Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-08-30
2000-08-08
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514682, 514357, 514255, 546329, 5462681, A61K 31495, A61K 3144, C07D21353, C07D42100
Patent
active
061002674
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
This invention relates to novel chemical compounds which are quinoline- or aphthalenecarboxamides. The claimed pharmaceutical compositions and methods use those compounds as active ingredients to inhibit calpain and thus are useful in the treatment of, for example, neurodegenerative disorders, strokes and traumatic brain injury.
BACKGROUND OF THE INVENTION
Calpains are calcium--dependent cysteine proteases present in a variety of tissues and cells. Excessive activation of calpain provides a molecular link between ischaemia or injury induced by increases in intraneuronal calcium and pathological neuronal degeneration. If the elevated calcium levels are left uncontrolled, serious structural damage to neurons may result. Recent research has suggested that calpain activation may represent a final common pathway in many types of brain damage. Selective inhibition of calpain would, therefore, be an attractive therapeutic approach in the treatment of neurodegenerative diseases. Exemplary of these diseases would be myocardial ischaemia, cerebral ischaemia, muscular dystrophy, stroke, Alzheimer's disease, or traumatic brain injury. The compounds of this invention may also be useful in the treatment of cataracts and platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
The compounds which are the active ingredients of the pharmaceutical compositions and methods of this invention are represented by the following formula: ##STR1## in which: X is CH or N; CH(CH.sub.3).sub.2 or CH.sub.2 PhOR.sub.2 ; COOCH.sub.2pyridyl (or substituted pyridyl); COCO(CH.sub.2).sub.n aryl, COCONHCH(R)COOH or COCH.sub.2 O--(3-phenylisoxazol-5-yl); ##STR2## Y=absent, phenyl, substituted phenyl, pyridyl or substituted pyridyl, or a pharmaceutically acceptable salt thereof.
Preferred compounds are those where the stereochemistry at the R group corresponds to that of the naturally occurring amino acids. Also preferred are those compounds where X is N, Z is CHO and R is CH.sub.2 Ph or --(CH.sub.2).sub.3 CH.sub.2 NR.sub.1 R.sub.3.
The following preferred compounds are representative of the compounds of the invention: e e e amide xamide amide line-carboxamide ne-carboxamide.
Compounds of Formula I where X is N are prepared by the methods described in Schemes 1-4. ##STR3##
The 2-substituted quinolines 1 where Q-Y is phenyl or para-biphenyl are available from Aldrich Chemical Company. 1 is converted to the amide alcohol 2 by standard coupling conditions [(S)-(-)-2-amino-3-phenyl-1-propanol, benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (BOP), triethylamine, methylene chloride)]. The amide alcohol may be purified by silica chromatography. Oxidation of 2 (the Dess-Martin reagent in methylene chloride is prefered, but not limiting) affords the aldehyde 3. This procedure can be repeated with a wide variety of 2-substituted quinoline-4carboxylates and with a wide variety of amino alcohol derivatives. Those derived from the naturally occurring amino acids are preferred.
Compounds of Formula I wherein the quinoline containing the desired substituent at C-2 is not commercially available are prepared by the methods described in Schemes 2-4. ##STR4##
2-Chloroquinoline-4-carboxylic acid, 4, is available from ICN Chemical Company. 4 is converted to the amide alcohol 5 by standard coupling conditions as in Scheme 1 [(S)-(-)-2-amino-3-phenyl-1-propanol, benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (BOP), triethylarnine, methylene chloride)]. The chloro substituent of 5 is then replaced with the desired Q-Y group by palladium catalyzed coupling chemistry (for acetylene coupling see Sakamoto et al., Chem. Pharm. Bull., 1984, 32, 4666-4669; for boronic acid coupling see Finch et al., J. Chem. Soc. Perkin I, 1994, 9, 1193-1203). In this way, the use of substituted acetylenes (2-pyridylacetylene) and boronic acid derivatives (2-phenylphenylboronic acid) are added to the C-2 position of the quinoline ring. The amide alcohol 2 may be purified by silica chromatography. Oxidation of 2
REFERENCES:
patent: 4970214 (1990-11-01), Murase et al.
Daines Robert A
Kingsbury William D
Mallamo John P
Pendrak Israil
Cephalon Inc.
Davis Zinna Northington
Kerekes Zoltan
Kinzig Charles M.
Robinson Binta
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