Title of Invention

QUINOLINE DERIVATIVES.

Abstract wherein R1, R2 and A are as defined in the description and claims, and pharmaceutically acceptable salts thereof as well as to pharmaceutical compositions comprising these compounds and to methods for their preparation. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
Full Text The present invention is concerned with novel quinoline derivatives, their
manufacture, pharmaceutical compositions containing them and their use as
medicaments. The active compounds of the present invention are useful in treating
obesity and other disorders.
In particular, the present invention relates to compounds of the general formula
(Figure Removed)
wherein
R1 is selected from the group consisting of hydrogen,
lower alkyl, lower alkenyl,
cycloalkyl or lower cycloalkylalkyl, wherein the cycloalkyl ring may be
unsubstituted or substituted by one or two groups selected from the group
consisting of lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl, and
lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or
substituted by one or two groups selected from lower alkyl and halogen;
R2 is selected from the group consisting of hydrogen,
lower alkyl, lower alkenyl,
cycloalkyl or lower cycloalkylalkyl, wherein the cycloalkyl ring may be
unsubstituted or substituted by one or two groups selected from the group
consisting of lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl, and
lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or
substituted by one or two groups selected from lower alkyl and halogen; or
R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-
or 7-membered saturated or partly unsaturated heterocyclic ring optionally
2containing a further heteroatom selected from nitrogen, oxygen or sulfur, said
saturated or partly unsaturated heterocyclic ring being unsubstituted or
substituted by one, two or three groups independently selected from the group
consisting of lower alkyl, halogen, halogenalkyl, cyano, hydroxy, hydroxyalkyl,
lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl;
A is selected from
(Figure Removed)

wherein
m is 0,1 or 2;
R3 is lower alkyl;
n is 0,1 or 2;
R7 is lower alkyl;
p is 0,1 or 2;
q is 0,1 or 2;
R5 is hydrogen or lower alkyl;
and pharmaceutically acceptable salts thereof.
The compounds of formula I are antagonists and/or inverse agonists at the
histamine 3 receptor (H3 receptor).
Histaraine (2-(4-imidazoIyl) ethylamine) is one of the aminergic
neurotransmitters which is widely distributed throughout the body, e. g. the
gastrointestinal tract (Burks 1994 in Johnson L.R. ed., Physiology of the
Gastrointestinal Tract, Raven Press, NY, pp. 211 - 242). Histamine regulates a variety
of digestive pathophysiological events like gastric acid secretion, intestinal motility
(Leurs et al., Br J. Pharmacol. 1991,102, pp 179-185), vasomotor responses, intestinal
inflammatory responses and allergic reactions (Raithel et al., hit. Arch. Allergy
Immunol. 1995, 108, 127-133). In the mammalian brain, histamine is synthesized in
histaminergic cell bodies which are found centrally in the tuberomammillary nucleus
of the posterior basal hypothalamus. From there, the cell bodies project to various
brain regions (Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagaki
et al., J. Comp. Neural 1988, 273, 283 - 300).
According to current knowledge, histamine mediates all its actions in both the
central nervous system (CNS) and in the periphery through four distinct histamine
receptors, the histamine HI, H2, H3 and H4 receptors.
H3 receptors are predominantly localized in the CNS. As an autoreceptor, H3
receptors constitutively inhibit the synthesis and secretion of histamine from
histaminergic neurons (Arrang et al., Nature 1983, 302, 832-837; Arrang et al.,
Neuroscience 1987, 23, 149-157). As heteroreceptors, H3 receptors also modulate the
release of other neurotransmitters such as acetylcholine, dopamine,-serotonin and
norepinephrine among others in both the central nervous system and in peripheral
organs, such as lungs, cardiovascular system and gastrointestinal tract (Clapham &
Kilpatrik, Br. J. Pharmacol. 1982, 107, 919- 923; Blandina et al. in The Histamine H3
Receptor (Leurs RL and Timmermann H eds, 1998, pp 27-40, Elsevier, Amsterdam,
The Netherlands). H3 receptors are constitutively active, meaning that even without
exogenous histamine, the receptor is tonically activated, hi the case of an inhibitory
receptor such as the H3 receptor, this inherent activity causes tonic inhibition of
neurotransmitter release. Therefore it may be important that a H3R antagonist would
also have inverse agonist activity to both block exogenous histamine effects and to
shift the receptor from its constitutively active (inhibitory) form to a neutral state.
The wide distribution of H3 receptors in the mammalian CNS indicates the
physiological role of this receptor. Therefore the therapeutic potential as a novel drug
development target in various indications has been proposed.
The administration of H3R ligands - as antagonists, inverse agonists, agonists or
partial agonists - may influence the histamine levels or the secretion of
neurotransmitters in the brain and the periphery and thus may be useful in the
treatment of several disorders. Such disorders include obesity, (Masaki et al;
Endocrinol. 2003, 144, 2741-2748; Hancock et al., European J. of Pharmacol. 2004,
487, 183-197), cardiovascular disorders such as acute myocardial infarction, dementia
and cognitive disorders such as attention deficit hyperactivity disorder (ADHD) and
Alzheimer's disease, neurological disorders such as schizophrenia, depression,
epilepsy, Parkinson's disease, and seizures or convulsions, sleep disorders,
narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction such as Morbus
Meniere, drug abuse and motion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-
It is therefore an object of the present invention to provide selective, directly
acting H3 receptor antagonists respectively inverse agonists. Such antagonists /
inverse agonists are useful as therapeutically active substances, particularly in the
treatment and/or prevention of diseases which are associated with the modulation of
H3 receptors.
In the present description the term "alkyl", alone or in combination with other
groups, refers to a branched or straight-chain monovalent saturated aliphatic
hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon
atoms, more preferably one to ten carbon atoms.
The term "lower alkyl" or "Ci-Cg-alkyl", alone or in combination, signifies a
straight-chain or branched-chain alkyl group with i to 6 carbon atoms, preferably a
straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly
preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms Examples
of straight-chain and branched Ci-C8 alkyl groups are methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric
heptyls and the isomeric octyls, preferably methyl and ethyl and most preferred
methyl.
The term "lower alkenyl" or "C2-Cg-alkenyl", alone or in combination, signifies
a straight-chain or branched alkyl group comprising an olefinic bond and up to 8,
preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl
groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-
butenyl and isobutenyl. A preferred example is 2-propenyl.
The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term
"lower alkoxy" refers to the group R'-O-, wherein R' is lower alkyl and the term
"lower alkyl" has the previously given significance. Examples of lower alkoxy groups
are e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy
and tert.butoxy, preferably methoxy and ethoxy and most preferred methoxy.
The term "lower alkoxyalkyl" or "alkoxy-Ci-Cg-alkyl" refers to lower alkyl
groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl
group is replaced by an alkoxy group as defined above. Among the preferred lower
alkoxyalkyl groups are methoxymethyl, methoxyethyl and ethoxymethyl, with
methoxymethyl being especially preferred.
The term "halogen" refers to fluorine, chlorine, bromine and iodine, with
fluorine, chlorine and bromine being preferred.
The term "lower halogenalkyl" or "halogen-Ci-Cg-alkyl" refers to lower alkyl
groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl
group is replaced by a halogen atom, preferably fluoro or chloro, most preferably
fluoro. Among the preferred halogenated lower alkyl groups are trifluoromethyl,
difluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially
preferred.
The term "lower halogenalkoxy" or "halogen-Ci-Cg-alkoxy" refers to lower
alkoxy groups as defined above wherein at least one of the hydrogen atoms of the
lower alkoxy group is replaced by a halogen atom, preferably fluoro or chloro, most
preferably fluoro. Among the preferred halogenated lower alkyl groups are
trifluoromethoxy, difluoromethoxy, fluormethoxy and chloromethoxy, with
trifluoromethoxy being especially preferred.
The term "lower hydroxyalkyl" or "hydroxy-Ci-C8-alkyl" refers to lower alkyl
groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl
group is replaced by a hydroxy group. Examples of lower hydroxyalkyl groups are
hydroxymethyl or hydroxyethyl.
The term "cycloalkyl" or "Cs-Cy-cycloalkyl" means a cycloalkyl ring containing
3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl. The cycloalkyl ring may be optionally substituted as defined herein.
Especially preferred is cyclopropyl.
The term "lower cycloalkylalkyl" or "Cs-Cy-cycloalkyl-Ci-Cg-alkyl" refers to
lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the
lower alkyl group is replaced by a cycloalkyl group as defined above. Examples of
preferred lower cycloalkylalkyl groups are cyclopropylmethyl or cyclopropylmethyl
wherein the cyclopropyl group is substituted by lower alkyl, lower hydroxyalkyl or
lower alkoxyalkyl, preferably methoxymethyl.
The term "heterocyclyl" means a monovalent saturated or partly unsaturated ring
incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen or sulfur.
The heterocyclyl ring may be optionally substituted as defined herein. Examples of
heterocyclyl moieties include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl,
pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,
dihydropyridyl, piperidyl, piperazinyl, morpholinyl, 01 thiomorpholinyl, azepinyl,
dihydropyrrolyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, dihydrofuryl,
tetrahydrofuryl, dihydropyranyl or tetrahydropyranyl. Especially preferred are
oxetanyl, piperidyl and morpholinyl.
The term "lower heterocyclylalkyl" or "heterocyclyl-Ci-Cg-alkyl" refers to lower
alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower
alky] group is replaced by a heterocyclyl group as defined above. An examples of a
preferred lower heterocyclylalkyl group is 3-fluorooxetan-3-yl.
The term "a 4-, 5-, 6- or 7-membered saturated or partly unsaturated
heterocyclic ring optionally containing a further heteroatom selected from nitrogen,
oxygen or sulfur" refers to a saturated or partly unsaturated N-heterocyclic ring, which
may optionally contain a further nitrogen, oxygen or sulfur atom, such as 2,5-
dihydropyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,
isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 3,6-dihydro-2H-pyridinyl. The heteroyclic ring may be
unsubstituted or substituted by one, two or three groups independently selected from
lower alkyl, lower alkoxy and halogen.
The term "carbamoyl" refers to the group -CO-NH2.
The term "pharmaceutically acceptable salts" refers to those salts which retain
the biological effectiveness and properties of the free bases or free acids, which are
not biologically or otherwise undesirable. The salts are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
and the like, preferably hydrochloric acid, and organic acids such as acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid,
salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic
acid, salicylic acid, N-acetylcystein and the like. In addition these salts
may be prepared form addition of an inorganic base or an organic base to the free acid.
Salts derived from an inorganic base include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived
from organic bases include, but are not limited to salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring substituted amines,
cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine,
diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, Nethylpiperidine,
piperidine, polymine resins and the like. The compound of formula I
can also be present in the form of zwitterions. Particularly preferred pharmaceutically
acceptable salts of compounds of formula I are the hydrochloride salts.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation
can be effected in the course of the manufacturing process or can take place e.g. as a
consequence of hygroscopic properties of an initially anhydrous compound of formula
1 (hydration). The term pharmaceutically acceptable salts also includes physiologically
acceptable solvates.
"Isomers" are compounds that have identical molecular formulae but that differ
in the nature or the sequence of bonding of their atoms or in the arrangement of their
atoms in space. Isomers that differ in the arrangement of their atoms in space are
termed "stereoisomers". Stereoisomers that are not mirror images of one another are
termed "diastereoisomers", and stereoisomers that are non-superimposable mirror
images are termed "enantiomers", or sometimes optical isomers. A carbon atom
bonded to four nonidentical substituents is termed a "chiral center".
hi detail, the present invention relates to compounds of the general formula
(Figure Removed)

