CZ20004428A3 - Cyclopentanone dihydropyridine compounds useful as potassium channel opening agents - Google Patents

Abstract

Compounds of formula I are effective in preventing diseases causing a disorder of potassium channel opening or in ameliorating diseases caused by potassium channel openers. Also provided are potassium channel opener compositions and methods of opening potassium channels in mammals.

Description

Technical field

New, water-soluble dihydropyridine compounds and their derivatives can open potassium channels and are thus effective in the treatment of various diseases.

State of the art

Potassium channels play a significant role in regulating the excitability of cell membranes. When potassium channels are open, changes in electrical potential occur across the cell membrane, resulting in a more polarized state. Many diseases or conditions can be treated with therapeutic agents that are able to open these potassium channels. See K. Lawson, Pharmacol. Ther., v. 70, pp. 39 - 63; (1996)

D.R.Gehlert et al., Prog. Neuro-Psychopharmacol & Biol. Psychiat., v. 18, pp. 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993); J.E.Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996). Such conditions or diseases include asthma, epilepsy, hypertension, impotence, migraine, pain, urinary incontinence, stroke, Raynaud's disease, eating disorders, functional bowel disorders, and neurodegeneration.

Potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can result from spontaneous, uncontrolled contractions of bladder smooth muscle, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle provides a way to improve or prevent urinary incontinence.

In the patent application DE 2003148, acridinedione and quinolone compounds are disclosed, patented for their effects as spasmolytics of the smooth muscle of the digestive and digestive tracts, the urogenital tracts and the respiratory system. The compounds disclosed in DE 2003148 are also patented for their antihypertensive properties. These compounds belong to the larger general chemical group of dihydropyridines. All examples described in DE 2003148 feature a cyclohexanone ring fused to a dihydropyridine nucleus and are therefore disadvantageous for their very low water solubility. This low solubility limits the ability of these agents as pharmaceuticals. When drugs are administered orally, the low water solubility can lead to erroneous absorption patterns. This can lead, depending on the patients, to a wide variability in drug absorption and potentially to toxic side effects. The compounds of the present invention are chemically different from the examples described in DE 2003148, since they must have a cyclopentanone ring fused to a dihydropyridine ring, structural elements which give the compounds of the invention the unusual and unexpected property of greater water solubility, on average 55 times higher water solubility than comparable analogues from DE 2003148.

Patents WO 9408966, EP 0539153 A1 and EP 0539154 A1 disclose acridindione and quinolone compounds which are patented for their efficacy in the treatment of urinary incontinence. These compounds belong to the larger general chemical group of dihydropyridines. All examples described in WO 9408966, EP 0539153 A1 and EP 0539154 A1 contain cyclohexanone rings fused to a dihydropyridine nucleus and as a result suffer from the disadvantage of very low aqueous solubility. This low solubility limits the potential of these agents as pharmaceuticals. When drugs are administered orally, low aqueous solubility can lead to erroneous absorption patterns. This can lead to wide variability in drug absorption between patients and potentially to toxic side effects. The compounds of the present invention are chemically distinct from those disclosed in WO94/08966, EP 0539153 A1 and EP 0539154 A1, as they must have a cyclopentanone ring fused to a dihydropyridine ring, structural elements which give the compounds of the invention the unusual and unexpected property of greater water solubility, on average 55 times higher water solubility than comparable analogues of the above-mentioned inventions.

Dihydropyridines of different chemical structures can have different biological effects. Dimmock, et al., (Eur. J. Med. Chem. 1988, 23, pp. 111 - 117) describe N3

methyldihydropyridines containing two cyclopentanone rings fused to a dihydropyridine nucleus. The only biological effect indicated was that this dihydropyridine nucleus was inactive against murine P388 lymphocytic leukemia. The compounds of the present invention are different from this compound in that they must be unsubstituted on the dihydropyridine nitrogen.

Patent EP 622366 A1 describes dihydropyridines substituted with quinolines as cardiovascular agents.

In patent EP 299727, 4-aryl(5,6-bicyclo)-2-(imidazol-1-ylalkoxymethyl)-dihydropyridines are described as platelet activating factor (PAF) antagonists.

WO 9012015-A describes dihydropyridines which are claimed as PAF antagonists. EP 173943-A describes dihydropyridines which are modifiers of enzymes involved in the metabolism of arachidonic acid. EP 186027-A describes dihydropyridines which have vasodilating properties. All of these patents describe dihydropyridines which generically patent cyclopentanone fused on one side of the dihydropyridine with carboxylic acid esters on the other side.

Thus, the compounds of the present invention are chemically distinct from the prior art, are water soluble, hyperpolarize the cell membrane, open potassium channels, relax smooth muscle cells, inhibit bladder contractions, and are effective in treating diseases that can be improved by opening potassium channels.

The essence of the invention

In its principal embodiment, the present invention provides compounds having the formula I:

AND,

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the dashed line represents the presence of an optional double bond; the substituent R ¹ is selected from the group consisting of aryl and heteroaryl;

A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and -C(O)R ² , wherein R ² is selected from the group consisting of alkyl, haloalkyl, and hydroxy; R ³ is selected from the group consisting of hydrogen, alkyl, and haloalkyl; and

A and R ³ taken together with the ring to which they are attached may form a 5-membered or 6-membered carbocyclic ring. Said 5-membered or 6-membered carbocyclic ring may contain 1 or 2 double bonds and may be substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, amide or prodrug thereof in combination with a pharmaceutically acceptable carrier.

Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, hypertension, Raynaud's disease, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

Detailed description of the invention

In one embodiment, the present invention provides compounds having formula I:

9 · 9 9 9 · · 9 9 9 9 9 999 •9 999 999

H

I, or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the dashed line represents the presence of an optional double bond; the substituent R ¹ is selected from the group consisting of aryl and heteroaryl;

A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and -C(O)R ² , wherein R ² is selected from the group consisting of alkyl, haloalkyl, and hydroxy; R ³ is selected from the group consisting of hydrogen, alkyl, and haloalkyl; and

A and R ³ taken together with the ring to which they are attached may form a 5-membered or 6-membered carbocyclic ring. Said 5-membered or 6-membered carbocyclic ring may contain 1 or 2 double bonds and may be substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

In another embodiment of the present invention, the compounds have formula I, wherein A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R ³ is hydrogen.

In another embodiment of the present invention, the compounds have formula I, wherein A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R ³ is selected from the group consisting of alkyl.

In another embodiment of the present invention, the compounds have formula I, wherein A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R ³ is selected from the group consisting of haloalkyl.

In another embodiment of the present invention, the compounds have formula I, wherein

And it is

-C(O)R ² , wherein the substituent R ² is selected from the group consisting of alkyl, haloalkyl, and hydroxy; and the substituent R ³ is hydrogen.

In another embodiment of the present invention, the compounds have formula I, wherein

And it is

-C(O)R ² , wherein the substituent R ² is selected from the group consisting of alkyl, haloalkyl, and hydroxy; and the substituent R ³ is selected from the group consisting of alkyl.

In another embodiment of the present invention, the compounds have formula I, wherein

And it is

-C(O)R ² , wherein the substituent R ² is selected from the group consisting of alkyl, haloalkyl, and hydroxy; and the substituent R ³ is selected from the group consisting of haloalkyl.

In another embodiment of the present invention, the compounds have formula I, wherein

And it is

-C(O)R ² , wherein the substituent R ² is a hydroxy group; and the substituent R ³ is selected from the group consisting of alkyl, with lower alkyl being preferred.

In another embodiment of the present invention, the compounds have formula I, wherein A is heteroaryl; and the substituent R ³ is selected from the group consisting of hydrogen, alkyl, and haloalkyl.

In another embodiment of the present invention, the compounds have formula I, wherein A is tetrazole; and the substituent R ³ is selected from the group consisting of hydrogen, alkyl, and haloalkyl.

In a preferred embodiment, the compounds of the present invention have formula II:

or their pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the dashed line represents the presence of an optional double bond

bonds; the index m is the number 1 - 2; the substituent R ¹ is selected from the group consisting of aryl and heteroaryl; B and C are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , where the substituents R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

In another preferred embodiment, the compounds of the present invention have formula III:

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the index m is 1-2; R ¹ is selected from the group consisting of aryl and heteroaryl; B and C are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

In another preferred embodiment, the compounds of the present invention have the formula IV:

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the index m is 1-2; R ¹ is selected from the group consisting of aryl and heteroaryl; B and C are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

In another preferred embodiment, the compounds of the present invention have the formula V:

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the index m is 1-2; R ¹ is selected from the group consisting of aryl and heteroaryl; B and C are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

In another more preferred embodiment of the present invention, compounds have the formula V, wherein the index m is 1; B is a hydrogen atom; C is a hydrogen atom; and R ¹ is aryl, wherein preferred aryl is phenyl substituted with 1,2,3,4 or 5 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkyloxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, sulfamyl, sulfo, sulfonate, thioureylene, ureylene and -C(O)NR ⁸⁰ R ⁸¹ , wherein R ⁸⁰ and R ⁸¹ are independently selected from hydrogen, alkyl, aryl and arylalkyl. The most preferred phenyl substituents are selected from the group consisting of cyano, halogen and nitro.

In another more preferred embodiment of the present invention, the compounds have formula V, wherein the index m is 1; B is hydrogen; C is hydrogen; and the substituent R ¹ is heteroaryl, more preferred heteroaryls include, but are not limited to, benzoxadiazole, benzoxazole, benzothiazole, benzothiadiazole, benzothiophene, benzofuran, furan, and thiophene. The most preferred heteroaryl is 2,1,3-benzoxadiazole.

