WO2008030390A2 - Ophthalmic compositions for treating ocular hypertension - Google Patents

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.

Description

TITLE OF THE INVENTION

OPHTHALMIC COMPOSITIONS FOR TREATING OCULAR HYPERTENSION

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S. C. § 119 from US Application No. 60/842,224, filed September 5, 2006.

BACKGROUND OF THE INVENTION Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.

There are several therapies for treating glaucoma and elevated intraocular pressure, but the efficacy and the side effect profiles of these agents are not ideal. Recently potassium channel blockers were found to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. Blockage of potassium channels can diminish fluid secretion, and under some circumstances, increase smooth muscle contraction and would be expected to lower IOP and have neuroprotective effects in the eye. (see US Patent Nos. 5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38, 1997; WO 89/10757, WO94/28900, and WO 96/33719).

SUMMARY OF THE INVENTION

This invention relates to the compounds of formula I and their use as potent potassium channel blockers or formulations thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular 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. More particularly this invention relates to the treatment of glaucoma and/or ocular hypertension (elevated intraocular pressure) using novel bidentate compounds having the structural formula I:

Formula I or a pharmaceutically acceptable salt, hydrolysable ester, enantiomer, diastereomer or mixture thereof: wherein, V and V independently represent:

Yl and Y2 independently represent O or H2;

Y represents -CO(CH2)_nR5-, -(CH2)_nR5, ^or -CH(OR)Rs;

Q and Q' are O, NR, or a bond;

W is a Ci-IO alkyl di-radical optionally interrupted by zero to three groups of Cβ-io aryl, C5-IO heteroaryl, C3.10 cycloalkyl, C5-10 heterocycle, zero to four groups of O, S, SO, SO2, or NR, or a combination thereof and optionally substituted with one to three groups of R^a;

- 2 - or W can be from one to three di-radical groups selected from the group consisting of C₆-IO aryl, C5-10 heteroaryl, C3-10 cycloalkyl, C5-10 heterocycle, wherein when there is more than one di- radical present, said di -radicals are connected with each other using zero to two C 1.5 alkyl di- radical, zero to four groups of O, S, SO, SO2, or NR, or a combination thereof and optionally substituted with one to three groups of Ra ;

X and X' represent -(CHR7)_p-;

Z, Zi, Z2, Z3, Z4, Z5, Z6, and Z7 are independently selected from CH or N;

R represents hydrogen, C 1-6 alkyl, -(CH2)nC3-8 cycloalkyl, -(CH2)nC3-lθ heterocyclyl, - (CH2)nC6-10 aryl, said alkyl, cycloalkyl and aryl optionally substituted with one to three groups of Ra;

R2 and R3 independently represent hydrogen, Ci_io alkyl, OH, -(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), C₅-IO aryl, -(CH₂)_nCl-6 alkoxy, CF₃, -(CH₂)nSO₂R, - (CH₂)_nS02N(R)2, -(CH₂)_nCON(R)₂, -(CH₂)_nCONHC(R)3, -(CH₂)I₁CONHC(R)₂CO₂R, - (CH₂)_nCOR8, -(CH₂)_nOPO(OR)₂, nitro, cyano or halogen, said alkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1 -3 groups of R^a;

Rl and R4 independently represent hydrogen, Ci-6 alkoxy, OH, Ci-6 alkyl, COOR, SOqCi-6 alkyl, COC 1-6 alkyl, SO3H, -O(CH₂)_nN(R)₂, -O(CH₂)_nCO₂R, -OPO(OH)₂, CF3, OCF3 - N(R)₂, nitro, cyano, Cl -6 alkylamino, or halogen; and

R5 represents hydrogen, Ci-io alkyl, -(CH₂)_nC6-10 aryl, NR₀Rd, -NR(CH₂)_nC6-10 aryl, - N((CH₂)_nC6-10 aryl)₂, -(CH₂)_nC3_io heterocyclyl, -NR(CH₂)_nC3-io heterocyclyl, - N((CH₂)_nC₃-10 heterocyclyl)₂, (C₆-IO aryl)O-, -(CH₂)_nOPO(OR)₂, -(CH₂)_nC₃-8 cycloalkyl, - COOR, -C(O)CO₂R, said aryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from Ra, wherein the Ra(s) can be attached to any carbon atom or heteroatom selected from N and S;

R_c and Rd independently represent H, C 1-6 alkyl, C₂-6 alkenyl, Cl -6 alkylSR, - (CH₂)_nO(CH₂)_mOR, -(CH₂)_nCi-₆ alkoxy, or -(CH₂)_nC3_8 cycloalkyl; or Rc and Rd 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;

R7 represents hydrogen, C l -6 alkyl, -(CH2)_nCOOR or -(CH2)_nN(R)2,

R8 represents -(CH2)_nC3-8 cycloalkyl, -(CH2)nC3-lO heterocyclyl, Cl -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, -O-, -CORg, -CONHRg, -CON(Rg)2, - O(CH2)_nCOOR, -NH(CH₂)_nOR, -COOR, -OCF3, CF₂CH₂OR, -NHCOR, -SO2R, -SO2NR2, - SR, (C₁-C₆ alkyl)O-, -(CH₂)n0(CH₂)m0R, -(CH₂)_nCl-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)NR_w(CH2)_nC3-10 heterocyclyl-R_w, -(C₁-C₆ alkyl)O(CH2)_nC3-10 heterocyclyl-R_w, -(C₁- C₆ alkyl)S(CH2)_nC3-l0 heterocyclyl-R_w, -(C₁-C₆ alkyl)-C3-io heterocyclyl-R_w, -(C2-6 alkenyl)NR_w(CH2)nC3-10 heterocyclyl-R_w, -(C2-6 alkenyl)O(CH2)nC3-10 heterocyclyl-R_w, - (C2-6 alkenyl)S(CH2)nC3-lO heterocyclyl-R_w, -(C2-6 alkenyl)-C3_io heterocyclyl-R_w, - (CH₂)nSO₂R, -(CH₂)nSO₃H, -(CH₂)_nPO(OR)₂, C₃-10cycloalkyl, C₆-IO aryl, C₃-IO heterocyclyl, C2-6 alkenyl, and C₁-C_{1 Q} alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C₁-C₆ alkyl, halogen, (CH2)_nOH, CN, NO2, C0N(R)2 and COOR;

R_w represents H, Cl -6 alkyl, -C(O)C i_₆ alkyl, -C(O)OCi -6 alkyl, -Sθ2N(R)2, -Sθ2Ci_₆ alkyl, - SO2C6-IO aryl, NO₂, CN or -C(O)N(R)₂;

m is 0-3; n is 0-3; p is 0-3 and q is 0-2.

This and other aspects of the invention will be realized upon inspection of the invention as a whole. DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel potassium channel blockers of Formula I. It also relates to a method for decreasing elevated intraocular pressure or treating glaucoma by administration, preferably topical or intra-camaral administration, of a composition containing a potassium channel blocker of Formula I described hereinabove and a pharmaceutically acceptable carrier.

Another embodiment of this invention is realized when Y is -(CH2)nR5 and all other variables are as originally described. A subembodiment of this invention is realized when n is O. Another embodiment of this invention is realized when Y is -CO(CH2)nR5 and all other variables are as originally described. A subembodiment of this invention is realized when n is 0.