wherein
R1 is selected from the group consisting of hydrogen,
lower alkyl, lower alkenyl,
eycloalkyl or lower cycloalkylalkyl, wherein the cycloalkyl ring may be
unsubstituted or substituted by one or two groups selected from the group
consisting of lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl, and
lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or
substituted by one or two groups selected from lower alkyl and halogen;
R2 is selected from the group consisting of hydrogen,
lower alkyl, lower alkenyl,
cycloalkyl or lower cycloalkylalkyl, wherein the cycloalkyl ring may be
unsubstituted or substituted by one or two groups selected from the group
consisting of lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl, and
lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or
substituted by one or two groups selected from lower alkyl and halogen; or
R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-
or 7-membered saturated or partly unsaturated heterocyclic ring optionally
containing a further heteroatom selected from nitrogen, oxygen or sulfur, said
saturated or partly unsaturated heterocyclic ring being unsubstituted or
substituted by one, two or three groups independently selected from the group
consisting of lower alkyl, halogen, halogenalkyl. cyano, hydroxy, hydroxyalkyl,
lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl;
A is selected from
(Figure Removed)

wherein
m is 0, 1 or 2;
R3 is lower alkyl;
n is 0, 1 or 2;
R7 is lower alkyl;
p is 0, 1 or 2;
q is 0, 1 or 2;
R5 is hydrogen or lower alkyl;
and pharmaceutically acceptable salts thereof.
Preferred compounds of formula I according to the present invention are those,
wherein R1 is selected from the group consisting of hydrogen, lower alkyl, lower
alkenyl, cycloalkyl, lower cycloalkylalkyl, wherein the cycloalkyl ring may be
unsubstituted or substituted by one or two groups selected from lower alkyl, lower
hydroxyalkyl or lower alkoxyalkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower
heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted
with one or two groups selected from lower alkyl or halogen, and
R2 is hydrogen or lower alkyl.
More preferred are compounds of formula I according to present invention,
wherein R1 is selected from the group consisting of lower alkyl, cycloalkyl, lower
cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted
lower alkoxyalkyl,
lower alkoxyalkyl, and lower heterocyclylalkyl wherein the heterocyclyl ring may be
unsubstituted or substituted with one or two groups selected from lower alkyl or
halogen,
and R2 is hydrogen or lower alkyl.
Especially preferred are those compounds of formula I, wherein R1 and R2 are
lower alkyl.
Another group of preferred compounds of formula I according to present
invention are those, wherein R1 and R2 together with the nitrogen atom to which they
are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated
heterocyclic ring optionally containing a further heteroatom selected from nitrogen,
oxygen or sulfur, said heterocyclic ring being unsubstituted or substituted by one, two
or three groups independently selected from lower alkyl, halogen, halogenalkyl,
cyano, hydroxy, hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and
carbamoyl.
Preferred compounds of formula I are those, wherein R1 and R2 together with
the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated
or partly unsaturated heterocyclic ring optionally containing a further heteroatom
selected from nitrogen, oxygen or sulfur, said heterocyclic ring being unsubstituted or
substituted by one, two or three groups independently selected from lower alkyl,
halogen, halogenalkyl, cyano, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and
carbamoyl.
More preferred are those compounds of formula I, wherein R1 and R2 together
with the nitrogen atom to which they are attached form a 4-, 5-, or 6- or 7-membered
saturated or partly unsaturated heterocyclic ring optionally containing a further
heteroatom selected from nitrogen, oxygen or sulfur, said heterocyclic ring being
unsubstituted or substituted by one, two or three groups independently selected from
lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower alkoxy, and oxo.
Even more preferred are compounds of formula I, wherein R1 and R2 together
with the nitrogen atom to which they are attached form a heterocyclic ring selected
from the group consisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine,
azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, said
heterocyclic ring being unsubstituted or substituted by one, two or three groups
independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy,
lower alkoxy, and oxo.
Especially preferred are compounds of formula I, wherein R1 and R2 together
with the nitrogen atom to which they are attached form a heterocyclic ring selected
from morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 3,6-dihydro-2Hpyridinyl,
piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-hydroxypiperidinyl,
4,4-difiuoropiperidinyl, 2,5-dihydropyrrolyl, 4-methylpiperidinyl, pyrrolidinyl, 2-
methylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-cyanopyrrolidinyl, 3-
hydroxypyrrolidinyl and azetidinyl.
Furthermore, compounds of formula I according to the present invention,
wherein A signifies
(Figure Removed)

and wherein m is 0, 1 or 2, and R3 is lower alkyl, are preferred.
Within this group, those compounds of formula I are preferred, wherein m is 0,
thus meaning pyrrolidine groups are preferred.
A further preferred group includes those compounds of formula I, wherein m is
1, thus meaning piperidine groups are also preferred.
Also preferred are compounds of formula I according to the present invention,
(Figure Removed)

and wherein n is 0, 1 or 2; and R4 is lower alkyl,, with those compounds, wherein n is
0, thus meaning pyrrolidine derivatives, being more preferred.
Further preferred compounds of formula I according to the present invention are
those, wherein A signifies
(Figure Removed)

