Title of Invention

"HETEROARYL SUBSTITUTED ACETONE DERIVATIVE OF FORMULA I"

Abstract Heteroaryl substituted acetone derivative of formula I wherein Q represents R1, OR1, SR1, SOR1, SO2R1, NR9R1 or a straight-chain C1-31 alkyl or C2-31 alkenyl or alkinyl residue which may be interrupted by 1 or 2 residues, independently selected from O, S, SO, SO2, NR9 and aryl which may be substituted with 1 or 2 substituents R4, and which may be substituted with 1-4 C1-6 alkyl residues and/or 1 or 2 aryl residues, wherein the aryl residues may be substituted with 1 or 2 substituents R4; Ar represents an aryl residue which may be substituted with 1 or 2 substituents R4; X represents N or CR5; Y represents N or CR6; R2 and R3 independently may stand for H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or R7- W, or b) together with the carbon atoms to which they are bound, for a 5- or 6- membered aromatic or heteroaromatic ring which may be substituted with 1 or 2 substituents R4.
Full Text The present invention relates to novel heteroaryl substituted acetone derivatives inhibiting the phospholipase A2 enzyme. These compounds are suited as drugs for preventing and treating diseases caused or contributorily caused by an increased activity of this enzyme, such as inflammations, pain, fever, allergies, asthma, psoriasis and endotoxic shock. The invention also relates to methods of synthesizing these compounds as well as pharmaceutical preparations containing these compounds.
The term "phospholipase A2" comprises the major and diverse group of enzymes which cleave phospholipids at the sn-2 position thereby forming free fatty acids and lysophospholipids. If the released fatty acid is arachidonic acid, the latter can be metabolized into the prostaglandins and thromboxanes via the cyclooxygenase route and into the leukotrienes and other hydroxylated fatty acids via the lipoxygenase route. The prostaglandins are considerably involved in the formation of pain and fever and in inflammatory responses. Leukotrienes are important mediators in the case of inflammatory processes and anaphylactic and allergic processes (Forth et al., Allgemeine und Spezielle Pharmakologie und Toxikologie, Spektrum Akademischer Verlag Heidelberg, Berlin, Oxford, 1998).
The lysophospholipids formed by phospholipase A2 have cell-damaging properties. Lysophosphatidylserine releases the histamine involved in allergic processes (Moreno et al., Agents Actions 1992, 36, 258). In addition, lysophosphatidylcholine is metabolized into the platelet-activating factor (PAF) which is also an important mediator, e.g. in the case of inflammations.

Various phosphoiipase A2 forms are known. They comprise Ca2+-dependent low-molecular secretory phospholipases A2 (sPLAa), CA2+-independent high-molecular phospholipases A2 (iPLA2), CA2+-dependent high-molecular cytosolic phospholipases A2 (cPLA2) and Ca2+-independent lipoprotein-associated phospholipases A2 (LP-PLA2), formerly also referred to as PAF acetylhydrolase (Six et at., Biochim. Biophys. Acta., 2000, 1488, 1-19). According to the current state of knowledge, the cytosolic phosphoiipase A2 (CPLA2) plays the key role in the biosynthesis of prostaglandins, leukotrienes, PAFs and fysophospholipids. This was demonstrated inter alia by studies with CPLA2 knock-out mice, i.e. mice no longer having this enzyme (Uozumi et at., Nature 1997, 390, 618-622; Bonventre et at., Nature 1997, 390, 622-625, Dennis et at., Journal of Experimental Medicine 2002, 196,349-357).
Thus, excess stimulation of this enzyme can result in a number of chronic and acute diseases, such as asthma, cerebral ischemia (Clemens etal., Stroke 1996, 27, 527-535), Alzheimer's disease (Stephenson et a!., Neurobiology of Stroke, 1996, 3, 51-63), rheumatoid arthritis (Huang et a!., Mediators of Inflammation, 1994, 3,307-308), chronic skin diseases and damage to the skin caused by U.V. rays (Gresham etal., American Journal of Physiology1996,270, C1037-C1050).
Inhibitors of cPLA2 can thus be useful for a number of inflammatory diseases.
Inhibitors of cytosolic Phosphoiipase A2 have already been described in the literature (Lehr, Drugs of the Future, 2000, 25, 823-832).
For example, 1,3-disubstituted propan-2-one compounds of AstraZeneca company are known (Connolly et al., Journal of Medicinal Chemistry, 2002, 45, 1348-1362) WO 00/34254 discloses compounds having an inhibitory effect on cytosolic phosphoiipase A2. Patent specifications U.S. 6,414,179, U.S. 2002/0037875 and U.S. 2002/0065246 disclose alpha amino-substituted, thio-substttuted and oxo-substituted ketones as well as alpha-substituted and beta-substituted trifluoromethylketones as inhibitors of cytosolic phosphoiipase A2. Moreover, EP 976 748 discloses certain pyrrolidine derivatives as inhibitors of cytosolic Phosphoiipase A2.
This document refers to the compounds containing phenyl groups while the compounds of the present invention contain heteroaryl groups.

