WO1985002177A1 - Halo bicyclo alkanones - Google Patents
Halo bicyclo alkanones Download PDFInfo
- Publication number
- WO1985002177A1 WO1985002177A1 PCT/US1984/001819 US8401819W WO8502177A1 WO 1985002177 A1 WO1985002177 A1 WO 1985002177A1 US 8401819 W US8401819 W US 8401819W WO 8502177 A1 WO8502177 A1 WO 8502177A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bicyclo
- dichloro
- exo
- heptan
- ether
- Prior art date
Links
- 125000001475 halogen functional group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 230000005764 inhibitory process Effects 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 125000005188 oxoalkyl group Chemical group 0.000 claims abstract 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims description 35
- VUYGPKBLCUWASV-UHFFFAOYSA-N 7,7-dichloro-4-(5-hydroxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical compound CCC(O)CCCCC1CCC2C(Cl)(Cl)C(=O)C12 VUYGPKBLCUWASV-UHFFFAOYSA-N 0.000 claims description 8
- JLRSEZNMECHORC-UHFFFAOYSA-N 7,7-dichloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical compound CCC(OC)CCCCC1CCC2C(Cl)(Cl)C(=O)C12 JLRSEZNMECHORC-UHFFFAOYSA-N 0.000 claims description 6
- CVGJUDLBSJEZBV-UHFFFAOYSA-N 7,7-dichloro-4-(5-oxoheptyl)bicyclo[3.2.0]heptan-6-one Chemical compound CCC(=O)CCCCC1CCC2C(Cl)(Cl)C(=O)C12 CVGJUDLBSJEZBV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- -1 hydroxy, methoxy, ethoxy Chemical group 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000012267 brine Substances 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HNHDVERBMSYLPY-UHFFFAOYSA-N 3-(5-methoxyheptyl)cyclopentene Chemical compound CCC(OC)CCCCC1CCC=C1 HNHDVERBMSYLPY-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 4
- 238000005695 dehalogenation reaction Methods 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000003822 preparative gas chromatography Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZDOCBSNRIWPBQW-UHFFFAOYSA-N 3,3-dichloro-6-(5-methoxyheptyl)-1,3a,4,5,6,6a-hexahydropentalen-2-one Chemical class C1C(=O)C(Cl)(Cl)C2C1C(CCCCC(CC)OC)CC2 ZDOCBSNRIWPBQW-UHFFFAOYSA-N 0.000 description 3
- JLNCBXIPQWXDHX-UHFFFAOYSA-N 6,6-dichloro-4-(5-hydroxyheptyl)bicyclo[3.2.0]heptan-7-one Chemical class CCC(O)CCCCC1CCC2C(=O)C(Cl)(Cl)C12 JLNCBXIPQWXDHX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910001115 Zinc-copper couple Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- VFDMCQVWSAENIU-UHFFFAOYSA-N 2,2,2-tribromoacetyl bromide Chemical compound BrC(=O)C(Br)(Br)Br VFDMCQVWSAENIU-UHFFFAOYSA-N 0.000 description 2
- IKKJHPGBHKMIFM-UHFFFAOYSA-N 2,2-dibromoethenone Chemical compound BrC(Br)=C=O IKKJHPGBHKMIFM-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- AZPWOLJQERBBBM-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetyl chloride Chemical compound FC(F)(Cl)C(Cl)=O AZPWOLJQERBBBM-UHFFFAOYSA-N 0.000 description 2
- BBKCAZJNOVFUEV-UHFFFAOYSA-N 6,6-dichloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-7-one Chemical compound CCC(OC)CCCCC1CCC2C(=O)C(Cl)(Cl)C12 BBKCAZJNOVFUEV-UHFFFAOYSA-N 0.000 description 2
- FOAIRILLANNOFE-UHFFFAOYSA-N 7,7-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCOC(CC)CCCCC1CCC2C(Cl)(Cl)C(=O)C12 FOAIRILLANNOFE-UHFFFAOYSA-N 0.000 description 2
- 241000972773 Aulopiformes Species 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- FFKZOUIEAHOBHW-UHFFFAOYSA-N N,4-dimethyl-N-nitrosobenzenesulfonamide Chemical compound O=NN(C)S(=O)(=O)C1=CC=C(C)C=C1 FFKZOUIEAHOBHW-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- XADFSXKNPLLSDY-UHFFFAOYSA-N bicyclo[3.2.0]heptan-6-one Chemical class C1CCC2C(=O)CC21 XADFSXKNPLLSDY-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000000979 retarding effect Effects 0.000 description 2
- 235000019515 salmon Nutrition 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical class C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 description 1
- QMBWLYLSCICOLD-UHFFFAOYSA-N 1-chloro-5-ethoxyheptane Chemical compound CCOC(CC)CCCCCl QMBWLYLSCICOLD-UHFFFAOYSA-N 0.000 description 1
- DZOJCPMYHAEOGE-UHFFFAOYSA-N 1-chloro-5-methoxyheptane Chemical compound CCC(OC)CCCCCl DZOJCPMYHAEOGE-UHFFFAOYSA-N 0.000 description 1
- TVWWMKZMZALOFP-UHFFFAOYSA-N 2,2-dichloroethenone Chemical compound ClC(Cl)=C=O TVWWMKZMZALOFP-UHFFFAOYSA-N 0.000 description 1
- OTTXCOAOKOEENK-UHFFFAOYSA-N 2,2-difluoroethenone Chemical compound FC(F)=C=O OTTXCOAOKOEENK-UHFFFAOYSA-N 0.000 description 1
- IKOKHHBZFDFMJW-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(2-morpholin-4-ylethoxy)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCCN1CCOCC1 IKOKHHBZFDFMJW-UHFFFAOYSA-N 0.000 description 1
- OAWAZQITIZDJRB-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)Cl OAWAZQITIZDJRB-UHFFFAOYSA-N 0.000 description 1
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 1
- KKTWCFKDIACBJB-UHFFFAOYSA-N 3,3-dichloro-4-(5-hydroxyheptyl)-2-methyl-1,3a,4,5,6,6a-hexahydropentalen-2-ol Chemical class C1C(C)(O)C(Cl)(Cl)C2C(CCCCC(O)CC)CCC21 KKTWCFKDIACBJB-UHFFFAOYSA-N 0.000 description 1
- QMOCPCDPTJGMBT-UHFFFAOYSA-N 3,3-dichloro-4-(5-methoxyheptyl)-1,3a,4,5,6,6a-hexahydropentalen-2-one Chemical class C1C(=O)C(Cl)(Cl)C2C(CCCCC(CC)OC)CCC21 QMOCPCDPTJGMBT-UHFFFAOYSA-N 0.000 description 1
- JNKUXNFGBDNAFQ-UHFFFAOYSA-N 3,3-dichloro-4-(5-methoxyheptyl)-2-methyl-1,3a,4,5,6,6a-hexahydropentalen-2-ol Chemical class C1C(C)(O)C(Cl)(Cl)C2C(CCCCC(CC)OC)CCC21 JNKUXNFGBDNAFQ-UHFFFAOYSA-N 0.000 description 1
- AYACZNDAPQPAGJ-UHFFFAOYSA-N 3,3-dichloro-6-(5-ethoxyheptyl)-1,3a,4,5,6,6a-hexahydropentalen-2-one Chemical compound C1C(=O)C(Cl)(Cl)C2C1C(CCCCC(CC)OCC)CC2 AYACZNDAPQPAGJ-UHFFFAOYSA-N 0.000 description 1
- BISUCIUWHNLXHV-UHFFFAOYSA-N 3,3-dichloro-6-(5-hydroxyheptyl)-1,3a,4,5,6,6a-hexahydropentalen-2-one Chemical compound C1C(=O)C(Cl)(Cl)C2C1C(CCCCC(O)CC)CC2 BISUCIUWHNLXHV-UHFFFAOYSA-N 0.000 description 1
- WJFNGSJFMUWHOH-UHFFFAOYSA-N 3,3-dichloro-6-(5-hydroxyheptyl)-2-methyl-1,3a,4,5,6,6a-hexahydropentalen-2-ol Chemical class C1C(C)(O)C(Cl)(Cl)C2C1C(CCCCC(O)CC)CC2 WJFNGSJFMUWHOH-UHFFFAOYSA-N 0.000 description 1
- NGPDAGLZRXEUEH-UHFFFAOYSA-N 3,3-dichloro-6-(5-methoxyheptyl)-2,3a,4,5,6,6a-hexahydro-1h-pentalen-2-ol Chemical compound C1C(O)C(Cl)(Cl)C2C1C(CCCCC(CC)OC)CC2 NGPDAGLZRXEUEH-UHFFFAOYSA-N 0.000 description 1
- HVQULWIUVZZUTG-UHFFFAOYSA-N 3,3-dichloro-6-(5-methoxyheptyl)-2-methyl-1,3a,4,5,6,6a-hexahydropentalen-2-ol Chemical class C1C(C)(O)C(Cl)(Cl)C2C1C(CCCCC(CC)OC)CC2 HVQULWIUVZZUTG-UHFFFAOYSA-N 0.000 description 1
- HLHNOIAOWQFNGW-UHFFFAOYSA-N 3-bromo-4-hydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C=C1Br HLHNOIAOWQFNGW-UHFFFAOYSA-N 0.000 description 1
- LPSWJRSLXCPGBK-UHFFFAOYSA-N 3-chlorocyclopentene Chemical compound ClC1CCC=C1 LPSWJRSLXCPGBK-UHFFFAOYSA-N 0.000 description 1
- LQHMQGDIJRFYLV-UHFFFAOYSA-N 4-(5-ethoxyheptyl)-3,3a,4,5,6,6a-hexahydro-1h-pentalen-2-one Chemical compound C1C(=O)CC2C(CCCCC(CC)OCC)CCC21 LQHMQGDIJRFYLV-UHFFFAOYSA-N 0.000 description 1
