a white solid, MS: 31 1 (MH+).
19.3
To 100 mg (0.32 mmol) of (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-
propionic acid methyl ester in glacial acetic acid (3 mL), 63 mg (0.35 mmol, 1.1 eq) of
(4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was
heated at 70°C for about 5 hours. Until completion, the reaction was monitored by
HPLC and TLC. An aqueous solution of NaHCOs was added until pH = 7 was reached,
and the mixture was extracted with EtOAc. The combined organic phases were dried
over NaaSCU, filtered and evaporated. A column chromatography on silica gel with
heptane/EtOAc 1:1 followed by a trituration with Et2O yielded 45 mg (34%) of
propionic acid methyl ester as a light yellow solid, MS: 418 (MH+).
Example 20
(RS,SR)-2-benzenesulfonyl-2-(7-bromo-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-propionic acid methyl ester
In analogy to example 19.3, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-
propionic acid methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(7-bromo-l,2,3,4-tetrahydro-cyclopenta[b]indol-
2-yl)-propionic acid methyl ester as a light yellow solid, MS: 461; 463 (MH+).
Example 21
(RS,SR)-2-benzenesulfonyl-2-(7-cyano-l,2,3,4-tetrahydro-cyclopenta[b)indol-2-yl)-
propionic acid methyl ester
In analogy to example 19.3, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-
propionic acid methyl ester and (4-cyano-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(7-cyano-l,2,3,4-tetrahydro-cyclopenta[b]indol-
2-yl)-propionic acid methyl ester as a light brown solid, MS: 409 (MH+).
Example 22
(RS,SR)-2-benzenesulfonyl-2-(7-methyl-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-propionic acid methyl ester
In analogy to example 19.3, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-
propionic acid methyl ester and (4-methyl-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(7-methyl-1,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-propionic acid methyl ester as a white solid, MS: 398 (MH+).
Example 23
(RS,SR-benzenesulfonyl 7-chloro1,2,3,4-tetrahydro-cyclopentafblindol^-yl)-
fluoro-acetic acid methyl ester
23.1
To a stirred solution of 1.34 g (4.5 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-
acetic acid methyl ester in 15 mL of DMF at 0°C, 199 mg (5.0 mmol, 1.1 eq) of NaH
(60%) were added. The reaction mixture was stirred at this temperature for one hour,
and 2.14 g (6.75 mmol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2
hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The
combined organic phases were dried over Na2SCO4, filtered and evaporated. The
resulting two diastereomers were separated by column chromatography on silica gel
with heptane/EtOAc (from 2:1 to 2:1) yielding 0.40 g (28%) of (RS,SK)-
benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid,
MS: 332 (MNH4
+) and 0.52 g (37%) of (RR,SS)- benzenesulfonyl-fluoro-(3-oxocyclopentyl)-
acetic acid methyl ester as a white solid, MS: 332 (MNH4+).
23.2
In analogy to example 19.3, from (7?5',5'/?)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-
acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoroacetic
acid methyl ester as a white solid, MS: 439 (MNH4+).
Example 24
(RS,SR-benzenesulfonyl-CV-bromo-l,2,3,4-tetrahydro-cyclopentalbjindoI-Z-yl)-
fluoro-acetic acid methyl ester
In analogy to example 19.3, from (RS,SRbenzenesulfonyl-fluoro-^-oxo-cyclopentyl)-
acetic acid methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-benzenesulfonyl-(7-bromo-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoroacetic
acid methyl ester as a white solid, MS: 466; 468 (MH+).
Example 25
cyclopenta[a]inden-2-yl)-fluoro-acetic acid methyl ester
In analogy to example 19.3, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-
acetic acid methyl ester and (6-chloro-pyridin-3-yI)-hydrazine hydrochloride was
prepared (RS,SR)-benzenesulfonyl-(5-chloro-l,2,3,8-tetrahydro-4,8-diazacyclopenta[
a]inden-2-yl)-fluoro-acetic acid methyl ester as a white solid, MS: 423
Example 26-27
(RS,SR)-benzenesulfonyl-(7-bromo-6-fluoro-l,2,3,4-tetrahydrocyclopenta[
b]indoI-2-yl)-fluoro-acetic acid methyl ester and (RS,SR)-
benzenesulfonyl-(7-bromo-8-fluoro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-acetic acid methyl ester
In analogy to example 19.3, from (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-
acetic acid methyl ester and (4-bromo-3-fluoro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-benzenesulfonyl-(7-bromo-6-fluoro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-acetic acid methyl ester as a light brown solid, MS:
484; 486 (MH+); (example 26) and (RS,SR)-benzenesulfonyl-(7-bromo-8-fluorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester as a light
brown solid, MS: 484; 486 (MH+); (example 27). The two regioisomers were obtained
in a ratio of 1:1 and separated by column chromatography on silica gel with
heptane/EtOAc2:l.
Example 28
(RS,SR)-2-(6-cMoro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-(naphtha\ene-lsulfonyl)-
propionic acid methyl ester
28.1
To a stirred suspension of 3.1 g (0.019 mol) of naphthalene-1-thiol and 2.94 g (0.021
mol, 1.1 eq) of K2CO3 in 100 mL of propan-2-one cooled at 0°C, 3.15 g (0.029 mol, 1.5
eq) of chloro-acetic acid methyl ester were added in one portion. The ice bath was
removed and the reaction mixture was stirred an additional 4 hours. The reaction was
filtered, the solvent evaporated and the resulting residue was taken up in 100 mL of
MeOH. 14.3 g (0.023 mol, 1.2 eq) of oxone (potassium peroxymonosulfate) were added
and the reaction mixture was stirred over night at RT. The salts were filtered off, the
solvent evaporated and the residue purified by column chromatography on silica gel
with heptane/EtOAc (from 4:1 to 1:2) to afford 2.78 g (55%) of (naphthalene-1-
sulfonyl)-acetic acid methyl ester as a light yellow oil, MS: 265 (MH+).
To a stirred solution of 2.75 g (0.010 mol) of (naphthalene-l-sulfonyl)-acetic acid
methyl ester in 100 mL of MeOH at RT, 0.19 mL (0.011 mol, 1.1 eq) of a solution of
sodium methoxide (5.4 M in MeOH) were added. After 15 min, 1.1 g (0.011 mol, 1.1
eq) of 2-cyclohexen-l-one were added. The reaction mixture was stirred at RT for 3
hours followed by an additional 4 hours at 60°C, diluted with aqueous NH4C1 and
extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered
and evaporated. Column chromatography on silica gel with heptane/EtOAc (from 4:1
to 1:2) yielded 1.78 g (48%) of (naphthalene-l-sulfonyl)-(3-oxo-cyclohexyl)-acetic acid
methyl ester as a racemic mixture of diastereomers, light orange oil, MS: 361 (MH+).
28.3
In analogy to example 3.1: 1.74 g (4.8 mmol) of (naphthalene-l-sulfonyI)-(3-oxocyclohexyl)-
acetic acid methyl ester was dissolved in 10 mL of DMF at 0°C. 232 mg
(5.3 mmol, 1.1 eq) of NaH (60%) were added and the reaction mixture was stirred 30
minutes before the addition of 1.03 g (7.2 mmol, 1.5 eq) of methyliodide. The reaction
was stirred over night, poured on water and extracted with EtOAc. The combined
organic phases were dried over Na2SCO4, filtered and evaporated. The resulting two
diastereomers were separated by column chromatography on silica gel with
AcOEt/heptane 2:1, yielded 0.30 g (17%) of (RS,SR) naphthalene- l-sulfonyl)-2-(3-
oxocyclohexyl)-propionic acid methyl ester as a white foam MS: 375 (MH+) and 0.42 g
(23%) of (RS,SR)-2-(naphthalene-l-sulfonyl)-2-(3-oxocyclohexyl)-propionic acid
methyl ester as a white solid MS: 375 (MH+).
28.4
In analogy to example 3.2, from (RS,SR)-2-(naphthalene-l-sulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(6-d\loro-2,3,4,9-tetrahydro- lH-carbazol-2-yl)-2-(naphthalenel-
sulfonyl)-propionic acid methyl ester as a brown solid, MS: 483 (MH+).
Example 29
sulfonyl)-propionic acid methyl ester
29.1
In analogy to example 28.1, from naphthalene-2-thioI and chloro-acetic acid methyl
ester was prepared (naphthalene-2-sulfonyl)-acetic acid methyl ester as a white solid,
MS: 265 (MH+).
29.2
In analogy to example 28.2, from (naphthalene-2-sulfonyl)-acetic acid methyl ester and
cyclohexen-1-one was prepared (naphthalene-2-sulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester as a racemic mixture of diastereomers, light orange oil, MS: 361
29.3
In analogy to example 28.3, from (naphthalene-2-sulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and methyliodide was prepared (RS,SR-2-(naphthalene-2-sulfonyl)-2-
(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 375 (MH+).
29.4
In analogy to example 3.2, from (RS,SR)-2-(naphthalene-2-sulfonyI)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)e-chloro-2,3,4,9-tetrahydro-l/f-carbazol2-yO
2-sulfonyl)-propionic acid methyl ester as a light yellow solid, MS: 483 (MH+).
Example 30
benzenesulfonyl)-propionic acid methyl ester
30.1
In analogy to example 28.1, from 3,4-dichloro-benzenethiol and chloro-acetic acid
methyl ester was prepared (3,4-dichloro-benzenesulfonyl)-acetic acid methyl ester as a
white solid, MS: 284 (MH+).
30.2
In analogy to example 28.2, from (3,4-dichloro-benzenesulfonyl)-acetic acid methyl
ester and cyclohexen-1-one was prepared (3,4-dichloro-benzenesulfonyl)-(3-oxocyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light yellow
solid, MS: 380 (MJ-T).
30.3
In analogy to example 28.3, from (3,4-dichloro-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester and methyliodide was prepared (RS,SR)-2-(3,4-d\ch\orobenzenesulfonyl)-
2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid,
MS: 394 (MH+).
30.4
In analogy to example 3.2, from (RS,SR)-2-(3,4-dichloro-benzenesulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l/H-carbazol-2-yl)-2-(3,4-
dichloro-benzenesulfonyl)-propionic acid methyl ester as a light brown solid, MS: 501
Example 31
propionic acid methyl ester
31.1
In analogy to example 28.1, from 3-methyl-benzenethiol and chloro-acetic acid methyl
ester was prepared (toluene-3-sulfonyl)-acetic acid methyl ester as a colorless oil, MS:
229 (MH+).
31.2
In analogy to example 28.2, from (toluene-3-sulfonyl)-acetic acid methyl ester and
cyclohexen-1-one was prepared (3-oxo-cyclohexyl)-(toluene-3-sulfonyl)-acetic acid
methyl ester as a racemic mixture of diastereomers, light yellow oil, MS: 325 (MH+).
31.3
In analogy to example 28.3, from (3-oxo-cyclohexyl)-(toluene-3-sulfonyl)-acetic acid
methyl ester and methyliodide was prepared (RS,SR)-2-(3-oxo-cycloriexyl)-(toluene-3-
sulfonyl)-propionic acid methyl ester as a white solid, MS: 339 (MH+).
31.4
In analogy to example 3.2, from (RS,SR)-2-(3-oxo-cyclohexyl)-(toluene-3-sulfonyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-(toluene-3-
sulfonyl)-propionic acid methyl ester as a light brown solid, MS: 446 (MH+).
Example 32
(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-lH-carba2.o\-2-yl)-2-(3-methoxybenzenesulfonyl)-
propionic acid methyl ester
32.1
In analogy to example 28.1, from 3-methoxy-benzenethiol and chloro-acetic acid
methyl ester was prepared (3-methoxy-benzenesulfonyl)-acetic acid methyl ester as a
light brown oil, MS: 245 (MH+).
32.2
In analogy to example 28.2, from (3-methoxy-benzenesulfonyl)-acetic acid methyl ester
and cyclohexen-1-one was prepared (3-methoxy-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light orange oil, MS:
341 (MH+).
32.3
In analogy to example 28.3, from (3-methoxy-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester and methyliodide was prepared RS,SR-methoxybenzenesulfonyl)-
2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a colorless oil,
MS: 355 (MH+).
32.4
In analogy to example 3.2, from RS,SR)-2-(3-methoxy-benzenesulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-(3-methoxybenzenesulfonyl)-
propionic acid methyl ester as a light brown solid, MS: 462 (MH+).
Example 33
(RS,SR)-2-(2-chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-
2-yl)-propionic acid methyl ester
33.1
In analogy to example 28.1, from 2-chloro-benzenethiol and bromo-acetic acid methyl
ester was prepared (2-chloro-benzenesulfonyl)-acetic acid methyl ester as a white solid,
MS: 249 (MH+).
33.2
In analogy to example 28.2, from (2-chloro-benzenesulfonyl)-acetic acid methyl ester
and cyclohexen-1-one was prepared (2-chloro-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 345
33.3
In analogy to example 28.3, from (2-chloro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and methyliodide was prepared (RS,SR)-2-(2-ch\orobenzenesulfonyl)-
2-(3-oxo-cyclohexyl)-propionic acid methyl ester as white crystals,
MS: 359 (MH+).
33.4
In analogy to example 3.2, from (RS,SR)-2-(2-chloro-benzenesulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chIoro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(2-chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-propionic acid methyl ester as a light brown solid, MS: 467 (MH+).
Example 34
(/RS,SR-2-(6-chloro-2,3,4,9-tetrahydro-lJ|y-carbazol-2-yl)-2-(2-methoxybenzenesulfonyl)-
propionic acid methyl ester
34.1
In analogy to example 28.1, from 2-methoxy-benzenethiol and chloro-acetic acid
methyl ester was prepared (2-methoxy-benzenesulfonyl)-acetic acid methyl ester as
white crystals, MS: 245 (MH+).
34.2
In analogy to example 28.2, from (2-methoxy-benzenesulfonyl)-acetic acid methyl ester
and cyclohexen-1-one was prepared (2-methoxy-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light yellow oil, MS:
341 (MH+).
34.3
In analogy to example 28.3, from (2-methoxy-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester and methyliodide was prepared (.&S',S7?)-2-(2-methoxybenzenesulfonyl)-
2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a light yellow
solid, MS: 355 (MH+).
34.4
In analogy to example 3.2, from (RS,SR)-2-(2-methoxy-benzenesulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-(2-methoxybenzenesulfonyl)-
propionic acid methyl ester as a light brown solid, MS: 462 (MH+).
Example 35
(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l/f-carbazoI-2-yl)-2-(4-fluorobenzenesulfonyl)-
propionic acid methyl ester
35.1
In analogy to example 28.1, from 4-fluoro-benzenethiol and bromo-acetic acid methyl
ester was prepared (4-fluoro-benzenesulfonyl)-acetic acid methyl ester as a colorless
oil, MS: 233 (MH+).
35.2
In analogy to example 28.2, from (4-fluoro-benzenesulfonyl)-acetic acid methyl ester
and cyclohexen-1-one was prepared (4-fluoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, white crystals, MS: 329
35.3
In analogy to example 28.3, from (4-fluoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and methyliodide was prepared (RS,SR)-2-(4-fluoro-benzenesulfonyl)-
2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a light yellow solid, MS: 343
35.4
In analogy to example 3.2, from (RS,SR)-2-(4-fluoro-benzenesulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-(4-fluorobenzenesulfonyl)-
propionic acid methyl ester as a white solid, MS: 450 (MH+).
Example 36
2-yl)-propionic acid methyl ester
36.1
In analogy to example 28.1, from 3-chloro-benzenethiol and bromo-acetic acid methyl
ester was prepared (3-chloro-benzenesulfonyl)-acetic acid methyl ester as a colorless
oil, MS: 249 (MH+).
36.2
In analogy to example 28.2, from (3-chloro-benzenesulfonyl)-acetic acid methyl ester
and cyclohexen-1-one was prepared (3-chloro-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light yellow oil, MS:
345 (MH+).
36.3
In analogy to example 28.3, from (3-chloro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and methyliodide was prepared (RS,SR)-2-(3-chIoro-
benzenesulfonyl)-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as white solid, MS:
359 (MH+).
36.4
In analogy to example 3.2, from (RS,SR)-2-(3-chloro-benzenesulfonyl)-2-(3-oxocyclohexyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(3-chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-propionic acid methyl ester as a white solid, MS: 467 (MH+).
Example 37
(RS,SR)-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-(4-fluorobenzenesulfonyl)-
acetic acid methyl ester
37.1
In analogy to example 12.1, from (4-fluoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-f\uoro-(4-
fluoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic acid methyl ester as a colorless oil,
MS: 347 (MH+).
37.2
In analogy to example 12.2, from (RS,SR)-fluoro-(4-fluoro-benzenesulfonyl)-(3-oxocyclohexyl)-
acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-(4-fluorobenzenesulfonyl)-
acetic acid methyl ester as a white solid, MS: 454 (MH+).
Example 38
(RS,SR)-(3-chloro-benzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-2-
yl)-fluoro-acetic acid methyl ester
38.1
In analogy to example 12.1, from (3-chloro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-(3-ch\oro-
benzenesulfonyl)- fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester as a white solid,
MS: 363 (MH+).
38.2
In analogy to example 12.2, from (RS,SR)-(3-chloro-benzenesulfonyl)- fluoro-(3-oxocyclohexyl)-
acetic acid methyl and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-(3-chloro-benzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-
2-yl)-fluoro-acetic acid methyl ester as a white solid, MS: 471 (MH+).
Example 39
benzenesulfonyl)-acetic acid methyl ester
39.1
In analogy to example 28.1, from 3-fluoro-benzenethiol and chloro-acetic acid methyl
ester was prepared (3-fluoro-benzenesulfonyl)-acetic acid methyl ester as a colorless
oil, MS: 233 (MH+).
39.2
In analogy to example 28.2, from (3-fluoro-benzenesulfonyl)-acetic acid methyl ester
and cyclohexen-1-one was prepared (3-fluoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light yellow oil, MS:
329 (MH+).
39.3
In analogy to example 12.1, from (3-f!uoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-acetic
acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-fluoro-(3-
fluoro-benzenesulfonyl)- (3-oxo-cyclohexyl)-acetic acid methyl ester as a white solid,
MS: 347 (MH+).
39.4
In analogy to example 12.2, from (RS,SR)-fluoro-(3-fluoro-benzenesulfonyl)-(3-oxocyclohexyl)-
acetic acid methyl and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared RS,SR(e-chloroRS,SR-tetrahydro-l/f-carbazoRS,SRyO-fluoro-C
benzenesulfonyl)-acetic acid methyl ester as a white solid, MS: 454 (MH+).
Example 40
benzenesulfonyl)-fluoro-acetic acid methyl ester
40.1
In analogy to example 28.1, from 3,4-difluoro-benzenethiol and chloro-acetic acid
methyl ester was prepared (3,4-difluoro-benzenesulfonyl)-acetic acid methyl ester as a
colorless oil, MS: 251 (MH+).
40.2
In analogy to example 28.2, from (3,4-difluoro-benzenesulfonyl)-acetic acid methyl
ester and cyclohexen-1-one was prepared (3,4-difluoro-benzenesulfonyl)-(3-oxocyclohexyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, light yellow
oil, MS:347(MH+).
40.3
In analogy to example 12.1, from (3,4-difluoro-benzenesulfonyl)-(3-oxo-cyclohexyl)-
acetic acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-(3,4-
difluoro-benzenesulfonyl)-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester as a white
solid, MS: 365 (MH+).
40.4
In analogy to example 12.2, from (RS,SR)-(3,4-difluoro-benzenesulfonyl)-fluoro-(3-
oxo-cyclohexyl)-acetic acid methyl ester and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-
(3,4-difluoro-benzenesulfonyl)-fluoro-acetic acid methyl ester as a white solid, MS: 472
Example 41
(RS,SR)-(6-chloro-2,3,4,9-tetrahydro-l/H-carbazol-2-yl)-fluoro-(pyridine-3-
sulfonyl)-acetic acid methyl ester
41.1
In analogy to example 28.1, from pyridine-3-thiol and chloro-acetic acid methyl ester
was prepared (pyridine-3-sulfonyl)-acetic acid methyl ester as a yellow oil, MS: 216
41.2
In analogy to example 28.2, from (pyridine-3-sulfonyl)-acetic acid methyl ester and
cyclohexen- 1 -one was prepared (3-oxo-cyclohexyl)-(pyridine-3-sulfonyI)-acetic acid
methyl ester as a racemic mixture of diastereomers, yellow oil, MS: 312 (MH+).
41.3
In analogy to example 12.1, from (3-oxo-cyclohexyl)-(pyridine-3-sulfonyl)-acetic acid
methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SRfluoro-O-oxocyclohexyl)-(
pyridine-3-sulfonyl)-acetic acid methyl ester as white crystals, MS: 330
41.4
In analogy to example 12.2, from (RS,SR)-fluoro-(3-oxo-cyclohexyl)-(pyridine-3-
sulfonyl)-acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-(pyridine-3-
sulfonyl)-acetic acid methyl ester as a light yellow solid, MS: 437 (MH+).
Example 42
(RS,SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-methoxybcnzenesulfonyl)-
acetic acid methyl ester
42.1
In analogy to example 19.1, from (3-methoxy-benzenesulfonyl)-acetic acid methyl ester
and cyclopent-2-enone was prepared (3-methoxy-benzenesulfonyl)-(3-oxocyclopentyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, white solid,
MS: 327 (MH+).
42.2
In analogy to example 23.1, from (3-methoxy-benzenesulfonyl)-(3-oxo-cyclopentyI)-
acetic acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-f\uoro-
(3-methoxy-benzenesulfonyl)-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white
solid, MS: 345 (MH+).
42.3
In analogy to example 23.2, from (RS,SR)-fluoro-(3-methoxy-benzenesulfonyl)-(3-oxocyclopentyl)-
acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-
methoxy-benzenesulfonyl)-acetic acid methyl ester as a white solid, MS: 452 (MH+).
Example 43
(RS,SR)-(3-chloro-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-acetic acid methyl ester
43.1
In analogy to example 19.1, from (3-chloro-benzenesulfonyl)-acetic acid methyl ester
and cyclopent-2-enone was prepared (3-chloro-benzenesulfonyl)-(3-oxo-cyclopentyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 348
(MNH4
+).
In analogy to example 23.1, from (3-chloro-benzenesulfonyl)-(3-oxo-cyclopentyl)-
acetic acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-(3-
chloro-benzenesulfonyl)-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white
solid, MS: 366 (MNH4
43.3
In analogy to example 23.2, from (RS,SR)-(3-chloro-benzenesulfonyl)-fluoro-(3-oxocyclopentyl)-
acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-(3-chloro-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-acetic acid methyl ester as a light brown solid, MS: 457
Example 44
(RS,SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yI)-fluoro-(pyridine-2-
sulfonyl)-acetic acid methyl ester
44.1
In analogy to example 28.1, from pyridine-2-thiol and chloro-acetic acid methyl ester
was prepared (pyridine-2-sulfonyl)-acetic acid methyl ester as a colorless oil, MS: 216
44.2
In analogy to example 19.1, from (pyridine-2-sulfonyl)-acetic acid methyl ester and
cyclopent-2-enone was prepared (3-oxo-cyclopentyl)-(pyridine-2-sulfonyl)-acetic acid
methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 298 (MH+).
44.3
In analogy to example 23.1, from (3-oxo-cyclopentyl)-(pyridine-2-sulfonyl)-acetic acid
methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SRRS,SR)-fluoro-(3-oxo-
72
cyclopentyl)-(pyridine-2-sulfonyl)-acetic acid methyl ester as a white solid, MS: 316
44.4
In analogy to example 23.2, from (RS,SR-fluoro-(3-oxo-cyclopentyl)-(pyridine-2-
sulfonyl)-acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared RS,SRtetrahydro-cyclopentafbjindol-yO-fluoro-
(pyridine-2-sulfonyl)-acetic acid methyl ester as a white solid, MS: 423 (MH+).
Example 45
(RS,SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-fluorobenzenesulfonyl)-
acetic acid methyl ester
45.1
In analogy to example 19.1, from (3-fluoro-benzenesulfonyl)-acetic acid methyl ester
and cyclopent-2-enone was prepared (3-fluoro-benzenesulfonyl)-(3-oxo-cyclopentyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 315
45.2
In analogy to example 23.1, from (3-fluoro-benzenesulfonyl)-(3-oxo-cyclopentyl)-
acetic acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-f\uoro-
(3-fluoro-benzenesulfonyl)-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white
solid, MS: 333 (MH+).
45.3
In analogy to example 23.2, from (RS,SR)-fluoro-(3-fluoro-benzenesulfonyl)-(3-oxocyclopentyl)-
acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared RS,SR(T-chloro-l ,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-
fluoro-benzenesulfonyl)-acetic acid methyl ester as a light brown solid, MS: 440
Example 46
benzenesulfonyl)-fluoro-acetic acid methyl ester
46.1
In analogy to example 19.1, from (3,4-difluoro-benzenesulfonyl)-acetic acid methyl
ester and cyclopent-2-enone was prepared (3,4-difluoro-benzenesulfonyl)-(3-oxocyclopentyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, colorless
oil, MS: 333 (MH+).
46.2
In analogy to example 23.1, from (3,4-difluoro-benzenesulfonyl)-(3-oxo-cyclopentyl)-
acetic acid methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-(3,4-
difluoro-benzenesulfonyl)-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a
white solid, MS: 351 (MH+).
46.3
In analogy to example 23.2, from (RS,SR)-(3,4-difluoro-benzenesulfonyl)-iluoro-(3-
oxo-cyclopentyl)-acetic acid methyl ester and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-(3,4-difluoro-benzenesulfonyl)-fluoro-acetic acid methyl ester as a light brown
solid, MS: 458 (MH+).
Example 47
sulfonyl)-acetic acid methyl ester
47.1
In analogy to example 19.1, from (pyridine-3-sulfonyl)-acetic acid methyl ester and
cyclopent-2-enone was prepared (pyridine-3-sulfonyl)-(3-oxo-cyclopentyl)-acetic acid
methyl ester as a racemic mixture of diastereomers, yellow oil, MS: 298 (MH+).
In analogy to example 23.1, from (pyridine-3-sulfonyl)-(3-oxo-cyclopentyl)-acetic acid
methyl ester and N-fluorobenzenesulfonimide was prepared (RS,SR)-fluoro-(3-oxocyclopentyl)-(
pyridine-3-sulfonyl)-acetic acid methyl ester as white crystals, MS: 333
(MNH4
+).
47.3
In analogy to example 23.2, from (RS,SR-fluoro-(3-oxo-cyclopentyl)-(pyridine-3-
sulfonyl)-acetic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-
(pyridine-3-sulfonyl)-acetic acid methyl ester as a light brown solid, MS: 423 (MH+).
Example 48
(RS,SR)-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-(pyridine-2-
sulfonyl)-propionic acid methyl ester
48.1
In analogy to example 19.2, from (3-oxo-cyclopentyl)-(pyridine-2-sulfonyl)-acetic acid
methyl ester (example 44.2) and methyliodide was prepared (RS,SR)-2-(3-oxocyclopentyl)-
2-(pyridine-2-sulfonyl)-propionic acid methyl ester as a white solid, MS:
312(MH+).
48.2
In analogy to example 19.3, from (RS,SR)-2-(3-oxo-cyclopentyl)-2-(pyridine-2-
sulfonyl)-propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride
was prepared (RS,SR)-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-
(pyridine-2-sulfonyl)-propionic acid methyl ester as a white solid, MS: 419 (MH+).
Example 49
(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-2-yl)-
propionic acid
To 50 mg (0.115 mmol) of (RS,SR)- 2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydrol//-
carbazol-2-yl)-propionic acid methyl ester (example 3) in 4 mL of THF/MeOH 1:1,
0.29 mL of 2M NaOH (0.58 mmol, 5 eq) were added. The reaction mixture was stirred
at 60°C for 3 hours, acidified to pH = 6 with aqueous NH4C1 and extracted with EtOAc.
The combined organic phases were dried over Na2SO4, filtered and evaporated. Column
chromatography on silica gel with CH2Cl2/MeOH 3:1 yielded 40 mg (82%) of(RS,SR)-
2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionic acid as a
white solid, MS: 435 (MNH4
+).
Example 50
(RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoroacetic
acid
In analogy to example 49, from (RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydrol/
H/-carbazol-2-yl)-fluoro-acetic acid methyl ester was prepared (RS,SR)-
benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetic acid as a
white solid, MS: 420 (M-H)'.
Example 51
tetra hy d ro- IH-ca rbazole
51.1
350 mg (0.81 mmol) of(RS,SR)- 2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-propionic acid methyl ester (from example 3) in 10 mL of THF at 0°C,
were treated with 39 mg (0.89 mmol, 1.1 eq) of NaH (55% in oil) portionwise within 30