Another embodiment of this invention is realized when Y is CH(OR)Rs and all other variables are as originally described. In another embodiment X and X' independently are -(CHR7)p-, p is 1-3 and all other variables are as originally described.

Still another embodiment of this invention is realized when Z is N and all other variables are as originally described.

Still another embodiment of this invention is realized when Z is CH and all other variables are as originally described.

Another embodiment of this invention is realized when Zi, Z2, Z3, Z4, Z5, Zβ, and Z7 are CH and all other variables are as originally described.

Yet another embodiment of this invention is realized when one of Q and Q' is NR and the other is O and all other variables are as originally described. Another embodiment of this invention is realized when both Q and Q' are NR and all other variables are as originally described.

Another embodiment of this invention is realized when W is a 2-10 alkyl di- radical interrupted by C6-10 ary^ C5-IO heterocyclyl, C3-IO cycloalkyl, or C5.10 heteraryl and optionally substituted with one to three groups of R^a ,and all other variables are as originally described.

Another embodiment of this invention is realized when W can be from one to three di-radical groups selected from the group consisting of C6-10 aryl C5-10 heteroaryl, C3-10 cycloalkyl, C5-IO heterocycle, wherein when there is more than one di-radical present, said di- radicals are connected with each other using zero to two C] .5 alkyl di-radical, zero to four groups of O, S, SO, SO2, or NR, or a combination thereof and optionally substituted with one to three groups ofR^a and all other variables are as originally described. -

Another embodiment of this invention is realized when R is H or Cl -6 alkyl and all other variables are as originally described. - . . -- - - - Another embodiment is realized when R4 is C 1-6 alkoxy and all other variables are as originally described.

Another embodiment of this invention is realized when V = V and all other variables are as originally described. - -

Another embodiment of this invention is realized when V≠V and all other variables are as originally described.

Still another embodiment of this invention is realized when V and V both are

and all other variables are as originally described. A sub-embodiment of this invention is realized when Zi, Z2, and Z3 are CH, Y is -C(O)(CH2)nR5 and Q and Q' are independently O or NR. Another sub-embodiment of this invention is realized when R4 is Cl -6 alkoxy. Another sub-embodiment of this invention is realized when both Q and Q' are NR. Still another sub-embodiment of this invention is realized when one of Q and Q' is NR and the other is O.

Another embodiment of this invention is realized when V and V both are

³ and all other variables are as originally described. A sub-embodiment of this invention is realized when Zi, Z2, and Z3 are CH, Y is -(CH2)nR-5 and Q and Q' are independently O or NR. Another sub-embodiment of this invention is realized when R4 is Ci_6 alkoxy. Another sub-embodiment of this invention is realized when both Q and Q' are NR. Still another sub-embodiment of this invention is realized when one of Q and Q' is NR and the other is O. Another embodiment of this invention is realized when V and V both are

invention is realized when Zi, Z2, and Z3 are CH, Y is -C(O)(CH2)nR5 and Q and Q' are independently O or NR. Another sub-embodiment of this invention is realized when R4 is Cl -6 alkoxy. Another sub-embodiment of this invention is realized when both Q and Q' are NR. Still another sub-embodiment of this invention is realized when one of Q and Q' is NR and the other is O.

Examples of compounds of this invention are found below, including those in Tables 1 through 6:

3-{Butyl[(3-fert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetyl]amino}-2,2-dimethylpropyl (3-terNbutyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetate;

3 - [ [(3 -ter/-Butyl- 7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)acetyl] (3 -methylbutyl)amino] -2,2- dimethylpropyl (3-tert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetate; ΛyV-Ethane- 1 ,2-diylbis { 2- [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 -yl] -N- ethylacetamide};

N,iV-Propane- 1 ,3 -diylbis { 2- [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 -yl] -N- ethylacetamide};

JVyV-Ethane- 1 ,2-diylbis[N-(tert-butyl)-2-(3-isobutyryl-6-methoxy- lH-indazol- 1 - yl)acetamide] ; 1 , 1 '- {Piperazine- 1 ,4-diylbis[(2-oxoethane-2, 1 -diyl)(6-methoxy- 1 H-indazole- 1,3- diyl)]}bis(2-methylpropan-l-one);.

Table 1

Table 2

Table 3

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

Preferred compounds used in this invention are:

3 - [ [(3 -tert-Butyl-T-methoxy^-oxoquinoxalin- 1 (2H)-yl)acetyl] (3 -methylbutyl)amino]-2,2- dimethylpropyl (3 -?er/-butyl-7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)acetate; 4-((3 ,3 -Dimethylbutyl) { [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 - yl] acetyl } amino)-2,2-dimethylbutyl [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 - - yl]acetate;

4- {Ethyl [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] amino } butyl (3 -isobutyryl-6-methoxy- lH-indazol-l-yl)acetate; 3 -[ [(3 -Isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] (3 -methylbutyl)amino]propyl (3 -isobutyryl- 6-methoxy- 1 H-indazol- 1 -yl)acetate;

4-[[(3-Isobutyryl-6-methoxy-lH-indazol-l-yl)acetyl](3-methylbutyl)amino]butyl (3-isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetate;

3 - { (3 ,3 -Dimethylbutyl) [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] amino } -2,2- dimethylpropyl (3 -isobutyryl-6-methoxy- 1 H-indazol- l-yl)acetate;

3 - { Isobutyl [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] amino } propyl (3 -isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetate;

4- { Cyclohexyl [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] amino } butyl (3 -isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetate; N,iV-Ethane- 1 ,2-diylbis[N-ethyl-2-(3-isobutyryl-6-methoxy- lH-indazol- 1 -yl)acetamide] ;

ΛyV-Propane- 1 ,3 -diylbis [N-ethyl-2-(3-isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetamide] ;

N-E%l-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-{2-[[(3-isobutyryl-6-methoxy-lH- indazol- 1 -yl)acetyl] (methyl)amino] ethyl } acetamide; N,Λ^-Ethane-l,2-diylbis[2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-isopropylacetamide];

N^-Propane-l^-diylbisP-CS-isobutyryl-ό-methoxy-lH-indazol-l-y^-TV-isopropylacetamide];

N-(I ,3 -Dimethylbutyl)-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)-JV-(2- { [(3 -isobutyryl-6- methoxy-lH-indazol-l-yl)acetyl]amino}ethyl)acetamide;

yl)acetamide];

N,N'-Ethane-l,2-diylbis[N-(tert-butyl)-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide];

N J^ -Ethane- 1 ,2-diylbis [iV-butyl-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetamide] ;

JV,./V-Butane- 1 ,4-diylbis [7V-ethyl-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetamide] ; iVjiY-Pentane- 1 ,5-diylbis[N-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol- 1 -yl)acetamide] ; iV-Ethyl-2-(3-isobutyryl-6-methoxy- lH-indazol- 1 -yϊ)-N-(5- { [(3 -isobutyryl-6-methoxy- IH- indazol- 1 -yl)acetyl]amino}pentyl)acetamide;

N,iV-Ηexane-l,6-diylbis[7V-ethyl-2-(3 -isobutyryl-6-methoxy- IH- indazol- l-yl)acetamide];

