USRE37438EExpiredUtility
Acetamidine derivatives and their use as inhibitors for the nitric oxide synthase
Est. expiryDec 20, 2014(expired)· nominal 20-yr term from priority
Inventors:Jeffrey Alan OplingerEdward Patrick GarveyEric FurfineBarry George ShearerJon Loren Collins
A61P 43/00C07D 277/40C07C 257/14C07C 311/46C07D 333/20C07C 335/36C07C 323/60A61K 31/155C07D 217/22C07D 213/74C07C 323/41C07D 231/12A61P 29/00A61K 31/416C07D 249/08C07C 2602/08C07D 233/56C07D 231/56C07C 257/18C07D 217/04
41
PatentIndex Score
4
Cited by
24
References
16
Claims
Abstract
A class of acetamidine derivatives of general formula (I) wherein R 1 is hydrogen, C 1-6 hydrocarbyl group optionally substituted by halo, halo, nitro, cyano or a group XR 3 wherein X is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl, provided that R 3 is not NR 5 R 6 when X is oxygen or S(O) n ; R 1a and R 1b are independently selected from hydrogen and halo; R 2 is a C 1-14 hydrocarbyl group which may optionally contain one or two heteroatoms, the group R 2 being optionally substituted by one or more groups independently selected from halo; N 3 ; nitro; CF 3 ; ZR 7 wherein Z is oxygen, C(O) m′ wherein m′ is 1 or 2, S(O) n′ wherein n′ is 0, 1 or 2, or a group NR 8 wherein R 8 is hydrogen or C 1-6 alkyl and R 7 is hydrogen, C 1-6 alkyl or a group NR 9 R 10 wherein R 9 and R 10 are independently hydrogen or C 1-6 alkyl; or R 2 is substituted by a group (a) wherein R 11 has a definition the same as for R 1 ; with the proviso that when R 1 is a C 1-6 alkyl group and R 2 is a C 1-14 hydrocarbyl substituted by two groups ZR 7 wherein one group ZR 7 is CO 2 H, the other group ZR 7 is not NH 2 ; and salts thereof, methods for the manufacture thereof, and therapies, particularly inhibtion of nitric oxide synthase, is disclosed.
Claims
exact text as granted — not AI-modifiedWe claim:
1. An A method of treating a condition requiring inhibition of NO synthase, the step of administering to a mammal in need thereof an effective amount of an acetamidine derivative of formula (I):
or a salt thereof, wherein
R 1 is
hydrogen,
a C 1-6 hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl; provided that R 3 is not NR 5 R 6 when X is oxygen or S(O) n ;
R 1a and R 1b are independently selected from hydrogen and halo;
R 2 is a group:
wherein p, q and r are independently 0, 1 or 2, and R 12 is selected from the group consisting of flouro, hydrogen, and NH 2 .
2. A method of treating a condition requiring inhibition of NO synthase, comprising the step of administering to a mammal in need thereof an effective amount of a compound of formula (1B):
wherein R 1 is
hydrogen,
a C 1-6 hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl, provided that R 3 is not NR 5 R 6 when X is oxygen or S(O) n ;
R 1a and R 1b are independently selected from hydrogen and halo, and
R 14 represents one or two substituents on the phenyl ring independently selected from halo, ZR 7 or a group:
wherein Z is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 8 wherein R 8 is hydrogen or C 1-6 alkyl, R 7 is hydrogen, C 1-6 alkyl, or a group NR 9 R 10 wherein R 9 and R 10 are independently hydrogen or C 1-6 alkyl, and R 11 has a definition the same as for R 1 , or
R 14 is a C 1-6 C 1-8 hydrocarbyl group optionally substituted by one or two groups which may be the same or different, and are selected from halo, ZR 7 or a group:
3. A method of treating a condition requiring inhibition of NO synthase, comprising the step of administering to a mammal in need thereof an effective amount of a compound of formula 1C:
wherein R 1 is
hydrogen,
a C 1-6 hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl, provided that R 3 is not NR 5 R 6 when X is oxygen or S(O) n ;
R 1a and R 1b are independently selected from hydrogen and halo;
R 15 is a bond or CH 2 ; and
Y is selected from the group consisting of optionally substituted phenyl and indanyl; wherein Y is optionally substituted by one or more groups independently selected from the group consisting of halo, amino, cyano, nitro, hydroxy, and C 1-6 hydrocarbyl optionally substituted by hydroxy, C 1-6 alkoxy, C 1-6 thioalkyl, CF 3 , N 3 N 3 , a group:
wherein n is 0, 1 or 2, C(O) m B′ or S(O) n B′ wherein m is 1 or 2, n is 0, 1 or 2 and B′ is amino or C 1-6 alkyl,
a group:
wherein n is 0, 1 or 2 and D and E are independently selected from the group consisting of hydrogen, hydroxy, amino, C 1-6 alkyl, —CNHCH 3 , —CO 2 t Bu,
a group:
—(CH 2 ) n —NH—(CH 2 ) n —A
—( CH 2 ) n —NH— ( CH 2 ) n′ —A
wherein n is 0, 1 or 2, n′ is 0, 1 or 2, and A is phenyl
a group:
— ( CH 2 ) n —G
wherein n is 0 , 1 or 2 and G is —CO
2
H, or —CO
2
C
1-6
alkyl.
