AU766428B2 - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents

Info

Publication number

AU766428B2

AU766428B2 AU46886/00A AU4688600A AU766428B2 AU 766428 B2 AU766428 B2 AU 766428B2 AU 46886/00 A AU46886/00 A AU 46886/00A AU 4688600 A AU4688600 A AU 4688600A AU 766428 B2 AU766428 B2 AU 766428B2

Authority

AU

Australia

Prior art keywords

substituted

alkyl

oxazin

dihydro

benzo

Prior art date

1999-05-04

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
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• 239000002379 progesterone receptor modulator Substances 0.000 title description 3
• 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 146
• 238000000034 method Methods 0.000 claims description 122
• 229910052757 nitrogen Inorganic materials 0.000 claims description 80
• 239000000203 mixture Substances 0.000 claims description 74
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 71
• 229910052799 carbon Inorganic materials 0.000 claims description 65
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• 229910052736 halogen Inorganic materials 0.000 claims description 47
• 125000000217 alkyl group Chemical group 0.000 claims description 41
• -1 oxazin-6-yl Chemical group 0.000 claims description 40
• 150000002367 halogens Chemical class 0.000 claims description 38
• 238000011282 treatment Methods 0.000 claims description 36
• 125000003118 aryl group Chemical group 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 33
• 125000001424 substituent group Chemical group 0.000 claims description 30
• 125000005842 heteroatom Chemical group 0.000 claims description 27
• 229910052760 oxygen Inorganic materials 0.000 claims description 25
• 125000003107 substituted aryl group Chemical group 0.000 claims description 25
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 125000000304 alkynyl group Chemical group 0.000 claims description 23
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
• 229920006395 saturated elastomer Polymers 0.000 claims description 20
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• 241000894007 species Species 0.000 claims description 19
• 125000003342 alkenyl group Chemical group 0.000 claims description 18
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 17
• 229910052717 sulfur Inorganic materials 0.000 claims description 17
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
• 241000124008 Mammalia Species 0.000 claims description 14
• 229940088597 hormone Drugs 0.000 claims description 12
• 239000005556 hormone Substances 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 12
• 230000001419 dependent effect Effects 0.000 claims description 11
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 9
• 150000001555 benzenes Chemical group 0.000 claims description 8
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 7
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
• 201000009273 Endometriosis Diseases 0.000 claims description 7
• 206010046798 Uterine leiomyoma Diseases 0.000 claims description 7
• 201000010260 leiomyoma Diseases 0.000 claims description 7
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• DGTZEHQWPNSIJS-UHFFFAOYSA-N 6-(3-chlorophenyl)-4-cyclopropyl-4-prop-1-ynyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C#CC)(C3CC3)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 DGTZEHQWPNSIJS-UHFFFAOYSA-N 0.000 claims description 5
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 5
• 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 5
• 210000000481 breast Anatomy 0.000 claims description 5
• 210000001072 colon Anatomy 0.000 claims description 5
• 210000004696 endometrium Anatomy 0.000 claims description 5
• 230000012173 estrus Effects 0.000 claims description 5
• 206010027191 meningioma Diseases 0.000 claims description 5
• 230000002632 myometrial effect Effects 0.000 claims description 5