- QJZSFNBYKFCWDK-UHFFFAOYSA-N 4-(5-methoxyheptyl)-1,2,3,3a,4,5,6,6a-octahydropentalen-2-ol Chemical compound C1C(O)CC2C(CCCCC(CC)OC)CCC21 QJZSFNBYKFCWDK-UHFFFAOYSA-N 0.000 description 1
- GMGBTXHWVCBYHC-UHFFFAOYSA-N 4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical compound CCC(OC)CCCCC1CCC2CC(=O)C12 GMGBTXHWVCBYHC-UHFFFAOYSA-N 0.000 description 1
- FXCZTRBXAGFKNV-UHFFFAOYSA-N 4-[5-[tert-butyl(dimethyl)silyl]oxypentyl]-7,7-dichlorobicyclo[3.2.0]heptan-6-one Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC1CCC2C(Cl)(Cl)C(=O)C12 FXCZTRBXAGFKNV-UHFFFAOYSA-N 0.000 description 1
- DCBJCKDOZLTTDW-UHFFFAOYSA-N 5-chloropentan-1-ol Chemical compound OCCCCCCl DCBJCKDOZLTTDW-UHFFFAOYSA-N 0.000 description 1
- JJTPNKNATNOUNE-UHFFFAOYSA-N 6,6-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-7-one Chemical class CCOC(CC)CCCCC1CCC2C(=O)C(Cl)(Cl)C12 JJTPNKNATNOUNE-UHFFFAOYSA-N 0.000 description 1
- BWXGAVRHZSGHBZ-UHFFFAOYSA-N 6,6-dichloro-4-(5-hydroxypentyl)bicyclo[3.2.0]heptan-7-one Chemical compound OCCCCCC1CCC2C(=O)C(Cl)(Cl)C12 BWXGAVRHZSGHBZ-UHFFFAOYSA-N 0.000 description 1
- YZMNRBLUZFGVSF-UHFFFAOYSA-N 6,6-dichloro-4-(5-methoxyheptan-2-yl)bicyclo[3.2.0]heptan-7-one Chemical compound CCC(OC)CCC(C)C1CCC2C(=O)C(Cl)(Cl)C12 YZMNRBLUZFGVSF-UHFFFAOYSA-N 0.000 description 1
- YDVZLMBVXPCMLI-UHFFFAOYSA-N 6,6-dichloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-7-ol Chemical compound CCC(OC)CCCCC1CCC2C(O)C(Cl)(Cl)C12 YDVZLMBVXPCMLI-UHFFFAOYSA-N 0.000 description 1
- PAJVFYCRUXQMFV-UHFFFAOYSA-N 6,6-dichloro-4-(5-oxoheptyl)bicyclo[3.2.0]heptan-7-one Chemical class CCC(=O)CCCCC1CCC2C(=O)C(Cl)(Cl)C12 PAJVFYCRUXQMFV-UHFFFAOYSA-N 0.000 description 1
- YQBDQFKWUPABNM-UHFFFAOYSA-N 7,7-dibromo-2-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCC(OC)CCCCC1CCC2C(=O)C(Br)(Br)C12 YQBDQFKWUPABNM-UHFFFAOYSA-N 0.000 description 1
- VIANRSRCHYHJQF-UHFFFAOYSA-N 7,7-dibromo-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCC(OC)CCCCC1CCC2C(Br)(Br)C(=O)C12 VIANRSRCHYHJQF-UHFFFAOYSA-N 0.000 description 1
- CYODKNTZRGLPNT-UHFFFAOYSA-N 7,7-dichloro-4-(5-hydroxyheptyl)bicyclo[3.2.0]heptan-6-ol Chemical compound CCC(O)CCCCC1CCC2C(Cl)(Cl)C(O)C12 CYODKNTZRGLPNT-UHFFFAOYSA-N 0.000 description 1
- RWEZRBCESGZEBF-UHFFFAOYSA-N 7,7-dichloro-4-(5-hydroxypentyl)bicyclo[3.2.0]heptan-6-one Chemical compound OCCCCCC1CCC2C(Cl)(Cl)C(=O)C12 RWEZRBCESGZEBF-UHFFFAOYSA-N 0.000 description 1
- PHFRIMRCUPKUJS-UHFFFAOYSA-N 7,7-dichloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-ol Chemical compound CCC(OC)CCCCC1CCC2C(Cl)(Cl)C(O)C12 PHFRIMRCUPKUJS-UHFFFAOYSA-N 0.000 description 1
- QQFAGRMDZZWVKH-UHFFFAOYSA-N 7,7-difluoro-2-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCC(OC)CCCCC1CCC2C(=O)C(F)(F)C12 QQFAGRMDZZWVKH-UHFFFAOYSA-N 0.000 description 1
- UVYGEZUWVZVKGV-UHFFFAOYSA-N 7,7-difluoro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCC(OC)CCCCC1CCC2C(F)(F)C(=O)C12 UVYGEZUWVZVKGV-UHFFFAOYSA-N 0.000 description 1
- JRSPLTAUIGJBCW-UHFFFAOYSA-N 7-chloro-2-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCC(OC)CCCCC1CCC2C(=O)C(Cl)C12 JRSPLTAUIGJBCW-UHFFFAOYSA-N 0.000 description 1
- DLOHPPBMWUVMFK-UHFFFAOYSA-N 7-chloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one Chemical class CCC(OC)CCCCC1CCC2C(Cl)C(=O)C12 DLOHPPBMWUVMFK-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101100129500 Caenorhabditis elegans max-2 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 201000000274 Carcinosarcoma Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 238000011111 UV-scan method Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 206010068168 androgenetic alopecia Diseases 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AWYMFBJJKFTCFO-UHFFFAOYSA-N bicyclo[3.2.0]heptane Chemical class C1CCC2CCC21 AWYMFBJJKFTCFO-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000003965 capillary gas chromatography Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- KDULJHFMZBRAHO-UHFFFAOYSA-N cioteronel Chemical compound C1C(=O)CC2C(CCCCC(CC)OC)CCC21 KDULJHFMZBRAHO-UHFFFAOYSA-N 0.000 description 1
- 238000009643 clonogenic assay Methods 0.000 description 1
- 231100000096 clonogenic assay Toxicity 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 150000001941 cyclopentenes Chemical class 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentenylidene Natural products C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QCOOHQTVMCSOJC-UHFFFAOYSA-N tert-butyl-(5-cyclopent-2-en-1-ylpentoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC1CCC=C1 QCOOHQTVMCSOJC-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/38—Acyl halides
- C07C53/40—Acetyl halides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/04—Saturated ethers
- C07C43/13—Saturated ethers containing hydroxy or O-metal groups
- C07C43/137—Saturated ethers containing hydroxy or O-metal groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/162—Unsaturated ethers containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/457—Saturated compounds containing a keto group being part of a ring containing halogen
- C07C49/467—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic
- C07C49/473—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic a keto group being part of a condensed ring system
- C07C49/477—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic a keto group being part of a condensed ring system having two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/487—Saturated compounds containing a keto group being part of a ring containing hydroxy groups
- C07C49/507—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic
- C07C49/513—Saturated compounds containing a keto group being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/517—Saturated compounds containing a keto group being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to a novel treatment of tumors, to halogenated bicyclo (3.2.0) heptane and bicyclo (3.3.0) octane derivatives and to compositions containing such derivatives useful for treatment of cancer. More specifically, this invention relates to the use in retarding and inhibiting development of tumors of a compound of the formula
- M 1 is halogen
- M 2 is halogen or hydrogen
- p is zero or one and one of the groups X and X' is hydrogen and the other is a group A.
- That group A is an alkyl group of two to nine carbon atoms with one substituent of the class consisting of hydroxy, methoxy, ethoxy and oxo groups.
- the alkyl groups can be ethyl, straight-chained and branched propyl, butyl, pentyl, hexyl, heptyl, octyl and nonyl containing such hydroxy, methoxy, ethoxy and oxo sub-stituents.
- Especially useful have been found such A groups as 5-hydroxyheptyl, 5-methoxyheptyl, 5-oxoheptyl, 5-hydroxy-5-methylheptyl and 5-hydroxy-5-ethylheptyl.
- Dihaloketene typically used for generation can be a compound M 1 M 2 CH-CO-Halogen, such as dichloroacetyl chloride, and a dehydrohalogenator, e.g. an amine such as triethylamine.
