N-substituted azaheterocyclic carboxylic acids and esters...

Details N-substituted azaheterocyclic carboxylic acids and esters... N-substituted azaheterocyclic carboxylic acids and esters...

1998-04-06

2001-05-29

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S277000, C514S351000, C514S357000, C546S203000, C546S204000, C546S285000

Reexamination Certificate

active

06239148

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation. The invention also relates to the use of the present compounds for the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) or aging, the present compounds knowing to interfere with neuropeptide containing C-fibres and hence inhibit the secretion and circulation of insulin antagonizing peptides like CGRP or amylin.
BACKGROUND OF THE INVENTION
The nervous system exerts a profound effect on the inflammatory response. Antidromic stimulation of sensory nerves results in localized vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151) and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro-intestinal and respiratory tracts. Hence inhibition of sensory nerve peptide release and/or activity, may be useful in treatment of, for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis.
Further, the potent effects of CGRP on skeletal muscle glycogen synthase activity and muscle glucose metabolism, together with the notion that this peptide is released from the neuromuscular junction by nerve excitation, suggest that CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993). This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or aging-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or aging.
In U.S. Pat. Nos. 4,383,999 and 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801, N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are claimed as GABA uptake inhibitors. EP 221572 claims that 1-aryfoxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.
In addition to the above cited references, U.S. Pat. No. 3,074,953 discloses 1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester as a psychotropic drug. Analogous 1-substituted 4-phenyl-4-piperidinecarboxylic acid ester derivatives to the above cited compound are described (J. Med. Chem. 1967, 10, 627-635 and J. Org. Chem. 1962, 27, 230-240) as analgesics, antispasmodics and psychotropics. In JP 49032544, JP 48040357, FR 2121423, GB 1294550 and DE 2101066, 1-substituted 4-dialkylamino-4-piperidinecarboxamides are disclosed as psychotropic agents, for the treatment of schizophrenia and as inhibitors of inflammation.
DESCRIPTION OF THE INVENTION
The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof of formula I
wherein
R
1
and R
2
independently are hydrogen, halogen, trifluoromethyl, NR
6
R
7
, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy; and
Y is >
N
—CH
2
—, >
C
H—CH
2
— or >
C
═CH— wherein only the underscored atom participates in the ring system; and
X is —O—, —S—, —C(R
6
R
7
)—, —CH
2
CH
2
—, —CH═CH—CH
2
—, —CH
2
—CH═CH—, —CH
2
—(C═O)—, —(C═O)—CH
2
—, —CH
2
CH
2
CH
2
—, —CH═CH—, —N(R
8
)—(C═O)—, —(C═O)—N(R
8
)—, —O—CH
2
—, CH
2
—O—, —S—CH
2
—, —CH
2
—S—, —(C═O)—, —N(R
9
)— or —(S═O)— wherein R
6
, R
7
, R
8
and R
9
independently are hydrogen or C
1-6
-alkyl; and
r is 1, 2 or 3; and
Z is selected from
wherein
n is 1 or 2; and
R
3
is —(CH
2
)
m
OH or —(CH
2
)
p
COR
4
wherein m is 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1 and wherein R
4
is —OH, —NH
2
, —NHOH or C
1-6
-alkoxy; and
R
5
is hydrogen, halogen, trifluoromethyl, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy; and
R
10
is hydrogen, C
1-6
-alkyl, C
1-6
-alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy; and
R
11
is hydrogen or C
1-6
-alkyl; and is optionally a single bond or a double bond;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
Preferably, the compounds of formula I exist as the individual geometric or optical isomers.
The compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts or—when the carboxylic acid group is not esterified—as pharmaceutically acceptable metal salts or—optionally alkylated—ammonium salts.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are hereby incorporated by reference.
The term “C
1-6
-alkyl” as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1,2,2-trimethylpropyl.
The term “C
1-6
-alkoxy” as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C
1-6
-alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term “halogen” means fluorine, chlorine, bromine or iodine.
Illustrative examples of compounds encompassed by the present invention include:
1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinecarboxamide;
1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-pipendinecarboxylic acid;
(1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinyl)methanol;
4-(4-Chlorophenyl)-1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinol;
4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinecarboxylic acid;
(2S,4R)-1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-hydroxy-2-pyrrolidinecarboxylic acid;
4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-morpholinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-

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