Various phospholipase A2 forms are known. They comprise Ca2+-dependent lowmolecular
secretory phospholipases A2 (sPLA2), CA2+-independent highmolecular
phospholipases A2 (iPLA2), CA2+-dependent high-molecular cytosolic
phospholipases A2 (cPLA2) and Ca2+-independent lipoprotein-associated
phospholipases A2 (LP-PLA2), formerly also referred to as PAF acetylhydrolase
(Six era/., Biochim. Biophys. Acta., 2000, 1488, 1-19). According to the current
state of knowledge, the cytosolic phospholipase A2 (cPLA2) plays the key role in
the biosynthesis of prostaglandins, leukotrienes, PAFs and lysophospholipids.
This was demonstrated inter alia by studies with cPLA2 knock-out mice, i.e. mice
no longer having this enzyme (Uozumi et al., Nature 1997, 390, 618-622;
Bonventre et al., Nature 1997, 390, 622-625, Dennis et al., Journal of
Experimental Medicine 2002, 796,349-357).
Thus, excess stimulation of this enzyme can result in a number of chronic and
acute diseases, such as asthma, cerebral ischemia (Clemens era/., Stroke 1996,
27, 527-535), Alzheimer's disease (Stephenson et al., Neurobiology of Stroke,
1996, 3, 51-63), rheumatoid arthritis (Huang et al., Mediators of Inflammation,
1994, 3, 307-308), chronic skin diseases and damage to the skin caused by U.V.
rays (Gresham et al., American Journal of Physiology 1996, 270, C1037-C1050).
Inhibitors of cPLA2 can thus be useful for a number of inflammatory diseases.
Inhibitors of cytosolic Phospholipase A2 have already been described in the
literature (Lehr, Drugs of the Future, 2000, 25, 823-832).
For example, 1,3-disubstituted propan-2-one compounds of AstraZeneca
company are known (Connolly et al., Journal of Medicinal Chemistry, 2002, 45,
1348-1362). WO 00/34254 discloses compounds having an inhibitory effect on
cytosolic phospholipase A2. Patent specifications U.S. 6,414,179, U.S.
2002/0037875 and U.S. 2002/0065246 disclose alpha amino-substituted, thiosubstituted
and oxo-substituted ketones as well as alpha-substituted and betasubstituted
trifluoromethylketones as inhibitors of cytosolic phospholipase A2.
Moreover, EP 976 748 discloses certain pyrrolidine derivatives as inhibitors of
cytosolic Phospholipase A2.
However, there is still a need for novel compounds which inhibit phospholipase
A2 and in particular cytosolic phospholipase A2. It has now been found
surprisingly that certain heteroaryl substituted acetone derivatives solve this
problem. The present invention thus relates to compounds of formula I
wherein
Q represents R1, OR1, SR1, SOR1, S02R1, NR9R1 or a straight-chain Ci-3i alkyl
or C2-3i alkenyl or alkynyl residue which may be interrupted by 1 or 2 residues,
independently selected from 0, S, SO, SO2, NR9 and aryl which may be
substituted with 1 or 2 substituents R4, and which may be substituted with 1 -4
Ci-e alkyl residues and/or 1 or 2 aryl residues, wherein the aryl residues may be
substituted with 1 or 2 substituents R4;
Ar represents an aryl residue which may be substituted with 1 or 2 R4
substituents;
X represents N or CR5;
Y represents N or CR6;
R1 represents H or an aryl residue which may be substituted with 1 or 2 R4
substituents;
R2 and R3
a) independently represent H, Ci-6 alkyl, C2-e alkenyl, C2-e alkynyl or R7-W, or
b) together with the carbon atoms to which they are bound represent a 5- or
6-membered aromatic or heteroaromatic ring which may be substituted
with 1 or 2 R4 substituents;
R4 represents Cm alkyl, halogen, CF3, CN, N02, OR9, S(0)0R9, COR9, COOR9,
CONR9R10, S03R9, S02NR9R10, tetrazblyl or R7-W;
R5 represents H or R4;
R6 represents H, Ci-6 alkyl, halogen, CF3j CN, NO2> OR9, SR9, COR9, COOR9,
CONR9R10, SO3R9, SO2NR9R10, tetrazolyl or R8-W;
R7 represents Ci.6 alkyl, C2-e alkenyl or C2.6 alkynyl;
R8 represents C2.6 alkyl, C2-e alkenyl or C2.6 alkynyl;
R9 represents H, d-e alkyl or aryl;
R19 represents H or C-|.6 alkyl;
W represents COOH, SO3H or tetrazolyl; and
o is 0, 1 or 2;
and the pharmaceutically compatible salts and esters thereof.
The pharmaceutically compatible salts may be base addition salt. They comprise
salts of the compounds with inorganic bases, such as alkali hydroxides, alkaline
earth hydroxides or with organic bases, such as mono-, di- or triethanolamine.
Acid addition salts are also included.
The pharmaceutically compatible esters of the compounds comprise in particular
esters which can easily be hydrolyzed physiologically, e.g. alkyl,
pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethylene
esters.
Unless otherwise stated, the expression ,,alkyl" comprises straight-chain,
branched or cyclic alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl,
neopentyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl,
cyclohexyl, etc.
The expression ,,alkenyl" comprises straight-chain, branched or cyclic alkenyl
groups, such as ethenyl, propenyl, butenyl, decenyl, heptadecenyl, cyclohexenyl,
etc.
The term ,,alkynyl" comprises straight-chain or branched alkynyl groups, such as
ethynyl, propynyl, butynyl, decynyl, heptadecynyl, etc.
The term ,,aryl" comprises phenyl, naphthyl, biphenyl and 5- or 6-membered
heterocyclic rings, containing 1 to 3 atoms selected from O, N or S and optionally
anellated using a benzene ring. Phenyl and indolyl, in particular phenyl, are
preferred.
The expression ..halogen" comprises a fluorine, chlorine, bromine or iodine atom,
the fluorine or chlorine atom being particularly preferred.
If residues such as R4, R7, R9 and/or R10 occur several times in a compound,
they can each be selected independently from one another.
The straight-chain d1-31 alkyl or C2,31 alkenyl or alkynyl residue, denoted by Q in
formula I, can be interrupted by 1 or 2 residues, independently selected from O,
S, SO, S02, NR9 and aryl. ..Interrupted" is understood to mean here that in
addition to the carbon atoms of its chain the residue may contain such a residue
both at any site within the chain and at the end of the chain, i.e. between the
carbon chain and Ar. The existing substituents which might additionally be
present, where appropriate, in the form of 1-4 d-e alkyl residues and/or 1 or 2
aryl residues may be bound to any carbon atom of the chain.
In the above described compounds of formula I Q preferably denotes
R1-(CHR11)P-A-Z2-B-Z1-
wherein A represents a bond or a straight-chain Ci-m alkyl or C2.m alkenyl or
alkynyl residue, B represents a bond or a straight-chain Ci-n alkyl or C2.n alkenyl
or alkynyl residue, R1 and R11 independently represent H or an aryl residue,
which may be substituted with 1 or 2 substituents R4, and Z1 and Z2
independently represent a bond, O, S, SO, SO2, NR9, CR9R10 or an aryl residue,
wherein the aryl residue may be substituted with 1 or 2 substituents R4. p here
stands for 0 or 1, m is an integer from 0 to 12 and n for an integer from 0 to 16.
The sum of m and n is preferably no greater than 17, in particular no greater than
Q is preferably:
R1-(CHR11)p-(CH2)m-Z2-(CH2)n-Z1-
wherein R1, R11, Z2, Z1, p, m and n are as defined above.
It is particularly preferred to select Q from:
R1-B-Z1-
R1-CHR11-B-Z1-
R1-A-Z2-B-Z1- and
R1-CHR11-A-Z2-B-Z1-,
in particular
R1-(CH2)n-Z1-
R1-CHR11-(CH2)n-Z1-
R1-(CH2)m-Z2-(CH2)n-Z1- and
R1-CHR11-(CH2)m-Z2-(CH2)n-Z1-.
Preferably R1 and R11 represent independently from one another, H or a phenyl
residue, in particular a non-substituted phenyl residue. If denoting an aryl
residue, Z1 and Z2 are preferably phenyl, in particular unsubstituted phenyl.
In a preferred embodiment Q stands for phenyl or C5.12 alkyl or alkoxy, more
preferably for Cy-io alkyl or alkoxy and most preferably for C8 alkyl in den
compounds of formula I according to the invention.
In the compounds of formula I according to the invention Ar represents an aryl
residue and preferably an aryl residue as defined above. It is particularly
preferred for Ar to represent a phenyl residue which preferably links the adjacent
groups Q and O in para position.
When R2 and R3 together with the carbon atoms to which they are bound form a
5- or 6-membered aromatic or heteroaromatic ring, this is preferably a benzo ring
or a 6-membered aromatic heterocyclic ring having 1 to 3 nitrogen atoms. These
rings may be substituted with 1 or 2 substituents R4, an R4 substituent and in
particular COOH, CH3, Cl, OCH3, CN, CHO, COOCH3 or CONH2 being
preferred.
In the heteroaryl residue of the acetone derivatives according to the invention, Y
preferably denotes CR6. R5 and R6 are preferably selected from H, COOH, tbutyl,
Cl, CHO, COCH3 or COOCH3.
Particularly suited heteroaryl residues for the acetone derivatives according to
the invention are pyrrolyl, pyrazolyl, indolyl, indazolyl, pyrrolyl-2-carboxylic acid,
pyrrolyl-3-carboxylic acid, indolyl-2-carboxylic acid, indolyl-3-carboxylic acid,
indolyl-4-carboxylic acid, indolyl-5-carboxylic acid, indolyl-6-carboxylic acid, 5-
methylindolyl, 5-chloroindolyl, 5-methoxyindolyl, indolyl-5-carbonitrile, indolyl-5-
carbaldehyde, indolyl-5-carboxylic acid methyl ester, 3-tert-butylindolyl-5-
carboxylic acid, 3-chloroindolyl-5-carboxylic acid, 3-formylindolyl-5-carboxylic
acid, 3-acetylindolyl-5-carboxylic acid, 3-methoxycarbonylindolyl-5-carboxylic
acid, 3-tert-butylindolyl-6-carboxylic acid and indolyl-5-carbamide.
The compounds according to the invention have proved to be potent
phospholipase A2 inhibitors. The compounds are thus usable as drugs for
preventing and treating diseases caused or contributorily caused by products or
secondary products of this enzyme, such as for treating the rheumatoid diseases
and for preventing and treating allergically induced diseases. The compounds
according to the invention thus represent inter alia effective analgesics,
antiphlogistics, antipyretics, antiallergics and broncholytics and are usable for
thrombosis prophylaxis and for the prophylaxis of anaphylactic shock and for
treating dermatologic diseases such as psoriasis, urticaria, acute and chronic
exanthemas of allergic and non-allergic genesis.
Therefore, the present invention also relates to pharmaceutical preparations
comprising a compound of general formula I or a pharmaceutically compatible
salt or ester thereof.
The compounds of formula I are particularly suited for the production of a
pharmaceutical preparation for preventing or treating diseases which are caused
or contributorily caused by an increased activity of phospholipase A2, preferably
of cytosolic phospholipase A2. These are e.g. diseases selected from
inflammations, pain, fever, allergies, asthma, psoriasis, cerebral ischemia,
Alzheimer's disease, chronic skin diseases, damage to the skin caused by U.V.
radiation, rheumatic diseases, thrombosis, anaphylactic shock, urticuria, acute
and chronic exanthemas and endotoxic shock.
The compounds according to the invention can either be administered as
individual therapeutic substances or as mixtures with other therapeutic active
substances. They can be administered as such but in general they are given as
a pharmaceutical preparation, i.e. as active substance mixtures having suitable
pharmaceutical carriers or diluents. The compounds or preparations can be
administered orally, parenterally, by inhalation, rectally or topically (including
dermally, transdermally, buccally and sublingually).
The kind of pharmaceutical preparation and pharmaceutical carrier or diluent
depends on the desired kind of administration. Oral preparations may be present
as tablets or capsules, for example, also in a retarded form, and may contain
conventional excipients, such as binders (e.g. syrup acacia, gelatin, sorbitol,
tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch,
calcium phosphate, sorbitol or glycine, lubricants (e.g. magnesium stearate,
talcum, polyethylene glycol or silica), disintegrating agents (e.g. starch) or
wetting agents (e.g. sodium lauryl sulfate). Oral liquid preparations may be
present as aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or
sprays, etc., or may be present as a dry powder for reconstitution with water or
another suitable carrier. Such liquid preparations may contain conventional
additives, e.g. suspending agents, flavoring agents, diluents, or emulsifiers. For
parenteral administration it is possible to use solutions or suspensions with
conventional pharmaceutical carriers. For administration by inhalation the
compounds may be present in a powdery, aqueous or partially aqueous solution
which can be used as an aerosol. Preparations for topical application may be
present e.g. as pharmaceutically compatible powders lotions, ointments, creams,
gels or as therapeutic systems which contain therapeutically active amounts of
the compounds according to the invention.
The necessary dosage depends on the form of pharmaceutical preparation used,
on the kind of application, the severity of the symptoms and the special subject
(human or animal) which is treated. The treatment is usually started with a dose
below the optimum dose. Thereafter, the dose is raised until the optimum effect
for the given conditions is achieved. In general, the compounds according to the
invention are administered the best in concentrations by which effective actions
can be achieved without detrimental or disadvantageous effects occurring. They
can be administered as a single dose or in several doses.
The effectiveness of the compounds according to the invention can be
determined by the inhibition of cytosolic phospholipase A2- To this end, cytosolic
phospholipase A2 is stimulated in intact human thrombocytes with calcium
ionophor A23187 so as to trigger the release of arachidonic acid from the
membrane phospholipids. In order to prevent the metabolization of the enzyme
product arachidonic acid via the cyclooxygenase route and the 12-lipoxygenase
route, the dual cyclooxygenase/12-lipoxygenase-inhibitor 5,8,11,14-
eicosatetraynoic acid is added. Following purification by means of solid phase
extraction, the released arachidonic acid is determined by reversed phase-HPLC
using U.V. detection. The inhibition of the enzyme by a test substance follows
from the ratio of the arachidonic acid amounts formed in the presence or
absence of the test substance. More detailed information on the test system is
made in Example 10.
The present invention also relates to a method of producing a compound of
formula I, wherein a compound of formula II
or a compound of formula III
H
is reacted with a compound of formula IV
and the alcohol formed is oxidized to give the desired ketone, wherein Q, Ar, X,
Y, R2 and R3 are as defined above and Abg stands for a leaving group such as
halogen, in particular bromine.
The below examples explain the invention without limiting it to the concrete
compounds.
All batches were carried out in a nitrogen protective gas atmosphere. Silica gel
60 of Merck company, Darmstadt, Germany, particle size 63 - 200/i/m or 15 - 40
//m (= flash chromatography), was used for the column chromatographic
purification.
Example 1
1 -(4-Octylphenoxy)-3-(pyrrol-1 -yl)propan-2-one
A. 1 -(4-Octylphenoxy)-3-(pyrrol-1 -yl)propan-2-ol
0.048 g (1.200 mmol) sodium hydride as 60% dispersion in mineral oil is
suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and
admixed with 0.077 g (1.15 mmol) pyrrole. Having stirred for one hour, a solution
of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane (Kuliev et al. Uch. Zap.
Azerb. Gos. Univ. Ser. Khim Nauk. 1964, 4, 97; Chem. Abstr. 1966, 65, 640c) in
10 ml absolute DMF is added drop-wise. The mixture is stirred for 19 hours,
hydrolyzed with a semi-saturated NaCI solution and extracted four times using
diethyl ether. The combined organic phases are concentrated to half the volume
on the rotary evaporator and washed three times with saturated NaCI solution.
Drying on sodium sulfate, filtration and reconcentration on the rotary evaporator
leave as a crude product a red oil which is purified on silica gel by means of
column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and
yields the product as a yellowish oil.
Yield: 0.229 g (0.695 mmol); 61 %
C2iH3iNO2 (329.5)
1H-NMR (CDCIa): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.31 (m, 10H), 1.58 (m, 2H),
2.55 (t, J = 8 Hz, 2H), 3.83-3.92 (m, 2H), 4.06-4.24 (m, 3H), 6.17 (t, J = 2 Hz,
2H), 6.70 (t, J = 2 Hz, 2H), 6.82 (d, J = 9 Hz, 2H), 7.10 (d, J = 9 Hz, 2H)
B. 1 -(4-Octylphenoxy)-3-(pyrrol-1 -yl)propan-2-one
1.24 g (12.1 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.100 g (0.304 mmol) 1-(4-octylphenoxy)-3-(pyrrol-1-yl)propan-2-ol in 10 ml
absolute DMSO. Having stirred for 19 hours, the solution is poured into a mixture
of 5% sodium hydrogen carbonate solution and saturated NaCI solution (1:1, v/v)
and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the
organic phases, concentration to half the volume on the rotary evaporator, three
wash steps using saturated NaCI solution, drying on sodium sulfate, filtration and*
reconcentration on the rotary evaporator leave a brownish oil which is purified on
silica gel by means of column chromatography (flow agent: petroleum ether/ethyl
acetate 97:3) and yields the product as a white solid.
Yield: 0.087 g (0.266 mmol); 88 %
Mp.: 58-59°C
C2iH29NO2 (327.5)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.26 (m, 10H), 1.58 (m, 2H),
2.56 (t, J = 8 Hz, 2H), 4.59 (s, 2H), 4.97 (s, 2H), 6.24 (t, J = 2 Hz, 2H), 6.61 (t, J
= 2 Hz, 2H), 6.80 (d, J = 9 Hz, 2H), 7.12 (d, J = 9 Hz, 2H)
Example 2
1 -(4-Octylphenoxy)-3-(pyrazol-1 -yl)propan-2-one
A. 1 -(4-Octylphenoxy)-3-(pyrazol-1 -yl)propan-2-ol
0.091 g (3.96 mmol) sodium is mixed with 5 ml absolute THF and with a solution
of 0.268 g (3.94 mmol) pyrazole in 15 absolute THF. Having stirred at room
temperature for 2 hours, a solution of 0.690 g (2.63 mmol) 2-(4-octyl13
phenoxymethyl)oxirane in 10 ml THF is added drop-wise and boiled under reflux
for 8 hours. The cooled reaction mixture is poured into semi-saturated NaCI
solution and extracted four times using diethyl ether. The combined organic
phases are concentrated to half the volume on the rotary evaporator. Washing
using a semi-saturated NaCI solution, drying on sodium sulfate, filtration and
reconcentration on the rotary evaporator leave as a crude product a yellow solid
which is purified on silica gel by means of column chromatography (flow agent:
petroleum ether/ethyl acetate 85:15) and recrystallized from petroleum ether and
yields the product as a white solid.
Yield: 0.716 g (2.17 mmol); 82 %
Mp.: 88°C
C2oH3oN2O2 (330.5)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 6 Hz, 3H), 1.28 (m, 10H), 1.58 (m, 2H),
2.55 (t, J = 8 Hz, 2H), 3.71-3.78 (m, 1H), 3.92-4.02 (m, 2H), 4.23-4.48 (m, 3H),
6.27 (t, J = 2 Hz, 1H), 6.83 (d, J = 9 Hz, 2H), 7.09 (d, J = 9 Hz, 2H), 7.45 (d, J = 2
Hz, 1H), 7.55 (d, J = 2Hz,1H)
B. 1 -(4-Octylphenoxy)-3-(pyrazol-1 -yl)propan-2-one
0.154 g (1.51 mmol) acetic anhydride is mixed with 5 ml absolute DMSO, stirred
at room temperature for 10 min and added drop-wise to a solution of 0.050 g
(0.152 mmol) 1-(4-octylphenoxy)-3-(pyrazol-1-yl)propan-2-ol in 10 ml absolute
DMSO. Having stirred at room temperature for 18 hours, the solution is poured
into a mixture of 5 % sodium hydrogen carbonate solution and saturated NaCI
solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether,
combination of the organic phases, concentration to half the volume on the rotary
evaporator, three wash steps with saturated NaCI solution, drying on sodium
sulfate, filtration and reconcentration on the rotary evaporator leave as a crude
product a yellowish solid which is purified on silica gel by means of column
chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the
product as a white solid.
Yield: 0.048 g (0.146 mmol); 96 %
Mp.: 85-87°C
(328.5)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.57 (m, 2H),
2.55 (t, J = 8 Hz, 2H), 4.63 (s, 2H), 5.26 (s, 2H), 6.36 (t, J = 2 Hz, 1H), 6.81 (d, J
= 9 Hz, 2H), 7.11 (d, J = 9 Hz, 2H), 7.43 (d, J = 2 Hz, 1 H), 7.59 (d, J = 2 Hz, 1 H)
Example 3
1 -(lndol-1 -yl)-3-(4-octylphenoxy)propan-2-one
A. 1 -(lndol-1 -yl)-3-(4-octylphenoxy)propan-2-ol
0.048 g (1.20 mmol) sodium hydride as 60 % dispersion in mineral oil are
suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and
mixed with a solution of 0.134 g (1.14 mmol) indole in 10 ml absolute DMF.
Having stirred for 1 1/2 hours, a solution of 0.300 g (1.14 mmol) 2-(4-
octylphenoxymethyl)oxirane in 10 ml absolute DMF is added drop-wise. The
mixture is stirred for 16 hours, hydrolyzed with a semi-saturated NaCI solution
and extracted four times using diethyl ether. The combined organic phases are
concentrated to half the volume on the rotary evaporator and washed three times
with saturated NaCI solution. Drying on sodium sulfate, filtration and
reconcentration on the rotary evaporator leave as a crude product an orange oil
which is purified on silica gel by means of column chromatography (flow agent:
petroleum ether/ethyl acetate 95:5) and yields the product as a yellow oil.
Yield: 0.356 g (0.938 mmol); 82 %
CasHsaNOs (379.5)
1H-NMR (CDCI3): 5 (ppm) = 0.93 (t, J = 7 Hz, 3H), 1.31 (m, 10H), 1.62 (m, 2H),
2.44 (s broad, 1H), 2.58 (t, J = 8 Hz, 2H), 3.84-3.94 (m, 2H), 4.29-4.45 (m, 3H),
6.52 (d, J = 3 Hz, 1H), 6.82 (d, J = 9 Hz, 2H), 7.11 (d, J = 9 Hz, 2H), 7.13-7.15
(m, 2H), 7.20-7.25 (m, 1H), 7.40 (d, J = 8 Hz, 1H), 7.64 (d, J = 8 Hz, 1H)
B. 1-(lndol-1-yl)-3-(4-octylphenoxy)propan-2-one
1.77 g (17.3 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.164 g (0.432 mmol) 1-(indol-1-yl)-3-(4-octylphenoxy)propan-2-ol in 10 ml
absolute DMSO. Having stirred for six hours, the solution is poured into a mixture
of 5 % sodium hydrogen carbonate solution and saturated NaCI solution (1:1,
v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination
of the organic phases, concentration to half the volume on the rotary evaporator,
three wash steps with saturated NaCI solution, drying on sodium sulfate, filtration
and reconcentration on the rotary evaporator leave as a crude product a yellow
oil which is purified on silica gel by means of column chromatography (flow
agent: petroleum ether/ethyl acetate 95:5) and recrystallized from petroleum
ether and yields the product as a white solid.
Yield: 0.106 g (0.281 mmol); 65 %
Mp.: 65°C
1H-NMR (CDCI3): 5 (ppm) = 0.90 (t, J = 7 Hz, 3H), 1 .30 (m, 10H), 1 .59 (m, 2H),
2.57 (t, J = 8 Hz, 2H), 4.59 (s, 2H), 5.16 (s, 2H), 6.60 (d, J = 3 Hz, 1H), 6.81 (d, J
= 9 Hz, 2H), 7.05 (d, J = 3 Hz, 1H), 7.12-7.16 (m, 4H), 7.19-7.23 (m, 1H), 7.65 (d,
J = 6 Hz, 1 H)
Example 4
1-(lndazol-1-yl)-3-(4-octylphenoxy)propan-2-one
16
A. 1-(lndazol-1-yl)-3-(4-octylphenoxy)propan-2-ol
0.048 g (1.20 mmol) sodium hydride as a 60 % dispersion in mineral oil is
suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and
mixed with a solution of 0.135 g (1.14 mmol) indazole. Having stirred for 1 hour,
a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml
absolute DMF is added drop-wise. The mixture is stirred for 40 hours, hydrolyzed
with a semi-saturated NaCI solution and extracted four times using diethyl ether.
The combined organic phases are concentrated to half the volume on the rotary
evaporator and washed three times with saturated NaCI solution. Drying on
sodium sulfate, filtration and reconcentration on the rotary evaporator leave a
white solid which is recrystallized from petroleum ether/ethyl acetate (80:20).
B. 1 -(lndazol-1 -yl)-3-(4-octylphenoxy)propan-2-one
1.07 g (10.5 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.100 g (0.263 mmol) 1-(indazol-1-yl)-3-(4-octylphenoxy)propan-2-ol in 10 ml
absolute DMSO. Having stirred for 20 hours, the solution is poured into a mixture
of 5 % sodium hydrogen carbonate solution and saturated NaCI solution (1:1,
v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination
of the organic phases, concentration to half the volume on the rotary evaporator,
three wash steps with saturated NaCI solution, drying on sodium sulfate, filtration
and reconcentration on the rotary evaporator leave as a crude product a yellow
oil which is purified on silica gel by means of column chromatography (flow
agent: petroleum ether/ethyl acetate 90:10) and yields the product as a white
solid.
Yield: 0.062 g (0.164 mmol)
Mp.: 66-67°C
C24H3oN2O2 (378.5)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26 (m, 10H), 1.57 (m, 2H),
2.55 (t, J = 8 Hz, 2H), 4.63 (s, 2H), 5.46 (s, 2H), 6.79 (d, J = 9 Hz, 2H), 7.11 (d, J
= 9 Hz, 2H), 7.16-7.20 (m, 2H), 7.37-7.41 (m, 1H), 7.75-7.77 (m, 1H), 8.08 (d, J =
1 Hz,1H)
Example 5
1 -[3-(4-Octylphenoxy)-2-oxopropyl]pyrrol-2-carboxylic acid
,
A. 1-Bromo-3-(4-octylphenoxy)propan-2-ol
1.17 g (4.46 mmol) 2-(4-octyl-phenoxymethyl)oxirane are dissolved in 10 ml
absolute dichloromethane and mixed with 1.34 g (22.3 mmol) silica gel and with
1.16 g (13.4 mmol) lithium bromide. The suspension is concentrated almost to
dryness on the rotary evaporator and allowed to stand at room temperature for 3
hours. The reaction batch is mixed with dichloromethane, filtrated on cotton wool
and concentrated on the rotary evaporator. Taking up the suspension in diethyl
ether, washing with water, drying on sodium sulfate, filtration and reconcentration
on the rotary evaporator yield the product as a yellowish oil.
Yield: 1.52 g (4.42 mmol); 99 %
C17H27BrO2 (343.3)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 6 Hz, 3H), 1.28 (m, 10H), 1.58 (m, 2H),
2.55 (t, J = 8 Hz, 2H), 3.55-3.71 (m, 2H), 4.04-4.21 (m, 3H), 6.84 (d, J = 9 Hz,
2H),7.11 (d,J = 9Hz, 2H)
B. [1 -Bromo-3-(4-octylphenoxy)propan-2-yl]acetate
0.41 g (5.18 mmo!) absolute pyridine is dissolved in 10 ml absolute
dichloromethane, cooled to 0°C and mixed with 0.41 g (5.22 mmol)
acetylchloride, A/-aetylpyridiniumchloride precipitating. Having stirred for 30
minutes, 0.50 g (1.46 mmol) 1-bromo-3-(4-octylphenoxy)propan-2-ol is dissolved
in 10 ml absolute dichloromethane and added drop-wise. The reaction batch is
stirred for another 3 hours at 0°C, diluted with dichloromethane and washed
twice with 5 % sodium hydrogen carbonate solution. The combined aqueous
phases are extracted again with dichloromethane and the combined organic
phases are washed with water. Following drying on sodium sulfate, filtration,
concentration on the rotary evaporator and mixing with toluene three times and
respective concentration on the rotary evaporator, a yellow oil is obtained as the
crude product, which is purified by means of column chromatography on silica
gel (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a
yellowish oil.
Yield: 0.56 g (1.45 mmol); 100 %
CigHagBrOa (385.3)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.59 (m, 2H),
2.13 (s, 3H), 2.55 (t, J = 8 Hz, 2H), 3.59-3.76 (m, 2H), 4.11-4.18 (m, 2H), 5.31
(m, 1H), 6.86 (d, J = 9 Hz, 2H), 7.10 (d, J = 9 Hz, 2H)
C. tert-Butylpyrrole-2-carboxylate
0.50 g (4.50 mmol) pyrrole-2-carboxylic acid is suspended in 15 ml absolute
benzene and boiled under reflux. A solution of 4.07 g (18.0 mmol) 90 % N,Ndimethylformamidedi-
terf-butylacetal in 15 ml absolute benzene is added dropwise
within 30 min. Following another heating under reflux for 30 minutes and
subsequent cooling, the reaction mixture is diluted with diethyl ether, washed
with 5 % sodium carbonate solution and with saturated NaCI solution. Drying on
sodium sulfate, filtration and concentration on the rotary evaporator leave as the
crude product a reddish solid which purified on silica gel by means of column
chromatography (flow agent: petroleum ether/ethyl acetate 95:5) yields the
product as a white solid.
Yield: 0.566 g (3.38 mmol); 75 %
Mp.: 87-89°C
C9H13NO2 (167.2)
1H-NMR (CDCI3): 6 (ppm) = 1.57 (s, 9H), 6.23 (m, 1H), 6.84 (m, 1H), 6.91 (m,
1H), 9.23 (s, broad, 1H)
D. te/?-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate
0.145 g (0.867 mmol) terf-butylpyrrole-2-carboxylate is dissolved in 10 ml
absolute DMSO, mixed with 0.107 g (0.952 mmol) potassium-te/f-butylate and
stirred at 110°C for 15 minutes. A solution of 0.333 g (0.864 mmol) [1-bromo-3-
(4-octylphenoxy)propan-2-yl]acetate in 10 ml absolute DMSO is added dropwise.
Following heating at 110°C for 30 minutes and subsequent cooling,
hydrolysis is carried out in saturated NaCI solution. Four extractions with diethyl
ether, combination of organic phases, concentration to half the volume on the
rotary evaporator, three wash steps with saturated NaCI solution, drying on
sodium sulfate, filtration and reconcentration on the rotary evaporator leave as
the crude product a yellow oil which is purified on silica gel by means of flash
column chromatography (flow agent: petroleum ether/ethyl acetate 80:20) and
yields the product as a colorless oil.
Yield: 0.169 g (0.358 mmol); 41 %
C28H4iNO5(471.6)
1H-NMR (CDCIa): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.55 (s, 9H),
1.60 (m, 2H), 2.01 (s, 3H), 2.54 (t, J = 8 Hz, 2H), 4.01 (dd, J = 11 Hz and J = 4
Hz, 1H),4.13(dd, J = 11 HzandJ = 4Hz, 1H), 4.49 (dd, J = 14 Hz and J = 8 Hz,
1 H), 4.86 (dd, J = 14 Hz and J = 4 Hz, 1 H), 5.43-5.48 (m, 1 H), 6.07 (dd, J = 4 Hz
and J = 2 Hz, 1 H), 6.79-6.83 (m, 3H), 6.88 (dd, J = 4 Hz and J = 2 Hz, 1 H), 7.08
(d, J = 9 Hz, 2H)
E. te/f-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate
0.150 g (0.318 mmol) terf-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-2-
carboxylate is dissolved in 10 ml absolute methanol, mixed with 1.26 ml (0.630
mmol) of a 0.5M sodium methanolate solution and stirred at room temperature
for 15 min. Following concentration to half the volume on the rotary evaporator,
the batch is diluted with diethyl ether. Washing of the organic phase with semisaturated
and with saturated NaCI solution, drying on sodium sulfate, filtration
and reconcentration on the rotary evaporator yield the product as a yellowish oil.
20
Yield: 0.133 g (0.310 mmol); 98 %
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.56 (s, 9H),
1.60 (m, 2H), 2.55 (t, J = 8 Hz, 2H), 3.57 (d, J = 4 Hz, 1H), 3.93 (d, J = 6 Hz, 2H),
4.30 (m, 1H), 4.46 (dd, J = 14 Hz and J = 6 Hz, 1H), 4.66 (dd, J = 14 Hz and J =
4 Hz, 1 H), 6.11 (dd, J = 4 Hz and J = 2 Hz, 1 H), 6.84 (m, 3H), 6.90 (dd, J = 4 Hz
and J = 2 Hz, 1 H), 7.08 (d, J = 9 Hz, 2H)
F. te/t-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-2-carboxylate
1.14 g (11.2 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.121 g (0.282 mmol) te/?-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-2-
carboxylate in 10 ml absolute DMSO. Having stirred for 16 hours, the batch is
poured into a mixture of 5 % sodium hydrogen carbonate solution and saturated
