US2002103376A1PendingUtilityA1

Dithiepino[6,5-b]pyridines, and related compositions and methods

49
Priority: Jun 14, 1999Filed: May 7, 2001Published: Aug 1, 2002
Est. expiryJun 14, 2019(expired)· nominal 20-yr term from priority
Inventors:James BullingtonJohn H. DoddDaniel A. Hall
A61P 9/00A61P 9/10A61P 9/12A61P 37/08A61P 27/06A61P 13/00A61P 11/06A61P 15/00A61P 11/00A61P 13/02A61P 15/06A61P 1/06C07D 495/04
49
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

This invention provides novel dithiepino[6,5-b]pyridines of the following formulae. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstriction activity. 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.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A compound of Formula I,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 (a) R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of H, 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 1  and R 2 );  
 (b) R 6  is selected from the group consisting of H, C 1-5  straight or branched alkyl, aryl, 3-piperidyl, N-substituted 3-piperidyl, N-substituted 2-pyrrolidinyl methylene, and substituted alkyl, wherein 
 said N-substituted 3-piperidyl and said N-substituted 2-pyrrolidinyl methylene may be substituted with C 1-8  straight or branched chain alkyl or benzyl, and said substituted alkyl may be substituted with C 1-8  alkoxy, C 2-8  alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy or NR′R″, wherein  
 (i) R′ and R″ are independently selected from the group consisting of H, C 1-8  straight or branched alkyl, C 3-7  cycloalkyl, phenyl, benzyl, and phenethyl, or (ii) R′ and R″ 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 said heterocyclic rings, said N-substituted derivative being substituted with H, C 1-8  straight or branched alkyl, benzyl, benzhydryl, phenyl and/or substituted phenyl (substituted with NO 2 , halogen, C 1-8  straight or branched chain alkyl, C 1-8  alkoxy and/or trifluoromethyl;  
 
 (c) R 7  is selected from the group consisting of H, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;  
 (d) R 8  is connected to the bis-sulfone ring via a single or double bond, as applicable, and is selected from the group consisting of H, 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′″CH 2 C=O, wherein (i) said substituted benzyl is substituted with halogen, trifluoromethyl, C 1-8  straight and/or branched alkyl or C 1-8  alkoxy, (ii) said substituted alkyl is substituted with amino, dialkyl amino, C 1-8  alkoxy, hydroxy and/or halogen, and (iii) R′″ is amino, dialkyl amino, C 1-8  alkoxy, hydroxy or halogen; and  
 (e) m, n, and their sum are each an integer from 0 to 4.  
 
     
     
         2 . The compound of  claim 1 , wherein R 6  is —(CH 2 ) 2 N(CH 3 )CH 2 PH.  
     
     
         3 . The compound of  claim 1 , wherein R 6  is methyl.  
     
     
         4 . The compound of  claim 3 , wherein R 4  is CF 3 , R 5  is F, R 7  is methyl, R 8  is methylene, m is 0 and n is 1.  
     
     
         5 . The compound of  claim 3 , wherein R 4  is CF 3 , R 5  is F, R 7  is methyl, R 8  is alkylhydroxy, m is 0 and n is 1.  
     
     
         6 . The compound of  claim 1 , wherein R 7  is methyl.  
     
     
         7 . The compound of  claim 6 , wherein R 6  is —(CH 2 ) 2 N(CH 2 )CH 2 PH.  
     
     
         8 . The compound of  claim 6 , wherein R 4  is CF 3  and R 5  is F.  
     
     
         9 . The compound of  claim 6 , wherein R 5  is Cl.  
     
     
         10 . The compound of  claim 6  wherein R 1  is F and R 5  is Cl.  
     
     
         11 . The compound of  claim 11  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-[methyl(phenylmethyl )amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         12 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(3,4,5-trifluorophenyl )-2-[methyl (2-thienylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         13 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-6-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-7-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         14 . The compound of  claim 1  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-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide, (9R).  
     
     
         15 . The compound of  claim 1  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-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide, (9S).  
     