In another preferred embodiment, the compounds of the present invention have the formula VI:

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the index m is 1-2; R ¹ is selected from the group consisting of aryl and heteroaryl; B and C are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl.

In another more preferred embodiment of the present invention, the compounds have the formula VI, wherein the index m is 2; B is hydrogen; C is hydrogen; R ¹ is aryl, where preferred aryl is phenyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkyloxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, sulfamyl, sulfo, sulfonate, thioureylene, ureylene and -C(O)NR ⁸⁰ R ⁸¹ , where R ⁸⁰ and R ⁸¹ are independently selected from hydrogen, alkyl, aryl and arylalkyl. The most preferred phenyl substituents are selected from the group consisting of cyano, halogen and nitro.

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulae I-VI or a pharmaceutically acceptable salt, ester, amide or prodrug thereof in combination with a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a disease in a mammal comprising administering an effective amount of a compound of Formulae I-VI or administering an effective amount of a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

In particular, the present invention relates to a method of treating asthma, epilepsy, hypertension, impotence, migraine, pain, urinary incontinence, stroke, Raynaud's disease, eating disorders, functional bowel disorders, neurodegeneration and stroke comprising administering an effective amount of a compound of formula I - or administering an effective amount of a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

Definition of terms

In the description and the appended claims, the following terms have the following meanings:

The term alkenyl, as used herein, refers to a branched or unbranched hydrocarbon chain having 2 to 10 carbon atoms and having at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Illustrative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2methyl-1-heptenyl, 3-decenyl, and the like.

The term alkoxy, as used herein, refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, as defined above.

Illustrative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

The term alkoxyalkoxy, as used herein, refers to an alkoxy group, as defined above, appended to the parent molecular moiety through another alkoxy group, as defined above. Representative examples of alkoxyalkoxy groups include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.

The term alkoxyalkyl, as used herein, refers to an alkoxy group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.

The term alkoxycarbonyl, as used herein, refers to an alkoxy group, as defined above, appended to the parent molecular moiety through a carbonyl group, as defined above. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.

The term alkyl, as used herein, refers to a branched or unbranched hydrocarbon chain having 1 to 10 carbon atoms. Illustrative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

The term alkylcarbonyl, as used herein, refers to an alkyl group, as defined above, appended to the parent molecular moiety through a carbonyl group, as defined above. Illustrative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.

The term alkylcarbonyloxy, as used herein, refers to an alkylcarbonyl group, as defined above, appended to the parent molecular moiety through an oxy group, as defined above. Representative examples of alkylcarbonyloxy groups include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.

The term alkylsulfinyl, as used herein, refers to an alkyl group, as defined above, appended to the parent molecular moiety through

a sulfinyl group as defined above. Illustrative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl, ethylsulfinyl, and the like.

The term alkylsulfonyl, as used herein, refers to an alkyl group, as defined above, appended to the parent molecular moiety through a sulfonyl group, as defined above. Illustrative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

The term alkylthio, as used herein, refers to an alkyl group, as defined above, attached to the parent molecular moiety through a thio group, as defined above. Illustrative examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

The term alkynyl, as used herein, refers to a branched or unbranched hydrocarbon chain group having 2 to 10 carbon atoms and having at least one carbon-carbon triple bond. Illustrative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, and the like.

The term amino, as used herein, refers to the group -NH 2 .

The term aminocarbonyl, as used herein, refers to the group C(O)NH ₂ .

The term alkylamino, as used herein, refers to an alkyl group, as defined above, appended to the parent molecular moiety through an amino group, as defined above. Representative examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, tert-butylamino, and the like.

The term dialkylamino, as used herein, refers to two independent alkyl groups, as defined above, attached to the parent molecular moiety through an amino group, as defined above. Illustrative examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, butylmethylamino, ethylhexylamino, and the like.

The term aryl, as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused at V »

··

999 99 999 a ring system having one or more aromatic rings. Illustrative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.

The aryl groups of the present invention may be substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, sulfamyl, sulfo, sulfonate, thioureylene, ureylene, -NR ⁸⁰ R ⁸¹ (wherein R ⁸⁰ and R ⁸¹ are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl) and C(O)NR ⁸² R ⁸³ (wherein R R ⁸² and R ⁸³ are independently selected from hydrogen, alkyl, aryl and arylalkyl

The term arylalkoxy, as used herein, refers to an aryl group, as defined above, appended to the parent molecular moiety through an alkoxy group, as defined above. Illustrative examples of arylalkoxy groups include, but are not limited to,

2-phenylethoxy group, 3-naphth-2-ylpropoxy group, 5-phenylpentyloxy group, etc.

The term arylalkoxycarbonyl, as used herein, refers to an arylalkoxy group, as defined above, appended to the parent molecular moiety through a carbonyl group, as defined above. Illustrative examples of arylalkoxy groups include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.

The term arylalkyl, as used herein, refers to an aryl group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above. Illustrative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.

The term aryloxy, as used herein, refers to an aryl group, as defined above, appended to the parent molecular moiety through an oxy group, as defined above.

The term azido, as used herein, refers to the group -N ₃ .

The term carbonyl, as used herein, refers to a group -C(O)-.

·· ► « ··

The term carboxy, as used herein, refers to a -CO2H group.

The term carboxyalkyl, as used herein, refers to a carboxy group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above. Illustrative examples of carboxyalkyl include, but are not limited to, 2-carboxyethyl, 3-carboxypropyl, and the like.

The term carboxy protecting group, as used herein, refers to a carboxylic acid protecting ester used to block or protect a carboxyl functional group while the reaction proceeds on other functional groups of the compound. Carboxy protecting groups are published in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, ^2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug, wherein the carboxy protecting group can be readily cleaved in vivo, e.g., by enzymatic hydrolysis, to release the biologically active parent compound. Further information on prodrugs can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol 14 of the ACS Symposium Series, American Chemical Society (1975), incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art as they are used in protecting the carboxyl groups of penicillin and cephalosporin regions, as described in U.S. Patent Nos. 3,840,556 and 3,719,667, the disclosures of which are incorporated herein by reference. Examples of esters effective as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, edited by EB Roche, Pergamon Press, New York (1987), incorporated herein by reference. Exemplary carboxy protecting groups are lower alkyl (e.g., methyl, ethyl, or tertiary butyl, etc.); benzyl (phenylmethyl) and its substituted benzyl derivatives, such substituents being selected from alkoxy, alkyl, halogen, and nitro, etc.

The term cyano, as used herein, refers to the group -CN.

The term cyanoalkyl, as used herein, refers to a cyano group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above. Illustrative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, and the like.

The term cycloalkyl, as used herein, refers to a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms. Illustrative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term cycloalkylalkyl, as used herein, refers to a cycloalkyl group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above. Illustrative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl, and the like.

The term ethylenedioxy, as used herein, refers to the group O(CH2) where the oxygen atoms of the ethylenedioxy group are attached to the same carbon atom or the oxygen atoms of the ethylenedioxy group are attached to two adjacent carbon atoms.

The term formyl, as used herein, refers to the group -C(O)H.

The term halo or halogen, as used herein, refers to -Cl, -Br, -I, or -F.

The term haloalkenyl, as used herein, refers to at least one halogen, as defined above, attached to the parent molecular moiety through an alkenyl group, as defined above. Illustrative examples of haloalkenyl include, but are not limited to, 4-chlorobuten-1-yl, 4,4,4-trifluorobuten-1-yl, and the like.

The term haloalkyl, as used herein, refers to at least one halogen, as defined above, attached to the parent molecular moiety through an alkyl group, as defined above. Illustrative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

The term haloalkoxy, as used herein, refers to at least one halogen, as defined above, attached to the parent molecular moiety through an alkoxy group, as defined above. Illustrative examples of haloalkoxy groups include, but are not limited to, 2-chloroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, and the like.

• 44 4· < 44 4 • •4 4 » 444 4 444

44 444 444

444 4 444 4 4

444 444 444

444 »4 44 444 44 444

The term "heteroaryl" as used herein refers to monocyclic or bicyclic ring systems. A monocyclic ring system exemplified by any 5-membered or 6-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. A 5-membered ring has 0-2 double bonds and a 6-membered ring has 0-3 double bonds. Illustrative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxalidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are illustrated in examples of any of the above monocyclic ring systems fused to an aryl group as defined above, to a cycloalkyl group as defined above, or other monocyclic ring systems as defined above. Illustrative examples of bicyclic ring systems include, but are not limited to, e.g., benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxin, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine.

The heteroaryl groups of this invention may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, ethylenedioxy, formyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro

group, oxo group, sulfamyl, sulfo group, sulfonate, thioureylene, ureylene, NR ⁸⁰ R ⁸¹ (wherein R ⁸⁰ and R ⁸¹ are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl) and -C(O)NR ⁸² R ⁸³ (wherein R ⁸² and R ⁸³ are independently selected from hydrogen, alkyl, aryl and arylalkyl.

The term hydroxy, as used herein, refers to the group -OH.

The term hydroxyalkenyl, as used herein, refers to a hydroxy group, as defined above, appended to the parent molecular moiety through an alkenyl group, as defined above. Illustrative examples of hydroxyalkenyl include, but are not limited to, 4-hydroxybuten-1-yl, 5-hydroxypenten-1-yl, and the like.

