PT2212283E - Carboxamidas de n-fenil-bipirrolidina substituídas e sua utilização terapêutica - Google Patents

Info

Publication number

PT2212283E

PT2212283E PT08839959T PT08839959T PT2212283E PT 2212283 E PT2212283 E PT 2212283E PT 08839959 T PT08839959 T PT 08839959T PT 08839959 T PT08839959 T PT 08839959T PT 2212283 E PT2212283 E PT 2212283E

Authority

PT

Portugal

Prior art keywords

methyl

bipyrrolidinyl

phenyl

amide

carboxylic acid

Prior art date

2007-10-17

Links

• Espacenet
• Global Dossier
• Discuss

• 230000001225 therapeutic effect Effects 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 170
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 40
• 201000010099 disease Diseases 0.000 claims abstract description 26
• 238000002360 preparation method Methods 0.000 claims abstract description 17
• 238000011282 treatment Methods 0.000 claims abstract description 11
• -1 bicyclo [2,2,1] heptyl Chemical group 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 41
• 230000000694 effects Effects 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• WSMQKESQZFQMFW-UHFFFAOYSA-N 5-methyl-pyrazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NN1 WSMQKESQZFQMFW-UHFFFAOYSA-N 0.000 claims description 16
• IJEUISLJVBUNRE-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-carboxylic acid Chemical compound CC1=NOC(C)=C1C(O)=O IJEUISLJVBUNRE-UHFFFAOYSA-N 0.000 claims description 15
• 208000035475 disorder Diseases 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• ADEHHNQEZMQYGS-UHFFFAOYSA-N 4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]aniline Chemical compound CC1CCCN1C1CN(C=2C=CC(N)=CC=2)CC1 ADEHHNQEZMQYGS-UHFFFAOYSA-N 0.000 claims description 11
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
• AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 claims description 11
• IHCCAYCGZOLTEU-UHFFFAOYSA-N 3-furoic acid Chemical compound OC(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-N 0.000 claims description 10
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 10
• JESWDXIHOJGWBP-JEAXJGTLSA-N (1r,4s)-bicyclo[2.2.1]heptane-3-carboxylic acid Chemical compound C1C[C@]2([H])C(C(O)=O)C[C@@]1([H])C2 JESWDXIHOJGWBP-JEAXJGTLSA-N 0.000 claims description 9
• 239000001257 hydrogen Substances 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
• SFHVXKNMCGSLAR-UHFFFAOYSA-N 2,2,3,3-tetramethylcyclopropanecarboxylic acid Chemical compound CC1(C)C(C(O)=O)C1(C)C SFHVXKNMCGSLAR-UHFFFAOYSA-N 0.000 claims description 7
• IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 claims description 7
• 125000001424 substituent group Chemical group 0.000 claims description 7
• SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 6
• 208000024827 Alzheimer disease Diseases 0.000 claims description 6
• JESWDXIHOJGWBP-UHFFFAOYSA-N bicyclo[2.2.1]heptane-3-carboxylic acid Chemical compound C1CC2C(C(=O)O)CC1C2 JESWDXIHOJGWBP-UHFFFAOYSA-N 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 230000007958 sleep Effects 0.000 claims description 6
• HXIYCKAAQPHZBM-UHFFFAOYSA-N 3-methyl-1,2-oxazole-5-carboxylic acid Chemical compound CC=1C=C(C(O)=O)ON=1 HXIYCKAAQPHZBM-UHFFFAOYSA-N 0.000 claims description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 125000002971 oxazolyl group Chemical group 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
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• 208000010877 cognitive disease Diseases 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• PXRXGHUTKHXUGF-UHFFFAOYSA-N 1,5-dimethylpyrazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NN1C PXRXGHUTKHXUGF-UHFFFAOYSA-N 0.000 claims description 3
• DKVILNAQMBVZGF-UHFFFAOYSA-N 2-cyclopentyl-n-[2-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]acetamide Chemical compound CC1CCCN1C1CN(C=2C=C(C)C(NC(=O)CC3CCCC3)=CC=2)CC1 DKVILNAQMBVZGF-UHFFFAOYSA-N 0.000 claims description 3
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
• 201000006417 multiple sclerosis Diseases 0.000 claims description 3
• 201000003631 narcolepsy Diseases 0.000 claims description 3
• ZETKRQDDYKMOPO-UHFFFAOYSA-N 2,2,3,3-tetramethyl-n-[4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]cyclopropane-1-carboxamide Chemical compound CC1CCCN1C1CN(C=2C=CC(NC(=O)C3C(C3(C)C)(C)C)=CC=2)CC1 ZETKRQDDYKMOPO-UHFFFAOYSA-N 0.000 claims description 2
• DKVILNAQMBVZGF-RXVVDRJESA-N 2-cyclopentyl-n-[2-methyl-4-[(3s)-3-[(2s)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]acetamide Chemical compound C[C@H]1CCCN1[C@@H]1CN(C=2C=C(C)C(NC(=O)CC3CCCC3)=CC=2)CC1 DKVILNAQMBVZGF-RXVVDRJESA-N 0.000 claims description 2
• YYOJXELLFPQIHG-UHFFFAOYSA-N 2-cyclopentyl-n-[3-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]acetamide Chemical compound CC1CCCN1C1CN(C=2C(=CC(NC(=O)CC3CCCC3)=CC=2)C)CC1 YYOJXELLFPQIHG-UHFFFAOYSA-N 0.000 claims description 2
• WRBZABSLXIGYJG-UHFFFAOYSA-N 2-cyclopentyl-n-[4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]acetamide Chemical compound CC1CCCN1C1CN(C=2C=CC(NC(=O)CC3CCCC3)=CC=2)CC1 WRBZABSLXIGYJG-UHFFFAOYSA-N 0.000 claims description 2