- the dihaloketene can also be generated from a trihaloacetyl halide by dehalogenation, e.g. using zinc activated with copper. This dihaloketene addition leads to formation of a mixture of isomers, in which the predominant one is the 2-A substituted 6-halogenated bicyclo (3.2.0) heptan-7-one of the formula
- silica gel can be packed in a column using a standard slurry method or a dry packed column can be used.
- a solvent mixture of a non-polar and more polar solvent is used.
- the non-polar solvent is typically an alkane such as pentane, hexane, heptane or the corresponding cycloalkane.
- the more polar solvent can be an ether, an alkyl alkanoate such as ethyl acetate, an alkanol such as methanol or ethanol or a haloalkane such as dichloromethane or chloroform. Isolation of the 7, 7-dihaloheptan-6-ones and 8,8-dihalooctan-7-ones and the endo isomers has been carried out using high performance liquid chromatography.
- Compounds of this invention and especially the 6-exo isomers can be used in pharmaceutical compositions for retarding and inhibiting the development of mammalian tumors. These compounds have a high degree of biological activity, displaying especially excellent utility in their capacity to selectively inhibit development of cancer cells. Special utility has been found in cancers known to be influenced by steroids. Cancer inhibition has been specifically demonstrated in a wide variety of cancers including those of breast, lung, kidney and colon. A convenient bioassay for evaluation of this activity, in which these compounds show excellent results, is the Salmon clonogenic assay, Cancer Res.
- compositions can be effectively administered topically in inert carriers suitable for that purpose, e.g. such alcohols as ethanol and 2-propanol, in salves, ointments, suspensions and emulsions. It has been observed that the compounds of this invention, on topical administration, increase elastin and decrease collagen, in that respect producing an effect resembling that of estrogens.
- Oral dosage unit formulations include tablets, capsules and other conventional oral forms. As a tablet the compounds are typically present in an amount of from about 1 to about 50% by weight, with the inert carrier constituting the remainder of the tablet. Tablets are compressed in a conventional manner, with typically one percent magnesium stearate being included in the mixture to be tabletted. Liquid oral dosage unit formulations may also be used in which the compounds are incorporated into vehicles conventionally used for lipid soluble compounds.
- Capsules can employ the oily product, preferably diluted with an inert carrier.
- the high potency of the 6-exo compounds permits relatively low dosages both systemically via oral or suppository route or through topical (transdermal) application.
- a concentration of the compounds of from about 0.01 to 5 percent by weight of the composition is useful.
- Topical application on an infrequent basis, including a sustained release delivery, may indicate a relatively higher amount of the compounds, preferably in the range of from about 0.05 to about 3 percent by weight.
- a relatively lower concentration of the compounds is indicated where a relatively larger surface area is treated.
- the compound is indicated for systemic delivery, oral, injection, suppository and sublingual forms may be used.
- the compound is administered as an oral dosage unit form, such as a tablet, capsule, powder or other traditional dosage unit form.
- the oral dosage unit form is a tablet which contains a relatively small amount of the compounds.
- a single oral dosage unit formulation when administered as one oral dosage unit formulation several times per day, generally up to about four times per day, will for a adult male of average weight comprise an amount of about 0.01 to about 40 mg per oral dosage unit form, and preferably from about 0.01 to about 2 mg per oral dosage unit form.
- the compounds of formula I are valuable chemical intermediates.
- Dehalogenation i.e. conversion of both the M 1 and M 2 groups to hydrogen, e.g. with zinc, yields potent anti-androgens useful in treatment of acne, keloids and male pattern baldness.
- Magnesium metal turnings (7.2 gm, 0.299 moles) are added to a three-neck, round-bottom flask equipped with a Friedrich condenser and kept under nitrogen gas. Tetrahydrofuran (300 ml) is transferred to the flask and the contents stirred. A clear, colorless solution of 1-chloro-5-methoxyheptane (48.1 gm, 0.292 moles) is added portionwise and refluxed. The final third portion is added and the mixture stirred for 3 hours. The dark yellow solution is cooled to -25°C, the condenser is removed and replaced with a dry ice addition funnel.
- the ether phase is washed with solutions of saturated sodium thiosulfate (75 ml) and brine (100 ml) .
- the solvent is removed under vacuum leaving a clear, light yellow oil.
- the crude product contains a mixture of the starting material, the desired alcohols and by-products. This mixture is applied to a chromatography column using a 4:1 hexane-ether mixture and eluted with 4:1 hexane-ether.
- Vacuum distillation at 0.5 mm pressure and about 130 °C yields a mixture of the exo- and endo-isomers of 6, 6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo (3.2.0.)heptan-7-one and 7, 7-dichloro-2-(5-hydroxyhept-1-yl) bicyclo-(3.2.0.)heptan-6-one.
- Example 2 The product obtained by the dichloroketene reaction with 3- (5-methoxyhept-1-yl) cyclopentene in Example 1 yields a product containing 2 different structural isomers in addition to the endo and exo forms.
- Both gas chromatography and high performance liquid chromatography confirm the presence of the three principal isomers in this group of 4 isomers.
- the fourth isomer appears to be present in a quantity less than 1%.
- Identification and separation of the three principal isomers can be accomplished by use of a Beckman high performance liquid chromatograph equipped with a 165 variable wavelength detector.
- a Beckman 15cm C-18 column with 5 micron packing was used for all analytical determinations.
- a 60:40 acetonitrile:water solution is used with a flow rate of 1 ml/min.
- the detector has wavelength scanning capabilities making it possible to determine the lambda maximum of these isomers. All three major peaks detected by the system had identical UV scans from 200-350 lambda with a lambda max 1 of 213 nm and a lambda max 2 of 319 nm, consistent with a carbonyl group.
- acetonitrile 1.5 ml of acetonitrile.
- a 60:40 acetonitrile:water solvent system is used with a flowrate of 20 ml/min.
- the detector monitors the samples at 210 and 318 nm.
- a total of 80 tubes (10 ml each) was collected and the samples were analyzed for the desired isomers by capillary gas chromatography. The appropriate tubes were then pooled together and the acetonitrile removed under vacuum.
- exo 6 , 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0)heptan-7-one can also be obtained from the mixture of exo and endo 6,6-dichloro and 7,7-dichloro isomers by applying the crude mixture directly on a flash chromatography column (e.g. 2.5 cm diameter, 200-430 mesh) and eluting with a 6:1 hexane-ether (v/v) solution,
- the resonance at 3.8 is due to the proton HA, coupled to the proton HB giving a doublet (8Hz) .
- a large coupling constant is due to the bridgehead protons, HA and HB.
- the resonance at 3.53 is ascribed to HD, the methine proton on the aliphatic chain.
- the proton HB is coupled to HA and largely one of the protons, HE. Based on molecular models it is most likely that the bond angle of HB and HF (endo) is close to 90o and therefore the coupling constant is very small compared to HE (exo).
- Example 2 In the initial Grignard reaction of Example 1, 52.2 gm of 1-chloro-5-ethoxyheptane are substituted for the 5-methoxy homolog and the reaction sequence is conducted as in Example 1. The resulting oily mixture is distilled at about 125 °C and about 0.5 mm pressure. Infrared absorption maxima are observed at 2970, 2934, 2869, 1805, 1462, 1370, 1343, 1224, 1158, 1106, 1081, 1030, 976, 969, 845, 816, 742 and 674 cm -1 . Separation of the isomers is conducted by the method of Example 3 to yield mainly the exo 6,6-dichloro-2- (5-ethoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one.
- a solution of 5 gm of the isomers obtained in Example 1 in 100 ml of ether is transferred to a 500 ml round bottom glass flask.
- Excess diazomethane is generated from 60 gm of p-tolylsulfonylmethylnitrosamide by reacting with potassium hydroxide in methanol. The reaction is allowed to proceed for 50 minutes after which glacial acetic acid is added portionwise to destroy the excess diazomethane.
- the solution is extracted with ether and dried over sodium sulphate. The solvent is removed under vacuum, leaving an orange oil.
- This oil is applied to a silica gel chromatography column; elution with a 4:1 mixture of hexane and ether and evaporation of the solvent yields the product as a clear liquid.
- Infrared maxima are observed at 2959, 2934, 2873, 2858, 2820, 1768, 1462, 1404, 1379, 1366, 1193, 1145, 1094, 923, 897, 778, 713, 663, 656, and 652 cm -1 .
- Example 2 6 gm of the mixture of isomers obtained in Example 1 are added to a 400 ml ether solution of diazomethane, generated from 45 gm of p-tolylsulfonylmethylnitrosamide.
- Example 8 Exo- and endo- isomers of 6 ,6-dichloro-2- (5-oxohept-1- yl) bicyclo (3.2.0) heptan-7-one and 7,7-dichloro-2- (5-oxohept-1-yl) bicyclo [3.2.0] heptan-6-one.
- a dry 100 ml 3-necked flask is heated and allowed to cool under nitrogen after which there is first added 2.3 gm of the mixture of isomers obtained in Example 2 followed by 17 ml of dichloromethane. To the stirred reaction mixture there is added 6.4 gm of pyridinium dichromate in a single portion. After 3 hours ether
- Example 2 To a dry 100 ml 3-necked round bottom flask under nitrogen, equipped with a pressure equalizing dropping funnel, thermometer, and a magnetic stirrer, there is added the mixture of isomers obtained in Example 1 (5 gm) and a catalytic amount (5 mg) of 2,2'-azobisisobutyronitrile. To the stirring solution there is added dropwise tri-n-butyltin hydride (4.7 gm) . The reaction mixture is maintained below 40° C in a water bath. After the addition is complete the reaction mixture is stirred at 30° C until a test of aliquot indicates the disappearance of the hydride, typically after about 3 hours.
