Case of renin inhibitors

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, having the formula I

wherein

R 1 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;

R 2 is —O(CH 2 ) 1-3 OCH 3 or —(CH 2 ) 1-3 OCH 3 ;

R 3 is selected from the group consisting of:

hydrogen,

and

—O(CH 2 ) 2 C(CH 3 ) 2 R 5 ;

R 4 is selected from the group consisting of:

hydrogen,

—C(O)OCH 3 ,

—C(O)NH—C 1 -C 6 alkyl,

—COOH,

R 5 is selected from the group consisting of —COOH, —COOC 1 -C 6 alkyl;

R 6 is selected from the group consisting of:

—COOR 9 ,

—CH 2 COOR 9 ,

—CON(CH 3 )SO 2 CH 3 ,

—CONHSO 2 CH 3 ,

—C(O)NH 2

—CH(CH 2 CH 3 )COOH,

—CONHSO 2 CH 3 ,

—NH 2 ,

R 7 and R 8 are independently selected from the group consisting of:

hydrogen,

—C 1-6 alkyl,

—OH,

—OCH 3 ,

—COOH,

—NH 2 , and

or R 7 and R 8 , together with the atom to which they are attached, form a C 3-8 cycloalkyl ring;

R 9 is selected from the group consisting of:

hydrogen,

—C 1 -C 6 alkyl,

—(CH 2 ) 2-4 CH(ONO 2 )CH 2 ONO 2 ,

—CH 2 C(O)N(CH 3 ) 2 ,

—CH 2 OCOC(CH 3 ) 3 ,

—CH 2 OCH 2 OCOCH 3 ,

—CH(CH 3 )OCOCH(CH 3 ) 2 ,

—CH(CH 3 )COOCH 2 CH 3 ,

—CH 2 CH 2 N(CH 3 ) 2 ,

—CH(CH 3 )OCOOCH 2 CH 3 ,

—CH(CH 3 )OCOOCH(CH 3 ) 2 ,

R 10 is selected from the group consisting of:

hydrogen,

—COOCH 3 ,

—COOCH(CH 3 )OCOCH 3 ,

W is a phenyl ring or a six-membered, aromatic ring containing one to four nitrogen atoms, wherein said rings are substituted by V in para position;

V is a bond; —(CH 2 ) r —; -A-(CH 2 ) s —; —CH 2 -A-(CH 2 ) t —; —(CH 2 ) s -A-; —(CH 2 ) 2 -A-(CH 2 ) u —; -A-(CH 2 ) v —B—; —CH 2 —CH 2 —CH 2 -A-CH 2 —; -A-CH 2 —CH 2 —B—CH 2 —; —CH 2 -A-CH 2 —CH 2 —B—; —CH 2 —CH 2 —CH 2 -A-CH 2 —CH 2 —; —CH 2 —CH 2 —CH 2 —CH 2 -A-CH 2 —; -A-CH 2 —CH 2 —B—CH 2 —CH 2 —; —CH 2 -A-CH 2 —CH 2 —B—CH 2 —; —CH 2 -A-CH 2 —CH 2 —CH 2 —B—; —CH 2 —CH 2 -A-CH 2 —CH 2 —B—; —O—CH 2 —CH(OCH 3 )—CH 2 —O—; —O—CH 2 —CH(CH 3 )—CH 2 —O—; —O—CH 2 —CH(CF 3 )—CH 2 —O—; —O—CH 2 —C(CH 3 ) 2 —CH 2 —O—; —O—CH 2 —C(CH 3 ) 2 —O—; —O—C(CH 3 ) 2 —CH 2 —O—; —O—CH 2 —CH(CH 3 )—O—; —O—CH(CH 3 )—CH 2 —O—; —O—CH 2 —C(CH 2 CH 2 )—O—; or —O—C(CH 2 CH 2 )—CH 2 —O—;

A and B are independently selected from the group consisting of —O—, —S—, —S(O)— and —S(O) 2 —;

U is unsubstituted aryl; mono-, di-, tri- or tetra-substituted aryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and —CF 3 ; or mono-, di-, or tri-substituted heteroaryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and —CF 3 ;

Q is methylene or ethylene;

n is the integer 0 or 1;

r is the integer 3, 4, 5, or 6;

s is the integer 2, 3, 4, or 5;

t is the integer 1, 2, 3, or 4;

u is the integer 1, 2, or 3; and

v is the integer 2, 3, or 4.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is methylene.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is phenyl substituted by V in the para position.

5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is —CH 2 CH 2 O—, —CH 2 CH 2 CH 2 O—, or —OCH 2 CH 2 O—, wherein the bivalent radical is linked to the group U of formula (I) via an oxygen atom.

6. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein V is —OCH 2 CH 2 O—.

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U is a mono-, di-, or tri-substituted phenyl wherein the substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and —CF 3 .

8. A compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein U is 2,6-dichloro-4-methyl-phenyl.

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —O(CH 2 ) 2 OCH 3 or —(CH 2 ) 3 OCH 3 .

10. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:

hydrogen,

 —OCH 2 CH 2 C(CH 3 ) 2 C(O)OCH 3 , and —OCH 2 CH 2 C(CH 3 ) 2 C(O)OH.

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are independently selected from the group consisting of:

hydrogen,

—CH 3 ,

—CH 2 CH 3 ,

—OH,

—OCH 3 ,

—COOH,

—NH 2 , and

or R 7 and R 8 , together with the atom to which they are attached, form a cycloalkyl ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

hydrogen,

—C(O)OCH 3 ,

—COOH,

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds listed in the following tables:

TABLE 1

—R 4

1-1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-20

1-21

1-22

1-23

1-24

1-25

1-26

1-27

1-28

1-29

1-30

1-31

1-32

1-33

1-34

1-35

1-36

1-37

1-38

1-39

1-40

1-41

1-42

1-43

1-44

1-45

1-46

1-47

1-48

1-49

1-50

1-51

1-52

1-53

1-54

1-55

1-56

1-57

1-58

1-59

1-60

1-61

1-62

1-63

1-64

1-65

1-66

TABLE 2

—R 3

2-1

2-2

2-3

2-4

2-5

2-6

2-7

2-8

TABLE 3

3-1

3-2

3-3

3-4

3-5

3-6

3-7

3-8

3-9

3-10

3-11

14. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method for the treatment of hypertension, comprising the administration to a patient of a pharmaceutically active amount of a compound according to claim 1 .