NaCI solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl
ether, combination of the organic phases, concentration to half the volume on the
rotary evaporator, three wash steps with saturated NaCI solution, drying on
sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a
crude product a yellow oil which is purified on silica gel by means of column
chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the
product as a yellowish oil.
Yield: 0.096 g (0.225 mmol); 80 %
C26H37N04 (427.6)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.52 (s, 9H),
1.60 (m, 2H), 2.55 (t, J = 8 Hz, 2H), 4.73 (s, 2H), 5.29 (s, 2H), 6.18 (m, 1H), 6.72
(m, 1 H), 6.86 (d, J = 8 Hz, 2H), 6.93 (m, 1 H), 7.11 (d, J = 8 Hz, 2H)
G. 1-[3-(4-Octylphenoxy)-2-oxopropyl]pyrrole-2-carboxylic acid
0.045 g (0.105 mmol) te/f-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-2-
carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 0.900
g (7.89 mmol) trifluoroacetic acid. After stirring at room temperature for 1 hour,
the batch is concentrated to dryness on the rotary evaporator. Two dissolutions
in toluene and respective concentration on the rotary evaporator leave as a
21
crude product a brownish solid which is recrystallized from methanol and some
water drops and yields the product as a beige solid.
Yield: 0.016 g (0.043 mmol); 41 %
Mp.: 157°C(decomp.)
CaaHagNCU (371.5)
1H-NMR (DMSO-de): 5 (ppm) = 0.84 (t, J = 7 Hz, 3H), 1.24 (m, 10H), 1.50 (s,
2H), 2.49 (t, J = 8 Hz, 2H), 4.86 (s, 2H), 5.27 (s, 2H), 6.11 (m, 1H), 6.81 (m, 1H),
6.83 (d, J = 8 Hz, 2H), 7.03 (m, 1H), 7.06 (d, J = 8 Hz, 2H)
Example 6
1 -[3-(4-Octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylic acid
VoH 'CH3 H3
CH3
A. tert-Butylpyrrole-3-carboxylate
22
0.50 g (4.50 mmol) pyrrole-3-carboxylic acid is suspended in 15 ml absolute
benzene and boiled under reflux. A solution 4.07 g (18.0 mmol) 90 % N,Ndimethylformamidedi-
terf-butylacetal in 15 ml absolute benzene is added dropwise
within 30 min. Following another heating under reflux for 30 minutes and
subsequent cooling, the reaction mixture is diluted with diethyl ether, washed
with 5 % sodium carbonate solution and saturated NaCI solution. Drying on
sodium sulfate, filtration and concentration on the rotary evaporator leave as a
crude product a yellow solid which is purified on silica gel by means of column
chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the
product as a white solid.
Yield: 0.433 g (2.59 mmol); 58 %
Mp.: 82-84°C
C9H13NO2 (167.2)
1H-NMR (CDCI3): 5 (ppm) = 1.55 (s, 9H), 6.59 (m, 1H), 6.72 (m, 1H), 7.34 (m,
1H), 8.75 (s, broad, 1H)
B. tert-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate
0.145 g (0.867 mmol) te/f-butylpyrrole-3-carboxylate is dissolved in 10 ml
absolute DMSO, mixed with 0.107 g (0.952 mmol) potassium-tert-butylate and
stirred at 110°C for 15 min. A solution of 0.333 g (0.864 mmol) [1-bromo-3-(4-
octylphenoxy)propan-2-yl]acetate in 10 ml absolute DMSO is added drop-wise.
Following 30 minutes of heating at 110°C and subsequent cooling, hydrolysis is
carried out in saturated NaCI solution. Four extractions with diethyl ether,
combination of the organic phases, concentration to half the volume on the rotary
evaporator, three wash steps using saturated NaCI solution, drying on sodium
sulfate, filtration and reconcentration on the rotary evaporator leave as a crude
product a yellow oil which is purified on silica gel by means of flash column
chromatography (flow agent: petroleum ether/ethyl acetate 93:7) and yields the
product as a colorless oil.
Yield: 0.104 g (0.221 mmol); 26 %
C28H4iNO5(471.6)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26 (m, 10H), 1.52 (s, 9H),
1.59 (m, 2H), 2.09 (s, 3H), 2.54 (t, J = 8 Hz, 2H), 3.89 (dd, J = 10 Hz and J = 6
23
Hz, 1H), 3.95 (dd, J = 10 Hz and J = 4 Hz, 1H), 3.89-4.25 (m, 2H), 5.30 (m, 1H),
6.50 (dd, J = 3 Hz and J = 2 Hz, 1H), 6.57 (m, 1H), 6.81 (d, J = 9 Hz, 2H), 7.09
(d,J = 9Hz, 2H), 7.20 (m, 1H)
C. terf-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate
0.104 g (0.221 mmol) terf-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-3-
carboxylate is dissolved in 10 ml absolute methanol, mixed with 0.88 ml (0.440
mmol) of a 0.5M sodium methanolate solution and stirred at room temperature
for 15 min. Following concentration to half the volume on the rotary evaporator,
the batch is diluted with diethyl ether. Washing of the organic phase with semisaturated
and with saturated NaCI solution, drying on sodium sulfate, filtration
and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Yield: 0.091 g (0.212 mmol); 96 %
C26H39NO4 (429.6)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.30 (m, 10H), 1.55 (s, 9H),
1.62 (m, 2H), 2.46 (s broad, 1H), 2.54 (t, J = 8 Hz, 2H), 3.86 (dd, J = 10 Hz and J
= 6 Hz), 3.92 (dd, J = 9 Hz and J = 5 Hz), 4.07 (dd, J = 14 Hz and J = 7 Hz), 4.16
(dd, J = 14 Hz and J = 5 Hz), 4.27 (m, 1H), 6.55 (dd, J = 3 Hz and J = 2 Hz, 1H),
6.63 (m, 1H), 6.82 (d, J = 9 Hz, 2H), 7.11 (d, J = 9 Hz, 2H), 7.27 (m, 1H)
D. terf-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylate
0.817 g (8.00 mmol) acetic anhydride is mixed with 10 ml absolute DMSO, stirred
at room temperature for 10 min and added drop-wise to a solution of 0.086 g
(0.200 mmol) terf-butyl-1 -[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-3-
carboxylate in 10 ml absolute DMSO. Having stirred for 19 hours, the solution is
poured into a mixture of 5 % sodium hydrogen carbonate solution and saturated
NaCI solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl
ether, combination of the organic phases, concentration to half the volume on the
rotary evaporator, three wash steps with saturated NaCI solution, drying on
sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a
crude product a brown oil which is purified on silica gel by means of flash column
chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the
product as a yellowish oil.
Yield: 0.065 g (0.152 mmol); 76 %
(427.6)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26 (m, 10H), 1.53 (s, 9H),
1.59 (m, 2H), 2.56 (t, J = 8 Hz, 2H), 4.63 (s, 2H), 4.99 (s, 2H), 6.50 (m, 1 H), 6.59
(dd, J = 3 Hz and J = 2 Hz, 1 H), 6.82 (d, J = 9 Hz, 2H), 7. 1 3 (m, 3H)
E. 1-[3-(4-Octylphenoxy)-2-oxopropyl]pyrrole-3-carboxyiic acid
0.049 g (0.115 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-3-
carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 0.988
g (8.67 mmol) tifluoroacetic acid. Having stirred at room temperature for 3 Vz
hours, the batch is concentrated to dryness on the rotary evaporator. Two
dissolution steps in toluene and respective concentrations on the rotary
evaporator leave as a crude product a greenish solid which is solved in diethyl
ether and precipitated with petroleum ether. Twenty minutes of centrifugation at
3000 rpm, decantation of the supernatant, displacement of the solvent residues
in the nitrogen flow and drying in a vacuum desiccator yield the product as a
beige solid.
Yield: 0.018 g ( 0.048 mmol); 42 %
Mp.: 125°C(decomp.)
C22H29NO4 (371 .5)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.57 (m, 2H),
2.56 (t, J = 8 Hz, 2H), 4.65 (s, 2H), 5.04 (s, 2H), 6.55 (m, 1H), 6.68 (m, 1H), 6.82
(d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 7.30 (m, 1H)
Example 7
1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-2-carboxylic acid
A. terf-Butylindole-2-carboxylate
1.00 g (6.21 mmol) indole-2-carboxylic acid is dissolved in 15 ml absolute THF,
mixed with 1.01 g (6.23 mmol) /V.AT-carbonyldiimidazole and stirred at room
temperature for 1 hour. Thereafter, 0.77 g (6.86 mmol) potassium-tert-butylate
and 9.12 g (123 mmol) te/t-butanol are added. Following heating under reflux for
6 hours, quenching using 5 ml water, filtrating off, rinsing with THF, drying on
sodium sulfate and concentration on the rotary evaporator, a brown solid is
obtained as the crude product. Preliminary purification by means of column
chromatography on silica gel using a short column with petroleum ether/ethyl
acetate 95:5 leaves a white solid which is purified on silica gel by means of
column chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and
yields the product as a white solid.
Yield: 0.325 g (1.496 mmol); 24 %
Mp.: 104-105°C
Ci3H15N02(217.3)
1H-NMR (CDCI3): 5 (ppm) = 1.65 (s, 9H), 7.14 (m, 2H), 7.31 (m, 1H), 7.43 (dd, J
= 8 Hz and J = 1 Hz, 1H), 7.68 (dd, J = 8 Hz and J = 1 Hz, 1H), 9.12 (s, broad,
1H)
B. te/f-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate
0.325 g (1.50 mmol) te/t-butylindole-2-carboxylate is dissolved in 15 ml absolute
DMSO, mixed with 0.184 g (1.64 mmol) potassium-ferf-butylate and stirred at
110°C for 15 min. A solution of 0.576 g (1.50 mmol) [1-bromo-3-(4-
octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO is added drop-wise.
Following 30 minutes of heating at 110°C and subsequent cooling, hydrolysis is
carried out in saturated NaCI solution. Four extractions with diethyl ether,
combination of the organic phases, concentration to half the volume on the rotary
evaporator, three wash steps with saturated NaCI solution, drying on sodium
sulfate, filtration and reconcentration on the rotary evaporator leave as a crude
product a yellow oil which is purified on silica gel by means of flash column
chromatography (flow agent: petroleum ether/ethyl acetate 99:1) and yields the
product as a colorless oil.
Yield: 0.246 g (0.472 mmol); 32 %
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.30 (m, 10H), 1.59 (m, 2H),
1.62 (s, 9H), 1.81 (s, 3H), 2.56 (t, J = 8 Hz, 2H), 4.17 (d, J = 4 Hz, 2H), 4.83 (dd,
J = 1 5 Hz and J = 8 Hz, 1 H), 5.07 (dd, J = 1 5 Hz and J = 5 Hz, 1 H), 5.57 (m, 1 H),
6.84 (d, J = 9 Hz, 2H), 7.09 (d, J = 9 Hz, 2H), 7.13 (m, 1H), 7.26 (s, 1H), 7.32 (m,
1 H), 7.57 (d, J = 8 Hz, 1 H), 7.64 (d, J = 8 Hz, 1 H)
C. terf-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate
0.213 g (0.408 mmol) terf-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-2-
carboxylate is dissolved in 10 ml absolute methanol, mixed with 1.64 ml (0.82
mmol) of a 0.5M sodium methanolate solution and stirred at room temperature
for 15 min. Following concentration to half the volume on the rotary evaporator,
the batch is diluted with diethyl ether. Washing of the organic phase with semisaturated
and with saturated NaCI solution, drying on sodium sulfate, filtration
and reconcentration on the rotary evaporator leave as a crude product a
yellowish oil which is purified on silica gel by means of column chromatography
(flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a
yellowish oil.
Yield: 0.152 g (0.317 mmol); 78 %
C3oH4iNO4 (479.7)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.59 (m, 2H),
1.63 (s, 9H), 2.55 (t, J = 8 Hz, 2H), 3.62 (s broad, 1H), 3.99 (dd, J = 10 Hz and J
= 6 Hz, 1 H), 4.04 (dd, J = 1 0 Hz and J = 5 Hz, 1 H), 4.42 (m, 1 H), 4.76 (dd, J = 1 5
Hz and J = 7 Hz, 1H), 4.81 (dd, J = 15 Hz and J = 5 Hz, 1H), 6.86 (d, J = 9 Hz,
27
2H), 7.1.0 (d, J = 9 Hz, 2H), 7.14 (m, 1H), 7.29 (m, 2H), 7.48 (d, J = 8 Hz, 1H),
7.69(d,J = 8Hz,1H)
D. terf-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-2-carboxylate
1.02 g (10.0 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.120 g (0.250 mmol) terf-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-2-
carboxylate in 10 ml absolute DMSO. Having stirred for 8 hours, the solution is
poured into a mixture of 5 % sodium hydrogen carbonate solution and saturated
NaCI solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl
ether, combination of the organic phases, concentration to half the volume on the
rotary evaporator, three wash steps using saturated NaCI solution, drying on
sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a
crude product a yellow oil which is purified on silica gel by means of column
chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the
product as a yellowish oil.
Yield: 0.113 g (0.237 mmol); 95 %
C3oH39NO4 (477.6)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.58 (s, 9H),
1.61 (m, 2H), 2.57 (t, J = 8 Hz, 2H), 4.73 (s, 2H), 5.57 (s, 2H), 6.87 (d, J = 9 Hz,
2H), 7.11-7.14 (m, 4H), 7.30 (m, 2H), 7.68 (d, J = 8 Hz, 1H)
E. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-2-carboxylic acid
0.046 g (0.096 mmol) fe/?-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-2-
carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 1.49
g (13.6 mmol) trifluoroacetic acid. Having stirred at room temperature for 1 Vz
hours, concentration to dryness is carried out on the rotary evaporator. Two
.dissolution steps in toluene and respective concentration on the rotary
evaporator leave as a crude product a yellowish solid which is recrystallized from
petroleum ether/ethyl acetate (67:33) and yields the product as a white solid.
Yield: 0.031 g (0.074 mmol); 77 %
Mp.:173°C
C26H3iN04(421.5)
1H-NMR (DMSO-ofe): 5 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.23 (m, 10H), 1.50 (m,
2H), 2.48 (t, J = 8 Hz, 2H), 4.99 (s, 2H), 5.60 (s, 2H), 6.86 (d, J = 9 Hz, 2H), 7.07
(d, J = 9 Hz, 2H), 7.12 (m, 1H), 7.26 (s, 1H), 7.29 (m, 1H), 7.54 (d, J = 8 Hz, 1H),
7.68 (d, J = 8 Hz, 1H)
Example 8
1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-3-carboxylic acid
A. te/f-Butylindole-3-carboxylate
1.00 g (6.21 mmol) indole-3-carboxylic acid is dissolved in 150 ml absolute THF,
mixed with 0.05 g (0.68 mmol) absolute DMF as well as with 1.48 g (12.5 mmol)
thionylchloride and stirred at room temperature for 1 hour. Following the dropwise
addition of 2.51 g (24.8 mmol) tiethylamine and of 9.20 g (124 mmol) tertbutanol
and heating under reflux for 2 hours, hydrolysis of the cooled reaction
mixture is carried out in water. Three extractions with diethyl ether, concentration
to half the volume on the rotary evaporator, washing with 5 % sodium carbonate
solution and with saturated NaCI solution, drying on sodium sulfate, filtration and
reconcentration on the rotary evaporator leave as a crude product a brown oil
which is purified on silica gel by means of column chromatography (flow agent:
petroleum ether/ethyl acetate 90:10) and yields the product as a yellow oil.
Yield: 1.05 g (4.83 mmol); 78 %
Ci3H15NO2(217.3)
1H-NMR (CDCI3): 5 (ppm) = 1.65 (s, 9H), 7.25 (m, 2H), 7.39 (m, 1H), 7.85 (d, J =
3 Hz, 1H), 8.15(m, 1H), 8.84 (s, broad, 1H)
B. tert-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate
0.50 g (2.30 mmol) terf-butylindole-3-carboxylate is dissolved in 15 ml absolute
DMSO, mixed with 0.28 g (2.50 mmol) potassium-tert-butylate and stirred at
110°C for 15 min. A solution of 0.89 g (2.31 mmol) [1-bromo-3-(4-
octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO is added drop-wise.
Following heating at 110°C for 30 minutes and subsequent cooling, hydrolysis is
carried out in saturated NaCI solution. Four extractions with diethyl ether,
combination of the organic phases, concentration to half the volume on the rotary
evaporator, three wash steps with saturated NaCI solution, drying on sodium
sulfate, filtration and reconcentration on the rotary evaporator leave as a crude
product a yellow oil which is purified on silica gel by means of flash column
chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the
product as a yellowish oil.
Yield: 0.56 g (1.07 mmol); 47 %
C32H43NO5(521.7)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.57 (m, 2H),
1.61 (s, 9H), 2.05 (s, 3H), 2.55 (t, J = 8 Hz, 2H), 3.97 (d, J = 5 Hz, 2H), 4.51 (dd,
J = 9 Hz and J = 6 Hz, 1 H), 4.56 (dd, J = 9 Hz and J = 6 Hz, 1 H), 5.43 (m, 1 H),
6.83 (d, J = 9 Hz, 2H), 7.10 (d, J = 9 Hz, 2H), 7.24 (m, 2H), 7.45 (m, 1H), 7.75 (s,
1H), 8.14 (m, 1H)
C. tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate
0.293 g (0.562 mmol) tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-3-
carboxylate is dissolved in 20 ml absolute methanol, mixed with 2.24 ml (1.12
mmol) of a 0.5M sodium methanolate solution and stirred at room temperature
for 15 min. Following concentration to half the volume on the rotary evaporator,
the batch is diluted with diethyl ether. Washing of the organic phase with semisaturated
and with saturated NaCI solution, drying on sodium sulfate, filtration
and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Yield: 0.269 g (0.561 mmol); 100 %
C3oH4iNO4 (479.7)
1H-NMR (CDCl3): 5 (ppm) = 0.90 (t, J = 7 Hz, 3H), 1.30 (m, 10H), 1.59 (m, 2H),
1.63 (s, 9H), 2.56 (t, J = 8 Hz, 2H), 2.66 (s, broad, 1H), 3.89 (dd, J = 10 Hz and J
= 5 Hz, 1H), 3.95 (dd, J = 10 Hz and J = 5 Hz, 1H), 4.30 (dd, J = 14 Hz and J = 6
Hz, 1H), 4.37 (m, 1H), 4.45 (dd, J = 14 Hz and J = 4 Hz, 1H), 6.81 (d, J = 8 Hz,
2H), 7.09 (d, J = 8 Hz, 2H), 7.25 (m, 2H), 7.40 (m, 1H), 7.98 (s, 1H), 8.16 (m, 1H)
D. terf-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3-carboxylate
2.02 g (19.8 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.237 g (0.494 mmol) terf-butyi-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3-
carboxylate in 10 ml absolute DMSO. Having stirred for 2 hours, the solution is
poured into a mixture of 5 % sodium hydrogen carbonate and saturated NaCI
solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether,
combination of the organic phases, concentration to half the volume on the rotary
evaporator, three wash steps with saturated NaCI solution, drying on sodium
sulfate, filtration and reconcentration on the rotary evaporator leave as a crude
product a yellow oil which is purified on silica gel by means of flash column
chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the
product as a yellowish oil.
Yield: 0.160 g (0.335 mmol); 68 %
C3oH39NO4 (477.6)
1H-NMR (CDCb): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.30 (m, 10H), 1.59 (m, 2H),
1.62 (s, 9H), 2.58 (t, J = 8 Hz, 2H), 4.66 (s, 2H), 5.22 (s, 2H), 6.85 (d, J = 9 Hz,
2H), 7.08 (dd, J = 7 Hz and J = 2 Hz, 1H), 7.15 (d, J = 9 Hz, 2H), 7.24 (m, 2H),
7.71 (s, 1 H), 8.17 (dd, J = 6 Hz and J = 2 Hz, 1 H)
E. 1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-3-carboxylic acid
0.072 g (0.151 mmol) te/?-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3-
carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 1.56
g (13.7 mmol) trifluoroacetic acid. Having stirred at room temperature for 1 hour,
concentration to dryness is carried out on the rotary evaporator. Two dissolution
steps in toluene and respective concentration on the rotary evaporator leave as
the crude product a reddish solid which is recrystallized from petroleum
ether/ethyl acetate (67:33) and yields the product as a white solid.
Yield: 0.055 g (0.130 mmol); 86 %
Mp.: 182-183°C
C26H3iNO4(421.5)
1H-NMR (DMSO-ofe): 6 (ppm) = 0.84 (t, J = 7 Hz, 3H), 1.24 (m, 10H), 1.51 (m,
2H), 2.49 (t, J = 8 Hz, 2H), 5.00 (s, 2H), 5.46 (s, 2H), 6.88 (d, J = 9 Hz, 2H), 7.10
(d, J = 9Hz(2H),7.18(m, 2H), 7.44 (m, 1H), 7.97 (s, 1H), 8.00 (m, 1H)
Example 9
1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
32
C8H17'
A. te/t-Butylindole-5-carboxylate
0.50 g (3.10 mmol) indole-5-carboxylic acid is suspended in 20 ml absolute
benzene and heated under reflux. A solution of 2.80 g (12.39 mmol) 90 % N,Ndimethylformamidedi-
terf-butylacetal in 20 ml absolute benzene is added dropwise
within 30 min. Following another heating under reflux for 30 minutes and
subsequent cooling, the reaction mixture is diluted with diethyl ether, washed
with 5 % sodium carbonate solution and with saturated NaCI solution. Drying on
sodium sulfate, filtration and concentration on the rotary evaporator leave as a
crude product a yellow oil which is purified on silica gel by means of column
chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the
product as a white solid.
Yield: 0.214 g (0.98 mmol); 32 %
Mp.:91-93°C
Ci3H15NO2(217.3)
1H-NMR (CDCI3): 5 (ppm) = 1.63 (s, 9H), 6.64 (m, 1H), 7.26 (m, 1H), 7.38 (d, J =
9 Hz, 1 H), 7.87 (dd, 1 H, J = 9 Hz and J = 2 Hz), 8.36 (m, 1 H), 8.40 (s, broad, 1 H)
B. te/t-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate
0.077 g (1.93 mmol) sodium hydride as a 60 % dispersion in mineral oil is
suspended in 15 ml absolute DMF, stirred at room temperature for 10 min, mixed
with a solution of 0.400 g (1.84 mmol) te/f-butylindole-5-carboxylate in 15 ml
absolute DMF and stirred at room temperature for one hour. A solution of 0.483
g (1.84 mmol) 2-(4-octyl-phenoxymethyl)oxirane in 15 ml absolute DMF is added
drop-wise. Following four hours of heating at 60°C and subsequent cooling,
hydrolysis is carried out in a semi-saturated NaCI solution. Four extractions with
diethyl ether, combination of the organic phases, concentration to half the
volume on the rotary evaporator, three wash steps with saturated NaCI solution,
drying on sodium sulfate, filtration and reconcentration on the rotary evaporator
leave as a crude product a yellow oil which is purified on silica gel by means of
flash column chromatography (flow agent: petroleum ether/ethyl acetate 90:10)
and yields the product as a colorless oil.
Yield: 0.765 g (1.60 mmol); 87 %
C3oH4iNO4 (479.7)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.58 (m, 2H),
1.62 (s, 9H), 2.55 (t, J = 8 Hz, 2H), 3.83 (dd, J = 10 Hz and J = 5 Hz, 1H), 3.93
(dd, J = 10 Hz and J = 4 Hz, 1H), 4.33 (m, 2H), 4.42 (m, 1H), 6.60 (dd, J = 3 Hz
and J = 1 Hz, 1H), 6.80 (d, J = 9 Hz, 2H), 7.08 (d, J = 9 Hz, 2H), 7.20 (d, J = 3
Hz, 1 H), 7.37 (d, J = 9 Hz, 1 H), 7.86 (dd, J = 9 Hz and J = 2 Hz, 1 H), 8.33 (d, J =
2 Hz, 1H)
C. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate
5.33 g (52.2 mmol) acetic anhydride are mixed with 30 ml absolute DMSO,
stirred at room temperature for 10 min and added drop-wise to a solution of
0.626 g (1.31 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-
carboxylate in 20 ml absolute DMSO. Having stirred for 17 hours, the solution is
poured into a mixture of 5 % sodium hydrogen carbonate solution and saturated
NaCI solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl
ether, combination of the organic phases, concentration to half the volume on the
rotary evaporator, three wash steps with saturated NaCI solution, drying on
sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a
crude product a yellow oil which is purified on silica gel by means of flash column
chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the
product as a colorless oil.
Yield: 0.232 g (0.486 mmol); 37 %
CaoHagNCU (477.6)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.30 (m, 10H), 1.61 (m, 2H),
1.63 (s, 9H), 2.59 (t, J = 8 Hz, 2H), 4.64 (s, 2H), 5.21 (s, 2H), 6.68 (dd, J = 3 Hz
and J = 1 Hz, 1H), 6.84 (d, J = 9 Hz, 2H), 7.09 (d, J = 9 Hz, 1H and d, J = 3 Hz,
1H), 7.15 (d, J = 9 Hz, 2H), 7.87 (dd, J = 9 Hz and J = 2 Hz, 1H), 8.35 (dd, J = 2
HzandJ = 1 Hz, 1H)
D. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indo!e-5-carboxylic acid
0.222 g (0.465 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-
carboxylate is dissolved in 60 ml absolute dichloromethane and mixed with 3.98
g (34.9 mmol) trifluoroacetic acid. Having stirred at room temperature for 4 hours,
concentration to dryness is carried out on the rotary evaporator. Two admixtures
with hexane and respective concentration to dryness on the rotary evaporator
leave as a crude product a brownish solid which is purified on an RP-HPLC
column by means of chromatography (stationary phase: cromasil, mobile phase
acetonitrile/water 80:20) and yields the product as a white solid.
Yield: 0.134 g (0.318 mmol); 68 %
Mp.: 122-124°C
C26H3iNO4(421.5)
1H-NMR (CDCb): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.59 (m, 2H),
2.58 (t, J = 8 Hz, 2H), 4.66 (s, 2H), 5.25 (s, 2H), 6.71 (d, J = 3 Hz, 1 H), 6.85 (d, J
= 8 Hz, 2H), 7.14 (m, 4H), 7.96 (d, J = 9 Hz, 1H), 8.49 (s, 1H)
Example 10
1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-4-carbocylie acid
A. terf-Butylindol-4-carboxylate
The preparation is based on indol-4-carboxylic acid in analogy to the synthesis of
step A of Example 9.
Mp.: 96°C
Ci3Hi5N02(217.3)
1H-NMR (CDC!3): 6 (ppm) = 1.68 (s, 9H), 7.17-7.19 (m, 1H), 7.21-7.25 (m, 1H),
7.33-7.34 (m, 1H), 7.57 (d, J = 8 Hz, 1H), 7.88 (dd, J = 8 Hz and J = 1 Hz, 1H),
8.39(s,broad,1H)
B. terf-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-4-carboxylate
The preparation is based on tert-butylindole-4-carboxylate in analogy to the
synthesis of step B of Example 9. Deviating therefrom, the reaction time is only 3
h. Chromatographic purification is initially carried out on silica gel (flow agent
petroleum ether/ethyl acetate 85:15) and then on RP18 material (flow agent
acetonitrile/water 80:20). The product accrues as an oil.
C3oH4iNO4 (479.7)
'H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.56-1.64
(m, 2H), 1.67 (s, 9H), 2.38 (s, broad, 1H), 2.55 (t, J = 8 Hz, 2H), 3.83 (dd, J = 9
Hz and J = 5 Hz, 1H), 3.92 (dd, J = 9 Hz and J = 5 Hz, 1H), 4.34-4.38 (m, 2H),
4.47 (dd, J = 17 Hz and J = 8 Hz, 1H), 6.79 (d, J = 9 Hz, 2H), 7.08 (d, J = 8 Hz,
2H), 7.13 (d, J = 3 Hz, 1H), 7.20-7.24 (m, 1H), 7.27 (d, J = 3 Hz, 1H), 7.57 (dd, J
= 8 Hz and J = 1 Hz, 1 H), 7.86 (d, J = 7 Hz, 1 H)
C. terf-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-4-carboxylate
The preparation is based on terf-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyi]-
indole-4-carboxylate in analogy to the synthesis of step C of Example 9.
Deviating therefrom, the reaction time is only 15 h. The Chromatographic
purification is carried out on silica gel (flow agent petroleum ether/ethyl acetate
93:7). The product accrues as a solid.
Mp.: 100°C
CsoHagNCU (477.6)
1H-NMR (CDCIa): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.56-1.60
(m, 2H), 1.67 (s, 9H), 2.57 (t, J = 8 Hz, 2H), 4.61 (s, 2H), 5.22 (s, 2H), 6.82 (d, J
= 9 Hz, 2H), 7.14 (d, J = 9 Hz, 2H), 7.16 (d, J = 3 Hz, 1H), 7.20-7.22 (m, 2H),
7.24-7.28 (m, 1 H), 7.88 (dd, J = 7 Hz and J = 1 Hz, 1 H)
D. 1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-4-carboxylic acid
63 mg (0.13 mmol) ketone are dissolved in 15 ml absolute dichloromethane and
mixed with 1.12 g (9.82 mmol) trifluoroacetic acid. Stirring at room temperature
for 2 hours is followed by concentration to dryness on the rotary evaporator.
Three admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate
(1:2) each and respective concentration to dryness on the rotary evaporator
leave as a crude product a solid which is recrystallized from petroleum
ether/ethyl acetate (2:1).
Yield: 48 mg (0.11 mmol); 86 %
Mp.: 160-161 °C
C28H31NO4(421.5)
1H-NMR (CDCI3): 6 (ppmj = 0.89 (t, J = 7 Hz, 3H), 1.28-1.32 (m, 10H), 1.56-1.63
(m, 2H), 2.58 (t, J = 8 Hz, 2H), 4.64 (s, 2H), 5.26 (s, 2H), 6.84 (d, J = 9 Hz, 2H),
7.15 (d, J = 9 Hz, 2H), 7.22 (d, 1H), 7.25-7.29 (m, 1H), 7.31 (d, J = 3 Hz, 1H),
7.35 (d, J = 8 Hz, 1H), 8.02 (d, J = 7 Hz, 1H)
Example 11
1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid
A. tert-Butylindole-6-carboxylate
The preparation is based on indole-6-carboxylic acid in analogy to the synthesis
of step A of Example 9. The product is additionally recrystallized from petroleum
ether.
Mp.: 100-101°C
C13H15N02(217.3)
1H-NMR (CDCI3): 6 (ppm) = 1.63 (s, 9H), 6.59 (m, 1H), 7.35 (m, 1H), 7.63 (d, J =
8 Hz, 1H), 7.77 (dd, J = 8 Hz and J = 1 Hz, 1H), 8.13 (m, 1H), 8.55 (s, broad, 1H)
B. fe/f-Buty[-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-6-carboxylate
The preparation is based on fert-butylindole-6-carboxylate in analogy to the
synthesis of step B of Example 9. Deviating therefrom, the reaction time is 5 h.
The chromatographic purification is initially carried out on silica gel (flow agent:
petroleum ether/ethyl acetate 9:1) and then on RP18 material (flow agent
acetonitrile/water 4:1). The product accrues as an oil.
C3oH4iNO4 (479.7)
1H-NMR (CDCIa): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26-1.30 (m, 10H), 1.56-1.60
(m, 2H), 1.62 (s, 9H), 2.45 (s, broad, 1H), 2.54 (t, J = 8 Hz, 2H), 3.84 (dd, J = 10
Hz and J = 5 Hz, 1H), 3.93 (dd, J = 10 Hz and J = 4 Hz, 1H), 4.33-4.37 (m, 2H),
4.48 (dd, J = 17 Hz and J = 8 Hz, 1H), 6.54 (dd, J = 3 Hz and J = 1 Hz, 1H), 6.80
(d, J = 9 Hz, 2H), 7.08 (d, J = 9 Hz, 2H), 7.30 (d, J = 3 Hz, 1H), 7.61 (d, J = 8 Hz,
1H),
7.75 (dd, J = 8 Hz and J = 1 Hz, 1 H), 8.11 (m, 1 H)
C. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylate
The preparation is based on tetf-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]-
indole-6-carboxylate in analogy to the synthesis of step C of Example 9.
Deviating therefrom, the reaction time is only 16 h. The product accrues as an
oil.
C3oH39NO4 (477.6)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.57-1.62
(m, 2H), 1.62 (s, 9H), 2.57 (t, J = 8 Hz, 2H), 4.64 (s, 2H), 5.28 (s, 2H), 6.62 (dd, J
= 3 Hz and J = 1 Hz, 1H), 6.84 (d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 7.16 (d,
J = 3 Hz, 1H), 7.63 (dd, J = 8 Hz and J = 1 Hz, 1 H), 7.74 (dd, J = 8 Hz and J = 1
Hz,1H),
7.89 (m,1H)
D. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid
59 mg (0.12 mmol) te/f-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-
carboxylate are dissolved in 15 ml absolute dichloromethane and mixed with
1.05 g (9.20 mmol) trifluoroacetic acid. After stirring at room temperature for 2 Vz
hours, concentration to dryness is carried out on the rotary evaporator. Three
admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate (1:2)
each and respective concentration to dryness on the rotary evaporator leave as
a crude product a solid which is purified on an RP-HPLC column (stationary
phase: cromasil, mobile phase: acetonitrile/water 9:1) by means of
chromatography.
Yield: 30 mg (0.07 mmol); 57 %
Mp.: 180°C
C26H3iNO4(421.5)
1H-NMR (DMSO-cfe): 5 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.21-1.27 (m, 10H), 1.48-
1.62 (m, 2H), 2.48 (t, J = 8 Hz, 2H), 5.00 (s, 2H), 5.48 (s, 2H), 6.55 (dd, J = 3 Hz
and J = 1 Hz, 1H), 6.86 (d, J = 9 Hz, 2H), 7.08 (d, J = 9 Hz, 2H), 7.46 (d, J = 3
Hz, 1H), 7.58-7.62 (m, 2H), 8.06 (d, J = 1 Hz, 1H)
Example 12
1-(5-Methylindol-1-yl)-3-(4-octylphenoxy)propan-2-one
A. 1 -(5-Methylindole-1 -yl)-3-(4-octy!phenoxy)propan-2-ol
The preparation is based on 5-methylindole in analogy to the synthesis of step B
of Example 9. Deviating therefrom, the reaction is carried out at room
temperature. The reaction time is 23 h. The chromatographic purification is
carried out on silica gel (flow agent: petroleum ether/ethyl acetate 95:5). The
product accrues as an oil.
C26H35NO2 (393.6)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.54-1.58
(m, 2H), 2.36 (s, broad, 1 H), 2.45 (s, 3H), 2.55 (t, J = 8 Hz, 2H), 3.85 (dd, J = 10
Hz and J = 5 Hz, 1H), 3.98 (dd, J = 10 Hz and J = 4 Hz, 1H), 4.31 (dd, J = 12 Hz
and J = 7 Hz, 1H), 4.33-4.38 (m, 1H), 4.40 (dd, J = 12 Hz and J = 5 Hz), 6.42
