CA2371726A1 - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents

Info

Publication number

CA2371726A1

CA2371726A1 CA002371726A CA2371726A CA2371726A1 CA 2371726 A1 CA2371726 A1 CA 2371726A1 CA 002371726 A CA002371726 A CA 002371726A CA 2371726 A CA2371726 A CA 2371726A CA 2371726 A1 CA2371726 A1 CA 2371726A1

Authority

CA

Canada

Prior art keywords

substituted

alkyl

oxazin

dihydro

dimethyl

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 239000002379 progesterone receptor modulator Substances 0.000 title description 4
• 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 title description 4
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 145
• 150000001875 compounds Chemical class 0.000 claims abstract description 137
• 238000000034 method Methods 0.000 claims abstract description 114
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 96
• 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 64
• 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 claims abstract description 54
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 43
• 150000002367 halogens Chemical class 0.000 claims abstract description 43
• 125000003118 aryl group Chemical group 0.000 claims abstract description 38
• 150000003839 salts Chemical class 0.000 claims abstract description 33
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 29
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 29
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 27
• 125000001424 substituent group Chemical group 0.000 claims abstract description 26
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 21
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 21
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
• 125000004426 substituted alkynyl group Chemical group 0.000 claims abstract description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 78
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 73
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• -1 -OH Chemical group 0.000 claims description 20
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• KVMSWMUZFCLLFV-UHFFFAOYSA-N 3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC(F)=CC(C#N)=C1 KVMSWMUZFCLLFV-UHFFFAOYSA-N 0.000 claims description 8
• 241000124008 Mammalia Species 0.000 claims description 8
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 8
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 7
• 229940088597 hormone Drugs 0.000 claims description 7
• 239000005556 hormone Substances 0.000 claims description 7
• HVXMMYUSBANZAI-UHFFFAOYSA-N 3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)benzonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(C#N)=C1 HVXMMYUSBANZAI-UHFFFAOYSA-N 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• UWIIXWIVGXAFAN-UHFFFAOYSA-N 6-(3-bromo-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(Br)=C1 UWIIXWIVGXAFAN-UHFFFAOYSA-N 0.000 claims description 5
• 230000001419 dependent effect Effects 0.000 claims description 5
• 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 description 4
• PPDYGKBOJSGKBD-UHFFFAOYSA-N 6-(3-bromophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(Br)=C1 PPDYGKBOJSGKBD-UHFFFAOYSA-N 0.000 claims description 4
• 201000009273 Endometriosis Diseases 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• 206010046798 Uterine leiomyoma Diseases 0.000 claims description 4
• 150000001555 benzenes Chemical group 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 201000010260 leiomyoma Diseases 0.000 claims description 4
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 4
• 125000004001 thioalkyl group Chemical group 0.000 claims description 4
• PNEKYSUBNQXRHM-UHFFFAOYSA-N 4,4-dimethyl-6-(1-methylpyrrol-2-yl)-1h-3,1-benzoxazin-2-one Chemical compound CN1C=CC=C1C1=CC=C(NC(=O)OC2(C)C)C2=C1 PNEKYSUBNQXRHM-UHFFFAOYSA-N 0.000 claims description 3
• QWIQKRAABPUAGQ-UHFFFAOYSA-N 4,4-dimethyl-6-[2-(1,2,4-thiadiazol-3-yl)phenyl]-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC=C1C=1N=CSN=1 QWIQKRAABPUAGQ-UHFFFAOYSA-N 0.000 claims description 3
• 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 description 3
• QYXWQJJMCRIUKE-UHFFFAOYSA-N 5-(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=C(F)C(C#N)=C1 QYXWQJJMCRIUKE-UHFFFAOYSA-N 0.000 claims description 3
• WRAWKFUWOAFTDQ-UHFFFAOYSA-N 5-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)furan-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=C(C#N)O1 WRAWKFUWOAFTDQ-UHFFFAOYSA-N 0.000 claims description 3
• MESNIJJPCGWIQB-UHFFFAOYSA-N 6-(3-acetylphenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound CC(=O)C1=CC=CC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1 MESNIJJPCGWIQB-UHFFFAOYSA-N 0.000 claims description 3
• 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 description 3
• JRDFVXBVDLMFJH-UHFFFAOYSA-N 6-(3-bromo-5-methylphenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound CC1=CC(Br)=CC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1 JRDFVXBVDLMFJH-UHFFFAOYSA-N 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 3