- the ether extracts are combined, dried over sodium sulfate, and the volume is reduced under vacuum leaving crude 6 , 6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]-pent-1-yl) bicyclo (3.2.0) heptan-7-one.
- the oil is kugelrohred under vacuum and subsequently chromatographed on silica gel using a 4:1 hexane: ether (v/v) solvent system.
- the fractions are pooled, as (determined by VPC and IR) and the solvent reduced under vaccum leaving a clear colorless oil.
- a solution of 18.1 gm of this product in 100 ml acetonitrile containing 5% of a 40% aqueous solution of hydrofluoric acid is stirred for 2 hours at room temperature, after which the reaction is partitioned between 200 ml water and 200 ml chloroform.
- the aqueous phase is separated and extracted with 3 portions of 50 ml of chloroform.
- the organic phase is washed with 75 ml of brine, dried over sodium sulphate and the volume is reduced under vacuum leaving a crude product.
- the material is chromatographed on silica gel by using 2:1 hexane:ether (v/v) solvent system.
- Example 11 Exo- and endo- isomers of 6 , 6-dibromo-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7 ,7-dibromo-2- (5-methoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one.
- the excess dibromoketene and phosphorus oxychloride are destroyed by the dropwise addition of water.
- the crude product is filtered and the filtrate is washed with 100 ml brine and a saturated solution of 100 ml sodium bicarbonate until the pH reaches 7.
- the organic phase is washed again with 100 ml brine and dried over sodium sulfate.
- the solvent is removed under vacuum leaving a brown liquid.
- the material is kugelrohred under vacuum and subsequently chromatographed on silica gel with 4:1 hexane: ether (v/v) as the elution solvent.
- the fraction is pooled (as determined by vapor phase chromatography) and the solvent removed under vacuum leaving a clear oil.
- Example 12 Exo- and endo- isomers of 6 , 6-difluoro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7 ,7-difluoro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0]heptan-6-one.
- To a 250 ml 3-necked flask are added 50 gm of chlorodifluoroacetic acid. The flask is cooled in an ice bath and stirred while 116.7 gm of phosphorus tribromide are slowly added in the course of 5 minutes. After completion of the reaction and subsequent refluxing for 2 hours, the chlorodifluoroacetyl chloride is distilled into an ice-cooled receiver as a colorless liquid.
- Zinc-copper catalyst (3 gm) is added to a stirred solution of 6 ,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo- (3.2.0)heptan-7-one (2 gm, 6 moles) in acetic acid (100 ml) under a nitrogen atmosphere.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A pharmaceutical composition for inhibition of tumors containing an effective dose of a compound of formula (I), wherein Q is CO, CH(OH) or C(OH)CH3, M1 is halogen, M2 is halogen or hydrogen, p is 0 or 1 and one of the groups x and x' is hydrogen and the other is a hydroxyalkyl, methoxyalkyl, ethoxyalkyl or oxoalkyl wherein the alkyl contains 2-9 carbon atoms, the group x preferably being in the exo position.
Description
HALO BICYCLO ALKANONES The present invention relates to a novel treatment of tumors, to halogenated bicyclo (3.2.0) heptane and bicyclo (3.3.0) octane derivatives and to compositions containing such derivatives useful for treatment of cancer. More specifically, this invention relates to the use in retarding and inhibiting development of tumors of a compound of the formula
wherein Q is C=O, CHOH or C(OH)CH3, M1 is halogen, M2 is halogen or hydrogen, p is zero or one and one of the groups X and X' is hydrogen and the other is a group A.
That group A is an alkyl group of two to nine carbon atoms with one substituent of the class consisting of hydroxy, methoxy, ethoxy and oxo groups. The alkyl groups can be ethyl, straight-chained and branched propyl, butyl, pentyl, hexyl, heptyl, octyl and nonyl containing such hydroxy, methoxy, ethoxy and oxo sub-stituents. Especially useful have been found such A groups as 5-hydroxyheptyl, 5-methoxyheptyl, 5-oxoheptyl, 5-hydroxy-5-methylheptyl and 5-hydroxy-5-ethylheptyl.
The compounds of the invention in which p is zero are conveniently prepared from a suitably A-substituted cyclopentene of the formula
by heating with a dihaloketene of the formula M1M2C=CO generating reagent. Dihaloketene typically used for generation can be a compound M1M2CH-CO-Halogen, such as dichloroacetyl chloride, and a dehydrohalogenator, e.g. an amine such as triethylamine. The dihaloketene can also be generated from a trihaloacetyl halide by dehalogenation, e.g. using zinc activated with copper. This dihaloketene addition leads to formation of a mixture of isomers, in which the predominant one is the 2-A substituted 6-halogenated bicyclo (3.2.0) heptan-7-one of the formula
in the exo form of that compound, as determined by nuclear magnetic resonance. Exo compounds of type II are also preferred as anti-tumor agents. The second most frequent isomer in that mixture is the exo form of the 2-A substituted 7-halogenated bicyclo-(3.2.0)heptan-6-one of the formula
Also obtained, though in smaller amount, are the endo isomers, the A group being in the endo position.
Separation of these isomers can be accomplished by chromatographic separation. Conventional chromatography columns can be used employing silica or alumina to isolate the exo 6,6-dihalo isomers. Thus, silica gel can be packed in a column using a standard slurry method or a dry packed column can be used. A solvent mixture of a non-polar and more polar solvent is used. The non-polar solvent is typically an alkane such as pentane, hexane, heptane or the corresponding cycloalkane. The more polar solvent can be an ether, an alkyl alkanoate such as ethyl acetate, an alkanol such as methanol or ethanol or a haloalkane such as dichloromethane or chloroform. Isolation of the 7, 7-dihaloheptan-6-ones and 8,8-dihalooctan-7-ones and the endo isomers has been carried out using high performance liquid chromatography.
The foregoing bicyclo (3.2.0) heptanes (p=0) , can be converted to the bicyclo (3.3.0) octanes (p=1) by reaction with diazomethane.
Compounds of this invention and especially the 6-exo isomers, can be used in pharmaceutical compositions for retarding and inhibiting the development of mammalian tumors. These compounds have a high degree of biological activity, displaying especially excellent utility in their capacity to selectively inhibit development of cancer cells. Special utility has been found in cancers known to be influenced by steroids. Cancer inhibition has been specifically demonstrated in a wide variety of cancers including those of breast, lung, kidney and colon. A convenient bioassay for evaluation of this activity, in which these compounds show excellent results, is the Salmon clonogenic assay, Cancer Res.
Reports, 65 , p. 1, 1981, in which compounds at the levels as low as 0.001 mcg/ml cause selective destruction of tumor cells.
These compositions can be effectively administered topically in inert carriers suitable for that purpose, e.g. such alcohols as ethanol and 2-propanol, in salves, ointments, suspensions and emulsions. It has been observed that the compounds of this invention, on topical administration, increase elastin and decrease collagen, in that respect producing an effect resembling that of estrogens.
While topical application of compositions containing these compounds constitutes one embodiment of the invention, other routes for pharmaceutical administration are also contemplated, particularly the oral and suppository routes. Oral dosage unit formulations include tablets, capsules and other conventional oral forms. As a tablet the compounds are typically present in an amount of from about 1 to about 50% by weight, with the inert carrier constituting the remainder of the tablet. Tablets are compressed in a conventional manner, with typically one percent magnesium stearate being included in the mixture to be tabletted. Liquid oral dosage unit formulations may also be used in which the compounds are incorporated into vehicles conventionally used for lipid soluble compounds. Suppositories with the compounds are also contemplated, to provide a rectal suppository administration of the drug and which form takes advantage of the usual suppository ingredients. Capsules can employ the oily product, preferably diluted with an inert carrier.
The high potency of the 6-exo compounds permits relatively low dosages both systemically via oral or suppository route or through topical (transdermal) application. A concentration of the compounds of from about 0.01 to 5 percent by weight of the composition is useful. Topical application on an infrequent basis, including a sustained release delivery, may indicate a relatively higher amount of the compounds, preferably in the range of from about 0.05 to about 3 percent by
weight. A relatively lower concentration of the compounds is indicated where a relatively larger surface area is treated.
Where the compound is indicated for systemic delivery, oral, injection, suppository and sublingual forms may be used. Preferably the compound is administered as an oral dosage unit form, such as a tablet, capsule, powder or other traditional dosage unit form. In a preferred embodiment, the oral dosage unit form is a tablet which contains a relatively small amount of the compounds. A single oral dosage unit formulation, when administered as one oral dosage unit formulation several times per day, generally up to about four times per day, will for a adult male of average weight comprise an amount of about 0.01 to about 40 mg per oral dosage unit form, and preferably from about 0.01 to about 2 mg per oral dosage unit form.