(dd, J = 3 Hz and J = 1 Hz, 1 H), 6.81 (d, J = 9 Hz, 2H), 7.03 (dd, J = 8 Hz and J
= 1 Hz, 1 H), 7.08 (d, J = 9 Hz, 2H), 7.09 (d, J = 3 Hz, 1 H), 7.29 (d, J = 8 Hz, 1 H),
7.41 (m, 1H)
B. 1-(5-Methylindole-1-yl)-3-(4-octylphenoxy)propan-2-one
The preparation is based on 1-(5-methylindole-1-yl)-3-(4-octylphenoxy)propan-2-
ol in analogy to the synthesis of step C of Example 9. Deviating therefrom, the
reaction time is 19 h. The chromatographic purification on silica gel is carried out
with the flow agent petroleum ether/ethyl acetate 97:3. The product accrues as a
solid.
M.: 75°C
C26H33NO2(391.6)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.55-1.59
(m, 2H), 2.44 (s, 3H), 2.56 (t, J = 8 Hz, 2H), 4.57 (s, 2H), 5.12 (s, 2H), 6.51 (d; J
= 3 Hz, 1H), 6.79 (d, J = 9 Hz, 2H), 7.00-7.02 (m, 3H), 7.11 (d, J = 9 Hz, 2H),
7.42-7.43 (m, 1H)
Example 13
1 -(5-Chloroindol-1 -yl)-3-(4-octylphenoxy)propan-2-one
A. 1 -(5-Chloroindol-1 -yl)-3-(4-octylphenoxy)propan-2-ol
The preparation is based on 5-chloroindole in analogy to the synthesis of step B
of Example 9. Deviating therefrom, the reaction is carried out at room
temperature. The reaction time is 17 h. The chromatographic purification on
silica gel is carried out with the flow agent petroleum ether/ethyl acetate 95:5.
The product accrues as an oil.
C25H32CINO2(414.0)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26-1.31 (m, 10H), 1.55-1.59
(m, 2H), 2.36 (s, broad, 1H), 2.55 (t, J = 8 Hz, 2H), 3.83 (dd, J = 10 Hz and J = 5
Hz, 1H), 3.92 (dd, J = 10 Hz and J = 4 Hz, 1H), 4.27-4.42 (m, 3H), 6.45 (dd, J = 3
Hz and J = 1 Hz, 1 H), 6.80 (d, J = 9 Hz, 2H), 7.09 (d, J = 9 Hz, 2H), 7.13 (dd, J =
9 Hz and J = 2 Hz, 1 H), 7.16 (d, J = 3 Hz, 1 H), 7.30 (d, J = 9 Hz, 1 H), 7.58 (d, J
= 2Hz,1H)
B. 1 -(5-Chloroindol-1 -yl)-3-(4-octylphenoxy)propan-2-one
The preparation is based on 1-(5-chloroindol-1-yl)-3-(4-octylphenoxy)propan-2-ol
in analogy to the synthesis of step C of Example 9. Deviating therefrom, the
reaction time is 16 h. The product accrues as a solid and is recrystallized from
petroleum ether.
Mp.: 77°C
C25H3oCIN02(412.0)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.28-1.32 (m, 10H), 1.56-1.60
(m, 2H), 2.57 (t, J = 8 Hz, 2H), 4.61 (s, 2H), 5.17 (s, 2H), 6.52 (dd, J = 3 Hz and J
= 1 Hz, 1H), 6.82 (d, J = 9 Hz, 2H), 6.99 (d, J = 9 Hz, 1H), 7.05 (d, J = 3 Hz, 1H),
7.12-7.15 (m, 3H), 7.60 (d, J = 2 Hz, 1 H)
Example 14
1-(5-Methoxyindol-1-yl)-3-(4-octylphenoxy)propan-2-one
A. 1 -(5-Methoxyindol-1 -y!)-3-(4-octylphenoxy)propan-2-ol
The preparation is based on 5-methoxyindole in analogy to the synthesis of step
B of Example 9. Deviating therefrom, the reaction is carried out at room
temperature and in the absence of light. The reaction time is 17 h. The
chromatographic purification is carried out on silica gel (flow agent: petroleum
ether/ethyl acetate 93:7). The product accrues as an oil.
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.55-1.59
(m, 2H), 2.35 (d, J = 5 Hz, 1 H), 2.55 (t, J = 8 Hz, 2H), 3.84 (dd, J = 1 0 Hz and J =
5 Hz, 1 H), 3.85 (s, 3H), 3.91 (dd, J = 10 Hz and J = 4 Hz, 1 H), 4.27-4 .40 (m, 3H),
6.43 (dd, J = 3 Hz and J = 1 Hz, 1H), 6.80 (d, J = 9 Hz, 2H), 6.86 (dd, J = 9 Hz
and J = 3 Hz, 1 H), 7.08 (d, J = 9 Hz, 2H), 7.09 (d, J = 3 Hz, 1 H), 7.1 1 (d, J = 3
Hz, 1H), 7.28 (d, J = 9 Hz, 1H)
B. 1 -(5-Methoxyindol-1 -yl)-3-(4-octylphenoxy)propan-2-one
The preparation is based on 1-(5-methoxyindol-1-yl)-3-(4-octylphenoxy)propan-
2-ol in analogy to the synthesis of step C of Example 9. Deviating therefrom, the
reaction time is 18 h. The reaction is carried in the absence of light. The product
accrues as a solid.
Mp.: 85°C
C26H33NO3 (407.6)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.55-1.57
(m, 2H), 2.56 (t, J = 8 Hz, 2H), 3.85 (s, 3H), 4.56 (s, 2H), 5.12 (s, 2H), 6.51 (dd, J
= 3 Hz and J = 1 Hz, 1 H), 6.80 (d, J = 9 Hz, 2H), 6.86 (dd, J = 9 Hz and J = 2 Hz,
1H), 7.01 (d, J = 9 Hz, 1H), 7.02 (d, J = 3 Hz, 1H), 7.10 (d, J = 2 Hz, 1H), 7.12 (d,
J = 9 Hz, 2H)
41
Example 15
1-(3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbonitrile
A. 1 -[2-Hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile
The preparation is based on indole-5-carbonitrile in analogy of the synthesis of
step B of Example 9. Deviating therefrom, the reaction time is 5 h. The
chromatographic purification is initially carried out on silica gel (flow agent:
dichloromethane) and then on RP18 material (flow agent acetonitrile/water
75:25). The product accrues as an oil.
C26H32N2O2 (404.5)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.28-1.32 (m, 10H), 1.55-1.61
(m, 2H), 2.47 (s, broad, 1H), 2.56 (t, J = 8 Hz, 2H), 3.85 (dd, J = 9 Hz and J = 5
Hz, 1H), 3.95 (dd, J = 9 Hz and J = 4 Hz, 1H), 4.33-4.39 (m, 2H), 4.47 (dd, J = 17
Hz and J = 7 Hz, 1H), 6.60 (dd, J = 3 Hz and J = 1 Hz, 1H), 6.83 (d, J = 9 Hz,
2H), 7.1 1 (d, J = 9 Hz, 2H), 7.29 (d, J = 3 Hz, 1 H), 7.41 (dd, J = 9 Hz and J = 2
Hz, 1 H), 7.46 (d, J = 9 Hz, 1 H), 7.97 (s, 1 H)
B. 1 -(3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbonitrile
The preparation is based on 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-
carbonitrile in analogy to the synthesis of step C of Example 9. Deviating
therefrom, the reaction time is 15 h. The chromatographic purification on silica
gel is carried out with the flow agent petroleum ether/ethyl acetate 90:10. The
product accrues as a solid and is recrystallized from petroleum ether/ethyl
acetate 95:5.
Mp.: 96°C
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1 .28-1 .32 (m, 10H), 1 .58-1 .62
(m, 2H), 2.59 (t, J = 8 Hz, 2H), 4.67 (s, 2H), 5.27 (s, 2H), 6.67 (dd, J = 3 Hz and J
= 1 Hz, 1 H), 6.85 (d, J = 9 Hz, 2H), 7.1 1 (d, J = 9 Hz, 1 H), 7.1 4 (d, J = 3 Hz, 1 H),
7.16 (d, J = 9 Hz, 2H), 7.41 (dd, J = 9 Hz and J = 2 Hz, 1H), 7.99 (dd, J = 2 Hz
andJ = 1Hz,
Example 16
1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbaldehyde
A. 1 -[2-Hydroxy-3-(4-octylphenoxy)propy!]indole-5-carbaldehyde
The preparation is based on indole-5-carbaldehyde in analogy to the synthesis of
step B of Example 9. The chromatographic purification is initially carried out on
silica gel (flow agent: dichloromethane) and then on RP18 material (flow agent:
acetonitrile/water 4:1). The product accrues as a solid.
M.: 79°C
'H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26-1.30 (m, 10H), 1.55-1.59
(m, 2H), 2.44 (s, broad, 1 H), 2.55 (t, J = 8 Hz, 2H), 3.86 (dd, J = 10 Hz and J = 5
Hz, 1H), 3.96 (dd, J = 10 Hz and J = 4 Hz, 1H), 4.34-4.40 (m, 2H), 4.48 (dd, J =
17 Hz and J = 7 Hz, 1H), 6.68 (dd, J = 3 Hz and J = 1 Hz, 1H), 6.80 (d, J = 9 Hz,
2H), 7.09 (d, J = 9 Hz, 2H), 7.26 (d, J = 3 Hz, 1H), 7.48 (d, J = 9 Hz, 1H), 7.76
(dd, J = 9 Hz and J = 2 Hz, 1H), 8.14 (d, J = 1 Hz, 1H), 10.00 (s, 1H)
B. 1 -(3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbaldehyde
The preparation is based on 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-
carbaldehyde in analogy to the synthesis of step C of Example 9. Deviating
therefrom, the reaction time is 16 h. The chromatographic purification on silica
gel is carried out with the flow agent petroleum ether/ethyl acetate 9:1. The
product accrues as a solid.
Mp.: 96°C
C26H3iN03 (405.5)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.28-1.32 (m, 10H), 1.59-1.63
(m, 2H), 2.58 (t, J = 8 Hz, 2H), 4.67 (s, 2H), 5.26 (s, 2H), 6.74 (dd, J = 3 Hz and J
= 1 Hz, 1H), 6.85 (d, J = 9 Hz, 2H), 7.12 (d, J = 3 Hz, 1H), 7.15 (d, J = 9 Hz, 2H),
7.16 (d, J = 9 Hz, 1H), 7.76 (dd, J = 9 Hz and J = 1 Hz, 1H), 8.16-8.17 (m, 1H),
10.02(s, 1H)
Example 17
Methyl-1-(3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate
43
A. Methyl- 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate
The preparation is based on methylindole-5-carboxylate in analogy to the
synthesis of step B of Example 9. Deviating therefrom, the reaction time is 6 h.
The product accrues as a solid.
Mp.: 58°C
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1 .27-1 .30 (m, 10H), 1 .55-1 .59
(m, 2H), 2.41 (s, broad, 1H), 2.55 (t, J = 8 Hz, 2H), 3.85 (dd, J = 10 Hz and J = 5
Hz, 1H), 3.93 (s, 3H), 3.95 (dd, J = 10 Hz and J = 5 Hz, 1H), 4.33-4.39 (m, 2H),
4.43-4.49 (m, 1H), 6.61 (dd, J = 3 Hz and J = 1 Hz, 1H), 6.80 (d, J = 9 Hz, 2H),
7.09 (d, J = 9 Hz, 2H), 7.22 (d, J = 3 Hz, 1 H), 7.40 (d, J = 9 Hz, 1 H), 7.90 (dd, J =
9 Hz and J = 2 Hz, 1 H), 8.39 (m, 1 H)
B. Methyl- 1 -(3-(4-octylphenoxy)-2-oxopropyl]indoie-5-carboxylate
The preparation is based on methyl- 1-[2-hydroxy-3-(4-octylphenoxy)propyl]-
indole-5-carboxylate in analogy to the synthesis of step C of Example 9.
Deviating therefrom, the reaction time is 1 9 h. The product accrues as a solid
and is recrystallized (without chromatographic purification) from petroleum
ether/ethyl acetate 94:6.
Mp.:118°C
C27H33NO4 (435.6)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.31 (m, 10H), 1.57-1.60
(m, 2H), 2.57 (t, J = 8 Hz, 2H), 3.92 (s, 3H), 4.63 (s, 2H), 5.22 (s, 2H), 6.67 (dd, J
= 3 Hz and J = 1 Hz, 1H), 6.83 (d, J = 9 Hz, 2H), 7.08-7.10 (m, 2H), 7.14 (d, J =
9 Hz, 2H), 7.89 (dd, J = 9 Hz and J = 2 Hz, 1 H), 8.39 (m, 1 H)
Example 18
3-tert-Buty!-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
44
The compound accrues in the synthesis of 1 -[3-(4-octylphenoxy)-2-
oxopropyl]indole-5-carboxylic acid (Example 10) as a by-product and can be
separated therefrom in the purification by means of RP-HPLC.
Mp.: 146-147°C
C3oH39NO4 (477.6)
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 6 Hz, 3H), 1.26-1.30 (m, 10H), 1.46 (s,
9H), 1.56-1-60 (m, 2H), 2.57 (t, J = 8 Hz, 2H), 4.62 (s, 2H), 5.15 (s, 2H), 6.82 (m,
3H), 7.09 (d, J = 9 Hz, 1H), 7.14 (d, J = 9 Hz, 2H),.7.93 (dd, J = 8 Hz and J = 1
Hz, 1H), 8.65 (s, 1H)
Example 19
3-Chloro-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
A. te/f-Butyl-3-chloroindole-5-carboxylate
A solution of 389 mg (1.79mmol) te/t-butylindole-5-carboxylate in 12ml
methanol is mixed with 335 mg (2.50 mmol) A/-chlorosuccinimide and stirred at
room temperature overnight. The methanol is removed by rotation and the
resulting residue is taken up in 15 ml ethyl acetate. The organic phase is washed
twice with 1M sodium hydrogen carbonate solution, dried on sodium sulfate and
concentrated by rotation. Column chromatographic processing of the residue on
silica gel (flow agent: hexane/ethyl acetate 9:1) yields a solid.
Yield: 190 mg (0.76 mmol); 42%).
Ci3H14CIN02 (251.1)
Mp.: 120°C
1H-NMR (CDCI3): 6 (ppm) = 1.64 (s, 9H), 7,22 (d, J = 1 Hz, 1H), 7.35 (d, J = 9
Hz, 1H), 7.90 (d, J = 9 Hz, 1H), 8.33 (d, J = 1 Hz, 1H), 8.39 (s, 1H)
B. te/t-Butyl-3-chloro-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate
The preparation is based on terf-butyl-3-chloroindole-4-carboxylate in analogy to
the synthesis of step B of Example 9. Deviating therefrom, the reaction time is 8
h. The chromatographic purification on silica gel is carried out with
dichloromethane as flow agent. The product accrues as an oil.
C3oH4oCINO4(514.1)
1H-NMR (CDCI3): 5 (ppm) = 0.86 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.59 (m, 2H),
1.63 (s, 9H), 2.53 (s, broad, 1H), 2.56 (t, J = 8 Hz, 2H), 3.83 (dd, J = 10 Hz and J
= 5 Hz, 1H), 3.93 (m, 1H), 4.28-4.40 (m, 2H), 4.28-4.40 (m, 3H), 6.79 (d, J = 9
Hz, 2H), 7.09 (d, J = 9 Hz, 2H), 7.21 (s, 1H), 7.36 (d, J = 9 Hz, 1H), 7.88 (dd, J =
9 Hz and J = 2 Hz, 1H), 8.30 (d, J = 2 Hz, 1H)
C. terf-Butyl-3-chloro-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate
The preparation is based on terf-butyl-3-chloro-1-[2-hydroxy-3-(4-octylphenoxy)-
propyl]indole-5-carboxylate in analogy to the synthesis of step C of Example 9.
The chromatographic purification on silica gel is carried out by means of the flow
agent petroleum ether/ethyl acetate 9:1. The product accrues as an oil.
C3oH38CIN04(512.1)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.26 (m, 10H), 1.59 (m, 2H),
1.64 (s, 9H), 2.58 (t, J = 8 Hz, 2H), 4.66 (s, 2H), 5.18 (s, 2H), 6.84 (d, J = 8 Hz,
2H), 7.06 (m, 2H), 7.16 (d, J = 8 Hz, 2H), 7.94 (d, J = 9 Hz, 1H), 8.31 (s, 1 H)
D. 3-Chloro-1 -[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
The preparation is based on te/?-butyl-3-chloro-1-[3-(4-octylphenoxy)-2-
oxopropyl]indole-5-carboxylate in analogy to the synthesis of step D of Example
9. The product accrues as a solid and is recrystallized (without chromatographic
purification) from hexane/tetrahydrofurane.
Mp.: 157°C
C26H3oCIN04 (456.0)
1H-NMR (CDCIa): 6 (ppm) = 0.88 (t, J = 6 Hz, 3H), 1.28 (m, 10H), 1.62 (m, 2H),
2.58 (t, J = 8 Hz, 2H), 4.68 (s, 2H), 5.22 (s, 2H), 6.91 (d, J = 8 Hz, 2H), 7.09 (m,
2H), 7.16 (d, J = 8 Hz, 2H), 7.97 (d, J = 9 Hz, 1H), 8.47 (s, 1H)
Example 20
3-Formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylicacid
A. te/f-Butyl-3-formylindole-5-carboxylate
0.4 ml (4.87 mmol) oxalylchloride are dissolved in a three-neck flask under
nitrogen in 15 ml absolute dichloromethane and cooled to 0°C. Thereafter, 0.4 ml
absolute dimethylformamide dissolved in 15ml absolute dichloromethane is
added. The mixture is stirred on ice cooling for 20 minutes, gas generation and
the formation of a colorless precipitate being observed. Then, 1.00 g (4.64 mmol)
te/f-butylindole-5-carboxylate is added and the reaction mixture is allowed to
heat to room temperature. Stirring is continued for another 20 min, the
suspension is transferred using tetrahydrofurane to a round flask and
concentrated on a rotary evaporator. The residue is taken up in 40 ml
tetrahydrofurane, mixed with 50 ml 20 % sodium acetate solution and heated
under reflux for 30 minutes. After cooling down, 30 ml 5 % sodium hydrogen
carbonate solution are added, extracted three times using ethyl acetate, the
volume of the combined organic phases is concentrated to about 150 ml and
washed with saturated NaCI solution. The organic phase is dried on sodium
sulfate and the solvent is removed on the rotary evaporator. Recrystallization of
the crude product from n-hexane/ethyl acetate supplies the product as a solid.
Yield: 0.81 g (3.30 mmol); 71 %
Ci4H15NO3 (245.3)
Mp.: 190°C
1H-NMR (DMSO-c/e): 5 (ppm) = 1.55 (s, 9H), 7.56 (dd, J = 9 Hz and J = 1 Hz,
1H), 7.81 (dd, J = 9 Hz and J = 2 Hz, 1H), 8.39 (d, J = 3 Hz, 1H), 8.67 (d, J = 2
Hz, 1H), 9.94 (s, broad, 1H), 12.40 (s, broad, 1H)
B. tert-Butyl-3-formyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate
The preparation is based on te/?-butyl-3-formylindole-5-carboxylate in analogy to
the synthesis of step B of Example 9. Deviating therefrom, the reaction batch is
heated to 120°C for 12 hours. The chromatographic purification on silica gel is
carried out using petroleum ether/ethyl acetate 3:2 as flow agent. The product
accrues as an oil.
C3iH4iNO5 (507.7)
'H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27 (m, 10H), 1.59 (m, 2H),
1.63 (s, 9H), 2.55 (t, J = 8 Hz, 2H), 3.07 (s, broad, 1H), 3.98 (m, 2H), 4.37 (dd, J
= 14 Hz and J = 7 Hz, 1H), 4.51 (m, 1H), 4.54 (dd, J = 14 Hz and J = 4 Hz, 1H),
6.82 (d, J = 9 Hz, 2H), 7.10 (d, J = 9 Hz, 2H), 7.41 (d, J = 9 Hz, 1H), 7.86 (s, 1H),
7.94 (d, J = 9 Hz, 1H), 8.81 (s, 1H), 9.86 (s, 1H)
C. tert-Butyl-3-formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate
The preparation is based on terf-butyl-3-formyl-1-[2-hydroxy-3-(4-octylphenoxy)-
propyl]indole-5-carboxylate in analogy to the synthesis of step C of Example 9.
Deviating therefrom, the reaction time is 20 h. The chromatographic purification
on silica gel is carried out using the flow agent petroleum ether/ethyl acetate 3:2.
The product accrues as an oil.
CaiHagNOs (505.3)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.63 (m, 11H),
2.58 (t, J = 8 Hz, 2H), 4.71 (s, 2H), 5.33 (s, 2H), 6.87 (d, J = 8 Hz, 2H), 7.08 (d, J
= 9 Hz, 1H), 7.17 (d, J = 8 Hz, 2H), 7.72 (s, 1H), 7.95 (d, J = 9 Hz, 1H), 8.92 (s,
1H), 10.05(s, 1H)
D. 3-Formyl-1 -[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
The preparation is based on fe/f-butyl-3-formyl-1-[3-(4-octylphenoxy)-2-
oxopropyl]indole-5-carboxylate in analogy to the synthesis of step D of Example
9. Deviating therefrom, the reaction time is only 3 h. The chromatographic
purification by means of RP-HPLC is carried out with the flow agent
acetonitrile/water 9:1. The product accrues as a solid
Mp.:193°C
C27H3iNO5 (449.5)
1H-NMR (DMSO-ofe): 5 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.24 (m, 10H), 1.51 (m,
2H), 2.51 (t, J = 8 Hz, 2H), 5.03 (s, 2H), 5.58 (s, 2H), 6.90 (d, J = 9 Hz, 2H), 7.11
(d, J = 9 Hz, 2H), 7.60 (d, J = 9 Hz, 1H), 7.86 (dd, J = 9 Hz and J = 2 Hz, 1H),
8.29 (s, 1 H), 8.74 (d, J = 2 Hz, 1 H), 9.97 (s, 1 H)
Example 21
3-Acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylicacid
A. Methyl-3-acetylindole-5-carboxylate
In a three-neck flask, 4.20 ml (9.25 mmol) of a 2.2 M ZnCI2 solution in 20 ml
absolute dichloromethane is charged under nitrogen and the solution is cooled to
0°C using an ice bath. Thereafter, 5.62 ml (8.99 mmol) of a 1.6 M n-butyllithium
solution are slowly added drop-wise. The reaction mixture is heated to room
temperature, stirred for 1 hour, then admixed with the solution of 1.50 g
(8.56 mmol) methylindole-5-carboxylate in 20 ml absolute dichloromethane and
stirred again at room temperature for one hour. Thereafter, the batch is cooled to
0°C and 1.28 ml (18.1 mmol) acetylchloride is carefully added so as to form an
orange suspension. The latter is stirred at room temperature for 1 hour. Then,
0.93 g (7.02 mmol) aluminum chloride is added. After another hour of stirring at
room temperature, hydrolysis with semi-saturated NaCI solution is carried out
and 100 ml ethyl acetate and 20 ml tetrahydrofurane are added. Three
extractions are carried out using ethyl acetate, the combined organic phases are
washed with saturated NaCI solution and the organic phase is dried on sodium
sulfate. The solvent is distilled off. Chromatographic purification of the residue on
silica gel (flow agent: hexane/ethyl acetate 3:2) yields the product as a solid.
Yield: 0.70 g (3.23 mmol); 38 %
Mp.: 235-236°C.
C12HnNO3(217.2)
1H-NMR (DMSO-ofe): 5 (ppm) = 2.49 (s, 3H), 3.87 (s, 3H), 7.53 (dd, J = 9 Hz and
J = 1 Hz, 1H), 7.82 (dd, J = 9 Hz and J = 2 Hz, 1H), 8.43 (d, J = 3 Hz, 1H), 8.85
(d, J = 1 Hz, 1H), 12.23 (s, broad, 1H)
B. 3-Acetylindole-5-carboxylic acid
0.686 g (3.16 mmol) methyl-3-acetylindole-5-carboxylate are dissolved under
heat in 10 ml tetrahydrofurane and 10 ml ethylene glycol and mixed with 7.08 g
(0.13 mol) potassium hydroxide. Having stirred under reflux for 30 minutes, the
reaction mixture is cooled to room temperature. The tetrahydrofurane is removed
on the rotary evaporator and the solution is acidified under ice cooling with 20 ml
6N hydrochloric acid. The precipitated light violet precipitate is sucked off and
dried.
Yield: 0.64 g (3.16 mmol)
Mp.: 364°C.
Cn Ho, NO3 (203.2)
1H-NMR (DMSO-c/e): 6 (ppm) = 2.47 (s, 3H), 7.50 (dd, J = 9 Hz and J = 1 Hz,
1H), 7.86 (dd, J = 9 Hz and J = 2 Hz, 1H), 8.41 (d, 1H), 8.82 (d, 1H), 12.17 (s,
broad, 1H), 12.57 (s, broad, 1H)
C. terf-Butyl-3-acetylindole-5-carboxylate
The preparation is based on 3-acetylindole-5-carboxylic acid in analogy to the
synthesis of step A of Example 9. The chromatographic purification on silica gel
is carried out with hexane/ethyl acetate 3:2 as flow agent.
Mp.:214°C
C15H17NO3 (259.1)
1H-NMR (DMSO-ofc): 5 (ppm) =1.56 (s, 9H), 2.46 (s, 3H), 7.50 (d, J = 8 Hz, 1H),
7.76 (d, J = 8 Hz, 1H), 8.40 (s, 1H), 8.78 (s, 1H), 12.17 (s, broad, 1H)
D. te/f-Butyl-3-acetyl-1 -[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate
The preparation is based on te/f-butyl-3-acetylindole-5-carboxylate in analogy to
the synthesis of step B of Example 9. Deviating therefrom, the reaction batch is
heated at 120°C for 26 h. The chromatographic purification on silica gel is
carried out using petroleum ether/ethyl acetate 3:2 as flow agent. The product
accrues as an oil.
C32H43N05(521.7)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.57 (m, 2H),
1.64 (s, 9H), 2.31 (s, 3H), 2.34 (s, broad, 1H), 2.55 (t, J = 8 Hz, 2H), 3.99 (m,
2H), 4.32 (dd, J = 14 Hz and J = 7 Hz, 1 H), 4.50 (m, 1 H), 4.53 (dd, J = 12 Hz and
J = 4 Hz, 1H), 6.75 (d, J = 9 Hz, 2H), 7.10 (d, J = 9 Hz, 2H), 7.38 (d, J = 9 Hz,
1 H), 7.83 (s, 1 H), 7.88 (dd, J = 7 Hz and J = 3 Hz, 1 H), 8.84 (d, J = 3 Hz, 1 H)
E. terf-Butyl-3-acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate
The preparation is based on tert-butyl-3-acetyl-1-[2-hydroxy-3-(4-octylphenoxy)-
propyl]indole-5-carboxylate in analogy to the synthesis of step C of Example 9.
The chromatographic purification on silica gel is carried out using the flow agent
petroleum ether/ethyl acetate 17:3. The product accrues as an oil.
C32H4iNO5(519.3)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.30 (m, 10H), 1.58 (m, 2H),
1.62 (s, 9H), 2.53 (s, 3H), 2.59 (t, J = 8 Hz, 2H), 4.69 (s, 2H), 5.29 (s, 2H), 6.86
(d, J = 7 Hz, 2H), 7.07 (d, J = 9 Hz, 1H), 7.17 (d, J = 7 Hz, 2H), 7.71 (s, 1H), 7.92
(dd, J = 9 Hz and J = 2 Hz, 1H), 9.00 (d, J = 2 Hz, 1H)
F. 3-Acetyl-1 -[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
The preparation is based on terf-butyl-3-acetyl-1-[3-(4-octylphenoxy)-2-
oxopropyl]indole-5-carboxylate in analogy to the synthesis of step D of Example
9. The product accrues as a solid and is recrystallized (without chromatographic
purification) from hexane/tetrahydrofurane.
Mp.: 197°C
1H-NMR (DMSO-ofe): 5 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.23 (m, 10H), 1.51 (m,
2H), 2.47 (m, 2H), 2.51 (s, 3H), 5.03 (s, 2H), 5.53 (s, 2H), 6.89 (d, J = 8 Hz, 2H),
7.10 (d, J = 8 Hz, 2H), 7.56 (d, J = 9 Hz, 1H), 7.81 (dd, J = 9 Hz and J = 1 Hz,
1H), 8.33 (s, 1H), 8.83 (d, J = 1 Hz, 1H)
Example 22
3-Methoxycarbonyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic
acid
A. 5-te/?-Butyl-3-methylindole-3,5-dicarboxylate
0.70 g (14.3 mmol) sodium cyanide is added to a solution of 0.70 g (2.83 mmol)
terf-butyl-3-formylindole-5-carboxylate in 30 ml methanol. A yellow solution forms
which is admixed spatula-wise with 4.92 g (57.2 mmol) activated brownstone.
Stirring is carried out at room temperature for 48 hours. Having added 80 ml
dichloromethane and 5 g Celite, the black suspension is sucked off on a suction
filter, the residue is washed with dichloromethane and the filtrate is extracted by
shaking for complexing excess cyanide ions with a freshly prepared iron(ll)
sulfate solution. The organic phase is washed with saturated NaCI solution, dried
on sodium sulfate and concentrated. The product is obtained as a solid.
Yield: 0.743 g (2.69 mmol); 94 %
Mp: 196°C.
Ci5H17N04 (275.3)
1H-NMR (CDCI3): 6 (ppm) = 1.58 (s, 9H), 3.94 (s, 3H), 7.42 (d, J = 9 Hz, 1H),
7.92 (d, 1H), 7.99 (d, 1H), 8.84 (d, J = 1 Hz, 1H), 9.36 (s, broad 1H)
B. 5-terf-Butyl-3-methyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3,5-
dicarboxylate
The preparation is based on 5-tert-butyl-3-methylindole-3,5-dicarboxylate in
analogy to the synthesis of step B of Example 9. Deviating therefrom, the
reaction batch is heated at 120°C for 14 h. The chromatographic purification on
silica gel is carried using petroleum ether/ethyl acetate 7:3 as flow agent. The
product accrues as an oil.
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.28 (m, 10H), 1.57 (m, 2H),
1.62 (s, 9H), 2.55 (t, J = 8 Hz, 2H), 2.78 (s, broad, 1H), 3.90 (m, 4H), 3.96 (dd,
1H), 4.37 (m, 2H), 4.47 (dd, J = 10 Hz and J = 4 Hz, 1H), 6.80 (d, J = 7 Hz, 2H),
7.10 (d, J = 7 Hz, 2H), 7.40 (d, J = 9 Hz, 1H), 7.91 (dd, J = 9 Hz and J = 2 Hz,
1H), 7.96 (s, 1H), 8.79 (d, J = 2 Hz, 1H)
C. 5-te/f-Butyl-3-methyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3,5-dicarboxylate
The preparation is based on 5-te/?-butyl-3-methyl-1-[2-hydroxy-3-(4-
octylphenoxy)propyl]indole-3,5-dicarboxylate in analogy to the synthesis of step
C of Example 9. The chromatographic purification on silica gel is carried out
using the flow agent hexane/ethyl acetate 4:1 . The product accrues as an oil.
C32H4iNO6 (535.7)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.29 (m, 10H), 1.59 (m, 2H),
1 .62 (s, 9H), 2.58 (t, J = 7 Hz, 2H), 3.93 (s, 3H), 4.69 (s, 2H), 5.27 (s, 2H), 6.85
(d, J = 9 Hz, 2H), 7.06 (dd, J = 9 Hz and J = 1 Hz, 1 H), 7.16 (d, J = 9 Hz, 2H),
7.72 (s, 1H), 7.90 (dd, J = 9 Hz and J = 2 Hz, 1H), 8.83 (dd, J = 2 Hz and J = 1
Hz, 1H)
D. 3-Methoxycarbonyl-1 -[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid
The preparation is based on 5-te/f-butyl-3-methyl-1-[3-(4-octylphenoxy)-2-
oxopropyl]indole-3,5-dicarboxylate in analogy to the synthesis of step D of
Example 9. Deviating therefrom, the reaction time is only 2 h. The product
accrues as a solid and is recrystallized (without chromatographic purification)
from hexane/tetrahydrofurane.
Mp.: 208°C
1H-NMR (DMSO-ofe): 6 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.22 (m, 10H), 1.50 (m,
2H), 2.53 (m, 2H), 3.83 (s, 3H), 5.00 (s, 2H), 5.52 (s, 2H), 6.88 (d, J = 9 Hz, 2H),
7.09 (d, J = 9 Hz, 2H), 7.57 (d, J = 9 Hz, 1H), 7.80 (dd, J = 9 Hz and J = 2 Hz,
1H), 8.16 (s, 1H), 8.65 (d, J = 1 Hz, 1H)
Example 23
3-ferf-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid
The compound accrues in the synthesis of 1-[3-(4-octylphenoxy)-2-
oxopropyl]indole-6-carboxylic acid (Example 11) as a by-product and can be
separated therefrom by purification using RP-HPLC.
Mp.: 145-146°C
C3oH39NO4 (477.6)
1H-NMR (CDCI3): 5 (ppm) = 0.89 (t, J = 6 Hz, 3H), 1.27-1.30 (m, 10H), 1.46 (s,
9H), 1.58-1.62 (m, 2H), 2.59 (t, J = 8 Hz, 2H), 4.64 (s, 2H), 5.23 (s, 2H), 6.86 (d,
J = 9 Hz, 2H), 6.96 (s, 1H), 7.16 (d, J = 9 Hz, 2H), 7.87 (m, 2H), 7.96 (m, 1H)
Example 24
1 -[3-(4-Decyloxyphenoxy)-2-oxopropyl]lndole-5-carboxylic acid
A. terf-Butyl-1-[3-(4-decyloxyphenoxy)-2-hydroxypropyl]indole-5-carboxylate
The preparation is based on tert-butylindole-5-carboxylate and 2-(4-
decyloxyphenoxymethyl)oxirane in analogy to the synthesis of step B of Example
9. Deviating therefrom, the reaction time is 5 h. The chromatographic purification
is initially carried out on silica gel (flow agent: petroleum ether/ethyl acetate
85:15) and then on RP18 material (flow agent acetonitrile/water 4:1). The
product accrues as an oil.
(523.7)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.34 (m, 12H), 1.42-1.46
(m, 2H), 1.62 (s, 9H), 1.75 (quin, J = 7 Hz, 2H), 2.45 (s, broad, 1H), 3.79 (dd, J =
10 Hz and J = 5 Hz, 1H), 3.88-3.91 (m, 3H), 4.32-4.36 (m, 2H), 4.43 (dd, J = 16
Hz and J = 8 Hz, 1H), 6.59 (dd, J = 3 Hz and J = 1 Hz, 1H), 6.78-6.85 (m, 4H),
7.19 (d, J - 3 Hz, 1H), 7.36 (d, J = 9 Hz, 1H), 7.85 (dd, J = 9 Hz and J = 2 Hz,
1H), 8.32 (m,1H)
B. terf-Butyl-1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylate
The preparation is based on te/t-butyl-1-[3-(4-decyloxyphenoxy)-2-
hydroxypropyl]indole-5-carboxylate in analogy to the synthesis of step C of
Example 9. The chromatographic purification on silica gel is carried out using the
flow agent petroleum ether/ethyl acetate 9:1. The product accrues as a solid.
C32H43N05(521.7)
1H-NMR (CDCI3): 5 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.27-1.34 (m, 12H), 1.41 -1.45
(m, 2H), 1.62 (s, 9H), 1.77 (quin, J = 7 Hz, 2H), 3.91 (t, J = 7 Hz, 2H), 4.59 (s,
2H), 5.21 (s, 2H), 6.67 (d, J = 3 Hz, 1H), 6.82-6.87 (m, 4H), 7.08 (d, J = 3 Hz,
1H), 7.09 (d, J = 9 Hz, 1H), 7.86 (dd, J = 9 Hz and J = 2 Hz, 1H), 8.34 (d, J = 1
Hz, 1H)
C. 1-[3-(4-Decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid
50 mg (0.096 mmol) ferf-butyl-1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-5-
carboxylate are dissolved in 15 ml absolute dichloromethane and mixed with
0.82 g (7.19 mmol) trifluoroacetic acid. Having stirred at room temperature for 4
hours, the batch is concentrated to dryness on the rotary evaporator. Three
admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate (4:1)
each and respective concentration to dryness on the rotary evaporator leave as
a crude product a solid which is purified on an RP-HPLC column by means of
chromatography (stationary phase: cromasil, flow agent: acetonitrile/water
90:10).
Yield: 25 mg (0.05 mmol); 56 %
Mp.: 137°C
CasHssNOs (465.6)
1H-NMR (CDCI3): 6 (ppm) = 0.89 (t, J = 7 Hz, 3H), 1.28-1.33 (m, 12H), 1.43-1.49
(m, 2H), 1.75-1.82 (m, 2H), 3.93 (t, J = 7 Hz, 2H), 4.63 (s, 2H), 5.25 (s, 2H), 6.72
(dd, J = 3 Hz and J = 1 Hz, 1H), 6.84-6.89 (m, 4H), 7.12 (d, J = 3 Hz, 1H), 7.14
(d, J = 9 Hz, 1 H), 7.97 (dd, J = 9 Hz and J = 2 Hz, 1 H), 8.50 (d, J = 1 Hz, 1 H)
Example 25
1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbamide
A. 1 -[2-Hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbamide
0.18 g (0.44 mmol) 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile
(Example 15A) is dissolved in 15 ml te/t-butanol, mixed with 0.23 g (3.6 mmol)
pulverized, 88 % potassium hydroxide and heated under reflux for 1 1 h. Having
cooled down, the mixture is hydrolyzed in water and acidified with 1N
hydrochloric acid. Three extractions with diethyl ether, concentration to half the
volume on the rotary evaporator, washing with water and with saturated NaCI
solution, drying on sodium sulfate, filtration and reconcentration on the rotary
evaporator leave as a crude product a yellowish solid which is purified on silica
gel by means of column chromatography (flow agent: petroleum ether/ethyl
acetate 1:1) and yields the product as a solid.
Yield: 0.13 g (0.31 mmol); 70 %
Mp.:118-119°C
1H-NMR (CDCI3): 6 (ppm) = 0.88 (t, J = 7 Hz, 3H), 1.26-1.30 (m, 10H), 1.55-1.58
(m, 2H), 2.52 (m, 2H), 3.85 (dd, J = 10 Hz and J = 5 Hz, 1H), 3.94 (dd, J = 10 Hz
and J = 4 Hz, 1H), 4.32-4.39 (m, 2H), 4.46 (dd, J = 17 Hz and J = 8 Hz, 1H),
5.40-6.28 (s, broad, 2H), 6.59 (d, J = 3 Hz, 1 H), 6.80 (d, J = 9 Hz, 2H), 7.09 (d, J
= 9 Hz, 2H), 7.23 (d, J = 3 Hz, 1H), 7.42 (d, J = 9 Hz, 1H), 7.66 (d, J = 9 Hz, 1H),
8.12 (s,1H)
B. 1 -[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbamide
The preparation is based on 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-
carbamide in analogy to the synthesis of step C of Example 9. Deviating
therefrom, the reaction time is 19 h. The chromatographic purification on silica
55
gel is carried out using the flow agent petroleum ether/ethyl acetate 1:1. The
product accrues as a solid.
M.: 162-163°C
1H-NMR (DMSO-db): 6 (ppm) = 0.84 (t, J = 7 Hz, 3H), 1.23-1.26 (m, 10H), 1.49-
1.53 (m, 2H), 2.47-2.51 (m, 2H), 4.97 (s, 2H), 5.39 (s, 2H), 6.54 (d, J = 3 Hz, 1H),
6.85 (d, J = 9 Hz, 2H), 7.07-7.10 (m, 3H), 7.33 (d, J = 3 Hz, 1H), 7.38 (d, J = 9
Hz, 1 H), 7.65 (d, J = 9 Hz, 1 H), 7.83 (s, broad, 1 H), 8.1 3 (s, 1 H)
Example 26
1-[3-(4-Heptyloxyphenoxy)-2-oxopropyl]indole-5-carbamide

