Ophthalmic compositions for treating ocular hypertension

1. A compound of the structural formula I:

where

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

wherein,

R represents hydrogen, or C 1-6 alkyl;

X represents —(CHR 7 ) p —, or —(CHR 7 ) p CO—;

Y represents —CO(CH 2 ) n —, (CH 2 ) n , —CH(OR)—, OR 6 , or SR 6 ;

Z═O or S;

M1, M2, and M3 are independently CH or N;

Q represents, N;

RY represents H, C 1-6 alkyl, —(CH 2 ) n C 3-8 cycloalkyl, —(CH 2 ) n C 3-10 heterocyclyl, —(CH 2 ) n C 5-10 heteroaryl, or —(CH 2 ) n C 6-10 aryl;

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 (CHR 7 ) q (CH 2 ) m C 1-6 alkoxy, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8 cycloalkenyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10 heterocyclyl, —N(R) 2 , —COOR, or —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl, or aryl optionally substituted with 1-5 groups selected from R a ;

R 3 represents hydrogen, C- 1-10 alkyl, C 2-6 alkenyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8 cycloalkyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m cycloalkenyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10 heterocyclyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m COOR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10 aryl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m NHR 8 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R) 3 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R 8 ) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m NHCOOR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R 8 )CO 2 R, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R 8 )COR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m NHCOR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CONH(R 8 ), aryl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 1-6 alkoxy, CF 3 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m SO 2 R, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m SO 2 N(R) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CON(R) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CONHC(R) 3 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CONHC(R) 2 CO 2 R, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m COR 8 , nitro, cyano or halogen, said alkyl, cycloalkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-5 groups of R a ;

R 4 and R 5 independently represent hydrogen, C 1-6 alkoxy, OH, C 1-6 alkyl, C 1-6 alkyl-S, C 1-6 alkyl-CO—, C 1-6 alkenyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl-S, C 3-8 cycloalkyl—CO—, COOR, SO 3 H, —O(CH 2 ) n N(R) 2 , —O(CH 2 ) n CO 2 R, —OPO(OH) 2 , CF 3 , —N(R) 2 , nitro, cyano, C 1-6 alkylamino, or halogen;

R 6 represents hydrogen, C 1-10 alkyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10 aryl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 5-10 heteroaryl, NR c R d , —NR—(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10 aryl, —N—((CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10 aryl) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10 heterocyclyl, —NR—(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10 heterocyclyl, —N—((CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10 heterocyclyl) 2 (C 6-10 aryl)O—, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8 cycloalkyl, —COOR, —C(O)CO 2 R, said aryl, cycloalkyl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from R a ;

R c and R d independently represent H, C 1-6 alkyl, C 2-6 alkenyl, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n C 5-10 heteroaryl, 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 cycloalkyl, 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, —COR 8 , —CONHR 8 , —CON(R 8 ) 2 , —O(CH 2 ) n COOR, —NH(CH 2 ) n OR, —COOR, —OCF 3 , —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—, —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 , —(CH 2 ) n OH, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m OPO(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, CN, NO 2 , —(CH 2 ) n OH, —(CH 2 ) n OPO(OR) 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 0-1.

2. A compound according to claim 1 wherein Q is —N— and Y is —CO(CH 2 ) n .

3. A compound according to claim 2 wherein n=0, Z is S, and R 6 is C 1-6 alkyl, (CH 2 ) n C 6-10 aryl, (CH 2 ) n C 5-10 heteroaryl, (CH 2 ) n C 3-10 heterocyclyl, NR c R d or (CH 2 ) n C 3-8 cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a .

4. A compound according to claim 3 wherein M1, M2 and M3 are CH, X is —(CHR 7 ) p CO—, p is 1-3, R 2 is C 1-10 alkyl or C 1-6 alkylOH and R 3 is (CH 2 ) n C 3-10 heterocyclyl, said heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a .

5. A compound according to claim 2 wherein n=0, Z is O, and R 6 is C 1-6 alkyl, (CH 2 ) n C 6-10 aryl, (CH 2 ) n C 5-10 heteroaryl, (CH 2 ) n C 3-10 heterocyclyl, NR c R d or (CH 2 ) n C 3-8 cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a .

6. A compound according to claim 5 wherein M1, M2 and M3 are CH, X is —(CHR 7 ) p CO—, p is 1-3, R 2 is C 1-10 alkyl or C 1-6 alkylOH and R 3 is (CH 2 ) n C 3-10 heterocyclyl, said heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a .

7. A compound according to claim 1 where a free hydroxyl group is present, said hydroxyl group optionally derivatized to give a phosphate group represented as —OPO(OH) 2 .

8. A compound which is:

N,N-Bibutyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide,

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-diisobutylacetamide,

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-dipropylacetamide,

N-Butyl-2-[2-(2,2-ethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofaran-3-yl]-N,N-bis(3-methylbutyl)acetamide,

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide,

N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-propylacetamide,

N-(3,3-Dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide,

N-(3,3-Dimethylbutyl)-2-[2-(2,2-ethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,

2-(2-Benzoyl-5-methoxy-1-benzofuran-3-yl)-N,N-dibutylacetamide,

2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-di-n-butylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-diisobutylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-dipropylacetamide;

N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;

2-[2-(2,2-methylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;

N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-propylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;

N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;

N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-methylacetamide;

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-methyl-N-(3-methylbutyl)acetamide;

2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-di-n-butylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-diisobutylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-dipropylacetamide;

N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;

N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-propylacetamide;

2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;

N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;

2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-di-n-butylacetamide;

2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-diisobutylacetamide;

2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-dipropylacetamide;

N-butyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethylacetamide;

2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;

N-butyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-propylacetamide;

2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;

N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl-1-benzothien-3-yl]-N-ethylacetamide;

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

9. A method for the treatment ocular hypertension or glaucoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of structural formula I.

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

11. The composition according to claim 10 wherein the compound of formula I is applied as a topical formulation, said topical formulation administered as a solution or suspension and optionally contains xanthan gum or gellan gum.

12. A composition according to claim 11 wherein one or more of an active ingredient belonging to the group consisting of: β-adrenergic blocking agent, parasympatho-mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, EP4 agonist, a prostaglandin or derivative thereof, hypotensive lipid, neuroprotectant, and/or 5-HT2 receptor agonist is optionally added.

13. A composition according to claim 12 wherein the β-adrenergic blocking agent is timolol, betaxolol, levobetaxolol, carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine; the sympathomimetic agent is epinephrine, brimonidine, iopidine, clonidine, or para-aminoclonidine, the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost, travaprost, unoprostone, rescula, or S1033, the hypotensive lipid is lumigan, the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is 1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.