US2003225120A1PendingUtilityA1
Dihydropyridine soft drugs, and related compositions and methods
Priority: May 30, 2000Filed: Mar 19, 2003Published: Dec 4, 2003
Est. expiryMay 30, 2020(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/02A61P 43/00A61P 37/08A61P 27/06C07D 211/90A61P 13/00C07D 495/04A61P 1/00C07D 497/04A61P 11/08A61P 13/02A61P 11/00A61P 15/06A61P 15/00A61P 11/06
48
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Claims
Abstract
This invention relates to novel dihydropyridine soft drugs of the formula ΦOOR 1 , where Φ is a dihydropyridine moiety. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibroncho-constriction activity. Use of such soft drug analogs permits the administration of greater doses of the claimed dihydropyridine compounds without intolerable systemic effects. Thus, this invention also provides pharmaceutical compositions, as well as methods, for preventing and treating disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, urinary tract disorders, gastrointestinal motility disorders and cardiovascular disorders, while avoiding unwanted systemic effects.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein
(a) Φ is a dihydropyridine ring-containing moiety, which moiety is bound to the carbonyl carbon of Formula (I) via a carbon atom in the meta position with respect to the pyridine ring nitrogen atom; and
(b) R 1 is selected from the group consisting of -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)OR′, -alkyl-aryl-C(O)OR′, -alkyl-OC(O)R′, -alkyl-C(O)R′, -alkyl-C(O)OR′, -alkyl-N(R″)C(O)R′, and -alkyl-N(R″)C(O)OR′, wherein
R I and R II are independently selected from the group consisting of hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO 2 , lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO 2 , alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C 1-4 carboalkoxy, alkylthio and/or trifluoromethyl).
2 . The compound of claim 1 , wherein R 1 is selected from the group consisting of -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl- or aryl-substituted cyclic carbonate, -aryl-C(O)OR′, -alkyl-aryl-C(O)OR′, -alkyl-C(O)R′, -alkyl-N(R″)C(O)R′ and -alkyl-N(R″)C(O)OR′.
3 . The compound of claim 2 , wherein R 1 is -alkyl-aryl-C(O)OR′ or -alkyl-N(R II )C(O)R I .
4 . The compound of claim 1 , wherein R 1 is -alkyl-OC(O)R′ or -alkyl-C(O)OR′.
5 . The compound of claim 1 , wherein R 1 is selected from the group consisting of —(CH 2 ) 2 OC(O)CH(CH 2 CH 3 ) 2 , —(CH 2 ) 2 OC(O)CH(CH 3 ) 2 , —(CH 2 ) 2 OC(O)PH—OCH(CH 3 ) 2 , —CH 2 OC(O)CH 2 N(CH 3 )CH 2 PH, —CH 2 OC(O)CH 2 —PH—N(CH 3 ) 2 , and —CH 2 OC(O)CH(CH 2 ) 6 .
6 . The compound of claim 1 having Formula (Ia), wherein
(a) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 );
(b) R 7 is connected to the bis-sulfone ring via a single or double bond, as applicable, and is selected from the group consisting of hydrogen, alkylhydroxy, alkenyl, amino, phenyl, benzyl, C 1-8 straight or branched alkyl, trifluoromethyl, alkoxymethyl, C 3-7 cycloalkyl, substituted benzyl, formyl, acetyl, t-butyloxy carbonyl, propionyl, substituted alkyl and R III CH 2 C═O, wherein (i) the substituted benzyl is substituted with halogen, trifluoromethyl, C 1-8 straight and/or branched alkyl or C 1-8 alkoxy, (ii) the substituted alkyl is substituted with amino, dialkyl amino, C 1-8 alkoxy, hydroxy and/or halogen, and (iii) R III is amino, dialkyl amino, C 1-8 alkoxy, hydroxy or halogen;
(c) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(d) m, n, and their sum are each an integer from 0 to 4.
7 . The compound of claim 6 wherein R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, and trifluoromethyl, R 7 is methylene or alkylhydroxy, m is 0, and n is 1.
8 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-ethyl-1-oxobutoxy)ethyl ester, 1,1,4,4-tetraoxide.
9 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1,4,4-tetraoxide.
10 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[[4-(1-methylethoxy)benzoyl]oxy]ethyl ester, 1,1,4,4-tetraoxide.
11 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(4-methyl-1-oxopentyl)oxy]ethyl ester, 1,1,4,4-tetraoxide.
12 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxo-3-phenylpropoxy)ethyl ester, 1,1,4,4-tetraoxide.
13 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(3-methyl-1-oxobutoxy)ethyl ester, 1,1,4,4-tetraoxide.
14 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cycloheptylcarbonyl)oxy]ethyl ester, 1,1,4,4-tetraoxide.
15 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(3-methoxybenzoyl)oxy]ethyl ester, 1,1,4,4-tetraoxide.
16 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 3-(benzoyloxy)propyl ester, 1,1,4,4-tetraoxide.
