USRE42132EExpiredUtility
Antitumoral D-homoestra-1,3,5(10)-trien-3-yl 2-substituted sulfamates

Assignee: STERIX LTDPriority: Feb 19, 2003Filed: Feb 19, 2004Granted: Feb 8, 2011
Est. expiryFeb 19, 2023(expired)· nominal 20-yr term from priority
Inventors:Alexander Hillisch Olaf Peters Christian Gege Gerhard Siemeister Eberhard Unger Bernd Menzenbach
A61P 43/00A61P 35/00C07J 63/00
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Claims
Abstract

This invention relates to 2-substituted D-homo-estra-1,3,5(10)-trien-3-yl sulfamates of general formula I (I), in which R3 means a C1-C5-alkyl or C1-C5-alkyloxy group as well as their use for the production of a pharmaceutical agent for treating tumor diseases, which can be influenced positively by the inhibition of tubulin polymerization. The compounds according to the invention are distinguished by a D-homo-substitution. They have a special action with respect to tubulin polymerization inhibition and can be used, for example, for treating prostate cancer
Claims

exact text as granted — not AI-modified
1. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate of formula I 
                 
 in which  
 R 1  and R 2  are, independently of one another, a hydrogen atom, a methyl group, a C 1 -C 4 -acyl group or a benzoyl group,  
 R 3  means a C 1 -C 5 -alkyl, a C 1 -C 5 -alkyloxy group or a radical —O—C n F m H o , wherein n=1, 2, 3, 4, 5 or 6, m&gt;1, and m+o=2n+1,  
 R 6  and R 7 , are, independently of one another, a hydrogen atom, a hydroxy group, an amino group or an NHR 8  group, wherein R 8  is an acetyl group, or  
 R 6  and R 7  together are an oxime NOH,  
 R 13  is a hydrogen atom or a methyl group,  
 R 19  is a hydrogen atom or a fluorine atom,  
 R 20  is a hydrogen atom or a fluorine atom or a hydroxy group or a C 1 -C 5 -alkyloxy group or C 1 -C 5 -alkyl group or a radical —C n F m H o , wherein n=1, 2, 3, 4, 5 or 6, m&gt;1 and m+o=2n+1, or a group SO 2 NR 1 R 2 , or  
 R 19  and R 20  together mean an oxygen atom, a methylene group, a difluoromethylene group or a monofluoromethylene group or an oxime NOR 21 , wherein R 21  is a hydrogen atom or a C 1 -C 5 -alkyl group,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
       2. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 3  represents a methyl, ethyl, methoxy, ethoxy or 2,2,2-trifluoroethoxy group. 
     
     
       3. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 2 , wherein R 3  represents a methoxy group. 
     
     
       4. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 6  and R 7  in each case represent a hydrogen atom. 
     
     
       5. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 19  represents a hydrogen atom. 
     
     
       6. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 20  represents a hydrogen atom or a hydroxy group. 
     
     
       7. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 1  represents a hydrogen atom. 
     
     
       8. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 2  represents a hydrogen atom or an acyl group. 
     
     
       9. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 , wherein R 13  represents a hydrogen atom or a methyl group. 
     