It is to be understood that the extremely small amount of the compound necessary means as a practical matter that a tablet of the usual size will have only a very small percentage of the compound, with the remainder comprising pharmaceutically inert ingredients or fillers such as talcum, maize starch, polyvinyl pyrrolidone and lactose, together with a small amount of a tabletting agent such as magnesium stearate.
The compounds of formula I are valuable chemical intermediates. Dehalogenation, i.e. conversion of both the M 1 and M2 groups to hydrogen, e.g. with zinc, yields potent anti-androgens useful in treatment of acne, keloids and male pattern baldness.
The following examples illustrate the invention:
Example 1 Exo- and endo- isomers of 6, 6-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heρtan-7-one and 7,7-dichloro-2- ( 5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-6-one.
Magnesium metal turnings (7.2 gm, 0.299 moles) are added to a three-neck, round-bottom flask equipped with a
Friedrich condenser and kept under nitrogen gas. Tetrahydrofuran (300 ml) is transferred to the flask and the contents stirred. A clear, colorless solution of 1-chloro-5-methoxyheptane (48.1 gm, 0.292 moles) is added portionwise and refluxed. The final third portion is added and the mixture stirred for 3 hours. The dark yellow solution is cooled to -25°C, the condenser is removed and replaced with a dry ice addition funnel. A clear solution of 3-chlorocyclopentene (29.9 gm, 0.292 moles) is added over one hour. Water is added, followed by hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with ether. The combined organic solutions are dried over sodium sulphate. The solvent is removed under vacuum and the crude product is then purified by fractional distillation, yielding 3- (5-methoxyhept-1-yl) cyclopentene as a clear, colorless oil, (b.p. about 54°C/0.1 mm).
To a 1,000 ml three-neck, round-bottom flask, equipped with a reflux condenser containing 3- (5-methoxyhept-1-yl) cyclopentene (15.0 gm, 0.076 moles) in 300 ml of hexane, freshly distilled dichloroacetyl chloride (35.1 gm, 0.240 moles) is added and the solution is stirred by a mechanical stirrer and heated to reflux. Triethylamine (25.2 gm, 0.249 moles), dissolved in 200 ml hexane, is added dropwise and the refluxing solution allowed to stir for 4 hours. The solvent is removed and then the residue is distilled and applied to a silica gel chromatography column of 2.5 cm diameter in a 4:1 hexane-ether solvent mixture. The product is eluted using a 4:1 hexane-ether solvent system. The fractions are monitored using vapor phase chromatography. The solvent is removed under vacuum. There are thus obtained mainly 6, 6-dichloro-2-(5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and a smaller amount of 7,7-dichloro-2- (5-methoxyhept-2-yl) bicyclo- (3.2.0) heptan-6-one, both mainly in the exo form.
Infrared analysis shows maxima at 2963, 2932, 2864, 2857, 2820, 1803, 1461, 1378, 1223, 1197, 1157, 1093, 1030,
968, 914, 842, 821, 802, 778, 740, and 673 cm-1. Substitution of C 14-labeled dichloroacetyl chloride yields the C 14-labeled isomers of the 6,6-dichloro and
7,7-dichloro derivatives above.
Example 2
Exo- and endo-isomers of 6, 6-dichloro-2-(5-hydroxyhept- 1-yl) bicyclo (3.2.0) heptan-7-one and 7, 7-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) heptan-6-one.
To a solution of acetonitrile (140 ml) containing a mixture of the isomers of dichloro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0.]heptanones (30.6 gm) obtained as in Example 1 is added sodium iodide (31.4 g) and trimethylsilyl chloride (11.4 g moles). The solution is stirred under an inert atmosphere for four hours after which time 50 ml water is added until the solution changes to a clear red color. The mixture is extracted with diethyl ether (150 ml) and the aqueous phase is discarded. The ether phase is washed with solutions of saturated sodium thiosulfate (75 ml) and brine (100 ml) . The solvent is removed under vacuum leaving a clear, light yellow oil. The crude product contains a mixture of the starting material, the desired alcohols and by-products. This mixture is applied to a chromatography column using a 4:1 hexane-ether mixture and eluted with 4:1 hexane-ether. Vacuum distillation at 0.5 mm pressure and about 130 °C yields a mixture of the exo- and endo-isomers of 6, 6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo (3.2.0.)heptan-7-one and 7, 7-dichloro-2-(5-hydroxyhept-1-yl) bicyclo-(3.2.0.)heptan-6-one. Infrared absorption maxima are observed at 3584, 3534, 3389, 3377, 2959, 2934, 2871, 2856, 1804, 1462, 1409, 1378, 1337, 1317, 1301, 1279, 1252, 1250, 1245, 1180, 1159, 1134, 1119, 1090, 1031, 965, 923, 896, 864, 811, 779, 742 and 676 cm-1.
Example 3 Separation of isomers
The product obtained by the dichloroketene reaction with 3- (5-methoxyhept-1-yl) cyclopentene in Example 1 yields a product containing 2 different structural isomers in addition to the endo and exo forms. The reaction of this isomeric product with trimethylsilyl iodide according to Example 2 forms a demethoxylated product which also contains the same group of isomers. Both gas chromatography and high performance liquid chromatography confirm the presence of the three principal isomers in this group of 4 isomers. The fourth isomer appears to be present in a quantity less than 1%.
Identification and separation of the three principal isomers can be accomplished by use of a Beckman high performance liquid chromatograph equipped with a 165 variable wavelength detector. A Beckman 15cm C-18 column with 5 micron packing was used for all analytical determinations. A 60:40 acetonitrile:water solution is used with a flow rate of 1 ml/min. The detector has wavelength scanning capabilities making it possible to determine the lambda maximum of these isomers. All three major peaks detected by the system had identical UV scans from 200-350 lambda with a lambda max 1 of 213 nm and a lambda max 2 of 319 nm, consistent with a carbonyl group.
Separation of the isomers is accomplished using a
Whatman Magnum 20 column with 50 micron packing of C-18.
A 0.5 gm sample of the isomeric mixture is dissolved in
1.5 ml of acetonitrile. A 60:40 acetonitrile:water solvent system is used with a flowrate of 20 ml/min. The detector monitors the samples at 210 and 318 nm. A total of 80 tubes (10 ml each) was collected and the samples were analyzed for the desired isomers by capillary gas chromatography. The appropriate tubes were then pooled together and the acetonitrile removed under vacuum. The aqueous phase was extracted with ether and the solvent again removed under vacuum and dried over sodium sulfate,
leaving clear yellow oils of 0.2 gm of exo 6, 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) heptan- 7-one and 0.1 gm of exo 7,7-dichloro-2-(5- hydroxyhept- 1-yl) bicyclo (3.2.0) heptan-6-one. The product last eluted, the exo- 6,6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0)heptan-7-one gives the following key NMR resonances: 1H 3.82, doublet (1H) , 3.53 multiplet (1H) , 3.37 (d of d) 1H, 2.40 quartet (1H) , 0.944 triplet (3H) . In the case of the exo 7,7-dichloro compound, second to be eluted, the following NMR regions were noted. 1H 4.03 d of d (1H) , 3.53 multiplet (1H) , 3.07 doublet (1H), 2.40 quartet (1H) and 0.948 triplet (3H) . Before the exo 7,7-dichloro compounds, smaller quantities of endo isomers are eluted. The following NMR resonances are noted 3.94 d of d (1H) , 3.53 multiplet (1H), 3.42 d of d (1H), 0.94 triplet (3H) .
The exo 6 , 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0)heptan-7-one can also be obtained from the mixture of exo and endo 6,6-dichloro and 7,7-dichloro isomers by applying the crude mixture directly on a flash chromatography column (e.g. 2.5 cm diameter, 200-430 mesh) and eluting with a 6:1 hexane-ether (v/v) solution,
collecting fractions in 20 ml tubes. The presence of the exo 6,6-dichloro product in tubes can be determined by gas chromatography by comparison with the pure exo 6,6-dichloro product obtained above using high performance liquid chromatography.
Structure assignment of exo 6,6 dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) heptan-7-one.
The resonance at 3.8 is due to the proton HA, coupled to the proton HB giving a doublet (8Hz) . Such a large coupling constant is due to the bridgehead protons, HA and HB. The resonance at 3.53 is ascribed to HD, the methine proton on the aliphatic chain. At 3.37, what appears to be a triplet is actually a doublet of doublets as it is due to HB, the other bridgehead proton. The proton HB is coupled to HA and largely one of the protons, HE. Based on molecular models it is most likely that the bond angle of HB and HF (endo) is close to 90º and therefore the coupling constant is very small
compared to HE (exo). There is a clean quartet at 2.4, most likely due to proton HF. As a result of the cupped shape of the molecule from the fused rings the endo chlorine atom is in closer proximity to proton HF, and therefore, results in a downfield shift. Irradation of HA collapses the apparent triplet at 3.37 to a doublet, since the coupling of HB to HE is unaffected by the irradiation. Irradiation of HB collapses the doublet of HA to a singlet also consistent with the proposed exo 6,6-dichloro isomer structure. If this were actually the endo 6,6-dichloro isomer then proton HA should be coupled to HC and HA would appear as an apparent triplet. Identification of exo 7 ,7-dichloro-2-(5-hydroxyhept-1- yl) bicyclo (3.2.0)heptan-6-one. There is an apparent triplet at 4.03, which is actually a doublet of doublets due to the coupling of HH with the protons of HG and HJ and shifted further downfield as a result of being located on the carbon adjacent to the carbonyl. There may be a small coupling of proton HH with HK (less than 1 Hz) . There is also a quartet at about 2.4 ppm due to proton HK. A doublet corresponding to proton HG at 3.07 is due to the coupling of proton HG to proton HH. There may be a small coupling with proton HI but based on molecular models the bond angles between these protons would be less than 1 Hz. Irradiation of proton HH collapses the doublet (due to proton HG) to a singlet also consistent with the 7,7-dichloro isomer structure. Irradiation of HG results in the change in the resonance of proton HH from an apparent triplet (actually doublet of doublets) to a doublet.