wherein p is 0, 1 or 2, q is 0, 1 or 2, and R5 is hydrogen or lower alkyl.
Within this group, those compounds of formula I are preferred, wherein p is 1,
thus meaning piperidine groups are preferred. Especially preferred are those
compounds of formula I, wherein p is 1 and q is 1 .
Furthermore, compounds wherein R5 is hydrogen, are preferred.
Examples of preferred compounds of formula I are the following:
[6-(l-isopropyl-piperidin-4-yloxy)-quinolm-2-yl]-(4-methoxy-piperidin-l-yl)-
methanone,
(2,5-dihydro-pyrrol-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-
methanone,
6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl-methylamide,
-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin- 1 -yl)-
methanone,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid tert-butylamide,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid
cyclopropylmethyl-propyl-amide,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -(2-methyl-piperidin- 1 -yl)-
methanone,
(4-hydroxy-piperidin- 1 -yl)-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -
methanone,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -(3-methyl-piperidin- 1 -yl)-
methanone,
(3,4-dihydro-lH-isoquinolin-2-yl)-[6-(3-piperidin-l-yl-propoxy)-naphthalen-2-
yl]-methanone 1:1 hydrochloride,
[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-thiomorpholin-4-ylmethanone,
[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidinl-
yl)-methanone,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl-(2-
methoxy-ethyl)-amide,
azetidin-1 -yl-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
(3,6-dihydro-2H-pyridin-1 -yl)-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-
yl]-methanone,
6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-
3-ylmethyl)-amide,
6-0-iopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (1-
methoxymethyl-cyclopropylmethyl)-amide,
{6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid [2-(tetrahydropyran-
4-yl)-ethyl]-amide,
[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-morpholin-4-yl-methanone,
6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid cyclohexylmethyl-
amide,
(4,4-difluoro-piperidin-1 -yl)-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yljmethanone,
(3-hydroxy-pyrrolidin-1 -yl)-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-
methanone,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -pyrrolidin-1 -yl-methanone,
(R)-l-[6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-
carbonitrile,
(1,1 -dioxo-thiomorpholin-4-yl)-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-
yl]-methanone,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid dimethylamide
(2,5-dihydro-pyrrol-l-yl)-[6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-
methanone,
([6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-l-yl)-
methanone,
6-( 1 -isopropyl-pyrrolidin-3 -yloxy)-quinoline-2-carboxylic acid ethyl-methylamide,
([6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(4-methyl-piperidin-l-yl)-
methanone,
[6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin-1 -yl)-
methanone,
6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid tert-butylamide,
6-(l -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid
cyclopropylmethyl-propyl-amide,
{[6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-methyl-piperidin-1 -yl)-
methanone,
[6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(3-methyl-piperidin-1 -yl)-
methanone,
6-(l-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid isopropylmethyl-
amide,
[6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-thiomorpholin-4-ylmethanone,
[6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidinl-
yl)-methanone,
6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid ethyl-(2-
methoxy-ethyl)-amide,
azetidin-l-yl-[6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,
(3,6-dihydro-2H-pyridin-1 -yl)-[6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinolin-2-
yl]-methanone,
6-(l-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid (3-fluorooxetan-
3-ylmethyl)-amide,
6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid (1 -
methoxymethyl-cyclopropylmethyl)-amide,
6-(l -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid [2-(tetrahydropyran-
4-yl)-ethyl]-amide,
(4,4-difluoro-piperidin-l-yl)-[6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-
methanone,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -morpholin-4-yl-methanone,
(4-methoxy-piperidin-1 -yl)-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-
methanone,
(4-methyl-piperidin-1 -yl)-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-
methanone
morpholin-4-yl-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
(2-methyl-pyrrolidin-1 -yl)-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-
methanone,
6-(3-piperidin-1 -yl-propoxy)-quinoline-2-carboxylic acid cyclopropylmethylpropyl-
amide,
[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-1 -yl)-
methanone,
(2,5-dihydro-pyrrol-l-yl)-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-
methanone,
6-(3-piperidin-1 -yl-propoxy)-quinoline-2-carboxylic acid ethyl-(2-methoxyethyl)-
amide,
azetidin-l-yl-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
(3,6-dihydro-2H-pyridin-1 -yl)-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-
methanone,
(4,4-difluoro-piperidin-1 -yl)-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-
methanone,
6-(3-piperidin-l -yl-propoxy)-quinoline-2-carboxylic acid cyclohexyl-methylamide,
' 6-(3-piperidin-l-yl-propoxy)-quinoline-2-carboxylic acid (1-methoxymethylcyclopropylmethyl)-
amide,
6-(3-piperidin-l-yl-propoxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-
ylmethyl)-amide,
6-(3-piperidin-1 -yl-propoxy)-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-
4-yl)-ethyl]-amide,
6-(3-piperidin-1 -yl-propoxy)-quinoline-2-carboxylic acid (tetrahydro-pyran-4-
yl)-amide,
(2-methyl-piperidin-1 -yl)-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-
methanone,
[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-pyrrolidin-l-yl-methanone,
(R)-1 -[6-(3-piperidin-1 -yl-propoxy)-quinoline-2-carbonyl]-pyrrolidine-2-
carbonitrile,
(l,l-dioxo~thiomorpholin-4-yl)-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-
methanone,
(4-methyl-piperidin-1 -yl)- {6-[2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-
yl}-methanone,
{6-[2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy] -quinolin-2-yl} -pyrrolidin-1 -ylmethanone,
(R)-1 - {6-[2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carbonyl} -
pyrrolidine-2-carbonitrile,
(1,1 -dioxo-thiomorpholin-4-yl)- {6- [2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy]-
quinolin-2-yl} -methanone,
(4-methoxy-piperidin-l-yl)-{6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-
2-yl}-methanone,
{6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-morpholin-4-ylmethanone,
azetidin-1 -yl- {6-[2-(l -methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl} -
methanone,
6-[2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid [2-
(tetrahydro-pyran-4-yl)-ethyl]-amide,
6-[2-(l -methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid (3-fluorooxetan-
3-ylmethyl)-amide,
(2-methyl-pyrrolidin-1 -yl)- {6-[2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-
yl}-methanone,
(S)-l-[6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-
carbonitrile,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methyl-piperidin-1 -yl)-
methanone,
(4-hydroxymethyl-piperidin-1 -yl)-[6-(l -isopropyl-piperidin-4-yloxy)-quinolin-
2-yl]-methanone,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutyl-amide,
6-(l-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid cyclohexylmethyl-
amide,
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula I of the present invention are the
following:
[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-l-yl)-
methanone,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolm-2-yl]-(2-memyl-pyrrolidin-1 -yl)-
methanone,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -(2-trifluoromethyl-pyrrolidin-
1 -yl)-methanone,
azetidin-l-yl-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-
3-ylmethyl)-amide,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (1 -
methoxymethyl-cyclopropylmethyl)-amide,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-pyrrolidin-1 -yl-methanone,
(R)-1 - [6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl] -pyrrolidine-2-
carbonitrile,
azetidin-1 -yl-[6-(3-piperidin-1 -yl-propoxy)-quinolin-2-yl]-methanone,
(R)-1 -[6-(3-piperidin-1 -yl-propoxy)-quinoline-2-carbonyl]-pyrrolidine-2-
carbonitrile,
(S)-1-[6-( 1-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-
carbonitrile,
and pharmaceutically acceptable salts thereof.
Furthermore, the pharmaceutically acceptable salts of the compounds of formula
I and the pharmaceutically acceptable esters of the compounds of formula I
individually constitute preferred embodiments of the present invention.
Compounds of formula I may form acid addition salts with acids, such as
conventional pharmaceutically acceptable acids, for example hydrochloride,
hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulphate, pyruvate,
citrate, lactate, mandelate, tartrate, and methanesulphonate. Preferred are the
hydrochloride salts. Also solvates and hydrates of compounds of formula I and their
salts form part of the present invention.
Compounds of formula I can have one or more asymmetric carbon atoms and
can exist in the form of optically pure ehantiomers, mixtures of enantiomers such as,
for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers,
diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically
active forms can be obtained for example by resolution of the racemates, by
asymmetric synthesis or asymmetric chromatography (chromatography with a chiral
adsorbens or eluant). The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula I in this invention
may be derivatised at functional groups to provide derivatives which are capable of
conversion back to the parent compound in vivo. Physiologically acceptable and
metabolically labile derivatives, which are capable of producing the parent
compounds of general formula I in vivo are also within the scope of this invention.
A further aspect of the present invention is the process for the manufacture of
compounds of formula I as defined above, which process comprises
reacting a compound of the formula II
O '
wherein R is lower alkyl,
with an alcohol of the formula III
HO-A III
wherein A is as defined herein before,
in the presence of a trialkylphosphine or triphenylphosphine and of a diazo compound
to obtain a compound of the formula IV
(Figure Removed)

and converting the ester of formula IV into the acid of formula V
(Figure Removed)

under acidic or basic conditions,
and coupling the compound of formula V with an amine of the formula VI
(Figure Removed)

wherein R1 and R2 are as defined herein before, with the help of an coupling
agent
under basic conditions to obtain a compound of the formula I
(Figure Removed)

wherein A, R1 and R2 are as defined herein before,
and if desired,
converting the compound obtained into a pharmaceutically acceptable salt.
Coupling agents for the reaction of compounds of formula V with amines of
formula VI are for example N,N'-carbonyldiimidazole (CDI), N,N'-
dicyclohexylcarbodiimide (DCC), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI), 1 -[bis(dimethylamino)rnethylene]-1H-1,2,3-triazolo[4,5-
b]pyridinium-3-oxide hexafluorophosphate (HATU), l-hydroxy-l,2,3-benzotriazole
(HOBT), or O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU).
In more detail, the compounds of formula I can be manufactured by the methods
given below, by the methods given in the examples or by analogous methods.
Appropriate reaction conditions for the individual reaction steps are known to a
person skilled in the art. Starting materials are either commercially available or can be
prepared by methods analogous to the methods given below, by methods described in
references cited in the text or in the examples, or by methods known in the art.
(Figure Removed)

