Ophthalmic Compositions for Treating Ocular Hypertension

1 . A compound of formula I:

or a pharmaceutically acceptable salt, ester including phosphate, enantiomer, diastereomer or mixture thereof:

wherein,

R and R y independently represent hydrogen, or C 1-6 alkyl;

R 1 represents hydrogen or C 1-6 alkyl, CF 3 , (CH 2 ) n C 3-10 cycloalkyl, (CH 2 ) n C 6-10 aryl, —(CH 2 ) n C 5-10 heteroaryl, C 1-6 alkoxy, OH, COR c , said alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy optionally substituted with 1-3 groups selected from R b ;

Q represents N, CR y , or O, wherein R 2 is absent when Q is O;

R 2 represents hydrogen, C 1-10 alkyl, C 2-10 hydroxylalkyl, C 1-6 alkyl SR, —(CH 2 ) n O(CH 2 ) m OR, (CH 2 ) m OR, —(CH 2 ) n (CHR 7 ) S (CH 2 ) m C 1-6 alkoxy, —(CH 2 ) n (CHR 7 ) S (CH 2 ) m C 3-8 cycloalkyl, —(CH 2 ) n (CHR 7 ) S (CH 2 ) m C 3-10 heterocyclyl, —(CH 2 ) n C 5-10 heteroaryl, —N(R) 2 , —COOR, or —(CH 2 ) n (CHR 7 ) S (CH 2 ) m C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from R a ;

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

or, when Q is N, R 2 and R 3 taken together with the intervening N atom form a 4-10 membered heterocyclic 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, when Q equals CR y , R 2 and R 3 taken together with the intervening CR y form a 4-10 membered carbocyclic or heterocyclic aromatic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from R a ,

R 4 represents hydrogen, C 1-6 alkoxy, halogen, cyano, OH, C 1-6 alkyl, COOR, SO 3 H, C 1-6 alkylcarbonyl, S(O) q R y , —O(CH 2 ) n N(R) 2 , —O(CH 2 ) n CO 2 R, —OPO(OH) 2 , CF 3 , —N(R) 2 , nitro, or C 1-6 alkylamino;

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, cycloalkyl, 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, —(CH 2 ) n COR 8 , —(CH 2 ) n CONHR 8 , —(CH 2 ) n CON(R 8 ) 2 , —O(CH 2 ) n COOR, —NH(CH 2 ) n OR, —COOR, —OCF 3 , —O—, —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—CH—, (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 —K—C(═K)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)-K—C(═K)N(R) 2 , —(CH 2 ) n SO 2 R, —(CH 2 ) n SO 3 H, —(CH 2 ) n PO(OR) 2 , —(CH 2 ) n OPO(OR) 2 , cyclohexyl, cyclopentyl, morpholinyl, piperidyl, pyrrolidinyl, thiophenyl, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl, C 2-6 alkenyl, and C 1 -C 10 alkyl, said alkyl, alkenyl, alkoxy, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, and isothiazolyl optionally substituted with 1-3 groups selected from C 1 -C 6 alkyl, and COOR;

K independently represents CH, CH 2 or NH;

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 b represents C 1-6 alkyl, —COOR, —SO 3 R, CN, (CH 2 ) n OR, C(O)O(CH 2 ) n C(O)R, —OPO(OH) 2 , —(CH 2 ) n C 6-10 aryl, or —(CH 2 ) n C 5-10 heteroaryl;

R c represents hydrogen, C 1-6 alkyl, or —(CH 2 ) n C 6-10 aryl;

m is 0-3;

n is 0-3;

q is 0-2; and

s is 0-2.

2 . A compound according to claim 1 wherein Q is N.

3 . A compound according to claim 2 wherein QR 2 R 3 is a dialkylamine or hydroxylamine and R 1 is —C(O)R c .

4 . The compound according to claim 1 of structural formula II:

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

wherein Q is N.

5 . The compound according to claim 1 of structural formula III:

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

wherein R 2 and R 3 are independently C 1-10 alkyl, (CH 2 ) n C 3-10 cycloalkyl, —(CH 2 ) n (CHR 7 ) S (CH 2 ) m C 6-10 aryl, (CH 2 ) n (CHR 7 ) S (CH 2 ) m C 3-10 heterocyclyl, said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with 1-3 groups selected from R a .

6 . The compound according to claim 1 which is:

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N,N-dipropylacetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N,N-dibutylacetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N-(cyclopropylmethyl)-N-propylacetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N-(cyclohexyl)-N-ethylacetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N-ethyl-N-butylacetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N,N-diisobutylacetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N,N-bis(3-methylbutyl)acetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N-ethyl-N-(3-methylbutyl)acetamide;

2-(3-Benzoyl-7-methoxy-1-naphthyl)-N-(3,3-dimethylbutyl)-N-ethylacetamide;

2-[7-Methoxy-3-(3-methylbutanoyl)-1-naphthyl]-N,N-bis(3-methylbutyl)acetamide;

2-(4-Benzoyl-7-methoxy-1-naphthyl)-N,N-bis(3-methylbutyl)acetamide;

2-(1-Benzoyl-7-methoxy-2-naphthyl)-N,N-dibutylacetamide;

2-(2-Benzoyl-7-methoxy-1-naphthyl)-N,N-dibutylacetamide;

4-Benzoyl-N-ethyl-7-methoxy-N-1,3-thiazol-2-yl-2-naphthamide;

2-(4-Benzoyl-7-methoxy-2-naphthyl)-N-ethyl-N-1,3-thiazol-2-ylacetamide;

or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.

7 . A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula I of claim 1 .

8 . A method for treating macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a neuroprotective effect comprising administration to a patient in need of such treatment a pharmaceutically effective amount of a compound of claim 1 ; or a pharmaceutically acceptable salt, ester including phosphate, enantiomer, diastereomer or mixture thereof.

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

10 . A composition according to claim 9 wherein one or more of an active ingredient belonging to the group consisting of: β-adrenergic blocking agent, parasympathomimetic 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.