6-Aminomorphinane Derivatives, Method for the Production and Use Thereof

Abstract

This invention relates to compounds of the formula (I).

1 . A compound of formula (I), 
     
       
         
         
             
             
         
       
     
     in which the substituents have the following meaning:
 R 1  is hydrogen; C 1 -C 6 -alkyl; C 2 -C 6 -alkenyl; C 2 -C 6 -alkinyl; C 1 -C 6 -monohydroxyalkyl; C 2 -C 6 -dihydroxyalkyl; C 3 -C 6 -trihydroxyalkyl; C 4 -C 16 -cycloalkylalkyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkyl is C 1 -C 6 -alkyl; C 5 -C 16 -cycloalkylalkenyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkenyl is C 2 -C 6 -alkenyl; C 5 -C 16 -cycloalkylalkinyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkinyl is C 2 -C 6 -alkinyl; C 7 -C 16 -arylalkyl, where aryl is C 6 -C 10 -aryl and alkyl is C 1 -C 6 -alkyl; C 8 -C 16 -arylalkenyl, where aryl is C 6 -C 10 -aryl and alkenyl is C 2 -C 6 -alkenyl; or C 8 -C 16 -arylalkinyl, where aryl is C 6 -C 10 -aryl and alkinyl is C 2 -C 6 -alkinyl; 
 the nitrogen joined with R 1  can also be quarternised by two substituents R 1 , which can be the same or different and which are defined as previously shown, and whereby the second, quarternised substituent can additionally have the meaning hydroxyl, oxyl (N oxide) as well as alkoxyl; 
 R 2  is hydrogen; C 1 -C 6 -alkyl; C 1 -C 6 -monohydroxyalkyl; C 2 -C 6 -dihydroxyalkyl; C 3 -C 6 -trihydroxyalkyl; C 2 -C 6 -alkenyl; C 2 -C 6 -alkinyl; C 4 -C 16 -cycloalkylalkyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkyl is C 1 -C 6 -alkyl; C 5 -C 16 -cycloalkylalkenyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkenyl is C 2 -C 6 -alkenyl; C 5 -C 16 -cycloalkylalkinyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkinyl is C 2 -C 6 -alkinyl; C 7 -C 11 -arylalkyl, where aryl is C 6 -C 10 -aryl and alkyl is C 1 -C 6 -alkyl; C 8 -C 11 -arylalkenyl, where aryl is C 6 -C 10 -aryl and alkenyl is C 2 -C 6 -alkenyl; C 8 -C 16 -arylalkinyl, where aryl is C 6 -C 10 -aryl and alkinyl is C 2 -C 6 -alkinyl; C 2 -C 6 -alkanoyl; C 3 -C 6 -alkenoyl; C 3 -C 6 -alkinoyl; C 7 -C 16 -arylalkanoyl, where aryl is C 6 -C 10 -aryl and alkanoyl is C 1 -C 6 -alkanoyl; C 9 -C 16 -arylalkenoyl, where aryl is C 6 -C 10 -aryl and alkenoyl is C 3 -C 6 -alkenoyl; or C 9 -C 16 -arylalkinoyl, where aryl is C 6 -C 10 -aryl and alkinoyl is C 3 -C 6 -alkinoyl; 