• IARMCEYEYXXEOS-UHFFFAOYSA-N 2-methyl-1,3-oxazole-4-carboxylic acid Chemical compound CC1=NC(C(O)=O)=CO1 IARMCEYEYXXEOS-UHFFFAOYSA-N 0.000 claims description 2
• PHKNKTBPYNCTGD-UHFFFAOYSA-N 3-pyridin-4-yl-1h-pyrazole-5-carboxylic acid Chemical compound N1C(C(=O)O)=CC(C=2C=CN=CC=2)=N1 PHKNKTBPYNCTGD-UHFFFAOYSA-N 0.000 claims description 2
• MFCDBOBISCCFMN-UHFFFAOYSA-N 5-(2-oxopyridin-1-yl)furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1N1C(=O)C=CC=C1 MFCDBOBISCCFMN-UHFFFAOYSA-N 0.000 claims description 2
• KYEPLUXUECKUNH-UHFFFAOYSA-N 5-methyl-n-[4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]-2-(trifluoromethyl)phenyl]-1h-pyrazole-3-carboxamide Chemical compound CC1CCCN1C1CN(C=2C=C(C(NC(=O)C3=NNC(C)=C3)=CC=2)C(F)(F)F)CC1 KYEPLUXUECKUNH-UHFFFAOYSA-N 0.000 claims description 2
• 208000005793 Restless legs syndrome Diseases 0.000 claims description 2
• 150000001408 amides Chemical class 0.000 claims description 2
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 2
• 230000033001 locomotion Effects 0.000 claims description 2
• KIDXBKRFIRDXFS-PXNSSMCTSA-N n-[2-methyl-4-[(3s)-3-[(2s)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]cyclopentanecarboxamide Chemical compound C[C@H]1CCCN1[C@@H]1CN(C=2C=C(C)C(NC(=O)C3CCCC3)=CC=2)CC1 KIDXBKRFIRDXFS-PXNSSMCTSA-N 0.000 claims description 2
• LFMNOHYCZLVTQR-UHFFFAOYSA-N n-[3-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide Chemical compound CC1CCCN1C1CN(C=2C(=CC(NC(=O)C3CC3)=CC=2)C)CC1 LFMNOHYCZLVTQR-UHFFFAOYSA-N 0.000 claims description 2
• YJTLIUOYMGJKGP-UHFFFAOYSA-N n-[4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide Chemical compound CC1CCCN1C1CN(C=2C=CC(NC(=O)C3CC3)=CC=2)CC1 YJTLIUOYMGJKGP-UHFFFAOYSA-N 0.000 claims description 2
• SJHGBCKOLDNGQX-UHFFFAOYSA-N n-[4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]oxane-4-carboxamide Chemical compound CC1CCCN1C1CN(C=2C=CC(NC(=O)C3CCOCC3)=CC=2)CC1 SJHGBCKOLDNGQX-UHFFFAOYSA-N 0.000 claims description 2
• UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 2
• 208000001797 obstructive sleep apnea Diseases 0.000 claims description 2
• 230000000737 periodic effect Effects 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 208000019116 sleep disease Diseases 0.000 claims description 2
• KWGIXLKUUUKGLB-RWMXSFHTSA-N (1r,4s)-n-[4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]bicyclo[2.2.1]heptane-3-carboxamide Chemical compound C1([C@@]2([H])CC[C@](C2)(C1)[H])C(=O)NC(C=C1)=CC=C1N(C1)CCC1N1CCCC1C KWGIXLKUUUKGLB-RWMXSFHTSA-N 0.000 claims 1
• 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims 1
• 239000003085 diluting agent Substances 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• MXIVMTFMGCHKJZ-UHFFFAOYSA-N n-[3-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]-1h-pyrazole-4-carboxamide Chemical compound CC1CCCN1C1CN(C=2C(=CC(NC(=O)C3=CNN=C3)=CC=2)C)CC1 MXIVMTFMGCHKJZ-UHFFFAOYSA-N 0.000 claims 1
• WZFYVAXGOJDHFD-UHFFFAOYSA-N n-[3-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]oxane-4-carboxamide Chemical compound CC1CCCN1C1CN(C=2C(=CC(NC(=O)C3CCOCC3)=CC=2)C)CC1 WZFYVAXGOJDHFD-UHFFFAOYSA-N 0.000 claims 1
• 208000020685 sleep-wake disease Diseases 0.000 claims 1
• 239000000543 intermediate Chemical class 0.000 abstract description 70
• 238000000034 method Methods 0.000 abstract description 36
• 102000004384 Histamine H3 receptors Human genes 0.000 abstract description 24
• 108090000981 Histamine H3 receptors Proteins 0.000 abstract description 24
• 210000003169 central nervous system Anatomy 0.000 abstract description 7
• KFIOZBMCNUODPK-UHFFFAOYSA-N n-phenyl-1-pyrrolidin-1-ylpyrrolidine-2-carboxamide Chemical class C1CCN(N2CCCC2)C1C(=O)NC1=CC=CC=C1 KFIOZBMCNUODPK-UHFFFAOYSA-N 0.000 abstract description 6
• 230000002265 prevention Effects 0.000 abstract description 3
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 145
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• 238000001819 mass spectrum Methods 0.000 description 82
• 239000000243 solution Substances 0.000 description 55
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• 230000008878 coupling Effects 0.000 description 38
• 238000010168 coupling process Methods 0.000 description 38
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
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• 238000006243 chemical reaction Methods 0.000 description 28
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
• 238000004809 thin layer chromatography Methods 0.000 description 26
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• 229910000027 potassium carbonate Inorganic materials 0.000 description 15
• 239000007858 starting material Substances 0.000 description 15
• 238000012360 testing method Methods 0.000 description 15
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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