Compounds of formula II can be manufactured starting from commercially
available 6-methoxy-quinoline (1) that can converted to the N-oxide 2 by reaction
with hydrogen peroxide and a solvent like acetic acid under refluxing conditions. The
6-methoxy-quinoline-1-oxide is reacted with silver cyanide and benzoyl chloride to
obtain the 6-methoxy-quinoline-2-carbonitrile 3 via a modification of the Reisset'sche
reaction (Ber., 38, 1610 (1905). Hydrolysis of the cyano group can be affected by
employing an acidic or basic medium. We find it convenient to use a base like sodium
hydroxide and after acidic treatment of the mixture we obtained the corresponding 6-
methoxy-quinoline-2-carboxylic acid 4. Removal of the methyl group with an acid
like hydrobromic acid 48% in water gives 6-hydroxy-quinoline-2-carboxylic acid (5).
The acid can be esterified with an alcohol like ethanol and an acid like sulfuric acid to
yield the 6-hydroxy-quinoline-2-carboxylic acid ester II, for example 6-hydroxyquinoline-
2-carboxylic acid ethyl ester (Ha).
The preparation of compounds of formula I of the present invention may be
carried out in sequential or convergent synthetic routes. Syntheses of the invention are
shown in the following scheme. The skills required for carrying out the reaction and
purification of the resulting products are known to those in the art. The substituents
and indices used in the following description of the processes have the significance
given above unless indicated to the contrary.
(Figure Removed)

Compounds of general formula I can be prepared according to scheme 2 as
follows:
a) The syntheses of ethers are widely described in literature and the procedures are
known to those in the art (For reaction conditions described in literature affecting
such reactions see for example: Comprehensive Organic Transformations: A
Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John
Wiley & Sons, New York, 1999). The transformation can be affected by
employing reaction conditions which are commonly utilised in the so called
"Mitsunobu reaction" which is known to those in the art and widely described
(Hughes, David L. The Mitsunobu reaction. Organic Reactions (John Wiley &
Sons, New York, 1992, 42, 335-656) We find it convenient to couple an ester of
formula II with alcohols of formula III (either commercially available or
accessible by methods described in references or by methods known in the art; as
appropriate) under conditions employing a phosphine like a trialkylphosphine such
as tributylphosphine ((n-Bub.P), triphenylphosphine (PhsP) and the like and a
diazo-compound like diethyl-azodicarboxylate (DEAD), diisopropylazodicarboxylate
(DIAD) (optionally polymer bound), tetramethyl
azodicarboxamide and the like in a solvent commonly used in such
transformations like tetrahydrofurane (THF), toluene, dichloromethane and the
like. There is no particular restriction on the nature of the solvent to be employed,
provided that it has no adverse effect on the reaction or the reagents involved and
that it can dissolve the reagents, at least to some extent. The reaction can take
place over a wide range of temperatures, and the precise reaction temperature is
not critical to the invention. We find it convenient to carry out the reaction with
heating from ambient temperature to reflux. The time required for the reaction
may also vary widely, depending on many factors, notably the reaction
temperature and the nature of the reagents. However, a period of from 0.5 h to
several days will usually suffice to yield the compounds of formula IV.
b) The hydrolysis of esters are widely described in literature and the procedures are
known to those in the art (For reaction conditions described in literature affecting
such reactions see for example:). The transformation can be affected by employing
acidic or basic medium. We find it convenient to use acidic conditions employing
an acid like HC1 and a solvent like dioxane, THF and the like. There is no
particular restriction on the nature of the solvent to be employed, provided that it
has no adverse effect on the reaction or the reagents involved and that it can
dissolve the reagents, at least to some extent. The reaction can take place over a
wide range of temperatures, and the precise reaction temperature is not critical to
the invention. We find it convenient to carry out the reaction with heating from
ambient temperature to reflux. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature and the
nature of the reagents. However, a period of from 0.5 h to several days will usually
suffice to yield the title compounds VI.
c) The coupling of carboxylic acids with amines is widely described in literature and
the procedures are known to those in the art (For reaction conditions described in
literature affecting such reactions see for example: Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard
C. Larock. John Wiley & Sons, New York, 1999). 6-Alkoxy-quinoline-2-
carboxylic acids of formula IV can conveniently be transformed to the respective
amide through coupling with an amine V (either commercially available or
accessible by methods described in references or by methods known in the art; as
appropriate) by employing the usage of coupling agents. For example coupling
agents like N,N'-carbonyldiimidazole (GDI), N,N'-dicyclohexylcarbodiimide
(DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-
[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide
hexafluorophosphate (HATU), l-hydroxy-l,2,3-benzotriazole (HOBT), Obenzotriazol-
l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and
the like can equally well be employed to affect such transformation. We find it
convenient to carry out the reaction in a solvent like dimethylformamide (DMF)
and in the presence of a base. There is no particular restriction on the nature of the
solvent to be employed, provided that it has no adverse effect on the reaction or
the reagents involved and that it can dissolve the reagents, at least to some extent.
Examples for suitable solvents include: DMF, dichloromethane (DCM), dioxane,
THF, and the like. There is no particular restriction on the nature of the base used
in this stage, and any base commonly used in this type of reaction may equally be
employed here. Examples of such bases include triethylamine and
diisopropylethylamine, and the like. The reaction can take place over a wide range
of temperatures, and the precise reaction temperature is not critical to the
invention. We find it convenient to carry out the reaction with heating from
ambient temperature to reflux. The time required for the reaction may also vary
widely, depending on many factors, notablv the reaction temperature and the
nature of the reagents. However, a period of from 0.5 h to several days will usually
suffice to yield amide derivatives of formula I.
As described above, the compounds of formula I of the present invention can be
used as medicaments for the treatment and/or prevention of diseases which are
associated with the modulation of H3 receptors. Examples of such diseases are
obesity, metabolic syndrome (syndrome X), neurological diseases including
Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive
impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy,
neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple
sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and
sleep disorders including narcolepsy, and other diseases including asthma, allergy,
allergy-induced airway responses, congestion, chronic obstructive pulmonary disease
and gastro-intestinal disorders. The use as medicament for the treatment and/or
prevention of obesity is preferred.
The invention therefore also relates to pharmaceutical compositions comprising
a compound as defined above and a pharmaceutically acceptable carrier and/or
adjuvant.
Further, the invention relates to compounds as defined above for use as
therapeutically active substances, particularly as therapeutic active substances for the
treatment and/or prevention of diseases which are associated with the modulation of
H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome
X), neurological diseases including Alzheimer's disease, dementia, age-related
memory dysfunction, mild cognitive impairment, cognitive deficit, attention deficit
hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine,
Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression,
addiction, motion sickness and sleep disorders including narcolepsy, and other
diseases including asthma, allergy, allergy-induced airway responses, congestion,
chronic obstructive pulmonary disease and gastro-intestinal disorders.
In another embodiment, the invention relates to a method for the treatment
and/or prevention of diseases which are associated with the modulation of H3
receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X),
neurological diseases including Alzheimer's disease, dementia, age-related memory
dysfunction, mild cognitive impairment, cognitive deficit, attention deficit
hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine,
Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression,
addiction, motion sickness and sleep disorders including narcolepsy, and other
diseases including asthma, allergy, allergy-induced airway responses, congestion,
chronic obstructive pulmonary disease and gastro-intestinal disorders. A method for
the treatment and/or prevention of obesity is preferred.
The invention further relates to the use of compounds of formula I as defined
above for the treatment and/or prevention of diseases which are associated with the
modulation of H3 receptors. Examples of such diseases are obesity, metabolic
syndrome (syndrome X), neurological diseases including Alzheimer's disease,
dementia, age-related memory dysfunction, mild cognitive impairment, cognitive
deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain,
inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke,
dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorders
including narcolepsy, and other diseases including asthma, allergy, allergy-induced
airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal
disorders. The use of compounds of formula I as defined above for the
treatment and/or prevention of obesity is preferred.
In addition, the invention relates to the use of compounds of formula I as
defined above for the preparation of medicaments for the treatment and/or prevention
of diseases which are associated with the modulation of H3 receptors. Examples of
such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases
including Alzheimer's disease, dementia, age-related memory dysfunction, mild
cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder,
epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple
sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and
sleep disorders including narcolepsy, and other diseases including asthma, allergy,
allergy-induced airway responses, congestion, chronic obstructive pulmonary disease
and gastro-intestinal disorders. The use of compounds of formula I as defined above
for the preparation of medicaments for the treatment and/or prevention of obesity is
preferred.
The compounds of formula I and their pharmaceutically acceptable salts possess
valuable pharmacological properties. Specifically, it has been found that the
compounds of the present invention are good histamine 3 receptor (H3R) antagonists
and/or inverse agonists.
The following test was carried out in order to determine the activity of the
compounds of formula (I).
Binding assay with 3H-(R)a-methvlhistamine
Saturation binding experiments were performed using HR3-CHO membranes
prepared as described in Takahashi, K, Tokita, S., Kotani, H. (2003) J. Pharmacol.
Exp. Therapeutics 307, 213-218.
An appropriate amount of membrane (60 to 80 jxg protein/well) was incubated
with increasing concentrations of 3H(R)oc-Methylhistamine di-hydrochloride (0.10 to
10 nM). Non specific binding was determined using a 200 fold excess of cold (R)a-
Methylhistamine dihydrobromide (500 nM final concentration). The incubation was
carried out at room temperature (in deep-well plates shaking for three hours). The
final volume in each well was 250 \il. The incubation was followed by rapid filtration
on GF/B filters (pre-soaked with 100 ul of 0.5% PEI in Tris 50 mM shaking at 200
rpm for two hours). The filtration was made using a cell-harvester and the filter plates
were then washed five times with ice cold washing buffer containing 0.5 M NaCl.
After harvesting, the plates were dried at 55 °C for 60min, then we added scintillation
fluid (Microscint 40, 40 microl in each well) and the amount of radioactivity on the
filter was determined in Packard top-counter after shaking the plates for two hours at
200 rpm at room temperature.
Binding Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl2x 6H2O pH 7.4.
Washing Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl2x6H2O and 0.5 M NaCl
pH 7.4.
Indirect measurement of affinity of HSR inverse agonists: twelve increasing
concentrations (ranging from 10 uM to 0.3 nM) of the selected compounds were
always tested in competition binding experiments using membrane of the human
HR3-CHO cell line. An appropriate amount of protein, e.g. approximately SOOcpm
binding of RAMH at Kd, were incubated for 1 hour at room temperature in 250 ul
final volume in 96-well plates in presence of 3H(R)a-Methylhistamine (1 nM final
concentration = Kd), Non-specific binding was determined using a 200 fold excess of
cold (R)cc -Methylhistamine dihydrobromide.
All compoundswere tested at a single concentration in duplicates. Compounds
that showed an inhibition of [3H]-RAMH by more than 50% were tested again to
determine IC50 in a serial dilution experiment. Ki's were calculated from IC50 based
on Cheng-Prusoff equation ( Cheng, Y, Prusoff, WH '1973) Biochem Pharmacol 22,
3099-3108).
The compounds of the present invention exhibit Kj values within the range of
about 1 nM to about 1000 nM, preferably of about 1 nM to about 100 nM, and more
preferably of about 1 nM to about 30 nM. The following table shows measured values
for some selected compounds of the present invention.
The following table shows measured values for some selected compounds of the
present invention.
(Figure Removed)