     
         16 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-hydroxyphenyl)-2,3,6,9-tetrahydro-7-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         17 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         18 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-3-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-7-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4- tetraoxide.  
     
     
         19 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl)-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         20 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(3,4,5-trifluorophenyl)-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         21 . The compound of  claim 1  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-methyl ester 1,1,4,4-tetraoxide.  
     
     
         22 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-5-nitrophenyl)-2,3,6,9-tetrahydro-7-methyl-methyl ester 1,1 ,4,4-tetraoxide.  
     
     
         23 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(pentafluorophenyl)-methyl ester 1,1,4,4-tetraoxide.  
     
     
         24 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,6-difluorophenyl)-2,3,6,9-tetrahydro-7-methyl-methyl ester 1,1,4,4-tetraoxide.  
     
     
         25 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-methyl ester 1,1,4,4-tetraoxide.  
     
     
         26 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-methyl ester 1,1,4,4-tetraoxide.  
     
     
         27 .The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-3-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-7-methyl-methyl ester 1,1,4,4-tetraoxide.  
     
     
         28 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2 ,3-difluorophenyl)-2,3,6,9-tetrahydro-7-methyl-methyl ester 1,1,4,4-tetraoxide.  
     
     
         29 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl)-methyl ester 1,1,4,4-tetraoxide.  
     
     
         30 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-3-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-7-methyl-3-methylene-methyl ester 1,1,4,4-tetraoxide.  
     
     
         31 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-3-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-7-methyl-3-methylene-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         32 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-3-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-3-(hydroxymethyl)-7-methyl-methyl ester 1,1,4,4-tetraoxide.  
     
     
         33 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-[2-fluoro-3-(trifluoromethyl)phenyl]-2,3,6,9-tetrahydro-3-(hydroxymethyl)-7-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         34 . The compound of  claim 1  which is: 5H-1,4-Dithiepino[6,5-b]pyridine-8-carboxylic acid, 2,3,6,9-tetrahydro-3-(hydroxymethyl )-7-methyl-9-(3-nitrophenyl)-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,4,4-tetraoxide.  
     
     
         35 . The compound of  claim 1  which is: 2H,6H-1,5-Dithiocino[3,2-b]pyridine-9-carboxylic acid, 3,4,7,10-tetrahydro-8-methyl-10-(3-nitrophenyl)-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,5,5-tetraoxide.  
     
     
         36 . The compound of  claim 1  which is: 2H,6H-1,5-Dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-[2-fluoro-6-(trifluoromethyl)phenyl]-3,4,7,10-tetrahydro-8-methyl-2-[methyl(phenyl methyl )amino]ethyl ester 1,1,5,5-tetraoxide.  
     
     
         37 . The compound of  claim 1  which is: 2H,6H-1,5-Dithiocino[3,2-b]pyridine-9-carboxylic acid, 3,4,7,10-tetrahydro-8-methyl-10-(pentafluorophenyl)-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,5,5-tetraoxide.  
     
     
         38 . The compound of  claim 1  which is: 2H,6H-1,5-Dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-[2-fluoro-3-(trifluoromethyl)phenyl]-3,4,7,10-tetrahydro-8-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,5,5-tetraoxide.  
     
     
         39 . The compound of  claim 1  which is: 2H,6H-1,5-Dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chlorophenyl)-3,4,7,10-tetrahydro-8-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,5,5-tetraoxide.  
     
     
         40 . The compound of  claim 1  which is: 2H,6H-1,5-Dithiocino[3,2-b]pyridine-9-carboxylic acid, 3,4,7,10-tetrahydro-8-methyl-10-(2-nitrophenyl)-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,5,5-tetraoxide.  
     
     
         41 . The compound of  claim 1  which is: 4H-1,3-Dithiino[5,4-b]pyridine-7-carboxylic acid, 8-[2-fluoro-3-(trifluoromethyl)phenyl]-5,8-dihydro-6-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,3,3-tetraoxide.  
     