N-Ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-(6-{[(3-isobutyryl-6-methoxy-lH- indazol- l-yl)acetyl]amino}hexyl)acetamide; N,7V-Ethane-l,2-diylbis[2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-propylacetamide];

N,iV-(Oxydiethane-2,l-diyl)bis[jV-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide];

N-(3,3-Dimethylbutyl)-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-(5-{[(3-isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetyl]amino}pentyl)acetamide;

NjN'-Pentane- 1 ,5 -diylbis [JV-(3 ,3 -dimethylbutyl)-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 - yl)acetamide];

N,iV-(Piperazine- 1 ,4-diyldipropane-3, 1 -diyl)bis[N-ethyl-2-(3 -isobutyryl-6-methoxy- lH-indazol- l-yl)acetamide];

N,N^*-(Piperazine- 1 ,4-diyldiethane-2, 1 -diyl)bis [7V-ethyl-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 - yl)acetamide]; N,_J/V-Ethane-l,2-diylbis{2-[3-(2,2-dimethylpropanoyl)-6-methoxy-l//-indazol-l-yl]-N- ethylacetamide} ; or a pharmaceutically acceptable salt, hydrolysable ester, enantiomer, diastereomer or mixture thereof. The invention is described herein in detail using the terms defined below unless otherwise specified.

The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S. H. Wilen Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190)

When any variable (e.g. aryl, heterocycle, R.1, R^ etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.

When R^a is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, unless otherwise defined, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which are fused. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkenyl is C2-C6 alkenyl. Alkoxy refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, with the alkyl group optionally substituted as described herein. Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like. Halogen (halo) refers to chlorine, fluorine, iodine or bromine. Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Examples of aryl groups are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferably phenyl, naphthyl or phenanthrenyl. Aryl groups may likewise be . - substituted as defined. Preferred substituted aryls include phenyl and naphthyl. The term heterocyclyl or heterocyclic, as used herein, represents a stable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated^ and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. The term heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydropyrrolyl, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamoφholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. Preferably, heterocycle is selected from 2-azepinonyl, benzimidazolyl, 2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl, 2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl, 2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.

The term "heteroatom" means O, S or N, selected on an independent basis. The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. This invention is also concerned with compositions and methods of treating ocular hypertension or glaucoma by administering to a patient in need thereof one of the compounds of formula I in combination with a β-adrenergic blocking agent such as timolol, betaxolol, levobetaxolol, carteolol, levobunolol, a parasympathomimetic agent such as epinephrine, iopidine, brimonidine, clonidine, para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140 and WO 01/72268), a prostaglandin such as latanoprost, travaprost, unoprostone, rescula, S 1033 (compounds set forth in US Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444); a hypotensive lipid such as lumigan and the compounds set forth in US Patent No. 5,352,708; a neuroprotectant disclosed in US Patent No. 4,690,931 , particularly eliprodil and R-eliprodil as set forth in WO 94/13275, including memantine; or an agonist of 5-HT2 receptors as set forth in PCT/USOO/31247, particularly l-(2-aminopropyl)-3-methyl-lH-imdazol-6-ol fumarate and 2-(3- chloro-6-methoxy-indazol-l-yl)-l-methyl-ethylamine. An example of a hypotensive lipid (the carboxylic acid group on the α-chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a C 1-6 alkoxy group such as OCH3 (PGF2_a I-OCH3), or a hydroxy group (PGF2a 1-OH).

Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are . gated by membrane potential and intracellular Ca2+.

The present invention is based upon the finding that maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower IOP. This finding suggests that maxi-K channel blockers are useful for treating other ophthamological dysfunctions such as macular edema and macular degeneration. It is known that lowering IOP promotes blood flow to the retina and optic nerve. Accordingly, the compounds of this invention are useful for treating macular edema and/or macular degeneration. It is believed that maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering IOP, which when coupled together benefits optic nerve health. As a result, this invention further relates to a method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof.

A number of marketed drugs function as potassium channel antagonists. The most important of these include the compounds Glyburide, Glipizide and Tolbutamide. These potassium channel antagonists are useful as antidiabetic agents. The compounds of this invention may be combined with one or more of these compounds to treat diabetes. Potassium channel antagonists are also utilized as Class 3 antiarrhythmic agents and to treat acute infarctions in humans. A number of naturally occuring toxins are known to block potassium channels including Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, and β-Bungarotoxin (β- BTX). The compounds of this invention may be combined with one or more of these compounds to treat arrhythmias.

Depression is related to a decrease in neurotransmitter release. Current treatments of depression include blockers of neurotransmitter uptake, and inhibitors of enzymes involved in neurotransmitter degradation which act to prolong the lifetime of neurotransmitters.

Alzheimer's disease is also characterized by a diminished neurotransmitter release. Three classes of drugs are being investigated for the treatment of Alzheimer's disease cholinergic potentiators such as the anticholinesterase drugs (e.g., physostigmine (eserine), and Tacrine (tetrahydroaminocridine)); nootropics that affect neuron metabolism with little effect elsewhere (e.g., Piracetam, Oxiracetam; and those drugs that affect brain vasculature such as a mixture of ergoloid mesylates amd calcium channel blocking drugs including Nimodipine. Selegiline, a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer's patients. Aluminum chelating agents have been of interest to those who believe Alzheimer's disease is due to aluminum toxicity. Drugs that affect behavior, including neuroleptics, and anxiolytics have been employed. Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics The present invention is related to novel compounds which are useful as potassium channel antagonists. The compounds within the scope of the present invention exhibit potassium channel antagonist activity and thus are useful in disorders associated with potassium channel malfunction. A number of cognitive disorders such as Alzheimer's Disease, memory loss or depression may benefit from enhanced release of neurotransmitters such as serotonin, dopamine or acetylcholine and the like. Blockage of Maxi-K channels maintains cellular depolarization and therefore enhances secretion of these vital neurotransmitters.

The compounds of this invention may be combined with anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam, ergoloid mesylates, selective calcium channel blockers such as Nimodipine, or monoamine oxidase B inhibitors such as Selegiline, in the treatment of

Alzheimer's disease. The compounds of this invention may also be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, β-Bungarotoxin (β-BTX) or a combination thereof in treating arrythmias. The compounds of this invention may further be combined with Glyburide, Glipizide, Tolbutamide or a combination thereof to treat diabetes.

The herein examples illustrate but do not limit the claimed invention. Each of the claimed compounds are potassium channel antagonists and are thus useful in the decribed neurological disorders in which it is desirable to maintain the cell in a depolarized state to achieve maximal neurotransmitter release. The compounds produced in the present invention are readily combined with suitable and known pharmaceutically acceptable excipients to produce compositions which may be administered to mammals, including humans, to achieve effective potassium channel blockage.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N'-dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, carnphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al. , "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.

The maxi-K channel blockers used can be administered in a therapeutically effective amount intravaneously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art. Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of solutions, suspensions, ointments, creams or as a solid insert. Ophthalmic formulations of this compound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing intraocular pressure, treating glaucoma, increasing blood flow velocity or oxygen tension. For a single dose, from between 0.01 to 5000 ng, preferably 0.1 to 500 ng, and especially 1 to 100 ng of the compound can be - applied to the human eye.

The pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non- injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like. The pharmaceutical preparation may also be in the form of a microparticle formulation. The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. The polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, gellan gum, and mixtures of said polymer.

Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs. The pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like.

The ophthalmic solution or suspension may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the mamalian eye will be about once or twice daily.

For topical ocular administration the novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy. The following examples given by way of illustration is demonstrative of the present invention.

Definitions of the terms used in the examples are as follows:

DMSO - dimethyl sulfoxide,

DCM - Dichloromethane BOP - Benzotriazol- 1 -yloxytris-(dimethylarnino)phosphonium hexafluorophosphate,

PyBOP - Benzotriazol- 1-yloxytris-pyrrolidino-phosphonium hexafluorophosphate,

HOBt - 1 -Hydroxybenzotriazole hydrate

EDC - N-(3-Dimethylaminopropyl)-Λ^-ethylcarbodiimide

LAH - lithium aluminum hydride TLC - thin layer chromatography,

SGC - silica gel chromatography, h = hr = hour,

THF - tetrahydrofuran,

DMF - dimethylformamide, min - minute,

LC/MS - liquid chromatography/mass spectrometry,

RP-HPLC - Reserve-phase high performance liquid chromatography, equiv = eq = equivalent,

The compounds of this invention can be made, with modification where appropriate, in accordance with Scheme 1. The compounds of this invention are illustrated with bis amide or amide ester class of compounds. Many methods are known for the preparation of these general classes of compounds. One method is to couple acid with a diamine or a hydroxylamine. Another would be using a carboxylic acid derivative such as acyl halide as the starting material instead of the acid itself. The examples below used the direct coupling of acid and a diamine or a hydroxylamine by way of illustration as shown in Scheme 1.

SCHEME 1

The preparations of some of the carboxylic acids disclosed in this invention are exemplified in WO2004/087051, WO2003/105847, WO2004/043354, WO2004/043932, WO2005/026128, WO2005/025568, WO2005/002520, WO2005/020917, WO2006/020003, WO2006/044232, and US Patent Applications 60/781904 and 60/812839 incorporated herein by reference in their entirety. Some of the diamines used in this invention are available commercially. Others were prepared using methods illustrated in Preparative Example section. The compounds in the illustrative examples showed preparation of compounds with the same acid on both heteroatoms. Anyone skilled in the art would realize that two different acid residues can be easily attached to these two heteroatoms by using anyone of methods such as further acylating the mono-acylated compounds such as those prepared in US Patent Application 60/781904 or using a mono-protected hydroxylamine or diamine in the first coupling with an acid or its derivative followed by de-protection and second coupling with a different acid or its derivative.

Preparative Example 1

Λ^N-Diethylhexane- 1 ,6-diamine Step A. ΛyV-Hexane-1 ,6-diyldiacetamide To a stirred mixture of 11.62 g 1 ,6-diaminehexane and 20.74 g triethylamine in 200 mL anhydrous DCM in ice bath under nitrogen was added a solution of 15.86 g acetyl chloride in 50 mL anhydrous DCM over 20 minutes. Five minutes after completing addition, the ice bath was removed and the resulting mixture was stirred at room temperature overnight. Filter the reaction mixture and wash the solid with hot EtOAc (2x75 mL) to give the first crop of crude product. Reflux the solid residue with 350 mL EtOAc for an hour and filter the mixture hot. Combine the filtrate and hot EtOAc wash (300 mL) of the filtered solid to give the second crop of the crude product. The combined crude product was re- crystallized from 400 mL boiling EtOAc to give the first crop of product as 7.11 g white solid. A second crop of 1.95 g product was obtained from mother liquor by re-crystallization from 200 mL EtOAc. ¹H NMR (δ, CDCl₃, 500 MHz) showed desired product with small amounts of triethylamine hydrochloride salt: 5.64 (v br s, 2NH), 3.26 (q, 6.7 Hz, 4H), 2.00 (s, 6H), 1.48-1.55 (m, 4H), 1.35-1.39 (m, 4H).

Step B . N,iV-Diethylhexane- 1 ,6-diamine

To a suspension of 2.26 g LAH in 300 mL anhydrous 1,4-dioxane was added 1.95 g N,N- hexane-l,6-diyldiacetamide from the Step A above in small portions with stir. This mixture was heated in a 12O⁰C oil bath with vigorous stir under nitrogen. After a vigorous reaction subsided, the rest of N,./V-hexane-l,6-diyldiacetamide (7.11 g) was added from the top of the condenser in small portions over 30 minutes together with 50 mL of dry dioxane. After refiuxing for 30 minutes following completion of the addition of the amide, the reaction mixture was cooled to room temperature and 7.98 g more LAH was added. The resulting mixture was heated in the oil bath for six days. After cooling to room temperature, the reaction mixture was quenched by addition of 0.2 mL portions of saturated aqueous Na₂SO₄ solution till no more gas was formed. Then the whole reaction mixture was evaporated to dryness under reduced pressure. The solid residue was transferred to a funnel and washed with 2x350 mL ether. The ether filtrate was concentrated under reduced pressure, filtered through a syringe filter to remove a small amount of precipitate, and evaporated to give the title compound as 5.28 g colorless liquid. ¹H NMR (CDCl₃, 500 MHz) δ 2.66 (q, 7.1 Hz, 4H), 2.61 (t, 7.2 Hz, 4H), 1.48-1.54 (m, 4H), 1.33-1.38 (m, 4H), 1.12 (t, 7.2 Hz, 6H).

Preparative Example 2

iV,7V-Diethyl butane- 1,4-diamine . . - - - - - — - — ^{. . .} -

The title compound was prepared using the same method as described in Preparative Example 1 above from 1 ,4-diaminobutane. ¹H NMR (CDCl₃, 500 MHz) δ 2.63-2.68 (m, 8H),

1.53-1.56 (m, 4H), 1.12 (t, 7.1 Hz, 6H).

Preparative Example 3

N,JV-Diethylpentane-l ,5 -diamine

The title compound was prepared using the same method as described in Preparative Example 1 above from 1 ,5-diaminopentane. ¹H NMR (CDCl₃, 500 MHz) δ 2.66 (q, 7.1 Hz, 4H), 2.62 (t, 7.4 Hz, 4H), 1.50-1.56 (m, 4H), 1.35-1.41 (m, 2H), 1.12 (t, 7.1 Hz, 6H).

Preparative Example 4

N,iV-Bis(3,3-dimethylbutyl)ethane- 1 ,2-diamine

Step A. N,N'-Ethane-l,2-diylbis(3,3-dimethylbutanamide)

The title compound was prepared using a method described in Step A Preparative Example 1 from ethylenediamine and 3,3-dimethylbutanoyl chloride, except aqueous/EtOAc was used to work-up the reaction mixture. ¹H NMR (CD₃OD, 500 MHz) δ 3.28 (s, 4H), 2.06 (s, 4H), 1.01 (s, 18H).

