WO2003014064A1 - Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists - Google Patents
Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists Download PDFInfo
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- WO2003014064A1 WO2003014064A1 PCT/EP2002/008493 EP0208493W WO03014064A1 WO 2003014064 A1 WO2003014064 A1 WO 2003014064A1 EP 0208493 W EP0208493 W EP 0208493W WO 03014064 A1 WO03014064 A1 WO 03014064A1
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- Prior art keywords
- straight
- branched
- chain
- represents hydrogen
- hydroxy
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- 239000005557 antagonist Substances 0.000 title claims description 13
- 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 title abstract description 6
- 108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 title abstract description 5
- FVSUYFWWFUVGRG-UHFFFAOYSA-N naphthalen-1-ylurea Chemical compound C1=CC=C2C(NC(=O)N)=CC=CC2=C1 FVSUYFWWFUVGRG-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 206010020853 Hypertonic bladder Diseases 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims abstract description 14
- 208000020629 overactive bladder Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 208000002193 Pain Diseases 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000004296 neuralgia Diseases 0.000 claims abstract description 10
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 8
- 238000011321 prophylaxis Methods 0.000 claims abstract description 8
- 208000028867 ischemia Diseases 0.000 claims abstract description 6
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 5
- 206010021639 Incontinence Diseases 0.000 claims abstract description 5
- 208000028389 Nerve injury Diseases 0.000 claims abstract description 5
- 208000004550 Postoperative Pain Diseases 0.000 claims abstract description 5
- 230000002917 arthritic effect Effects 0.000 claims abstract description 5
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 5
- 230000008764 nerve damage Effects 0.000 claims abstract description 5
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 5
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 5
- 201000001119 neuropathy Diseases 0.000 claims abstract description 5
- 230000007823 neuropathy Effects 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 137
- 239000001257 hydrogen Substances 0.000 claims description 136
- 229910052736 halogen Inorganic materials 0.000 claims description 71
- -1 1,2-oxazolyl Chemical group 0.000 claims description 66
- 150000002431 hydrogen Chemical class 0.000 claims description 64
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 58
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 57
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 57
- 150000002367 halogens Chemical class 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 43
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- 238000000034 method Methods 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 21
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 20
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 19
- 125000004423 acyloxy group Chemical group 0.000 claims description 17
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- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 239000004202 carbamide Substances 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 6
- PMCOWOCKUQWYRL-UHFFFAOYSA-N 2,4-dimethylpyrimidine Chemical group CC1=CC=NC(C)=N1 PMCOWOCKUQWYRL-UHFFFAOYSA-N 0.000 claims description 6
- AGQOIYCTCOEHGR-UHFFFAOYSA-N 5-methyl-1,2-oxazole Chemical group CC1=CC=NO1 AGQOIYCTCOEHGR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 6
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
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- 241001465754 Metazoa Species 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
