US2004147552A1PendingUtilityA1
Methods of treating select neuronal inflammatory disorders using hydroxyalkylquinolines
Priority: Sep 7, 2000Filed: Jan 9, 2004Published: Jul 29, 2004
Est. expirySep 7, 2020(expired)· nominal 20-yr term from priority
Inventors:Leslie Dunaway
A61K 31/47
40
PatentIndex Score
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Cited by
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Claims
Abstract
Methods of treating select mammalian disorders using a leukotriene antagonist are described. The methods involve administering to the mammal a therapeutically effective amount of a compound having the formula: The methods may be employed to treat disorders such as traumatic spinal cord injury, graying of the scalp hair, herpes simplex, herpes zoster, Bell's palsy, multiple sclerosis, and Gillian-Barre.
Claims
exact text as granted — not AI-modifiedThat Which is Claimed is:
1 . A method of treating a disorder, selected from the group consisting of traumatic spinal cord injury, graying of scalp hair, herpes simplex, herpes zoster, Bell's palsy, multiple sclerosis, and Gillian-Barre, in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound having the formula:
wherein:
R 1 is H, halogen, —CF 3 , —CN, —NO 2 , or N 3 ;
R 2 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 , —CH 2 F, —CHF 2 , CH 2 CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R 2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R 3 is H or R 2 ;
R 4 is halogen, —NO 2 , —CN, —OR 3 , —SR 3 , NR 3 R 3 , NR 3 C(O)R 7 or R 3 ;
R 5 is H, halogen, —NO 2 , —N 3 , —CN, —SR 2 , —NR 3 R 3 , —OR 3 , lower alkyl, or —C(O)R 3 ;
R 6 is —(CH 2 ) s —C(R 7 R 7 ) —(CH 2 ) s —R 8 or —CH 2 C(O)NR 12 R 12 ;
R 7 is H or C 1 -C 4 alkyl;
R 8 is the radical W—R 9 ;
R 9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R 11 is lower alkyl, —C(O)R 14 , unsubstituted phenyl, or unsubstituted benzyl;
R 12 is H, or R 11 ;
R 13 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 14 is H or R 13 ;
R 16 is H, C 1 -C 4 alkyl, or OH;
R 17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 18 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 19 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 21 is H or R 17 ;
R 22 is R 4 , CHR 7 OR 3 , or CHR 7 SR 2 ;
m is 0-8;
m′is 2 or 3;
n and n′ are independently 0 or 1,
p and p′ are independently 0-8;
m+n+p is 1-10 when r is 1 and X 2 is O, S, S(O), or S(O) 2 ;
m+n+p is 0-10 when r is 1 and X 2 is CR 3 R 16 ;
m+n+p is 0-10 when r is 0;
m′+n′+p′ is 2-10;
r and r′ are independently 0 or 1;
s is 0-3;
Q 1 is —C(O)OR 3, 1H (or 2H)-tetrazol-5-yl, —C(O)OR 6 , —C(O)NHS(O) 2 R 13 , —CN, —C(O)NR 12 R 12 , NR 21 S(O) 2 R 13 , —NR 12 C(O)NR 12 R 12 , —NR 21 C(O)R 18 , —OC(O)NR 12 R 12 , —C(O)R 19 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 12 R 12 , —NO 2 , NR 21 C(O)OR 17 , —C(NR 12 R 12 )═NR 12 , —C(R 13 )═NOH;
Q 2 is OH;
W is O, S, or NR 3 ;
X 2 and X 3 are independently O, S, S(O), S(O) 2 , or CR 3 R 16 ; with the proviso that at least one is S or SO 2 ;
Y is —CR 3 ═CR 3 —;
Z 1 and Z 2 are independently —HET(—R 3 —R 5 )—; and
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof.
2 . A method according to claim 1 wherein the mammal is man.
3 . A method according to claim 1 wherein the compound has the formula:
wherein the substituents are as follows:
*
R 1
Y
A
B
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,4-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
C≡C
SCH 2 (S)CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
S(CH 2 ) 2 CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NH 2
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NHMe
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NMe 2
RS
7-Br
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CH(CH 2 CH═CH 2 )CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)C(CH 2 OCH 2 )OH
4 . A method according to claim 3 wherein the mammal is man.
5 . A method of treating a disorder selected from the group consisting of traumatic spinal cord injury, graying of scalp hair, herpes simplex, herpes zoster, Bell's palsy, multiple sclerosis, and Gillian-Barre, in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.
6 . A method according to claim 5 wherein the mammal is man.