If the aliphatic chain were in the endo position instead of the exo position, proton HG would be coupled to HI and thus give a resonance of an apparent triplet (doublet of doublets) instead of a doublet at 3.07.
Based on molecular models the bond angle between proton
HG and HI is almost 90°and would therefore have a very small coupling.
Example 4 Exo- and endo- isomers of 6,6-dichloro-2-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one and 7,7-dichloro-2- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one.
In the initial Grignard reaction of Example 1, 52.2 gm of 1-chloro-5-ethoxyheptane are substituted for the 5-methoxy homolog and the reaction sequence is conducted as in Example 1. The resulting oily mixture is distilled at about 125 °C and about 0.5 mm pressure. Infrared absorption maxima are observed at 2970, 2934, 2869, 1805, 1462, 1370, 1343, 1224, 1158, 1106, 1081, 1030, 976, 969, 845, 816, 742 and 674 cm-1. Separation of the isomers is conducted by the method of Example 3 to yield mainly the exo 6,6-dichloro-2- (5-ethoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one.
Example 5 Exo- isomer of 6, 6-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-ol.
To a solution of 50 ml of methanol, 30 ml of water, and 8 gm of sodium hydroxide, there is added in pellet form 0.2 gm of sodium borohydride in a single portion. 1 gm of exo 6, 6-dichloro-2- (5-methoxyheptyl) bicyclo (3.2.0) -heptan-7-one is added and the reaction mixture is heated at 45 °C for 10 hours. The solution is then cooled in an ice bath and concentrated hydrochloric acid is added dropwise until the solution has reached a pH of 1. The reaction mixture is then extracted 3 times with 75 ml ether. The combined ether extracts are washed with sodium bicarbonate and dried over sodium sulphate. The solvent is removed under vacuum, leaving 0.4 gm of a clear yellow product showing infrared maxima at 3447 (broad), 2960, 2934, 2873, 2858, 2824, 1462, 1418, 1375, 1335, 1263, 1178, 1163, 1094, 1042, 962, 936, 920, 858, 849, 842 and 682 cm-1.
Substitution of 1 gm of 7, 7-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-6-one yields 7,7-dichloro- 2- (5-methoxyhept-1-yl) bicyclo (3.2.0)heptan-6-ol with a very similar infrared spectrum. Use of exo 6, 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0) heptan-7-one of Example 3 as starting materials yields exo 6, 6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo- (3.2.0) heptan-7-ol.
Example 6 Exo- and endo- isomers of 6,6-dichloro-2-(5-methoxyhept- 1-yl) bicyclo (3.3.0) octan-7-one and 8 , 8-dichloro-2- (5-methoxyhept-1-yl) -7-bicyclo (3.3.0) octan-7-one and 5-hydroxyhept-1-yl-derivatives.
A solution of 5 gm of the isomers obtained in Example 1 in 100 ml of ether is transferred to a 500 ml round bottom glass flask. Excess diazomethane is generated from 60 gm of p-tolylsulfonylmethylnitrosamide by reacting with potassium hydroxide in methanol. The reaction is allowed to proceed for 50 minutes after which glacial acetic acid is added portionwise to destroy the excess diazomethane. The solution is extracted with ether and dried over sodium sulphate. The solvent is removed under vacuum, leaving an orange oil. This oil is applied to a silica gel chromatography column; elution with a 4:1 mixture of hexane and ether and evaporation of the solvent yields the product as a clear liquid. Infrared maxima are observed at 2959, 2934, 2873, 2858, 2820, 1768, 1462, 1404, 1379, 1366, 1193, 1145, 1094, 923, 897, 778, 713, 663, 656, and 652 cm-1. Substitution in this reaction of the individual isomers obtained by the separation procedure in Example 3 leads to the corresponding exo- and endo- isomers of 6,6-dichloro-2- (5-methoxyhept-1-yl) bicyclo (3.3.0) octan-7-one and 8, 8-dichloro2- (5-methoxyhept-1-yl) bicyclo [3.3.0] - octan-7-one.
Reaction of the product of Example 4 with diazomethane yields the 6,6-dichloro-2- (5-ethoxy-1-heptyl) bicyclo
(3.3.0) octan-7-one which, on dechlorination with zinc and acetic acid, produces 2- (5-ethoxyhept-1-yl) bicyclo (3.3.0) - octan-7-one, IR 2971, 2934, 2860, 1742, 1483, 1462, 1405, 1370, 1345, 1333, 1301, 1243, 1202, 1160, 1111, 1082, 982, 977 and 722 cm-1.
Demethylation of exo 6, 6-dichloro-2-(5-methoxyhept-1-yl) bicyclo (3.3.0) octan-7-pne by the procedure of Example 2 produces exo 6,6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo (3.3.0) octan-7-one Infrared maxima occur at about 3416, 2955, 2868, 2856, 1801, 1462, 1131, 1118, 1029, 987, 967, 741 and 675 cm-1.
Example 7 Exo- and endo- isomers of 6 ,6-dichloro-2- (5-methoxyhept-1-yl) 7-methylbicyclo (3.3.0) octan-7-ol and 8 , 8-dichloro-2- (5-methoxyhept-1-yl) -7-methylbicyclo (3.3.0) octan-7-ol.
6 gm of the mixture of isomers obtained in Example 1 are added to a 400 ml ether solution of diazomethane, generated from 45 gm of p-tolylsulfonylmethylnitrosamide.
The reaction is allowed to proceed for 5 hours after which glacial acetic acid is added dropwise to neutralize the excess diazomethane. The ether solution is washed with sodium bicarbonate and dried over sodium sulphate. The solvent is removed under vacuum, leaving an orange oil. This oil is applied in hexane and ether to a silica gel chromatography column and elution with 4:1 hexane-ether yields the product as a clear liquid. Infrared maxima are observed at 3430, 2931, 2856, 1658, 1461, 1379, 1362, 1328, 1325, 1316, 1244, 1195, 1173, 1162, 1093, 1027, 984, 950, and 923 cm-1. Substitution in this reaction of the individual isomers obtained in Example 3 leads to the corresponding exo- and endo- isomers of 6, 6-dichloro-2- (5-hydroxyhept-1-yl) -7-methylbicyclo (3.3.0) octan-7- ol and 8,8-dichloro-2- (5-hydroxy-hept-1-yl) -7-methylbicyclo (3.3.0) octan-7-ol, the exo-6,6-dichloro isomer being the principal product.
Example 8 Exo- and endo- isomers of 6 ,6-dichloro-2- (5-oxohept-1- yl) bicyclo (3.2.0) heptan-7-one and 7,7-dichloro-2- (5-oxohept-1-yl) bicyclo [3.2.0] heptan-6-one. A dry 100 ml 3-necked flask is heated and allowed to cool under nitrogen after which there is first added 2.3 gm of the mixture of isomers obtained in Example 2 followed by 17 ml of dichloromethane. To the stirred reaction mixture there is added 6.4 gm of pyridinium dichromate in a single portion. After 3 hours ether
(4x50 ml) is added and the solution is shaken vigorously to dissolve any product trapped in the precipitated chromium salts. The solution is filtered through a sintered glass filter with a silica pad. The filtrate is washed successively with 75 ml of water and then 75 ml brine and dried over sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The 5-oxohept-1-yl product is purified by silica gel chromatography using 4:1 hexane: ether (v/v) as the eluting solvent. The fractions containing the product, as determined by vapor phase chromatography, are pooled and the solvent is removed under vacuum leaving a clear yellow oil.
Separation of isomers yielding mainly the exo 6,6-dichloro isomer follows the procedure of Example 3. Infrared maximum were observed at:
2932, 2859, 1799, 1707, 1653, 1457, 1410, 1371, 1289, 1261, 1222, 1161, 1111, 1051, 1027, 963, 953, 915, 862, 843, 803, 733, and 671 cm-1. Example 9
Exo- and endo- isomers of 6-chloro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7-chloro-2- (5-methoxyhept-l-yl) bicyclo [3.2.0]heptan-6-one.
