Renin inhibitors
The present invention relates to biphenyl-based renin inhibitor compounds having amino-terminal groups, and their use in treating cardiovascular events and renal insufficiency.
1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, having the formula (I)
wherein
Ar 1 is an unsubstituted or substituted phenyl ring or an unsubstituted or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with one, two or three substituents independently selected from the group consisting of:
1) OH,
2) CN,
3) halogen,
4) N 3 ,
5) NO 2 ,
6) COOH,
7) OCF 2 H,
8) CF 3 ,
9) C 1 -C 6 alkyl,
10) C 2 -C 6 alkenyl,
11) C 1 -C 6 alkoxy,
12) C(O)NHC 1 -C 6 alkyl
13) NHC(O)C 1 -C 6 alkyl
14) S(O) n C 1 -C 6 alkyl,
15) OCH 2 CH 2 OAr 4 , and
16) CH 2 CH 2 CH 2 OAr 4 ,
wherein substituents (9)-(14) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of:
a) OH,
b) COOH,
c) CN,
d) CF 3 ,
e) C 1 -C 6 alkyl,
f) C 1 -C 6 alkoxy, and
g) S(O) n C 1 -C 6 alkyl;
Ar 2 is a substituted phenyl ring or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with Ar 3 and can be substituted with one or two substituents independently selected from the group consisting of:
1) OH,
2) CN,
3) halogen,
4) N 3 ,
5) NO 2 ,
6) COOH,
7) OCF 2 H,
8) CF 3 ,
9) C 1 -C 6 alkyl,
10) C 2 -C 6 alkenyl,
11) C 1 -C 6 alkoxy,
12) C(O)NHC 1 -C 6 alkyl,
13) NHC(O)C 1 -C 6 alkyl,
14) S(O) n C 1 -C 6 alkyl,
15) O—C 1 -C 6 alkyl, and
16) C(O)OC 1 -C 6 alkyl
wherein substituents (9)-(16) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of:
a) OH,
b) COOH,
c) CN,
d) CF 3 ,
e) C 1 -C 6 alkyl,
f) C 1 -C 6 alkoxy, and
g) S(O) n C 1 -C 6 alkyl;
Ar 3 is a substituted phenyl ring or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with R 1 and R 2 , and wherein the N heteroatom of the pyridinyl ring is optionally oxidized;
R 1 is in the ortho position to the Ar 2 —Ar 3 bond and is selected from the group consisting of
1) halogen,
2) CF 3 ,
3) CN,
4) (CH 2 ) 1-3 OR 3 ,
5) O(CH 2 ) 1-2 OR 3 ,
6) (CH 2 ) 1-3 NHAc,
7) (CH 2 ) 1-3 OC(O)NH 2 ,
8) (CH 2 ) 1-3 COOR 3 ,
9) (CH 2 ) 1-3 CN,
10) (CH 2 ) 1-3 C(O)NH 2 ,
11) S(O) n C 1 -C 6 alkyl,
12) C 1 -C 6 alkoxy,
13) OCH 2 Ph,
14) CH 2 —N-morpholine,
15) CH═CHCOOR 3 ,
16) CH 2 — N -4-piperidinone, and
17) (CH 2 ) 1-2 C(O)NR 3 R 4 ,
R 2 is selected from the group consisting of
1) hydrogen,
2) OH,
3) CN,
4) halogen,
5) N 3 ,
6) NO 2 ,
7) COOH,
8) OCF 2 H,
9) CF 3 ,
10) C 1 -C 6 alkyl,
11) C 2 -C 6 alkenyl,
12) C 1 -C 6 alkoxy,
13) C(O)NHC 1 -C 6 alkyl,
14) NHC(O)C 1 -C 6 alkyl, and
15) S(O) n C 1 -C 6 alkyl,
wherein substituents (10)-(15) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of:
a) OH,
b) COOH,
c) CN,
d) CF 3 ,
e) C 1 -C 6 alkyl,
f) S(O) n C 1 -C 6 alkyl, and
g) tetrazolyl;
R 3 and R 4 are independently selected from the group consisting of
1) hydrogen,
2) CF 2 H,
3) CH 2 CF 3 ,
4) C 1 -C 6 alkyl, and
5) C 2 -C 6 alkenyl;
Ar 4 is an unsubstituted or substituted phenyl ring or unsubstituted or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with one, two or three substituents independently selected from the group consisting of:
1) CN,
2) halogen,
3) N 3 ,
4) NO 2 ,
5) OCF 2 H,
6) CF 3 ,
7) C 1 -C 6 alkyl,
8) C 2 -C 6 alkenyl,
9) C 1 -C 6 alkoxy, and
10) S(O) n C 1 -C 6 alkyl,
wherein substituents (7)-(10) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of:
a) OH,
b) COOH,
c) CN,
d) CF 3 ,
e) C 1 -C 6 alkoxy,
f) S(O) n C 1 -C 6 alkyl; and
n=0, 1 or 2.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 is an unsubstituted or substituted phenyl ring or an unsubstituted or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with one or two or three substituents independently selected from the group consisting of halogen and —OCH 2 CH 2 OAr 4 .
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is a substituted phenyl ring or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with Ar 3 and can be substituted with one or two substituents independently selected from the group consisting of halogen, CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and
—C(O)O C 1 -C 6 alkyl.
4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 3 is a substituted phenyl ring or substituted pyridinyl ring, wherein the substituted phenyl ring and substituted pyridinyl ring are substituted with R 1 and R 2 , and wherein the N heteroatom of the pyridinyl ring is optionally oxidized.
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is in the ortho position to the Ar 2 —Ar 3 bond and is selected from the group consisting of
1) halogen,
2) CF 3 ,
3) CN,
4) (CH 2 ) 1-3 OH,
5) (CH 2 ) 1-3 OCH 3 ,
6) O(CH 2 ) 1-2 OCH 3 ,
7) O(CH 2 ) 1-2 OCH 2 CH 3 ,
8) (CH 2 ) 1-3 NHAc,
9) (CH 2 ) 1-3 OC(O)NH 2 ,
10) (CH 2 ) 1-3 COOCH 3 ,
11) (CH 2 ) 1-3 CN,
12) (CH 2 ) 1-3 C(O)NH 2 ,
13) S(O) n CH 3 ,
14) C 1 -C 6 alkoxy,
15) OCH 2 Ph,
16) CH 2 —N-morpholine,
17) CH═CHCOOR 3 ,
18) CH 2 — N -4-piperidinone, and
19) (CH 2 ) 1-2 C(O)N(CH 3 ) 2 .
6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl.
7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 4 is a substituted phenyl ring substituted with three substituents independently selected from the group consisting of halogen and C 1 -C 6 alkyl.
8. A compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein Ar 4 is
9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of
10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A method for the treatment of a disease which is selected from the group consisting of hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, diabetic nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, restenosis post angioplasty, hyperaldosteronism, and scleroderma, comprising administering a pharmaceutically active amount of a compound according to claim 1 to a patient in need of treatment of the disease.