The term hydroxyalkyl, as used herein, refers to a hydroxy group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2ethyl-4-hydroxyheptyl, and the like.

The term lower alkoxy, as used herein, refers to a lower alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, as defined above. Illustrative examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like.

The term lower alkyl, as used herein, refers to a branched or unbranched hydrocarbon chain group having 1 to 4 carbon atoms. Illustrative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.

The term mammal, as used herein, has its general meaning and includes human subjects.

The term mercapto, as used herein, refers to the group -SH.

The term methylenedioxy, as used herein, refers to the group OCH ₂ O-, where the oxygen atoms of the methylenedioxy group are attached to two adjacent carbon atoms.

The term nitro, as used herein, refers to the group -NO ₂ .

The term oxo, as used herein, refers to the =O moiety.

The term oxy, as used herein, refers to the -0- moiety.

The term sulfamyl, as used herein, refers to the group SO ₂ NR ⁹⁴ R ⁹⁵ , where the substituents R ⁹⁴ and R ⁹⁵ are independently selected from hydrogen, alkyl, aryl and arylalkyl as defined above.

The term sulfinyl, as used herein, refers to the group -S(O)-.

The term sulfo, as used herein, refers to the group -SO ₃ H.

The term sulfonate, as used herein, refers to the group S(O) ^2OR96 , where the substituent ^R96 is selected from alkyl, aryl and arylalkyl as defined above.

The term sulfonyl, as used herein, refers to the group -SO ₂ -.

The term thio, as used herein, refers to the -S- moiety.

The term thioureylene, as used herein, refers to NR ⁹⁷ C(S)NR ⁹⁸ R ⁹⁹ , where the substituents R ⁹⁷ , R ⁹⁸ and R ⁹⁹ are independently selected from hydrogen, alkyl, aryl and arylalkyl as defined above.

The term ureylene, as used herein, refers to -NR ⁹⁷ C(O)NR ⁹⁸ R ⁹⁹ , where the substituents R ⁹⁷ , R ⁹⁸ and R ⁹⁹ are independently selected from hydrogen, alkyl, aryl, arylalkyl as defined above.

Preferred compounds of formula I include:

8-(3-Bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, 8-(3-Cyanophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, 8-(4-Chloro-3-nitrophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, 8-(3-Nitrophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, 8-(3-Chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, 8-(3, 4-Dichlorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, 8-(2,1,3-benzoxadiazol-5-yl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione and

8-(3-Iodo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione and

9-(3-Bromo-4-fluorophenyl)-5,6,7,9-tetrahydro-1H-cyclopenta[b]quinoline-1,8(4H)-dione, 4-(3-Bromo-4-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1/-/cyclopenta[b]pyridine-3-carboxylic acid and their pharmaceutically acceptable salts, esters, amides or prodrugs thereof.

Preparation of compounds of the invention

The compounds and methods of the present invention will be better understood in connection with the following synthetic schemes and methods, which illustrate the methods by which the compounds of the invention may be prepared.

The compounds of the present invention can be prepared by various synthetic routes. Representative procedures are shown in Schemes 1-9. For Schemes 1-9, ^R1 is selected from aryl and heteroaryl; A is selected from hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and -C(O) ^R2 , wherein ^R2 is selected from alkyl, haloalkyl, and hydroxy; ^R3 is selected from hydrogen, alkyl, and haloalkyl; A and the substituent R ³ taken together with the carbon atoms to which they are attached may form a 5-membered or 6-membered carbocyclic ring which may contain 1 or 2 double bonds and may be substituted with 1 or 2 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , where the substituents R ⁴ and R ⁵ are independently selected from hydrogen and lower alkyl; and the dashed line may indicate an optional double bond.

Scheme 1 O

(i) (ii) (iii)

(iv) ^NHs (ii) (v)

H (vii)

As shown in Scheme 1, dihydropyridines of formula (vii), where the substituents R ¹ , R ³ and A are as defined in formula I, can be prepared by one of three main routes. According to route A, 1,3-cyclopentanedione (i) can be reacted with aldehyde (ii) and the corresponding enamine component (iii) under heating in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile. Further heating with acid, e.g. hydrochloric, sulfuric or toluenesulfonic, may be required to complete the reaction. According to Method B, 3-amino-2-cyclopenten-1-one (iv) can be reacted with aldehyde (ii) and the corresponding carbonyl component (v) using the same reaction conditions as in Method A. According to Method C, 1,3-cyclopentanedione (i) together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, can be reacted under the same conditions as in Method A with the enone (vi) component, which was prepared from aldehyde (ii) and carbonyl component (v). In an alternative Method C, 3-amino-2-cyclopenten-1-one (iv) can be substituted for 1,3-cyclopentadione (i) and the ammonia source and the same reaction conditions as in Method A are used.

As shown in Scheme 2, dihydropyridines of formula (viii), where the substituent R ¹ is as defined in formula I, can be prepared by reacting 2 equivalents of 1,3-cyclopentanedione (i) with aldehyde (ii) and an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, with heating in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile. Further heating with an acid, e.g. hydrochloric, sulfuric or toluenesulfonic, may be required to complete the reaction. In alternative method C, 1,3-cyclopentanedione (1) can be reacted with aldehyde (ii) and 3-amino-2-cyclopenten-1-one (iv) with heating in the same solvents as above. Further heating with acid, e.g. hydrochloric, sulfuric or toluenesulfonic, may be required to complete the reaction.

Scheme 3

(ix) (vi)

As shown in Scheme 3, dihydropyridines of formula (x), where the substituents R ¹ , R ³ and A are as defined in formula I, can be prepared by one of two main routes. According to route A, 1,3-cyclopentenedione (ix) can be reacted with aldehyde (ii) and the corresponding carbonyl component (v) together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, under heating in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile. Further heating with an acid, e.g. hydrochloric, sulfuric or toluenesulfonic, may be required to complete the reaction. Alternatively, the corresponding enamine (iii) can be substituted for the carbonyl component (v) and the ammonia source using the same reaction conditions. According to method B, 1,3-cyclopentenedione (i) together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, can be reacted under the same conditions as in method A with the enone (vi) component, which was prepared from the aldehyde (ii) and the carbonyl component (v).

Scheme 4

As shown in Scheme 4, dihydropyridines of general formula (xii), where the substituent R ¹ is as defined in formula I, can be prepared by reacting 1,3-cyclopentenedione (ix) with aldehyde (ii) and 3-amino-2-cyclohexen-1-one (xi) under heating in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile.

Scheme 5

O

(xiii) (xv)

As shown in Scheme 5, dihydropyridines of formula (xvii), where R ¹ and A are as defined in formula I, can be prepared by one of two main routes. According to route A, 1,3-cyclopentanedione or 1,3-cyclopentedione, as described in (xiii), together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, can be heated in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile, with the enone component (xiv) being

prepared from the aldehyde (ii) and the carbonyl component (xv). The intermediate hemiaminal (xvi) or the desired dihydropyridine (xvii) can be isolated. In the case where the hemiaminal (xvi) is isolated, it can be converted to the dihydropyridine (xvii) by heating with an acid, e.g. hydrochloric, sulfuric or toluenesulfonic, under an inert atmosphere, e.g. nitrogen or argon. This dehydration reaction can also be achieved using POCl ₃ in pyridine to carry out the complete reaction. Alternatively, 3-amino-2-cyclopenten-1-one (iv) can be substituted for 1,3-cyclopentanedione (xiii), wherein the double bond is absent, and ammonia in Method A. According to Method B, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, can be heated in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile with a carbonyl component (xv). Any hemiaminal intermediate (xvi) obtained in this manner can be converted to the above dihydropyridine (xvii).

• ·

Scheme 6

As shown in Scheme 6, dihydropyridines of formula (xxi), wherein the substituents R ¹ and R ³ are as defined in Formula I and the substituent R is selected from the group consisting of alkyl, arylalkyl, cyanoalkyl and a carboxy protecting group, can be prepared by one of three main routes. According to Route A, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) can be reacted with aldehyde (ii) and the corresponding enamine component (xviii) under heating in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile. Further heating with an acid, e.g. hydrochloric, sulfuric or toluenesulfonic, may be required to complete the reaction. According to Method B, 3-amino-2-cyclopenten-1-one (iv) can be reacted with aldehyde (ii) and the corresponding carbonyl component (v) using the same reaction conditions as in Method A. According to Method C, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, can be reacted under the same conditions as for Method A with the enone (xx) component, which was prepared from aldehyde (ii) and carbonyl component (xix). In an alternative Method C, 3-amino-2-cyclopenten-1-one (iv) can be substituted for 1,3-cyclopentanedione (xiii), wherein the double bond is not present, and the ammonia source using the same reaction conditions.

As shown in Scheme 7, dihydropyridines (xxiii) can be prepared from carboxylic acid esters (xxi), where the substituents R ¹ and R ³ are as defined in Formula I and the substituent R is selected from the group consisting of alkyl, arylalkyl, cyanoalkyl and a carboxy protecting group. The esters can be cleaved to the carboxylic acids (xxii) under various conditions depending on the nature of the substituent R. In cases where the substituent R is an alkyl group, this method can be best carried out using boron trichloride (BCb) in a solvent, e.g., dichloromethane or chloroform. For cases where the substituent R is cyanoethyl, this cleavage can be carried out by reaction with a base, e.g., potassium carbonate in a solvent. Other types of esters can be removed by methods known to those skilled in the art, e.g., by treatment with an acid or hydrogenolysis. The carboxylic acid group (xxii) can also be removed by decarboxylation to give the dihydropyridines (xxiii). Typical conditions include heating in a solvent, e.g. ethanol or toluene, in the absence or presence of an acid, e.g. hydrochloric, sulfuric or toluenesulfonic acid, under an inert atmosphere, e.g. nitrogen or argon.