4. The An acetamidine derivative of claim 1 which is:
N-(3-(Hydroxymethyl)phenyl)acetamidine;
N-(3-(Aminomethyl)phenyl)acetamidine;
N-(3-((Methylamino)methyl)phenyl)acetamidine;
N-(Dimethylamino)methyl)phenyl)acetamidine;
N-(3-(Aminomethyl)phenyl)-2-fluoroacetamidine;
N-(3-(2-Aminoethyl)phenyl)acetamidine; or
a salt thereof.
5. The An acetamidine derivative of claim 1 which is:
N-(3-(Aminomethyl)benzyl)acetamidine;
N-(4-(Aminomethyl)benzyl)acetamidine;
N-(3-(Aminomethyl)benzyl)-3-fluoroacetamidine;
N-(3-(Aminomethyl)benzyl-2-aminoacetamidine;
N-(3-(Aminomethyl)benzyl)-2,2,2-trifluororacetamidine;
N-((1H-Indazol-6-yl)methyl)acetamidine; or
N-((3-Amino-5-indanyl)methyl)acetamidine; or
a salt thereof.
6. The acetamidine derivative of claim 1 5 which is:
N-(3-(Aminomethyl)benzyl)acetamidine;
N-(4-(Aminomethyl)benzyl)acetamidine;
N-(3-(Aminomethyl)benzyl)-3-fluoroacetamidine;
N-(3-(Aminomethyl)benzyl)-3-aminoacetamidine;
N-((3-Amino-5-indanyl)methyl)acetamidine;
or a salt thereof.
7. A pharmaceutical formulation comprising at least one compound as defined in claim 1 of formula ( I ) :
or a salt thereof, wherein
R
1
is
hydrogen,
a C
1-6
hydrocarbyl group substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C ( O ) m wherein m is 1 or 2 , S ( O ) n wherein n is 0 , 1 or 2 , or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl; provided that R 3 is not NR 5 R 6 when X is oxygen or S(O) n ;
R
1a
and R
1b
are independently selected from hydrogen and halo;
R
2
is a group:
wherein p, q and r are independently 0 , 1 or 2 , and R
12
is selected from the group consisting of flouro, hydrogen, and NH
2
;
together with one or more pharmaceutically acceptable carriers, diluents, or excipients.
8. A method of treating a condition requiring inhibition of NO synthase, comprising the step of administering to a mammal in need thereof an effective amount of an acetamidine derivative of claim 1 .
9. The method of claim 8 1 wherein the compound inhibits one of the NO synthase isoenzymes with little or no inhibition of the other isoenzymes.
10. A method for the prophylaxis or treatment of shock states resulting from overproduction of NO by iNOS, said method comprising administering an acetamidine derivative of claim 1 formula ( I ) :
or a salt thereof, wherein
R
1
is
hydrogen,
a C
1-6
hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C ( O ) m wherein m is 1 or 2 , S ( O ) n wherein n is 0 , 1 or 2 , or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl; provided that R 3 is not NR 5 R 6 when X is oxygen or S ( O ) n ;
R
1a
and R
1b
are independently selected from hydrogen and halo;
R 2 is a group:
wherein p, q and r are independently 0 , 1 or 2 , and R
12
is selected from the group consisting of flouro, hydrogen, and NH
2
;
in an amount effective to prevent or treat shock states resulting from overproduction of NO by iNOS.