     
       10. A 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamateaccording to  claim 1  , which is
 1) 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 2) 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 3) 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 4) 2-Methoxy-17a-homoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 5) 2-Methoxy-6-oximino-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 6) 2-Methoxy-6-(O-methyloximino)-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 7) 6α-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 8) 6α-Acetylamino-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 9) 2-Methoxy-6-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 10) 17aα-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 11) 17aβ-Hydroxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 12) 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl bissulfamate  
 13) 2-Methoxy-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl bis-(N-acetyl)-sulfamate  
 14) 17a-Difluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 15) 17aα-Fluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 16) 17aβ-Fluoro-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 17) 2-Methoxy-17a-oximino-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 18) 2-Methoxy-17a-(methyloximino)-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 19) 2,17aβ-Dimethoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 20) 2,17aβ-Dimethoxy-17a-homoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 21) 17aβ-Ethoxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 22) 17aβ-Ethoxy-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 23) 2-Methoxy-17aβ-(n-propoxy)-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 24) 2-Methoxy-17aβ-methyl-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 25) 17aβ-Difluoromethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 26) 17aβ-Fluoromethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 27) 17aβ-Ethyl-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 28) 2-Methoxy-17a(20)-methylene-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 29) 17a(20)-Difluoromethylene-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 30) 17a(20)-Fluoromethylene-2-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 31) 2-Methoxy-17a-oxo-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 32) 2-Methoxy-17a-oxo-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 33) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 34) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 35) 2-Methoxy-6-oximino-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 36) 2-Methoxy-6-(O-methyloximino)-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 37) 6α-Hydroxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 38) 6α-Acetylamino-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 39) 17aβ-Hydroxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 40) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-triene-3,17aβ-diyl bissulfamate  
 41) 2-Methoxy-17a,18a-dihomoestra-1,3,5(10)-triene-3,17aβ-diyl bis-(N-acetyl)-sulfamate  
 42) 17a-Difluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 43) 17aα-Fluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 44) 17aβ-Fluoro-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 45) 2-Methoxy-17a-oximino-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 46) 2-Methoxy-17a-(methyloximino)-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 47) 2,17aβ-Dimethoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 48) 17aβ-Ethoxy-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 49) 2-Methoxy-17aβ-(n-propoxy)-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 50) 2-Methoxy-17aβ-methyl-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 51) 17aβ-Difluoromethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 52) 17aβ-Fluoromethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 53) 17aβ-Ethyl-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 54) 2-Methoxy-17a(20)-methylene-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 55) 17a(20)-Difluoromethylene-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 56) 17a(20)-Fluoromethylene-2-methoxy-17a,18a-dihomoestra-1,3,5(10)-trien-3-yl sulfamate  
 57) 2-Ethyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 58) 2-Ethyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 59) 2-Ethyl-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 60) 2-Ethyl-17a-homoestra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate  
 61) 2-Ethyl-17aβ-hydroxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate  
 62) 2-Ethyl-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl bissulfamate  
 63) 2-Ethyl-17a-homoestra-1,3,5(10)-triene-3,17aβ-diyl bis-(N-acetyl)-sulfamate  
 64) 2-Ethyl-17aβ-methoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate or  
 65) 2-Ethyl-17aβ-ethoxy-17a-homoestra-1,3,5(10)-trien-3-yl sulfamate.  
 
     
     
       11. A pharmaceutical composition comprising at least one compound of formula I according to  claim 1  and a pharmaceutically compatible carrier and optionally one or more additional active ingredients. 
     
     
       12. A method of preparing a pharmaceutical composition according to  claim 11 , comprising bringing together into a composition a 2-substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate and a pharmaceutically acceptable carrier. 
     
     
       13. A method for treating a tumor disease that can be positively influenced by the inhibition of tubulin polymerization, wherein said tumor disease is selected from the group consisting of breast cancer, prostate cancer, colon cancer, non-small-cell-lung cancer and primary dermal microvascular endothelial cell proliferation comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 . 
     
     
       14. A method according to  claim 13 , further comprising administering at least one additional active ingredient. 
     
     
       15. A method according to  claim 13 , wherein the disease treated is a disease of a male or female gonad, of a male or female sex organ, or of a mammary gland, that can be positively influenced by the inhibition of tubulin polymerization and wherein said disease is selected from the group consisting of breast cancer, prostate cancer, colon cancer, non-small-cell-lung cancer and primary dermal microvascular endothelial cell proliferation. 
     
     
       16. A method according to  claim 13 , which is for treating breast cancer. 
     
     
       17. A method according to  claim 13 , which is for treating prostate cancer. 
     
     
       18. A method according to  claim 13 , which is for treating colon cancer, non-small-cell-lung cancer, or primary dermal microvascular endothelial cell proliferation. 
     
     
       19. A method for treating breast cancer comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 . 
     
     
       20. A method for treating prostate cancer comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 . 
     
     
       21. A method for treating colon cancer comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 . 
     
     
       22. A method for treating non-small-cell-lung cancer comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 . 
     
     
       23. A method for treating primary dermal microvascular endothelial cell proliferation comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 1 . 
     
     
       24. A method for treating breast cancer, prostate cancer, colon cancer, non-small-cell-lung cancer, or primary dermal microvascular endothelial cell proliferation comprising administering to a subject in need thereof an effective amount of a 2-Substituted D-homoestra-1,3,5(10)-trien-3-yl sulfamate according to  claim 10 . 
     
     
       25. A  2 - Substituted D - homoestra -   1 , 3 , 5   (   10   )- trien -   3   - yl sulfamate according to    claim 1   , wherein R   20    is a hydrogen atom or a fluorine atom or a hydroxy group or C   1 - C   5 - alkyloxy group or a C   1 - C   5 - alkyl group or radical —C   n   F   m   H   o .
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