To a dry 100 ml 3-necked round bottom flask under nitrogen, equipped with a pressure equalizing dropping funnel, thermometer, and a magnetic stirrer, there is added the mixture of isomers obtained in Example 1 (5 gm)
and a catalytic amount (5 mg) of 2,2'-azobisisobutyronitrile. To the stirring solution there is added dropwise tri-n-butyltin hydride (4.7 gm) . The reaction mixture is maintained below 40° C in a water bath. After the addition is complete the reaction mixture is stirred at 30° C until a test of aliquot indicates the disappearance of the hydride, typically after about 3 hours. Then 35 ml water and 75 ml ether are added and the organic phase is separated and washed with 50 ml brine and dried over sodium sulfate. Evaporation of the solvent under vacuum leaves the crude product, which is then chromatographed on silica gel using 4:1 hexane:ether (v/v) as the elution solvent. The fractions are pooled (as determined by VPC) and the solvent is removed under vacuum leaving the product as a clear colorless oil. (2.5 gm)
Infrared maxima observed: 2960, 2932, 2871, 2855, 1804, 1461, 1448, 1034, 1023, 968, 817, 743, 703 and 676 cm-1. Individual isomers are obtained by the method of Example 3.
Example 10 6 ,6-dichloro-2-(5-hydroxypent-1-yl) bicyclo (3.2.0) heptan--7-one and isomers
To a dry 500 ml 3-necked flask equipped with a magnetic stirrer and under a nitrogen atmosphere there are added 36 gm of 5-chloropentanol and 17.6 gm t-butyl-dimethylsilyl chloride. A suspension of 39.6 gm of imidazole in 40 ml of dimethylformamide is added in a single portion to the stirring solution. After 20 hours, 150 ml water and 100 ml ether are added. The organic phase is separated and 150 ml water and 100 ml ether are added. The organic phase is separated. The aqueous phase is extracted three times with 75 ml ether. The
ether solution is washed with 100 ml brine. The ether extracts are combined, dried over sodium sulphate and the volume is reduced under vacuum to yield (5-chloro-1- pentyloxy) (2,2-diraethylethyl) dimethylsilane. Infrared maxima observed at:
2954, 2929, 2895, 2857, 1470, 1461, 1445, 1434, 1405, 1388, 1360, 1312, 1290, 1256, 1216, 1153, 1106, 982, 938, 911, 836, 812, 776, 727, 657 cm-1.
3- (5- [ (1, 1-dimethylethyl) dimethylsiloxy] pent-1-yl)- cyclopentene is prepared by the method of Example 1. The crude product is kugelrohred under vacuum and the product subsequently chromatographed on silica gel using 4:1 hexane:ether (v/v) as the solvent system. The fractions are pooled and the solvent removed under vaccum leaving a clear colorless oil.
27.4 gm of this product in 75 ml of anhydrous ether and 19.4 gm of zinc copper couple are added to a 500 ml
3-necked flask equipped with a magnetic stirrer, reflux condenser and a pressure equalizing funnel under a nitrogen atmosphere.
An etheral solution containing 37 gm of trichloroacetyl chloride and 30.6 gm of phosphorus oxychloride are added dropwise over 2 hours to the stirring solution. The reaction mixture is heated to reflux for 2 hours, after which the reaction is cooled and the zinc is removed by filtration. The filtrate is cooled and water and sodium bicarbonate are added to neutralize the reaction. The organic phase is separated and the aqueous phase is extracted 3 x 75 ml of ether. The ether extracts are combined, dried over sodium sulfate, and the volume is reduced under vacuum leaving crude 6 , 6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]-pent-1-yl) bicyclo (3.2.0) heptan-7-one. The oil is kugelrohred under vacuum and subsequently chromatographed on silica gel using a 4:1 hexane: ether (v/v) solvent system. The fractions are pooled, as (determined by VPC and IR) and the solvent reduced under vaccum leaving a
clear colorless oil.
A solution of 18.1 gm of this product in 100 ml acetonitrile containing 5% of a 40% aqueous solution of hydrofluoric acid is stirred for 2 hours at room temperature, after which the reaction is partitioned between 200 ml water and 200 ml chloroform. The aqueous phase is separated and extracted with 3 portions of 50 ml of chloroform. The organic phase is washed with 75 ml of brine, dried over sodium sulphate and the volume is reduced under vacuum leaving a crude product. The material is chromatographed on silica gel by using 2:1 hexane:ether (v/v) solvent system. The fractions are pooled and the solvent is removed under vacuum leaving a clear colorless oil of 6,6-dichloro-2-(5-hydroxypent-1-yl)bicyclo(3.2.0)heptan-7-one and 7,7-dichloro-2-(5-hydroxypent-1-yl) bicyclo (3.2.0) heptan-6-one. The first named product in the exo form, is isolated by the procedure in Example 3. Infrared maxima: 3440, 2935, 2864, 1803, 1650, 1465, 1410, 1247, 1160, 1073, 1050, 930, 750, 735 and 610 cm-1.
Example 11 Exo- and endo- isomers of 6 , 6-dibromo-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7 ,7-dibromo-2- (5-methoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one. To a dry 500 ml 3-necked round bottom flask equipped with pressure equalizing dropping funnel, stirrer and condenser are added 34.3 gm of tribromoacetic acid under nitrogen. Then 41.5 gm phosphorus tribromide is added dropwise with stirring. The reaction, proceeding with evolution of gas, is completed in 2 hours and the crude tribromoacetyl bromide is distilled at about 75°C and 10 mm.
Under an inert atmosphere there are added to a 500 ml 3-necked round bottom flask equipped with a magnetic stirrer, reflux condenser, and a pressure equalizing dropping funnel 6.5 gm of zinc-copper couple and 15 gm of
3- (5-methoxyhept-1-yl) cyclopentene dissolved in 100 ml of ether. A solution of 15.1 gm of tribromoacetyl bromide and phosphorus oxychloride (15.6 gm) in 100 ml ether is added dropwise to the stirring solution over 1 hour to generate dibromoketene. The reaction is heated to reflux and allowed to stir until there is no more starting material present as evidenced by vapor phase chromatography. The excess dibromoketene and phosphorus oxychloride are destroyed by the dropwise addition of water. The crude product is filtered and the filtrate is washed with 100 ml brine and a saturated solution of 100 ml sodium bicarbonate until the pH reaches 7. The organic phase is washed again with 100 ml brine and dried over sodium sulfate. The solvent is removed under vacuum leaving a brown liquid. The material is kugelrohred under vacuum and subsequently chromatographed on silica gel with 4:1 hexane: ether (v/v) as the elution solvent.
The fraction is pooled (as determined by vapor phase chromatography) and the solvent removed under vacuum leaving a clear oil.
Example 12 Exo- and endo- isomers of 6 , 6-difluoro-2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one and 7 ,7-difluoro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0]heptan-6-one. To a 250 ml 3-necked flask are added 50 gm of chlorodifluoroacetic acid. The flask is cooled in an ice bath and stirred while 116.7 gm of phosphorus tribromide are slowly added in the course of 5 minutes. After completion of the reaction and subsequent refluxing for 2 hours, the chlorodifluoroacetyl chloride is distilled into an ice-cooled receiver as a colorless liquid.
To a dry 250 ml 3-necked round-bottom flask under an inert atmosphere is added 9.7 gm of zinc-copper couple and 80 ml anhydrous ether. 15.1 gm of chlorodifluoroacetyl chloride in 20 ml ether are added dropwise to the stirring solution and the etheral difluoroketene monomer is distilled into a receiver cooled with an ice bath. To
the distillate is added 15 gm of 3- (5-methoxyhept-1-yl)-cyclopentene in 20 ml ether. The reaction is stirred for 1 hour after which time 50 ml of cold water are added. The solution is washed with 75ml saturated sodium bicarbonate. The organic phase is separated, washed with 75ml brine and dried over sodium sulfate. The solvent is removed under vacuum leaving a green oil. The product is kugelrohred under reduced pressure and chromatographed on silica gel using a 4:1 hexanetether (v/v) solvent system. The fractions are pooled (as determined by VPC) and the solvent removed under vacuum leaving a clear light yellow oil. Infrared maxima observed at:
2921, 2847, 2689, 2669, 2650, 2645, 2636, 2621, 2609, 2528, 2517, 2510, 2506, 1771, 1457, 1373, 1358, 1280, 1193, 1160, 1126, 1092, 968, 911, 838, 775, 715, 650 and 646 cm-1.
Anti-Tumor Testing The compounds were tested against a variety of tumors in the Salmon essay (Cancer Res. Report 65:1; 1981). Thus, in a typical test, 3 plates containing 40, 43 and 45 colonies of CHOW-5 (Chinese hamster ovary) cell line were incubated using a solution of 10 meg of exo 6,6-dichloro-2- (5-hydroxyhept-1-yl) bicyclo (3.2.0) -heptan-7-one. All treated colonies were destroyed. All controls survived.
In tests against Walker 256 rat carcinosarcoma, 105 cells were implanted i.p. and the rats were treated i.p. daily on days 1-5. Exo 6 ,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo (3.2.0)heptan-7-one was dissolved in peanut oil. Untreated control rats lived an average of 8.0 days. Rats treated with 20% polyethylene glycol 400 in oil lived 8.5 days. Rats given 1 g/kg of the drug lived 12.5 days, significantly longer.
