# US 7,410,992 B2 · Ophthalmic compositions for treating ocular hypertension

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- Number: US 7,410,992 B2
- Document ID: US7410992B2
- Status: Granted
- Kind: B2
- Application number: 10/569,921
- Filed: 2004-08-31
- Published: 2007-01-11
- Granted: 2008-08-12
- Earliest claimed: 2003-09-04
- Assignees: Merck & Co., Inc.
- Inventors: Meng Hsin Chen; James B. Doherty; Luping Liu; Swaminathan Natarajan; Robert M. Tynebor
- Web page: https://patentgrep.com/patent/US7410992B2

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/06: Antiarrhythmics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 9/65038: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

This invention relates to potent potassium channel blocker compounds of Formula (I) or a formulation thereof for the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans, or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof: formula (II) represents C6-10 aryl or C3-10 heterocyclyl, said aryl or heterocyclyl optionally substituted with 1-3 groups selected from Ra; Z represents (CH2)nPO(OR)(OR*).

## Claims

### Claim 1

A compound of the structural formula I:
or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof:
wherein,
R represents hydrogen, or C1-6 alkyl;
Rc and Rd independently represent hydrogen or halo;
Re represents N or O;
X represents —(CHR7)p—, —(CHR7)pCO—;
Y represents —CO(CH2)n—, CH2, or —CH(OR)—;
Q represents CRy;
Ry represents H, or C1-6 alkyl;
Rw represents H, C1-6 alkyl, —C(O)C1-6 alkyl, —C(O)OC1-6 alkyl, —SO2N(R)2, —SO2C1-6 alkyl, —SO2C6-10 aryl, NO2, CN or —C(O)N(R)2;
R2 represents hydrogen, C1-10 alkyl, OH, C2-6 alkenyl, C1-6 alkylSR, —(CH2)nO(CH2)mOR, —(CH2)nC1-6 alkoxy, —(CH2)nC3-8 cycloalkyl, —(CH2)nC3-10 heterocyclyl, —N(R)2, —COOR, or —(CH2)nC6-10 aryl, said alkyl, heterocyclyl, or aryl optionally substituted with 1-3 groups selected from Ra;
R3 represents hydrogen, C1-10 alkyl, —(CH2)nC3-8 cycloalkyl, —(CH2)nC3-10 heterocyclyl, —(CH2)nCOOR, —(CH2)nC6-10 aryl, —(CH2)nNHR8, —(CH2)nN(R)2, —(CH2)nN(R8)2, —(CH2)nNHCOOR, —(CH2)nN(R8)CO2R, —(CH2)nN(R8)COR, —(CH2)nNHCOR, —(CH2)nCONH(R8), aryl, —(CH2)nC1-6 alkoxy, CF3, (CH2)nSO2R, —(CH2)nSO2N(R)2, —(CH2)nCON(R)2, —(CH2)nCONHC(R)3, —(CH2)nCONHC(R)2CO2R, —(CH2)nCOR8, nitro, cyano or halogen, said alkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-3 groups of Ra;
or, R2 and R3 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 Ra;
R4 and R5 independently represent hydrogen, C1-6 alkoxy, OH, C1-6 alkyl, COOR, SO3H, —O(CH2)nN(R)2, —O(CH2)nCO2R, —OPO(OH)2, CF3, OCF3, —N(R)2, nitro, cyano, C1-6 alkylamino, or halogen;
represents C6-10 aryl or C3-10 heterocyclyl, said aryl or heterocyclyl optionally substituted with 1-3 groups selected from Ra;
Z represents (CH2)nPO(OR)(OR*);
R* represents hydrogen, or C1-6 alkyl;
R7 represents hydrogen, C1-6 alkyl, —CH2)nCOOR or —(CH2)nN(R)2,
R8 represents —(CH2)nC3-8 cycloalkyl, —(CH2)n 3-10 heterocyclyl, C1-6 alkoxy or —(CH2)nC5-10 heteroaryl, —(CH2)nC6-10 aryl said heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from Ra;
Ra represents F, Cl, Br, I, CF3, N(R)2, NO2, CN, —COR8, —CONHR8, —CON(R8)2, —O(CH2)nCOOR, —NH(CH2)nOR, —COOR, —OCF3, —NHCOR, —SO2R, —SO2NR2, —SR, (C1-C6 alkyl)O—, —(CH2)nO(CH2)mOR, —(CH2)nC1-6 alkoxy, (aryl)O—, —(CH2)nOH, (C1-C6 alkyl)S(O)m—, H2N—C(NH)—, (C1-C6 alkyl)C(O)—, (C1-C6 alkyl)OC(O)NH—, —(C1-C6 alkyl)NRw(CH2)nC3-10 heterocyclyl-Rw, —(C1-C6 alkyl)O(CH2)nC3-10 heterocyclyl-Rw, —C1-C6 alkyl)S(CH2)nC3-10 heterocyclyl-Rw, —(C1-C6 alkyl)-C3-10 heterocyclyl-Rw, —(CH2)n-Z1-C(=Z2)N(R)2, —(C2-6 alkenyl)NRw(CH2)nC3-10 heterocyclyl-Rw, —C2-6 alkenyl)O(CH2)nC3-10 heterocyclyl-Rw, —(C2-6 alkenyl)S(CH2)nC3-10 heterocyclyl-Rw, —C2-6 alkenyl)-C3-10 heterocyclyl-Rw, —(C2-6 alkenyl)-Z1-C(=Z2)N(R)2, —(CH2)nSO2R, —(CH2)nSO3H, —(CH2)nPO(OR)2, C3-10cycloalkyl, C6-10 aryl, C3-10 heterocyclyl, C2-6 alkenyl, and C1-C10 alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C1-C6 alkyl, CN, NO2, OH, CON(R)2 and COOR;
Z1 and Z2 independently represents NRw, O, CH2, or S;
g is 0-1;
m is 0-3;
n is 0-3; and
p is 0-3.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein Y is —CO(CH2)n, p is 1-3 and X is —CHR7)p or —(CHR7)pCO—.

