Ophthalmic compositions for treating ocular hypertension

1. A compound of the structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof: wherein,

R represents hydrogen, or C 1-6 alkyl;

X represents —(CHR 7 ) p —, —(CHR 7 ) p CO—, wherein p is not zero;

Y represents —CO(CH 2 ) n —;

Q represents CRy;

Ry represents H, or C 1-6 alkyl;

R w represents H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, —SO 2 N(R) 2 , —SO 2 C 1-6 alkyl, —SO 2 C 6-10 aryl, NO 2 , CN or —C(O)N(R) 2 ;

R 2 represents hydrogen, C 1-10 alkyl, OH, C 2-6 alkenyl, C 1-6 alkylSR, —(CH 2 ) n O(CH 2 ) m OR, —(CH 2 ) n C 1-6 alkoxy, —(CH 2 ) n C 3-8 cycloalkyl, —(CH 2 ) n C 3-10 heterocyclyl, —N(R) 2 , —COOR, or —(CH 2 ) n C 6-10 aryl, said alkyl, heterocyclyl, or aryl optionally substituted with 1–3 groups selected from R a ;

R 3 represents hydrogen, C 1-10 alkyl, —(CH 2 ) n C 3-8 cycloalkyl, —(CH 2 ) n C 3-10 heterocyclyl, —(CH 2 ) n COOR, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n NHR 8 , —(CH 2 ) n N(R) 2 , —(CH 2 ) n N(R 8 ) 2 , —(CH 2 ) n NHCOOR, —(CH 2 ) n N(R 8 )CO 2 R, —(CH 2 ) n N(R 8 )COR, —(CH 2 ) n NHCOR, —(CH 2 ) n CONH(R 8 ), aryl, —(CH 2 ) n C 1-6 alkoxy, CF 3 , —(CH 2 ) n SO 2 R, —(CH 2 ) n SO 2 N(R) 2 , —(CH 2 ) n CON(R) 2 , —(CH 2 ) n CONHC(R) 3 , —(CH 2 ) n CONHC(R) 2 CO 2 R, —(CH 2 ) n COR 8 , nitro, cyano or halogen, said alkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1–3 groups of R a ;

or R 2 and R 3 taken together with the intervening Q form a 3–10 membered carbocyclic or heterocyclic carbon ring optionally interrupted by 1–2 atoms of O, S, C(O) or NR, and optionally having 1–4 double bonds, and optionally substituted by 1–3 groups selected from R a ;

or R 2 and R 3 taken together with the intervening Q represent OR;

R 4 and R 5 independently represent hydrogen, C 1-6 alkoxy, OH, C 1-6 alkyl, COOR, SO q C 1-6 alkyl, COC 1-6 alkyl, SO 3 H, —O(CH 2 ) n N(R) 2 , —O(CH 2 ) n CO 2 R, —OPO(OH) 2 , CF 3 , OCF 3 —N(R) 2 , nitro, cyano, C 1-6 alkylamino, or halogen; and

R 6 represents hydrogen, C 1-10 alkyl, —(CH 2 ) n C 6-10 aryl, NR c R d , —NR(CH 2 ) n C 6-10 aryl, —N((CH 2 ) n C 6-10 aryl) 2 , —(CH 2 ) n C 3-10 heterocyclyl, —NR(CH 2 ) n C 3-10 heterocyclyl, —N((CH 2 ) n C 3-10 heterocyclyl) 2 (C 6-10 aryl)O—, —(CH 2 ) n C 3-8 cycloalkyl, —COOR, —C(O)CO 2 R, said aryl, heterocyclyl and alkyl optionally substituted with 1–3 groups selected from R a , wherein the R a (s) can be attached to any carbon atom or heteroatom selected from N and S;

R c and R d independently represent H, C1–6 alkyl, C 2-6 alkenyl, C 1-6 alkylSR, —(CH 2 ) n O(CH 2 ) m OR, —(CH 2 ) n C 1-6 alkoxy, or —(CH 2 ) n C 3-8 cycloalkyl;

or R c and R d taken together with the intervening N atom form a 4–10 membered heterocyclic carbon ring optionally interrupted by 1–2 atoms of O, S, C(O) or NR, and optionally having 1–4 double bonds, and optionally substituted by 1–3 groups selected from R a ;