min. 0.10 mL (1.22 mmol, 1.5 eq) of l-chloro-2-methoxy-ethane was added and the ice
bath removed. After 2 hours, the reaction was quenched by addition of aqueous NH4C1
sat., extracted with EtOAc and the organic phases dried over Na2SO4. Evaporation of
the solvent afforded (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxyrnethyl-2,3,4,9-
tetrahydro-lH-carbazol-2yl)-propionic acid methyl ester as yellow solid, MS: 493
(MNH4
+). The crude material was used in the next step without further purification.
51.2
To 402 mg (0.84 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-
2,3,4,9-tetrahydro-l//-carbazol-2yl)-propionic acid methyl ester in 6 mL of THF, 1.0
mL (1.0 mmol, 1.2 eq) of LJA1H4 in THF was added at RT. After 30 min, the reaction
mixture was poured into water and extracted with EtOAc, dried over Na2SO4, and
evaporation of the solvent afforded (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-
methoxymethyl-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propan-l-ol as a colorless oil,
MS: 465 (MNHU+). The crude material was used in the next step without further
purification.
51.3
130 mg (0.29 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-
2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propan-l-ol in 5 mL of THF at 0°C were treated
with 14 mg (0.32 mmol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min. 30(aL
(0.43 mmol, 1.5 eq) of Mel were added and the reaction mixture was stirred an
additional 2 hours, partitioned between EtOAc and a saturated aqueous solution of
NH4C1. The organic phase was washed with brine, dried over Na2SCO4, and evaporated.
Column chromatography with heptane/EtOAc 1:2 gave 96 mg (72%) of (RS,SR)-2-( 1 -
benzenesulfonyl-2-methoxy-l-methyl-ethyl)-6-chloro-9-methoxymethyl-2,3,4,9-
tetrahydro-l//-carbazole as a white solid, MS: 479 (MNH4+).
51.4
95 mg (0.20 mmol) ofRS,SR(l-benzenesulfonyl-methoxy-l-methyl-ethyO-echloro-
9-methoxymethyl-2,3,4,9-tetrahydro-l//-carbazole were dissolved in 8 mL of
MeOH/THF 1:1, and 5 drops of HC1 12M were added. The temperature was raised to
55°C and the solution was stirred for 6 hours. By adding 2M NaHCO3 the solution was
neutralized to pH = 7, and the mixture was extracted with EtOAc. Column
chromatography on silica gel with heptane/EtOAc 2:1 yielded 11 mg (13%) of(RS,SR)-
2-(l-benzenesulfonyl-2-methoxy-l-methyl-ethyl)-6-chloro-2,3,4,9-tetrahydro-l//-
carbazole as a white solid, MS: 418 (MH+).
Example 52
propionitrile
52.1
To 9.4 g (0.052 mol) of benzenesulfonyl-acetonitrile in 200 mL of DME at -50°C, 7.8
mL (0.052 mol, 1 eq) of TMEDA and 32.4 mL (0.052 mL, 1 eq) of «BuLi (1.6M in
hexane) were added and stirring was continued for 45 min. To the resulting white
suspension, 4.98 g (0.052 mol, 1 eq) of cyclohex-2-enone were added and the
temperature was raised to -10°C within 4 hours. The reaction mixture was poured into
180 mL of 1M HC1, extracted with EtOAc, and the combined organic phases dried over
Na2SC4. Evaporation of the solvent and recrystallisation from AcOEt/EtaO yielded 8.25
g (57%) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile as a racemic mixture of
diastereomers, white crystals, MS: 278 (MH+) (in analogy to: E.Hatzigrigoriou,
L.Wartski, Synth. Comm., 1983, 14(4), 319-235).
52.2
4.0 g (0.014 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile in 40 mL of DMF
were treated with 0.69 g (0.016 mol, 1.1 eq) of NaH (55% in oil) portionwise within 30
min at 0°C. 3.07 g (0.022 mol, 1.5 eq) of methyliodide were added, and the ice bath was
removed. After 2 hours, the reaction mixture was poured into water and extracted with
EtOAc. The combined organic phases were dried over NaaSC, filtered and evaporated.
Column chromatography over silica gel with AcOEt/heptane 1:1 afforded 4 g (98%) of
2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile as a racemic mixture of
diastereomers, white solid, MS: 292 (MH+).
52.3
To 322 mg (1.10 mmol) of 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile in 10
mL of glacial acetic acid, 193 mg (1.21 mmol, 1.1 eq) of (4-methyl-phenyl)-hydrazine
hydrochloride were added and stirring was continued at RT over night. An aqueous
solution of NaHCO3 was added until pH = 7, and the product was extracted with
EtOAc, the organic phase was dried overNa2SO4, filtered and evaporated. The resulting
two diastereomers were separated by column chromatography on silica gel with
AcOEt/heptane 1:4, and triturated with Et2O. 158 mg (38%) of (RR,SS)-2-
benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionitrile and
123 mg (29%) of (RS,SR)-2-benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-propionitrile were isolated as light yellow solids, MS: 379 (MH+).
Example 53
(RS,SR)-2-benzenesu!fonyl-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-2-yl)-
propionitrile
In analogy to example 53.3, from 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile
and (4-chloro-phenyl)-hydrazine hydrochloride was prepared (RR,SS)-2-
benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-propionitrile and
(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionitrile as a white solid, MS: 397 (M-H)~.
Example 54
acetonitrile
54.1
3.85 g (0.014 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile in 40 mL of
DMF were treated with 0.68 g (0.016 mol, 1.1 eq) of NaH (55% in oil) portionwise
within 30 min at 0°C. 4.81 g (0.015 mol, 1.1 eq) of N-fluorobenzenesulfonimide were
added, and the ice bath was removed. After 2 hours, the reaction mixture was poured
into water, extracted with EtOAc. The combined organic phases were dried over
Na2SO4, filtered and evaporated, yielding 4g of a crude oil, consisting of a mixture of
the racemic diastereomer of benzenesulfonyl-fiuoro-(3-oxo-cyclohexyl)-acetonitrile,
which was used in the next step without further purification.
54.2
In analogy to example 52.3, from benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-
acetonitrile and (4-chloro-phenyl)-hydrazine hydrochloride was prepared (RR,SS)-
benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetonitrile and
(RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoroacetonitrile
as a light yellow solid, MS: 402 (M).
Example 55
fluoro-N-methyl-acetamide
To 400 mg (0.92 mmol) of (RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-fluoro-acetic acid methyl ester (from example 12) in a sealed tube were
added 20 mL of methylamine (33% wt. solution in EtOH) and 13 mg (0.27 mmol, 0.3
eq) of sodium cyanide. The reaction mixture was stirred at 90°C for 2 hours, and the
solvent was evaporated. Column chromatography on silica gel with EtOAc yielded 340
mg (86%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-
yI)-2-fluoro-N-methyl-acetamide as a white solid, MS: 435 (MH+).
Example 56
(RS,SR)-2-benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-2-fluoro-N-methyl-acetamide
In analogy to example 55, from (RS,SR)-benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-acetic acid methyl ester (from example 23) was
prepared (RS,SR)-2-benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-
2-yl)-2-fluoro-N-methyl-acetamide as a white solid, MS438 (MNH4
Example 57
(RS£R)-2-(6-cMoro-2,3,4,9-tetrahydro-lH-carb*zol-2-y\)-2-ttuoro-2-(3-ttuoroben/
enesulfonyO-N-methyl-acetamide
In analogy to example 55, from (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-ltf-carbazoI-2-
yl)-fluoro-(3-fluoro-benzenesulfonyl)-acetic acid methyl ester (from example 39) was
prepared (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-2-(3-
fluoro-benzenesulfonyl)-N-methyl-acetamide as a white solid, MS: 470 (MNH4
.
Example 58
(RS,SR)-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-2-(3-
fluoro-benzcncsulfonyl)-N-methyl-acetamide
In analogy to example 55, from (RS,SR)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-(3-fluoro-benzenesulfonyl)-acetic acid methyl ester
(from example 45) was prepared (RS,SR)-2-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yI)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N-methyl-acetamide as
a white solid, MS: 439 (MH+).
Example 59
(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-2-yl)-2-
fluoro-N,N-dimethyl-acetamide
59.1
To 950 mg (2.18 mmol) of (RS,SR-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydrol//-
carbazol-2-yl)-2-fluoro-N-methyl-acetamide (from example 56) in 10 mL of
CH2C12 at RT were added 0.60 mL (4.36 mmol, 2 eq) of Et3N, 27 mg (0.22 mmol, 0.1
eq) of DMAP and 571 mg (2.62 mmol, 1.2 eq) of carbonic acid di-tert-butyl ester. The
reaction mixture was stirred at RT for 2 hours and extracted with 1M HC1. The organic
phases were dried over Na2SCO4, filtered and evaporated. Column chromatography
afforded 682 mg (59%) of (RS,SR-2-(benzenesulfonyl-fluoro-methylcarbamoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as
white solid, MS: 552 (MNH4
680 mg (1.27 mmol) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 10 mL of
DMF were treated with 83 mg (1.90 mmol, 1.5 eq) of NaH (55% in oil) portionwise
within 30 min at 0°C. 217 mg (1.52 mmol, 1.2 eq) of methyl iodide were added and the
reaction was stirred an additional 30 min, and then poured into water and extracted with
EtOAc. The crude material was dissolved in 10 mL of CHjC, and 1 mL of TFA was
added at RT. Aqueous NaaCOa was added until pH = 7 was reached, and the organic
phases were dried on Na2SO4, filtered and evaporated. Column chromatography on
silica gel with heptane/EtOAc 1:1 yielded 420 mg (65%) of (RS,SR)-2-benzenesulfonyl-
2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-N,N-dimethyl-acetamide as a
white solid, MS: 449 (MH+).
Example 60
(RS,SR)-2-benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indoI-2-
yl)-2-fluoro-N,N-dimethyl-acetamide
In analogy to example 59, from (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-
tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-N-methyl-acetamide (from example 57)
was prepared (RS,SR)-2-benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-2-fluoro-N,N-dimethyl-acetamide as a white solid, MS: 452
(MNH/).
Example 61
benzenesulfonyl)-N,N-dimethyl-acctamide
In analogy to example 59, from (RS,SR2-(6-chloro-2,3,4,9-tetrahydro-l/f-carbazol-2-
yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N-methyl-acetamide (from example 58) was
prepared (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-2-(3-
fluoro-benzenesulfonyl)-N,N-dimethyl-acetamide as a white solid, MS: 467 (MH).
Example 62
fluoro-benzenesulfonyl)-N,N-dimethyl-acetamide
In analogy to example 59, from (RS,SR)-2-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-2-fluoro-(3-fluoro-benzenesulfonyl)-N-methyl-acetamide
(from example 58) was prepared (RS,SR(T-chloro-RS,SR
cyclopenta[b]indol-2-yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N,N-dimethylacetamide
as a white solid, MS: 453 (MH+).
Example 63
2-yl)-2-fluoro-N-methyl-acetamide
60 mg (0.112 mmol) of (^^^-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester (from example
59.1) in 3 mL of THF were treated with 7 mg (0.168 mmol, 1.5 eq) of NaH (55% in oil)
at 0°C over 40 min. 38 mg (0.224 mmol, 2eq) of bromomethly-benzene were added and
the reaction mixture was stirred over night at RT. The solvent was evaporated, the
residue was dissolved in 3 mL of Cl-feCfe, 1 mL of TFA was added, and the reaction
mixture was stirred over night at RT. Evaporation of the solvent and purification of the
residue by preparative HPLC (C18 column) yielded 35 mg (60%) of (RS,SR)-2-
benzenesuIfonyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-
N-methyl-acetamide as a white solid, MS: 525 (MH+).
Example 64
cyano-benzyl)-2-fluoro-N-methyl-acetamide
In analogy to example 63, from RS,SR-(benzenesulfonyl-fluoro-methylcarbamoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 4-
bromomethyl-benzonitrile was prepared (RS,SR)-2-benzenesulfonyl-2-(6-chIoro-
2,3,4,9-tetrahydro-l/H/-carbazol-2-yl)-N-(4-cyano-benzyl)-2-fluoro-N-methyl-acetamide
as a white solid, MS: 551 (MH+).
Example 65
carbazol-2-yl)-2-fluoro-N-methyl-acetamide
In analogy to example 63, from (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 1-
bromo-4-bromomethyl-benzene was prepared (RS,SR)-2-benzenesulfonyl-N-(4-bromobenzyl)-
2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-N-methyl-acetamide
as a white solid, MS: 603;605 (MH+).
Example 66
(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-m-carbazol-2-yl)-N-
(3,5-difluoro-benzyl)-2-fluoro-N-methyl-acetamide
In analogy to example 63, from (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbarnoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 1-
bromomethyl-3,5-difluoro-benzene was prepared (RS,SR)-2-benzenesulfonyl-2-(6-
chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-N-(3,5-difluoro-benzyl)-2-fluoro-Nmethyl-
acetamide as a light brown solid, MS: 561 (M).
Example 67
(RS,SR)-4-({[2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-2-yl)-
2-fluoro-acetyl]-methyl-amino}-methyI)-benzoic acid methyl ester
In analogy to example 63, from (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbarnoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 4-
bromomethyl-benzoic acid methyl ester was prepared (RS,SR)-4-({[2-benzenesulfonyl-
2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-
methyl)-benzoic acid methyl ester as a light brown solid, MS: 583 (M).
Example 68
(RS,SR)-3-({[2-benzenesulfoiiyl-2-(6-chloro-2,3,4,9-tetrahydro-l^-carbazol-2-yl)-
2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid methyl ester
In analogy to example 63, fromRS,SR(benzenesulfonyl-fluoro-methylcarbamoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 3-
bromomethyl-benzoic acid methyl ester was prepared (RS,SR)-3-({[2-benzenesulfonyl-
2-(6-chloro-2,3,4,9-tetrahydro-l/H-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-
methyl)-benzoic acid methyl ester as a white solid, MS: 583 (M).
Example 69
(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-m-carbazol-2-yl)-N-(2-
cyano-benzyl)-2-fluoro-N-methyl-acetamide
In analogy to example 63, from (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbarnoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 2-
bromomethyl-benzonitrile was prepared (RS,SR)-2-benzenesulfonyl-2-(6-chloro-
2,3,4,9-tetrahydro-l//-carbazol-2-yl)-N-(2-cyano-benzyl)-2-fluoro-N-methyl-acetamide
as a white solid, MS: 550 (M).
Example 70
yl)-2-fluoro-N-methyl-acetamide
In analogy to example 63, from (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbarnoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 3-
bromo-propene was prepared (RS,SR)-N-allyl-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-
tetrahydro-l//-carbazol-2-yl)-2-fluoro-N-methyl-acetamide as a white solid, MS: 475
Example 71
cyano-benzyl)-2-fluoro-N-methyl-acetamide
In analogy to example 63, fromRS,SR-(benzenesulfonyl-fluoro-methylcarbamoylmethyl)-
6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester and 3-
bromomethyl-benzonitrile was prepared (RS,SR)-2-benzenesulfonyl-2-(6-chloro-
2,3 ,4,9-tetrahydro- 1 RS,SRcarbazol-2-yl)-N-(3 -cyano-benzy l)-2-fluoro-N-methy 1-acetam ide
as a white solid, MS: 550 (M).
Example 72
2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid
To 88 mg (0.151 mmol} of (RS,SR)-3{[2-benzenesulfonyl-2-(6-chloro-2,3,4,9-
tetrahydro-l//-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-benzoic acid methyl ester
(from example 69) in 5 mL of THF/MeOH 1 :1, 1 mL of 1M NaOH was added and the
reaction mixture was stirred over night at RT. Aqueous NH4C1 was added until pH = 7
was reached, the product was extracted with EtOAc, dried over Na2SO4, filtered and
solvent evaporated. Recrystallisation in Et2O yielded 66 mg (77%) of (RS,SR)-3-({[2-
benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-acetyl]-
methyl-amino}-methyl)-benzoic acid as a white solid, MS: 570 (MH+).
Example 73
2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l/T-carbazol-2-yl)-2-
fluoro-N-(3-hydroxymethyl-benzyl)-N-methyI-acetamide
To 61 mg (0.107 mmol) of (RS,SR)-3-({[2-benzenesulfonyI-2-(6-chloro-2,3,4,9-
tetrahydro-l//-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid
(from example 73) in 3 mL of THF at 0°C, 160 uL (0.107 mmol, 1 eq) of BH3.THF
(1M in THF) were added, and the reaction mixture stirred for an additional hour, and
then partitioned between EtOAc and water. The organic layer was dried over NaaSO
filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 2:1
yielded 50 mg (84%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-2-fluoro-N-(3-hydroxymethyl-benzyl)-N-methyl-acetamide as a white
solid, MS: 555 (M).
Example 74
(RS,SR)-2-[benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazoI-2-yl)-methyl]-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole
74.1
To a stirred solution of 5.0 g (0.023 mol) of benzenesulfonyl-acetic acid methyl ester in
10 mL of MeOH at RT, 3.50 g (0.070 mol, 3 eq) of hydrazine hydrate were added.
After one hour, the solvent and the excess of hydrazine were removed under reduced
pressure, yielding 4.90 g (quantitative) of benzenesulfonyl-acetic acid hydrazide as a
colorless oil, MS: 232 (MNH4
+).
74.2
To a stirred solution of 1.50 g (7.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 5
mL of acetic acid, 1.44 g (14.0 mmol, 2 eq) of acetic anhydride were added, and the
solution was heated at reflux for 1 hour. The reaction mixture was diluted with water,
extracted with EtOAc, the organic phase dried over Na2SO4, filtered and evaporated, to
afford 1.40 g (78%) of acetic acid N'-(2-benzenesulfonyl-acetyl)-hydrazide as a white
solid, MS: 274 (MNH4
+).
74.3
To a stirred solution of 1.40 g (5.5 mmol) of acetic acid N'-(2-benzenesulfonyl-acetyl)-
hydrazide in 50 mL of acetonitrile, 1.02 g (6.5 mmol, 1.2 eq) of phosphorus
oxychloride were added, and the solution heated at reflux for 3 hours. The reaction
mixture was diluted with water, extracted with EtOAc, the organic phase dried over
Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc
yielded 0.90 g (70%) of 2-benzenesulfonylmethyl-5-methyl-[l,3,4]oxadiazole as a
white solid, MS: 239 (MH+).
74.4
To 650 mg (2.73 mmol) of 2-benzenesulfonylmethyl-5-methyl-[l,3,4]oxadiazole in 35
mL of MeOH at 0°C, 50 (j,L (0.27 mmol, 0.1 eq) of a solution of sodium methoxide (5.4
M in MeOH) were added. After 15 min, 246 mg (3.0 mmol, 1.1 eq) of cyclopent-2-
enone were added. The reaction mixture was stirred at 0°C and was allowed to reach
RT within 4 hours, diluted with saturated aqueous NFLtCl and extracted with EtOAc.
The combined organic phases were dried over Na2SC»4, filtered and evaporated. Column
chromatography on silica gel with EtOAc gave 750 mg (86%) of 3-[benzenesulfonyl-
(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, white solid, MS: 321 (MH+).
74.5
375 mg (1.17 mmol) of 3-[benzenesulfonyl-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-
cyclopentanone in 10 mL of DMF, were treated with 52 mg (1.29 mmol, 1.1 eq) of NaH
(55% in oil) over 30 min. 554 mg (1.75 mmol, 1.5 eq) of N-fluorobenzenesulfonimide
were added, and after 2 hours, the reaction mixture was diluted with saturated aqueous
and extracted with EtOAc. The combined organic phases were dried over
4, filtered and evaporated. The resulting two diastereomers were separated by
column chromatography on silica gel with EtOAc/heptane 2:1 yielding 80 mg (20%) of
cyclopentanone as a colorless oil, MS: 339 (MH+) and 75 mg (19%) of (RR,SS)-3-
[benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a
white solid, MS: 339 (MH+).
74.6
In analogy to example 23.2, from 80 mg (0.23 mmol) of (RS,SR-S-fbenzenesulfonylfluoro-(
5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and 49 mg (0.26
mmol, 1.15 eq) of (4-chloro-phenyl)-hydrazine hydrochloride was prepared 38 mg
(36%) of (RS,SR-2-[benzenesulfonyl-fluoro-(5-methyl-[l ,3,4]oxadiazol-2-yl)-methyl]-
7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole as light orange crystals, MS: 446
The enantiomers were separated by preparative chiral HPLC. Column: chiralpak AD,
solvent: 20%isopropanol/heptane to give (S)-2-[(R)-Benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole and
(R)-2-[(S)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole.
Example 75
l,2,3,4-tctrahydro-cyclopenta[b]indole
75.1
375 mg (1.17 mmol) of 3-[benzenesulfonyl-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyI]-
cyclopentanone in 10 mL of DMF, were treated with 52 mg (1.29 mmol, 1.1 eq) of NaH
(55% in oil) over 30 min. 300 mg (2.32 mmol, 1.8 eq) of methyliodide were added, and
after 2 hours, the reaction mixture was diluted with saturated aqueous NHUCl and
extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered
and evaporated. The resulting two diastereomers were separated by column
chromatography on silica gel with EtOAc/heptane 1:2, yielding 95 mg (24%) of
(^,^)-3-[l-benzenesulfonyl-l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-
cyclopentanone as a white solid, MS: 335 (MH+) and 90 mg (23%) of (RR,SS)-l-[\-
benzenesulfonyl-l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-cyclopentanone as a white
solid, MS: 335 (MH+).
75.2
In analogy to example 19.3, from 90 mg (0.27 mmol) of (^^-S-fl-benzenesulfonyll-(
5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-cyclopentanone and 58 mg (0.33 mmol, 1.2
eq) of (4-chloro-phenyl)-hydrazine hydrochloride was prepared 35 mg (30%) of
l,2,3,4-tetrahydro-cyclopenta[b]indole as a light yellow solid, MS: 442 (MH+).
Example 76
tetrahyd ro-cyclopenta [b] indole
76.1
To 1.73 g (8.07 mmol) of benzenesulfonyl-acetic acid hydrazide were added 20 mL of
trimethyl orthoformate and 1.26 g (8.07 mmol, 1 eq) of phosphorous oxychloride. The
reaction mixture was stirred one hour at RT, and concentrated under reduced pressure.
Column chromatography on silica gel with EtOAc/hexane 2:1 yielded 930 mg (52%) of
2-benzenesulfonylmethyl-[l,3,4]oxadiazole as a white solid, MS: 225 (MH+).
76.2
In analogy to example 74.4, from 2-benzenesulfonylmethyl-[l,3,4]oxadiazole and
cyclopent-2-enone was prepared 3-(benzenesulfonyl-[l,3,4]oxadiazol-2-yl-methyl)-
cyclopentanone as a racemic mixture of diastereomers. The product was used directly in
the next step without further characterisation.
76.3
In analogy to example 74.5, from 3-(benzenesulfonyl-[l,3,4]oxadiazol-2-yl-methyl)-
cyclopentanone and N-fluorobenzenesulfonimide were prepared (RS,SR)-3-
(benzenesulfonyl-fluoro-[l,3,4]oxadiazol-2-yl)-methyl)-cyclopentanone as a white
solid, MS: 342 (MNH4
+) and (RS,SR-3-(benzenesulfonyl-fluoro-[l,3,4]oxadiazol-2-yl)-
methyl)-cyclopentanone as a white solid, MS: 342 (MNlV).
76.4
In analogy to example 74.6, from (RS,SR)-3-(benzenesulfonyl-fluoro-[l,3,4]oxadiazol-
2-yl)-methyl)-cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-(benzenesulfonyl-fluoro-[l,3,4]oxadiazol-2-yl-methyl)-7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indole as light yellow solid, MS: 449 (MNH4
+).
Example 77
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole
77.1
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 30 mL of phosphorus
oxychloride, 1.47 g (17.0 mmol, 1.2 eq) of cyclopropanecarboxylic acid were added,
and heated at reflux for 2 hours. The reaction mixture was very carefully poured onto
ice, extracted with EtOAc, filtered and evaporated. Column chromatography on silica
gel with EtOAc/heptane 2:1 yielded 1.49g (41%) of 2-benzenesulfonylmethyl-5-
cyclopropyl-[l,3,4]oxadiazole as a white solid, MS: 265 (MH+).
77.2
In analogy to example 74.4, from 2-benzenesulfonylmethyl-5-cyclopropyl-
[l,3,4]oxadiazole and cyclopent-2-enone was prepared 3-[benzenesulfonyl-(5-
cyclopropyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, white solid, MS: 347 (MH+).
77.3
In analogy to example 74.5, from 3-[benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-
2-yl)-methyl]-cyclopentanone and N-fluorobenzenesulfonimide were prepared (RS,SR)-
3-[benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-
cyclopentanone as a white solid, MS: 365 (MH+) and RS,SR)-3-[benzenesulfonyl-(5-
cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-cyclopentanone as a white solid,
MS: 365 (MH+).
77.4
In analogy to example 74.6, from (RS,SR)- 3-[benzenesulfonyl-(5-cyclopropyl-
[1,3,4]oxadiazol-2-yl)-fluoro-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (/?5',5'/?)-2-[benzenesulfonyl-(5-cyclopropyl-
[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole
as light brown solid, MS: 472 (MH+).
Example 78
(RS,SR)-2-[benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-
6-chloro-2,3,4,9-tetrahydro-l/f-carbazole
78.1
To 2.47 g (9.3 mmol) of 2-benzenesulfonylmethyl-5-cyclopropyl-[l,3,4]oxadiazole in
25 mL of MeOH at 0°C, 170 ^L (0.93 mmol, 0.1 eq) of a solution of sodium
methoxyde (5.4 M in MeOH) were added. After 15 min, 895 mg (9.3 mmol, 1 eq) of
cyclohex-2-enone were added. The reaction mixture was stirred from 0°C to RT over 4
hours, diluted with saturated aqueous NI-LtCl and extracted with EtOAc. The combined
organic phases were dried over Na2SO4, filtered and evaporated. Column
chromatography on silica gel with EtOAc/heptane 2:1 gave 1.48 g (44%) of 3-
[benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclohexanone as a
racemic mixture of diastereomers, white solid, MS: 361 (MH+).
78.2
In analogy to example 74.5, from 3-[benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-
2-yl)-methyl]-cyclohexanone and N-fluorobenzenesulfonimide were prepared (RS,SR)-
3-[benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-
cyclohexanone as a white solid, MS: 379 (MH+) and (RS,SR--[benzenesulfonyl-(5-
cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyI]-cyclohexanone as a white solid, MS:
379 (MH+).
78.3
In analogy to example 12.2, from RS,SR)-3-[benzenesulfonyl-(5-cyclopropyl-
[l,3,4]oxadiazol-2-yl)-fiuoro-methyl]-cyclohexanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-2-[benzenesulfonyl-(5-cyclopropyl-
[1,3,4]oxadiazol-2-yl)-fluoro-methyl]-6-chloro-2,3,4,9-tetrahydro-l//-carbazole as a
yellow solid, MS: 486 (MH+).
Example 79
fluoro-methyl]-[l,3,4|oxadiazol-2-yl}-dimethyl-amine
79.1
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 100 mL of
3.41 g (21.0 mmol, 1.5 eq) of dichloromethylene-dimethyl-ammonium chloride and
3.90 mL (28.0 mmol, 2 eq) of triethyl-amine were added. The solution was stirred at
reflux for 1 hour, partitioned between aqueous NaOH 0.5M and EtOAc. The combined
organic phases were dried over Na2SCO4, filtered, evaporated, and column
chromatography on silica gel with CH2Cl2/MeOH 100:1 afforded 0.59 g 715%) of (5-
benzenesulfonylmethyl-[l,3,4]oxadiazol-2-yl)-dimethyl-amine as a white solid, MS:
268 (MH+).
79.2
In analogy to example 74.4, from (5-benzenesulfonylmethyl-[l,3,4]oxadiazol-2-yl)-
dimethyl-amine and cyclopent-2-enone was prepared 3-[benzenesulfonyl-(5-
dimethylamino-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, light yellow solid, MS: 350 (MH+).
79.3
In analogy to example 74.5, from 3-[benzenesulfonyl-(5-dimethylamino-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and N-fluorobenzenesulfonimide were
prepared (RS,SR)-3-[benzenesulfonyl-(5-dimethylamino-[13,4]oxadiazol-2-yl)-fIuoromethylj-
cyclopentanone as a white solid, MS: 368 (MH+) and (RS,SR)-3-
[benzenesulfonyl-(5-dimethylamino-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-
cyclopentanone as a white solid, MS: 368 (MH+).
In analogy to example 74.6, from (RS,SR)- 3-[benzenesulfonyl-(5-dimethylamino-
[1 ,3,4]oxadiazol-2-yl)-fluoro-rnethyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-amine as a
white solid, MS: 475 (MH+).
Example 80
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-amine; HCI salt
To 15 mg (0.031 mmol) of RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethylamine in 5 mL