### Claim 3 (depends on 2)

The compound according to claim 2 wherein Z is PO(OR)(OR*), R2 and R3 are independently hydrogen, C1-10 alkyl or C 1-6alkylOH, Y is —CO(CH2)n.

### Claim 4 (depends on 3)

The compound according to claim 3 wherein
is a 6 membered heteroaryl or phenyl optionally substituted with 1-3 groups selected from Ra.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein
is pyridyl optionally substituted with 1-3 groups selected from Ra.

### Claim 6

A compound which is:
di-tert-butyl 4-{[1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1-H-indazole-3-yl]carbonyl}benzylphosphate;
4-{[1-(3,3-dimethyl-2-oxybutyl)-6-methoxy-1-H-indazol-3-yl]carbonyl}benzyl di-hydrogen phosphate;
2-[(5-{[1-(3,3-dimethyl-2-oxobutyl-6-methoxy-1-H-indazol-3-yl)carbonyl}pyridine-2-yl)oxy]ethyl di-hydrogen phosphate;
(5-{[1-3,3dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3-yl]carbonyl}pyridine-2-yl)methyl dihydrogen phosphate;
2-(5-{[1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3yl]carbonyl}pyridine-2-yl)-2,2-diflouroethyl di-hydrogen phosphate; and
2-(5-{[7-bromo-1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3-yl]carbonyl}puyridin-2-yl)-2,2-difluoroethyl di-hydrogen phosphate,
or a pharmaceutically acceptable salt, in vivo hydrolysable ester, enantiomer, diastereomer or mixture thereof.

### Claim 7

A compound which is:
di-tert-butyl 4-{[1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1-H-indazole-3-yl]carbonyl}benzylphosphate in the form of a monosodium or disodium salt;
4-{[3,3-dimethyl-2-oxybutyl)-6-methoxy-1-H-indazol-3-yl]carbonyl}benzyl di-hydrogen phosphate in the form of a monosodium or disodium salt;
2-[(5-{[1-(3,3-dimethyl-2-oxobutyl-6-methoxy-1-H-indazol-3-yl)carbonyl}pyridine-2-yl)oxy]ethyl di-hydrogen phosphate in the form of a monosodium or disodium salt;
(5-{[1-3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3-yl]carbonyl}pyridine-2-yl)methyl dihydrogen phosphate in the form of a monosodium or disodium salt;
2-(5-{[1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3yl]carbonyl}pyridine-2-yl)-2,2-diflouroethyl di-hydrogen phosphate in the form of a monosodium or disodium salt; and
2-(5-{[7-bromo-1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3-yl]carbonyl}puyridin-2-yl)-2,2-difluoroethyl di-hydrogen phosphate in the form of a monosodium or disodium salt.

### Claim 8 (depends on 1)

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