A. 1 -Oxiranylmethylindole-5-carbonitrile
2.07 g (42 mmol) pulverized, 88 % potassium hydroxide, 3.0 g (0.021 mol)
indole-5-carbonitrile and 0.68 g (2 mmol) tetrabutylammoniumbromide are jointly
weighed out in the given order and mixed with 9.9ml (126 mmol)
epichlorohydrine with stirring. Stirring is continued overnight. Following
hydrolysis and three extractions using ethyl acetate, the combined organic
phases are washed three times with water. Drying of the organic phase using
sodium sulfate and concentration of the solvent on the rotary evaporator leaves a
solid which is purified on silica gel by column chromatography (flow agent:
hexane/ethyl acetate 7:3).
Yield: 3.34 g (17 mmol); 80 %
Mp.: 92°C
Ci2H10N2O (198.2)
1H-NMR (CDCJ3): 6 (ppm) = 2.29 (dd, J = 5 Hz and J = 3 Hz, 1H), 2.77 (m, 1H)f
3.22 (m, 1H), 4.08 (dd, J = 15 Hz and J = 6 Hz, 1H), 4.47 (dd, J = 15 Hz and J =
3 Hz, 1H), 6.54 (d, J = 3 Hz, 1H), 7.20 (d, J = 3 Hz, 1H), 7.40 (m, 2H), 7.92 (s,
1H)
B. 1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbonitrile
0.13 g (2.47 mmol) sodium hydride as 60 % dispersion in mineral oil is
suspended in 10 ml absolute DMF under nitrogen, stirred at room temperature
for 10 min and mixed with the solution of 0.5 g (2.39 mmol) 4-heptyloxyphenol in
5 mi absolute DMF. Having stirred for 1 hour, a solution of 475 mg (2.39 mmol)
1-oxiranylmethylindole-5-carbonitrile in 5 ml absolute DMF is added and stirring
is continued at room temperature overnight. Thereafter, the suspension is
hydrolyzed with semi-saturated NaCI solution and extracted three times with
ethyl acetate. The extracts are washed with saturated NaCI solution, dried on
sodium sulfate and the solvent is distilled off. The residue is purified on silica gel
by means of column chromatography (flow agent: hexane/ethyl acetate 1:1), the
product accruing as an oil.
Yield: 0.48 g (1.18 mmol); 49 %
C25H3oN2O3 (406.5)
MS (El): m/z (%) = 406 (100) M+, 309 (20), 308 (92), 199 (62), 181 (25), 156
(36), 155 (60), 110(69)
C. 1 -[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbamide
455 mg (1.12 mmol) 1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-
carbonitrile are dissolved in 10 ml tert-butanol. Having added 1.10 g (22.4 mmol)
pulverized, 88 % potassium hydroxide, the batch is heated to 100°C for 3 hours.
After cooling the reaction solution, hydrolysis using 50 ml distilled water and
neutralization with 1 N hydrochloric acid are carried out. The aqueous phase is
extracted three times with ethyl acetate and the combined organic phases are
washed once with water and then twice with saturated sodium chloride solution.
Following drying on sodium sulfate, the solvent is removed on the rotary
evaporator. The residue is purified on silica gel by means of column
chromatography (flow agent: ethyl acetate), the product accruing as a solid.
Yield: 245 mg (0.58 mmol); 52 %
Mp.: 114°C
C25H32N2O4 (424.5)
MS (El): m/z (%) = 424 (67) IVT, 328 (21), 327 (100), 174 (18), 173 (69)
D. 1 -[3-(4-Heptyloxyphenoxy)-2-oxopropyl]indole-5-carbamide
The preparation is based on 1-[3-(4-heptyloxyphenoxy)-2-hydroxypropyl]indole-
5-carbamide in analogy to the synthesis of step C of Example 9. Deviating
therefrom, the reaction time is 20 h. The product is extracted from the reaction
batch by means of ethyl acetate. The chromatographic purification on silica gel is
carried out with the flow agent ethyl acetate. Following recrystallization from
hexane/ethyl acetate, the product accrues as a solid.
M.: 157°C
1H-NMR (DMSO-ofe): 5 (ppm) = 0.82 (t, J = 7 Hz, 3H), 1.20-1.36 (m, 6H), 1.37-
1.42 (m, 2H), 1.62 (quin, J = 7 Hz, 2H), 3.87 (t, J = 7 Hz, 2H), 4.93 (s, 2H), 5.39
(s, 2H), 6.54 (d, J = 3 Hz, 1H), 6.82-6.93 (m, 4H), 7.21 (s, 1H), 7.37 (d, J = 3 Hz,
1H), 7.41 (d, J = 8 Hz, 1H), 7.66 (dd, J = 8 Hz and J = 2 Hz, 1H), 7.82 (s, 1H),
8.19(d,J = 2Hz, 1H)
Example 27
1-[3-(Biphenyl-4-yloxy)-2-oxopropyl]indole-5-carbamide
A. 1-[3-(Biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-carbonitrile
0.34 g (2.02 mmol) 4-phenyl phenol are dissolved in 5 ml absolute THF under
nitrogen and mixed drop-wise with 0.1ml (1.0 mmol) terf-butyllithium with
constant stirring. The mixture is stirred at room temperature for 5 min. Thereafter,
the solution of 0.20 g (1.0 mmol) 1-oxiranylmethylindole-5-carbonitrile (Example
26A) in 5 ml absolute THF is added drop-wise. The batch is heated at 100°C for
4 hours. Having cooled down, the batch is mixed with 100 ml diethyl ether and
extracted three times using water. The aqueous phase is extracted twice using
ethyl acetate and the combined organic phases are dried on sodium sulfate,
filtrated and the solvent is removed in vacua. The residue is purified on silica gel
by means of column chromatography (flow agent: hexane/ethyl acetate 7:3). The
product is obtained as a solid.
Yield: 0.37 g (1.0 mmol); 100 %
Mp.:133°C
C24H2oN2O2 (368.4)
1H-NMR (DMSO-ofe): 5 (ppm) = 3.90-3.92 (m, 2H), 4.20 (m, 1H), 4.27 (dd,
J = 15 Hz and J = 7 Hz, 1H), 4.42 (dd, J = 15 Hz and J = 4 Hz, 1H), 5.45 (d, J = 5
Hz, 1H), 6.60 (d, J = 3 Hz, 1H), 7.04 (d, J = 9 Hz, 2H), 7.30 (d, J = 8 Hz, 1H),
7.40 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 7.58 (d, J = 3 Hz, 1H), 7.59 (d, J =
7 Hz, 1 H), 7.62 (m, 2H), 7.72 (d, J = 8 Hz, 1 H), 8.35 (s, 1 H)
B. 1 -[3-(Biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-carbamide
The preparation is based on 1 -[3-(biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-
carbonitrile in analogy to the synthesis of step C of Example 26. The product is
obtained as a solid.
Mp.: 155°C
C24H22N2O3 (386.4)
1H-NMR (DMSO-ofe): 5 (ppm) = 3.88-3.92 (m, 2H), 4.19 (s, broad, 1H), 4.27 (dd,
J = 14 Hz and J = 7 Hz, 1H), 4.41 (dd, J = 14 Hz and J = 4 Hz, 1H), 5.48 (s,
broad, 1H), 6.51 (d, J = 3 Hz, 1H), 7.02 (d, J = 9 Hz, 2H), 7.10 (s, broad, 1H),
7.28-7.32 (m, 1H), 7.36-7.43 (m, 3H), 7.48-7.63 (m, 6H), 7.83 (s, broad, 1H),
8.17(5, 1H)
C. 1 -[3-(Biphenyl-4-yloxy)-2-oxopropyl]indole-5-carbamide
The preparation is based on 1-[3-(biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-
carbamide in analogy to the synthesis of step D of Example 26. The product is
obtained as a solid.
Mp.: 120°C
C24H2oN2O3 (384.4)
1H-NMR (DMSO-cfe): 6 (ppm) = 5.09 (s, 2H), 5.21 (s, 2H), 6.57 (d, J = 3 Hz, 1H),
7.09 (d, J = 9 Hz, 2H), 7.11 (s, broad, 1H), 7.28-7.33 (m, 1H), 7.35 (d, J = 3 Hz,
1H), 7.38-7.45 (m, 3H), 7.57-7.70 (m, 4H), 7.85 (s, broad, 1H), 8.17 (s, 1H)
Example 28
1-[3-(Biphenyl-3-yloxy)-2-oxopropyl]indole-5-carbamide
A. 1-[3-(Biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-carbonitrile
The preparation is based on 3-phenyl phenol and 1-oxiranylmethylindole-5-
carbonitrile in analogy to the synthesis of step A of Example 27. The product
accrues as a solid.
Mp.: 120°C
C24H2oN2O2 (368.4)
1H-NMR (DMSO-cfe): 5 (ppm) = 3.95 (m, 2H), 4.19 (m, 1H), 4.32 (dd, J = 14 Hz
and J = 7 Hz, 1H), 4.48 (dd, J = 14 Hz and J = 4 Hz, 1H), 5.49 (d, J = 5 Hz, 1H),
6.61 (d, J = 3 Hz, 1H), 6.94 (m, 1H), 7.18 (d, J = 2 Hz, 1H), 7.24 (d, J = 8 Hz,
1H), 7.37 (m, 2H), 7.42-7.51 (m, 3H), 7.58 (d, J = 3 Hz, 1H), 7.65 (m, 2H), 7.72
(d, J = 8 Hz, 1H), 8.09(3,1 H)
B. 1 -[3-(Biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-carbamide
The preparation is based on 1-[3-(biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-
carbonitrile in analogy to the synthesis of step C of Example 26. The product is
obtained as a solid.
Mp.:162°C
C24H22N2O3 (386.4)
1H-NMR (DMSO-ofe): 5 (ppm) = 3.95 (m, 2H), 4.20 (s, broad, 1H), 4.29 (dd,
J = 15 Hz and J = 7 Hz, 1H), 4.42 (dd, J = 15 Hz and J = 4 Hz, 1H), 5.43 (s,
broad, 1H), 6.45 (d, J = 3 Hz, 1H), 6.97 (dd, J = 8 Hz and J = 2 Hz, 2H), 7.17 (s,
broad, 1H), 7.18 (d, J = 2 Hz, 1H), 7.22 (d, J = 8 Hz, 1H), 7.31-7.39 (m, 2H),
7.41-7.51 (m, 3H), 7.60-7.69 (m, 3H), 7.84 (s, broad, 1H), 8.12 (s, 1H)
C. 1 -[3-(Biphenyl-3-yloxy)-2-oxopropyl]indole-5-carbamide
The preparation is based on 1-[3-(biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-
carbamide in analogy to the synthesis of step D of Example 26. The
chromatographic purification is initially carried out on silica gel using the flow
agent hexane/ethyl acetate 3:7 and then on an RP-HPLC column (cromasil)
using the flow agent acetonitrile/water/formic acid (70:30:0.02). The product
accrues as a solid.
1H-NMR (DMSO-ofe): 6 (ppm) = 5.18 (s, 2H), 5.44 (s, 2H), 6.58 (d, J = 3 Hz, 1H),
6.98 (dd, J = 8 Hz and J = 3 Hz, 1H), 7.18 (s, broad, 1H), 7.20-7.25 (m, 2H),
7.25-7.45 (m, 6H), 7.60-7.71 (m, 3H), 7.83 (s, broad, 1H), 8.18 (s, 1H)
Example 29
1-[3-(Biphenyl-2-yloxy)-2-oxopropyl]indole-5-carbamide
A. 1-[3-(Biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-carbonitrile
The preparation is based on 2-phenyl phenol and 1-oxiranylmethylindole-5-
carbonitrile in analogy to the synthesis of step A of Example 27. The product
accrues as a solid.
Mp.: 117°C
C24H2oN2O2 (368.4)
1H-NMR (DMSO-cfe): 5 (ppm) = 3.84 (dd, J = 10 Hz and J = 6 Hz, 1H), 3.94 (dd, J
= 10 Hz and J = 4 Hz, 1H), 4.01-4.08 (m, 1H), 4.09-4.13 (m, 1H), 4.29-4.33 (m,
1H), 5.41 (d, J = 5 Hz, 1H), 6.57 (d, J = 3 Hz, 1H), 7.01-7.11 (m, 2H), 7.21-7.39
(m, 6H), 7.43-7.51 (m, 2H), 7.61 (d, J = 7 Hz, 1H), 8.03 (s, 1H)
B. 1-[3-(Biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-carbamide
The preparation is based on 1-[3-(biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-
carbonitrile in analogy to the synthesis of step C of Example 26. The product is
obtained as a solid.
Mp.: 150°C
C24H22N2O3 (386.4)
1H-NMR (DMSO-ofe): 6 (ppm) = 3.85 (dd, J = 9 Hz and J = 6 Hz, 1H), 3.92 (dd, J
= 9 Hz and J = 4 Hz, 1H), 4.00-4.10 (m, 2H), 4.20-4.30 (m, 1H), 5.38 (d, J = 4
Hz, 1H), 6.45 (d, J = 3 Hz, 1H), 6.98-7.12 (m, 4H), 7.23 (d, J = 3 Hz, 1H), 7.25-
7.50 (m, 5H), 7.52-7.61 (m, 3H), 7.81 (s, broad, 1H), 8.11 (s, 1H)
C. 1 -[3-(Biphenyl-2-yloxy)-2-oxopropyl]indole-5-carbamide
The preparation is based on 1-[3-(biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-
carbamide in analogy to the synthesis of step D of Example 26. The product
accrues as a solid.
C24H2oN2O3 (384.4)
1H-NMR (DMSO-ofe): 6 (ppm) = 5.04 (s, 2H), 5.32 (s, 2H), 6.52 (d, J = 3 Hz, 1H),
7.01-7.83 (m, 13H), 7.91 (s, broad, 1H), 8.18 (d, J = 1 Hz, 1H)
Example 30
1 -[3-(1 -Heptylindol-5-yloxy)-2-oxopropyl]indole-5-carbamide
A. 5-Benzyloxy-1-heptylindole
0.22 g (4.45 mmol) pulverized, 88 % potassium hydroxide, 0.5 g (2.24 mmol)
5-benzyloxyindole and 0.07 g (0.22 mmol) tetrabutylammoniumbromide are
weighed out in the given order and mixed with 1.41ml (8.96 mmol) 1-
bromoheptane with vigorous stirring. The mixture is stirred at room temperature
overnight. Having added 30 ml water, three extractions using diethyl ether are
carried out. The organic phase is washed three times with saturated NaCI
solution, dried on sodium sulfate and the solvent is removed in vacua. The
residue is purified on silica gel by means of column chromatography (flow agent:
hexane/ethyl acetate 95:5). The product accrues as an oil.
Yield: 530 mg (0.16 mmol), 74 %
1H-NMR (CDCI3): 5 (ppm) = 0.80 (t, J = 7 Hz, 3H), 1.13-1.27 (m, 8H), 1.75 (quin,
J = 7 Hz, 2H), 4.00 (t, J = 7 Hz, 2H), 5.05 (m, 2H), 6.31 (d, J = 3 Hz, 1H), 6.87
(dd, J = 9 Hz and J = 3 Hz, 1H), 6.98 (d, J = 3 Hz, 1H), 7.08 (d, J = 3 Hz, 1H),
7.16 (d, J = 9 Hz, 1 H), 7.24 (t, J = 7 Hz, 1 H), 7.31 (m, 2H), 7.41 (d, J = 7 Hz, 2H)
B. 1-Heptylindol-5-ol
0.5 g (1.55 mmol) 5-benzyloxy-1-heptylindole is dissolved in a Schlenk flask in
10 ml methanol and 4 ml dichloromethane. 0.06 g Pd (10 %)/C is added and the
mixture is rinsed with nitrogen for 15 minutes. Thereafter, a balloon filled with
hydrogen is placed on the Schlenk piston and hydrogenation is carried out at
room temperature for 12 h. The batch is filtrated on a frit and the solvent is
removed in vacua. The residue is purified on silica gel by means of column
chromatography (flow agent: hexane/ethyl acetate 9:1). The product accrues as
an oil.
Yield: 0.33 g (1.43 mmol); 90 %
C24H2oN2O3 (384.4)
1H-NMR (DMSO-ofe): 5 (ppm) = 0.82 (t, J = 7 Hz, 3H), 1.21 (m, 8H), 1.72 (quin, J
= 7 Hz, 2H), 4.05 (t, J = 7 Hz, 2H), 6.18 (d, J = 3 Hz, 1H), 6.61 (dd, J = 9 Hz and
J = 2 Hz,1 H), 6.82 (d, J = 2 Hz, 1 H), 7.20 (m, 2H), 8.63 (s, 1 H).
C. 1 -[3-(1 -Heptylindol-5-yloxy)-2-hydroxypropyl]indole-5-carbonitrile
The preparation is based on 1-heptylindol-5-ol and 1-oxiranylmethylindole-5-
carbonitrile in analogy to the synthesis of step B of Example 26. The
chromatographic purification on silica gel is carried out using the flow agent
hexane/ethyl acetate 4:1. The product accrues as an oil.
C27H3iN3O2 (429.6)
1H-NMR (DMSO-cfe): 6 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.13-1.28 (m, 8H), 1.71
(quin, J = 7 Hz, 2H), 3.81-3.91 (m, 1H), 4.02 (m, 1H), 4.08 (t, J = 7 Hz, 2H), 4.15
(s, broad, 1 H), 4.31 (dd, J = 14 Hz and J = 7 Hz, 1 H), 4.46 (dd, J = 14 Hz and J =
4 Hz, 1 H), 5.41 (s, broad, 1 H), 6.28 (d, J = 3 Hz, 1 H), 6.58 (d, J = 3 Hz, 1 H), 6.80
(dd, J = 9 Hz and J = 2 Hz, 1H), 6.95 (d, J = 2 Hz, 1H), 7.28 (d, J = 3 Hz, 1H),
7.34 (d, J = 9 Hz, 1H), 7.42 (dd, J = 9 Hz and J = 2 Hz, 1H), 7.44 (d, J = 3 Hz,
1 H), 7.68 (d, J = 9 Hz, 1 H), 8.06 (d, J = 2 Hz, 1 H)
D. 1 -[3-(1 -Heptylindol-5-yloxy)-2-hydroxypropyl]indole-5-carbamide
The preparation is based on 1-[3-(1-heptylindol-5-yloxy)-2-hydroxypropyl]indole-
5-carbonitrile in analogy to the synthesis of step C of Example 26. The product
accrues as a solid.
Mp.: 114°C
CgyHagNaOa (447.6)
1H-NMR (DMSO-afe): 5 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.13-1.28 (m, 8H), 1.71
(quin, J = 7 Hz, 2H), 3.81-3.91 (m, 1H), 4.02 (q, J = 7 Hz, 1H), 4.08 (t, J = 7 Hz,
2H), 4.15(m, 1H),4.31 (dd, J = 14 Hz and J = 7 Hz, 1H), 4.46 (dd, J = 14 Hz and
J = 4 Hz, 1H), 5.40 (d, J = 5 Hz, 1H), 6.28 (d, J = 3 Hz, 1H), 6.48 (d, J = 3 Hz,
1H), 6.80 (dd, J = 9 Hz and J = 2 Hz, 1H), 6.95 (d, J = 2 Hz, 1H), 7.08 (s, broad,
1H), 7.28 (d, J = 3 Hz, 1H), 7.34 (d, J = 9 Hz, 1H), 7.42 (dd, J = 9 Hz and J = 2
Hz, 1H), 7.44 (d, J = 3 Hz, 1H), 7.68 (d, J = 9 Hz, 1H), 7.81 (s, broad, 1H), 8.12
(d,J = 2Hz, 1H)
E. 1 -[3-(1 -Heptylindol-5-yloxy)-2-oxopropyl]indole-5-carbamide
The preparation is based on 1-[3-(1-heptylindol-5-yloxy)-2-hydroxypropyl]indole-
5-carbamide in analogy to the synthesis of step C of Example 9. Deviating
therefrom, the reaction time is 20 h. The product is extracted from the reaction
batch by means of ethyl acetate. The chromatographic purification on silica gel is
made using the flow agent ethyl acetate. Following recrystallization from
hexane/ethyl acetate, the product accrues as a solid.
Mp.:171°C
C27H3iN3O3 (445.6)
1H-NMR (DMSO-cfe): 5 (ppm) = 0.83 (t, J = 7 Hz, 3H), 1.13-1.28 (m, 8H), 1.71
(quin, J = 7 Hz, 2H), 4.08 (t, J = 7 Hz, 2H), 4.97 (s, 2H), 5.42 (s, 2H), 6.28 (d, J =
3 Hz, 1 H), 6.48 (d, J = 3 Hz, 1 H), 6.80 (dd, J = 9 Hz and J = 2 Hz, 1 H), 6.95 (d, J
= 2 Hz, 1H), 7.12 (s, broad, 1H), 7.28 (d, J = 3 Hz, 1H), 7.34 (d, J = 9 Hz, 1H),
7.42 (dd, J = 9 Hz and J 0 2 Hz, 1H), 7.44 (d, J = 3 Hz, 1H), 7.68 (d, J = 9 Hz,
1 H), 7.82 (s, broad, 1 H), 8.12 (d, J = 2 Hz, 1 H)
Example 31
Pharmacological test
The effectiveness of the compounds according to the invention can be
determined by the inhibition of cytosolic phospholipase A2. The test method used
was described earlier (Lehr M. era/., Arch. Pharm. Pharm. Med. Chem. 2000,
333, 312-314). Here, the arachidonic acid formed by cytosolic phospholipase A2
in intact human platelets following stimulation using calcium ionophor A23187 is
detected in the presence and absence of test substances.
The compounds of Examples 2, 5, 6, 7, 8 and 9 according to the invention were
tested by means of this test system. At a concentration of 10 //M they inhibited
the activity of cytosolic phospholipase A2 by 40% to 95%, which proves their
effectiveness.