7 . A method for the effective treatment and/or long term suppression of symptoms of Herpes virus infection in a mammal, such a method being comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound having the formula:
wherein:
R 1 is H, halogen, —CF 3 , —CN, —NO 2 , or N 3 ;
R 2 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 , —CH 2 F, —CHF 2 , CH 2 CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R 2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R 3 is H or R 2 ;
R 4 is halogen, —NO 2 , —CN, —OR 3 , —SR 3 , NR 3 R 3 , NR 3 C(O)R 7 or R 3 ;
R 5 is H, halogen, —NO 2 , —N 3 , —CN, —SR 2 , —NR 3 R 3 ,—OR 3 , lower alkyl, or —C(O)R 3 ;
R 6 is —(CH 2 ) s —C(R 7 R 7 )—(CH 2 ) s —R 8 or —CH 2 C(O)NR 12 R 12 ;
R 7 is H or C 1 -C 4 alkyl;
R 8 is the radical W—R 9 ;
R 9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R 11 is lower alkyl, —C(O)R 14 , unsubstituted phenyl, or unsubstituted benzyl;
R 12 is H, or R 11 ;
R 13 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 14 is H or R 13 ;
R 16 is H, C 1 -C 4 alkyl, or OH;
R 17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 18 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 19 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 21 is H or R 17 ;
R 22 is R 4 , CHR 7 OR 3 , or CHR 7 SR 2 ;
m is 0-8;
m′ is 2 or 3;
n and n′ are independently 0 or 1,
p and p′ are independently 0-8;
m+n+p is 1-10 when r is 1 and X 2 is O, S, S(O), or S(O) 2 ;
m+n+p is 0-10 when r is 1 and X 2 is CR 3 R 16 ;
m+n+p is 0-10 when r is 0;
m′+n′+p′ is 2-10;
r and r′ are independently 0 or 1;
s is 0-3;
Q 1 is —C(O)OR 3, 1H (or 2H)-tetrazol-5-yl, —C(O)OR 6 , —C(O)NHS(O) 2 R 13 , —CN, —C(O)NR 12 R 12 , NR 21 S(O) 2 R 13 , —NR 12 C(O)NR 12 R 12 , —NR 21 C(O)R 18 , —OC(O)NR 12 R 12 , —C(O)R 19 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 12 R 12 , —NO 2 , —NR 21 C(O)OR 17 , —C(NR 12 R 12 )═NR 12 , —C(R 13 )═NOH;
Q 2 is OH;
W is O, S, or NR 3 ;
X 2 and X 3 are independently O, S, S(O), S(O) 2 , or CR 3 R 16 ; with the proviso that at least one is S or SO 2 ;
Y is —CR 3 ═CR 3 —;
Z 1 and Z 2 are independently —HET(—R 3 —R 5 )—; and
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof.
8 . A method as in claim 7 wherein the mammal is man.
9 . A method as in claim 8 wherein the Herpes virus is Herpes simplex I (HSV I), Herpes simplex II (HSV II) or Herpes zoster.
10 . A method as in claim 8 or 9 wherein said compound has the formula:
wherein the substituents are as follows:
*
R 1
Y
A
B
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,4-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
C≡C
SCH 2 (S)CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
S(CH 2 ) 2 CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NH 2
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NHMe
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NMe 2
RS
7-Br
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CH(CH 2 CH═CH 2 )CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)C(CH 2 OCH 2 )OH
11 . A method as in claim 8 or 9 wherein said compound is 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.
12 . A method for the effective treatment of traumatic spinal cord injury in a mammal, such a method comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound having the formula:
wherein:
R 1 is H, halogen, —CF 3 , —CN, —NO 2 , or N 3 ;
R 2 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 , —CH 2 F, —CHF 2 , CH 2 CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R 2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R 3 is H or R 2 ;
R 4 is halogen, —NO 2 , —CN, —OR 3 , —SR 3 , NR 3 R 3 , NR 3 C(O)R 7 or R 3 ;
R 5 is H, halogen, —NO 2 , —N 3 , —CN, —SR 2 , —NR 3 R 3 , —OR 3 , lower alkyl, or —C(O)R 3 ;
R 6 is —(CH 2 ) s —C(R 7 R 7 )—(CH 2 ) s —R 8 or —CH 2 C(O)NR 12 R 12 ;
R 7 is H or C 1 -C 4 alkyl;
R 8 is the radical W—R 9 ;
R 9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R 11 is lower alkyl, —C(O)R 14 , unsubstituted phenyl, or unsubstituted benzyl;
R 12 is H, or R 11 ;
R 13 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 14 is H or R 13 ;
R 16 is H, C 1 -C 4 alkyl, or OH;
R 17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 18 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 19 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 21 is H or R 17 ;
R 22 is R 4 , CHR 7 OR 3 , or CHR 7 SR 2 ;
m is 0-8;
m′ is 2 or 3;
n and n′ are independently 0 or 1;
p and p′ are independently 0-8;
m+n+p is 1-10 when r is 1 and X 2 is O, S, S(O), or S(O) 2 ;
m+n+p is 0-10 when r is 1 and X 2 is CR 3 R 16 ;
m+n+p is 0-10 when r is 0;
m′+n′+p′ is 2-10;
r and r′ are independently 0 or 1;
s is 0-3;
Q 1 is —C(O)OR 3, 1H (or 2H)-tetrazol-5-yl, —C(O)OR 6 , —C(O)NHS(O) 2 R 13 , —CN, —C(O)NR 12 R 12 , NR 21 S(O) 2 R 13 , —NR 12 C(O)NR 12 R 12 , —NR 21 C(O)R 18 , —OC(O)NR 12 R 12 , —C(O)R 19 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 12 R 12 , —NO 2 , —NR 21 C(O)OR 17 , —C(O)OR 17 , —C(NR 12 R 12 )═NR 12 , —C(R 13 )═NOH;
Q 2 is OH;
W is O, S, or NR 3 ;
X 2 and X 3 are independently O, S, S(O), S(O) 2 , or CR 3 R 16 ; with the proviso that at least one is S or SO 2 ;
Y is —CR 3 ═CR 3 —;
Z 1 and Z 2 are independently —HET(—R 3 —R 5 )—; and
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof.