of Et2O/EtOAc 3:1, HCI gas was bubbled into the solution until a white precipitate was
formed. The solvent was removed, and the solid dried under vacuo, yielded 14 mg
(87%)of(RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-
2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-amine; HCI salt as a white solid,
MS: 475 (MH+).
Example 81
(RS,SR)-2-[benzenesulfonyI-fluoro-(3-methyl-[l,2,4]oxadiazol-5-yl)-methyl]-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole
81.1
10.8 g (0.098 mol) of benzenethiol in 70 mL of DMF at 0°C, were treated with 4.31 g
(0.108 mol, 1.1 eq) of NaH (55% in oil) over 40 min. 17.19 g (0.103 mol, 1.05 eq) of
bromo-acetic acid ethyl ester were added, and stirring was continued over night. The
reaction mixture was partitioned between aqueous NH4C1 and EtOAc, dried over
Na2SO4, filtered and evaporated, to afford 15.4 g (80%) of phenylsulfanyl-acetic acid
ethyl ester as a colorless oil, MS: 197 (MH+).
81.2
565 mg (7.65 mmol, 1.5 eq) of N-hydroxy-acetamidine in 50 ml of THF were treated at
RTwith 306 mg (7.65 mmol, 1.5 eq) of NaH portionwise within 30 min. 1.0 g (5.1
mmol) of phenylsulfanyl-acetic acid ethyl ester was added in a THF solution, and
stirring was continued for 1 hour at 60°C. The reaction mixture was diluted with
saturated aqueous NH4C1, extracted with EtOAc, filtered and evaporated. Column
chromatography on silica gel with EtOAc/heptane 1:1 yielded 480 mg (46%) of 3-
methyl-5-phenylsulfanylmethyl-[l,2,4]oxadiazole as a colorless oil.
81.3
To 450 mg (2.2 mmol) of 3-methyl-5-phenylsulfanylmethyl-[l,2,4]oxadiazole in 50 mL
of CHC13 at RT, 1.08 g (4.4 mmol, 2 eq) of mCPBA were added, and stirred 2 hours.
The reaction mixture was washed with an aqueous solution of NaHCOs and the organic
phase dried over NajSO^ filtered and evaporated. Column chromatography on silica gel
with EtOAc/heptane 1:1 afforded 385 mg (74%) of 5-benzenesulfonylmethyI-3-methyl-
[l,2,4]oxadiazole as a white solid, MS: 239 (MH+).
81.4
In analogy to example 74.4, from 5-benzenesulfonylmethyl-3-methyl-[l,2,4]oxadiazole
and cyclopent-2-enone was prepared 3-[benzenesulfonyl-(3-methyl-[l,2,4]oxadiazol-5-
yl)-methyl]-cyclopentanone as a racemic mixture of diastereomers, white solid, MS:
321 (MH+).
81.5
In analogy to example 74.5, from 3-[benzenesulfonyl-(3-methyl-[l,2,4]oxadiazol-5-yl)-
methyl]-cyclopentanone and N-fluorobenzenesulfonimide were prepared (RS,SR)-3-
[benzenesulfonyl-fluoro-(3-methyl-[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone as a
white solid, MS: 339 (MH+) and (RS,SR)-3-[benzenesulfonyl-fluoro-(3-methyl-
[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone as a white solid, MS: 339 (MH+).
81.6
In analogy to example 74.6, from
[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-2-[benzenesulfonyl-fluoro-(3-methyl-
[l,2,4]oxadiazol-5-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole as a
light brown solid, MS: 446 (MH+).
Example 82
fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester
82.1
To a stirred suspension of 10.0 g (0.1 17 mol) of nitriloacetic acid methyl ester and 8.17
g of (0.1 17 mol, 1 eq) of hydroxylamine.hydrochloride in 250 mL of MeOH at RT, 21.8
mL (0.1 17 mol, 1 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added.
Stirring was continued for 3 hours, and the reaction was filtered and concentrated under
vacuum. The resulting yellow gum was extracted several times with Cl-bCb, and the
organic phase filtrated over decalite, and evaporated, to afford 1.1 g (8%) of aminohydroxyimino-
acetic acid methyl ester as a white solid.
82.2
300 mg (2.54 mmol) of amino-hydroxyimino-acetic acid methyl ester and 428 mg (2.29
mmol, 0.9 eq) of phenylsulfanyl-acetyl chloride were stirred in 10 mL of THF at RT for
1 hour. The solvent was evaporated, the residue dissolved in dioxane, and the reaction
mixture was heated at reflux over night in the presence of molecular sieves. Filtration,
concentration under vacuum and column chromatography over silica gel with
EtOAc/heptane 1:1 yielded 310 mg (49%) of 5-phenylsulfanylmethyl-
[l,2,4]oxadiazole-3-carboxylic acid methyl ester as light yellow oil, MS: 268
(MNH4
In analogy to example 81.3, from 5-phenylsulfanylmethyl-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester was prepared 5-benzenesulfonylmethyl-[l,2,4]oxadiazole-
3-carboxylic acid methyl ester as a white solid, MS: 283 (MH+).
82.4
In analogy to example 74.4, from 5-benzenesulfonylmethyl-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester and cyclopent-2-enone was prepared 5-[benzenesulfonyl-
(3-oxo-cyclopentyl)-methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester as a
racemic mixture of diastereomers, colorless oil, MS: 382 (MNH4+).
82.5
In analogy to example 74.5, from 5-[benzenesulfonyl-(3-oxo-cyclopentyl)-methyl]-
[l,2,4]oxadiazole-3-carboxylic acid methyl ester and N-fluorobenzenesulfonimide were
prepared (RS,SR)-5-[benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-methyl]-
[l,2,4]oxadiazole-3-carboxylic acid methyl ester as a white solid, MS: 400 (MNH4
+)
and (RS,SR-tbenzenesulfonyl-fluoro-CS-oxo-cyclopentyO-methylJ-RS,SRoxadiazole-
3-carboxylic acid methyl ester as a white solid, MS: 400 (MNH4+).
82.6
In analogy to example 74.6, from (RS,SR)-5-[benzenesulfonyl-fluoro-(3-oxocyclopentyl)-
methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester and (4-chlorophenyl)-
hydrazine hydrochloride was prepared (RS,SRS,SR)-5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester as a light orange solid, MS: 490 (MH+).
Example 83
(RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indoI-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methanoI
To a stirred solution of 80 mg (0.16 mmol) of (./RS,SRbenzenesulfonyl--chlorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester (from example 83) in 10 mL of THF at RT, 180 j L (0.17
mmol, 1.1 eq) of LiAlH4 (1M in THF) were added. After 1 hour, the reaction mixture
was partitioned between aqueous NH4C1 and EtOAc. The organic phase was dried over
Na2SCO4, filtered and evaporated. Column chromatography on silica gel with
EtOAc/heptane 1:1 gave 19 mg (25%) of (RS,SR)-{5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-
methanol as a light yellow solid, MS: 462 (MH+).
Example 84
fliioro-methyl]-[l,2,4]oxadiazole-3-carboxy lie acid
To a stirred solution of 600 mg (1.22 mmol) of (JRS,SR)-5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester in 5 mL of MeOH/THF 1:1, were added 980 mg (24.5
mmol, 20 eq) of NaOH in solution in 3 mL of water. After 2 hours at RT, aqueous
NH4C1 was added until pH = 7 was reached, the product was extracted with EtOAc,
dried over NaaSCO, filtered and solvent evaporated. Column chromatography on silica
gel with CH2Cl2/MeOH 8:2 yielded 300 mg (52%) of (RS,SR)-5-[benzenesulfonyl-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid as a white solid, MS: 430 (M-COOH).
Example 85
(RS,SR-fbenzenesulfonyKT-chloro-lRS,SR-tetrahydro-cyclopentalbJindol-l-yl)-
fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid amide
To a stirred solution of 70 mg (0.14 mmol) of (RS,SR)-5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester in 3 mL of EtOH, were added 0.5 mL of an ammonium
hydroxide solution (25% in water) and stirred over night. The reaction mixture was
partitioned between EtOAc and water. The organic phase was dried over Na2SC4,
filtered and evaporated. Recrystallisation in Et2O afforded 60 mg (86%) of (RS,SR)-5-
[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-
[l,2,4]oxadiazole-3-carboxylic acid amide as a light orange crystals, MS: 475 (MH+).
Example 86
(RS,SR-fbenzenesulfonyl-CT-chloro-RS,SR-tetrahydro-cyclopentalblindol-l-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-amine
86.1
In analogy to example 82.1, from dimethyl-cyanamide and hydroxylamine
hydrochloride was prepared amino-hydroxyimino-dimethyl amine as a light orange
solid and used directly in the next step without purification and characterisation. In
analogy to example 82.2, from this derivative and phenylsulfanyl-acetic acid ethyl ester
was prepared dimethyl-(5-phenylsulfanylmethyl-[l,2,4]oxadiazol-3-yl)-amine as a
colorless oil, MS: 236 (MH+).
86.2
In analogy to example 81.3, from dimethyl-(5-phenylsulfanylmethyl-[l,2,4]oxadiazol-
3-yl)-amine and mCPBA was prepared (5-benzenesulfonylmethyl-[l,2,4]oxadiazol-3-
yl)-dimethyl-amine as a white solid, MS: 268 (MH+).
86.3
In analogy to example 74.4, from (5-benzenesulfonylmethyl-[l,2,4]oxadiazol-3-yl)-
dimethyl-amine and cyclopent-2-enone was prepared 3-[benzenesulfonyl-(3-
dimethylamino-[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, yellow solid, MS: 350 (MH+).
86.4
In analogy to example 74.5, from 3-[benzenesulfonyl-(3-dimethylamino-
[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone and N-fluorobenzenesulfonimide were
prepared (RS,SR)-3-[benzenesulfonyl-(3-dimethylamino-[l,2,4]oxadiazol-5-yl)-fluoromethyl]-
cyclopentanone as a white solid, MS: 368 (MH+) and (RS,SR)- 3-
[benzenesulfonyl-(3-dimethylamino-[l,2,4]oxadiazol-5-yl)-fluoro-methyl]-
cyclopentanone as a white solid, MS: 368 (MH+).
86.5
In analogy to example 74.6, from (RS,SR)-3-[benzenesulfonyl-(3-dimethylamino-
[1,2,4]oxadiazol-5-yl)-fluoro-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-amine as a
white solid, MS: 475 (MH+).
Example 87
(RS,SR)-7-chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(3-methyl-[l,2,4]oxadiazol-
5-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[6]indole
87.1
In analogy to example 81.1, 4.34 g (0.030 mol) of 3-chloro-benzenethiol in 50 mL of
DMF at 0°C were treated with 1.32 g (0.033 mol, 1.1 eq) of NaH (55% in oil) over 45
min. 4.82 g (0.032 g, 1.05 eq) of bromo-acetic acid ethyl ester were added, and stirring
was continued for 2 hours. Workup and purification gave 5.9 g (91%) of (3-chlorophenylsulfanyl)-
acetic acid methyl ester as a colorless oil.
87.2
In analogy to example 81, from (3-chloro-phenylsulfanyl)-acetic acid methyl ester and
N-hydroxy-acetamidine was prepared 5-(3-chloro-phenylsulfanylmethyl)-3-methyl-
[l,2,4]oxadiazole as a colorless oil, MS: 241 (MH+).
87.3
In analogy to example 81.3, from 5-(3-chloro-phenylsulfanylmethyl)-3-methyI-
[l,2,4]oxadiazole and mCPBA was prepared 5-(3-chloro-benzenesulfonylmethyl)-3-
methyl-[l,2,4]oxadiazole as a white solid, MS: 273 (MH+).
87.4
In analogy to example 81.4, from 5-(3-chloro-benzenesulfonylmethyl)-3-methyl-
[l,2,4]oxadiazole and cyclopent-2-enone was prepared 3-[(3-chloro-benzenesulfonyl)-
(3-methyl-[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, light yellow oil, MS: 355 (MH+).
87.5
In analogy to example 81.5, from 3-[(3-chloro-benzenesulfonyl)-(3-methyl-
[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone and N-fluorobenzenesulfonimide were
prepared (RS,SR)-3-[(3-chloro-benzenesulfonyl)-fluoro-(3-methyl-[l,2,4]oxadiazol-5-
yl)-methyl]-cyclopentanone as a white solid and (RS,SR)-3-[(3-chlorobenzenesulfonyl)-
fluoro-(3-methyl-[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone as a
white solid.
87.6
In analogy to example 81.6, from (RS,SR)-3-[(3-chloro-benzenesulfonyl)-fluoro-(3-
methyl-[l ,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-7-chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(3-
methyl-[l ,2,4]oxadiazol-5-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[A]indole as a
white solid, MS: 480 (MH+).
102
Example 88
(RS,SR)-7-chIoro-2-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-
2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indoIe
88.1
In analogy to example 81.3, from (3-chloro-phenylsulfanyl)-acetic acid methyl ester and
mCPBA was prepared (3-chloro-phenylsulfonyl)-acetic acid methyl ester as a colorless
oil, MS: 256 (MNH4
+).
88.2
In analogy to example 74.1, from (3-chloro-phenylsulfonyl)-acetic acid methyl ester
and hydrazine hydrate was prepared (3-chloro-phenylsulfonyI)-acetic acid hydrazide as
a white solid, MS: 249 (MH+).
88.3
In analogy to example 74.2, from (3-chloro-phenylsulfonyl)-acetic acid hydrazide and
acetic anhydride was prepared acetic acid N'-(2-benzenesulfonyl-acetyl)-hydrazide as a
white solid, MS: 291 (MH+).
88.4
In analogy to example 74.3, from acetic acid N'-(2-benzenesulfonyl-acetyl)-hydrazide
and phosphorus oxychloride was prepared 2-(3-chloro-benzenesulfonylmethyl)-5-
methyl-[l,3,4]oxadiazole as viscous oil, MS: 273 (MH+).
88.5
In analogy to example 74.4, from 2-(3-chloro-benzenesulfonylmethyl)-5-methyl-
[l,3,4]oxadiazole and cyclopent-2-enone was prepared 3-[(3-chloro-benzenesulfonyl)-
(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, white solid, MS: 355 (MH+).
88.6
In analogy to example 74.5, from 3-[(3-chloro-benzenesulfonyl)-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and N-fluorobenzenesulfonimide were
prepared (RS,SR)-3-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[ 1,3,4]oxadiazol-2-
yl)-methyl]-cyclopentanone as a white solid, MS: 373 (MH+) and (RS,SR)-3-[(3-chlorobenzenesulfonyl)-
fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a
white solid, MS: 373 (MH+).
88.7
In analogy to example 74.6, from (RS,SR)-3-[(3-chloro-benzenesulfonyl)-fluoro-(5-
methyl-[ 1,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-7-chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(5-
methyl-[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole as a light
brown solid, MS: 480 (MH+).
Example 89
(RS,SR)-2-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-
yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione
89.1
32 g (0.217 mol) of isoindole-l,3-dione in 160 mL of DMF were treated with 11.75 g
(0.294 mol, 1.35 eq) of NaH (60% in oil) over 45 min at 0°C. 22.17 g (0.294 mol, 1.35
eq) of chloro-acetonitrile were added, and the reaction was stirred over night. The
reaction mixture was poured into 1.5 L of water, and the precipitate was collected by
filtration, washed with Et2O and dried under high vacuum to afford 36.1 g (89%) of
(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-acetonitrile as a white solid, MS: 187 (MH+).
89.2
To a mixture of 35.4 g (0.190 mol) of (l,3-dioxo-l,3-dihydro-isoindol-2-yl)-acetonitrile
and 14.78 g (0.213 mol, 1.12 eq) of hydroxylamine hydrochloride in 100 mL of DMF,
were added 38.7 mL (0.209 mol, 1.1 eq) of a solution of sodium methoxide (5.4 M in
MeOH) dropwise at RT. After 2 hours, the reaction mixture was poured into 1 L of cold
water, and the precipitate was collected by filtration and dried under high vacuum. This
gave 37.7 g (90%) of 2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-./V-hydroxy-acetamidine
as a white solid, MS: 220 (MH+).
89.3
To 10 g (0.046 mol) of 2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-Ar-hydroxy-acetamidine
dissolved in 500 mL of DMF, 1.84 g (0.046 mol, 1 eq) of magnesium oxide were
added. After 15 min, 8.5 g (0.046 mol, 1 eq) of phenylsulfanyl-acetyl chloride were
added, and the temperature was raised to 105°C and the solution was stirred overnight.
The reaction mixture was partitioned between aqueous NI-RS,SRand EtOAc, dried over
Na2SO4. Column chromatography on silica gel with EtOAc/Heptane 1:1 yielded 8.7 g
(55%) of 2-(5-phenylsulfanylmethyl-[l,2,4]oxadiazol-3-ylmethyl)-isoindole-l,3-dione
as a light yellow solid, MS: 352 (MH+).
89.4
In analogy to example 81.3, from 2-(5-phenylsulfanylmethyl-[l,2,4]oxadiazol-3-
ylmethyl)-isoindole-l,3-dione was prepared 2-(5-benzenesulfonylmethyl-
[l,2,4]oxadiazol-3-ylmethyl)-isoindole-l,3-dione as a white solid, MS: 384 (MH+).
89.5
In analogy to example 74.4, from 2-(5-benzenesulfonylmethyl-[l,2,4]oxadiazol-3-
ylmethyl)-isoindole-l,3-dione and cyclopent-2-enone was prepared 2-{5-
[benzenesulfonyl-(3-oxo-cyclopentyl)-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-isoindole-
1,3-dione as a racemic mixture of diastereomers, white solid, MS: 452 (MH+).
89.6
In analogy to example 74.5, from 2-{5-[benzenesulfonyl-(3-oxo-cyclopentyl)-methyl]-
[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione and N-fluorobenzenesulfonimide was
prepared 2-{5-[benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-methyl]-[l,2,4]oxadiazol-
3-ylmethyl}-isoindole-l,3-dione as a racemic mixture of diastereomers, white solid,
MS: 484 (MH+).
89.7
To 1.90 g (3.92 mmol) of 2-{5-[benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-methyl]-
[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione (as mixture of diastereomers) in 50
mL of glacial acetic acid, 870 mg (4.70 mmol, 1.2 eq) of (4-chloro-phenyI)-hydrazine
hydrochloride were added. The reaction mixture was heated from 50 to 75°C over 2
hours. The solvent was removed under vacuum, and an aqueous solution of NaHCO3
was added until ph=7, and the product was extracted with EtOAc. The combined
organic phases were dried over Na2SCO4, filtered and evaporated. A column
chromatography on silica gel with EtOAc/Heptane 1:2 yielded 530 mg (23%) of
(RS,SR)-2-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione as a light yellow
solid, MS: 608 (MNH4
+), and 417 mg (18%) of (RS,SR)-2-{5-[benzenesulfonyl-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
ylmethyl}-isoindole-l,3-dione as a light yellow solid, MS: 608 (MNH4+).
Example 90
(RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indoI-2-
yl)-fluoro-methyI]-[l,2,4]oxadiazol-3-yl}-methylamine
To a stirred suspension of 420 mg (0.71 mmol) of (RS,SR)-2-{5-[benzenesulfonyl-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
ylmethyl}-isoindole-l,3-dione in 50 mL of EtOH, was added 0.10 mL (2.13 mmol, 3
eq) of hydrazine hydrate. The reaction mixture was heated to 80°C for 3 hours, before it
was partitioned between EtOAc and aqueous HC1 IN. The organic phases were dried
over Na2SCO4, filtered and evaporated. Column chromatography on silica gel with
CH2Cl2/MeOH 95:5 afforded 210 mg (64%) of (RS,SR)-C-{5-[benzenesulfonyl-(7-
chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[ 1,2,4]oxadiazol-3-
yl}-methylamine light brown solid, MS: 461 (MH+).
Example 91
(IRS,SR-IS-Ibenzenesulfonyl-CT-chloro-ljl-tetrahydro-cyclopentalblindol-l-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-dimethyl-amine
To a stirred solution of 41 mg (0.089 mmol) of
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
yl}-methylamine in MeOH (5 mL), was added 0.07 mL of a formaldehyde solution in
water (36%, 0.89 mmol, 10 eq), 12 mg (0.18 mmol, 2 eq) and 1 drop of AcOH. After
one hour, the reaction mixture was diluted with water and extracted with EtOAc. The
organic phase was dried over Na2SCO4, filtered, and evaporated. Column
chromatography on silica gel with EtOAc afforded 9 mg (21%) of (RS,SR)-{5-
[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-
[l,2,4]oxadiazol-3-ylmethyl}-dimethyl-amine as a white solid, MS: 489 (MH+).
Example 92
(RS,SR)-{5-[benzenesulfonyl-(7-chIoro-l,2,3,4-tetrahydro-cycIopenta[b]indol-2-yl)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-diethyI-amine
In analogy to example 91, from (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-
tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methylamine
was prepared (RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-diethyl-amine as
a white solid, MS: 518 (MH+).
Example 93
107
(RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yI)-
fluoro-methyl]-[l,2,4]oxadiazol-3-ylmcthyl}-diethyl-amine; HC1 salt
In analogy to example 80, from (RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-
tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-
diethyl-amine was prepared RS,SR)-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-diethyl-amine;
HC1 salt as a white solid, MS: 518 (MH+).
Example 94
(RS,SR)-2-(benzenesulfonyl-benzooxazol-2-yl-fluoro-methyl)-7-chloro-l,2,3,4-
tetrahydro-cyclopenta[b]indole
94.1
A solution of 35 g (0.263 mol) of 2-methyl-benzooxazole in CCU (300 mL) was treated
with 47 g (0.263, 1 eq) of NBS and 1 g of benzoyl peroxide. The mixture was refluxed
(100°C) over night then cooled. Succinimide was filtered off and the mixture was
evaporated to dryness. Column chromatography yielded 9.2 g (17%) of 2-bromomethylbenzooxazole
as a light yellow oil, MS: 210, 212 (MH+). (H. Uno, M. Kurokawa, Y.
Masuda, Chem. Pharm. Bull., 1981, 29, 2359).
94.2
To 9.1 g (0.043 mol) of 2-bromomethyl-benzooxazole in CH3CN (300 mL) were added
7.39 g (0.045 mol, 1.05 eq) of benzenesulfmic acid sodium salt and 2.27 g (8.6 mmol,
0.2 eq) of 18-crown-6. Stirring was continued overnight, solvent evaporated and a
column chromatography afforded 8.1 g (70%) of 2-benzenesulfonylmethylbenzooxazole
as a white solid, MS: 274 (H+). (Y. Nagao, S. Yamada, E. Fujita, Tet.
., 1983,24,2291)
94.3
In analogy to example 74.4, from 2-benzenesulfonylmethyl-benzooxazoIe and
cyclopent-2-enone was prepared 3-(benzenesulfonyl-benzooxazol-2-yl-methyl)-
cyclopentanone as a racemic mixture of diastereomers, light yellow oil, MS: 356
94.4
In analogy to example 74.5, from 3-(benzenesulfonyl-benzooxazol-2-yl-methyl)-
cyclopentanone and N-fluorobenzenesulfonimide was prepared 3-(benzenesulfonylbenzooxazol-
2-yl-fluoro-methyl)-cyclopentanone as a racemic mixture of
diastereomers, white solid, MS: 374 (MH+).
94.5
In analogy to example 89.7, from 3-(benzenesulfonyl-benzooxazoI-2-yl-fluoro-methyl)-
cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was prepared (RS,SR)-
2-(benzenesulfonyl-benzooxazol-2-yl-fluoro-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indole as a white solid, MS: 481 (MH+).
The enantiomers were separated by preparative chiral HPLC. Column: chiralpak AD,
solvent: 20%isopropanol/heptane.
Example 95
yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-acetamide
To a stirred solution of 57 mg (0.123 mmol) of
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
yl}-methylamine in 5 mL of THF, 20 L (0.123 mmol, 1 eq) of Huenig base and 1 1.6
I^L (0.123 mmol, 1 eq) of acetic anhydride were added at 0°C. After 30 min., the
reaction mixture was quenched by addition of an aqueous solution of NaHCOs and
extracted with Ch^C^. The combined organic phases were dried over Na2SCO4, filtered
and evaporated. Column chromatography on silica gel gave 30 mg (48%) of(RS,SR)-N-
{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoromethyl]-[
l,2,4]oxadiazol-3-ylmethyl}-acetamide as a light yellow solid, MS: 503
Example 96
(RS,SR)-A'-{5-[benzenesulfonyl-(7-chloro-l,24-tetrhydro-cyclopenta[b]indol-2-
yI)-fluoro-methyll-|l,2,4]oxadiazol-3-ylmethyl}-benzamide
To a stirred solution of 44 mg (0.095 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
yl}-methylamine in 5 mL of THF, 19 jiL (0.114 mmol, 1.2 eq) of Huenig's base and 11
uL (0.095 mmol, 1 eq) of benzoyl chloride were added at 0°C. After 2 hours, the
reaction mixture was quenched by addition of an aqueous solution of NaHCOs and
extracted with CHaCb. The combined organic phases were dried over NaaSO filtered
and evaporated. Column chromatography on silica gel EtOAc/Heptane 1:1 gave 28 mg
(51%) of (RS,SRIS-tbenzenesulfonyly-chloro-l-tetrahydrocyclopenta[
b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-benzamide as a
white solid, MS: 565 (M).
Example 97
propionic acid methyl ester
Analogously to example 3.2, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-
propionic acid methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride was
prepared RS,SR)-2-benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-
propionic acid methyl ester as a white solid, MS: 475 (M, IBr).
Example 98
(RS,SR)-2-benzenesulfony\-2-(6-dimethylamino-2,3,4,9-tetrahydro-lH-csirbazo\-2-
yl)-propionic acid methyl ester
98.1
To 1.2 g (2.52 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-propionic acid methyl ester (from example 99) in 40 mL of THF were
added 31 mg (0.25 mmol, 0.1 eq) of DMAP and 660 mg (3.02 mmol, 1.2 eq) of
carbonic acid di-tert-butyl ester at 0°C. The reaction mixture was stirred at RT for 2
hours. EtOAc and a solution of aqueous NaHCOs were added, the phases were
separated, and the organic one was extracted with 1M KHSO4. The organic phases were
dried over Na2SC4, filtered and evaporated. Column chromatography afforded 1.3 g
(90%) of (RS,SRt-l-benzenesulfonyl-l -methoxycarbonyl-ethyl)-6-bromo-1,2,3,4-
tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS: 575 (M,l Br).
98.2
Under argon a flask was charged with 24 mg of (0.03 mmol, 0.05 eq)
tris(dibenzylidene-acetone) dipalladium, 16 mg (0.05 mmol, 0.1 eq) of 2(ditertbutylphosphino)
biphenyl and 85 mg (0.88 mmol, 1.7 eq) of sodium tert-butylate,
evacuated and backfilled with argon. 300 mg (0.52 mmol) of (RS,SR)-2-(-lbenzenesulfonyl-
l-methoxycarbonyl-ethyl)-6-bromo-l,2,3,4-tetrahydro-carbazole-9-
carboxylic acid tert-butyl ester in 15 ml of toluene were added, followed by a solution
of 1.95 ml 2M (3.9 mmol, 7.5 eq) of dimethylamine in THF. The solution was heated to
80°C overnight in a sealed tube. The mixture was diluted with EtOAc and a saturated
solution of Na2COs was added. The inorganic layer was extracted with EtOAc. The
combined organic phases were washed with brine and dried over Na2SO4. Column
chromatography yielded 68 mg (24 %) of RS,SR-(-l-benzenesulfonyl-lmethoxycarbonyl-
ethyl)-6-dimethylamino-l,2,3,4-tetrahydro-carbazole-9-carboxylic
acid tert-butyl ester as orange oil, MS: 541 (MH+).
98.3
To 42 mg (9.3 mmol) of (RS,SR)-2-(-l-benzenesulfonyl-l-methoxycarbonyl-ethyl)-6-
dimethylamino-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 1 ml of
CH2C12 were added 0.06 ml of TFA at 0°C. The solution was stirred at RT for 5h, a
NaHCOs solution was added, and the inorganic phase was extracted with CH2CI2,
washed with brine and dried over Na2SO4. Column chromatography on ISOLUTE Flash
NH2 (Separtis, aminopropyl-modified silicagel) with EtOAc/heptane 2:1, followed by
tituration with ether/heptane yielded 190 mg (56%) of RS,SR-benzenesulfonylRS,SR
dimethylamino-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-propionic acid methyl ester as
light green amorphous material, MS: 441 (MH+).
Example 99
(6-bromo-2,3,4,9-tetrahydro-lH-carbazol-2-yI)-methanesulfonyl-aceticacid methyl
ester
99.1
Analogously to example 1.1, from methyl methylsulfonylacetate and 2-cyclohexen-lone
were prepared methanesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester as a
racemic mixture of diastereomers, orange amorphous material, MS: 249 (MH+).
99.2
Analogously to example 1.2, from methanesulfonyl-(3-oxo-cyclohexyl)-acetic acid
methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride was prepared (6-bromo-
2,3,4,9-tetrahydro-lH-carbazol-2-yl)-methanesulfonyl-acetic acid methyl ester as a
racemic mixture of diastereomers, light brown solid, MS: 400 (MH+,lBr).
Example 100
propionic acid methyl ester
100.1
Analogously to example 3.1, from a racemic mixture of diastereomers of
methanesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester (from example 101.1) and
methyl iodide was prepared a racemic mixture of diastereomers of 2-methanesulfonyl-
2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a colorless foam, MS: 263 (MH+).
100.2
Analogously to example 1.2, from a racemic mixture of diastereomers of 2-
methanesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester and (4-bromophenyl)-
hydrazine hydrochloride were prepared the following 2 racemic diastereomers
which could be separated by column chromatography to yield (RS,SR)-2-(6-bromo-
2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester,
MS: 414 (MH+,lBr), and WSS)-2-(6-bromo-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-
methanesulfonyl-propionic acid methyl ester, MS: 414 (MH+,lBr).
Example 101
(RS,SR)-2-(6-diinethylamino-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-2-
methanesulfonyl-propionic acid methyl ester
101.1
Analogously to example 98.1, from (RS,SRbromoRS,SRg
carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester (from example 102.2)
was prepared (RS,SR)-6-bromo-RS,SR -methanesulfonyl-1 -methoxycarbonyl-ethyl)-
l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS:
531(M+NH4+, IBr).
101.2
Analogously to example 98.2, from (RS,SR)-6-bromo-2-(l-methanesulfonyl-1-
methoxycarbonyl-ethyl)-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester
was prepared (RS,SR)-6-dimethylamino-2-(l-methanesulfonyl-l-methoxycarbonyl-
ethyl)-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as light yellow
solid, MS: 479 (MH+).
101.3
Analogously to example 98.3, from RS,SR)-6-dimethylamino-2-(l-methanesulfonyl-lmethoxycarbonyl-
ethyl)-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester
was prepared (RS,SR)-2-(6-dimethylamino-2,3,4,9-tetrahydro-1 H-carbazol-2-yI)-2-
methanesulfonyl-propionic acid methyl ester as light green foam, MS: 378 (M).
Example 102
(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[A]indol-2-yl)-
acetic acid methyl ester
102.1
A solution of 8.0 g (42 mmol) of 3-bromothiophenol was treated with 7.1 g (47 mmol)
of methyl bromoacetate and potassium carbonate. The resulting suspension was stirred
at reflux for 24 hrs, cooled to RT and neutralized with a saturated aqueous solution of
NH4C1. Diethylether was added, the phases were separated and the aqueous one was
extracted twice with diethylether. The combined organic phases were dried over
Na2SO4, filtered and evaporated to give 12.1 g (99%) of (3-bromo-phenylsulfanyl)-
acetic acid methyl ester as a light yellow oil, MS: 279 (MNH4
+, IBr).
102.2
A solution of 6.0 g (23 mmol) of (3-bromo-phenylsulfanyl)-acetic acid methyl ester in
50 mL of dichloroethane was treated with 6.2 g (25 mmol) of 3-chloroperbenzoic acid.
After 30 min of stirring another 6.2 g (25 mmol) of 3-chloroperbenzoic acid were
added, the resulting suspension was stirred overnight at RT and then treated with a 0.5
M aqueous solution of sodium thiosulfate. The phases were separated and the aqueous
one extracted twice with diethylether. The combined organic phases were washed with
a ca. 1M aqueous NaHCO3 solution, dried over Na2SO4, filtered and evaporated to give
6.3 g (93%) of (3-bromo-benzenesulfonyl)-acetic acid methyl ester as a colorless oil,
MS:312(MNH4
+, IBr).
102.3
In analogy to example 74.4, from (3-bromo-benzenesulfonyl)-acetic acid methyl ester
and cyclopent-2-enone was prepared (3-bromo-benzenesulfonyl)-(3-oxo-cyclopentyl)-
acetic acid methyl ester as a racemic mixture of diastereomers, colorless gum, MS: 394
(MNH4
+, IBr).
102.4
In analogy to example 1.2, from (3-bromo-benzenesulfonyl)-(3-oxo-cyclopentyl)-acetic
acid methyl ester (racemic mixture of diastereomers) and (4-chlorophenyl)-hydrazine
hydrochloride was prepared (3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indol-2-yl)-acetic acid methyl ester as a racemic mixture of diastereomers,
orange solid, MS: 484 (MH+, IBr).
Example 103
(RS,
cyclopenta[b]indol-2-yl)-propionic acid methyl ester
103.1
In analogy to example 3.1, but omitting the separation of the diastereomers, from (3-
bromo-benzenesulfonyl)-(3-oxo-cyclopentyl)-acetic acid methyl ester (racemic mixture
of diastereomers) and iodomethane was prepared 2-(3-bromo-benzenesulfonyl)-2-(3-
oxo-cyclopentyl)-propionic acid methyl ester as a racemic mixture of diastereomers,
colorless oil, MS: 408 (MNH4
+, IBr).
103.2
In analogy to example 3.2 from 2-(3-bromo-benzenesulfonyl)-2-(3-oxo-cyclopentyl)-
propionic acid methyl ester (racemic mixture of diastereomers) and (4-chlorophenyl)-
hydrazine hydrochloride was prepared (3-bromo-benzenesulfonyl)-2-(7-chloro-1,2,3,4-
tetrahydro-cyclopenta[6]indol-2-yl)-propionic acid methyl ester as a racemic mixture of
diastereomers. The diastereomers were separated by chromatography on silica gel with
heptane/EtOAc to give (RS,SR)-2-(3-bromo-benzenesulfonyl)-2-(7-chloro-1,2,3,4-
tetrahydro-cyclopenta[RS,SR>]indol-2-yl)-propionic acid methyl ester as a brown solid, MS:
498 (MH+, IBr) and (RR, RS,SR(3-bromo-benzenesulfonyl)-2-(7-chloro-1,2,3,4-
tetrahydro-cyclopenta[6]indol-2-yl)-propionic acid methyl ester as an orange solid, MS:
498 (MH+, IBr).
Example 104
(RS, 5/f)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-(3-pyrroIidin-lyl-
benzenesulfonyl)-propionic acid methyl ester
A solution of 40 mg (0.08 mmol) (RS, S T b r o m o - b e n z e n e s u l f o n y - c h l o r o -
l,2,3,4-tetrahydro-cyclopenta[Z]indol-2-yl)-propionic acid methyl ester (example 103)
in toluene was treated with 13 mg (0.13 mmol) of NaOfBu, 2 mg (0.007 mmol) of 2-
(di-rbutylphosphino)biphenyl, 0.03 mL (0.4 mmol) of pyrrolidine and 4 mg (0.004
mmol) of tris(dibenzylideneacetone)dipalladium. The resulting suspension was stirred
at 80° for 4 hrs , treated with a diluted aqueous NaHCO3-solution and extracted twice
with EtOAc. The combined organic phases were dried over NaaSO filtered and
evaporated to give 14 mg (35%) of (RS, )-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indol-2-yl)-2-(3-pyrrolidin-l-yl-benzenesulfonyl)-propionic acid methyl
ester as a light brown solid, MS: 488 (MH+).
Example 105
(RS,SR) 2-[l-(3-bromo-benzenesulfonyl)-l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-
7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole
105.1
In analogy to examples 74.1-74.3, from (3-bromo-benzenesulfonyl)-acetic acid methyl
ester was prepared 2-(3-bromo-benzenesulfonylmethyl)-5-methyl-[l,3,4]oxadiazole as a
light yellow oil. MS: 319 (MH+, IBr).
105.2
In analogy to example 74.4, from 2-(3-bromo-benzenesulfonylmethyl)-5-methyl-
[l,3,4]oxadiazole and cyclopent-2-enone was prepared 3-[(3-bromo-benzenesuIfonyl)-
(5-methyl-[l,3,4]oxadiazol-2-yI)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, white solid, MS: 400 (MH+, IBr).
105.3
In analogy to example 103.1, from 3-[(3-bromo-benzenesulfonyl)-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyI]-cyclopentanone (racemic mixture of diastereomers) and
iodomethane was prepared 3-[l-(3-bromo-benzenesulfonyl)-l-(5-methyl-
[l,3,4]oxadiazol-2-yl)-ethyl]-cyclopentanone as a racemic mixture of diastereomers,
yellow oil, MS: 414 (MH+, IBr).
105.4
In analogy to example 103.2, from 3-[l-(3-bromo-benzenesulfonyl)-l-(5-methyl-
[l,3,4]oxadiazol-2-yl)-ethyl]-cyclopentanone (racemic mixture of diastereomers) and
(4-chlorophenyI)-hydrazine hydrochloride were prepared (RS, SR) 2-[l-(3-bromobenzenesulfonyl)-
l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-7-chloro-1,2,3,4-
tetrahydro-cyclopenta[b]indole as a dark brown gum, MS: 522 (MH+, IBr) and (RR,
SS) 2-[ 1 -(3-bromo-benzenesulfonyl)-1 -(5-methyI-[ 1,3,4]oxadiazol-2-yl)-ethyI]-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole as a dark brown solid, MS: 522 (MH+,
IBr).
Example 106
(RS, S7f)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-
methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[A]indole
106.1
In analogy to example 12.1, from 3-[(3-bromo-benzenesulfonyl)-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone (racemic mixture of diastereomers) and
N-fluorobenzenesulfonimide was prepared 3-[(3-bromo-benzenesulfonyl)-fluoro-(5-
methyl-[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, white solid, MS: 418 (MH+, IBr).
106.2
In analogy to example 103.2, from 3-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone (racemic mixture of diastereomers) and
(4-chlorophenyl)-hydrazine hydrochloride was prepared RS,SR-2-[(3-bromobenzenesulfonyl)-
fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-
tetrahydro-cyclopenta[6]indole as a brown gum, MS: 526 (MH+, IBr) and RS,SR-2-
[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indole as a light brown solid, MS: 526 (MH+, IBr).
Example 107
(RS, SR) 2-[(5-benzyl-[l,3,4]oxadiazol-2-yl)-(3-bromo-benzenesulfonyl)-fluoromethyl]-
7-chloro-l,2,3,4-tetrahydro-cycIopenta[6]indoIe
107.1
In analogy to example 74.1, from 3-bromobenzenesulfonyl-acetic acid methyl ester
(example 102.2) and hydrazine hydrate was prepared 3-bromobenzenesulfonyl-acetic
acid hydrazide as a colorless oil, MS: 294 (MH+, IBr).
107.2
In analogy to example 74.2, from 3-bromobenzenesulfonyl-acetic acid hydrazide and
phenylacetyl chloride was prepared phenyNacetic acid Af-[2-(3-bromobenzenesulfonyl)-
acetyl]-hydrazide as a white solid, MS: 412 (MH+, IBr).
107.3
In analogy to example 74.3, by treatment of phenyl-acetic acid JV-[2-(3-bromobenzenesulfonyl)-
acetyl]-hydrazide with phosphorous oxychloride was prepared 2-
benzyl-5-(3-bromo-benzenesulfonylmethyl)-[l,3,4]oxadiazole as an orange oil, MS:
394 (MH+, IBr).
107.4
In analogy to example 74.4, from 2-benzyl-5-(3-bromo-benzenesulfonylmethyl)-
[l,3,4]oxadiazole and cyclopent-2-enone was prepared 3-[(5-benzyl-[l,3,4]oxadiazol-2-
yl)-(3-bromo-benzenesulfonyl)-methyl]-cyclopentanone as a racemic mixture of
diastereomers, colorless gum, MS: 476 (MH+, IBr).
107.5
In analogy to example 12.1, from 3-[(5-benzyl-[l,3,4]oxadiazol-2-yl)-(3-bromobenzenesulfonyl)-
methyl]-cyclopentanone (racemic mixture of diastereomers) and Nfluorobenzenesulfonimide,
was prepared 3-[(5-benzyl-[l,3,4]oxadiazol-2-yl)-(3-bromobenzenesulfonyl)-
fluoro-methyl]-cyclopentanone as a racemic mixture of diastereomers
light yellow solid, MS: 494 (MH+, IBr).
107.6
In analogy to example 103.2 from 3-[(5-benzyl-[l,3,4]oxadiazol-2-yl)-(3-bromobenzenesulfonyl)-
fluoro-methyl]-cyclopentanone (racemic mixture of diastereomers)
and (4-chlorophenyl)-hydrazine hydrochloride was prepared (RS,SR)-2-[(5-benzyl-
[ 1,3,4]oxadiazol-2-yl)-(3-bromo-benzenesulfonyl)-fluoro-methyl]-7-chloro-1,2,3,4-
tetrahydro-cyclopentaRS,SR]indole as a yellow solid, MS: 602 (MH+, IBr) and RS,SR-2-
[(5-benzyl-[l,3,4]oxadiazol-2-yl)-(3-bromo-benzenesulfonyl)-fluoro-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indole as a brown solid, MS: 602 (MH+, IBr).
Example 108
(RS, SR) {3-[(7-chloro-l,2,3,4-tetrahydro-cyclopenta[indol-2-yl)-fluoro-(5-
methyl-[l,3,4]oxadiazol-2-yl)-methanesulfonyl]-phenyl}-dirnethyl-amine
In analogy to example 104 from (RRS,SR)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-
methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopentaRS,SR]indole
(example 106) and dimethylamine in THF was prepared (RS, SR) {3-[(7-chloro-l,2,3,4-
tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-
methanesulfonyl]-phenyl}-dimethyl-amine as a yellow gum, MS: 489 (MH+).
Example 109
(RS, SR)- 7-chloro-2-[(3-ethynyl-benzenesulfonyI)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[6]indole
A solution of 76 mg (0.133 mmol) of (RS,
methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[Z)]indole
(example 106) in 1.5 mL of DMF was treated with 1 mg (0.005 mmol) of Cul, 37 mg
(0.29 mmol) of D1PEA, 17 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium
and 71 mg (0.72 mmol) of ethynyltrimethylsilane and the resulting suspension stirred at
80°C during 4 hrs. Diluted aqueous NaOH was added and the mixture extracted twice
with dichloromethane. The combined organic layers were dried over Na2SCO4 , filtered
and evaporated. Chromatography on silica gel with heptane/EtOAc (1:1) gave 33 mg
(48%) of (RS,SR)-7-chloro-2-[(3-ethynyl-benzenesulfonyl)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[6]indole as a yellow solid,
MS: 471 (MH+).
Example 110
(RS,
benzenesulfonyl)-fluoro-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[A]indole
110.1
In analogy to example 74.2, from 3-bromobenzenesulfonyl-acetic acid hydrazide
(example 107.1) and 4-benzyloxyphenylacetyl chloride was prepared (4-benzyloxyphenyl)-
acetic acid JV-[2-(3-bromo-benzenesulfonyl)-acetyl]-hydrazide as a light yellow
solid, MS: 518 (MH+, IBr).
110.2
In analogy to examples 74.3, by treatment of (4-benzyloxy-phenyl)-acetic acid W-[2-(3-
bromo-benzenesulfonyl)-acetyl]-hydrazide with phosphorous oxychloride was prepared
2-(4-benzyloxy-benzyl)-5 -(3 -bromo-benzenesu lfonylmethyl)-[ 1,3,4]oxad iazole as a
light yellow solid, MS: 500 (MH+, IBr).
110.3
In analogy to example 74.4, from 2-(4-benzyloxy-benzyl)-5-(3-bromobenzenesulfonylmethyl)-[
l,3,4]oxadiazole and cyclopent-2-enone was prepared 3-[[5-
(4-benzyloxy-benzyl)-[l,3,4]oxadiazol-2-yl]-(3-bromo-benzenesulfonyl)-methyl]-
cyclopentanone as a racemic mixture of diastereomers, white solid, MS: 582 (MH+,
IBr).
110.4
In analogy to example 12.1, from 3-[[5-(4-benzyloxy-benzyl)-[l,3,4]oxadiazol-2-yl]-(3-
bromo-benzenesulfonyl)-methyl]-cyclopentanone (racemic mixture of diastereomers)
and N-fluorobenzenesulfonimide, was prepared 3-[[5-(4-benzyloxy-benzyl)-
[1,3,4]oxadiazol-2-yl]-(3-bromo-benzenesulfonyl)-fluoro-methyl]-cyclopentanone as a
racemic mixture of diastereomers white solid, MS: 600 (MH+, IBr).
110.5
In analogy to example 103.2 from 3-[[5-(4-benzyloxy-benzyl)-[l,3,4]oxadiazol-2-yl]-
(3-bromo-benzenesulfonyl)-fluoro-methyl]-cyclopentanone (racemic mixture of
diastereomers) and (4-chlorophenyl)-hydrazine hydrochloride was prepared (RS, SR)-2-
[5-(4-benzyloxy-benzyl)-[l,3,4]oxadiazol-2-yl-(3-bromo-benzenesulfonyl)-fluoromethyl]-
7-chloro-l,2,3,4-tetrahydro-cyclopenta[Z]indole as a brown solid, MS: 708
(MH+, IBr) and (RS,SR)-2-[5-(4-benzyloxy-benzyl)-[l,3,4]oxadiazol-2-yl-(3-bromobenzenesuIfonyl)-
fluoro-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indole as a
yellow solid, MS: 708 (MH+, IBr).
Example 111
(RS, .S^)-7-chloro-2-[(3-ethyl-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-
2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[A]indole
A solution of 22 mg (0.05 mmol) (RS,SR S-ethynyl-benzenesulfonyl)-
fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[Z)]indole
in 0.5 mL of methanol was treated with 1 mg of palladium on activated charcoal (10%)
and stirred intensely under Hb (atmospheric pressure) during 5 hrs. Filtration and
evaporation of the solvent gave 21 mg (92%) of (RS, SR) 7-chloro-2-[(3-ethylbenzenesulfonyl)-
fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydrocyclopenta[
6]indole, as a yellow solid, MS: 475 (MH+).
Example 112
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl
ester
112.1
In analogy to example 74.2, from 3-bromobenzenesulfonyl-acetic acid hydrazide
(example 107.1) and methyl 4-chlororcarbonylbenzoate was prepared 4-{N-[2-(3-
bromo-benzenesulfonyl)-acetyl]-hydrazinocarbonyl}-benzoic acid methyl ester, as a
light yellow solid, MS: 456 (MH+, IBr).
112.2
In analogy to example 74.3, by treatment of 4-{RS,SR2-(3-bromo-benzenesulfonyl)-
acetyl]-hydrazinocarbonyl}-benzoic acid methyl ester with phosphorous oxychloride
was prepared 4-[5-(3-bromo-benzenesulfonylmethyl)-[l,3,4]oxadiazol-2-yl]-benzoic
acid methyl ester as a light yellow solid, MS: 438 (MH+, IBr).
112.3
In analogy to example 74.4, from 4-[5-(3-bromo-benzenesulfonylmethyl)-
[l,3,4]oxadiazol-2-yl]-benzoic acid methyl ester and cyclopent-2-enone was prepared
4-{5-[(3-bromo-benzenesulfonyl)-(3-oxo-cyclopentyl)-methyl]-[l,3,4]oxadiazol-2-yl}-
benzoic acid methyl ester as a racemic mixture of diastereomers, white solid, MS: 520
(MH+, IBr).
112.4
In analogy to example 12.1, from 4-{5-[(3-bromo-benzenesulfonyl)-(3-oxocyclopentyl)-
methyI]-[l,3,4]oxadiazol-2-yl} -benzoic acid methyl ester (racemic
mixture of diastereomers) and N-fluorobenzenesuIfonimide was prepared 4-{5-[(3-
bromo-benzenesulfonyl)-fluoro-(3-oxo-cyclopentyl)-methyl]-[l,3,4]oxadiazol-2-yl}-
benzoic acid methyl ester as a racemic mixture of diastereomers white solid, MS: 538
(MH+, IBr).
112.5
In analogy to example 103.2, from 4-{5-[(3-bromo-benzenesulfonyl)-fluoro-(3-oxocyclopentyl)-
methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl ester (racemic
mixture of diastereomers) and (4-chlorophenyl)-hydrazine was prepared (RS, SR) 4-
(5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[ZO]indol-2-yl)-
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl ester as a brown solid, MS:
646 (MH+, IBr) and (RS,SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-
tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid
methyl ester as a light brown solid, MS: 646 (MH+, IBr).
Example 113
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyI)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[£]
indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoicacid
A solution of 13 mg (0.02 mmol) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[A]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-
yl}-benzoic acid methyl ester in a 1:1 mixture of 0.5 mL of THF and 0.5 mL of 1M
aqueous LiOH was stirred at RT during one hour. Diluted aqueous HC1 was added and
the mixture extracted twice with dichloromethane. Drying of the combined organic
phases over Na2SCO4, filtration and evaporation of the solvent gave ca 13 mg
(quantitative) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l, 2,3,4-
tetrahydro-cyclopenta[Z]indol-2-yl)-fluoro-rnethyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid
as a yellow solid, MS: 632 (MH+, IBr).
Example 114
(RS, SR) (4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
A]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-phenyl)-methanol
A solution of 12 mg (0.02 mmol) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-
yl}-benzoic acid methyl ester in 0.5 mL of THF was treated with 3 mg (0.08 mmol) of
lithium aluminiumhydride and stirred at RT for one hour. The mixture was treated with
a mixture of ice cubes and water and extracted twice with dichlormothane. Drying of
the combined organic phases over Na2SO4, filtration and evaporation gave 10 mg (86%)
of (RS, SR) (4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-
yclopenta[Z]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-phenyl)-methanol as a
yellow solid, MS: 618 (MH+, IBr).
Example 115
(RS, SR) 2-{benzenesulfonyI-fluoro-[5-(4-iodo-benzyI)-[l,3,4]oxadiazol-2-yl]-
methyl}-7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indole
115.1
A solution of 1 g (4.7 mmol) of benzenesulfonyl-acetic acid hydrazide (example 74.1)
in 4 mL of THF was treated with 391 mg (4.7 mmol) of iodophenylacetic acid, 126 mg
(0.93 mmol) of 1-hydroxybenzotriazole and 2.8 g (28 mmol) of N-methylmorpholine.
The mixture was stirred during 15 min at 0°C, treated with 1.25 g (6.5 mmol) of EDCl
and stirred during 12 hrs. The crude was treated with diluted aqueous NFUCl and
extracted twice with EtOAc. Drying of the combined organic layers over Na2SCO4,
filtration and evaporation gave 2 g (93%) of benzenesulfonyl-acetic acid N'-[2-(4-iodophenyl)-
acetyl]-hydrazide as a brown oil, MS: 266 (MH+).
115.2
In analogy to example 74.3, by treatment of (4-iodo-phenyl)-acetic acid N-[2-
(benzenesulfonyl)-acetyl]-hydrazide with phosphorous oxychloride was prepared 2-
benzenesulfonylmethyl-5-(4-iodo-benzyl)-[l,3,4]oxadiazole as a light yellow solid,
MS: 441 (MH+).
115.3
In analogy to example 74.4, from 2-benzenesulfonylmethyl-5-(4-iodo-benzyl)-
[l,3,4]oxadiazole and cyclopent-2-enone was prepared 3-{(benzenesulfonyl)-[5-(4-
iodo-benzyl)-[l,3,4]oxadiazol-2-yl]-methyl}-cyclopentanone as a racemic mixture of
diastereomers, light brown gum, MS: 523 (MH+).
115.4
In analogy to example 12.1, from 3-{(benzenesulfonyl)-[5-(4-iodo-benzyl)-
[l,3,4]oxadiazol-2-yl]-methyl}-cyclopentanone (racemic mixture of diastereomers) and
N-fluorobenzenesulfonimide, was prepared 3-{(3-bromo-benzenesulfonyl)-fluoro-[5-
(4-iodo-benzyl)-[l,3,4]oxadiazol-2-yl]-methyl}-cyclopentanone as a racemic mixture of
diastereomers that was separated by chormatography on silica gel with EtOAc/heptane
1:2 to give to give N-fluorobenzenesulfonimide, was prepared (RS, SR) 3-
{(benzenesu lfonyl)-fluoro-[5-(4-iodo-benzyl)-[ 1,3,4]oxadiazol-2-yl]-methyl} -
cyclopentanone as a white solid MS: 541 (MH+), and (RR, SS) 3-{(benzenesulfonyl)-
fluoro-[5-(4-iodo-benzyl)-[l,3,4]oxadiazol-2-yl]-methyl}-cyclopentanone as a white
solid MS: 541 (MH+).
115.5
In analogy to example 103.2 from (RS, SR) 3-{(benzenesulfonyl)-fluoro-[5-(4-iodobenzyl)-[
l ,3,4]oxadiazol-2-yl]-methyl}-cyclopentanone and (4-chlorophenyl)-
hydrazine hydrochloride was prepared (RS, SR) 2-{benzenesulfonyl-fluoro-[5-(4-iodobenzyl)-[
l,3,4]oxadiazol-2-yl]-methyl}-7-chloro-l,2,3,4-tetrahydro-cyclopenta[/)]indole
light yellow solid, MS: 648 (MH+).
Example 116
(RS, SR) 4-{5-[(benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[A]indol-
2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yI}-benzoicacid
A solution of 17 mg (0.027 mmol) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-
yl}-benzoic acid in 1 mL of methanol was treated with 1 mg of palladium on activated
charcoal (10%) and intensely stirred during 2 hrs under H2 (atmospheric pressure).
Filtration and evaporation of the solvent gave 14 mg (94%) of (RS, SR) 4-{5-
[(benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoromethyl]-[
l,3,4]oxadiazol-2-yl}-benzoic acid as a white solid, MS: 553 (MH+).
Example 117
(RS, SR) 4-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-
yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yImethyl}-benzoic acid
A solution of 66 mg (0.10 mmol) of (RS, SR) 2-{benzenesulfonyl-fluoro-[5-(4-iodobenzyl)-[
1,3,4]oxadiazol-2-yl]-methyl} -7-chloro-1,2,3,4-tetrahydro-cyclopenta[Z] indole
(example 115) in 0.5 mL of DMF and 0.5 mL of water was treated with 1 mg of Nal
and 2 mg (0.009 mmol) of palladium acetate. The mixture was then stirred for 144 hrs
under CO (atmospheric pressure), treated with 2M aqueous HC1 and extracted with
dichloromethane. Drying of the combined organic phases over RS,SRfiltration and
evaporation of the solvent gave 45 mg (78%) of (RS, SR) 4-{5-[benzenesulfonyl-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[A]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-
ylmethylj-benzoic acid as a light brown solid, MS: 566 (MH+).
Example 118
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzamide
A solution of 63 mg (0.1 mmol) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-
chloro-l,2,3,4-tetrahydro-cyclopenta[Z)]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-
yl}-benzoic acid (example 113) in 0.5 mL of DMF was treated with 27 mg (0.511
mmol) of NFUCl, 61 mg (0.6 mmol) of N-methylmorpholine, 3 mg (0.02 mmol) and of
1-hydroxybenzotriazole. The mixture was stirred for 15 at 0°C and treated with 29 mg
(0.15 mmol) of EDCI and stirred at RT for 10 hrs. A diluted aqueous solution of HC1
was added and the mixture extracted with EtOAc. The combined organic phases were
dried over Na2SC4, filtered and the solvent evaporated to give 60 mg of (RS, SR) 4-{5-
[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-eyclopenta[RS,SRndol-2-yl)-
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzamide as a brown solid, MS: 630 (MH+,
IBr).
Example 119
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopentafAlindol-
l-ylJ-fluoro-methylj-RS,SRoxadiazol-l-ylJ-RS,SRmethylbenzamide
In analogy to example 118, from (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-
benzoic acid (example 113) and methylamine hydrochloride was prepared (RS, SR) 4-
{5-[(3-bromo-benzenesulfonyI)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-Ar-methyl-benzamide as a brown solid, MS: 643
(MH+, IBr).
Example 120
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydrocyclopenta[
A]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-RS,SR-dimethylbenzamide
In analogy to example 118, from (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazoI-2-yl}-
benzoic acid (example 113) and dimethylamine hydrochloride was prepared (RS, SR) 4-
{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[ZRS,SR]indol-2-yl)-
fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-RS,SR-dimethyl-benzamide as a brown solid, MS:
657 (MH+, IBr).
Example 121
bromo-l,2,3,4-tetrahydro-cyclopenta[6]indole
In analogy to example 74.6, from (RS,SRbenzenesulfonyl-fluoroRS,SRS-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone (example 74.5) and (4-bromo-phenyl)-
hydrazine hydrochloride was prepared (RS,SR-f-benzenesulfonyl-fluoro-CS-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-bromo-l,2,3,4-tetrahydro-cyclopenta[Z]indole as light
brown solid, MS: 489 (M, IBr).
Example 122
(RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-
piperidin-l-yl-l,2,3,4-tetrahydro-cycIopenta[A]indole
122.1
Analogously to example 98.1, from (RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-bromo-l,2,3,4-tetrahydro-cyclopenta[6]indole (from
example 121) was prepared (RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-bromo-2,3-dihydro-l//-cyclopenta[6]indole-4-
carboxylic acid tert-buty\ ester as light brown foam, MS: 589 (M, IBr).
122.2
Analogously to example 98.2, from (RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-bromo-2,3-dihydro-l//-cyclopenta[A]indole-4-
carboxylic acidRS,SR-butyl ester and piperidine was prepared (RS,SR)-2-
[benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-piperidin-l-yl-2,3-
dihydro-l//-cyclopenta[6]indole-4-carboxylic acid tert-butyl ester as light orange foam,
MS: 595 (MH+).
122.3
Analogously to example 98.3, from (RS,SR)-2-[benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-piperidin-l-yl-2,3-dihydro-l//-cyclopenta[Z)]indole-4-
carboxylic acid tert-buiyl ester was prepared (RS,SR)-2-[-benzenesulfonyl-fluoro-(5-
methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-piperidin-l-yl-l,2,3,4-tetrahydrocyclopenta[
6]indole as colorless semisolid, MS: 494 (M).
Example 123
(RS,SR)- N-{2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-
l,2,3,4-tetrahydro-cyclopenta[6]indol-7-yl}-N-methyl-amine
123.1
Analogously to example 98.2, from (RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-bromo-2,3-dihydro-l//-cyclopenta[6]indole-4-
carboxylic acid tert-bulyl ester (from example 122.1) and methylamine was prepared
(RS,SR)-2-[benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-
methylamino-2,3-dihydro-l//-cyclopenta[6]indole-4-carboxylic acid tert-buty\ ester,
MS: 541 (MFf).
123.2
Analogously to example 98.3, from (RS,SR)-2-[benzenesulfonyl-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-7-methylamino-2,3-dihydro-l//-cyclopenta[ft]indole-4-
carboxylic acid tert-buty\ ester was prepared (RS,SR)- N-{2-[-benzenesulfonyl-fluoro-
(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[Z)]indol-7-yl}-
N-methyl-amine as light yellow oil, MS: 441 (MH+).
Example 124
2-[benzenesulfonyl-fluoro-(5-trifluoromethyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[A]indole
124.1
Analogously to example 74.2 and 74.3, from benzenesulfonyl-acetic acid hydrazide
(from example 74.1) and TFA was prepared 2-benzenesulfonylmethyl-5-
trifluoromethyl-[l,3,4]oxadiazole as pink crystalline material, MS: 293 (MH+).
124.2
At 0°C 170 mg (0.5 mmol, 0.2 eq) of Cs2CO3 were added to a stirred solution of 760
mg (2.6 mmol) of 2-benzenesulfonylmethyl-5-trifluoromethyl-[l,3,4]oxadiazole in 30
mL of THF. After 45 min, 0.23 mL (2.9 mmol) of 2-cyclopenten-l-one were added.
The reaction mixture was stirred at RT for 15 hours, diluted with saturated aqueous
NFLiCl and extracted with EtOAc. The combined organic phases were dried over
Na2SC4, filtered and evaporated. Column chromatography on silica gel with
heptane/EtOAc 1:1 yielded 0.88 mg (90%) of 3-[benzenesulfonyl-(5-trifluoromethyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as colorless foam, 375 (MH+).
124.3
In analogy to example 12.1, from 3-[benzenesulfonyl-(5-trifluoromethyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone at -20°C was prepared 3-
[benzenesulfonyl-fluoro-(5-trifluoromethyl-[l,3,4]oxadiazol-2-yl)-methyl]-
cyclopentanone as white solid, MS: 393 (MH+).
124.4
In analogy to example 74.6, from 3-[benzenesulfonyl-fluoro-(5-trifIuoromethyl-
[l,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared a racemic mixture of diastereomers of 2-[benzenesulfonylfluoro-(