Step B. N,N-Bis(3,3-dimethylbutyl)ethane-l,2-diamine

A solution of 8.15 g 7V^V-ethane-l,2-diylbis(3,3-dimethylbutanamide) from Step A above in 200 mL anhydrous THF was cooled with an ice bath and 3.2 g LAH was added in small portions with stir. The resulting mixture was refluxed under nitrogen overnight. After cooling to O⁰C, a total of 3.5 mL water was added to the reaction mixture in small portions over time followed by 3.5 mL 15% aqueous NaOH and 3.5x3 mL water. The resulting mixture was stirred for 30 minutes, filtered through Celite, and the solid washed with THF several times. The combined filtrate and wash was concentrated under reduced pressure, diluted with ether, filtered through a syringe filter to remove solid, and evaporated to give title compound. ¹H NMR (CDCl₃, 500 MHz) δ 2.74 (s, 4H), 2.59-2.63 (m, 4H), 1.39-1.42 (m, 4H), 0.92 (s, 18H). Preparative Example 5 H

H jV,iV-Dipropylethane- 1 ,2-diamine Step A. 7V,./V'-Ethane-l,2-diyldipropanamide

The title compound was prepared from ethylenediamine and propionyl chloride in DCM at rt using about 2 equivalents of polymer-bound piperidine scavenger. After filtering and evaporation, the title compound was used in the next step without further purification. ¹H NMR

(CD₃OD, 500 MHz) δ 7.92 (br s, 2NH), 3.27-3.28 (m, 4H), 2.20 (q, 7.6 Hz, 4H), 1.12 (t, 7.7 Hz, 6H).

Step B. N,7V-Dipropylethane-l,2-diamine

The title compound was prepared from N,iV-ethane-l,2-diyldipropanamide from Step A above using a method similar to what was described for Step B, Preparative Example 4. ¹H NMR (CDCl₃, 500 MHz) δ 2.72 (s, 4H), 2.57 (t, 7.4 Hz, 4H), 1.47-1.54 (m, 4H), 0.92 (t, 7.5 Hz, 6H).

Preparative Example 6

2,2'-Piperazine- 1 ,4-diylbis(7V-ethylethanamine) Step A. N,N'-(Piperazine-l,4-diyldiethane-2,l-diyl)diacetamide The title compound was prepared from acetyl chloride and 2,2'-piperazine-l,4-diyldiethanamine using the method of Step A Preparative Example 1 except the whole reaction mixture was evaporated to dry and the crude residue reduced in the next step.

Step B. 2,2'-Piperazine-l,4-diylbis(N-ethylethanamine) The title compound was prepared from N,N'-(piperazine-l,4-diyldiethane-2,l-diyl)diacetamide from Step A above using method in Step B Preparative Example 4. ¹H NMR (CDCl₃, 500 MHz) δ 2.74 (t, 6.3 Hz, 4H), 2.69 (q, 7.1 Hz, 4H), 2.52 (t, 6.3 Hz, 4H), 2.45-2.52 (m, 8H), 1.14 (t, 7.1 Hz, 6H). Preparative Example 7

3 ,3 '-piperazine- 1 ,4-diylbis(7V-ethylpropan- 1 -amine)

The title compound was prepared from 3, 3 '-piperazine- 1,4-diyldipropan-l -amine using the same method described for Preparative Example 6. ¹H NMR (CDCl₃, 500 MHz) δ 2.64-2.68 (m, 8H), 2.5 (v br s, 8H), 2.41 (t, 7.3 Hz, 4H), 1.68-1.73 (m, 4H), 1.12 (t, 7.3 Hz, 6H). - -

Preparative Example 8

iV,iV-bis(3,3-dimethylbutyl)pentane-l ,5-diamine

Step A. Λ^-Pentane-l,5-diylbis(3,3-dimethylbutanamide)

The title compound was prepared from 1,5-diaminopentane and 3,3-dimethylbutanoyl chloride using method in Step A Preparative Example 4. ¹H NMR (CDCl₃, 500 MHz) δ 5.56 (br s, 2 NH), 3.265 (dt, 6.9 & 6.9 Hz, 4H), 2.06 (s, 4H), 1.52-1.58 (m, 4H), 1.35-1.41 (m, 2H), 1.06 (s, 18H).

Step B. ΛyV-bis(3, 3 -dimethylbutyl)pentane- 1,5 -diamine

The title compound was prepared from N,iV-pentane-l,5-diylbis(3,3- dimethylbutanamide) from Step A above using method in Step B Preparative Example 1. ¹H NMR (CDCl₃, 500 MHz) δ 2.60-2.66 (m, 8H), 1.52-1.58 (m, 4H), 1.36-1.44 (m, 6H), 0.93 (s, 18H).

Example 1

3-{Butyl[(3-tert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetyl]amino}-2,2-dimethylpropyl β-tert-butyl^-methoxy^-oxoquinoxalin- 1 (2H)-yl)acetate

This compound (MS: 4.66 min. (m/Z 704.4) was isolated during the preparation of compound A - Preparation of Compound A

The Compound A was prepared from 6 mg ((3-ter/-Butyl-7-methoxy-2-oxoquinoxalin- l(2H)-yl)acetic acid, 6 μL di-n-butylamine, 8 mg EDC, 6 mg HOBt, and 15 μL DIEA in 1 mL DMF at room temperature and purified using preparative HPLC followed by lyophilization.

Example 2

3 - [ [(3 -tert-Butyl-7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)acetyl](3 -methylbutyl)amino] -2,2- dimethylpropyl (3-tert-butyl-7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)acetate

This compound LC-MS: 4.74 min. (m/Z 718.4)was isolated during the preparation of compound B - Preparation of Compound B

The Compound B was prepared from 6 mg ((3-tert-Butyl-7-methoxy-2- oxoquinoxalin-l(2H)-yl)acetic acid, 6 μL di-n-butylamine, 8 mg EDC, 6 mg HOBt, and 15 μL DIEA in 1 mL DMF at room temperature and purified using preparative HPLC followed by lyophilization.

Examples 3-7

Examples 3-7 in Table 1 were prepared from [2-(2,2-dimethylpropanoyl)-6-methoxy-lH- benzimidazol-1-yl] acetic acid and appropriate hydroxylamine (HNR(ROH)) using methods similar to that used in Example 1 or 2.

Table 1.

Examples 8-19

Examples 8—19 in Table 2 were prepared from (3-isobutyryl-6-methoxy-lH- indazol-l-yl)acetic acid and appropriate hydroxylamine (ΗNR(R'OΗ)) using methods similar to that used in Example 1 or 2.

Table 2.

Example 22

N,N'-Ethane-l,2-diylbis{2-[2-(2,2-dimethylpropanoyl)-6-methoxy-lH-benzimidazol-l-yl]-7V- ethylacetamide} A solution of 15 mg [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 - yl]acetic acid, 17.5 mg HOBt, 36 μL DIEA, and 3.0 mg NJ\T -diethyl ethylenediamine in 0.50 mL DMF was treated with 34.7 mg EDC at room temperature overnight. The reaction mixture was purified directly on RP-HPLC using 70-100% MeCN gradient in water with 0.1% TFA to give the title compound after lyophilization. LC-MS: 4.17 min. (m/Z: 661.2).