• 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 3
• UNTRVRJHIUBUIT-UHFFFAOYSA-N 6-(3-chlorophenyl)-4-methyl-1,4-dihydro-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)OC(=O)NC2=CC=C1C1=CC=CC(Cl)=C1 UNTRVRJHIUBUIT-UHFFFAOYSA-N 0.000 claims description 3
• YKEDHPYOLSKGHE-UHFFFAOYSA-N 6-(3-ethynylphenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CC(C#C)=C1 YKEDHPYOLSKGHE-UHFFFAOYSA-N 0.000 claims description 3
• QTVMSASXEDWDST-UHFFFAOYSA-N 6-(5-bromopyridin-3-yl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CN=CC(Br)=C1 QTVMSASXEDWDST-UHFFFAOYSA-N 0.000 claims description 3
• FKJUYZPFOJIRIG-UHFFFAOYSA-N 6-chloro-4-methyl-4-(trifluoromethyl)-1h-3,1-benzoxazin-2-one Chemical compound C1=C(Cl)C=C2C(C)(C(F)(F)F)OC(=O)NC2=C1 FKJUYZPFOJIRIG-UHFFFAOYSA-N 0.000 claims description 3
• CDVKDGYSTHYNBL-UHFFFAOYSA-N [6-(3-cyano-5-fluorophenyl)-4,4-dimethyl-3,1-benzoxazin-2-yl] dihydrogen phosphate Chemical compound C1=C2C(C)(C)OC(OP(O)(O)=O)=NC2=CC=C1C1=CC(F)=CC(C#N)=C1 CDVKDGYSTHYNBL-UHFFFAOYSA-N 0.000 claims description 3
• 210000000481 breast Anatomy 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• FEVGHBLMPKIPFU-UHFFFAOYSA-N tert-butyl 2-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)pyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=C1C1=CC=C(NC(=O)OC2(C)C)C2=C1 FEVGHBLMPKIPFU-UHFFFAOYSA-N 0.000 claims description 3
• 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 description 2
• 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 description 2
• VHIBSIPZVHZJEI-UHFFFAOYSA-N 3-(2-oxospiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)benzonitrile Chemical compound O1C(=O)NC2=CC=C(C=3C=C(C=CC=3)C#N)C=C2C21CCCCC2 VHIBSIPZVHZJEI-UHFFFAOYSA-N 0.000 claims description 2
• LTCHZBXTHMXHAR-UHFFFAOYSA-N 3-(4,4-dicyclopropyl-2-oxo-1h-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC(C=2C=C3C(C4CC4)(C4CC4)OC(=O)NC3=CC=2)=C1 LTCHZBXTHMXHAR-UHFFFAOYSA-N 0.000 claims description 2
• NLEVEIAQKTVSTO-UHFFFAOYSA-N 3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-5-(trifluoromethoxy)benzonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC(OC(F)(F)F)=CC(C#N)=C1 NLEVEIAQKTVSTO-UHFFFAOYSA-N 0.000 claims description 2
• JGYMUYVJOIEFFQ-UHFFFAOYSA-N 3-(4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)-5-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC(C=2C=C3C(C)(C)OC(=O)NC3=CC=2)=C1 JGYMUYVJOIEFFQ-UHFFFAOYSA-N 0.000 claims description 2
• UAMDLTQRXMVMJV-UHFFFAOYSA-N 3-[1-(diethoxymethyl)-4,4-dimethyl-2-oxo-3,1-benzoxazin-6-yl]-5-fluorobenzonitrile Chemical compound C=1C=C2N(C(OCC)OCC)C(=O)OC(C)(C)C2=CC=1C1=CC(F)=CC(C#N)=C1 UAMDLTQRXMVMJV-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
• QRNMAUBTQDBSSM-UHFFFAOYSA-N 3-fluoro-5-(2-oxospiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)benzonitrile Chemical compound FC1=CC(C#N)=CC(C=2C=C3C4(CCCCC4)OC(=O)NC3=CC=2)=C1 QRNMAUBTQDBSSM-UHFFFAOYSA-N 0.000 claims description 2
• PKVIKTBQZZTING-UHFFFAOYSA-N 3-fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1h-3,1-benzoxazin-6-yl)benzonitrile Chemical compound C1=C2C(C)(C)OC(=O)NC2=C(F)C=C1C1=CC(F)=CC(C#N)=C1 PKVIKTBQZZTING-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
• SMKZYKBPVNAOJL-UHFFFAOYSA-N 4,4-dimethyl-6-(1h-pyrrol-2-yl)-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC=CN1 SMKZYKBPVNAOJL-UHFFFAOYSA-N 0.000 claims description 2
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• CHSVPWMJSJAVAI-UHFFFAOYSA-N 4,4-dimethyl-6-[3-(1,3-thiazol-2-yl)phenyl]-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C(C=1)=CC=CC=1C1=NC=CS1 CHSVPWMJSJAVAI-UHFFFAOYSA-N 0.000 claims description 2
• RHSCGZFJZHKZNC-UHFFFAOYSA-N 4,4-dimethyl-6-[3-(2h-tetrazol-5-yl)phenyl]-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C(C=1)=CC=CC=1C1=NN=NN1 RHSCGZFJZHKZNC-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
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• 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 description 2
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• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
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• XKXYGOFFUINVOY-UHFFFAOYSA-N 6-(3,5-difluorophenyl)-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=CC=C1C1=CC(F)=CC(F)=C1 XKXYGOFFUINVOY-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
• COCHTGRDEIHWSU-UHFFFAOYSA-N 6-(3-bromo-5-fluorophenyl)-1,4,4-trimethyl-3,1-benzoxazin-2-one Chemical compound C=1C=C2N(C)C(=O)OC(C)(C)C2=CC=1C1=CC(F)=CC(Br)=C1 COCHTGRDEIHWSU-UHFFFAOYSA-N 0.000 claims description 2
• QXXOGHDDSWRZPI-UHFFFAOYSA-N 6-(3-chloro-4-fluorophenyl)-8-fluoro-4,4-dimethyl-1h-3,1-benzoxazin-2-one Chemical compound C1=C2C(C)(C)OC(=O)NC2=C(F)C=C1C1=CC=C(F)C(Cl)=C1 QXXOGHDDSWRZPI-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
• 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 description 2
• 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 description 2
• 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 description 2
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