We Claim:
Heteroaryl substituted acetone derivative of formula I
(Formula Removed)
wherein
Q represents R1, OR1, SR1, SOR1, SO2R1, NR9R* or a straight-chain C1-31 alkyl or C2-31 alkenyl or alkinyl residue which may be interrupted by 1 or 2 residues, independently selected from O, S, SO, SO2, NR9 and aryl which may be substituted with 1 or 2 substituents R4, and which may be substituted with 1-4 C1-6 alkyl residues and/or 1 or 2 aryl residues, wherein the aryl residues may be substituted with 1 or 2 substituents
R4;
Ar represents an aryl residue which may be substituted with 1 or 2 substituents R4;
X represents N or CR5;
Y represents N or CR6;
R1 represents H or an aryl residue which may be substituted with 1 or 2 substituents R4;
R2 and R3
a) independently may stand for H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or R7-W,
or

b) together with the carbon atoms to which they are bound, for a 5- or 6-membered aromatic or heteroaromatic ring which may be substituted with 1 or 2 substituents R4;
R4 represents C1-6 alkyl, halogen, CF3, CN, NO2, OR9, S(O)oR9, COR9, COOR9, CONR9R10, SO3R9, SO2NR9R10, tetrazolyl or R7-W;
R5 represents H or R4;
R6 represents H, C1-6 alkyl, halogen, CF3, CN, NO2, OR9, S(O)0R9, COR9, COOR9, CONR9R10, SO3R9, S02NR9R10, tetrazolyl or R8-W;
R7 represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R8 represents C2-6 alkyl, C2-6 alkenyl or C2-6 alkynyl;
R9 represents H, C1-6 alkyl or aryl;
R10 represents H or C1-6 alkyl;
W represents COOH, SO3H or tetrazolyl; and
o represents 0, 1 or 2;
and the pharmaceutically compatible salts and esters thereof.
2. Compounds as claimed in claim 1, wherein Q represents
R1-(CHR11)p-A-Z2-B-Z1-
wherein
A represents a bond or a straight-chain C1-m alkyl residue or C2-m alkenyl or alkinyl residue;
B represents a bond or a straight chain C1-n alkyl residue or C2-11 alkenyl or alkynyl residue;

