US 6,372,733 B1 · Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases

Abstract

Disclosed herein are compounds of Formula I 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 diseases and disorders include hypotension, septic shock, toxic shock syndrome, hemodialysis, IL-2 therapy such as in in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn, eczema or psoriasis and respiratory conditions such as bronchitis, asthma, oxidant-induced lung injury and acute respiratory distress (ARDS), glomerulonephritis, restenosis, inflammatory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteoarthritis, rheumatoid arthritis, septic arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis.

Claims12

Dependent claims

A compound selected from the group consisting of:

(a) hexahydro-5-imino-3-propyl-1,4-thiazepine hydrochloride,
(b) hexahydro-5-imino-6-propyl-1,4-thiazepine hydrochloride,
(c) hexahydro-5-imino-7-methyl-1,4-thiazepine hydrochloride,
(d) hexahydro-5-imino-2-methyl-1,4-thiazepine hydrochloride,
(e) hexahydro-5-imino-6-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride,
(f) hexahydro-5-imino-3-(3-methyl-2-n-butenyl)-1,4-thiazepine hydrochloride,
(g) hexahydro-5-imino-6-(2-methyl-propyl)-1,4-thiazepine hydrochloride,
(h) hexahydro-5-imino-3-(2-methyl-propyl)-1,4-thiazepine hydrochloride,
(i) hexahydro-5-imino-6-methyl-1,4-thiazepine hydrochloride,
(j) hexahydro-5-imino-3-methyl-1,4-thiazepine hydrochloride,
(k) hexahydro-5-imino-3-ethyl-1,4-thiazepine hydrochloride,
(l) hexahydro-5-imino-3-butyl-1,4-thiazepine hydrochloride,
(m) hexahydro-5-imino-3-(2-methyl-3-propenyl)-1,4-thiazepine hydrochloride,
(n) (±)-trans-decahydro-4-imino-benzo[b]-1,4-thiazepine acetic acid salt,
(o) hexahydro-5-imino-3(S)-propyl-1,4-thiazepine acetic acid salt,
(p) hexahydro-5-imino-3(R)-propyl-1,4-thiazepine acetic acid salt,
and pharmaceutically acceptable salts thereof.

14 more elements

A pharmaceutical composition comprising a pharmaceutical carrier and a non-toxic effective amount of the compound of Formula I