Scheme 8

''

As shown in Scheme 8, hemiaminals of formula (xxv), wherein R ¹ is as defined in Formula I and R is selected from the group consisting of alkyl, arylalkyl, cyanoalkyl and a carboxy protecting group, can be prepared by one of three main methods. According to Method A, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) and aldehyde (ii) together with an ammonia source, e.g. ammonia in ethanol, ammonium acetate or ammonium hydroxide, can be heated in a protic solvent, e.g. ethanol, methanol, isopropanol, etc. or in dimethylformamide (DMF) or acetonitrile with the β-ketoester component (xxiv). According to Method B, 3-amino-2-cyclopenten-1-one (iv) can be substituted for 1,3-cyclopentanedione (xiii), wherein the double bond is absent, and the ammonia source under the same reaction conditions as in Method A. The hemiaminal intermediate (xxv) or the desired dihydropyridine (xxvi) can be isolated. In the case where the hemiaminal (xxv) is isolated, it can be converted to the dihydropyridine (xxvi) by heating with an acid, e.g. hydrochloric, sulfuric or toluenesulfonic acid, under an inert atmosphere, e.g. nitrogen or argon, to complete the reaction. This dehydration reaction

can also be carried out using POCl ₃ in pyridine. Carboxylic acid esters (xxvi) can be cleaved to carboxylic acids (xxvii) under various conditions depending on the nature of the R substituent. In cases where the R substituent is an alkyl group, this method can best be carried out using boron trichloride (BCl 3 ) in a solvent, e.g. dichloromethane or chloroform. For cases where the R substituent is cyanoethyl, this cleavage can be carried out by reaction with a base, e.g. potassium carbonate in a solvent. Other types of esters can be removed by methods known to those skilled in the art, e.g. by acid treatment or hydrogenolysis. The carboxylic acid group (xxvii) can also be removed by decarboxylation to give the dihydropyridines (xxviii). Typical conditions include heating in a solvent, e.g., ethanol or toluene, in the absence or presence of an acid, e.g., hydrochloric, sulfuric, or toluenesulfonic acid, under an inert atmosphere, e.g., nitrogen or argon.

(xxxiv) (xxxii)

As shown in Scheme 9, where the substituents R ¹ and R ³ are as defined in Formula I, examples of the present invention that have a chiral center and thus exist in racemic form can be separated into their individual enantiomers by the methods shown in Scheme 9. Racemic carboxylic acids (xxi) can be converted to the intermediate acid chloride using thionyl chloride, oxalyl chloride or similar reagents. Generally, the acid chloride is not isolated, but is reacted directly with (R) or (S) mandelic acid to prepare a mixture of diastereoisomeric mandelic acid esters (xxiv) and (xxx), which can be separated by column chromatography on a silica gel column. The individual separated mandelic acid esters (xxiv) and (xxx) can be resolved into the enantiomerically pure carboxylic acids (xxxiii) and (xxxi) by reaction with BCb in a solvent such as dichloromethane or chloroform. Alternatively, the mandelic acid esters (xxiv) and (xxx) can first be converted to the corresponding methyl esters by reaction with sodium methoxide in methanol before resolution to the carboxylic acids described above. Other methods for separating the carboxylic acids (xxiv) and (xxx) into their individual enantiomers include reacting the racemic carboxylic acid (xxi) with α,-methylbenzylamine or phenylglycinol and separating the diastereoisomeric salts by crystallization. The carboxylic acid group of the individual enantiomers (xxxiii) and (xxxi) can also be removed by decarboxylation to give the chiral dihydropyridines (xxxiv) and (xxxii). Typical conditions include heating in a solvent, e.g., ethanol or toluene, in the absence or presence of acids, e.g., hydrochloric acid, sulfuric acid or toluenesulfonic acid, under an inert atmosphere, e.g., nitrogen or argon. Racemic compounds of the present invention can also be separated into individual enantiomers by chiral chromatography.

Abbreviations

The following abbreviations were used: K ₂ CO ₃ for potassium carbonate, LIAIH4 for lithium aluminum hydride, AIH ₃ for aluminum hydride, BH ₃ for borohydride, BH ₃ «DMS for borohydride and dimethyl sulfide complex, DMF for dimethylformamide, DMSO for dimethyl sulfoxide, Et ₃ N for triethylamine, Et ₂ O for diethyl ether, EtOAc for

ethyl acetate, EtOH for ethanol, KOtBu for potassium tert-butoxide, LDA for lithium diisopropylamide, MeOH for methanol, NaOMe for sodium methoxide, NaOH for sodium hydroxide, HCl for hydrochloric acid, H ₂ /Pd for hydrogen atom and palladium as catalyst, iPrOH for isopropyl alcohol and THF for tetrahydrofuran, cat. TFA for catalytic trifluoroacetic acid, TFA for catalytic trifluoroacetic acid, PPIVCCU for triphenylphosphine/tetrachloromethane and η-BuLi for n-butyllithium.

The compounds and methods of the present invention will be better understood in connection with the following examples, which are illustrative in nature and are not intended to limit the scope of the invention in any way. All citations are incorporated herein by reference.

Examples of embodiments of the invention

Example 1

8-(3-Bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7dione

A solution of 3-aminocyclopent-2-en-1-one (97 mg, 1.0 mmol), 1,3-cyclopentanedione (98 mg, 1.0 mmol) and 3-bromo-4-fluorobenzaldehyde (203 mg, 0.99 mmol) in ethyl alcohol (4 mL) was heated at 80°C for 3 days in a sealed flask. The reaction was cooled, the solvent evaporated and the crude residue was subjected to flash chromatography (5% methanol/methylene chloride) to give 133 mg of the hemiaminal intermediate. This intermediate was treated with 1.0 M HCl/diethyl ether (1 mL) in ethyl alcohol at reflux overnight. The reaction was cooled, the solvent evaporated, the solid triturated with hot ethyl acetate, combined, washed with ethyl acetate and dried to give 96 mg of the desired compound as a solid.

¹ H NMR (DMSO-de) δ 2.32 (m, 4H), 2.55-2.80 (m, 4H), 4.51 (s, 1H), 7.21 (m, 2H), 7.44 (dd, 1H), 10.63 (s, 1H);

MS (APCI-) m/z 360 (M-H)';

Analytical calcd for _C17H13BrFNO2 : C, _56.37 ; H, 3.61; N, 3.86. Found: C, 56.80; H, 3.89; N, 3.53.

Example 2

8-(3-Cyanophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione

3-Cyanobenzaldehyde (0.131 g, 1.00 mmol) was treated according to the method of Example 1. Purification by flash chromatography (5% methanol/methylene chloride) gave 0.136 g of the desired compound as a gray solid.

¹ H NMR (DMSO-d ₆ ) δ 2.32 (t, 4H), 2.68 (m, 4H), 4.58 (s, 1H), 7.43 (t, 1H), 7.55 (m, 3H), 10.61 (s, 1H);

MS (APCl·) m/z 291 (M+H) ⁺ , MS (APCl·) m/z 289 (MH)';

Analytical calcd for C18H14N2O2*0.6H2O: C, 71.80; H, 5.09; N, 9.30. Found: C, 71.48; H, 5.22; N, 8.90.

Example 3

8-(4-Chloro-3-nitrophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione 4-Chloro-3-nitrobenzaldehyde (0.186 g, 1.00 mmol) was worked up according to the method of Example 1. The product was combined, washed with ethyl alcohol and dried to give 0.110 g of the desired compound as a grey solid.

¹ H NMR (DMSO-de) δ 2.32 (t, 4H), 2.68 (m, 4H), 4.62 (s, 1H), 7.52 (d, 1H), 7.62 (d, 2H), 7.80 (s, 1H), 10.68 (s, 1H);

MS (ARCI*) m/z 345 (M+H) ⁺ , MS (APCl-) m/z 343 (MH)';

Analytical calcd for _{C17H13CIN2O4.0.2H2O} : C, 58.61; H, 3.88; N, 8.04. Found: C, 58.57; H, 4.24; N, 7.66.

Example 4

8-(3-Nitrophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione

3-Nitrobenzaldehyde (0.151 g, 1.00 mmol) was treated according to the method of Example 1. The solid was collected, washed with ethyl alcohol and dried to give 0.120 g of the desired compound as a yellow solid.

¹ H NMR (DMSO-d ₆ ) δ 2.32 (t, 4H), 2.70 (m, 4H), 4.67 (s, 1H), 7.54 (t, 1H), 7.65 (d, 1H), 8.01 (m, 2H), 10.68 (s, 1H);

MS (APCl·) m/z 311 (M+H) ⁺ , MS (APCI-) m/z 309 (MH)';

Analytical calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.56; H, 4.55; N, 8.95.

Example 5

8-(3-Chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione

3-Chloro-4-fluorobenzaldehyde (0.158 g, 1.00 mmol) was treated according to the method of Example 1. The solid was collected, washed with methylene chloride and dried to give 0.113 g of the title compound as a pink solid.