The compounds of formula (I) and their pharmaceutically acceptable salts and
esters can be used as medicaments, e.g. in the form of pharmaceutical preparations for
enteral, parenteral or topical administration. They can be administered, for example,
perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine
capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of
suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions,
or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner
which will be familiar to any person skilled in the art by bringing the described
compounds of formula (I) and their pharmaceutically acceptable, into a galenical
administration form together with suitable, non-toxic, inert, therapeutically
compatible solid or liquid carrier materials and, if desired, usual pharmaceutical
adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also
organic carrier materials. Thus, for example, lactose, corn starch or derivatives
thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine
capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid
polyols (depending on the nature of the active ingredient no carriers are, however,
required in the case of soft gelatine capsules). Suitable carrier materials for the
production of solutions and syrups are, for example, water, polyols, sucrose, invert
sugar and the like. Suitable carrier materials for injection solutions are, for example,
water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for
suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or
liquid polyols. Suitable carrier materials for topical preparations are glycerides, semisynthetic
and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,
liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistencyimproving
agents, flavour-improving agents, salts for varying the osmotic pressure,
buffer substances, solubilizers, colorants and masking agents and antioxidants come
into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula (I) can vary within wide limits
depending on the disease to be controlled, the age and the individual condition of the
patient and the mode of administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily dosage of about 1 mg to
about lOOOmg, especially about 1 mg to about lOOmg, comes into consideration.
Depending on the dosage it is convenient to administer the daily dosage in several
dosage units.
The pharmaceutical preparations conveniently contain about 0.1-500 mg,
preferably 0.5-100 mg, of a compound of formula (I),
The following examples serve to illustrate the present invention in more detail.
They are, however, not intended to limit its scope in any manner.
Examples
Intermediate 1
6-Hvdroxy-quinoline-2-carboxvlic acid ethyl ester
a) 6-Methoxv-quinoline 1-oxide
6-Methoxy quinoline (15 g, 0.094 mol) was dissolved in acetic acid (97 ml) and
treated with hydrogen peroxide (37 ml). The mixture was stirred to 100 °C for 2
hours. After vaporation to dryness 100 ml of water was added to the residue until a
precipitate appears. Filtration and washing with water gives a yellow precipitate that is
dried under vacuum to yield 13.5 g of the title compound as a light yellow solid (82
%). MS (m/e): 176.3 (M+ H) +.
30
b) 6-Methoxv-quinoline-2-carbonitrile
6-Methoxy-quinoline-l -oxide (13.48 g, 0.076mol) in 30 ml chloroform was
treated with 3.87 g (0.028 mol) of benzoyl chloride and 3.65 g (0.0 27 mol) of silver
cyanide. The mixture was stirred for 4 hours at room temperature and stirred to reflux
for additional 14 h. After evaporation of the solvent to half volume the mixture was
cooled to 0 °C and a precipitate of silver salt appeared. The mixture was filtered and
the solution was concentrated and the solid residue was washed in diethyl ether and
dried under vacuum to yield 1 1 g (82 %) of the title compound as light brown solid.
MS(m/e)=185.3(M+H)+.
c) 6-Methoxy-quinoline-2-carboxylic acid
6-Methoxy-quinoline-2-carbonitrile (9.3 g, 0.050 mol) in 96 ml methanol was
treated with 240 ml of 20% NaOH and the mixture was heated to 120 °C in a sealed
tube overnight. After cooling to 0 °C a precipitate appeared. The mixture was filtered
to get a sodium salt that was suspended in water. HC1 25% *vas added until pH 3-4 to
get the acid as a precipitate that was filtered and dried under vacuum. The mother
liquid of the first filtration was acidified with HC1 25% until pH 3-4 until a precipitate
appeared. The precipitate was filtered and the solid was washed in water and dried
under vacuum to yield 9.6 g (86 %) of the title compound as light brown solid. MS
(m/e)=204(M+H)+.
d) 6-Hydroxy-quinoline-2-carboxylic acid
(Figure Removed)

