US2008108605A1PendingUtilityA1
Anxiolytic agents with reduced sedative and ataxic effects
Est. expiryMar 28, 2022(expired)· nominal 20-yr term from priority
A61P 25/18A61P 25/22A61P 25/00A61P 1/08C07D 495/04C07D 243/20C07D 495/14C07D 471/04C07D 498/04C07D 487/04C07D 519/00C07D 243/12C07D 243/24C07D 487/06C07D 243/14
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Claims
Abstract
Orally active benzodiazepine derivatives and their salts are disclosed. These compounds and their salts have anxiolytic and anticonvulsant activity with reduced sedative/hypnotic/muscle relaxant/ataxic effects.
Claims
exact text as granted — not AI-modified1 - 8 . (canceled)
9 . A compound of formula I or a salt thereof,
wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1 is one of O═, H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , or cyclopropyl; R 2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position; and R 10 is N or CH, and R 9 is N or
wherein when R 9 is
R 1 is ═O and R 10 is N, and wherein when R 9 is not
R 1 is not ═O.
10 . The compound according to claim 9 or a salt thereof, wherein the compound is
where R is H or Si(CH 3 ) 3 , R′ is H or CH 3 , and X′ is H, F, Cl, Br or NO 2 .
11 . The compound according to claim 9 or a salt thereof, wherein the compound is:
where R is H or Si(CH 3 ) 3 .
12 . The compound according to claim 11 , wherein the compound is
13 . A compound according to claim 9 or a salt thereof, wherein the compound is:
where R is H or Si(CH 3 ) 3 .
14 . A compound of Formula II or a salt thereof having rings A, B, C and D,
wherein R is H, CH 3 , Si(CH 3 ) 3 , t-butyl, or cyclopropyl; R 12 is N or CH, R 13 is phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, or 2-pyridyl N—O, n is an integer from 1 to 2 inclusive and ring C is saturated or unsaturated.
15 . A compound of Formula III or a salt thereof having rings A, B, and C,
wherein R is H, CH 3 , Si(CH 3 ) 3 , t-butyl, or cyclopropyl; R 8 is C═O, C═S, or C—NHCH 3 , R 13 is phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, or 2-pyridyl N—O, n is an integer from 1 to 2 inclusive and ring C is saturated or unsaturated.
16 . A method for the treatment and/or prevention of convulsions comprising administering to a patient in need of such treatment an effective amount of a compound selected from the group consisting of compounds according to Formulas I-VII or a salt thereof,
wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position; and R 10 is N, CH, C—CO 2 —R 5 ,
where n is 0 to 4,
where n is 1 or 2,
wherein Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 5 is a branched or straight chain C 1 to C 4 halogenated or unhalogenated alkyl or a methyl cyclopropyl;
R 6 is a branched or straight chain C 1 to C 4 alkyl or a methyl cyclopropyl;
R 1 ′ is one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , or cyclopropyl;
R 2 ′ is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position; and wherein when R 10 is C—CO 2 —R 5 , R 1 is one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , CH 2 C≡CH, or cyclopropyl;
otherwise, R 1 is one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , or cyclopropyl; and wherein when R 10 is
B is O or NH and wherein —BCH 2 B— is optionally replaced with —N(R 7 )—N(R 7 )—, where R 7 is one of H, CH 3 , alkyl, or cycloalkyl; and when R 10 is
B is O or NH or —N(R 7 )—N(R 7 )—, where R 7 is one of H, CH 3 , alkyl, or cycloalkyl;
and R 9 is N or
wherein when R 9 is
R 1 is ═O and R 10 is N;
R 3 is one of H, OH, OCON(CH 3 ) 2 , COOH, COOCH 3 , COOC 2 H 5 ,
wherein if R 3 is
n is 0 to 4; Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 1 and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , or cyclopropyl;
R 2 and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2 at the 2′-position, or
wherein if R 3 is
Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1 and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 or cyclopropyl; R 2 and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2 at the 2′-position; B is O or NH and wherein —BCH 2 B— is optionally replaced with —N(R 7 )—N(R 7 )—, where R 7 is one of H, branched or straight chain C 1 to C 4 alkyl, cyclopropyl or methyl cyclopropyl,
wherein if R 3 is
Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 1 and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 or cyclopropyl;
R 2 and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position;
B is O, NH, or —N(R 7 )—N(R 7 )—, where R 7 is one of H, branched or straight chain C 1 to C 4 alkyl, cyclopropyl or methyl cyclopropyl, wherein R 2 is not phenyl when R 3 is H, R 1 is H or CH 3 and Y and Z taken together form a phenyl ring;
wherein R 8 is C═O, C═S, or C—NHCH 3 ;
R 11 is O or N and R 4 is H, O or C,
wherein when R 11 is O, R 4 is H, and R 8 is C═O;
when R 11 is N, R 4 is C and R 11 and R 4 are taken together with an intervening nitrogen atom to form a pyrazole ring;
when R 11 is N, R 4 is O and R 11 and R 4 are taken together with an intervening carbon atom to form an oxazole ring; or
when R 11 is N, R 4 is C and R 11 and R 4 are taken together with two intervening carbon atoms to form a pyridine ring;
and R 12 is N or CH, R 13 is phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, or 2-pyridyl N—O, and if the compound is according to Formulas II or III, n is an integer from 1 to 2 inclusive and ring C is saturated or unsaturated.