• 210000001672 ovary Anatomy 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 230000001817 pituitary effect Effects 0.000 claims description 5
• 210000002307 prostate Anatomy 0.000 claims description 5
• 201000009030 Carcinoma Diseases 0.000 claims description 4
• 208000009956 adenocarcinoma Diseases 0.000 claims description 4
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 3
• 125000005605 benzo group Chemical group 0.000 claims description 3
• 238000002657 hormone replacement therapy Methods 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• PRCXSDHAGJJCKC-UHFFFAOYSA-N 6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=C(F)C(Cl)=C1 PRCXSDHAGJJCKC-UHFFFAOYSA-N 0.000 claims description 2
• VMPIROWONHUKCP-UHFFFAOYSA-N 6-(3-chlorophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 VMPIROWONHUKCP-UHFFFAOYSA-N 0.000 claims description 2
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 2
• 239000003814 drug Substances 0.000 claims 9
• 125000005843 halogen group Chemical group 0.000 claims 9
• 201000010099 disease Diseases 0.000 claims 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 8
• 230000001613 neoplastic effect Effects 0.000 claims 8
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 8
• BVPSAWJCIXNPDT-UHFFFAOYSA-N 6-(3-chlorophenyl)-4,4-bis(prop-1-ynyl)-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C#CC)(C#CC)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 BVPSAWJCIXNPDT-UHFFFAOYSA-N 0.000 claims 6
• HZDVGBZUSRBRKH-UHFFFAOYSA-N 6-(3-chlorophenyl)-4-methyl-4-prop-1-ynyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C#CC)(C)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 HZDVGBZUSRBRKH-UHFFFAOYSA-N 0.000 claims 5
• 125000006664 (C1-C3) perfluoroalkyl group Chemical group 0.000 claims 3
• OVZBDRQFIYMAJF-UHFFFAOYSA-N 6-(3-chlorophenyl)-4-ethynyl-4-methyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C#C)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 OVZBDRQFIYMAJF-UHFFFAOYSA-N 0.000 claims 3
• 125000001153 fluoro group Chemical group F* 0.000 claims 2
• 230000001939 inductive effect Effects 0.000 claims 2
• WBRVELFLQXWPBG-UHFFFAOYSA-N 2-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)thiophene-3-carbonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C=1SC=CC=1C#N WBRVELFLQXWPBG-UHFFFAOYSA-N 0.000 claims 1
• IDIRENXOSJYSCR-UHFFFAOYSA-N 2-[3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)phenyl]acetonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(CC#N)=C1 IDIRENXOSJYSCR-UHFFFAOYSA-N 0.000 claims 1
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
• SFDGJDBLYNJMFI-UHFFFAOYSA-N 3,1-benzoxazin-4-one Chemical compound C1=CC=C2C(=O)OC=NC2=C1 SFDGJDBLYNJMFI-UHFFFAOYSA-N 0.000 claims 1
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 1
• MMRUWYPAERDHDX-UHFFFAOYSA-N 3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(C#N)=C1F MMRUWYPAERDHDX-UHFFFAOYSA-N 0.000 claims 1
• GRRPAAFLOYWEHA-UHFFFAOYSA-N 3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-5-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1 GRRPAAFLOYWEHA-UHFFFAOYSA-N 0.000 claims 1
• JBBNXDUWXGONHM-UHFFFAOYSA-N 3-[3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)phenyl]prop-2-ynenitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(C#CC#N)=C1 JBBNXDUWXGONHM-UHFFFAOYSA-N 0.000 claims 1
• NTBMICWLTLYFGW-UHFFFAOYSA-N 3-chloro-5-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)benzonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC(Cl)=CC(C#N)=C1 NTBMICWLTLYFGW-UHFFFAOYSA-N 0.000 claims 1
• YMIYWAUOFRPGBF-UHFFFAOYSA-N 3-fluoro-5-[1-(methoxymethyl)-4,4-dimethyl-2-oxo-3,1-benzoxazin-6-yl]benzonitrile Chemical compound C=1C=C2N(COC)C(=O)OC(C)(C)C2=CC=1C1=CC(F)=CC(C#N)=C1 YMIYWAUOFRPGBF-UHFFFAOYSA-N 0.000 claims 1
• MEIWUXZPJSPWJO-UHFFFAOYSA-N 4,4-diethyl-6-(3-nitrophenyl)-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(CC)(CC)OC(=O)NC2=CC=C1C1=CC=CC([N+]([O-])=O)=C1 MEIWUXZPJSPWJO-UHFFFAOYSA-N 0.000 claims 1