-quinoline-2-carboxylic acid (4 g, 0.019 mol) was suspended in
hydrobromic acid 48% in water (80 ml) and the mixture was heated at 125 °C
overnight. After cooling to 0 °C ammonium hydroxide was added until the pH was 6-
31
7 followed by addition of HC1 until the pH was 3-4 and the compound precipitated.
The solid was filtrated, washed with water and dried under vacuum to yield 3.5 g
(0.0185 mol, 97% of theory) of the title compound as a yellow solid MS (m/e>= 190.1
e) 6-Hvdroxv-qumoline-2-carboxylic acid ethyl ester
6-Hydroxy-quinoline-2-carboxylic acid (2.3 g, 0.012 mol) was dissolved in
absolute ethanol (150 ml). Sulfuric acid (0.550ml, 0.0096 mol) was added and the
mixture was refluxed for 16 hours. After cooling to room temperature the ethanol was
evaporated and 60 ml of ethyl acetate, 50 ml of cooled water were added. The pH was
adjusted to 7 with solid NaHCOs. Extraction and concentration of the organic phase
gave the title product as a light yellow solid that was used for the next steps without
purification (2.1 g, 81% of theory). MS (m/e)= 218.4 (M+ H)+.
Intermediate 2
(6-(l-IsoDroDvl-piDeridin-4-vloxv)-auinoline-2-carboxylic acid 1:1 hvdrochloride
a) 6-(l-Isopropvl-piperidin-4-vloxv)-quinoline-2-carboxylic acid ethyl ester
A mixture of 1 g (0.0046 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl
ester, 2.4 g (0.0092 mol) of triphenylphospine (Fluka), 2.4 g (0.0092 mol) of 1-
isopropyl-piperidin-4-ol and 1.6 ml (0.0092 mol) of di-tert.-butyl azadicarboxylate
40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35 °C.
The mixture was filtered through a pad of silica and washed with 30 ml THF. The
mixture was evaporated to dryness and purified on silica eluting with a gradient of
DCM/ MeOH 98/2. The product fractions were evaporated and the residue was
triturated with diethyl ether to yield after drying under vacuum 1.3 mg (83 %) of the
title compound as white solid. MS (m/e): 343.3 (M+ H)+.
b) 6-(l-Isopropvl-piperidin-4-vloxv)-quinoline-2-carboxylic acid 1:1 hvdrochloride
6-(l-Isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl ester (1.1 g,
0.0033 mol) was dissolved in dioxane (25 ml). HCI 37% (2.06 ml, 0.066 mol) was
added and the mixture was stirred at 85 °C for 16 hours. Dioxane was evaporated and
toluene (3x15 ml) was used to remove the remaining water by azeotropic destination.
After evaporation of the toluene the title compound was obtained as a yellow solid
after drying under vacuum (1.3 g, 100% of theory). MS (m/e)= 315.2 (M+ H)+.
Intermediate 3
6-(l-Isopropvl-pvrrolidin-3-vloxv)-quinoline-2-carboxylic acid acid 1;1
hvdrochloride
a) 6-(l-Isopropvl-pyiTolidin-3-vloxv)-quinoline-2-carboxvlic acid ethyl ester
A mixture of 0.960 g (0.0044 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl
ester, 2.32 g (0.0088 mmol) of triphenylphospine (Fluka), 0.739g (0.0057 mmol) of 1-
isopropyl-3-pyrrolidinol and 1.61 ml (0.0088 mmol) of di-tert.-butyl azadicarboxylate
40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35 °C.
The mixture was filtered through a pad of silica and washed with 30 ml of THF. The
mixture was evaporated to dryness and purified on silica eluting with a gradient of
DCM/ MeOH 98/2. The product fractions were evaporated and the residue was
triturated with diethyl ether to yield after drying under vacuum 1.35 g (94 %) of the
title compound as white solid. MS (m/e): 329.3 (M+ H)+.
b) 6-(l-Isopropvl-pyrrolidin-3-vloxvVquinoline-2-carboxvlic acid acid 1:1
hvdrochloride
6-(l-Isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid ethyl ester (0.5
g, 0.002 mol) was dissolved in dioxane (20 ml). HCI 37% (0.94 ml, 0.03 mol) was
added and the mixture was stirred at 85 °C for 16 hours. Dioxane was evaporated and
toluene ( 3 x 15 ml) was used to remove the remaining water by azeotropic
destination. After evaporation of the toluene the title compound was obtained as a
yellow solid after drying under vacuum (0.570 g, 100 % of theory). MS (m/e)= 301.2
Intermediate 4
6-(3-Piperidin-l-yl-propoxy)-quinoline-2-carboxvlic acid 1:1 hvdrochloride
a) 6-(3-Piperidin-l-vl-propoxv)-quinoline-2-carboxvlic acid ethyl ester
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl
ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 3-
piperidin-1-yl-propan-l-ol and 0.68 ml (0.004 mmol) of di-tert.-butyl
azadicarboxylate 40% in toluene in 40 ml THF was stirred for a prolonged period of
time at 35 °C. The mixture was filtered through a pad of silica and washed with 30 ml
THF. The mixture was evaporated to dryness and purified on silica eluting with a
gradient of DCM/ MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The product fractions
were evaporated and the residue was triturated with diethyl ether to yield after drying
under vacuum 0.600 g (93 %) of the title compound as white solid. MS (m/e): 343.3
(M+ H)+.
b) 6-(3-Piperidin-l-vl-proDoxvVquinoline-2-carboxvlic acid 1:1 hvdrochloride
HCI
6-(3-Piperidin-l-yl-propoxy)-quinoline-2-carboxylic acid ethyl ester (0.6 g, 0.002
mol) was dissolved in dioxane (20 ml). HCI 37% (1.08 ml, 0.035 mol) was added and
the mixture was stirred at 85 °C for 16 hours. Dioxane was evaporated and toluene ( 3
x 10 ml) was used to remove the remaining water by azeotropic destination. After
evaporation of the toluene the title compound was obtained as a yellow solid after
drying under vacuum (0.592 g, 96% of theory). MS (m/e)= 315.3(M+ H)+.
Intermediate 5
6-[2-(l-Methvl-pvrrolidin-2-vtVethoxv1-qumoline-2-carboxvlic acid 1;1
hydrochloride
al 6-F2-( 1 -Methvl-pvrrolidm-2-vl)-ethoxv1-quinoline-2-carboxvlic acid ethyl ester
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl
ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 1-
methyl-2-pyrrolidineethanol and 0.68 ml (0.004 mmol) di-tert.-butyl azadicarboxylate
40% in toluene in 40 ml THF was stirred for a prolonged period of time at 35 °C. The
mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture
was evaporated to dryness and purified on silica eluting with a gradient of DCM/
MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The product fractions were evaporated
and the residue was triturated with diethyl ether to yield after drying under vacuum
0.317 g (53 %) of the title compound as white solid. MS (m/e): 329.2 (M+ H)+.
b) 6-[2-(l-Methvl-pvrrolidin-2-vl)-ethoxy]-quinoline-2-carboxvlic acid 1:1
hydrochloride
6-[2-(l-Methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid ethyl ester (0.310
g, 0.001 mol) was dissolved in dioxane (10 ml). HC1 37% (0.580 ml, 0.019 mol) was
added and the mixture was stirred at 85 °C for 16 hours. Dioxane was evaporated and
toluene (3x10 ml) was used to remove the remaining water by azeotropic destination.
After evaporation of the toluene the title compound was obtained as a yellow solid
after drying under vacuum (0.395g, 96% of theory). MS (m/e)- 301.3 (M+ H)+.
Example 1
(2.5-Dihvdro-pyrrol-l-vlH6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-vl1-
methanone
6-(l-Isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride
(30 mg, 0.086 mmol, see intermediate 2) was dissolved in DMF (0.300 ml). 1,1'-
Carbonyl-diimidazole (17 mg, 0.10 mmol) was added and the mixture was stirred for
half an hour. 4-Methoxy-piperidine was added (6 mg, 0.014 mmol) and the mixture
was stirred overnight. The mixture was diluted with 0.4 ml methanol and subjected to
preparative HPLC purification on reversed phase material eluting with a gradient of
acetonitrile/water/ triethylamine. The product fractions were evaporated to dryness to
yield 4.7 mg (14 %) of the title compound as light brown solid. MS (m/e): 412.4
(MH+, 100%).
According to the procedure described for the synthesis of example 1 further
derivatives have been synthesised from 6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-
carboxylic acid 1:1 hydrochloride and the respective amines . The results are shown in
(Table Removed)

(2.5-Dihydro-pyrrol-l-vl)-[6-(l-isopropvl-pvrrolidin-3-yloxv)-quinolin-2-vl1-
methanone
According to the procedure described for the synthesis of example 1, (2,5-
dihydro-pyrrol-1 -yl)-[6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone
was synthesized from 6-(l-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid
1:1 hydrochloride (intermediate 3) and 2,5-dihydropyrrole (commercially available).
The title compound was yielded in 18 % (5.7mg) as off-white solid. MS (m/e): 352.5
(MH+, 100%).
Accordingly, further derivatives have been synthesised from 6-(l-isopropylpyrrolidin-
3-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride and the respective
amines. The results are shown in table 2 and comprise examples 28 to 46.
(Table Removed)

Example 47
f4-Methoxv-piperidin-l-ylVf6-f3-piperidin-l-vl-propoxy)-quinolin-2-vUmethanone
According to the procedure described for the synthesis of example 1, (4-
methoxy-piperidin-l-yl)-[6-(3-piperidm-l-yl-propoxy)-quinolin-2-yl]-methanone was
synthesized from 6-(3-piperidin-l-yl-propoxy)-quinoline-2-carboxylic acid 1:1
hydrochloride (intermediate 4) and 4-methoxy-piperidine (commercially available).
The title compound was yielded in 22% (7.8mg) as off-white solid. MS (m/e): 412.4
(MH+, 100%).
Accordingly, further derivatives have been synthesised from 6-(3-piperidin-1-ylpropoxy)-
quinoline-2-carboxylic acid 1:1 hydrochloride and the respective amines.
The results are shown in table 3 and comprise examples 48 to 66.
xample 67
(Table Removed)

(4-Methvl-piperidin-l-vn-(6-[2-(l-methvl-pvrrolidin-2-ylVethoxvl-quinolin-2-
vll-methanone
According to the procedure described for the synthesis of example 1, (4-methylpiperidin-
1 -yl)- {6-[2-(l -methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl} -methanone
was synthesized from 6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic
acid 1:1 hydrochloride (intermediate 5) and 4-methyl-piperidine (commercially
available). The title compound was yielded in 13% (4.2mg) as white solid. MS (m/e):
382.4(MH+, 100%).
According to the procedure described for the synthesis of example 67 further
derivatives have been synthesised from 6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-
quinoline-2-carboxylic acid 1:1 hydrochloride and the respective amines. The results
are shown in table 4 and comprise examples 68 to 76.
(Table Removed)