5-trifluoromethyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indole as brown oil, MS: 500 (MH, 1C1)+.
Example 125
(-(ltetrahyd
ro-cyclopenta [b] indole
131
125.1
In analogy to example 19.3, from (RS,SR)- 2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-
propionic acid methyl ester and (4-chloro-phenyl)-hydrazine hydrochloride was
prepared (RS,SR)-2-benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-
2-yl)-propionic acid methyl ester as a light brown solid.
125.2
130 mg (0.31 mmol) (RS,SR-2-benzenesulfonyl-2-(7-chloro-l,2,3,4-tetrahydrocyclopenta[/]
indol-2-yl)-propionic acid methyl ester were dissolved in 7 mL CH2C12 at
RT. 90 nL (0.62mmol, 2 eq) triethylamine, 4 mg (0.031 mmol, 0.1 eq) DMAP and 81
mg (0.37 mmol, 1.2 eq) BOC2O were added. The reaction mixture was stirred for 2
hours. The reaction was quenched with 10 mL of an aqueous 1M solution of HC1. The
organic layer was separated and the aquous layer was washed with CH2Cl2. The
combined organic layers were dried over Na2SC4, filtered and evaporated to dryness to
yield to 152 mg (94%) (tf£S7?)-2-(l-benzenesulfonyl-l-methoxycarbonyl-ethyl)-7-
chloro-2,3-dihydro-l//-cyclopenta[Zindole-4-carboxylic acid tert-butyl ester as a white
powder, M: 535 (MNH4
+).
125.3
152 mg (0.29 mmol) (RS,SR-2-(l-benzenesulfonyl-l-methoxycarbonyl-ethyl)-7-
chloro-2,3-dihydro-17/-cyclopenta[Z]indole-4-carboxylic acid ter/-butyl ester were
dissolved in 3 mL dry THF at RT. 0.32 mL (0.32 mmol, 1.1 eq) of LiAlH4 (1M in THF)
were added dropwise. The reaction mixture was stirred for 1 hour and 40 minutes. The
reaction was quenched with a saturated NaHCOs solution. The organic phase was
washed with brine, dried over Na2SC4, filtered and evaporated. Column
chromatography on silica gel (EtOAc/heptane 1:2) yielded 50 mg (35%) (RS,SR)-2-(]-
benzenesulfonyl-2-hydroxy-l-methyl-ethyl)-7-chloro-2,3-dihydro-l//-
cyclopenta[6]indole-4-carboxylic acid /er/-butyl ester as a white powder.
125.4
50 mg (0.1 mmol) (RS,SR-2-(l-benzenesulfonyl-2-hydroxy-l-methyl-ethyl)-7-chloro-
2,3-dihydro-l/f-cyclopenta[fe]indole-4-carboxylic acid tert-butyl ester were dissolved in
5mL dry THF at 0°C. 5 mg (0.11 mmol, 1.1 eq) NaH (55%) were added and the
reaction mixture was stirred for 20 minutes. 10 |j,L (0.15 mmol, 1.5 eq) methyliodide
were then added and the reaction was stirred for 1 hour at 0°C. The reaction was
quenched with a saturated NaHCOs solution. The organic phase was washed with brine,
dried over Na2SO4, filtered and evaporated to dryness to yield 52 mg (100%) (RS,SR)-
2-( 1 -benzenesulfonyl-2-methoxy-1 -methyl-ethyl)-7-chloro-2,3-dihydro-1Hcyclopenta[
RS,SR]indole-4-carboxylic acid tert-butyl ester as a white powder.
125.5
52 mg (0.1 mmol) (RS,SR)-2-(\-benzenesulfonyl-2-methoxy-1 -methyl-ethyl)-7-chloro-
2,3-dihydro-RS,SRcyclopenta[ZRS,SR]indole-4-carboxylic acid tert-butyl ester were dissolved in
4 mL CH2Cl2 at 0°C. Then, 1 mL of TFA was added dropwise and the temperature was
slowly raised to RT and the reaction was stirred for 20 minutes. The reaction was
quenched with a saturated NaHCOs solution. The organic phase was dried over
Na2SC4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane
1:2) yielded 11 mg (26%) (RS,SR)-2-(\-benzenesulfonyl-2-methoxy-1 -methyl-ethyl)-7-
chloro-l,2,3,4-tetrahydro-cyclopenta[6]indole as a white powder, MS: 404 (MH+).
Example 126
(RS^SR) -2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l/T-carbazol-2-yl)-2-
fluoro-Af-methyl-Af-(3-methyl-but-2-enyI)-acetamide
126.1
In analogy to example 1.1, from methylphenylsulfonylacetate and cyclohexen-1-one
was prepared benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester as a racemic
mixture of diastereomers, light yellow oil, MS: 311 (MH+).
126.2
In analogy to example 74.5, from benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid
methyl ester and N-fluorobenzensulfonimide was prepared (RS,SR) benzenesulfonylfluoro-(-
3-oxo-cyclohexyl)-acetic acid methyl ester as an yellow oil, MS: 346 (MNH4
126.3
In analogy to example 19.3, from (.RS,SR)-benzenesulfonyl-fluoro-(-3-oxo-cyclohexyl)-
acetic acid methyl ester and 4-chlorophenylhydrazine hydrochloride was prepared
(RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-fluoro-acetic
acid methyl ester as an orange solid.
126.4
In analogy to example 55, from RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydrol//-
carbazol-2-yl)-fluoro-acetic acid methyl ester and methylamine was prepared
(RS,SR) -2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l/V-carbazol-2-yl)-2-fluoro-
Af-methyl-acetamide as a white solid, MS: 435 (MH+).
126.5
0.924 g (0.002 mol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-l//-
carbazol-2-yl)-2-fluoro-Af-methyl-acetamide were dissolved in 20 mL CH2Cl2 at RT.
Then, 0.59 mL triethylamine (0.004 mol, 2 eq), 26 mg DMAP (0.2 mmol, 0.1 eq) and
0.556 g BOC2O (0.003 mol, 1.2 eq) were added. The reaction mixture was stirred for
2H30. The reaction was quenched with a saturated NFUC1 aqueous solution, and the
product extracted with RS,SR. The combined organic phases were dried on Na2SC4,
filtered and evaporated. The crude material was precipitated in diethyl ether. The
solvent was removed and the remaining solid was dried under vaccum to yield to 0.840
g (74%) of (RS, SR) -2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chlorol,
2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-buty\ ester as a white solid, MS: 552
(MNH4
+).
126.6
To a stirred solution of 60 mg (0.11 mmol) of (RS,SR) -2-(benzenesulfonyl-fluoromethylcarbamoyl-
methyl)-6-chloro-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tertbutyl
ester in 3 mL THF was added on 7 mg NaH (60% in oil, 0.165 mmol, 1.5 eq) at
0°C. The reaction mixture was stirred for 40 minutes and then, 52 joL (0.22 mmol, 2 eq)
l-bromo-3-methyl-but-2-ene (1 mL in THF) was added and the reaction mixture was
stirred for 2 hours at 0°C and then overnight at RT. The solvent was evaporated. Then,
1 mL CFbCb was added and after dissolution, 1 mL TFA and 1 mL RS,SRwere added
at RT. The reaction mixture was stirred overnight. The solvent was then evaporated and
purification by prep. HPLC gave 9 mg (19%) of (RS,SRbenzenesulfonylRS,SR
chloro-2,3,4,9-tetrahydro-l//-carbazol-2-yl)-2-fluoro-Ar-methyl-A/-(3-methyl-but-2-
enyl)-acetamide as a white solid, MS: 503 (MH+).
Example 127
(RS,SR)-5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[A]indol-2-yl)-
fluoro-methyl]-|l,2,4]oxadiazole-3-carbonitrilc
127.1
In analogy to example 82.1, from nitriloacetic acid methyl ester and hydroxylamine
hydrochloride was prepared amino-hydroxyimino-acetic acid methyl ester as a white
solid.
127.2
In analogy to example 82.2, from amino-hydroxyimino-acetic acid methyl ester and
phenylsulfanyl-acetyl chloride was prepared 5-phenylsulfanylmethyl-[l,2,4]oxadiazole-
3-carboxylic acid methyl ester as an yellow oil, MS: 521 (MH+).
127.3
In analogy to example 81.3, from 5-phenylsulfanylmethyl-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester and mCPBA was prepared 5-benzenesulfonylmethyl-
[l,2,4]oxadiazole-3-carboxylic acid methyl ester as a white solid, MS: 282 (MH+).
127.4
In analogy to example 74.4, from 5-benzenesulfonylmethyl-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester and cyclopent-2-enone was prepared 5-[benzenesulfonyl-
(3-oxo-cyclopentyl)-methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester as a
racemic mixture of diastereomers, colorless oil, MS: 382 (MNH4+).
127.5
In analogy to example 74.5, from 5-[benzenesulfonyl-(3-oxo-cyclopentyl)-methyl]-
[l,2,4]oxadiazole-3-carboxylic acid methyl ester and N-fluorobenzenesulfonimide were
prepared (RS,SRtbenzenesulfonyl-fluoro-RS,SRoxo-cyclopentyO-methyl]-
[l,2,4]oxadiazole-3-carboxylic acid methyl ester as a white solid, MS: 400 (MNH4+)
and (RS,SR)-5-[benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-methyl]-[l,2,4]oxadiazole-
3-carboxylic acid methyl ester as a white solid, MS: 400 RS,SR.
127.6
In analogy to example 19.3, from (RS,SR)-5-[benzenesulfonyl-fluoro-(3-oxocyclopentyl)-
methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester and (4-chlorophenyl)-
hydrazine hydrochloride was prepared RS,SR)-5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid methyl ester as a light orange solid, MS: 490 (MH+).
127.7
In analogy to example 85, from (RS, S7?)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-
tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid
methyl ester and ammonium hydroxide solution (25% in water) was prepared (RS,SR)-
5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoromethyl]-[
l,2,4]oxadiazole-3-carboxylic acid amide, as a yellow oil, MS: 475 (MH+).
127.8
To a stirred solution of 170 mg (0.35 mmol) of RS,SR)-5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[Z»]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carboxylic acid amide in 2 mL acetonitrile at RT was added 0.5 mL phosphorous
oxychloride. The dark brown solution was stirred for 1 hour and then the temperature
was raised to 50°C and stirred overnight. After cooling down to RT, 0.5 mL
phosphorous oxychloride were added. The reaction mixture was stirred for 2 hours
under reflux condition. The solvent was partially evaporated and the resulting oil was
dissolved with EtOAc and washed with saturated NaHCO3 solution. The organic phase
was dried over Na2SC4, filtered and evaporated. Column chromatography on silica gel
(EtOAc/heptane 1:1) yielded 20 mg (12%) (RS, S7?)-5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-
carbonitrile as a light red solid, MS: 457 (MH+).
Example 128
(RS,SR)-{5-[benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-
fluoro-methyl]-(l,2,4]oxadiazol-3-yl}-dimethyl-amine
128.1
To a stirred solution of 20.4 g (0.285 mol) of dimethylcyanamide in 500 mL of MeOH
at RT, was added 19.820 g (0.285 mol, 1 eq) hydroxylamine and then 52.82 mL (0.285
mol, 1 eq) sodium methylate were slowly added (exothermic reaction). The reaction
mixture was stirred overnight. The mixture was filtered in order to remove the salt,
MeOH was evaporated and the mixture was diluted with chloroform. The precipitate
was filtered off and the filtrate was evaporated to dryness to yield to 29.4 g (95%) of 3-
hydroxy-1,1-dimethyl- guanidine as an orange oil.
128.2
In analogy to example 81.1, from phenylthiol and bromomethylethyl ester was prepared
phenylsulfanyl-acetic acid ethyl ester as a colorless oil, MS: 197 (MH+).
128.3
To a stirred suspension of 14 g (0.129 mol, 1.4 eq) of 3-hydroxy-l,l-dimethylguanidine
in 300 mL dry THF at 0°C was added portionwise 6.191 g (0.155 mol, 1.2
eq) of NaH (60% in oil). The resulting heavy suspension was stirred at RT for 1 hour 30
minutes. Then, 28.126 g (0.129 mol) phenylsulfanyl-acetic acid ethyl ester were slowly
added. The reaction mixture was stirred at RT for 2 hours and then at 65°C for 1 hour.
The reaction was quenched by addition of a saturated aqueous solution of NH4C1 and
the product extracted with EtOAc. The combined organic phase was dried on NaaSCU,
filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane, 1:9 to
1:2) yielded 19.370 g (64%) dimethyl-(5-phenylsulfanylmethyl-[l,2,4]oxadiazol-3-yl)-
amine as a colorless oil, MS: 236 (MH+).
128.4
In analogy to example 81.3, from dimethyl-(5-phenylsulfanylmethyl-[l,2,4]oxadiazol-
3-yl)-amine and wCPBA was prepared (5-benzenesulfonylmethyl-[l,2,4]oxadiazol-3-
yl)-dimethyl-amine as a white solid, MS: 268 (MH+).
128.5
In analogy to example 74.4, from (5-benzenesulfonylmethyl-[l,2,4]oxadiazol-3-yl)-
dimethyl-amine and 2-cyclohexen-l-one was prepared 3-[benzenesulfonyl-(3-
dimethylamino-[l,2,4]oxadiazol-5-yl)-methyl]-cyclohexanone as a racemic mixture of
diastereomers, light brown solid, MS: 364 (MNH4+).
128.6
In analogy to example 74.5, from 3-[benzenesulfonyl-(3-dimethylamino-
[l,2,4]oxadiazol-5-yl)-methyl]-cyclohexanone and N-fluorobenzenesulfonimide was
prepared (RS,SR)-3-[benzenesulfonyl-(3-dimethylamino-[l,2,4]oxadiazol-5-yl)-fluoromethyl]-
cyclohexanone as a colorless oil, MS:382 (MH+) and (RS,SR)- 3-
[benzenesulfonyl-(3-dimethylamino-[l,2,4]oxadiazol-5-yl)-fluoro-methyl]-
cyclohexanone as a colorless oil, MS: 382 (MH+).
128.7
In analogy to example 19.3, from (RS,SR)- 3-[benzenesulfonyl-(3-dimethylamino-
[ 1,2,4]oxadiazol-5-yl)-fluoro-methyl]-cyclohexanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared (RS,SR)-{5-[benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydrol//-
carbazol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-amine as a light
yellow solid, MS: 489 (MH+).
Example 129
(RS,SR)-4-[({5-[-benzenesuIfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-
2-yI)-fluoro-methyl]-[l,2,4]oxadiazoi-3-ylraethyl}-amino)-methyl]-benzoic acid
methyl ester
129.1
In analogy to example 89.7, from (RS,SR)-2-{5-[benzenesulfonyl-fluoro-(3-oxocyclopentyl)-
methyl]-[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione (example 89.6)
and (4-chloro-phenyl)-hydrazine hydrochloride was prepared -(RS,SR)-2-{RS,SR
[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-
[l,2,4]oxadiazol-3-ylmethyl}-isoindole-l,3-dione as a light yellow powder, MS: 608
(MNH4
+).
129.2
To a suspension of 420 mg (0.7 mmol) of (RS,SR)-2-{5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[ft]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
ylmethyl}-isoindole-l,3-dione in 50 mL EtOH at RT, was added 0.1 mL (2.1 mtnol, 3
eq) hydrazine. The reaction mixture was heated at 80°C over 3 hours 30 minutes. After
cooling down, the reaction was quenched with a 1M solution of HC1, and extracted
with EtOAc. The combined organic phases were dried over Na2SO4, filtered and
evaporated. Column chromatography on silica gel (CH2Cl2/MeOH 95/5) yielded 210
mg (64%) of (RS,SR-tbenzenesulfonylKV-chloroRS,SRtetrahydrocyclopenta[
Z]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methylamine as a light
brown powder, MS: 461 (MH+).
129.3
To a stirred solution of 50 mg (0.1 mmol) of ( R S , S R f b e n z e n e s u l f o n y l T - c h l o r o -
l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-
methylamine in 5 mL MeOH at 0°C was added 19 mg (0.1 mmol, 1 eq) of methyl 4-
formylbenzoate, 7 mg (0.1 mmol, leq) sodium cyanoborohydride and one drop of acetic
acid. The reaction mixture was stirred at 0°C for 20 minutes and then the temperature
was raised to RT and the reaction quenched with saturated aqueous solution of
NaHCOs. The reaction mixture was poured on water and extracted with EtOAc. The
organic phase were dried over Na2SC4, filtered and evaporated. Column
chromatography on silica gel (heptane/EtOAc 1:1) yielded 30 mg (45%) o f (RS,SR- 4 -
[({5 -[benzenesu lfonyl-(7-ch loro-1,2,3,4-tetrahydro-cyclopenta[b] indol-2-yl)-fluoromethyl]-[
l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a
light yellow powder, MS: 609 (MH+).
Example 130
yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid
methyl ester
In analogy to example 129.3, from (RS,SR-tbenzenesulfonyKT-chloro-l, 2,3,4-
tetrahydro-cyclopenta[Z)]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methylamine
and methyl-3-formylbenzoate was prepared (RS,SR[({S-tbenzenesulfonyl
l,2,3,4-tetrahydro-cyclopenta[A]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a light yellow powder, MS: 609
Example 131
RS,SR)-{4-[({5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cycIopenta[A]indol-
2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-phenyl}-
methanol
To a stirred solution of 27 mg (0.04 mmol) of
chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
ylmethyl}-amino)-methyl]-benzoic acid methyl ester (example 129.3) in 2 mL THF at
0°C, 40 nl (0.04 mmol, 1 eq) lithium aluminum hydride (1M solution in THF) were
added. The reaction mixture was stirred at 0°C for 1 hour and then at RT for 30
minutes. The reaction was quenched with a saturated NaHCCh aqueous solution, and
the crude product extracted with EtOAc. The combined organic phases were dried over
Na2SC4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc
2:8) yielded 12 mg (48%) of RS,SR)-{4-[({5-[benzenesulfonyl-(7-chloro-l, 2,3,4-
tetrahydro-cyclopenta[Z] indol-2-yl)-fluoro-methyl]-[ 1 ,2,4]oxadiazol-3-ylmethyl } -
amino)-methyl]-phenyl}-methanol as a light yellow powder, MS: 581 (MH+).
Example 132
(RS,SR)-2-(benzenesulfonyl-pyridin-2-yl-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indole
132.1
To a stirred suspension of 2.5 g (0.010 mol) of 2-bromomethyl-pyridine hydrobromide
in 10 mL of CH3CN at RT, was added 1.78 mL (0.0105 mol, 1.05 eq.) of Hunig's base.
After complete dissolution of the salt, 1.62 g (0.010 mol, 1 eq.) of sodium benzene
sulfmat and 0.52 g (0.002 mol, 0.2 eq.) were added. The mixture was stirred at RT for
48 hours, and then the reaction was quenched by addition of water, and the product
extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered
and dried under vacuum to afford 1.86 g (80%) of 2-benzenesulfonylmethyl-pyridine.
132.2
In analogy to example 74.4, from 2-benzenesulfonylmethyl-pyridine and cyclopenten-2-
one was prepared 3-(benzenesulfonyl-pyridin-2-yl-methyl)-cyclopentanone as a racemic
mixture of diastereomeres.
132.3
In analogy to example 19.3, from 3-(benzenesulfonyl-pyridin-2-yl-methyl)-
cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was prepared (RR, SS)-
2-(benzenesulfonyl-pyridin-2-yl-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indole and RS,SR)-2-(benzenesulfonyl-pyridin-2-yl-methyl)-7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indole as a white solid, MS: 423 (MH+).
Example 133
(RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cycIopenta[A]indol-2-
yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-2,2,2-trifluoro-acetamide
133.1
In analogy to example 129.2, fromRS,SR)-2-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-
tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-
isoindole-l,3-dione (example 129.1) and hydra/ine was preparedRS,SR
[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-
[I,2,4]oxadiazol-3-yl}-methylamine as a light brown powder, MS: 461 (MH+).
133.2
To a stirred solution of 46 mg (0.1 mmol) of (/?.S',5'7?)-C-{5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-
methylamine in 3mL CHaCb at RT, was added 10 |J (0.1 mmol, 1 eq) trifluoroacetic
acid and 80 jal pyridine (1 mmol, 10 eq). Stirring was continued overnight, and the
reaction mixture was evaporated to dryness. Column chromatography on silica gel
(heptane/EtOAc 6:4) yielded 6 mg (12%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chlorol,
2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-
ylmethyl}-2,2,2-trifluoro-acetamide as a light yellow powder, MS: 557 (MH+).
Example 134
2-[benzenesulfonyl-fluoro-(3-phenyI-[l,2,4]oxadiazol-5-yl)-methyl]-7-chlorol,
2,3,4-tetrahydro-cyclopenta[6]indole
134.1
From N-hydroxy-benzamidine and chloro acetyl chloride [described in Heterocycles,
26(1), 163-73, 1987] was prepared 5-chloromethyl-3-phenyl-[l,2,4]oxadiazole.
134.2
To a stirred solution of 525 mg (2.7 mmol) of 5-chloromethyl-3-phenyl-
[l,2,4]oxadiazole in acetonitrile at RT, 465 mg (2.8 mmol, 1.05 eq) of sodium
benzenesulfinate and 143 mg (0.5 mmol, 0.2 eq) of 18-crown-6 were added. Stirring
was continued overnight, and an additional 50 mg (0.3 mmol, 0.12 eq) of sodium
benzenesulfinate were added and the reaction mixture was allowed to stirr for one
further hour. The solvent was evaporated and the resulting oil was taken up in EtOAc,
washed with a saturated NaHCOs solution. The organic phase was dried over Na2SO4,
filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 8:2)
yielded 622 mg (77%) of 5-benzenesulfonylmethyl-3-phenyl-[l,2,4]oxadiazole as a
white solid, MS: 301 (MH4).
134.3
In analogy to example 74.4, from 5-benzenesulfonylmethyl-3-phenyl-[l,2,4]oxadiazole
and cyclopenten-2-one was prepared 3-[benzenesulfonyl-(3-phenyl-[l,2,4]oxadiazol-5-
yl)-methyl]-cyclopentanone as a racemic mixture of diastereoisomers, white solid, MS:
400 (MNH4
+).
134.4
In analogy to example 74.5, from 3-[benzenesulfonyl-(3-phenyl-[l,2,4]oxadiazol-5-yl)-
methylj-cyclopentanone and N-fluorobenzensulfonimide was prepared 3-
[benzenesulfonyl-fluoro-(3-phenyl-[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanoneasan
off-white viscous oil, MS: 401 (MH+).
134.5
In analogy to example 19.3, from 3-[benzenesulfonyI-fluoro-(3-phenyl-
[l,2,4]oxadiazol-5-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared 2-[benzenesulfonyl-fluoro-(3-phenyl-[l,2,4]oxadiazol-5-
yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[6]indole as a brown solid, MS: 508
Example 135
(RS,SR-Ibenzenesulfonyl-CT-chloroRS,SR-tetrahydro-cyclopentalbjindol-l-yl)-
fluoro-methyl]-oxazole-4-carboxylic acid methyl ester
135.1
17.140 g (0.123 mol) of aminoacetic acid ethyl ester hydrochloride and 15.175 g (0.123
mol, 1 eq) of acetimidic acid ethyl ester hydrochloride were stirred in solution in 300
mL ice cold water. 200 mL diethyl ether and then 16.97 g (0.123 mol, 1 eq) K2CO3
were added. The reaction mixture was stirred for 10 minutes. The organic phase was
separated and dried over Na2SC4, filtered and evaporated to dryness to yield to 15.229
g (72%) of (l-ethoxy-ethylideneamino)-acetic acid ethyl ester as a light yellow oil.
135.2
To a stirred suspension of 3.222 g (36 mmol, 1.05 eq) of potassium ethoxide in 30mL
diethyl ether and 5mL EtOH at 0°C, a solution of 3.849 g (52 mmol, 1.5 eq) ethyl
formate and 6 g (35 mmol) (l-ethoxy-ethylideneamino)-acetic acid ethyl ester in 30 mL
diethyl ether and 5 mL EtOH is then slowly added. The reaction mixture is stirred for
one hour at 0°C. After addition of 40 mL diethyl ether, the reaction mixture was stirred
at RT overnight. The reaction mixture was filtered and the obtained solid was washed
with diethyl ether and dried under vaccum to yielded 5 g (60%) of potassium 2-
ethoxycarbonyl-2-(l-ethoxy-ethylideneamino)-ethenolate as an orange solids.
135.3
5 g (25 mmol) of potassium 2-ethoxycarbonyl-2-(l-ethoxy-ethylideneamino)-ethenolate
were completely dissolved in 15 mL acetic acid at RT, and then the solution was heated
to 110°C overnight. After cooling down, 100 mL EtOAc were added and the solution is
neutralized with saturated NaHCCh solution. The organic phase was separated, dried
over Na2SC4, filtered and evaporated. Column chromatography on silica gel
(heptane/EtOAc 1:2) yielded 1.74 g (45%) of 2-methyl-oxazole-4-carboxylic acid ethyl
ester as an yellow oil, MS: 156 (MH+).
135.4
To a stirred solution of 1.74 g (11 mmol) of 2-methyl-oxazole-4-carboxylic acid ethyl
ester in 1.5 mL tetrachloromethane at RT, 2.994 g (17 mmol, 1.5 eq) Nbromosuccinimide
and 50 mg (0.2 mmol, 0.02 eq) benzoyl peroxyde were added. The
reaction mixture was stirred under reflux overnight. The reaction mixture was filtered,
the filtrate was extracted with Cl^Cfe and ^28203 solution. The combined organic
phases were dried over Na2SO4, filtered and evaporated to dryness to yield 265 mg
(10%) of 2-bromomethyl-oxazole-4-carboxylic acid ethyl ester as an yellow oil, MS:
235 (MH+).
135.5
In analogy to example 134.2, from 2-bromomethyl-oxazole-4-carboxylic acid ethyl
ester and sodium benzosulfinat was prepared 2-benzenesulfonylmethyl-oxazole-4-
carboxylic acid ethyl ester as a white solid, MS: 296 (MH+).
135.6
In analogy to example 74.4, from 2-benzenesulfonylmethyl-oxazole-4-carboxylic acid
ethyl ester and cyclopenten-2-one was prepared 2-[benzenesulfonyl-(3-oxocyclopentyl)-
methyl]-oxazole-4-carboxylic acid methyl ester as a racemic mixture of
diastereoisomers, as an yellow oil, MS: 364 (MH+).
135.7
In analogy to example 74.5, from 2-[benzenesulfonyl-(3-oxo-cyclopentyl)-methyl]-
oxazole-4-carboxylic acid methyl ester and N-fluorobenzensulfonimide was prepared 2-
[benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-methyl]-oxazole-4-carboxylic acid methyl
ester as a racemic mixture of diastereoisomers, as a white oil, MS: 382 (MH+).
135.8
In analogy to example 19.3, from 2-[benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-
methyl]-oxazole-4-carboxylic acid methyl ester and (4-chloro-phenyl)-hydrazine
hydrochloride was prepared RS,SR)-2-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-
144
cyclopenta[6]indol-2-yl)-fluoro-methyl]-oxazole-4-carboxylic acid methyl ester as a
brown oil, MS: 489 (MH+).
Example 136
2-(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
6]indole
136.1
In analogy to example 134.2, from 2-(bromomethyl)-l,3-benzothiazole and sodium
benzenesulflnate was prepared 2-benzenesulfonylmethyl-benzothiazole as a crystalline
orange solid, MS: 290 (MH+).
136.2
In analogy to example 74.4, from 2-benzenesulfonylmethyl-benzothiazole and
cyclopenten-2-one was prepared 3-(benzenesulfonyl-benzothiazol-2-yl-methyl)-
cyclopentanone as a racemic mixture of diastereoisomers, as a white powder, MS: 372
136.3
In analogy to example 74.5, from 3-(benzenesulfonyl-benzothiazol-2-yl-methyl)-
cyclopentanone and N-fluorobenzensulfonimide was prepared 3-(benzenesulfonylbenzothiazol-
2-yl-fluoro-methyl)-cyclopentanone as a racemic mixture of
diastereoisomers, as a yellow foam, MS: 390 (MH+).
136.4
In analogy to example 19.3, from 3-(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-
cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was prepared 2-
(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-7-chloro-l,2,3,4-tetrahydrocyclopenta[
b]indole as a racemic mixture of diastereoisomers, brown oil, MS: 497
Example 137
(RS,SR)-2-[benzenesuIfonyl-(4,5-dimethyl-oxazol-2-yl)-methyI]-7-chloro-l,2,3,4-
tetrahydro-cyclopenta [b] indole
137.1
In analogy to example 135.4, from trimethyloxazole was prepared 2-bromomethyl-4,5-
dimethyl-oxazole, as a brown oil, MS: 190 (MH+).
137.2
In analogy to example 134.2, from 2-bromomethyl-4,5-dimethyl-oxazole and sodium
benzosulfmate was prepared 2-benzenesulfonylmethyl-4,5-dimethyl-oxazole, as a light
yellow oil, MS: 364 (MH+).
137.3
In analogy to example 74.4, from 2-benzenesulfonylmethyl-4,5-dimethyl-oxazole and
cyclopenten-2-one was prepared 3-[benzenesulfonyl-(4,5-dimethyl-oxazol-2-yl)-
methyl]-cyclopentanone as a racemic mixture of diastereoisomers, light yellow oil, MS:
334 (MH+).
137.4
In analogy to example 19.3, from 3-[benzenesulfonyl-(4,5-dimethyl-oxazol-2-yl)-
methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was prepared
(RS,SR)-2-[benzenesulfonyl-(4,5-dimethyl-oxazol-2-yl)-methyl]-7-chloro-1,2,3,4-
tetrahydro-cyclopenta[6]indole, as a light yellow oil, MS: 441 (MH+).
Examples
Example A
Film coated tablets containing the following ingredients can be manufactured in a
conventional manner:
Ingredients
Per tablet
Kernel:
Compound of formula (I) lO.Omg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
PovidoneK30 12.5 mg 15.0 mg
Sodium starch glycolate 12.5 mg 17.0 mg
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6mg
Talc 1.3mg 2.6 mg
Iron oxyde (yellow) 0.8 mg 1.6 mg
Titan dioxide 0.8 mg 1.6mg
The active ingredient is sieved and mixed with microcristalline cellulose and the
mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is
mixed with sodium starch glycolate and magesiumstearate and compressed to yield
kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous
solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a conventional
manner:
Ingredients • Per capsule
Compound of formula (I) 25.0mg
Lactose ISO.Omg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg
Polyethylene Glycol 400 150.0 mg
Acetic Acid q.s. ad pH 5.0
Water for injection solutions ad 1.0 ml
The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water
for injection (part). The pH is adjusted to 5.0 by Acetic Acid. The volume is adjusted to
1.0 ml by addition of the residual amount of water. The solution is filtered, filled into
vials using an appropriate overage and sterilized.