Example 23

N, TV-Propane- 1 ,3 -diylbis { 2- [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 -yl] -N- ethylacetamide} The title compound was prepared using the method in Example 22 from [2-(2,2- dimethylpropanoyl)-6-methoxy-l H-benzimidazol- l-yl]acetic acid and N,N* -diethyl- 1,3- propanediamine. LC-MS: 4.11 min. (m/Z: 675.3). Examples 24-33

Examples 24-33 in Table 3 were obtained from (3-ter/-butyl-7-methoxy-2- oxoquinoxalin-l(2H)-yl)acetic acid and appropriate amine (HNR'-R'-NRΗ) using method described in Example 22. Instead of conducting the reaction at room temperature, these reactions were carried out at 45°C for 2 to 6 hours.

Table 3.

Examples 34-53

Examples 34-53 in Table 4 were obtained from (3-isobutyryl-6-methoxy-lH-indazol-l- yl)acetic acid and appropriate amine (HNR'-R'-NR'Η) using method described in Example 22. Some reactions were conducted at 40°C for a few hours.

Table 4.

Examples 54~58

Examples 54-53 in Table 5 were obtained from [3-(2,2-dimethylpropanoyl)-6-methoxy- l//-indazol-l-yl] acetic acid and appropriate amine (HNR'-R'-NR'Η) using method described in Example 22. Some reactions were conducted at 40°C for a few hours.

Table 5.

Examples 59-61

Examples 59-61 in Table 6 were prepared from [3-(2,2-dimethylpropanoyl)-6-methoxy- lH-indazol-1-yl] acetic acid and appropriate hydroxylamine (HR⁵N(ROH)) using methods similar to that used in Example 1 or 2.

Table 6.

N,N'-Ethane-l,2-diylbis[N-(fert-butyl)-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide]

A suspension of 30.1 mg (3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetic acid in 1 mL DCM was treated with 38 μL oxalyl chloride and 10 μL DMF at room temperature for 2.5 hours. The reaction mixture was evaporated to dryness and the residue taken up in 1 mL dry DCM and treated with 8.6 mg N^-di-tert-butylethane-l^-diamine and 15 μL triethylamine over night. Purification of the reaction mixture on RP-ΗPLC afforded the title compound following lyophilization. LC-MS: 4.19 min. (m/Z: 711.5, 689.5, 577.4, 633.5). Example 63

1 , 1 '- {Piperazine- 1 ,4-diylbis[(2-oxoethane-2, 1 -diyl)(6-methoxy- lH-indazole- 1 ,3-diyl)] } bis(2- methylpropan-1-one)

The title compound was prepared from piperazine and (3-isobutyryl-6-methoxy-lH- indazol-l-yl)acetic acid using the method of Example 22. LC-MS: 3.63 min. (m/Z: 603.2, 625.2).

FUNCTIONAL ASSAYS A. Maxi-K Channel

The activity of the compounds can also be quantified by the following assay.

The identification of inhibitors of the Maxi-K channel is based on the ability of expressed Maxi-K channels to set cellular resting potential after transfection of both alpha and betal subunits of the channel in HEK-293 cells and after being incubated with potassium channel blockers that selectively eliminate the endogenous potassium conductances of HEK-293 cells. Ln the absence of maxi-K channel inhibitors, the transfected HEK-293 cells display a hyperpolarized membrane potential, negative inside, close to E_K (-80 mV) which is a consequence of the activity of the maxi-K channel. Blockade of the Maxi-K channel by incubation with maxi-K channel blockers will cause cell depolarization. Changes in membrane potential can be determined with voltage-sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC₂DMPE) and an acceptor oxanol (DiSBAC₂(3)).

Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential. Under normal conditions, when the inside of the cell is negative with respect to the outside, oxanol is accumulated at the outer leaflet of the membrane and excitation of coumarin will cause FRET to occur. Conditions that lead to membrane depolarization will cause the oxanol to redistribute to the inside of the cell, and, as a consequence, to a decrease in FRET. Thus, the ratio change (donor/acceptor) increases after membrane depolarization, which determines if a test compound actively blocks the maxi-K channel.

The HEK-293 cells were obtained from the American Type Culture Collection , 12301 Parklawn Drive, Rockville, Maryland, 20852 under accession number ATCC CRL-1573. Any restrictions relating to public access to the microorganism shall be irrevocably removed upon patent issuance.

Transfection of the alpha and betal subunits of the maxi-K channel in HEK-293 cells was carried out as follows: HEK-293 cells were plated in 100 mm tissue culture treated dishes at a density of 3x10⁶ cells per dish, and a total of five dishes were prepared. Cells were grown in a medium consisting of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine serum, IX L-Glutamine, and IX Penicillin/Streptomycin, at 37⁰C, 10% CO₂. For transfection with Maxi-K hα(pCIneo) and Maxi-K hβ 1 (pIRESpuro) DNAs, 150 μl FuGENEό™ was added dropwise into 10 ml of serum free/phenol-red free DMEM and allowed to incubate at room temperature for 5 minutes. Then, the FuGENEό™ solution was added dropwise to a DNA solution containing 25 μg of each plasmid DNA, and incubated at room temperature for 30 minutes. After the incubation period, 2 ml of the FuGENEό™ /DNA solution was added dropwise to each plate of cells and the cells were allowed to grow two days under the same conditions as described above. At the end of the second day, cells were put under selection media which consisted of DMEM supplemented with both 600 μg/ml G418 and 0.75 μg/ml puromycin. Cells were grown until separate colonies were formed. Five colonies were collected and transferred to a 6 well tissue culture treated dish. A total of 75 colonies were collected. Cells were allowed to grow until a confluent monolayer was obtained. Cells were then tested for the presence of maxi-K channel alpha and betal subunits using an assay that monitors binding of ¹²⁵I-iberiotoxin-D19Y/Y36F to the channel. Cells expressing ¹²⁵I-iberiotoxin-D19Y/Y36F binding activity were then evaluated in a functional assay that monitors the capability of maxi-K channels to control the membrane potential of transfected HEK-293 cells using fluorescence resonance energy transfer (FRET) ABS technology with a VIPR instrument. The colony giving the largest signal to noise ratio was subjected to limiting dilution. For this, cells were resuspended at approximately 5 cells/ml, and 200 μl were plated in individual wells in a 96 well tissue culture treated plate, to add ca. one cell per well. A total of two 96 well plates were made. When a confluent monolayer was formed, the cells were transferred to 6 well tissue culture treated plates. A total of 62 wells were transferred. When a confluent monolayer was obtained, cells were tested using the FRET-functional assay. Transfected cells giving the best signal to noise ratio were identified and used in subsequent functional assays. For functional assays: The transfected cells (2E+06 Cells/mL) are then plated on 96-well poly-D-lysine plates at a density of about 100,000 cells/well and incubated for about 16 to about 24 hours. The medium is aspirated of the cells and the cells washed one time with 100 μl of Dulbecco's phosphate buffered saline (D-PBS). One hundred microliters of about 9 μM coumarin (CC₂DMPE)-0.02% pluronic-127 in D-PBS per well is added and the wells are incubated in the dark for about 30 minutes. The cells are washed two times with 100 μl of Dulbecco's phosphate-buffered saline and 100 μl of about 4.5 μM of oxanol (DiSB AC₂(3)) in (rnM) 140 NaCl, 0.1 KCl, 2 CaCl₂, 1 MgCl₂, 20 Hepes-NaOH, pH 7.4, 10 glucose is added. Three micromolar of an inhibitor of endogenous potassium conductance of HEK-293 cells is added. A maxi-K channel blocker is added (about 0.01 micromolar to about 10 micromolar) and the cells are incubated at room temperature in the dark for about 30 minutes.