17 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[[(1,2,3,4-tetrahydro-2-naphthalenyl)carbonyl]oxy]ethyl ester, 1,1,4,4-tetraoxide.
18 . The compound of claim 6 which is 5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[[4-(trifluoromethyl)benzoyl]oxy]ethyl ester, 1,1,4,4-tetraoxide.
19 . The compound of claim 6 which is 2H,6H-[1,5]dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chloro-6-fluorophenyl)-3,4,7,10-tetrahydro-8-methyl-, 2-[[4-(1-methylethoxy)benzoyl]oxy]ethyl ester, 1,1,5,5-tetraoxide.
20 . The compound of claim 6 which is 2H,6H-[1,5]dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chloro-6-fluorophenyl)-3,4,7,10-tetrahydro-8-methyl-, 2-[(3-cyanobenzoyl)oxy]ethyl ester, 1,1,5,5-tetraoxide.
21 . The compound of claim 6 which is 2H,6H-[1,5]dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chloro-6-fluorophenyl)-3,4,7,10-tetrahydro-8-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 1,1,5,5-tetraoxide.
22 . The compound of claim 1 having Formula (Ib), wherein
(a) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 );
(b) R 7 is SO or SO 2 ; and
(c) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno.
23 . The compound of claim 22 , wherein R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, trifluoromethyl and NO 2 , and R 8 is methyl.
24 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(acetyloxy)ethyl ester, 5,5,10,10-tetraoxide.
25 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(benzoyloxy)ethyl ester, 5,5,10,10-tetraoxide.
26 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 5,5,10,10-tetraoxide.
27 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl ester, 5,5,10,10-tetraoxide.
28 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-aminoethyl ester, 5,5,10,10-tetraoxide.
29 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, tetrahydro-2-oxo-3-furanyl ester, 5,5,10,10-tetraoxide.
30 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(2,2-dimethyl-1-oxopropoxy)ethyl ester, 5,5,10,10-tetraoxide.
31 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(benzoylamino)ethyl ester, 5,5,10,10-tetraoxide.
32 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[[(2S)-2-(6-methoxy-2-naphthalenyl)-1-oxopropyl]oxy]ethyl ester, 5,5,10,10-tetraoxide.
33 . The compound of claim 22 which is 1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[[(2E)-1-oxo-3-phenyl-2-propenyl]oxy]ethyl ester, 5,5,10,10-tetraoxide.
34 . The compound of claim 1 having Formula (Ic), wherein
(a) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 ); and
(b) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno.
35 . The compound of claim 34 wherein R 8 is methyl and R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, trifluoromethyl and NO 2 .
36 . The compound of claim 1 having Formula (Id), wherein
(a) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 );
(b) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(c) R 9 is oxygen or sulfur.
37 . The compound of claim 36 wherein R 9 is oxygen.
38 . The compound of claim 37 wherein R 8 is methyl, and R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, trifluoromethyl and NO 2 .
39 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1,1-dioxide.
40 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, (2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl ester, 1,1-dioxide.
41 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-hydroxyethyl ester, 1,1-dioxide.
42 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1-dioxide.
43 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1-dioxide.
44 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cyclopropylcarbonyl)oxy]ethyl ester, 1,1-dioxide.
45 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(acetyloxy)ethyl ester, 1,1-dioxide.
46 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 1,1-dioxide.
47 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(benzoyloxy)ethyl ester, 1,1-dioxide.
48 . The compound of claim 36 which is 5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 3-(benzoyloxy)propyl ester, 1,1-dioxide.
49 . The compound of claim 1 having Formula (Ie), wherein
(a) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 ); and
(b) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno.
50 . The compound of claim 49 wherein R 8 is methyl and R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, trifluoromethyl and NO 2 .
51 . The compound of claim 1 having Formula (If), wherein
(a) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 );
(b) R 10 is selected from the group consisting of aryl, 3-pyridyl, 2-thieno and 3-thieno; and
(c) p is an integer from 1 to 5.
52 . The compound of claim 51 wherein p is 2.
53 . The compound of claim 51 wherein R 10 is selected from phenyl, 3-pyridyl, and 2-thieno.
54 . The compound of claim 51 wherein R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, OH, halogen, trifluoromethyl and NO 2 .