 R 3  is hydrogen; C 1 -C 6 -alkyl; C 2 -C 6 -alkenyl; C 7 -C 16 -arylalkyl, where aryl is C 6 -C 10 -aryl and alkyl is C 1 -C 6 -alkyl; C 8 -C 16 -arylalkenyl, where aryl is C 6 -C 10 -aryl and alkenyl is C 2 -C 6 -alkenyl; alkoxyalkyl, where alkoxy is C 1 -C 6 -alkoxy and alkyl is C 1 -C 10 -alkyl; CO 2 (C 1 -C 6 -alkyl); CO 2 H; or CH 2 OH; 
 R 4  is hydrogen; C(N-boc)(NH-boc); C 1 -C 6 -alkyl; C 2 -C 10 -alkenyl; C 2 -C 6 -alkinyl; C 4 -C 16 -cycloalkylalkyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkyl is C 1 -C 8 -alkyl; C 5 -C 16 -cycloalkylalkenyl, where cycloalkyl is C 3 -C 16 -cycloalkyl and alkenyl is C 2 -C 6 -alkenyl; C 5 -C 16 -cycloalkylalkinyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkinyl is C 2 -C 6 -alkinyl; C 7 -C 1 -arylalkyl, where aryl is C 6 -C 10 -aryl and alkyl is C 1 -C 10 -alkyl; C 8 -C 16 -arylalkenyl, where aryl is C 6 -C 10 -aryl and alkenyl is C 2 -C 6 -alkenyl; C 8 -C 16 -arylalkinyl, where aryl is C 6 -C 10 -aryl and alkinyl is C 2 -C 6 -alkinyl; C 2 -C 6 -alkanoyl; C 3 -C 6 -alkenoyl; C 3 -C 6 -alkinoyl; C 7 -C 16 -arylalkanoyl, where aryl is C 6 -C 10 -aryl and alkanoyl is C 1 -C 6 -alkanoyl; C 9 -C 16 -arylalkenoyl, where aryl is C 6 -C 10 -aryl and alkenoyl is C 3 -C 6 -alkenoyl; C 9 -C 16 -arylalkinoyl, where aryl is C 6 -C 10 -aryl and alkinoyl is C 3 -C 6 -alkinoyl; iminomethyl, formamidinyl, C 1 -C 6 -N-alkyl- and N,N′-dialkylformamidinyl; C 2 -C 6 -N-alkenyl- and N,N′-dialkenylformamidinyl; C 2 -C 6 -N-alkinyl- and N,N′-dialkinylformamidinyl; C 4 -C 16 -N-cycloalkylalkyl- and N,N′-dicycloalkylalkylformamidinyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkyl is C 1 -C 6 -alkyl; C 5 -C 16 -N-cylcoalkylalkenyl- and N,N′-dicycloalkylalkenylformamidinyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkenyl is C 2 -C 6 -alkenyl; C 5 -C 16 -N-cycloalkylalkinyl- and N,N′-dicycloalkylalkinylformamidinyl, where cycloalkyl is C 3 -C 10 -cycloalkyl and alkinyl is C 2 -C 6 -alkinyl; or C 7 -C 16 -N-arylalkyl- and N,N′-diarylalkylformamidinyl, where aryl is C 6 -C 10 -aryl and alkyl is C 1 -C 6 -alkyl; 
 R 5  and R 6  are independently selected from the group consisting of hydrogen, CH 2 COOC(CH 3 ) 3 , CH 2 COOH, CH(CH 3 )COOC(CH 3 ), CH(CH 3 )COOH, CH(CH 2 Ph)COOC(CH 3 ) 3 , CH(CH 2 Ph)COOH, C(NH)NH 2  and C(N-boc)(NH-boc); 
 X is oxygen; and 
 Y is oxygen; 
 and a pharmaceutically acceptable acid addition salt of the compound. 
 