¹ H NMR (DMSO-d ₆ ) δ 2.32 (t, 4H), 2.67 (m, 4H), 4.51 (s, 1H), 7.16 (m, 1H), 7.25 (t, 1H), 7.32 (d, 1H), 10.61 (s, 1H);

MS (APCI ⁺ ) m/z 318 (M+H) ⁺ , MS (APCI-) m/z 316 (MH)·;

Analytical calculated for _Ci7Hi3CIFNO2 *0.25CH2Cl2.

Example 6

8-(3,4-Dichlorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione

3,4-Dichlorobenzaldehyde (0.175 g, 1.00 mmol) was treated according to the method of Example 1. The solid was collected, washed with ethyl alcohol and dried to give 0.164 g of the title compound as a pink solid.

¹ H NMR (DMSO-d ₆ ) δ 2.32 (t, 4H), 2.67 (m, 4H), 4.52 (s, 1H), 7.17 (d, 1H), 7.38 (s, 1H), 7.49 (d, 1H), 10.64 (s, 1H);

MS (APCI ⁺ ) m/z 334 (M+H) ⁺ ; MS (APCI-) m/z 332 (MH)';

Analytical calcd for C17H13Cl2NO2* _0.25CH2Cl2 : C, 58.29; H, 3.83; N, 3.94. Found: C, 58.14; H, 4.18; N, 3.92.

Example 7

8-(2,1,3-Benzoxadiazol-5-yl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,ε]pyridine-1,7dione

2,1,3-Benzoxadiazole-5-aldehyde (0.296 g, 2.00 mmol), prepared according to the method of Gaska (Eur. J. Med. Chem. 1996, 31, 3), was processed according to the method of Example 1. The crude product was purified by flash chromatography on a silica gel column (10% ethanol/methylene chloride) to give 0.10 g of the desired compound.

Melting point 272-273°C;

¹ H NMR (DMSO-d ₆ ) δ 2.34 (t, 4H), 2.53-2.81 (m, 4H), 4.68 (s, 1H), 7.63 (d, 2H), 7.92 (d, 1H), 10.71 (s, 1H);

MS (ESI) m/z 308 (M+H) ⁺ ;

Analytical calcd for C12H13N3O3*0.75H2O: C, 63.64; H, 4.55; N, 13.09. Found: C, 63.76; H, 4.36; N, 12.74.

Example 8

8-(3-Iodo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione

Example 8A

3-Amino-4-fluorobenzyl alcohol

3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0°C was treated with 1.0 M BH ₃ THF (50 mL) with stirring overnight at room temperature. An additional 130 mL of 1.0 M BH ₃ *THF was added and stirred for 10 h. The reaction mixture was quenched by addition of methanol, stirred for 3 h at room temperature, the solvent was evaporated, and the product was partitioned between aqueous sodium bicarbonate/methylene chloride. The organic layer was dried (sodium sulfate), filtered, and the solvent was evaporated. The crude product was purified by flash chromatography on a silica gel column (ethyl acetate/hexane 1:1) to give 7.0 g of the desired compound.

¹ H NMR (CDCl ₃ ) δ 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

•» · ·

Example 8B

4-Fluoro-3-iodobenzyl alcohol

The product of Example 8A (7.0 g, 50 mmol) in water (100 mL) at 0°C was slowly treated with concentrated sulfuric acid (30 mL) to maintain the temperature below 10°C, then treated dropwise with aqueous sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated at 60°C for 2 hours, cooled, and extracted with methylene chloride. The organic phase was washed with 10% sodium hydroxide, 1 M sodium thiosulfate, 10% hydrochloric acid, aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and the solvent was evaporated. The crude product was purified by flash chromatography on a silica gel column (ethyl acetate/hexane 7:3) to give 6.4 g of the desired compound.

¹ H NMR (CDCl 3 ) δ 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).

Example 8C

4-Fluoro-3-iodobenzaldehyde

The product from Example 8B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol) and stirred overnight. Additional manganese dioxide (2.25 g) was added to the reaction mixture and stirred overnight. The slurry was filtered and the solvent was evaporated. The crude product was purified by flash chromatography on a silica gel column (ethyl acetate/hexane 1:4) to give 1.9 g of the desired compound.

¹ H NMR (CDCb) δ 7.23 (t, 1H), 7.89 (m, 1H), 8.32 (dd, 1H), 9.91 (s, 1H).

Example 8D

8-(3-Iodo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione 4-Fluoro-3-iodobenzaldehyde (0.50 g, 2.0 mmol) was treated according to the method of Example 1 to give 0.30 g of the desired compound.

• 0

0 0 • 0 • ·· 00 0 0« 0 · · 0 00 ·· 000 • 0 0 0 0 0 • 00 0· 00 ··· • 00 00 000 ¹ H NMR (DMSO-d ₆ ) δ 2.82 (t, 4H), 2.55-2.79 (m, 4H), 4.48 (s, 1H), 7.1 (t, 1H), 7.16 (m, 1H), 7.58 (dd, 1H);

MS (ESI) m/z 410 (M+H) ⁺ ;

Analytical calcd for _C17H13FINO2 : C, _49.89 ; H, 3.20; N, 3.42. Found: C, 49.62; _H , 3.36; N, 3.28.

Example 9

9-(3-Bromo-4-fluorophenyl)-5,6,7,9-tetrahydro-1/7-cyclopenta[b]quinoline-1,8(4H)-dione A solution of 4-cyclopentene-1,3-dione (1.14 g, 10.2 mmol), 3-bromo-4fluorobenzaldehyde (2.05 g, 10.1 mmol) and 3-amino-2-cyclohexenone (1.14 g, 10.2 mmol) in absolute ethanol (50 mL) was stirred with a magnetic stirrer and heated at reflux for 36 h. The mixture was vacuum filtered and the solid was washed with ethyl acetate-hexane. The filtrate was concentrated and the residue was chromatographed on a silica gel column (100 g) eluting with EtOAc-hexanes (75:25), then EtOAc, and finally EtOAc-EtOH (95:5). The product was obtained as a brown crystalline solid (720 mg, 1.92 mmol).

Melting point > 260.

¹ H NMR (DMSO-de) δ 1.79 (m, 1H); 1.90 (m, 1H), 2.20 (m, 2H), 2.54 (m, 2H), 4.86 (s, 1H), 7.15 (m, 4H), 7.38 (dd, 1H, J=6.8, 2.0 Hz), 9.52 (s, 1H);

MS (APCI ⁺ ) m/z 390 (M+18) ⁺ ;

Analytical calcd for _C18H13BrFNO2 : C, 57.77; H, 3.50; N, 3.74. Found: C, 57.62; H, 3.56; N, 3.58.

Example 10

4-(3-bromo-4-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylic acid

Example 10A Methyl 4-(3-bromo-4-fluorophenyl)-2-methyl-5-oxo-4,56,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

9

9

3-Bromo-4-fluorobenzaldehyde (3.045 g, 15 mmol), methyl acetoacetate (2.09 g, 18 mmol) and 3-aminocyclopent-2-enone (1.45 g, 15 mmol) were heated at 65°C in methanol for 5 days. The reaction was allowed to cool to room temperature and the white precipitate was collected, washed with methanol and dried to give

2.29 g of the desired compound. Flash chromatography (5% methanol/methylene chloride) of the filtrate provides an additional 1.46 g of the desired compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.45 (s, 3H), 3.60 (s, 3H), 4.90 (s, 1H), 6.33 (s, 1H), 6.98 (t, 1H), 7.23 (m, 1H), 7.37 (d, 1H);

MS (APCl.) m/z 380 (M+H)';

Analytical calcd for _C17H17BrFNO3 : C, 53.70; H, 3.98; N, 3.68. Found: C, 53.57; H, 3.91; N, 3.48.

Example 10B

4-(3-bromo-4-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylic acid

A suspension of the product from Example 10A (1.90 g, 5.0 mmol) in methylene chloride (10 mL) at 5°C under nitrogen was treated with 1M boron trichloride in methylene chloride (40 mL), stirred overnight, quenched with ice water (100 mL) and ethyl acetate (30 mL), and the water removed. The suspension of the product in ethyl acetate was filtered, the filter cake was washed with ethyl acetate, and dried to give 1.26 g of the desired compound as an orange-pink solid.

Melting point 211-214°C;

¹ H NMR (DMSO-de) δ 2.24 (t, 2H), 2.33 (s, 3H), 2.55 (t, 2H), 4.68 (s, 1H), 7.17 (m, 1H), 7.23 (t, 1H), 7.38 (d, 1H), 9.72 (s, 1H), 11.87 (s, 1H);

MS (APCl') m/z 364 (M-H)';

Analytical calcd for _C16H13BrFNO3 * _0.25H2O .· C, 51.84; _H , 3.67; N, 3.78. Found: C, 51.62; H, 3.90; N, 3.62.

Determination of potassium channel opening activity

Determination of membrane hyperpolarization

Compounds were evaluated for potassium channel opening activity using primary cultured guinea pig bladder (GPB) cells.