R11 represents H or an aryl residue which may be substituted with 1 or 2 substituents R4;
Z1 and Z2 independently represent a bond, 0, S, SO, SO2, NR9, CR9R10 or an aryl residue, wherein the aryl residue may be substituted with 1 or 2 substituents R4;
R1, R4, R9 and R10 are as defined in claim 1;
p represents 0 or 1;
m represents an integer from 0 to 12;
and
n represents an integer from 0 to 16.
3. Compounds as claimed in claim 2, wherein m + n≤ 17.
4. Compounds as claimed in claim 2 or 3, wherein Q is selected from R1-B-Z1-
R1-CHR11-B-Z1-
R1-A-Z2-B-Z1- and
R1-CHR11-A-Z^B-Z1-
and A, B, R1, R11, Z1, Z2, n and m are as defined in claim 2.
5. Compounds as claimed in claim 4, wherein Q represents phenyl or C5-12 alkyl or alkoxy, preferably C7-10 alkyl or alkoxy.
6. Compounds as claimed in any of the preceding claims, wherein Ar represents a phenyl or indolyl residue.
7. Compounds as claimed in any of the preceding claims, wherein R2 and R3

a) independently represent H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or R7-Wor
b) together with the carbon atoms to which they are bound form a benzo ring or a 6-membered aromatic heterocyclic ring having 1-3 nitrogen atoms, wherein the benzo ring or the heterocyclic ring may be substituted with 1 or 2 substituents R4, and R4 is defined as in claim 1.
Compounds as claimed in claim 7, wherein R2 and R3 represent H or together with the carbon atoms to which they are bound form a benzo ring which may be substituted with a substituent R4, preferably COOH, CH3, CI, OCH3, CN, CHO, COOCH3 or CONH2.
Compounds as claimed in any of the preceding claims, wherein X = CR5 and Y = CR6 or X = N and Y = CR6, wherein R5 and R6 are as defined in claim 1 and preferably represent H, COOH, t-butyl, CI, CHO, COCH3 or COOCH3.
Pharmaceutical preparation comprising a compound of general formula I as claimed in any of claims 1 to 9 or a pharmaceutically compatible salt or ester thereof.
A pharmaceutical preparation as claimed in claim 10 for preventing or treating diseases which are caused or contributorily caused by an increased activity of phospholipase A2.
A pharmaceutical preparation as claimed in claim 11, wherein the disease is selected from inflammations, pain, fever, allergies, asthma, psoriasis, cerebral ischemia, Alzheimer's disease, chronic skin diseases, damage to the skin by U.V. rays, rheumatic diseases, thrombosis, anaphylactic shock, urticaria, acute and chronic exanthemas and endotoxic shock."
A method of producing a compound of formula I as claimed in claim 1, wherein an oxirane derivative of formula-II -