13 . A method as in claim 12 wherein the mammal is man.
14 . A method as in claim 13 wherein said compound has the formula:
wherein the substituents are as follows:
*
R 1
Y
A
B
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,4-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
C≡C
SCH 2 (S)CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
S(CH 2 ) 2 CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NH 2
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NHMe
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NMe 2
RS
7-Br
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CH(CH 2 CH═CH 2 )CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)C(CH 2 OCH 2 )OH
15 . A method as in claim 13 wherein said compound is 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.
16 . A method for the treatment and long-term suppression, in a mammal, of symptoms of neuronal inflammatory conditions not due to repetitive motion, said conditions being selected from the group consisting of a Herpes virus infection, traumatic spinal cord injury and graying of scalp hair, such method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound having the formula:
wherein:
R is H, halogen, —CF 3 , —CN, —NO 2 , or N 3 ;
R 2 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 , —CH 2 F, —CHF 2 , CH 2 CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R 2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R 3 is H or R 2 ;
R 4 is halogen, —NO 2 , —CN, —OR 3 , —SR 3 , NR 3 R 3 , NR 3 C(O)R 7 or R 3 ;
R 5 is H, halogen, —NO 2 , —N 3 , —CN, —SR 2 , —NR 3 R 3 , —OR 3 , lower alkyl, or —C(O)R 3 ;
R 6 is —(CH 2 ) s —C(R 7 R7)—(CH 2 ) s —R 8 or —CH 2 C(O)NR 12 R 12 ;
R 7 is H or C 1 -C 4 alkyl;
R 8 is the radical W—R 9 ;
R 9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R 11 is lower alkyl, —C(O)R 14 , unsubstituted phenyl, or unsubstituted benzyl;
R 12 is H, or R 11 ;
R 13 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 14 is H or R 13 ;
R 16 is H, C 1 -C 4 alkyl, or OH;
R 17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 18 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 19 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 21 is H or R 7 ;
R 22 is R 4 , CHR 7 OR 3 , or CHR 7 SR 2 ;
m is 0-8;
m′ is 2 or 3;
n and n′ are independently 0 or 1;
p and p′ are independently 0-8;
m+n+p is 1-10 when r is 1 and X 2 is O, S, S(O), or S(O) 2 ;
m+n+p is 0-10 when r is 1 and X 2 is CR 3 R 16 ;
m+n+p is 0-10 when r is 0;
m′+n′+p′ is 2-10;
r and r′ are independently 0 or 1;
s is 0-3;
Q 1 is —C(O)OR 3, 1H (or 2H)-tetrazol-5-yl, —C(O)OR 6 , —C(O)NHS(O) 2 R 13 , —CN, —C(O)NR 12 R 12 , NR 21 S(O) 2 R 13 , —NR 12 C(O)NR 12 R 12 , —NR 21 C(O)R 18 , —OC(O)NR 12 R 12 , —C(O)R 19 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 12 R 12 , —NO 2 , —NR 21 C(O)OR 17 , —C(NR 12 R 12 )═NR 12 , —C(R 13 )═NOH;
Q 2 is OH;
W is O, S, or NR 3 ;
X 2 and X 3 are independently O, S, S(O), S(O) 2 , or CR 3 R 16 ; with the proviso that at least one is S or SO 2 ;
Y is —CR 3 ═CR 3 ═;
Z 1 and Z 2 are independently —HET(—R 3 —R 5 )—; and
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof.
17 . A method as in claim 16 wherein the mammal is man.
18 . A method as in claim 17 wherein the neuronal inflammatory condition is Multiple sclerosis, Guillian-Barre syndrome or Bell's palsy.