R 7 represents hydrogen, C 1-6 alkyl, —(CH 2 ) n COOR or —(CH 2 ) n N(R) 2 ,

R 8 represents —(CH 2 ) n C 3-8 cycloalkyl, —(CH 2 ) n 3-10 heterocyclyl, C 1-6 alkoxy or —(CH 2 ) n C 5-10 heteroaryl, —(CH 2 ) n C 6-10 aryl said heterocyclyl, aryl or heteroaryl optionally substituted with 1–3 groups selected from R a ;

R a represents F, Cl, Br, I, CF 3 , N(R) 2 , NO 2 , CN, —O—, —COR 8 , —CONHR 8 , —CON(R 8 ) 2 , —O(CH 2 ) n COOR, —NH(CH 2 ) n OR, —COOR, —OCF 3 , CF 2 CH 2 OR, —NHCOR, —SO 2 R, —SO 2 NR 2 , —SR, (C 1 –C 6 alkyl)O—, —(CH 2 ) n O(CH 2 ) m OR, —(CH 2 ) n C 1-6 alkoxy, (aryl)O—, —(CH 2 ) n OH, (C 1 –C 6 alkyl)S(O) m —, H 2 N—C(NH)—, (C 1 –C 6 alkyl)C(O)—, (C 1 –C 6 alkyl)OC(O)NH—, —(C 1 –C 6 alkyl)NR w (CH 2 ) n C 3-10 heterocyclyl-R w , —(C 1 –C 6 alkyl)O(CH 2 ) n C 3-10 heterocyclyl-R w , —(C 1 –C 6 alkyl)S(CH 2 ) n C 3-10 heterocyclyl-R w , —(C 1 –C 6 alkyl)—C 3-10 heterocyclyl-R w , —(CH 2 ) n -Z 1 -C(=Z 2 )N(R) 2 , —(C 2-6 alkenyl)NR w (CH 2 ) n C 3-10 heterocyclyl-R w , —(C 2-6 alkenyl)O(CH 2 ) n C 3-10 heterocyclyl-R w , —(C 2-6 alkenyl)S(CH 2 ) n C 3-10 heterocyclyl-R w , —(C 2-6 alkenyl)-C 3-10 heterocyclyl-R w , —(C 2-6 alkenyl)-Z 1 -C(=Z 2 )N(R) 2 , —(CH 2 ) n SO 2 R, —(CH 2 ) n SO 3 H, —(CH 2 ) n PO(OR) 2 , C 3-10 cycloalkyl, C 6-10 aryl, C 3-10 heterocyclyl, C 2-6 alkenyl, and C 1 –C 10 alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1–3 groups selected from C 1 –C 6 alkyl, halogen, (CH 2 ) n OH, CN, NO 2 , CON(R) 2 and COOR;

Z 1 and Z 2 independently represents NR w , O, CH 2 , or S;

m is 0–3;

n is 0–3;

p is 0–3 and

q is 0–2.

2. A compound according to claim 1 wherein R 6 is C 1-10 alkyl, (CH 2 ) n C 6-10 aryl, (CH 2 ) n C 3-10 heterocyclyl, NR c R d or (CH 2 ) n C 3-8 cycloalkyl, said aryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.

3. A compound according to claim 1 wherein Y is —CO(CH 2 ) n , n is 0, R 2 is C 1-10 alkyl or C 1-6 alkylOR and R 3 is C 1-10 alkyl, (CH 2 ) n C 3-10 heterocyclyl, X is —(CHR 7 ) p CO—, and p is 1–3 said heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.

4. A compound in accordance with claim 1 which is:

TABLE 1

R1

R2

TABLE 2

wherein R 1 is

and X is N or CH;

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.

5. A composition comprising a compound of formula I of claim 1 and a pharmaceutically acceptable carrier.

6. The compound in accordance with claim 1 wherein Y is —CO(CH 2 ) n , n is 0, R 2 , R 3 and R 6 are independently C 1-10 alkyl, X is —(CHR 7 ) p CO—, and p is 1, Ry is C 1-6 alkyl, R 7 is hydrogen, R 4 and R 5 independently are hydrogen and C 1-6 alkoxy, said and alkyl optionally substituted with 1 to 3 groups of R a or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.

7. The compound in accordance with claim 4 which is

wherein:

R1

R2

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.

8. A compound which is

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.