The plates are loaded into a voltage/ion probe reader (VIPR) instrument, and the fluorescence emission of both CC₂DMPE and DiSBAC₂(3) are recorded for 10 sec. At this point, 100 μl of high-potassium solution (mM): 140 KCl, 2 CaCl₂, 1 MgCl₂, 20 Hepes-KOH, pH 7.4, 10 glucose are added and the fluorescence emission of both dyes recorded for an additional 10 sec. The ratio CC₂DMPE/DiSBAC₂(3), before addition of high-potassium solution equals 1. In the absence of maxi-K channel inhibitor, the ratio after addition of high-potassium solution varies between 1.65-2.0. When the Maxi-K channel has been completely inhibited by either a known standard or test compound, this ratio remains at 1. It is possible, therefore, to titrate the activity of a Maxi-K channel inhibitor by monitoring the concentration-dependent change in the fluorescence ratio.

The compounds of this invention were found to cause concentration-dependent inhibition of the fluorescence ratio with ICso's in the range of about 10 nM to about 500 μM, more preferably from about 10 nM to about 50 nM.

Claims

WHAT IS CLAIMED IS:

1. A compound of the structural formula I:

Formula I or a pharmaceutically acceptable salt, hydrolysable ester, enantiomer, diastereomer or mixture thereof: wherein, V and V independently represent:

Yl and Y2 independently represent O or H2;

Y represents -CO(CH2)_nR5-, -(CH2)_nR5, or -CH(OR)Rs;

Q and Q' are independently selected from O, NR, or a bond;

W is a Ci-io alkyl di-radical optionally interrupted by zero to three groups of C6-10 ^aryl_» C5-10 heteroaryl, C3-10 cycloalkyl, C5.10 heterocycle, zero to four groups of O, S, SO, SO2, or NR, or a combination thereof and optionally substituted with one to three groups of R&; or W can be from one to three di -radical groups selected from the group consisting of Cβ-lO aryl_* C5-10 heteroaryl, C3-IO cycloalkyl, C5-10 heterocycle, wherein when there is more than one di- radical present, said di-radicals are connected with each other using zero to two Cl .5 alkyl di- radical, zero to four groups of O, S, SO, SO2, or NR, or a combination thereof and optionally substituted with one to three groups of R^a ;

X and X' represent -(CHR7)p-;

Z, Zi , Z₂, Z3, Z4, Z5, Z6, and Z7 are independently selected from CH or N;

R represents hydrogen, Ci -6 alkyl, -(CH2)nC3-8 cycloalkyl, -(CH2)nC3-10 heterocyclyl, - (CH2)nC6-10 ^h said alkyl, cycloalkyl and aryl optionally substituted with one to three groups of Ra;

R2 and R3 independently represent hydrogen, Cl -10 alkyl, OH, -(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^N(Rg)COR, - (CH2)_nNHC0R, -(CH2)_nCONH(R8), C5-IO aryl, -(CH₂)_nCi-6 alkoxy, CF3, .(CH₂)_nSO₂R, - (CH2)_nSO₂N(R)2, -(CH₂)nCON(R)₂, -(CH₂)nCONHC(R)₃, -(CH₂)_HCONHC(R)₂CO₂R, - (CH₂)_nCOR8, -(CH₂)_nOPO(OR)₂, nitro, cyano or halogen, said alkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-3 groups of R^a;

Rl and R4 independently represent hydrogen, Cl -6 alkoxy, OH, Cl -6 alkyl, COOR, SOqC i-6 alkyl, COCi-6 alkyl, SO3H, -O(CH₂)_nN(R)₂, -O(CH₂)_nCO₂R, -OPO(OH)₂, CF3, OCF3 - N(R)₂, nitro, cyano, Cl -6 alkylamino, or halogen; and

R5 represents hydrogen, C MO alkyl, -(CH₂)_nC6-10 aryl, NR₀Rd, -NR(CH₂)_nC6-10 aryl, - N((CH₂)_nC6-10 aryl)₂, -(CH₂)_nC3-l0 heterocyclyl, -NR(CH₂)_nC3-io heterocyclyl, - N((CH₂)_nC3-10 heterocyclyl)₂, (C6-10 aryl)O-, -(CH₂)_nOPO(OR)₂, -(CH₂)_nC₃-8 cycloalkyl, - COOR, -C(O)CO₂R, said aryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from R^a, wherein the Ra(s) can be attached to any carbon atom or heteroatom selected

R_c and Rd independently represent H, C 1-6 alkyl, C2-6 alkenyl, C 1-6 alkylSR, - (CH2)nO(CH₂)mOR, -(CH₂)_nCi-6 alkoxy, or -(CH₂)_nC₃-8 cycloalkyl; or R_c and Rd 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;

Rγ represents hydrogen, Ci_6 alkyl, -(CH2)_nCOOR or -(CH2)_nN(R)2,

R8 represents -(CH2)nC3-8 cycloalkyl, -(CH2)nC3-10 heterocyclyl, Cl -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, -O-, -COR8, -CONHR8, -CON(Rs)₂, - O(CH₂)_nCOOR, -NH(CH₂)_nOR, -COOR, -OCF3, CF₂CH₂OR, -NHCOR, -SO₂R, -SO₂NR₂, - SR, (C₁-C₆ alkyl)O-, -(CH₂)_nO(CH₂)_mOR, -(CH₂)_nCl-6 alkoxy, (aryl)O-, -(CH₂)_nOH, (C₁- C₆ alkyl)S(O)_m-, H₂N-C(NH)-, (C₁-C₆ alkyl)C(O)-, (C_rC₆ alkyl)OC(O)NH-, -(C₁-C₆ alkyl)NR_w(CH₂)_nC3-io heterocyclyl-R_w, -(C₁-C₆ alkyl)0(CH₂)_nC3-io heterocyclyl-R_w, -(C₁- C₆ alkyl)S(CH₂)_nC3-io heterocyclyl-R_w, -(C₁-C₆ alkyl)-C3-io heterocyclyl-R_w, -(C2-6 alkenyl)NR_w(CH2)nC3-10 heterocyclyl-R_w, -(C2-6 alkenyl)O(CH2)nC3-l0 heterocyclyl-R_w, - (C2-6 alkenyl)S(CH2)_nC3-i0 heterocyclyl-R_w, -(C2-6 alkenyl)-C3-io heterocyclyl-R_w, - (CH₂)_nSO₂R, -(CH₂)_nSO₃H, -(CH₂)_nPO(OR)2, Cs-lOcycloalkyl, C₆-IO aryl, C₃-IO heterocyclyl, C₂-6 alkenyl, and C₁-C₁Q alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C₁-C₆ alkyl, halogen, (CH2)_nOH, CN,

NO2, CON(R)2 and COOR;

R_w represents H, Cl -6 alkyl, -C(O)C 1-6 alkyl, -C(O)OCi -6 alkyl, -Sθ2N(R)2, -SO2C1-6 alkyl, - SO2C6-IO aryl, NO₂, CN or -C(O)N(R)₂;

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 V and V both are

, Zi, Z2, and Z3 are CH, Y is -C(O)(CH2)_nR5, Q and Q' are independently O or NR and R4 is C].6 alkoxy or a pharmaceutically acceptable salt, hydrolysable ester, enantiomer, diastereomer or mixture thereof.