or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, with the proviso that when side b has a double bond a hydrogen atom is bonded to the nitrogen atom in the ring and when side a has a double bond a hydrogen atom is bonded to the nitrogen atom not in the ring,
X is S(O)m,
m is 0, 1 or 2;
R1, R2, R3 and R4 are each independently selected from the group consisting of:
(a) hydrogen,
(b) C1-12alkoxy,
(c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2,
(d) mono C1-12alkylamino,
(e) (di-C1-12alkyl)amino,
(f) C1-12alkylcarbonyl,
(g) C1-12alkyl,
(h) C2-12alkenyl,
(i) C2-12alkynyl,
(j) C5-10cycloalkyl,
(k) hetero C5-10ocycloalkyl,wherein the hetero C5-10-cycloalkyl contains 1 or 2 heteroatoms selected from S, O and N,
(l) aryl selected from phenyl and 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) C1-12alkyl-C(O)NH,
(o) C1-12alkoxy-C(O)NH,
(p) C1-12alkylamino-C(O)NH,
(q) C1-12alkyl-S(O)2NH,
(r) C1-12alkylamino-C(O),
(s) C1-12alkylamino-S(O)2,
(t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl and triazolyl,
(u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl and pyridyl,
(v) phenylamnino-C(O)NH,
(w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl,
(x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl and triazolyl,
(y) phenylamino-S(O)2,
(z) hydroxy,
(aa) amino,
(ab) oxo and
(ac) C(O)OR7 wherein R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl and C1-6alkyl,
each of (b) to (y) being optionally mono or di-substituted, the substituents being independently selected from:
(1) hydroxy,
(2) carboxy,
(3) —NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl and C1-6alkyl,
(4) —NR7C(O)R8
(5) —NR7C(O)NHR8,
(6) —NR7C(O)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl and C1-6alkyl,
(7) —NR7S(O)2R9,
(8) —OR7,
(9) —C(O)OR9,
(10) —C(O)NR7R8,
(11) —C(O)R7,
(12) —S(O)kR7,
(13) —S(O)2NR7R8,
(14) halo selected from F, Cl, Br and I,
(15) -trifluoromethyl,
(16) —C(═NR7)—NHR8,
(17) hetero C5-10ocycloalkyl,wherein the hetero C5-10-cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(18) aryl, selected from phenyl and naphthyl, and
(19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl,
(b) isooxazolyl,
(c) isothiazolyl,
(d) oxadiazolyl,
(e) oxazolyl,
(f) pyridyl,
(g) tetrazolyl,
(h) thiazolyl,
(i) thienyl and
(j) triazolyl,
or when two members of the group R1, R2, R3 and R4 reside on the same carbon atom of Formula I, or two of the group R1, R2, R3 and R4 reside on adjacent atoms of Formula I, said two members along with the optional substituents thereon may optionally be joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O and S,
R5 is selected from the group consisting of:
(a) hydrogen,
(b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from:
(1) hydroxy,
(2) carboxy,
(3) —NR7R8,
(4) —OR7,
(5) —C(O)OR7,
(6) —S(O)kR7,
(7) halo selected from F, Cl, Br and I,
(8) trifluoromethyl and
(9) phenyl, optionally mono or di-substituted with a substituent selected from hydroxy, halo, C1-4alkyl, and C1-4alkoxy,
(c) —C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, —S(O)2NR7R8 and optionally substituted C1-6alkyl, wherein said substituent is selected from
(1) —NR12R13, wherein R12 and R13 are each independently selected from H, C1-6alkyl, phenyl and benzyl,
(2) -OR12,
(3) —C(O)OR12,
(4) —S(O)kR12, where m is 0, 1 or 2,
(5) halo selected from F, Cl, Br and I,
(6) optionally substituted aryl wherein aryl and aryl substituents are as defined above,
(7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above,
(8) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, and
(9) hetero C5-10-cycloalkyl,wherein the hetero C5-10-cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(d) —C(O)R11,
(e) —C(O)OR11,
(f) aryl, selected from phenyl and naphthyl, and
(g) cyclohexyl.

109 more elements

A pharmaceutical composition comprising a pharmaceutical carrier and a non-toxic effective amount of the compound of Formula I

or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, with the proviso that when side b has a double bond a hydrogen atom is bonded to the nitrogen atom in the ring and when side a has a double bond a hydrogen atom is bonded to the nitrogen atom not in the ring,
X is S(O)m,
m is 0, 1 or 2;
R1 and R2 are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano,
(e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl,
(g) C1-6alkyl,
(h) C1-6alkoxy,
(i) C1-6alkylthio,
(j) C1-6alkylcarbonyl,
(k) mono- and di-C1-6alkylamino,
(l) aryl, where aryl is phenyl and naphthyl,
(m) aryloxy, where aryl is phenyl and naphthyl,
(n) cycloalkyl, wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring, and
(o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl,
(2) furanyl,
(3) thienyl,
(4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and
(7) triazolyl,
each of (g) to (o) being optionally mono- or di-substituted, the substituents being independently selected from
(1) hydroxy,
(2) C1-4alkyl,
(3) C1-3alkoxy,
(4) amino,
(5) mono- and di-C1-6alkylamino,
(6) carboxyl,
(7) C1-3alkylthio,
(8) C1-3alkyl-S(O)k—, where k is 1 or 2,
(9) C1-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo,
(11) oxo, and
(12) amidino,
R3 and R4 reside on the same carbon atom of Formula I, or reside on adjacent atoms of Formula I, and R3 and R4 are joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5 or 6 atoms, said monocyclic ring optionally containing one or 2 hetero atoms selected from N, O or S, and
R5 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkylcarbonyl,
(c) aroyl, wherein the aroyl group is benzoyl,
(d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl,
(e) R6R7N—SO2—NH—C(═O)—, wherein R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl
(3) aryl, wherein the aryl group is selected from phenyl, and
(4) R6 and R7 may be joined together with the nitrogen atom to which they are attached to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,
each of (b) to (e) being mono- or di-substituted, the substituents being independently selected from
(1) hydroxy,
(2) C1-3alkoxy,
(3) amino,
(4) mono- and di-C1-6alkylamino,
(5) carboxyl,
(6) C1-3alkylthio,
(7) C1-3alkyl-S(O)k—, where k is 1 or 2,
(8) C1-4alkoxycarbonyl,
(9) halo selected from fluoro, chloro, bromo, and iodo,
(10) oxo, and
(11) amidino.