To prepare bladder smooth muscle cells, the bladder was removed from a male guinea pig (Hartley, Charles River, Wilmington, MA) weighing 300-400 g and placed in ice-cold Ca ²⁺ -depleted Krebs solution (composition. mM: KCl, 2.7; KH ₂ PO ₄ , 1.5; NaCl, 75; Na ₂ HPO ₄ , 9.6; Na ₂ HPO ₄ *7H ₂ O, 8; MgSO ₄ , 2; glucose, 5; HEPES, 10; pH 7.4). Cells were isolated by the above enzymatic dissociation with minor modifications (Klockner, U. and Isenberg, G., Pflugers Arch. 1985, 405, 329-339), incorporated herein by reference. The bladder was dissected into several small pieces and incubated in 5 ml of Krebs solution containing 1 mg/ml collagenase (Sigma, St. Louis, MO) and 0.2 mg/ml pronase (Calbiochem, La Jolla, CA) with constant agitation in a cell incubator for 30 minutes. The mixture was then centrifuged at 1300 xg for 5 minutes and the pellets were resuspended in Dulbecco's PBS (GIBCO, Gaithersburg, MD) and centrifuged again to remove any remaining enzyme. The cell pellets were resuspended in 5 ml of growth medium (composition: Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 100 units/ml streptomycin, and 0.25 mg/ml amphotericin B) and further dissociated by pipetting the suspension with flame-sterilized Pasteur pipettes and passing through a polypropylene mesh membrane (Spectrum, Houston, TX). The cell density was adjusted to 100,000 cells/ml by resuspension in growth medium. For membrane potential studies, cells were plated in black 96-well clear-bottom plates (Packard) at a density of 20,000 cells/plate and maintained in a cell incubator with 90% air: 10% _CO2 until confluent. Verification of smooth muscle cell type was performed by cytoskeletal labeling using mouse monoclonal anti-human smooth muscle actin (Biomeda, Foster City, CA).

Functional activity in potassium channels was measured by evaluating changes in membrane potential using the bis-oxonal dye DiBAC(4) ₃ (Molecular Probes) in a 96-well Fluorescent Imaging Plate Kinetic Assay System.

Reader”=FLIPR) (KS Schroeder et al., J. Biomed. Screen., v. 1, pp. 75 - 81 (1996)). DIBAC(4) ₃ is an anionic potentiometric sensor that partitions into two phases, the cellular phase and the extracellular solution phase, depending on the membrane potential. With increasing membrane potential (e.g., depolarization of K ⁺ ), the sensor further partitions into the cellular phase; this is measured as an increase in fluorescence due to interactions of the dye with intracellular lipids and proteins. Conversely, decreasing membrane potential (hyperpolarization by potassium channel openers) causes a decrease in fluorescence.

Confluent A10 smooth muscle cells or guinea pig bladder cells cultured in 96-well black plates were rinsed 2 x 200 ml of buffer (composition, mM: HEPES, 20; NaCl, 120; KCl, 2; CaCl ₂ . 2; MgCl 2 , 1; glucose, 5; pH 7.4 at 25°C) containing 5 μΜ DIBAC(4) ₃ and incubated with 180 ml of buffer in a cell incubator for 30 minutes at 37°C to ensure distribution of the dye across the membrane. After recording the baseline fluorescence for 5 minutes, reference or test compounds prepared at a tenfold concentration in buffer were added directly to the plates. Changes in fluorescence were monitored for an additional 25 minutes. Hyperpolarization responses were corrected for any intrinsic noise and normalized to responses observed with 10 μΜ of the reference compound P1075 (determined as 100%), a potent opener of smooth muscle Katp channels (Quast et al., Mol. Pharmacol., v. 43 474-481 (1993)).

Five concentrations of P1075 or test compounds (logarithmic or half-logarithmic dilutions) were calculated and the values of the maximal steady-state hyperpolarization (expressed as % relative to P1075) plotted as a function of concentration. EC50 values (the concentration that elicits 50% of the maximal response for the test sample) were calculated by nonlinear regression analysis using a four-variable sigmoidal equation. The maximal responses of each compound (expressed as % relative to P1075) are shown below. A stock solution of compounds was prepared in 100% DMSO and further dilutions were made in buffer and added to 96-well plates.

Table 1

Membrane hyperpolarization (MHP) in guinea pig bladder (GPB) cells

Example # Maximum response (%P1075) _EC50 (μM) 1 102 0.071 2 65 5.3 3 113 0.053 4 123 0.34 5 72 0.14 6 94 0.10 7 98 0.13 8 93 0.013 9 100 0.063 10 103.5 2.68

In vitro functional models

The compounds were evaluated for functional activity to open potassium channels using tissue sections obtained from Landrace pig bladders.

Landrace pig bladders were obtained from Landrace sows weighing 9-30 kg. These subjects were sacrificed by intraperitoneal injection of pentobarbital solution, Somlethal®, JA Webster Inc., Sterling MA. The entire bladder was removed and immediately placed in Krebs's saline bicarbonate solution (composition, mM: NaCl, 120; NaHCO ₃ , 20; dextrose, 11; KCl, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 1.5; KH ₂ PO ₄ , 1.2; K ₂ EDTA, 0.01, equilibrated in 5% CO ₂ /95% O ₂ pH 7.4 at 37°C). Propranolol (0.004 mM) was included in all assays to block β-adrenoceptors. The trigeminal and superior portions were removed. Strips 3-5 mm wide and 20 mm long were prepared from the remaining tissue, cut radially, and the mucosa was removed.

0·· 000 ·· • 00 ·· 0· ·· · ··

0' layer. One end was attached to a solid glass rod and the other to a Grass FT03 transducer at a pre-basal load of 1.0 grams. The solid glass rod contained two parallel platinum electrodes to provide a 0.05 Hz, 0.5 millisecond field stimulation at 20 volts. This low frequency stimulation elicited a stable contraction response of 100-500 centigrams. Tissues were allowed to equilibrate for at least 60 minutes and treated with 80 mM KCl. A control concentration (cumulative) response curve was generated for each tissue using P1075, a potassium channel opener, as a control agonist. P1075 completely eliminated stimulated contractions in a dose-dependent manner over a concentration range of 10' ⁹ - 10' ⁵ M at 1/2 log steps. After 60 minutes of washing, a concentration (cumulative) response curve was generated for the test agonist in the same manner as for the control agonist P1075. The maximal potency of each compound is shown below (expressed as % relative to P1075). The amount of agent required to achieve 50% of the maximal response (ED ₅₀ ) for the test sample was calculated using “ALLFIT” (DeLean et al., Am. J. Physiol., 235, E97 (1980)) and the agonist potency was expressed as pD ₂ (negative logarithm). The agonist potency was also expressed as an index relative to P1075.

The index was calculated by dividing the ED50 value for P1075 by the ED50 value of the test agonist in the indicated tissue. Each tissue was used for only one test agonist and the data obtained from each tissue were averaged to obtain an average potency index. These data are presented in Table 2.

Table 2

Functional activity of potassium channel opening in parts isolated from the urinary bladder

Landrace pig bladders Example # Efficiency (%P1075) pD2 Index 1 98 6.8 0.48 2 96 5.2 0.017 3 98 6.6 0.35

According to the data in Tables 1 and 2, the compounds of the present invention reduce stimulated bladder contractions.

In vivo data

The ability of the compounds of the present invention to treat urinary incontinence can be illustrated by the ability of the compounds of the present invention to inhibit in vivo bladder contractions. The following method can be used to illustrate the in vivo efficacy of the compounds of the invention. It is important to note that several compounds known from the literature do not have sufficient solubility in the dosage carrier used for intravenous administration.

In vivo bladder efficiency protocol (isovolumetric contraction model)

Male CD rats (400-450 g) were anesthetized with urethane (0.6 g/kg ip + 0.6 g/kg sc). The left femoral artery and vein were cannulated with polyethylene (PE50) tubing for arterial blood pressure measurement and test compound administration. A third polyethylene catheter (PE-60) was inserted 3-4 mm into the tip of the upper bladder and secured using 5-0 silk smooth suture. The bladder was emptied through this catheter and gentle manual pressure was applied to the lower abdomen. The urinary catheter was connected using a Y-connector to the • ·· · 4 · ·· 4 ··· · 4 444 9 4 44

44,494,449

444 4 494 4 ·

494 494 444

499 44 44 444 49 444 pressure transducer and injection pump. The urethra was then ligated using 4-0 silk suture and the bladder was slowly filled by constant infusion of room temperature saline at a flow rate of 1 ml/min until spontaneous rhythmic contractions were evident (1.0 - 1.3 ml). After the contractions were established, bladder pressure and vascular pressure were monitored for 20 minutes before and after a dose of vehicle alone (equivalent parts of β-cyclodextrin stock solution (100 g β-cyclodextrin dissolved in 200 ml) and sterile water). After that, three doses of test compound were cumulatively administered intravenously (iv) at 20 minute intervals. Each dosing solution (1 ml/kg) was warmed to body temperature before administration and infused over 3 minutes to minimize dosing artifacts on the bladder pressure curve. Data were averaged for each of the last 10 minutes and reported as percent change from control. Mean arterial pressure and area under the bladder contraction curve were determined from the respective waveforms using a Modular Instruments, Inc. automated data acquisition system and data were averaged over the last 10 minutes of the twenty-minute period. The doses required to reduce mean arterial pressure by 15% (MAP ED15%) and to reduce area under the bladder contraction curve by 30% (AUC ED30%) relative to control doses were estimated using routine Excel processing.

The compound of Example 3 of the present invention (Table 3, Figure 1), was dosed at 0.01, 0.1 and 1 pmol/kg. The AUC ED ₃₀ value for Example 3 was determined to be 0.1 μηΊθΙ/kg. In comparison to the compound of Example A (Table 3, Figure 1), analogous to the compound of Example 3, which was insufficiently soluble in the dosage vehicle to establish the same dose-response relationship and calculate the AUC ED ₃₀ .