Example 77
(SVl-[6-(l-IsopropvI-piperidin-4-vloxv)-quinoline-2-carbonyll-pyrrolidine-2-
carbonitrile
According to the procedure described for the synthesis of example 1, (S)-l-[6-
(1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl] -pyrrolidine-2-carbonitrile was
synthesized from 6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1
hydrochloride, (S)-cyanopyrrolidine (commercially available) and O-(benzotriazol-lyl)-
N,N,N',N'-tetrainethyluromum tetrafluoroborate instead of 1,1 '-carbonyldiimidazole.
The title compound was yielded in 45% (50 mg) as colorless foam. MS
(m/e): 392.9 (M).
Example 78
[6-(l-Isopropvl-piperidin-4-YloxyVquinoHn-2-vll-(4-methvl-piperidin-l-vl^-
methanone
According to the procedure described for the synthesis of example 1, [6-(lisopropyl-
piperidin-4-yloxy)~quinolin-2-yl] -(4-methyl-piperidin-1 -yl)-methanone was
synthesized from 6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1
hydrochloride, 4-methylpiperidine (commercially available) and l,l'-carbonyldiimidazole.
MS (m/e): 396.6 (M+H).
Example.79
(4-Hydroxymethvl-piperidin-l-YlVt6-(l-isopropyl-piperidin-4-vloxy>-qMinolin-2-
yll-methanone
According to the procedure described for the synthesis of example 1, (4-
hydroxymethyl-piperidin-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-
methanone was synthesized from 6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-
carboxylic acid 1:1 hydrochloride, 4-hydroxymethyi piperidine (commercially
available) and l,r-carbonyl-diimidazole. MS (m/e): 412.5 (M+H).
Example 80
6-{l-Isopropvl-piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutvl-amide
According to the procedure described for the synthesis of example 1, (6-(lisopropyl-
piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutyl-amide was
synthesized from 6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1
hydrochloride, isobutylamine (commercially available) and l,r-carbonyl-diimidazole.
MS (m/e): 370.6 (M+H).
Example 81
6-(l-Isopropyl-pyrrolidm-3-yloxy)-q uinoline-2-carboxylic acid cyclohexylmethyl-
amide
According to the procedure described for the synthesis of example 27, 6-(lisopropyl-
pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide
was synthesized from 6-(l-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid
1:1 hydrochloride (intermediate 3), N-methylcyclohexylamine (commercially
available) and 1,1 '-carbonyl-diimidazole. MS (rh/e): 396.4 (M+H).
Example A
Film coated tablets containing the following ingredients can be manufactured in
a conventional manner:
Ingredients Per tablet
Kernel:
Compound of formula (I) lO.Omg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
PovidoneK30 12.5mg 15.0mg
Sodium starch glycolate 12.5 mg. 17.0 mg
Magnesium stearate 1.5 nig 4.5 mg
(Kernel Weight) 120.0mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6mg
Talc 1.3mg 2.6 mg
Iron oxyde (yellow) 0.8 mg 1.6 mg
Titanium dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcristalline cellulose and the
mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate
is mixed with sodium starch glycolate and magesiumstearate and compressed to yield
kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous
solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a
conventional manner:
Ingredients Per capsule
Compound of formula (I) 25.0 mg
Lactose ISO.Omg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg
Gelatine 150.0mg
Phenol 4.7 mg
Sodium carbonate to obtain a final pH of 7
Water for injection solutions ad 1.0 ml
Example D
Soft gelatin capsules containing the following ingredients can be manufactured
in a conventional manner:
Capsule contents
Compound of formula (I) . S.Omg
Yellow wax 8.0 mg
Hydrogenated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oil HO.Omg
Weight of capsule contents 165.Omg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karion 83 8.0 mg (dry matter)
Titanium dioxide 0.4 mg
Iron oxide yellow 1.1 mg
The active ingredient is dissolved in a warm melting of the other ingredients and
the mixture is filled into soft gelatin capsules of appropriate size. The filled soft
gelatin capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a
conventional manner:
Compound of formula (I) 50.0 mg
Lactose, fine powder 1015.Omg
Microcristalline cellulose (AVICELPH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidone K 3 0 10.0 mg
Magnesiumstearate 10.0 mg
Flavoring additives 1.0 mg
The active ingredient is mixed with lactose, microcristalline cellulose and
sodium carboxymethyl cellulose and granulated with a mixture of
polyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and
the flavouring additives and filled into sachets.




We Claim:
1. A compound of the general formula
(Formula Removed)

wherein
R1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl,
cycloalkyl or C1-C8 cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group consisting of C1-C8 alkyl, C1-C8 hydroxyalkyl and C1-C8 alkoxyalkyl, C1-C8 hydroxyalkyl, C1-C8 jdkoxyalkyl, and
C1-C8 heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted by one or two groups selected from C1-C8 alkyl and halogen;
R2 is selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl,
cycloalkyl or C1-C8 cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group consisting of C1-C8 alkyl, C1-C8 hydroxyalkyl and C1-C8 alkoxyalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, and
C1-C8 heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted by one or two groups selected from C1-C8 alkyl and halogen; or
R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-
membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated or partly unsaturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from the group consisting of C1-C8 alkyl, halogen, halogenalkyl, cyano, hydroxy, hydroxyalkyl, C1-C8 alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl;


A is selected from

(Formula Removed)

wherein
m is 0,1 or 2; R3 is C1-C8 alkyl; n is 0,1 or 2; R7 is C1-C8 alkyl; p is 0,1 or 2; q is 0,1 or 2; R5 is hydrogen or C1-C8 alkyl; and pharmaceutically acceptable salts there of.
2. The compound as claimed in claim 1, wherein R1 is selected from the group consisting
of hydrogen, C1-C8 alkyl, C2-C8 alkenyl,
cycloalkyl or C1-C8 cycloalkylalkyl, wherein the cycloalkyl ring may be imsubstituted or
substituted by one or two groups selected from C1-C8 alkyl, C1-C8 hydroxyalkyl or C1-C8
alkoxyalkyl,
C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, and
C1-Cg heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted with
one or two groups selected from C1-C8 alkyl or halogen, and
R2 is hydrogen or C1-C8 alkyl.
3. The compound as claimed in claims 1 or 2, wherein R1 is selected from the group
consisting of C1-C8 alkyl,


cycloalkyl or C1-C8 cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or
substituted by C1-C8 alkoxyalkyl,
C1-C8 alkoxyalkyl, and
C1-C8 heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with
one or two groups selected from C1-C8 alkyl or halogen,
and R2 is hydrogen or C1-C8 alkyl.
4. The compound as claimed in claim 3, wherein R1 and R2 are C1-C8 alkyl.
5. The compound as claimed in any one of claims 1 to 4, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from C1-C8 alkyl, halogen, halogenalkyl, cyano, hydroxy, C1-C8 alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl.
6. The compound as claimed in any one of claims 1 to 5, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from C1-C8 alkyl, halogen, halogenalkyl, cyano, hydroxy, C1-C8 alkoxy, and oxo.
7. The compound as claimed in any one of claims 1 to 6, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from C1-C8 alkyl, halogen, halogenalkyl, cyano, hydroxy, C1-C8 alkoxy, and oxo.
8. The compound as claimed in any one of claims 1 to 7, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 3,6-dihydro-2H-pyridinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-hydroxypiperidinyl, 4,4-difluoropiperidinyl, 2,5-dihydropyrrolyl, 4-methylpiperidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-cyanopyrrolidinyl, 3-hydroxypyrrolidinyl and azetidinyl.


9. The compound as claimed in any one of claims 1 to 8, wherein A signifies

(Formula Removed)

wherein m is 0,1 or 2, and R3 is C1-C8 alkyl.
10. The compound as claimed in claim 9, wherein m is 0.
11. The compound as claimed in claim 9, wherein m is 1.
12. The compound as claimed in any one of claims 1 to 8, wherein A signifies

(Formula Removed)

wherein n is 0,1 or 2; and R4 is C1-C8 alkyl.
13. The compound as claimed in claim 12, wherein n is 0.
14. The compound as claimed in any one of claims 1 to 8, wherein A signifies


(Formula Removed)

wherein p is 0,1 or 2, q is 0,1 or 2, and R5 is hydrogen or C1-C8 alkyl.
15. The compoimd as claimed in claim 14, wherein p is 1.


16. The compound as claimed in claim 14 or 15, wherein R' is hydrogen.
17. The compound as claimed in claim 1, selected from the group consisting of [6-{l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-l-yl)-methanone, (2,5-dihydro-pyrrol-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-metlianone, 6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl-methyl-amide, [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin-l-yl)-methanone, 6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid tert-butylamide,
6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid cyclopropylmethyl-propyl-amide,
6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-methyl-piperidin-l-yl)-methanone,
(4-hydroxy-piperidin-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(3-methyl-piperidin-l-yl)-methanone,
(3,4-dihydro-1 H-isoquinolin-2-yl)-[6-{3 -piperidin-1 -yl-propoxy)-naphthalen-2-yl] -methanone 1:1
hydrochloride,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-thiomorpholin-4-yl-methanone,
[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-1 -yl)-methanone,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide,
azetidin-1 -yl-[6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
(3,6-dihydro-2H-pyridin-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-
amide,
6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (1-methoxymethyl-
cyclopropylmethyl)-aniide,
{6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-ethyl]-
amide,
[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-morpholin-4-yl-methanone,
6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide,
(4,4-difluoro-piperidin-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
(3-hydroxy-pyrrolidin-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
[6-{ 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-pyrrolidin-1 -yl-methanone,
(R)-1 -[6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,
(l,l-dioxo~thiomorpholin-4-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid dimethylamide,
(2,5-dihydro-pyrrol-l-yl)-[6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,
([6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-l-yl)-methanone,
6-( 1 -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid ethyl-methyl-amide,