11. The method of claim 10 wherein the condition is selected from the group consisting of septic shock, shock caused by fulminant heptic failure, shock caused by therapy with one or more cytokines and shock caused by therapy with cytokine-inducing agents.
12. A method of treating a condition requiring inhibition of NO synthase, which comprises the step of administering to a mammal a pharmaceutical formulation according to claim 7 in an amount effective to inhibit NO synthase.
13. A method for the prophylaxis or treatment of an auto-immune disease or an inflammatory disease, said method comprising administering an acetamidine derivative of claim 1 formula ( 1 ) :
or a salt thereof, wherein
R
1
is
hydrogen,
a C
1-6
hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C ( O ) m wherein m is 1 or 2 , S ( O ) n wherein n is 0 , 1 or 2 , or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl; provided that R 3 is not NR 5 R 6 when X is oxygen or S ( O ) n ;
R
1a
and R
1b
are independently selected from hydrogen and halo;
R
2
is a group:
wherein p, q and r are independently 0 , 1 or 2 , and R
12
is selected from the group consisting of flouro, hydrogen, and NH
2
;
in an amount effective to prevent or treat an auto-immune disease or an inflammatory disease.
14. A method for the prophylaxis or treatment of a condition resulting from the overproduction of NO by nNOS, said method comprising administering an acetamidine derivative of claim 1 formula ( I ) :
or a salt thereof, wherein
R
1
is
hydrogen,
a C
1-6
hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C ( O ) m wherein m is 1 or 2 , S ( O ) n wherein n is 0 , 1 or 2 , or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl; provided that R 3 is not NR 5 R 6 when X is oxygen or S ( O ) n ;
R
1a
and R
1b
are independently selected from hydrogen and halo;
R
2
is a group:
wherein p, q and r are independently 0 , 1 or 2 , and R
12
is selected from the group consisting of flouro, hydrogen, and NH
2
;
in an amount effective to prevent or treat conditions resulting from the overproduction of NO by nNOS.
15. A process for the preparation of a compound of formula (1)
or a salt thereof, wherein
R 1 is
hydrogen,
a C 1-6 hydrocarbyl group optionally substituted by halo,
halo,
nitro,
cyano or
a group XR 3 wherein X is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 4 wherein R 4 is hydrogen or C 1-6 alkyl; and R 3 is hydrogen, C 1-6 alkyl, or a group NR 5 R 6 wherein R 5 and R 6 are independently hydrogen or C 1-6 alkyl, provided that R 3 is not NR 5 R 6 when X is oxygen or S(O) n ;
R 1a and R 1b are independently selected from hydrogen and halo;
R 2 is a C 1-14 hydrocarbyl group the group R 2 being optionally substituted by one or more groups independently selected from halo; N 3 ; nitro; CF 3 ; ZR 7 wherein Z is oxygen, C(O) m wherein m is 1 or 2, S(O) n wherein n is 0, 1 or 2, or a group NR 8 wherein R 8 is hydrogen or C 1-6 alkyl and R 7 is hydrogen, C 1-6 alkyl or a group NR 9 R 10 wherein R 9 and R 10 are independently hydrogen or C 1-6 alkyl; or R 2 is substituted by a group
wherein R 11 has a definition the same as R 1 ;
with the proviso that when R 1 is a C 1-6 alkyl group and R 2 is a C 1-14 hydrocarbyl substituted by two groups ZR 7 wherein one group ZR 7 is CO 2 H, the other group ZR 7 is not NH 2 ; N-( 3 -( aminomethyl ) benzyl ) acetamidine
said process comprising the reaction of an amine of formula (II):
H 2 N—R 2
tert- butyl N -( 3 - aminomethyl ) benzyl
or a protected derivative thereof;
with benzylthioacetamidate hydrochloride
followed by deprotection if necessary.
16. The acetamidine derivative of claim 5 which is N-( 3 -( aminomethyl ) benzyl ) acetamidine or a salt thereof.Cited by (0)
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