19 . A method as in claim 17 or 18 wherein said compound has the formula:
wherein the substituents are as follows:
*
R 1
Y
A
B
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,4-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
C≡C
SCH 2 (S)CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
S(CH 2 ) 2 CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NH 2
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NHMe
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NMe 2
RS
7-Br
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CH(CH 2 CH═CH 2 )CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)C(CH 2 OCH 2 )OH
20 . A method as in claim 17 or 18 wherein said compound is 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.
21 . A method for inhibiting, in a mammal, the graying of scalp hair which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound having the formula:
wherein:
R is H, halogen, —CF 3 , —CN, —NO 2 , or N 3 ;
R 2 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 , —CH 2 F, —CHF 2 , CH 2 CF 3 , substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R 2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R 3 is H or R 2 ;
R 4 is halogen, —NO 2 , —CN, —OR 3 , —SR 3 , NR 3 R 3 , NR 3 C(O)R 7 or R 3 ;
R 5 is H, halogen, —NO 2 , —N 3 , —CN, —SR 2 , —NR 3 R 3 , —OR 3 , lower alkyl, or —C(O)R 3 ;
R 6 is —(CH 2 ) s —C(R 7 R 7 )—(CH 2 ) s —R 8 or —CH 2 C(O)NR 12 R 2 ;
R 7 is H or C 1 -C 4 alkyl;
R 8 is the radical W—R 9
R 9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R 11 is lower alkyl, —C(O)R 14 , unsubstituted phenyl, or unsubstituted benzyl;
R 12 is H, or R 11 ;
R 13 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 14 is H or R 13 ;
R 16 is H, C 1 -C 4 alkyl, or OH;
R 17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 18 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 19 is lower alkyl, lower alkenyl, lower alkynyl, —CF 3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R 21 is H or R 17 ;
R 22 is R 4 , CHR 7 OR 3 , or CHR 7 SR 2 ;
m is 0-8;
m′ is 2 or 3;
n and n′ are independently 0 or 1;
p and p′ are independently 0-8;
m+n+p is 1-10 when r is 1 and X 2 is O, S, S(O), or S(O) 2 ;
m+n+p is 0-10 when r is 1 and X 2 is CR 3 R 16 ;
m+n+p is 0-10 when r is 0;
m′+n′+p′ is 2-10;
r and r′ are independently 0 or 1;
s is 0-3;
Q 1 is —C(O)OR 3, 1H (or 2H)-tetrazol-5-yl, —C(O)OR 6 , —C(O)NHS(O) 2 R 13 , —CN, —C(O)NR 12 R 12 , NR 21 S(O) 2 R 13 , —NR 12 C(O)NR 12 R 12 , —NR 21 C(O)R 18 , —OC(O)NR 12 , —C(O)R 19 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 12 R 12 , —NO 2 , —NR 21 C(O)OR 17 , —C(NR 12 R 12 )═NR 12 , —C(R 13 )═NOH;
Q 2 is OH;
W is O, S, or NR 3 ;
X 2 and X 3 are independently O, S, S(O), S(O) 2 , or CR 3 R 16 ; with the proviso that at least one is S or SO 2 ;
Y is —CR 3 ═CR 3 —;
Z 1 and Z 2 are independently —HET(—R 3 —R 5 )—; and
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof.
22 . A method as in claim 21 wherein the mammal is man.
23 . A method as in claim 21 or 22 wherein the compound has the formula:
wherein the substituents are as follows:
*
R 1
Y
A
B
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(1,4-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,3-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
C≡C
SCH 2 (S)CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
C≡C
S(CH 2 ) 2 CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
RS
7-Cl
CH═CH
SCH 2 CHMeCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NH 2
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NHMe
RS
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 NMe 2
RS
7-Br
C≡C
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CH(CH 2 CH═CH 2 )CO 2 H
(CH 2 ) 2 (1,2-phe)CMe 2 OH
S
7-Cl
CH═CH
SCH 2 CHEtCO 2 H
(CH 2 ) 2 (1,2-phe)C(CH 2 OCH 2 )OH
24 . A method as in claim 21 or 22 wherein the compound is 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.
25 . An article of manufacture for human pharmaceutical use, comprising packaging material and a container comprising 1-(((1 (R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl) phenyl)-3-(2-(2-hydroxy-2-propyl) phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof, wherein said packaging material comprises a label which indicates that said cyclopropaneacetic acid, or said pharmaceutically acceptable salt thereof, is suitable for treatment, or alleviation of symptoms, of one or more disorders selected from the group consisting of traumatic spinal cord injury, graying of scalp hair, herpes simplex, herpes zoster, Bell's palsy, multiple sclerosis, and Gillian-Barre.
26 . An article according to claim 25 , wherein said container is selected from the group consisting of a blister pack, a bottle and a silica gel desiccant canister.Join the waitlist — get patent alerts
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