• DXRDETPOBPURRD-UHFFFAOYSA-N 4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=CC=C2C(C)(C)OC(=O)NC2=C1 DXRDETPOBPURRD-UHFFFAOYSA-N 0.000 claims 1
• YYHMNNAXMFGWBB-UHFFFAOYSA-N 4,4-dimethyl-6-(1-methyl-5-nitropyrrol-2-yl)-1h-3,1-benzoxazin-2-one Chemical compound C1=C([N+]([O-])=O)N(C)C(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1 YYHMNNAXMFGWBB-UHFFFAOYSA-N 0.000 claims 1
• AXVHYEZJTTVOJH-UHFFFAOYSA-N 4,4-dimethyl-6-(3-nitrophenyl)-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC([N+]([O-])=O)=C1 AXVHYEZJTTVOJH-UHFFFAOYSA-N 0.000 claims 1
• DZRIKLQQKVBDJJ-UHFFFAOYSA-N 4,4-dimethyl-6-[3-(2-trimethylsilylethynyl)phenyl]-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(C#C[Si](C)(C)C)=C1 DZRIKLQQKVBDJJ-UHFFFAOYSA-N 0.000 claims 1
• OTDVEVBRJYVJHY-UHFFFAOYSA-N 4-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CSC(C#N)=C1 OTDVEVBRJYVJHY-UHFFFAOYSA-N 0.000 claims 1
• GNFOFPBRTHXTEC-UHFFFAOYSA-N 4-(8-fluoro-4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=C(F)C=C1C1=CSC(C#N)=C1 GNFOFPBRTHXTEC-UHFFFAOYSA-N 0.000 claims 1
• QAXWFQCRQFUILZ-UHFFFAOYSA-N 5-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-4-ethylthiophene-2-carbonitrile Chemical compound C1=C(C#N)SC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1CC QAXWFQCRQFUILZ-UHFFFAOYSA-N 0.000 claims 1
• SHQHKBVTNRRGGP-UHFFFAOYSA-N 5-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-4-propylthiophene-2-carbonitrile Chemical compound C1=C(C#N)SC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1CCC SHQHKBVTNRRGGP-UHFFFAOYSA-N 0.000 claims 1
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• OXOFQEFTKANGHA-UHFFFAOYSA-N 6-(3,4-difluorophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=C(F)C(F)=C1 OXOFQEFTKANGHA-UHFFFAOYSA-N 0.000 claims 1
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• DUGCMPPGABAONL-UHFFFAOYSA-N 6-(3,5-dinitrophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 DUGCMPPGABAONL-UHFFFAOYSA-N 0.000 claims 1
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• LGLOOLWMNDHTKN-UHFFFAOYSA-N 6-(3-bromo-5-fluorophenyl)-4,4-dicyclopropyl-1h-3,1-benzoxazin-2-one Chemical compound FC1=CC(Br)=CC(C=2C=C3C(C4CC4)(C4CC4)OC(=O)NC3=CC=2)=C1 LGLOOLWMNDHTKN-UHFFFAOYSA-N 0.000 claims 1
• QFJFPUFDMQGULL-UHFFFAOYSA-N 6-(3-chloro-5-fluorophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC(F)=CC(Cl)=C1 QFJFPUFDMQGULL-UHFFFAOYSA-N 0.000 claims 1
• UVVCMVFRQNXKIS-UHFFFAOYSA-N 6-(3-chlorophenyl)-4,4-dicyclopropyl-1h-3,1-benzoxazin-2-one Chemical compound ClC1=CC=CC(C=2C=C3C(C4CC4)(C4CC4)OC(=O)NC3=CC=2)=C1 UVVCMVFRQNXKIS-UHFFFAOYSA-N 0.000 claims 1
• ZFMGZMLOROWZPV-UHFFFAOYSA-N 6-(3-chlorophenyl)-4,4-diethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(CC)(CC)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 ZFMGZMLOROWZPV-UHFFFAOYSA-N 0.000 claims 1
• RTYILLPPQLHABM-UHFFFAOYSA-N 6-(3-chlorophenyl)-4-phenyl-1,4-dihydro-3,1-benzoxazin-2-one Chemical compound ClC1=CC=CC(C=2C=C3C(C=4C=CC=CC=4)OC(=O)NC3=CC=2)=C1 RTYILLPPQLHABM-UHFFFAOYSA-N 0.000 claims 1
• GKEMTHTTWRREOR-UHFFFAOYSA-N 6-(3-chlorophenyl)spiro[1h-3,1-benzoxazine-4,1'-cyclopentane]-2-one Chemical compound ClC1=CC=CC(C=2C=C3C4(CCCC4)OC(=O)NC3=CC=2)=C1 GKEMTHTTWRREOR-UHFFFAOYSA-N 0.000 claims 1
• GHUCLESPYZSUQU-UHFFFAOYSA-N 6-(3-chlorophenyl)spiro[3,1-benzoxazine-4,1'-cyclohexane] Chemical compound C1CCC2(CC1)C3=C(C=CC(=C3)C4=CC(=CC=C4)Cl)N=CO2 GHUCLESPYZSUQU-UHFFFAOYSA-N 0.000 claims 1
• CSEZCWXODWQLCM-UHFFFAOYSA-N 6-(3-fluoro-5-methoxyphenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound COC1=CC(F)=CC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1 CSEZCWXODWQLCM-UHFFFAOYSA-N 0.000 claims 1
• JZLBNVXFYMIYPW-UHFFFAOYSA-N 6-(3-fluoro-5-thiophen-3-ylphenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C(C=1)=CC(F)=CC=1C=1C=CSC=1 JZLBNVXFYMIYPW-UHFFFAOYSA-N 0.000 claims 1
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• 239000012267 brine Substances 0.000 description 42
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