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;

R 1 represents hydrogen or C 1-6 alkyl, CF 3 , C 1-6 alkoxy, COR c , CO 2 R 8 , CONHCH 2 CO 2 R, N(R) 2 , said alkyl and alkoxy optionally substituted with 1-3 groups selected from R b ;

X represents —(CHR 7 ) p —;

Y is not present, —CO(CH 2 ) n —, or —CH(OR)—;

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

R y 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, 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, —(CH 2 ) n C 5-10 heteroaryl, —N(R) 2 , —COOR, or —(CH 2 ) n C 6-10 aryl, said alkyl, heterocyclyl, aryl or heteroaryl 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 C 5-10 heteroaryl, —(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 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 COR 8 , nitro, cyano or halogen, said alkyl, 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 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 4 and R 5 independently represent hydrogen, C 1-6 alkoxy, OH, C 1-6 alkyl, COOR, SO 3 H, O(CH 2 ) n N(R) 2 , O(CH 2 ) n CO 2 R, C 1-6 alkylcarbonyl, S(O)qR y , OPO(OH) 2 , CF 3 , N(R) 2 , nitro, cyano or halogen;

R 6 represents hydrogen, C 1-10 alkyl, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n C 5-10 heteroaryl, (C 6-10 aryl)O—, —(CH 2 ) n C 3-10 heterocyclyl, —(CH 2 ) n C 3-8 cycloalkyl, —COOR, —C(O)CO 2 R, said aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 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, 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, —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 , cyclohexyl, 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, CN, (CH 2 ) n tetrazolyl, COOR, SO 3 H, OH, F, Cl, Br, I, —O(CH 2 ) n CH(OH)CH 2 SO 3 H, and

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

R b represents C 1-6 alkyl, —COOR, —SO 3 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

p is0-1.

2 . A compound of the structural formula I wherein X represents CHR 7 .

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

4 . A compound according to claim 1 wherein Y is CH(OR).

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

6 . A compound according to claim 1 wherein Q is CH.

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

8 . A compound according to claim 6 wherein R 7 is hydrogen or C 1-6 alkyl.

9 . A compound according to claim 6 wherein Q is N and n is 0.

10 . A compound according to claim 1 wherein Y is —CO(CH 2 ) n , Q is N, n is 0, 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 .

11 . A compound selected from Tables 1 through 14 which is:

TABLE 1

Wherein R represents:

and R* represents:

or hydrogen;

TABLE 2

Wherein R represents:

R* represents:

or hydrogen and R{circumflex over ( )} represents hydrogen or methyl;

TABLE 3

Wherein R represents:

R* represents:

or chlorine

and R{circumflex over ( )} represents hydrogen or methyl;

TABLE 4

R represents methyl or methoxy and R* represents methyl, H or COCH;

R′ represents methyl or methoxy;

R{circumflex over ( )} represents hydrogen or COOEt;

R′′′ represents COOH or COOtBu; a

R″ represents: COOMe, H, COOH, or

TABLE 5

R* represents hydrogen or methyl;

R y represents methyl or CF 3 ;

R represents methyl, (CH2) 2 SCH 3 ,

R{circumflex over ( )} represents:

R+ represents:

(CH 2 ) 2 CO 2 H, chlorine,

TABLE 6

Wherein n represents 1-2;

R{circumflex over ( )} represents hydrogen or methyl

R represents:

and R′ represents:

chlorine,

TABLE 7

Y = O, or S(O)R and p = 0-2

R is:

TABLE 8

Y = OCH 3 , Cl, Br, CH 2 CH 3 , or CN

R is:

TABLE 9

Y = CH 3 or CH 2 CH 3

R is:

TABLE 10

Y = OCH 3 , CN, or Cl; X = H, or F;

Z = Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2

R is:

TABLE 11

Wherein R represents:

R 1 represents:

R2 represents: hydrogen or methyl

TABLE 12

Wherein R represents:

R 1 represents:

R2 represents: hydrogen or methyl

TABLE 13

TABLE 14

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

12 . 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 claim 1 .

13 . The method according to claim 12 wherein the compound of formula I is applied as a topical formulation selected from solution topical formulation and a suspension topical formulation.

14 . A method according to claim 13 in which the topical formulation optionally contains xanthan gum or gellan gum.

15 . A method according to claim 13 wherein an active ingredient belonging to the group consisting of: δ-adrenergic blocking agent, parasympathomimetic agent, EP4 agonist, carbonic anhydrase inhibitor, and a prostaglandin or a prostaglandin derivative is optionally added to the formulation.

16 . A method according to claim 15 wherein the δ-adrenergic blocking agent is timolol; the parasympathomimetic agent is pilocarpine; the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost or rescula, and the prostaglandin derivative is a hypotensive lipid derived from PGP2α prostaglandins.

17 . 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 providing 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, enantiomer, diastereomer or mixture thereof.

18 . The method according to claim 17 wherein the compound of formula I is applied as a topical formulation.

19 . A method according to claim 18 in which the topical formulation optionally contains xanthan gum or gellan gum.

20 . A method of preventing repolarization or hyperpolarization of a mammalian cell wherein the cell contains a potassium channel comprising the administration to a mammal, including a human, in need thereof, of a pharmacologically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof

21 . A method of treating Alzheimer's Disease, depression, cognitive disorders, arrhythmia disorders and/or diabetes in a patient in need thereof comprising administering a pharmaceutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.