We Claim:
1. Tetrahydrocarbazole compounds of the formula (I)
(Formula Removed)
wherein
n is an integer selected from 0 to 3;
R1 is independently selected from the group consisting of halogen, -CN, -NO2,
-SO2Me, C1-C6 alkyl, trifluoromethoxy, -OR11, piperidinyl, pyrrolidinyl, and -N(R11)(R11), wherein R11 is independently selected from C1-C6 alkyl and H,
X1, X2, X3, and X4 are independently selected from nitrogen and carbon, provided that no more than two of X1, X2, X3, and X4 can be nitrogen at one time, and when two of X1, X2, X3, and X4 are nitrogen, n is 0,1, or 2;
k is an integer from 0 to 1;
R2 is H;
R3 is H, alkyl, or halogen;
R4 is aryl, heteroaryl, alkylaryl or alkylheteroaryl, all being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, alkyl, -OR41, C2-C7 alkynyl, and NR42R43, wherein R41 is C1-C6 alkyl or -H, R42 and R43 independently from each other are hydrogen or alkyl, or NR42R43 is piperidinyl or pyrrolidinyl, or R4 is alkyl;
R5 is selected from the group consisting of
(Formula Removed)
said aryl and heteroaryl being optionally substituted at one or more positions with one or more susbtituents independently selected from the group consisting of H, halogen, C1-C6 alkyl and (CH2)VR53, wherein
R51 is selected from the group consisting of H, alkyl, C2-C8 alkenyl and alkylaryl, said alkylaryl being optionally substituted at one or more positions with one or more of C1-C6 alkyl, -CN, halogen, -COOR54, and -CH2OR54, wherein R54 is alkyl or -H;
R52 is C1-C6 alkyl or-H;
R53 is H, alkyl, cycloalkyl, -COOR55, -NCR55)(R56), -CH2OH, -CN, CF3, -CONH2,
-CH2OR55 or -CONR55R56, wherein R55 is independently selected from the group consisting of alkyl ,-H, -C(O)-aryl, -C(O)-alkyl, or -C(O)-heteroaryl, and R56 is selected from the group consisting of H, alkyl, C(O)CF3, -C(O)-aryl, -C(O)-alkyl,
-C(O)-heteroaryl, alkylaryl and alkylheteroaryl, and wherein said aryl, heteroaryl, alkylaryl and alkyl-heteroaryl are optionally substituted at one or more positions with one or more of alkyl, -CN, halogen, -COOR57, and -CH2OR57, wherein R57 is C1-C6 alkyl or -H, or R55 and R56 together with the atom to which they are attached form a ring;
or R53 is aryl which can optionally be substituted with benzyloxy, carboxy, C1-C6-alkoxy-carbonyl, hydroxy-C1-C6-alkyl, halogen, carbamoyl, C1-C6-alkyl-carbamoyl, di-C1-C6-alkyl-carbamoyl,
m is an integer selected from 0 to 2;
v is an integer selected from 0 to 4;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters thereof.
2. The compounds as claimed in claim 1, wherein
n is an integer selected from 0 to 3;
R1 is independently selected from the group consisting of halogen, -CN, -NO2,
-SO2Me C1-C6 alkyl, trifluoromethoxy, -OR11, and -N(R11)(R11), wherein R11 is
independently selected from C1-C6 alkyl and H; X1, X2, X3, and X4 are independently selected from nitrogen and carbon, provided that
no more than two of X , X , X , and X can be nitrogen at one time, and when
two of X , X , X , and X are nitrogen, n is 0,1, or 2; k is an integer from 0 to 1; R2 is H;
R3 is H, alkyl, or halogen; R4 is aryl, heteroaryl, alkylaryl or alkylheteroaryl, all being optionally substituted
with from one to five substituents independently selected from the group
consisting of halogen, alkyl and -OR41, wherein R41 is C1-C6 alkyl or -H, or R4 is
alkyl;
R5 is selected from the group consisting of
(Formula Removed)
said aryl and heteroaryl being optionally substituted at one or more positions with one or more susbtituents independently selected from the group consisting of H, halogen, C1-C6 alkyl and (CH2)vR53, wherein
R51 is selected from the group consisting of H, alkyl, allyl and alkylaryl, said alkylaryl being optionally substituted at one or more positions with one or more of C1-C6 alkyl, -CN, halogen, -COOR54, and -CH2OR54, wherein R24is alkyl or -H;
R52 isC1-C6alkylor-H;
R53is H, alkyl, cycloalkyl, -COOR55, -NCR55)(R56), -CH2OH, -CN, -CONH2, -CH2OR55 or -CONR55R56, wherein R55 is independently selected from the group consisting of alkyl ,-H, -C(O)-aryl, -C(O)-alkyl, or -C(O)-heteroaryl, and R56 is selected from the group consisting of H, alkyl, -C(O)-aryl, -C(O)-alkyl, -C(O)-heteroaryl, alkylaryl and alkylheteroaryl, and wherein said aryl, heteroaryl, alkylaryl and alkyl-heteroaryl are optionally substituted at one or more positions with one or more of alkyl, -CN, halogen, -COOR57, and -CH2OR57, wherein R57 is C1-C6 alkyl or -H, or R55 and R56 together with the atom to which they are attached form a ring;
m is an integer selected from 0 to 2;
v is an integer selected from 0 to 4; and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters thereof.
3. The compounds as claimed in any one of claims 1 to 2, wherein each of X1, X2, X3, and X4 is carbon.
4. The compounds as claimed in any one of claims 1 to 2, wherein X1 is nitrogen and each of X2, X3, and X4 is carbon.
5. The compounds as claimed in any one of claims 1 to 4, wherein n is 1, X2 is carbon and R1 is directly attached to the X2 carbon.
6. The compounds as claimed in claim 5, wherein R1 is selected from the group consisting of halogen, cyano, nitro, SO2Me, C1-C6 alkyl, N(Me)2, NHMe and piperidinyl.
7. The compounds as claimed in claim 6, wherein R1 is halogen.
8. The compounds as claimed in claim 7, wherein R1 is C1.
9. The compounds as claimed in any of claims 1 to 3, wherein n is 2.
10. The compounds as claimed in claim 9, wherein each R1 is halogen.
11. The compounds as claimed in claim 10, wherein X2 is carbon, and one of the R groups is directly attached to the X carbon.
12. The compounds as claimed in any one of claims 1 to 11, wherein k is 0.
13. The compounds as claimed in any one of claims 1 to 12, wherein R3 is H, halogen or methyl.
14. The compounds as claimed in any one of claims 1 to 13, wherein R3 is F or methyl.
15. The compounds as claimed in any one of claims 1 to 14, wherein R4 is aryl or heteroaryl, all being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, alkyl, -OR41, C1-C6 alkynyl, and NR42R43, wherein R41 is C1-C6 alkyl or -H, R42 and R43 independently from each other are hydrogen or alkyl, or NR42R43 is piperidinyl or pyrrolidinyl, or R4 is C1-C6 alkyl
16. The compounds as claimed in any one of claims 1 to 15, wherein R4 is selected from the group consisting of napthyl, pyridinyl, methyl, phenyl or mono-or di-substituted phenyl, wherein the phenyl substituents are halogen, N(C1-C6 alkyl)2 or OR41, and wherein R41 is defined as in claim 1.
17. The compounds as claimed in any one of claims 1 to 16, wherein R4 is phenyl, or mono- or di-substituted phenyl, wherein the one or more substituents are halogen.
18. The compounds as claimed in any one of claims 1 to 17, wherein R4 is phenyl, 4-chlorophenyl, 3-fluorophenyl, or 3,4-difluorophenyl.
19. The compounds as claimed in any one of claims 1 to 16, wherein R4 is phenyl, 3-bromophenyl or 3-dimethylaminophenyl.
20. The compounds as claimed in any one of claims 1 to 19, wherein R5 is selected from the group consisting of
(Formula Removed)
said heteroaryl being optionally substituted at one or more positions with one or more substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl and (CH2)VR53, wherein
R51 is selected from the group consisting of H, alkyl, allyl and alkylaryl, said alkylaryl being optionally substituted at one or more positions with one or more of C1-C6 alkyl, -CN, halogen, -COOR54, and -CH2OR54, wherein R54 is alkyl or -H;
R52 isC1-C6alkylor-H;
R53 is H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, -CONH2,
-CH2OR55 or -CONR55R56, wherein R55 is independently selected from the
group consisting of alkyl ,-H, -C(O)-aryl, -C(O)-alkyl, or -C(O)-heteroaryl,
and R56 is selected from the group consisting of H, alkyl, -C(O)-aryl,
-C(O)-alkyl, -C(O)-heteroaryl, alkylaryl and alkylheteroaryl, and wherein
said aryl, heteroaryl, alkylaryl and alkyl-heteroaryl are optionally substituted
at one or more positions with one or more of alkyl, -CN, halogen, -COOR57,
and -CH2OR57, wherein R57 is C1-C6 alkyl or -H, or R55 and R56
together with the atom to which they are attached form a ring;
m is an integer selected from 0 to 2; and
v is an integer selected from 0 to 4.
21. The compounds as claimed in any of claims 1 to 20, wherein m is 0.
22. The compounds as claimed in claim 19 or 21, wherein R5 is selected from the group consisting of
(Formula Removed)
wherein R51 is selected from the group consisting of H, alkyl, allyl, alkylaryl optionally mono- or di- substituted at with one or more of C1-C6 alkyl, -CN, halogen, or -COOR54, wherein R54 is alkyl or -H; and R52 is C1-C6 alkyl or H and, wherein m is defined as in claim 1.
23. The compounds as claimed in claim 20 or 21, wherein R5 is selected from the
groupconsisting of
(Formula Removed)
said heteroaryl being optionally substituted at one or more positions with one or more susbtituents independently selected from the group consisting of H, halogen, C1-C6 alkyl and (CH2)VR53 and, wherein m, v and R53 are defined as in claim 1.
24. The compounds as claimed in claim 23, wherein said heteroaryl is selected
from the group consisting of
(Formula Removed)
wherein v and R53 are as defined in claim 19, R58 is independently selected from H, halogen and C1-C6 alkyl, D1 is O or S, and D2 is O, S, or NR58, and wherein, when said compound contains two (CH2)vR53 groups, said groups may be optionally joined together along with the atoms to which they are attached to form a ring.
25. The compounds as claimed in any one of claims 1 to 19, wherein R5 is selected from the group consisting of
(Formula Removed)
wherein aryl is selected from the group consisting of:
(Formula Removed)
wherein R53 is as described in claim 1, and wherein X5, X6, X7, X8 and X9 are selected from carbon and nitrogen with the proviso that no more than two of Xs, X6, X7, X8 and X9 can be N at one time, and wherein m and v are defined as in claim 1.
26. The compounds as claimed in claim 25, wherein m is 0.
27. The compounds as claimed in any one of claims 1 to 19, wherein R5 is a heteroaryl selected from the group consisting of oxadiazolyl, oxazolyl and benzothiazolyl, which heteroaryl is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy carbonyl or phenyl, which phenyl is optionally substituted with carboxy, C1-C6 alkyl carbonyl, carbamoyl or di (C1-C6 alkyl) carbamoyl.
28. The compounds as claimed in claim 27, wherein R5 is 5-methyl-
(l,3,4)oxadiazol-2-yl, 5-(4-benzoic acid methyl ester)-(l,3,4)oxadiazol-2-yl, 5-(4-
benzoic acid)-(l,3,4)oxadiazol-2-yl, 5-(4-benzamide)-(l,3,4)oxadiazol-2-yl, 5-(4-
dimethylbenzamide)-(l,3,4)oxadiazol-2-yl, 4-(carboxylic acid methyl ester)-
oxazo-2-yl or benzothiazol-2-yl.
29. The compounds as claimed in any of claims 1 to 28, characterized by formula
(la)
(Formula Removed)
wherein R1, R2, R3, R4, R5, n, k, X1, X2, X3 and X4 are as defined in any of claims 1 to 28.
30. The compounds as claimed in any of claims 1 to 28, characterized by formula
(Ib)
(Formula Removed)
wherein R1, R2, R3, R4, R5, n, k, X1, X2, X3 and X4 are as defined in any of claims 1 to 28.
31. The compounds as claimed in any one of claims 1 to 30, selected from the
group consisting of
Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester;
Benzenesulfonyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-nitro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(2,3,4,9-tetrahydro- 1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-methanesulfonyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(8-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-fluoro-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-cyano-2,3,4,9-tetrahydro-1 H-carbazol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-methyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(5-chloro-l,2,3,8-tetrahydro-4,8-diaza-cyclopenta[a]inden-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-bromo-6-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-(naphthalene-l-sulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-(naphthalene-2-sulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-(3,4-dichloro-benzenesulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-(toluene-3-sulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-(3 -methoxy-benzenesulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(2-Chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-(2-methoxy-benzenesulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(6-Chlorc-2,3,4,9-tetrahydro- 1H-carbazol-2-yl)-2-(4-fluoro-benzenesulfonyl)-propionic acid methyl ester;
(RS,SR)-2-(3-Chloro-benzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-(4-fluoro-benzenesulfonyl)-acetic acid methyl ester;
(RS,SR)-(3-Chloro-benzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-(3-fluoro-benzenesulfonyl)-acetic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-(3,4-difluoro-benzenesulfonyl)-fluoro-acetic acid methyl ester;
(RS,SR)-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-(pyridine-3-sulfonyl)-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-methoxy-benzenesulfonyl)-acetic acid methyl ester;
(RS,SR)-(3-Chloro-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-(7-Chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(pyridine-2-sulfonyl)-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-fluoro-benzenesulfonyl)-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-(3,4-difluoro-benzenesulfonyl)-fluoro-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(pyridine-3-sulfonyl)-acetic acid methyl ester;
(RS,SR)-2-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-(pyridine-2-sulfonyl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1 H-carbazol-2-yl)-fluoro-acetic acid;
(RS,SR)-2-(l-Benzenesulfonyl-2-methoxy-l-methyl-ethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole;
(RS,SR)-2-Benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionitrile;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionitrile;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetonitrile;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N-methyl-acetamide;
(RS,SR)-2-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1 H-carbazol-2-yl)-2-fluoro-N,N-dimethyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-N,N-dimethyl-acetamide;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N,N-dimethyl-acetamide;
(RS,SR)-2-(7-Chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N,N-dimethyl-acetamide;
(RS,SR)-Benzenesulfonyl-N-benzyl-1-(6-chloro-2,3,4,-tetrahydro- 1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-N-(4-cyano-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-N-(4-bromo-benzyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-N-(3,5-difluoro-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-4-({[2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid methyl ester;
(RS,SR)-3-({[2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-N-(2-cyano-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-N-Allyl-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-N-(3-cyano-benzyl)-2-fluoro-N-methyl-acetamide;
(RS,SR)-3-({[2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-acetyl]-methyl-amino}-methyl)-benzoic acid;
(RS,SR)-2-Benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-(3-hydroxymethyl-benzyl)-N-methyl-acetamide;
(RS,SR)-2-[Benzenesulfonyl-fluoro-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(S)-2-[(R)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(R)-2-[(S)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[l -Benzenesulfonyl-1 -(5-methyl-[ 1,3,4]oxadiazol-2-yl)-ethyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-(Benzenesulfonyl-fluoro-[l,3,4]oxadiazol-2-yl-methyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[Benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[Benzenesulfonyl-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-fluoro-methyl]-6-chloro-2,3,4,9-tetrahydro-1H-carbazole;
(RS,SR)- {5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-
amine;
(RS,SR)- {5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-
amine;
(RS,SR)-2-[Benzenesulfonyl-fluoro-(3-methyl-[ 1,2,4]oxadiazol-5-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid methyl ester;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methanol;
(RS,SR)-5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l ,2,4]oxadiazole-3-carboxylic acid;
(RS,SR)-5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-carboxylic acid amide;
(RS,SR)- {5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-
amine;
(RS,SR)-Chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(3-methyl-[l,2,4]oxadiazol-5-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-7-Chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2- {5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-isoindole-1,3 -dione;
(RS,SR)-C- {5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-methylamine;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[ 1,2,4]oxadiazol-3-ylmethyl} -dimethyl-amine;
(RS,SR)- {5-[Benzenesulfonyl-(7-chloro-l ,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-
diethyl-amine;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-
diethyl-amine;
(RS,SR)-2-(Benzenesulfonyl-benzooxazol-2-yl-fluoro-methyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-N-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-
acetamide;
(RS,SR)-N-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-
benzamide;
(RS,SR)-2-Benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester;
(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-methanesulfonyl-acetic acid methyl ester
(RS,SR)-2-(6-Bromo-2,3,4,9-tetrahydro- 1H-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester;
(RS,SR)-2-(6-Dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters thereof.
32. The compounds as claimed in any one of claims 1 to 31, selected from the group consisting of
(RS,SR)-Benzenesulfonyl-2-(6-chloro-,2,3,4,9-tetrahydro-1H-carbazol-2-
yl)-propionic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-
fluoro-acetic acid methyl ester;
(RS,SR)-2-Benzenesulfonyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-propionic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-Benzenesulfonyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-acetic acid methyl ester;
(RS,SR)-(3 -Chloro-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fiuoro-acetic acid methyl ester;