     
         42 . The compound of  claim 1  which is: 4H-1,3-Dithiino[5,4-b]pyridine-7-carboxylic acid, 8-(2-chlorophenyl)-5,8-dihydro-6-methyl-2-[methyl(phenylmethyl)amino]ethyl ester 1,1,3,3-tetraoxide.  
     
     
         43 . A compound of Formula (II),  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 (a) R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of H, 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 1  and R 2 );  
 (b) R 7  is selected from the group consisting of H, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;  
 (c) R 8  is connected to the bis-sulfone ring via a single or double bond, as applicable, and is selected from the group consisting of H, 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′″CH 2 C=O, wherein (i) said substituted benzyl is substituted with halogen, trifluoromethyl, C 1-8  straight and/or branched alkyl or C 1-8  alkoxy, (ii) said substituted alkyl is substituted with amino, dialkyl amino, C 1-8  alkoxy, hydroxy and/or halogen, and (iii) R′″ is amino, dialkyl amino, C 1-8  alkoxy, hydroxy or halogen;  
 (d) R 9  is selected from -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′ and R″ 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);  
 
 (e) m, n, and their sum are each an integer from 0 to 4; and  
 (f) p is an integer from 0 to 4.  
 
     
     
         44 . The compound of  claim 43 , wherein R 9  is -aryl-alkyl—OC(O)R′.  
     
     
         45 . The compound of  claim 43 , wherein R 9  is -alkyl—N(R″)C(O)R′.  
     
     
         46 . The compound of  claim 45  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-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl ester, 1,1,4,4-tetraoxide.  
     
     
         47 . The compound of  claim 43 , wherein R 9  is -alkyl—OC(O)R′.  
     
     
         48 . The compound of  claim 47  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.  
     
     
         49 . The compound of  claim 47  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.  
     
     
         50 . The compound of  claim 47  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.  
     
     
         51 . The compound of  claim 47  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.  
     
     
         52 . The compound of  claim 47  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.  
     
     
         53 . A pharmaceutical composition comprising the compound of  claim 1  or  43  and a pharmaceutically acceptable carrier.  
     
     
         54 . 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 53 .  
     
     
         55 . 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 53 .  
     
     
         56 . The method of  claim 54  or  55 , wherein the disorder is selected from the group consisting of hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, a gastrointestinal motility disorder and a cardiovascular disorder.  
     
     
         57 . The method of  claim 56 , wherein the disorder is asthma.  
     
     
         58 . The method of  claim 56 , wherein the cardiovascular disorder is selected from the group consisting of hypertension, ischemia, angina, congestive heart failure, myocardial infarction and stroke.  
     
     
         59 . An apparatus for administering to a subject the pharmaceutical composition of  claim 53 , 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.  
     
     
         60 . A process for preparing the compound of  claim 1   
       
         
           
           
               
               
           
         
       
       wherein m, n, and their sum are each an integer from 1 to 4, which process comprises the steps of 
 (a) reacting the compound of Formula 1a with the compound of Formula 1b  
                     
 to form the compound of Formula 1c;  
                     
 (b) reacting the compound of Formula 1c with m-chloroperoxybenzoic acid to form the compound of Formula 1d; and  
                     
 (c) reacting the compound of Formula 1d with the compounds of Formulae 1e and 1f  
                     
 to form the compound of  claim 1 .  
 
     
     
         61 . The process of claim  60 , wherein R 8  of the compound of Formula I is a methylene group formed from a methylol group using a dehydrating agent.  
     
     
         62 . A process of preparing the compound of  claim 43 ,  
       
         
           
           
               
               
           
         
       
       which process comprises the steps of 
 (a) reacting the compound of Formula 3a′ with formic acid to form the compound of Formula 3b′; and  
                     
 (b) reacting the compound of Formula 3b with R 9 Br or R 9 Cl to form the compound of  claim 43 .  
 
     
     
         63 . The process of claim  62 , wherein R 7  is methyl.

Join the waitlist — get patent alerts

Track US2002103376A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.