([6-(l-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yi]-(4-raethyl-piperidin-l-yl)-methanone,
[6-(14sopropyl-pyiTolidin-3-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin-l-yl)-methanone,
6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolme-2-carboxylic acid tert-butylamide,
6-(1-isopropyl-pyrroUdin-3-yloxy)-quinoline-2-carboxylic acid cyclopropylmethyl-propyl-amide,
{[6-(1-isopropyl-pyrrolidin-3-yloxy)-q;iinolin-2-yl]-(2-methyl-piperidin-l-yl)-methanone,
[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(3-methyl-piperidin-l-yl)-methanone,
6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid isopropyl-methyl-amide,
[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-thiomorpholin-4-yl-methanone,
[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-l-yl)-
methanone,
6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide,
azetidin-1 -yl-[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,
(3,6-dihydro-2H-pyridin-l-yl)-[6-(14sopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,
6-{1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid(3-fluoro-oxetan-3-ylmethyl)-
amide,
6-{1-isopropyl-pyrrolidin-3-yloxy)-quinoluie-2-carboxylic acid (1 -methoxymethyl-
cyclopropylmethyl)-aimde,
6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid [2-{tetrahydro-pyran-4-yl)-ethyl]-
amide,
(4,4-difluoro-piperidin-1-yl)-[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,
[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-morpholin-4-yl-methanone,
(4-methoxy-piperidin-1-yl)-[6-(3-piperidin-l -yl-propoxy)-quinolin-2-yl]-methanone,
(4-methyl-piperidin-l -yl)-[6-(3-piperidin-l -yl-propoxy)-quinolin-2-yl]-methanone,
morpholin-4-yl-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
(2-methyl-pyrrolidin-l-yl)-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
6-{3-piperidin-l -yl-propoxy)-quxnoline-2-carboxylic acid cyclopropylmethyl-propyl-amide,
[6-{3-piperidin-l-yI-propoxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-l-yl)-methanone,
(2,5-dihydro-pyrrol-l -yl)-[6-(3-piperidin-l -yl-propoxy)-quinolin-2-yl]-methanone,
6-(3-piperidin-l -yl-propoxy)-quinoline-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide,
azetidin-1 -yl-[6-{3-piperidin-l -yl-propoxy)-quinolin-2-yl]-methanone,
(3,6-dihydro-2Hl-pyridin-l-yl)-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
(4,4-difluoro-piperidin-1 -yl)-[6-(3 -piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,
6-(3-piperidin-l-yl-propoxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide,
6-(3-piperidin-l -yl-propoxy)-quinoliae-2-carboxylic acid (1 -methoxymethyl-cyclopropylmethyl)-
amide,
6-{3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,


6-(3-piperidm-l-yl-propoxy)-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-ethyl]-
amide,
6-(3-piperidin-l -yl-propoxy)-quinoline-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide,
(2-methyl-piperidin-l-yl)-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
[6-(3-piperidin-l -yl-propoxy)-quinolin-2-yl]-pyrrolidin-l -yl-methanone,
(R)-l-[6-(3-piperidin-l-yl-propoxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,
(1,1 -dioxo--thiomorpholin-4-yl)-[6-(3 -piperidin-1 -yl-propoxy)-quinolin-2-yl]-methanone,
(4-methyl-piperidin-l-yl)-{6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,
{6-[2-(l -methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl} -pyrrolidin-1 -yl-methanone,
(R)-l-{6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carbonyl}-pyrrolidine-2-carbonitrile,
(1,1 -dioxo-thiomorphoIin-4-yl)- {6-[2-(l -methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl} -
methanone,
(4-methoxy-piperidin-1 -yl)- {6-[2-( 1 -methyl-pyrrolidin-2-yl)-ethoxy] -quinolin-2-yl} -methanone,
{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl} -morpholin-4-yl-methanone,
azetidin-l-yl-{6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,
6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-
ethyl]-amide,
6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-
ylmethyl)-amide,
(2-methyl-pyrrolidin-l-yl)-{6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,
(S)-l-[6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,
[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methyl-piperidin-l-yl)-methanone,
(4-hydroxymethyl-piperidin-l-yl)-[6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,
6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutyl-amide,
6-(l -isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide,
and pharmaceutically acceptable salts thereof.
18. The compound as claimed in claim 1, is further selected from the group consisting of [6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-l -yl)-methanone, [6-( 1 -isopropyl-piperidin-4-yloxy)-quinolin-2-yl] -(2-methyl-pyrrolidin-1 -yl)-methanone, [6-(l-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-l-yl)-methanone, azetidin-1 -yl-[6-(l -isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone, 6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,
6-( 1 -isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (1 -methoxymethyl-cyclopropylmethyl)-amide,


[6-(l-isopropyl-piperidin-4-yloxy)-quinoIin-2-yl]-pyrrolidin-l-yl-methanone,
(R)-1 -[6-(l -isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrToIidine-2-carbonitrile,
azetidin-l-yl-[6-(3-piperidin-l-yl-propoxy)-quinolin-2-yl]-methanone,
(R)-l-[6-(3-piperidin-l-yl-propoxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,
(S)-l-[6-(l-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,
and pharmaceutically acceptable salts thereof.
19. A process for the manufacture of compounds as claimed in any one of claims 1 to 18, which process comprises
a) reacting a compound of the formula II


(Formula Removed)

wherein R is C1-C8 alkyl, with an alcohol of the formula III

(Formula Removed)

wherein A is as defined in claim 1, in the presence of a trialkylphosphine or triphenylphosphine and of a diazo compound to obtain a compound of the formula IV

(Formula Removed)

and converting the ester of formula IV into the acid of formula V


(Formula Removed)
under acidic or basic conditions,
and coupling the compound of formula V with an amine of the formula VI
(Formula Removed)
wherein R1 and R2 are as defined in claim 1, with the help of an coupling agent under basic conditions to obtain a compound of the formula I

(Formula Removed)


wherein A, R1 and R2 are as defined in claim 1, and if desired, converting the compound obtained into a pharmaceutically acceptable salt.
20. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 18 including pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or adjuvant.
21. The pharmaceutical composition as claimed in claim 20 for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
22. The compoimd as claimed in any one of claims 1 to 18 for use as therapeutically active substance.
23. The compound as claimed in any one of claims 1 to 18 for use as therapeutically active substances for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.


24. The compound as claimed in any one of claims 1 to 18 including pharmaceutically acceptable salt and a pharmaceutical composition thereof is useful for the preparation of medicaments for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors such as obesity.

Documents:

3162-delnp-2007-abstract.pdf

3162-delnp-2007-assignments.pdf

3162-delnp-2007-Claims-(02-06-2011).pdf

3162-delnp-2007-claims.pdf

3162-delnp-2007-Correspondence Others-(02-06-2011).pdf

3162-delnp-2007-correspondence-others-1.pdf

3162-delnp-2007-correspondence-others.pdf

3162-delnp-2007-description (complete).pdf

3162-delnp-2007-form-1.pdf

3162-delnp-2007-form-18.pdf

3162-delnp-2007-form-2.pdf

3162-delnp-2007-Form-3-(02-06-2011).pdf

3162-delnp-2007-form-3.pdf

3162-delnp-2007-form-5.pdf

3162-delnp-2007-GPA-(02-06-2011).pdf

3162-delnp-2007-gpa.pdf

3162-delnp-2007-pct-210.pdf

3162-delnp-2007-pct-304.pdf

3162-delnp-2007-pct-409.pdf

abstract.jpg


Patent Number 248904
Indian Patent Application Number 3162/DELNP/2007
PG Journal Number 36/2011
Publication Date 09-Sep-2011
Grant Date 07-Sep-2011
Date of Filing 27-Apr-2007
Name of Patentee F.HOFFMANN-LA ROCHE AG
Applicant Address GRENZACHERSTRASSE 124, CH-4070 BASEL (CH)
Inventors:
# Inventor's Name Inventor's Address
1 GATTI MCARTHUR, SILVIA RAMSTERINERSTRASSE 28, CH-4052 BASEL, SWITZERLAND.
2 HERTEL, CORNELIA BERGWEG 2, CH-4142 MUENCHENSTEIN, SWITZERLAND.
3 NETTEKOVEN, MATTHIAS,HEINRICH WINKELMATTEN 9, 79639 GRENZACH-WYHLEN, GERMANY
4 RAAB, SUSANNE UNTEREGGWEG 7, CH-4147 AESCH, SWITZERLAND.
5 RICHTER, HANS WINKELMATTEN 6, 79639 GRENZACH-WYHLEN, GERMANY
6 ROCHE, OLIVIER 6, RUE DES TILLEULS, F-68220 FOLGENSBOURG,FRANCE.
7 RODRIGUEZ-SARMIENTO, ROSA MARIA KLINGELBERGSTRASSE 87, CH-4056 BASEL, SWITZERLAND.
8 SCHULER, FRANZ BAHNHOFSTRASSE 56, CH-4125 RIEHEN, SWITZERLAND.
PCT International Classification Number C07D 401/06
PCT International Application Number PCT/EP2005/010814
PCT International Filing date 2005-10-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04105145.9 2004-10-19 EUROPEAN UNION