(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(3-fluoro-benzenesulfonyl)-acetic acid methyl ester;
(RS,SR)-(7-Chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-(3,4-difluoro-benzenesulfonyl)-fluoro-acetic acid methyl ester;
(RS,SR)-2-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-2-(3-fluoro-benzenesulfonyl)-N,N-dimethyl-acetamide;
(RS,SR)-2-[Benzenesulfonyl-fluoro-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(S)-2-[(R)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(R)-2-[(S)-Benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[Benzenesulfonyl-(5-cyclopropyl-[ 1,3,4]oxadiazol-2-yl)-fluoro-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-{5-[Benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-dimethyl-
amine;
(RS,SR)-2-[Benzenesulfonyl-fluoro-(3-methyl-[ 1,2,4]oxadiazol-5-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)- {5-[Benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-yl}-dimethyl-
amine;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters thereof.
33. The compounds as claimed in any one of claims 1 to 30, selected from the group consisting of
(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-acetic acid methyl ester;
(RS, SR)-2-(3-bromo-benzenesulfonyl)-2-(7-chloro-l ,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-propionic acid methyl ester;
(RS, SR)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-2-(3-
pyrrolidin-l-yl-benzenesulfonyl)-propionic acid methyl ester;
(RS, SR) 2-[l-(3-bromo-benzenesulfonyl)-l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) 2-[(5-benzyl-[l ,3,4]oxadiazol-2-yl)-(3-bromo-benzenesulfonyl)-fluoro-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) {3-[(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-methanesulfonyl]-phenyl} -dimethyl-amine;
(RS, SR)-7-chloro-2-[(3-ethynyl-benzenesulfonyl)-fluoro-(5-methyl-
[l,3,4]oxadiazol-2-yl)-methyl]-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR)-2-[5-(4-benzyloxy-benzyl)-[ 1,3,4]oxadiazol-2-yl-(3-bromo-
benzenesulfonyl)-fluoro-methyl]-7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indole;
(RS, SR)-7-chloro-2-[(3-ethyl-benzenesulfonyl)-fluoro-(5-methyl-
[ 1,3,4] oxadiazol-2-yl)-methyl] -1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) 4- {5-[(3-bromo-benzenesulfonyl)-(7-chloro-l ,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl ester;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid;
(RS, SR) (4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-phenyl)-
methanol;
(RS, SR) 2-{benzenesulfonyl-fluoro-[5-(4-iodo-benzyl)-[l,3,4]oxadiazol-2-yl]-methyl} -7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) 4-{5-[(benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid;
(RS, SR) 4-{5-[benzenesulfonyl-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-ylmethyl}-benzoic acid;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzamide;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-N-methyl-
benzamide;
(RS, SR) 4- {5-[(3-bromo-benzenesulfonyl)-(7-chloro-l ,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-N,N-
dimethyl-benzamide;
(RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-bromo-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[-benzenesulfonyl-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-piperidin-1 -yl-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)- N- {2-[-benzenesulfonyl-fluoro-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-methyl] -1,2,3,4-tetrahydro-cyclopenta[b] indol-7-yl} -N-methyl-amine;
2-[benzenesulfonyl-fluoro-(5-trifluoromethyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-( 1 -benzenesulfonyl-2-methoxy-1 -methyl-ethyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-benzenesulfonyl-2-(-6-chloro-2,3,4,9-tetrahydro-1 H-carbazol-2-yl)-2-fluoro-N-methyl-N-(3-methyl-but-2-enyl)-acetamide;
(RS,SR)-5-[-benzenesulfonyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazole-3-carbonitrile;
(RS,SR)-{5-[-benzenesulfonyl-(-6-chloro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)-fluoro-methyl]-[ 1,2,4]oxadiazol-3-yl} -dimethyl-amine;
(RS,SR)-4-[( {5-[-benzenesulfonyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester;
(RS,SR)-3-[({5-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester;
(RS,SR)- {4-[( {5-[-benzenesulfonyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-phenyl} -methanol;
(RS,SR)-2-(benzenesulfonyl-pyridin-2-yl-methyl)-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-N-{5-[(S)-benzenesulfonyl-((R)-7-chloro-l,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,2,4]oxadiazol-3-ylmethyl}-2,2,2-
trifluoro-acetamide
2-[benzenesulfonyl-fiuoro-(3-phenyl-[l,2,4]oxadiazol-5-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[-benzenesulfonyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-oxazole-4-carboxylic acid methyl ester;
2-(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS,SR)-2-[-benzenesulfonyl-(4,5-dimethyl-oxazol-2-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
34. The compounds as claimed in any one of claims 1 to 30, selected from the group consisting of
(RS, SR)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[l,3,4]oxadiazol-2-yl)-methyl]-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indole;
(RS, SR) {3-[(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-(5-methyl- [1,3,4]oxadiazol-2-yl)-methanesulfonyl] -phenyl} -dimethyl-amine;
(RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid methyl ester;
(RS, SR) 4- {5-[(3-bromo-benzenesulfonyl)-(7-chloro-l ,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzoic acid;
(RS, SR) 4- {5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-benzamide;
(RS, SR) 4- {5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-
cyclopenta[b]indol-2-yl)-fluoro-methyl]-[l,3,4]oxadiazol-2-yl}-N,N-
dimethyl-benzamide;
(RS,SR)-2-[-benzenesulfonyl-(-7-chloro-l,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-oxazole-4-carboxylic acid methyl ester;
2-(benzenesulfonyl-benzothiazol-2-yl-fluoro-methyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole;
and pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters thereof.