60 more elements

A pharmaceutical composition comprising a pharmaceutical carrier and a non-toxic effective amount of the compound of Formula I

or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, with the proviso that when side b has a double bond a hydrogen atom is bonded to the nitrogen atom in the ring and when side a has a double bond a hydrogen atom is bonded to the nitrogen atom not in the ring,
X is S(O)m,
m is 0, 1 or 2;
R1, R2, R3 and R4 are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano,
(e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl,
(g) C1-6alkyl,
(h) C1-6alkoxy,
(i) C1-6alkylthio,
(j) C1-6alkylcarbonyl,
(k) mono- and di-C1-6alkylamino,
(l) aryl, where aryl is phenyl and naphthyl,
(m) aryloxy, where aryl is phenyl and naphthyl,
(n) cycloalkyl, wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring, and
(o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl,
(2) furanyl,
(3) thienyl,
(4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and
(7) triazolyl,
each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from
(1) hydroxy,
(2) C1-4alkyl,
(3) C1-3alkoxy,
(4) amino,
(5) mono- and di-C1-6alkylamino,
(6) carboxyl,
(7) C1-3alkylthio,
(8) C1-3alkyl-S(O)k—, where k is 1 or 2,
(9) C1-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo,
(11) oxo, and
(12) amidino, and
R5 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkylcarbonyl,
(c) aroyl, wherein the aroyl group is benzoyl,
(d) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl,
(e) R6R7N-SO2—NH—C(═O)—, wherein R6 and R7 are independently selected from the group consisting of
(1) hydrogen,
(2) C1-6alkyl,
(3) aryl, wherein the aryl group is selected from phenyl, and
(4) R6 and R7 may be joined together with the nitrogen atom to which they are attached to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,
each of (b) to (e) being mono- or di-substituted, the substituents being independently selected from
(1) hydroxy,
(2) C1-3alkoxy,
(3) amino,
(4) mono- and di-C1-6alkylamino,
(5) carboxyl,
(6) C1-3alkylthio,
(7) C1-3alkyl-S(O)k—, where k is 1 or 2,
(8) C1-4alkoxycarbonyl,
(9) halo selected from fluoro, chloro, bromo, and iodo,
(10) oxo, and
(11) amidino.

59 more elements

A pharmaceutical composition comprising a pharmaceutical carrier and a non-toxic effective amount of a compound of the following formula