DEHALOGENATION
A. To a single-neck 100ml, round-bottom flask equipped with a condenser are added 6,6-dichloro-2- (5-methoxyhept- 1-yl) -bicyclo (3.3.0)octan-7-one or the 8,8-dichloro-7-one isomer (45.9 gm) . The solution is stirred by magnetic stirring and powdered zinc metal (92 gm) and glacial acetic acid (312 ml) are added and the solution allowed to reflux for six hours, during which time white ZnCl2 precipitates out of solution. The solution is filtered, washed with NaHCO3 and extracted three times with ether. The ether extracts are combined and dried over sodium sulphate. The resulting yellow oil is chromatographed with silica gel and eluted with 3:1 hexane:ether. The fractions are combined, yielding 2-(5-methoxyhept-1-yl)-bicyclo (3.3.0) octan-7-one as a clear, colorless oil.
IR 2928, 2853, 2828, 1740, 1460, 1402, 1735, 1158, 1122, 1093, 1050, 1035, 960, 740 cm-1.
B. Zinc-copper catalyst (3 gm) is added to a stirred solution of 6 ,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo- (3.2.0)heptan-7-one (2 gm, 6 moles) in acetic acid (100 ml) under a nitrogen atmosphere.
The solution is stirred at room temperature for one hour, then refluxed for 13 hours, after which time the mixture is filtered through a sintered glass funnel and the etheral solution dried over Na2SO4. The solvent is removed under vacuum, leaving the crude product. Chromatography on silica gel yields 2- (5-methoxyhept-1-yl) bicyclo (3.2.0) heptan-7-one (1.2 gm) . IR: 2959, 2933, 2859, 2820, 1778, 1461, 1406, 1386, 1316, 1303, 1260, 1236, 1197, 1154, 1091, 1024, 921, 862, 819 cm-1.
C. Dehalogenation of 6 ,6-dichloro-2-(5-methoxyhept-1-yl)-bicyclo(3.3.0)octan-7-ol produces 2- (5-methoxyhept-1-yl)-bicyclo (3.3.0) octan-7-ol.
IR: 3501, 2960, 2932, 2856, 2822, 2736, 1657, 1638, 1635, 1461, 1374, 1303, 1261, 1248, 1246, 1239, 1161, 1132, 1093, 1037, 998, 963, 943, 920, 750, 724 and 690 cm-1.
Claims
1. A pharmaceutical composition for inhibition of tumors which contains an effective dose of a compound of the formula
wherein Q is CO, CH(OH) or C(OH)CH3, M1 is halogen, M2 is halogen or hydrogen, p is 0 or 1 and one of the groups X and X' is hydrogen and the other is a hydroxyalkyl, methoxyalkyl, ethoxyalkyl or oxoalkyl wherein the alkyl contains 2-9 carbon atoms.
2. A composition of claim 1 wherein M1 and M2 are chlorine.
3. A composition of claim 2 wherein p is zero.
4. A composition of claim 3 wherein Q is CO.
5. A composition of claim 4 wherein the compound is exo 6 ,6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo [3.2.0] -heptan-7-one.
6. A composition of claim 4 wherein the compound is exo 6,6-dichloro-2- (5-methoxyhept-1-yl) bicyclo [3.2.0] -heptan-7-one.
8. A composition of claim 4 wherein X is oxalkyl.
10. A compound of the formula
M2 is halogen or hydrogen, p is 0 or 1 and X is a hydroxyalkyl, methoxyalkyl, ethoxyalkyl or oxoalkyl wherein the alkyl contains 2-9 carbon atoms.
11. A compound of Claim 10 wherein M1 and M2 are chlorine.
12. A compound of Claim 11 wherein p is zero.
13. A compound of Claim 12 wherein Q is CO.
14. A compound of Claim 13 which is exo 6, 6-dichloro-2-(5-hydroxyhept-1-yl) bicyclo [3.2.0] heptan- 7-one.
15. A compound of Claim 13 which is exo 6,6-dichloro- 2-(5-methoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one.
17. A compound of claim 13 wherein X is oxoalkyl.
18. A compound of claim 17 which is exo
6 , 6-dichloro-2- (5-oxohept-1-yl) bicyclo (3.2.0) heptan-7-one.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55029083A | 1983-11-08 | 1983-11-08 | |
US550,290 | 1983-11-08 | ||
US56717283A | 1983-12-30 | 1983-12-30 | |
US567,172 | 1983-12-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1985002177A1 true WO1985002177A1 (en) | 1985-05-23 |
Family
ID=27069402
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1984/001819 WO1985002177A1 (en) | 1983-11-08 | 1984-11-08 | Halo bicyclo alkanones |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP0162894A4 (en) |
WO (1) | WO1985002177A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3849505A (en) * | 1971-09-24 | 1974-11-19 | Reckitt & Colmann Prod Ltd | Bicyclic polyols |
US4292432A (en) * | 1979-02-09 | 1981-09-29 | Sumitomo Chemical Company, Limited | Novel aldol derivatives and production thereof |
US4322435A (en) * | 1978-01-06 | 1982-03-30 | Sankyo Company Limited | Prostacyclin compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3705240A (en) * | 1966-11-21 | 1972-12-05 | Geigy Chem Corp | Phosphoric acid esters,intermediates for making the same,and pest control by means of said esters |
ATE38028T1 (en) * | 1982-05-06 | 1988-11-15 | Cbd Corp | CYCLOALIPHATIC MEDICINAL COMPOSITIONS. |
-
1984
- 1984-11-08 WO PCT/US1984/001819 patent/WO1985002177A1/en not_active Application Discontinuation
- 1984-11-08 EP EP19840904279 patent/EP0162894A4/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3849505A (en) * | 1971-09-24 | 1974-11-19 | Reckitt & Colmann Prod Ltd | Bicyclic polyols |
US4322435A (en) * | 1978-01-06 | 1982-03-30 | Sankyo Company Limited | Prostacyclin compounds |
US4292432A (en) * | 1979-02-09 | 1981-09-29 | Sumitomo Chemical Company, Limited | Novel aldol derivatives and production thereof |
Non-Patent Citations (1)
Title |
---|
See also references of EP0162894A4 * |
Also Published As
Publication number | Publication date |
---|---|
EP0162894A4 (en) | 1987-01-22 |
EP0162894A1 (en) | 1985-12-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Johnson et al. | Synthesis and stereochemistry of prostacyclin and synthesis of 6-ketoprostaglandin F1. alpha. | |
Barrett et al. | Stereochemistry and synthesis of. alpha.-agarofuran | |
Kelly et al. | Synthesis of schumanniophytine and isoschumanniophytine | |
Hudrlik et al. | Reactions of. alpha.,. beta.-epoxysilanes with Grignard reagents. Generation and trapping of. alpha.-trimethylsilyl aldehydes and ketones | |
Dauben et al. | Formal total synthesis of (.+-.)-isocomene | |
Lannoye et al. | General approach to the synthesis of polyquinenes via the Weiss reaction. 6. Progress toward the synthesis of dicyclopentapentalenes | |
Coates et al. | Stereoselective total synthesis of (.+-.)-gymnomitrol via reduction-alkylation of. alpha.-cyano ketones | |
Aristoff et al. | Synthesis of benzopyran prostaglandins, potent stable prostacyclin analogs, via an intramolecular Mitsunobu reaction | |
Welch et al. | Stereoselective total syntheses of (.+-.)-gymnomitrol and (.+-.)-gymnomitrene | |
WO1985002177A1 (en) | Halo bicyclo alkanones | |
US4689349A (en) | Anti-tumor halo bicyclo alkanones | |
Snider et al. | Sequential ene reactions-II: Synthesis of bicyclic adducts with angular methyl groups. in situ oppenauer oxidation' | |
KR900004401B1 (en) | Tetraenyl prostaglandins | |
Caine et al. | Photochemical rearrangements of cross-conjugated cyclohexadienones. Application to the synthesis of (-)-4-epiglobulol and (+)-4-epiaromadendrene | |
US4585760A (en) | Dimethylfurano heterocyclic analogs of daunomycin | |
Roush et al. | Total synthesis of verrucarol: a stereoselective synthesis of 13, 14-dinor-15-hydroxytrichothec-9-ene | |
Lawson et al. | . alpha.-Bromo spiroketals: stereochemistry and elimination reactions | |
US4159273A (en) | Tricyclic mono-chromone-2-carboxylic acids | |
US3647821A (en) | Substituted naphthofuran compounds | |
Orsini et al. | 9, 10-syn-Podocarpane diterpenoids. An approach to the tricyclic skeleton by Diels-Alder cycloaddition. Related crystal structure determination and theoretical aspects | |
US4238606A (en) | Tricyclic mono-chromone-2-carboxylic acids | |
NZ204882A (en) | Omega-(n-bicyclo(3.2.0)hept-6-ylideneamino)oxyalkanoic acids | |
US3714195A (en) | Ethylenedioxy derivatives of substituted naphthalenone compounds | |
US3565958A (en) | D-homoestra-1,3,5(10)-trienes and 1,3,5(10)9(11)-tetraenes | |
Posner et al. | Short nonannelation approach to synthesis of oxygenated eudesmane sesquiterpenes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Designated state(s): JP |
|
AL | Designated countries for regional patents |
Designated state(s): AT BE CH DE FR GB LU NL SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1984904279 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1984904279 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1984904279 Country of ref document: EP |