Documents:

5055-DELNP-2006-Abstract-(18-11-2011).pdf

5055-delnp-2006-abstract.pdf

5055-delnp-2006-assignment.pdf

5055-DELNP-2006-Claims-(18-11-2011).pdf

5055-DELNP-2006-Claims-(30-11-2011).pdf

5055-delnp-2006-claims.pdf

5055-DELNP-2006-Correspondence Others-(18-11-2011).pdf

5055-DELNP-2006-Correspondence Others-(30-11-2011).pdf

5055-delnp-2006-correspondence-others-1.pdf

5055-delnp-2006-correspondence-others.pdf

5055-delnp-2006-description (complete).pdf

5055-delnp-2006-form-1.pdf

5055-delnp-2006-form-18.pdf

5055-DELNP-2006-Form-2-(18-11-2011).pdf

5055-delnp-2006-form-2.pdf

5055-DELNP-2006-Form-3-(18-11-2011).pdf

5055-delnp-2006-form-3.pdf

5055-delnp-2006-form-5.pdf

5055-DELNP-2006-GPA-(18-11-2011).pdf

5055-delnp-2006-gpa.pdf

5055-delnp-2006-pct-210.pdf

5055-delnp-2006-pct-304.pdf

5055-delnp-2006-pct-409.pdf

abstract.jpg


Patent Number 250758
Indian Patent Application Number 5055/DELNP/2006
PG Journal Number 04/2012
Publication Date 27-Jan-2012
Grant Date 24-Jan-2012
Date of Filing 01-Sep-2006
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address GRENZACHERSTRASSE 124 CH-4070 BASEL (SWITZERLAND)
Inventors:
# Inventor's Name Inventor's Address
1 DEHMLOW, HENRIETTA RITTERSTRASSE 85, D-79639 GRENZACH-WYHLEN, GERMANY.
2 KUHN, BERND SONNMATTWEG 42, CH-4410 LIESTAL, SWITZERLAND.
3 MASCIADRI, RAFFAELLO KLYBECKSTRASSE 228, CH-4057 BASEL, SWITZERLAND.
4 PANDAY, NARENDRA MUELLHEIMERSTRASSE 55, CH-4057 BASEL, SWITZERLAND.
5 RATNI, HASANE 4, RUE LOUIS PASTEUR, F-68440 HABSHEIM, FRANCE.
6 WRIGHT, MATTHEW, BLAKE PFEFFINGERSTRASSE 16, CH-4053 BASEL, SWITZERLAND.
PCT International Classification Number C07D 209/86
PCT International Application Number PCT/EP2005/002869
PCT International Filing date 2005-03-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04101252.7 2004-03-26 EUROPEAN UNION