Table 3

In vivo inhibition of bladder contractions

Example R (Figure 1) n (Figure 2) AUC ED ₃₀ (μl/kg) 3 3-NO ₂ ,4-C1 1 0.1 A 3-NO ₂ ,4-C1 2 *

(‘indicates inability to detect data due to insolubility of the compound in the medium)

The data in Table 3 demonstrate the ability of the compounds of the present invention to inhibit in vivo bladder contractions formulated with a dosage carrier used for intravenous administration.

Demonstration of how the compounds of the invention are soluble in water

The aqueous solubility was determined by shaking for 60 hours at room temperature in 50 mM NaH ₂ PC>4 buffer at pH 6.5 and 7.4. The determination was performed using reverse phase HPLC. The solubility is expressed in nanomoles per milliliter in Table 4.

Table 4

Solubility in water

Example R (Figure 1) n (Figure 1) pH7.4 (nmol/ml) pH 6.5 (nmol/ml) 3 3-NO ₂ ,4-Cl 1 129 129 A 3-NOa, 4-Cl 2 2.4 2.4 1 3-Br, 4-F 1 227 205 B 3-Br, 4-F 2 3.6 5.1 2 3-CN 1 1290 1300 C 3-CN 2 24.5 25.8 4 3-NO ₂ 1 164 158 D 3-NO ₂ 2 2.4 2.7

The data in Table 4 illustrate that representative compounds of the invention having two

The 5-membered carbocyclic rings fused to a dihydropyridine core, Examples 1 - 4 (Table 4, Figure 1), show enormous solubility compared to analogous compounds having two 6-membered rings fused to a dihydropyridine core, Examples A - D (Table 4, Figure 1).

The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of the substituents on the chiral carbon atom. The terms “R” and “S” as used herein are those configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. In particular, the stereochemistry at position 8 and the point of attachment of the R ¹ substituent, as shown in Formulae I and II, may be independently either (R) or (S), unless otherwise specifically noted. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention

They can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures thereof, followed by resolution of the mixture by methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereoisomers by recrystallization or chromatography, and recovering the optically pure product from the auxiliary, or (2) directly separating the mixture of optical enantiomers on chiral chromatographic columns.

The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating agent or excipient of any type. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose or sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppositories; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, e.g., propylene glycol; esters, e.g., ethyl oleate and ethyl aurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; saline; ethyl alcohol and phosphate buffer solution, as well as other non-toxic compatible lubricants, e.g. sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and aromatics, preservatives and antioxidants may be present in the preparation, at the discretion of the person preparing the preparation.

The present invention provides pharmaceutical compositions comprising the compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

Further included within the scope of the present invention are pharmaceutical compositions comprising one or more compounds of Formulae I-II prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable excipients. The pharmaceutical compositions may be prepared for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of the present invention may be administered to humans or other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (powders, ointments, drops), buccally, or as an oral or nasal spray. The term "parenteral" as used herein refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intraarticular injection and infusion.

Pharmaceutical preparations of the present invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.) and suitable mixtures thereof, vegetable oils (e.g. olive oil) and injectable organic esters, e.g. ethyl oleate. Intrinsic fluidity can be maintained, e.g., by the use of coating agents, e.g., lecithin, in the case of dispersions, by maintaining the desired particle size and by the use of surfactants.

These preparations may also contain adjuvants, e.g. preservatives, detergents, emulsifiers and dispersants. Prevention against the action of microorganisms may be provided by the inclusion of various antibacterial and antifungal agents, e.g. paraben, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, e.g. sugar, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form may be caused by the admixture of agents (such as aluminum monostearate and gelatin) which delay absorption.

In some cases, in order to prolong the effects of a drug, it is often desired to slow the absorption of the drug from subcutaneous or intramuscular injection, which can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The rate of absorption of the drug is then determined by the solubility of the substance, which depends on the crystal size and crystalline form.

Alternatively, prolonged absorption of a parenterally administered drug can be achieved by dissolving or suspending the drug in an oil carrier.

Suspensions, in addition to the active compounds, may contain suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitols and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

If desired and for more efficient distribution, the compounds of the present invention may be incorporated into slow release or precise delivery systems, e.g., polymeric matrices, liposomes, and microspheres. They may be sterilized, e.g., by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid preparations which may be dissolved in sterile water or some other sterile injectable medium used immediately prior to use.

The active compounds may also be in microencapsulated form, if desired, with one or more of the above excipients. Solid dosage forms, e.g., tablets, dragees, capsules, pills, and granules, may be prepared with coatings and shells, e.g., enteric coatings, or other coatings well known in the pharmaceutical arts. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, e.g., sucrose, lactose, or starch, and such dosage forms may also contain, as is common practice, other substances other than inert diluents, e.g., tabletting lubricants and other tabletting acids, e.g., magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain a buffering agent. Solid dosage forms may optionally contain an opacifying agent and may be such preparations that release the active ingredients only or preferentially in a particular part of the intestinal tract, or may be somewhat delayed. Examples of encapsulated preparations that may be used include polymeric substances and waxes.

Injectable depot forms are made by preparing microscopically encapsulated matrices of drugs in biodegradable polymers, e.g. polylactidepolyglycolide. The rate of drug release can be controlled (regulated) depending on

99

99 999

9 9 9 ·· • * • 9

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999 99 9 the ratio of drug to polymer and the nature of the polymer particles used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable preparations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizing agent in the form of sterile solid preparations which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Injectable preparations, e.g., sterile injectable aqueous or oleaginous suspensions, may be prepared by methods known in the art using suitable dispersing agents, suspending agents, and detergents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in a nontoxic, parenterally acceptable diluent or solvent, e.g., a solution in 1,3-butanediol. Acceptable carriers and solvents include water, saline, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a suspending medium. For this purpose, any bland, fixed oil may be employed, including monoglycerides or diglycerides. In addition, fatty acids, e.g., oleic acid, are employed in the preparation of injectable solutions.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and orthosilicic acid, b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, e.g., glycerol, d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and calcium carbonate, e.g., solution inhibitors, e.g., paraffin, f) absorption accelerators, e.g., quaternary ammonium compounds, g) detergents, e.g., cetyl alcohol, and glycerol monostearate, h) adsorbents, e.g., kaolin, and

• ·· 9 9 9 9 99 ·· • 4 • 4 9 9 9 9 99 • · 9 • • • 9 9 9 9 9 9 • • 99 99 99 999 ·· • 4

bentonite kaolin and (i) lubricants, e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent.

Solid preparations of a similar type can also be used as fillers in loosely filled and densely filled gelatin capsules using such excipients as lactose or milk sugar, as well as polyethylene glycols of high relative molecular weight, etc.

Solid dosage forms, e.g. tablets, dragees, capsules, pills and granules, may be prepared with a coating and protective layers, e.g. enteric coating and other coatings well known in the pharmaceutical arts. Solid dosage forms may optionally contain opacifying agents and may also be free of such preparations which release the active ingredients only or preferentially in a certain part of the intestinal tract, optionally to some extent prolonged. Examples of encapsulated preparations which may be used include polymeric substances and waxes.

Formulations for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing the compounds of the invention with suitable, non-irritating excipients or carriers, e.g. cocoa butter, polyethylene glycols or wax suppositories, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters, and mixtures thereof.

In addition to inert diluents, oral preparations may also include adjuvants, e.g., detergents, emulsifying and suspending agents, sweetening, flavoring, and aromatic agents.

Dosage forms for oral or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also included within the scope of this invention.

Ointments, pastes, creams and gels may contain, in addition to the active compound according to the invention, excipients, e.g. animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays may contain, in addition to the compounds of the invention, excipients, e.g. lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof. Sprays may further contain conventional propellants, e.g. chlorofluorocarbons.

Transdermal patches have the advantage of providing controlled delivery of a compound into the body. Such dosage forms can be formed by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the passage of the compound through the skin. The rate of passage through the skin can be controlled either by a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolamellar or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and usable lipid capable of forming liposomes may be used. The present liposomal formulations may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, etc. Preferred lipids are synthetic or natural phospholipids and phosphatidylcholines (lecithins) used together or separately. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), pages 33 et seq.

• ·

The term "pharmaceutically acceptable cation" as used herein refers to a positively charged inorganic or organic ion that is generally considered suitable for human consumption. Examples of pharmaceutically acceptable cations are hydrogen, alkali metal (lithium, sodium and potassium), magnesium, calcium, iron and ferric, ammonium, alkyl ammonium, dialkyl ammonium, trialkyl ammonium, tetraalkyl ammonium, diethanol ammonium ion and choline. The cations can be exchanged by methods known in the art, e.g., by ion exchange.

The term "pharmaceutically acceptable salts, esters and amides" as used herein refers to carboxylate salts, amino acid addition salts, zwitterions, esters and amides of compounds of formula I which are, within the scope of good medical judgment, suitable for use in contact with tissues of humans and lower animals without causing toxicity, irritation, allergic reactions, etc., are proportionate to a reasonable benefit/risk ratio and are effective for their intended use.

The term "pharmaceutically acceptable salt" as used herein refers to salts that are known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of the amino group formed with inorganic acids, e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids, e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by other methods known in the art, e.g., ion exchange. Other pharmaceutically acceptable salts include nitrate, bisulfate, borate, formate, butyrate, valerate,

3-phenylpropionate, camphor ester, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonic acid ester, methanesulfonate, 2-hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate, glycerophosphate, pectinate, lauryl sulfate, etc. metal salts, e.g. sodium, potassium, magnesium or calcium salt or amino salts, e.g. ammonium, triethylamine salts, etc. all of which can be prepared according to general methods.