wherein:
side a or side b has a double bond, with the proviso that when side b has a double bond a hydrogen atom is bonded to the nitrogen atom in the ring and when side a has a double bond a hydrogen atom is bonded to the nitrogen atom not in the ring,
R1, R2 and R3 are each independently selected from the group consisting of:
(a) hydrogen,
(b) C1 12alkoxy,
(c) C1-12alkyl-S(O)k wherein k is 0, 1 or 2,
(d) mono C1-12alkylamino,
(e) (di-C1-12alkyl)amino,
(f) C1-12alkylcarbonyl,
(g) C1-12alkyl,
(h) C2-12alkenyl,
(i) C2-12alkynyl,
(j) C5-10cycloalkyl,
(k) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl contains 1 or 2 heteroatoms selected from S, O and N,
(1) aryl selected from phenyl and 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) C1-12alkyl-C(O)NH,
(o) C1-12alkoxy-C(O)NH,
(p) C1-12alkylamino-C(O)NH,
(q) C1-12alkyl-S(O)2NH,
(r) C1-12alkylamino-C(O),
(s) C1-12alkylamino-S(O)2,
(t) aryl-C(O)NH where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl and triazolyl,
(u) aryloxy-C(O)NH where aryl is selected from phenyl, naphthyl and pyridyl,
(v) phenylamino-C(O)NH,
(w) aryl-S(O)2NH where aryl is selected from phenyl and naphthyl,
(x) aryl-C(O) where aryl is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl and triazolyl,
(y) phenylamino-S(O)2,
(z) hydroxy,
(aa) amino,
(ab) oxo and
(ac) C(O)OR7 wherein R7 is selected from hydrogen, phenyl, benzyl, cyclohexyl and C1-6alkyl,
each of (b) to (y) being optionally mono or di- substituted, the substituents being independently selected from:
(1) hydroxy,
(2) carboxy,
(3) —NR7R8, where R8 is selected from hydrogen, phenyl, benzyl, cyclohexyl and C1-6alkyl,
(4) —NR7C(O)R8
(5) —NR7C(O)NHR8,
(6) —NR7C(O)OR9,where R9 is selected from phenyl, benzyl, cyclohexyl and C1-6alkyl,
(7) —NR7S(O)2R9,
(8) —OR7,
(9) —C(O)OR9,
(10) —C(O)NR7R8,
(11) —C(O)R7,
(12) —S(O)kR7,
(13) —S(O)2NR7R8,
(14) halo selected from F, Cl, Br and I,
(15) -trifluoromethyl,
(16) —C(═NR7)-NHR8,
(17) hetero C5-10ocycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N,
(18) aryl, selected from phenyl and naphthyl, and
(19) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(a) imidazolyl,
(b) isooxazolyl,
(c) isothiazolyl,
(d) oxadiazolyl,
(e) oxazolyl,
(f) pyridyl,
(g) tetrazolyl,
(h) thiazolyl,
(i) thienyl and
(j) triazolyl,
or when two members of the group R1, R2 and R3 reside on the same carbon atom of Formula I, or two of the group R1, R2, R3 and R4 reside on adjacent atoms of Formula I, said two members along with the optional substituents thereon may optionally be joined, such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O and S,
R4 is selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) amino,
(d) cyano,
(e) fluoro, chloro, bromo, and iodo,
(f) trifluoromethyl,
(g) C1-6alkyl,
(h) C1-6alkoxy,
(i) C1-6alkylthio,
j) C1-6alkylcarbonyl,
(k) mono- and di-C1-6alkylamino,
(l) aryl, where aryl is phenyl and naphthyl,
(m) aryloxy, where aryl is phenyl and naphthyl,
(n) cycloalkyl, wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring, and
(o) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) pyridyl,
(2) furanyl,
(3) thienyl,
(4) pyrazinyl,
(5) pyrimidyl,
(6) thiazolyl, and
(7) triazolyl,
each of (g) to (o) being optionally mono- or di-substituted, the substituents being independently selected from
(1) hydroxy,
(2) C1-4alkyl,
(3) C1-3alkoxy,
(4) amino,
(5) mono- and di-C1-6alkylamino,
(6) carboxyl,
(7) C1-3alkylthio,
(8) C1-3alkyl-S(O)k—, where k is 1 or 2,
(9) C1-4alkoxycarbonyl,
(10) halo selected from fluoro, chloro, bromo, and iodo,
(11) oxo, and
(12) amidino, and
R5 is selected from the group consisting of:
(a) hydrogen,
(b) linear and branched C1-12alkyl, optionally mono or di- substituted, the substituents being independently selected from:
(1) hydroxy,
(2) carboxy,
(3) —NR7R8,
(4) —OR7,
(5) —C(O)OR7,
(6) —S(O)kR7,
(7) halo selected from F, Cl, Br and I,
(8) trifluoromethyl and
(9) phenyl, optionally mono or di-substituted with a substituent selected from hydroxy, halo, C1-4alkyl, and C1-4alkoxy,
(c) —C(O)NR10R11, where R10 and R11 are each independently hydrogen, phenyl, cyclohexyl, —S(O)2NR7R8 and optionally substituted C1-6alkyl, wherein said substituent is selected from
(1) —NR12R13, wherein R12 and R13 are each independently selected from H, C1-6alkyl, phenyl and benzyl,
(2) —OR12,
(3) —C(O)OR12,
(4) —S(O)kR12, where m is 0, 1 or 2,
(5) halo selected from F, Cl, Br and I,
(6) optionally substituted aryl wherein aryl and aryl substituents are as defined above,
(7) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above,
(8) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, and
(9) hetero C5-10-cycloalkyl,wherein the hetero C5-10cycloalkyl contains 1 or 2 heteroatoms selected from S, O and N,
(d) —C(O)R11,
(e) —C(O)OR11,
(f) aryl, selected from phenyl and naphthyl, and
(g) cyclohexyl.

143 more elements

Dependencies are inferred from the claim text.

Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases

Life of this patent

Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases

Life of this patent

Abstract

Claims12