Heterocyclic compounds

Details Heterocyclic compounds Heterocyclic compounds

1999-03-10

2001-04-10

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S217000, C514S228200, C514S232800, C514S253030, C514S297000, C540S479000, C540S591000, C540S592000, C544S060000, C544S126000, C544S361000, C546S104000

Reexamination Certificate

active

06214816

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel N-substituted azaheterocyclic compounds in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, to the use of the compounds for preparing compositions for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, and to methods of treating said painful, hyperalgesic and/or inflammatory conditions. The invention also relates to the use of the present compounds for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin, the present compounds being known to interfere with neuropeptide containing C-fibres. Hence the present compounds can be used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) in order to improve the glucose tolerance as well as ageing-associated obesity.
BACKGROUND OF INVENTION
The nervous system exerts a profound effect on the inflammatory response. Antidromic stimulation of sensory nerves results in localised 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, glaucoma, gastrointestinal diseases or migraine.
Furthermore, the fact that the C-fibers innervate the liver, the intestines and the pancreas suggests that they control various function. The peptidergic innervation has been shown to control glucose tolerance in rodents (Karlsson et al. Am. J. Physiol. 267, R1071-R1077, 1994, Guillot et al. Life Sci. 969-977, 1996).
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 ageing-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 and other sensory neuropeptides may be useful in the treatment of insulin resistance related to type 2 diabetes or ageing.
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-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake. WO 9518793 discloses N-substituted azaheterocyclic carboxylic acids and esters thereof.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula 1, wherein X, Y, R
1
, R
2
, Z and r are as defined in the detailed part of the present description.
The present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance and ageing-associated obesity.
In another aspect, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
In another aspect of the present invention there is provided a method of treating painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as a method of treating indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance and ageing-associated obesity.
The method of treatment may be described as the treatment, prevention, elimination, alleviation or amelioration of one of the above indications, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
A further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance and ageing-associated obesity.
Further objects will become apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to novel N-substituted azaheterocyclic compounds of the general formula I
wherein R
1
and R
2
independently are hydrogen, halogen, trifluoromethyl, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy; and
Y is >N—CH
2
—, >C═CH— or >CH—CH
2
— wherein only the underscored atom participates in the ring system; and
X is ortho-phenylene, —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
—O—, —OCH
2
O—, —S—CH
2
—, —CH
2
—S—, —(CH
2
)N(R
8
)—, —N(R
8
)(CH
2
)—, —N(CH
3
)SO
2
—, —SO
2
N(CH
3
)—, CH(R
10
)CH
2
—, —CH
2
CH(R
10
), —(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 wherein R
10
is C
1-6
-alkyl or phenyl; and
r is 0, 1 or 2; and
Z is selected from
 wherein A is —CH
2
—, —O—, —S— or —N(R
5
)— wherein R
5
is H or C
1-6
-alkyl; and
R
3
is —(CH
2
)
m
OH or —(CH
2
)
p
COR
4
wherein m and p independently are 1, 2, 3 or 4 and R
4
is OH, NH
2
, NHOH or C
1-6
-alkoxy; or
a pharmaceutically acceptable salt thereof.
The compounds of formula I may exist as geometric and optical isomers and all isomers, as separeted, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. Isomers may be se

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