55 . The compound of claim 1 having Formula (Ig), wherein
(a) Z is N or CR 2 ;
(b) Y is N or CR 3 ;
(c) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 );
(d) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;
(e) R 11 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(f) R 12 is selected from hydrogen, -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)OR′, -alkyl-OC(O)R′, -alkyl-C(O)R′, -alkyl-C(O)OR′, -alkyl-N(R″)C(O)R′, -alkyl-N(R″)C(O)OR′, -alkyl-S—R′, alkyl, aryl-substituted alkyl, aryl, —(CH 2 ) 2 N(CH 3 )CH 2 PH, —CH 2 CH 2 —N(Me)—CH 2 -heteroaryl, 3-piperidyl, N-substituted 3-piperidyl, and N-substituted 2-pyrrolidinyl methylene, wherein
(i) R I and R II are independently selected from hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO 2 , lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO 2 , alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C 1-4 carboalkoxy, alkylthio and/or trifluoromethyl);
(ii) the alkyl may be substituted with alkoxy, C 2 -C 8 alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy, and/or NR IV R V , wherein
R IV and R V are independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl, or R IV and R V together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno and an N-substituted derivative of the heterocyclic rings (the N-substituted derivative being substituted with hydrogen, alkyl, benzyl, benzhydryl and/or phenyl optionally substituted with hydrogen, NO 2 , halogen, alkyl, alkoxy and/or trifluoromethyl); and
(iii) the N-substituted 3-piperidyl and the N-substituted 2-pyrrolidinyl methylene are optionally substituted with alkyl or benzyl.
56 . The compound of claim 55 , wherein R 12 is selected from hydrogen, alkyl, and aryl-substituted alkyl.
57 . The compound of claim 56 , wherein R 12 is selected from hydrogen, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH 2 —O—CH 3 , —CH 2 CH 2 —S—CH 3 , cyclopentane and benzyl.
58 . The compound of claim 55 , wherein Z is CR 2 .
59 . The compound of claim 55 , wherein Y is CR 3 .
60 . The compound of claim 55 which is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-(tetrahydro-2-oxo-3-furanyl) ester.
61 . The compound of claim 55 which is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-[2-(tetrahydro-2-oxo-3-furanyl)ethyl] ester.
62 . The compound of claim 55 which is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] ester.
63 . The compound of claim 55 which is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-[(2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl] ester.
64 . The compound of claim 1 having Formula (Ih), wherein
(a) Z is N or CR 2 ;
(b) Y is N or CR 3 ;
(c) R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, halogen, cyano, NO 2 , alkyl, C 1-8 alkoxy, C 1-8 alkylsulfonyl, C 1-4 carboalkoxy, C 1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R 2 and R 3 );
(d) R 8 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;
(e) R 11 is selected from the group consisting of hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(f) R 12 is selected from the group consisting of hydrogen, -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)OR′, -alkyl-OC(O)R′, -alkyl-C(O)R′, -alkyl-C(O)OR′, -alkyl-N(R″)C(O)R′, -alkyl-N(R″)C(O)OR′, -alkyl-S—R′, alkyl, aryl-substituted alkyl, aryl, —(CH 2 ) 2 N(CH 3 )CH 2 PH, —CH 2 CH 2 —N(Me)—CH 2 -heteroaryl, 3-piperidyl, N-substituted 3-piperidyl, and N-substituted 2-pyrrolidinyl methylene, wherein
(i) R I and R II are independently selected from hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO 2 , lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO 2 , alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C 1-4 carboalkoxy, alkylthio and/or trifluoromethyl);
(ii) the alkyl may be substituted with alkoxy, C 2 -C 8 alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy, and/or NR IV R V , wherein
R IV and R V are independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl, or R IV and R V together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno and an N-substituted derivative of the heterocyclic rings (the N-substituted derivative being substituted with hydrogen, alkyl, benzyl, benzhydryl and/or phenyl optionally substituted with hydrogen, NO 2 , halogen, alkyl, alkoxy and/or trifluoromethyl); and
(iii) the N-substituted 3-piperidyl and the N-substituted 2-pyrrolidinyl methylene are optionally substituted with alkyl or benzyl.
65 . The compound of claim 64 wherein R 12 is aryl.
66 . The compound of claim 65 wherein R 12 is phenyl.
67 . The compound of claim 64 wherein Z is CR 2 .
68 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
69 . A method of treating a subject suffering from a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a therapeutically effective dose of the pharmaceutical composition of claim 68 .
70 . A method of inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of claim 68 .
71 . The method of claim 69 or 70 , wherein the disorder is selected from hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, a gastrointestinal motility disorder and a cardiovascular disorder.
72 . The method of claim 69 or 70 , wherein the cells whose actions contribute to the disorder are lung cells.
73 . The method of claim 71 , wherein the disorder is asthma.
74 . The method of claim 73 , wherein the subject has normal or low blood pressure.
75 . An apparatus for administering to a subject the pharmaceutical composition of claim 68 , comprising a container and the pharmaceutical composition therein, whereby the container has a means for delivering to the subject a therapeutic and/or prophylactic dose of the pharmaceutical composition.
76 . A process for preparing the compound of claim 1 ,
which process comprises reacting the compound of Formula 1a
with R 1 Br or R 1 Cl in the presence of K 2 CO 3 or CsCO 3 in dimethyl-formamide to form the compound of Formula I.
77 . A process for preparing the compound of claim 1 ,
which process comprises converting the compound of Formula (2a)
to the compound of Formula I in the presence of formic acid.
78 . A process for preparing the compound of claim 1 ,
which process comprises converting the compound of Formula (2b)
to the compound of Formula I in the presence of aqueous NaOH.Join the waitlist — get patent alerts
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