The term "pharmaceutically acceptable ester" as used herein refers to esters of the compounds of the present invention that are hydrolyzed in vivo and

include those which are readily cleaved in the human body to leave the parent compound or its salt. Examples of pharmaceutically acceptable, non-toxic esters of the present invention include C1-to- _C6 alkyl esters and _C5 -to- _C7 cycloalkyl esters, however, C1-to-C4 alkyl esters are preferred. Esters of compounds of formula I can be prepared according to general methods.

The term "pharmaceutically acceptable amide" as used herein refers to non-toxic amides of the present invention derived from ammonia, primary C1-C6 alkylamines, and secondary C1- _C6 dialkylamines. In the case of secondary amines, the amines may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amides, and C1- _C2 dialkyl secondary amides are preferred. Amides of compounds of formula I can be prepared according to general methods. It is also contemplated that amides of the present invention include amino acid and peptide derivatives of compounds of formula I.

The term "pharmaceutically acceptable prodrug" or "prodrug" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of good medical judgment, suitable for use in contact with human and lower animal tissue without causing toxicity, irritation, allergic reactions, etc. and proportionate to a reasonable benefit/risk ratio and effective for their intended use. The prodrugs of the present invention can be rapidly transformed in vivo to the parent compound of the above formula, e.g. by hydrolysis in blood. Further details can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series and in Edward B. Roche, Ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), herein incorporated by reference.

The term "prodrug ester group" as used herein refers to any of several ester-forming groups that are hydrolyzable under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as other similar groups known in the art. Other examples of prodrug ester groups can be found in the book "Pro-drugs as Novel Delivery Systems" by Higuchi and Stella, as cited above.

Dosage forms for topical administration of the compounds of this invention include powders, sprays, inhalants and creams. The active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers or propellants as required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated within the scope of the present invention.

The actual dosage level of the active ingredient of the active compounds in the pharmaceutical compositions of the present invention may vary depending on the amount of active compound(s) effective to achieve the desired therapeutic response in the individual patient, the compositions, and the route of administration. The selected dosage level will depend on the activity of the individual compound, the route of administration, the severity of the condition being treated, and the prior medical history of the patient being treated. However, to achieve the desired therapeutic effect, it is known from experience that the dosage of the compound is started at lower levels than desired and gradually increased until the desired effect is achieved.

The present invention includes pharmaceutically active metabolites formed in vivo by biotransformation of compounds of formulae I-VI. The term "pharmaceutically active metabolite" as used herein refers to a compound formed in vivo by biotransformation of compounds of formulae I-VI. The present invention includes compounds of formulae I-VI and their metabolites. Further details can be found in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, incorporated herein by reference.

The compounds of the present invention, including but not limited to those specified in the Examples, have potassium channel opening activity in mammals (especially humans). As potassium channel openers, the compounds of the present invention are useful for the treatment and prevention of diseases such as asthma, epilepsy, hypertension, Raynaud's disease, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.

The ability of the compounds of the present invention to treat asthma, epilepsy, hypertension, Raynaud's disease, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke can be demonstrated according to the methods described (D.E. Nurse et al., Br. J. Urol., v. 68, pp. 27-31 (1991); B.B. Howe et al., J. Pharmacol. Exp. Ther., v. 274, pp. 884-890 (1995); K. Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996); D.R. Gehlert et al., Neuro-Psychopharmacol & Biol.Psychiat., v. 18, pp. 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95 - 127 (1993); J.

E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996); D. Spanswick et al., Nature, v. 390, pp. 521-25 (December 4, 1997)).

The aqueous liquid formulations of the present invention are particularly effective for the treatment and prevention of asthma, epilepsy, hypertension, Raynaud's disease, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.

When the compounds of the present invention are used for the treatment of the above-mentioned diseases or for the treatment of other diseases, a therapeutically effective amount of one of the compounds of the present invention may be used in pure form or in the form of a pharmaceutically acceptable salt, ester or prodrug. Alternatively, the compound may be administered as a pharmaceutical composition comprising the desired compound in combination with one or more pharmaceutically acceptable excipients. By the term "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to treat the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is understood that the total daily use of the compounds and compositions of the present invention is at the discretion of the attending physician, using sound medical judgment. The specific, therapeutically effective dosage level for any individual patient will depend on a variety of factors including the disease being treated and the severity of that disease; the activity of the specific compound being used; the use of the specific composition; the age, body weight, general health, sex and lifestyle of the patient; the time of application, route of application, and rate of excretion of the specific compound used; the duration of treatment; the drugs used in combination or in concert with the specific compound used; and similar factors well known in medical practice.

The total daily dose of the compounds of this invention administered to humans or lower mammals may range from about 0.003 to 10 mg/kg/day. For oral administration, doses in the range of about 0.01 to about 5 mg/kg/day are more preferred. If desired, the effective daily dose for administration may be divided into several doses; consequently, a single dose may contain such amounts or fractions thereof as to constitute the daily dose.

Claims (32)

PATENT CLAIMS A compound having the formula I; I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein the dotted line indicates the presence of an optional double bond; R ¹ is selected from the group consisting of aryl and heteroaryl; A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and -C (O) R ² , wherein R ² is selected from the group consisting of alkyl, haloalkyl and hydroxy; R ³ is selected from the group consisting of hydrogen, alkyl and haloalkyl; and A and R ³ joined together with the ring to which they are attached may form a 5-membered or 6-membered carbocyclic ring. Said 5-membered or 6-membered carbocyclic ring may contain 1 or 2 double bonds and may be substituted by 1 or 2 substituents selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy groups , haloalkenyl, haloalkyl, halo, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo and -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl. The compound of claim 1, wherein A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R ³ is hydrogen. The compound of claim 1, wherein A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R ³ is selected from the group consisting of alkyl. The compound of claim 1, wherein A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R ³ is selected from the group consisting of haloalkyl. The compound of claim 1, wherein A is -C (O) R ² ; wherein R ² is selected from the group consisting of alkyl, haloalkyl and hydroxy and R ³ is hydrogen. The compound of claim 1, wherein A is -C (O) R ² ; wherein R ² is selected from the group consisting of alkyl, haloalkyl and hydroxy and R ³ is selected from the group consisting of alkyl. The compound of claim 6, wherein R ² is hydroxy. A compound according to claim 7 having the formula 4- (3-bromo-4-fluorophenyl) -2-methyl-5-oxo-4,5,6,7-tetrahydro-1 H -cyclopenta [b] pyridine-3-carboxyl group. The compound of claim 1, wherein A is -C (O) R ² ; wherein R ² is selected from the group consisting of alkyl, haloalkyl and hydroxy and R ³ is selected from the group consisting of haloalkyl. The compound of claim 1, wherein A is heteroaryl; and R ³ is selected from the group consisting of hydrogen, alkyl and haloalkyl. The compound of claim 1, wherein A is tetrazole; and R ³ is selected from the group consisting of hydrogen, alkyl and haloalkyl. A compound according to claim 1 having the formula II: or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein m is an integer of 1 or 2; and B and C are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halo, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and - NR ⁴ R ⁵ wherein R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and lower alkyl. A compound according to claim 12 having the formula III: or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. A compound according to claim 12 having the formula IV: or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. A compound according to claim 12 having the formula V: or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. The compound of claim 15, wherein R ¹ is aryl; m is 1; B is hydrogen; and C is hydrogen. The compound of claim 15, wherein R ¹ is phenyl; m is 1; B is hydrogen; and C is hydrogen. 9 9 A compound according to claim 17 selected from the group consisting of 8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7 dione, 8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7-dione, 8- (4-Chloro-3-nitrophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7-dione, 8- (3-Nitrophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7-dione, 8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7-dione, 8- (3,4-Dichlorophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7-dione, and 8- (3-Iodo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7 dione. The compound of claim 15, wherein R ¹ is heteroaryl; m is 1; B is hydrogen; and C is hydrogen. The compound of claim 15, wherein R ¹ is selected from the group consisting of benzoxadiazole, benzoxazole, benzothiazole, benzothiadiazole, benzothiophene, benzofuran, furan, and thiophene; m is 1; B is hydrogen; and C is hydrogen. The compound of claim 15, wherein R ¹ is 2,1,3-benzoxadiazole; ·· t · index m is 1; B is hydrogen; and C is hydrogen. 22. The compound of claim 21 which is 8- (2,1,3-Benzoxadiazol-5-yl) _-2> 3,4,5,6,8-hexahydrodicyclopenta [b, e] pyridine-1,7-dione. A compound according to claim 12 having the formula VI: VI, or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. The compound of claim 23, wherein the index m is 2; R ¹ is aryl; B is hydrogen; and C is hydrogen. The compound of claim 23, wherein the index m is 2; R ¹ is phenyl; B is hydrogen; and C is hydrogen. • r • 44 49 4 99 94 4 · · 9 44 · ··············· · 944 The compound of claim 25 which is 9- (3-bromo-4-fluorophenyl) 5,6,7,9-tetrahydro-1H-cyclopenta [b] quinolin-1,8 (4H) -dione. 27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier. 28. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12 in combination with a pharmaceutically acceptable carrier. 29. A method of treating a disease in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of claim 1. 30. A method of treating a disease in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of claim 12. The method of claim 29, wherein said disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's disease, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke. 32. The method of claim 30 wherein said disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's disease, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.