is reacted with a compound of formula IV
(Formula Removed)
and the alcohol formed is oxidized into the desired ketone, wherein Q, Ar, X, Y, R2 and R3 are as defined in claim 1 and Abg represents a leaving group, such as halogen, in particular bromine.


Documents:

3196-DELNP-2005-Abstract-(26-12-2008).pdf

3196-delnp-2005-abstract.pdf

3196-DELNP-2005-Claims-(26-12-2008).pdf

3196-delnp-2005-Claims-(28-05-2009).pdf

3196-delnp-2005-claims.pdf

3196-DELNP-2005-Correspondence-Others-(24-08-2009).pdf

3196-DELNP-2005-Correspondence-Others-(26-12-2008).pdf

3196-DELNP-2005-Correspondence-Others-(27-04-2010).pdf

3196-delnp-2005-correspondence-others.pdf

3196-DELNP-2005-Description (Complete)-(26-12-2008).pdf

3196-delnp-2005-description (complete).pdf

3196-DELNP-2005-Form-1-(26-12-2008).pdf

3196-delnp-2005-form-1.pdf

3196-delnp-2005-form-18.pdf

3196-DELNP-2005-Form-2-(26-12-2008).pdf

3196-delnp-2005-form-2.pdf

3196-DELNP-2005-Form-3-(26-12-2008).pdf

3196-delnp-2005-form-3.pdf

3196-delnp-2005-form-5.pdf

3196-DELNP-2005-GPA-(26-12-2008).pdf

3196-delnp-2005-gpa.pdf

3196-delnp-2005-pct-210.pdf

3196-delnp-2005-pct-237.pdf

3196-delnp-2005-pct-304.pdf

3196-delnp-2005-pct-326.pdf

3196-delnp-2005-pct-338.pdf

3196-delnp-2005-pct-373.pdf

3196-DELNP-2005-Petition-137-(26-12-2008).pdf


Patent Number 234878
Indian Patent Application Number 3196/DELNP/2005
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 18-Jun-2009
Date of Filing 19-Jul-2005
Name of Patentee MERCKLE GMBH
Applicant Address GERMAN COMPANY OF LUDWIG-MERCKLE-STR.3,89143 BLAUBEUREN,GERMANY.
Inventors:
# Inventor's Name Inventor's Address
1 MATTHIAS LEHR AM SCHLAUTBACH 155,48329 HAVIXBECK,GERMANY
2 JOACHIM LUDWIG SONNENSTRASSE 43,48143 MUNSTER,GERMANY.
PCT International Classification Number C07D 207/16
PCT International Application Number PCT/EP97/03842
PCT International Filing date 1997-07-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 103 05 089.2 2003-02-07 Germany