3. A compound according to claim 1 wherein V and V both are

^τ , Zi , ∑2, and Z3 are CH, Y is -(CH2)_nR5, Q and Q' are independently O or NR, and R4 is Cl -6 alkoxy, or a pharmaceutically acceptable salt, hydrolysable ester, enantiomer, diastereomer or mixture thereof.

4. A compound according to claim 1 wherein V and V both are

, Zi , Z2, and Z3 are CH, Y is -C(O)(CH2)_nR5, Q and Q' are independently

O or NR, and R4 is Cl -6 alkoxy, or a pharmaceutically acceptable salt, hydrolysable ester, enantiomer, diastereomer or mixture thereof.

5. A compound below including Tables 1 through 6:

3-{Butyl[(3-tert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetyl]amino}-2,2-dimethylpropyl

(3-/er/-butyl-7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)acetate;

3 -[ [(3 -tert-Butyl-7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)acetyl] (3 -methylbutyl)amino] -2,2- dimethylpropyl (3-tert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetate; N,N'-Ethane-l,2-diylbis{2-[2-(2,2-dimethylpropanoyl)-6-methoxy-lH-benzimidazol-l-yl]-N- ethylacetamide};

N,N'-Propane-l,3-diylbis{2-[2-(2,2-dimethylpropanoyl)-6-methoxy-l//-benzimidazol-l-yl]-N- ethylacetamide};

N,iV-Ethane- 1 ,2-diylbis[N-(/er/-butyl)-2-(3-isobutyryl-6-methoxy- 1 H-indazol- 1 - yl)acetamide] ; 1 , 1 '-{Piperazine- 1 ,4-diylbis[(2-oxoethane-2, 1 -diyl)(6-methoxy-lH-indazole- 1 ,3- diyl)] } bis(2-methylpropan- 1 -one); . Table 1

Table 2

Table 4

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

6. A compound according to claim 5 which is:

3 - [ [(3 -tert-Butyl-T-methoxy^-oxoquinoxalin- 1 (2H)-yl)acetyl] (3 -methylbutyl)amino]-2,2- dimethylpropyl (3-tert-butyl-7-methoxy-2-oxoquinoxalin-l(2H)-yl)acetate;

4-((3 ,3 -Dimethylbutyl) { [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 - yl]acetyl } amino)-2,2-dimethylbutyl [2-(2,2-dimethylpropanoyl)-6-methoxy- 1 H-benzimidazol- 1 - yl]acetate;

4- {Ethyl [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl]amino } butyl (3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetate;

3-[[(3-Isobutyryl-6-methoxy-lH-indazol-l-yl)acetyl](3-methylbutyl)amino]propyl (3 -isobutyryl- 6-methoxy- 1 H-indazol- 1 -yl)acetate;

4- [[(3 -Isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] (3 -methyl butyl)amino] butyl (3 -isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetate; 3 - { (3 ,3 -Dimethylbutyl) [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl]amino } -2,2- dimethylpropyl (3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetate;

3-{Isobutyl[(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetyl]amino}propyl (3-isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetate;

4- { Cyclohexyl [(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetyl] amino } butyl (3 -isobutyryl-6- methoxy-1 H-indazol- l-yl)acetate;

NJΫ -Ethane- 1 ,2-diylbis[vV-ethyl-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetamide] ;

N,N'-Propane-l,3-diylbis[jV-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide];

7V-Ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-iV-{2-[[(3-isobutyryl-6-methoxy-lH- indazol-l-yl)acetyl](methyl)amino]ethyl}acetamide; N,N'-Ethane-l,2-diylbis[2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-iV-isopropylacetamide];

7V,7V-Propane- 1 ,3 -diylbis [2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)-7V-isopropylacetamide] ;

N-(3,3-Dimethylbutyl)-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-(2-{[(3-isobutyryl-6- methoxy- 1 H-indazol- 1 -yl)acetyl] amino } ethyl)acetamide;

N,jV-Ethane- 1 ,2-diylbis [N-(3, 3 -dimethylbutyl)-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 - yl)acetamide];

N,./V-Ethane- 1 ,2-diylbis[N-(ter/-butyl)-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)acetamide] ;

N,N'-Ethane-l,2-diylbis[jV-butyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide];

N,N'-Butane-l,4-diylbis[N-ethyl-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- l-yl)acetamide];

7V,N'-Pentane-l,5-diylbis[N-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide]; N-Ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-N-(5-{[(3-isobutyryl-6-methoxy-lH- indazol- 1 -yl)acetyl] amino } pentyl)acetamide;

N,N'-Hexane-l,6-diylbis[N-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide]; jV-Ethyl-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -y\)-N-(6- { [(3 -isobutyryl-6-methoxy- 1 H- indazol- 1 -yl)acetyl] amino } hexyl)acetamide; τV,jV-Ethane-l,2-diylbis[2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)-7V-propylacetamide]; iV,jV-(Oxydiethane-2,l-diyl)bis[N-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol-l-yl)acetamide];

N-(3, 3 -Dimethylbutyl)-2-(3 -isobutyryl-6-methoxy- 1 H-indazol- 1 -yl)-N-(5- { [(3-isobutyryl-6- methoxy-lH-indazol-l-yl)acetyl]amino}pentyl)acetamide; N^-Pentane-l ,5-diylbis[N-(3,3-dimethylbutyl)-2-(3-isobutyryl-6-methoxy-lH-indazol-l- yl)acetamide];

N,Λ''-(Piperazine-l,4-diyldipropane-3,l-diyl)bis[N-ethyl-2-(3-isobutyryl-6-methoxy-lH-indazol- l-yl)acetamide];

N^-CPiperazine- 1 ,4-diyldiethane-2, 1 -diyl)bis[N-ethyl-2-(3-isobutyryl-6-methoxy- 1 H-indazol- 1 - yl)acetamide];

N,N'-Ethane-l,2-diylbis{2-[3-(2,2-dimethylpropanoyl)-6-methoxy-lH-indazol-l-yl]-7V- ethylacetamide}; or a pharmaceutically acceptable salt, hydroysable ester, 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, hydrolysable ester, enantiomer, diastereomer or mixture thereof.

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

10. The composition according to Claim 9 wherein the compound of formula I is applied as a topical formulation, said topical formulation administered as a solution or suspension and optionally containing xanthan gum or gellan gum.

11. A composition according to claim 9 wherein 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.

12. A composition according to claim 11 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 S 1033, the hypotensive lipid is lumigan, the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is l-(2-aminopropyl)-3 -methyl- lH-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-l-yl)-l-methyl-ethylamine.

13. Use of a compound of formula I in the preparation of a medicament for treating ocular hypertension, glaucoma, macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a providing a neuroprotective effect.