Oxindole derivatives carrying an oxetane substituent and use thereof for treating vasopressin-related diseases

Abstract

The present invention relates to novel substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-related disorders.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         X 1  and X 2  are N or CH, with the proviso that X 1  and X 2  are not simultaneously N; 
         X 3  is a bond, C 1 -C 4 -alkylene, C 1 -C 4 -haloalkylene or CO; 
         X 4  is N or CH; 
         X 5  is C—R 1  or N; 
         R 1 , R 2  and R 3 , independently of each other, are selected from hydrogen, halogen, cyano, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy; 
         R 4  is selected from C 1 -C 3 -alkoxy; 
         R 5  is selected from hydrogen and C 1 -C 3 -alkoxy; 
         R 6  is selected from cyano and halogen; 
         R 7  is selected from hydrogen, halogen and cyano; 
         R 8  and R 9 , independently of each other and independently of each occurrence, are selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, with the proviso that R 8  and R 9  are not halogen, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy if they are bound to a carbon atom in α-position to a nitrogen ring atom; or
 two non-geminal radicals R 8  form together a group —(CH 2 ) n —, where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced a methyl group; or 
 two non-geminal radicals R 9  form together a group —(CH 2 ) n —, where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced a methyl group; 
 
         each R 10  is independently selected from halogen, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; 
         a is 0, 1, 2, 3 or 4; 
         b is 0, 1, 2, 3 or 4; and 
         c is 0, 1, 2, 3 or 4; 
         and the N-oxides, stereoisomers and pharmaceutically acceptable salts thereof, and the compound of the formula I, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope. 
       
     
     
         2 . The compound as claimed in  claim 1 , wherein at least one hydrogen atom has been replaced by a deuterium atom. 
     
     
         3 . The compound as claimed in any of  claims 1  or  2 , where R 1 , R 2  and R 3 , independently of each other, are selected from hydrogen, fluorine, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy. 
     
     
         4 . The compound as claimed in  claim 3 , where R 1 , R 2  and R 3 , independently of each other, are selected from hydrogen, fluorine, cyano, methyl and methoxy. 
     
     
         5 . The compound as claimed in  claim 4 , where R 1  is selected from hydrogen, fluorine, methyl and methoxy. 
     
     
         6 . The compound as claimed in any of  claims 4  or  5 , where R 2  is selected from hydrogen, cyano and methoxy. 
     
     
         7 . The compound as claimed in any of  claims 4  to  6 , where R 3  is selected from hydrogen, fluorine and methyl. 
     
     
         8 . The compound as claimed in any of the preceding claims, where R 4  is selected from methoxy and ethoxy. 
     
     
         9 . The compound as claimed in any of the preceding claims, where R 5  is hydrogen or methoxy, preferably hydrogen. 
     
     
         10 . The compound as claimed in any of the preceding claims, where R 6  is selected from cyano, fluorine and chlorine. 
     
     
         11 . The compound as claimed in any of the preceding claims, where R 7  is selected from hydrogen and fluorine. 
     
     
         12 . The compound as claimed in any of the preceding claims, where each R 8  is independently selected from halogen and C 1 -C 4 -alkyl, preferably from F, Cl and CH 3 , with the proviso that R 8  is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom, or two non-geminal radicals R 8  form together a group —CH 2 —. 
     
     
         13 . The compound as claimed in any of the preceding claims, where each R 9  is independently selected from halogen and C 1 -C 4 -alkyl, preferably from F, Cl and CH 3 , with the proviso that R 9  is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom, or two non-geminal radicals R 9  form together a group —CH 2 —. 
     
     
         14 . The compound as claimed in  claim 13 , where two non-geminal radicals R 9  form together a group —CH 2 —. 
     
     
         15 . The compound as claimed in  claim 14 , where the two non-geminal radicals R 9  forming together a group —CH 2 — are bound in 2- and 5-position, relative to the 1-position of X 2 . 
     
     
         16 . The compound as claimed in any of the preceding claims, where each R 10  is independently selected from halogen and C 1 -C 4 -alkyl, preferably from F, Cl and CH 3 . 
     
     
         17 . The compound as claimed in any of the preceding claims, where X 3  is a bond or CH 2 . 
     
     
         18 . The compound as claimed in  claim 17 , where X 3  is a bond. 
     
     
         19 . The compound as claimed in any of the preceding claims, where X 4  is N. 
     
     
         20 . The compound as claimed in any of  claims 1  to  18 , where X 4  is CH. 
     
     
         21 . The compound as claimed in any of the preceding claims, where X 5  is C—R 1 . 
     
     
         22 . The compound as claimed in any of  claims 1  to  20 , where X 5  is N. 
     
     
         23 . The compound as claimed in any of the preceding claims, where a is 0, 1 or 2, preferably 0. 
     
     
         24 . The compound as claimed in any of the preceding claims, where b is 0, 1 or 2, preferably 0 or 2. 
     
     
         25 . The compound as claimed in any of the preceding claims, where c is 0, 1 or 2, preferably 0. 
     
     
         26 . The compound as claimed in  claim 1 , selected from
 (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;   N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide;   (S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;   (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;   (S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;   N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide;   N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-((1 S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxamide;   (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxy-2,3-dimethylphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide;   (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)piperazine-1-carboxamide;   and the N-oxides, stereoisomers or pharmaceutically acceptable salts thereof.   
     
     
         27 . A pharmaceutical composition comprising at least one compound of the formula I as defined in any of the preceding claims and/or an N-oxide, a stereoisomer or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 
     
     
         28 . The compound as claimed in any of  claims 1  to  26 , for use as a medicament. 
     
     
         29 . The compound as claimed in any of  claims 1  to  26 , for the treatment and/or prophylaxis of vasopressin-related diseases. 
     
     
         30 . The use of compounds of the formula I as defined in any of  claims 1  to  26  or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-related diseases. 
     
     
         31 . The use of compounds of the formula I as defined in any of  claims 1  to  26  or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur,
 hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, impairments of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, impairments of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, travel sickness; 
 affective disorders; 
 anxiety disorders and stress-dependent anxiety disorders; 
 memory and cognitive impairments such as Alzheimer's disease, mild cognitive impairment and cognitive impairment associated with schizophrenia; 
 psychoses and psychotic disorders; 
 Cushing's syndrome and other stress-dependent diseases; 
 sleep disorders; 
 depressive disorders, such as major depression, seasonal depression, bipolar disorders, treatment-resistant depression, dysthymic disorders or childhood onset mood disorders; 
 vasomotor symptoms, thermoregulatory dysfunctions; 
 drug or pharmaceutical dependencies, dependencies mediated by other factors; 
 stress caused by withdrawal of one or more factors mediating the dependence; 
 stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors; drug-use disorders; 
 schizophrenia and psychosis; 
 and/or for delaying micturition. 
 
     
     
         32 . A method for treating disorders defined as in any of  claims 30  or  31 , in which an effective amount of at least one compound of the formula I as defined in any of  claims 1  to  26  or of at least one N-oxide, stereoisomer or pharmaceutically acceptable salt thereof or of a pharmaceutical composition as claimed in  claim 27  is administered to a patient.