   
   
       2 . The compound of  claim 1 , wherein R 1  is C 1 -C 6 -alkyl or C 4 -C 16 -cycloalkylalkyl. 
   
   
       3 . The compound of  claim 2 , wherein R 1  is methyl, ethyl or cycloalkyl. 
   
   
       4 . The compound of  claim 2 , wherein R 1  is cyclopropylmethyl. 
   
   
       5 . The compound of  claim 1 , wherein R 2  is C 1 -C 8 -alkyl. 
   
   
       6 . The compound of  claim 5 , wherein R 2  is methyl, ethyl or propyl. 
   
   
       7 . The compound of  claim 1 , wherein R 3  and R 4  are, independently, hydrogen or C 1 -C 6 -alkyl. 
   
   
       8 . The compound of  claim 7 , wherein the C 1 -C 6 -alkyl is methyl. 
   
   
       9 . The compound of  claim 1 , wherein R 4  is C(N-boc)(NH-boc). 
   
   
       10 . The compound of  claim 1 , wherein R 6  is hydrogen and R 5  is selected from the group consisting of CH 2 COOC(CH 3 ) 3 , CH 2 COOH, CH(CH 3 )COOC(CH 3 ), CH(CH 3 )COOH, CH(CH 2 Ph)COOC(CH 3 ) 3 , CH(CH 2 Ph)COOH, C(NH)NH 2  and C(N-boc)(NH-boc). 
   
   
       11 . The compound of  claim 1 , wherein R 5  and R 6  are (i) hydrogen and (ii) one of C(NH)NH 2  and C(N-boc)(NH-boc), wherein (i) if R 5  is hydrogen, R 6  is C(NH)NH 2  or C(N-boc)(NH-boc), and (ii) if R 6  is hydrogen, R 5  is C(NH)NH 2  or C(N-boc)(NH-boc) 
   
   
       12 . The compound of  claim 11 , wherein R 6  is hydrogen and R 5  is C(NH)NH 2  or C(N-boc)(NH-boc). 
   
   
       13 . The compound of  claim 1 , selected from the group consisting of (i) 4,5α-epoxy-6β-[N,N′-bis-(tert.-butoxycarbonyl)guanidinyl]-14β-methoxy-17-methylmorphinan-3-ol, (ii) 4,5α-epoxy-6β-guanidinyl-14β-methoxy-17-methylmorphinan-3-ol, and (iii) 4,5α-epoxy-6α-[N,N′-bis-(tert.-butoxycarbonyl)guanidinyl]-14β-methoxy-17-methylmorphinan-3-ol. 
   
   
       14 . The compound of  claim 1 , wherein the pharmaceutically acceptable acid addition salt is selected from the group consisting of a hydrochloride, a hydrobromide, a sulphate, a phosphate, a tetrafluoroborate, an acetate, a tartrate, a lactate, a benzoate, a stearate, a pamoate, a methane sulphonate, a salicylate, a fumarate, a maleinate, a succinate, an aspartate, a citrate, an oxalate, a trifluoroacetate and an orotate. 
   
   
       15 . A composition comprising a compound of  claim 1  or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier substance. 
   
   
       16 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier substance. 
   
   
       17 . A method for the treatment of pain comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 . 
   
   
       18 . A method for the treatment of intestinal disease comprising administering to a subject afflicted with intestinal disease an effective amount of a compound according to  claim 1 . 
   
   
       19 . The method according to  claim 18  wherein the intestinal disease is selected from the group consisting of chronic inflammation of the small and large intestines, diarrhea and obstipation. 
   
   
       20 . The method according to  claim 19  wherein the chronic inflammation results in irritable colon syndrome. 
   
   
       21 . A method for the treatment of rheumatic disease comprising administering to a subject afflicted with rheumatic disease an effective amount of a compound according to  claim 1 . 
   
   
       22 . The method according to  claim 21  wherein the rheumatic disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, arthrosis, spondylosis, lumbago, lupus erythematosus and spondylarthropathy. 
   
   
       23 . A method for the treatment of tumors and cancer comprising administering to a subject afflicted with a tumor or cancer an effective amount of a compound according to  claim 1 . 
   
   
       24 . A method for the treatment of obesity comprising administering to an obese subject an effective amount of a compound according to  claim 1 . 
   
   
       25 . A method for suppressing the rejection of transplants comprising administering to a transplant donor or recipient an effective amount of a compound according to  claim 1 . 
   
   
       26 . A method of preventing or treating intestinal obstruction (ileus) comprising administering to a subject afflicted with intestinal obstruction (ileus) an effective amount of a compound according to  claim 1 . 
   
   
       27 . A method for the treatment of the withdrawal of drug addiction comprising administering to a subject withdrawing from drug addiction an effective amount of a compound according to  claim 1 . 
   
   
       28 . The method according to  claim 27  wherein the addiction is to opiates, cocaine or alcohol. 
   
   
       29 . A method for the treatment of a psychiatric disease comprising administering to a subject afflicted with a psychiatric disease an effective amount of a compound according to  claim 1 .