US 5,629,322 A · Cyclic amidine analogs as inhibitors of nitric oxide synthase

Abstract

Disclosed herein are compounds of Formula I ##STR1## and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These disease and disorders include hypotension, septic shock, toxic shock syndrom, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn or psoriasis and respiratory conditions such as bronchitis, asthma, and acure respiratory distress (ARDS), myocarditis, heart failure, atherosclerosis, arthritis, rheumatoid arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis. Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, mulitple sclerosis, Korsakoff's disease, imbecility related to cerebral vessel disorder, ischemic brain edema, sleeping disorders, schizophrenia, depression, PMS, anxiety, drug addiction, pain, migraine, immune complex disease, as immunosupressive agents and for preventing or reversing tolerance to opiates and diazepines.

A compound of Formula Ia ##STR31## or a pharmaceutically acceptable salt thereof wherein:

side a or side b has a double bond;
X is selected from C.sub.12 R.sub.13, O, S(O).sub.m, NH, and --N(C.sub.1-6 alkyl)--;
m is 0, 1 or 2;
R.sub.1, R.sub.12, and R.sub.13 are each independently selected from the group consisting of
(a) hydrogen,
(b) C.sub.1-12 alkoxy,
(c) C.sub.1-12 alkylS(O).sub.k wherein k is 0, 1 or 2,
(d) mono C.sub.1-12 alkylamino,
(e) (di-C.sub.1-12 alkyl)amino,
(f) C.sub.1-12 alkylcarbonyl,
(g) C.sub.1-12 alkyl,
(h) C.sub.2-12 alkenyl,
(i) C.sub.2-12 alkynyl,
(j) C.sub.5-10 cycloalkyl,
(k) hetero C.sub.5-10 cycloalkyl, wherein the hetero C.sub.5-10 cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(l) aryl, selected from phenyl or naphthyl,
(m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl,
(2) benzofuranyl,
(3) benzooxazolyl,
(4) furanyl,
(5) imidazolyl,
(6) indolyl,
(7) isooxazolyl,
(8) isothiazolyl,
(9) oxadiazolyl,
(10) oxazolyl,
(11) pyrazinyl,
(12) pyrazolyl,
(13) pyridyl,
(14) pyrimidyl,
(15) pyrrolyl,
(17) isoquinolyl,
(18) tetrazolyl,
(19) thiadiazolyl,
(20) thiazolyl,
(21) thienyl, and
(22) triazolyl,
(n) amino,
(o) oxo,
(p) C(O)OH,
(q) C(O)OR.sub.6, R.sub.6 is selected from hydrogen, phenyl, cyclohexyl or C.sub.1-6 alkyl,
each of (b) to (m) being optionally mono or di-substituted the substituents being independently selected from
(1) hydroxy,
(2) carboxy,
(3) --NR.sub.6 R.sub.7, where R.sub.7 is selected from hydrogen, phenyl, cyclohexyl or C.sub.1-6 alkyl,
(4) --OR.sub.6,
(5) --C(O)OR.sub.6,
(6) --S(O).sub.k R.sub.6,
(7) halo selected from F, Cl, Br and I,
(8) --C(.dbd.NR.sub.6)--NHR.sub.7,
(9) --S--C(.dbd.NR.sub.6)--NHR.sub.7,
(r) hydroxy;
R.sub.4, R.sub.5 and R.sub.5a are each independently selected from the group consisting of
(a) hydrogen,
(b) linear and branched C.sub.1-12 alkyl, optionally mono or di-substituted, the substituents being independently selected from
(1) hydroxy,
(2) carboxy,
(3) --NR.sub.6 R.sub.7,
(4) --OR.sub.6,
(5) --C(O)OR.sub.6,
(6) --S(O).sub.k R.sub.6,
(7) halo selected from F, Cl, Br and I,
(8) phenyl, optionally mono or di-substituted with hydroxy, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy,
(c) --C(O)NR.sub.8 R.sub.9, where R.sub.8 and R.sub.9 are each independently hydrogen, phenyl, cyclohexyl or C.sub.1-6 alkyl, said C.sub.1-6 alkyl optionally substituted by
(1) hydroxy,
(2) amino,
(3) carboxy,
(4) --NR.sub.10 R.sub.11, wherein R.sub.10 and R.sub.11 are each independently H, Cl.sub.1-6 alkyl, phenyl or benzyl,
(5) --OR.sub.10,
(6) --C(O)OR.sub.10,
(7) --S(O).sub.m R.sub.10, where m is 0, 1 or 2,
(8) halo selected from F, Cl, Br and I,
(9) optionally substituted aryl wherein aryl and aryl substituents are as defined above,
(10) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above,
(11) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above,
(12) optionally substituted hetero C.sub.5-10 cycloalkyl wherein hetero cycloalkyl and hetero cycloalkyl substituents are as defined above,
(d) --C(S)NR.sub.8 R.sub.9,
(e) --C(O)R.sub.9,
(f) --C(O)OR.sub.9,
(g) --C(S)R.sub.9,
(h) phenyl,
(i) cyclohexyl,
provided that R.sub.4 is present only when side a is a single bond and R.sub.5a is present only when side b is a single bond.

81 more elements

Facts

Application

08/468,120Filed 6 Jun 1995 · continuation in part

Priority

15 Nov 1994

Granted

13 May 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 215/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 11/00
Drugs for disorders of the respiratory system
A61P 25/00
Drugs for disorders of the nervous system

Cyclic amidine analogs as inhibitors of nitric oxide synthase

Life of this patent

Cyclic amidine analogs as inhibitors of nitric oxide synthase

Life of this patent

Abstract

Claims16