17 . The method of claim 16 wherein the compound is
where R is H or Si(CH 3 ) 3 .
18 . The method of claim 16 wherein the compound is
where R is H or Si(CH 3 ) 3 .
19 . The method according to claim 16 , wherein the compound is
where R is H or Si(CH 3 ) 3 .
20 . The method of claim 16 wherein the compound is
where R is H or Si(CH 3 ) 3 .
21 . The method of claim 16 wherein the compound is
where R is H or Si(CH 3 ) 3 .
22 . A method for the treatment and/or prevention of anxiety comprising administering to a patient in need of such treatment an effective amount of a compound selected from the group consisting of compounds according to Formulas I-VII or a salt thereof,
wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 2 is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position; and R 10 is N, CH, C—CO 2 —R 5 ,
where n is 0 to 4,
where n is 1 or 2,
wherein Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 5 is a branched or straight chain C 1 to C 4 halogenated or unhalogenated alkyl or a methyl cyclopropyl.
R 6 is a branched or straight chain C 1 to C 4 alkyl or a methyl cyclopropyl;
R 1 ′ is one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , or cyclopropyl;
R 2 ′ is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position; and wherein
when R 10 is C—CO 2 —R 5 , R 1 is one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , CH 2 C≡CH, or cyclopropyl;
otherwise, R 1 is one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , or cyclopropyl; and wherein when R 10 is
B is O or NH and wherein —BCH 2 B— is optionally replaced with —N(R 7 )—N(R 7 )—, where R 7 is one of H, CH 3 , alkyl, or cycloalkyl; and when R 10 is
B is O or NH or —N(R 7 )—N(R 7 )—, where R 7 is one of H, CH 3 , alkyl, or cycloalkyl;
and R 9 is N or
wherein when R 9 is
R 1 is ═O and R 10 is N;
R 3 is one of H, OH, OCON(CH 3 ) 2 , COOH, COOCH 3 , COOC 2 H 5 ,
wherein if R 3 is
n is 0 to 4; Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 1 and R 1 1 are independently one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , or cyclopropyl;
R 2 and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2 at the 2′-position, or
wherein if R 3 is
Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 1 and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 or cyclopropyl;
R 2 and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2 at the 2′-position;
B is O or NH and wherein —BCH 2 B— is optionally replaced with —N(R 7 )—N(R 7 )—, where R 7 is one of H, branched or straight chain C 1 to C 4 alkyl, cyclopropyl or methyl cyclopropyl,
wherein if R 3 is
Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
R 1 and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 or cyclopropyl;
R 2 and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2 at the 2′-position;
B is O, NH, or —N(R 7 )—N(R 7 )—, where R 7 is one of H, branched or straight chain C 1 to C 4 alkyl, cyclopropyl or methyl cyclopropyl, wherein R 2 is not phenyl when R 3 is H, R 1 is H or CH 3 and Y and Z taken together form a phenyl ring;
wherein R 8 is C═O, C═S, or C—NHCH 3 ;
R 11 is O or N and R 4 is H, O or C,
wherein when R 11 is O, R 4 is H, and R 8 is C═O;
when R 11 is N, R 4 is C and R 11 and R 4 are taken together with an intervening nitrogen atom to form a pyrazole ring;
when R 11 is N, R 4 is O and R 11 and R 4 are taken together with an intervening carbon atom to form an oxazole ring; or
when R 11 is N, R 4 is C and R 11 and R 4 are taken together with two intervening carbon atoms to form a pyridine ring;
and R 12 is N or CH, R 13 is phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, or 2-pyridyl N—O, and if the compound is according to Formulas II or III, n is an integer from 1 to 2 inclusive and ring C is saturated or unsaturated.
23 . The method of claim 22 wherein the compound is
where R is H or Si(CH 3 ) 3 .
24 . The method of claim 22 wherein the compound is
where R is H or Si(CH 3 ) 3 .
25 . The method according to claim 22 , wherein the compound is
where R is H or Si(CH 3 ) 3 .
26 . The method of claim 22 wherein the compound is
where R is H or Si(CH 3 ) 3 .
27 . The method of claim 22 wherein the compound is
where R is H or Si(CH 3 ) 3 .Join the waitlist — get patent alerts
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