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- 230000008569 process Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
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- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- QUVYSWLSKTVGPN-UHFFFAOYSA-N 1-(2,4-dichloro-7-hydroxynaphthalen-1-yl)-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C12=CC(O)=CC=C2C(Cl)=CC(Cl)=C1NC(=O)NC1=CC=CC(C(F)(F)F)=C1 QUVYSWLSKTVGPN-UHFFFAOYSA-N 0.000 claims description 2
- RWKJHDPYVBHRGC-UHFFFAOYSA-N 1-(2,4-dichloro-7-hydroxynaphthalen-1-yl)-3-naphthalen-2-ylurea Chemical compound C1=CC=CC2=CC(NC(=O)NC3=C(Cl)C=C(Cl)C4=CC=C(C=C43)O)=CC=C21 RWKJHDPYVBHRGC-UHFFFAOYSA-N 0.000 claims description 2
- UAJQYFDXIZOATJ-UHFFFAOYSA-N 1-(2-chloro-7-hydroxy-4-methylnaphthalen-1-yl)-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound C12=CC(O)=CC=C2C(C)=CC(Cl)=C1NC(=O)NC1=CC=C(Cl)C(C(F)(F)F)=C1 UAJQYFDXIZOATJ-UHFFFAOYSA-N 0.000 claims description 2
- OTBWGGGWPKILAZ-UHFFFAOYSA-N 1-(2-chloro-7-hydroxynaphthalen-1-yl)-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound C12=CC(O)=CC=C2C=CC(Cl)=C1NC(=O)NC1=CC=C(Cl)C(C(F)(F)F)=C1 OTBWGGGWPKILAZ-UHFFFAOYSA-N 0.000 claims description 2
- NQQNJZDLZJFIOJ-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-(2,4-dibromo-7-hydroxynaphthalen-1-yl)urea Chemical compound C12=CC(O)=CC=C2C(Br)=CC(Br)=C1NC(=O)NC1=CC=CC(Cl)=C1 NQQNJZDLZJFIOJ-UHFFFAOYSA-N 0.000 claims description 2
- HMAQYLBTVQMQEW-UHFFFAOYSA-N 1-(7-hydroxynaphthalen-1-yl)-3-(3-phenoxyphenyl)urea Chemical compound C12=CC(O)=CC=C2C=CC=C1NC(=O)NC(C=1)=CC=CC=1OC1=CC=CC=C1 HMAQYLBTVQMQEW-UHFFFAOYSA-N 0.000 claims description 2
- LDIVDCFRZPZVRB-UHFFFAOYSA-N 1-(7-hydroxynaphthalen-1-yl)-3-(3-phenylphenyl)urea Chemical compound C12=CC(O)=CC=C2C=CC=C1NC(=O)NC(C=1)=CC=CC=1C1=CC=CC=C1 LDIVDCFRZPZVRB-UHFFFAOYSA-N 0.000 claims description 2
- BEWBRYIDOSDRIG-UHFFFAOYSA-N 1-(7-hydroxynaphthalen-1-yl)-3-(4-phenoxyphenyl)urea Chemical compound C12=CC(O)=CC=C2C=CC=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=CC=C1 BEWBRYIDOSDRIG-UHFFFAOYSA-N 0.000 claims description 2
- YWBIXRPISDZDFB-UHFFFAOYSA-N 1-(7-hydroxynaphthalen-1-yl)-3-[4-(trifluoromethyl)phenyl]urea Chemical compound C12=CC(O)=CC=C2C=CC=C1NC(=O)NC1=CC=C(C(F)(F)F)C=C1 YWBIXRPISDZDFB-UHFFFAOYSA-N 0.000 claims description 2
- ZRSZJNHYCMSVMV-UHFFFAOYSA-N 1-[(4-bromophenyl)methyl]-3-(2-chloro-7-hydroxynaphthalen-1-yl)urea Chemical compound C12=CC(O)=CC=C2C=CC(Cl)=C1NC(=O)NCC1=CC=C(Br)C=C1 ZRSZJNHYCMSVMV-UHFFFAOYSA-N 0.000 claims description 2
- DUKGABGSVDUZQB-UHFFFAOYSA-N 1-[3-(2-chlorophenyl)phenyl]-3-(2,4-dichloro-7-hydroxynaphthalen-1-yl)urea Chemical compound C12=CC(O)=CC=C2C(Cl)=CC(Cl)=C1NC(=O)NC(C=1)=CC=CC=1C1=CC=CC=C1Cl DUKGABGSVDUZQB-UHFFFAOYSA-N 0.000 claims description 2
- TUHPCXUFNGDOIQ-UHFFFAOYSA-N 1-[4-(4-chlorophenoxy)phenyl]-3-(7-hydroxynaphthalen-1-yl)urea Chemical compound C12=CC(O)=CC=C2C=CC=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 TUHPCXUFNGDOIQ-UHFFFAOYSA-N 0.000 claims description 2
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008275 solid aerosol Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000012762 unpaired Student’s t-test Methods 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 239000000105 vanilloid receptor agonist Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- CAWZRIXWFRFUQB-IOSLPCCCSA-N α,β Methylene ATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)CP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O CAWZRIXWFRFUQB-IOSLPCCCSA-N 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/38—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by doubly-bound oxygen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/42—Y being a carbon atom of a six-membered aromatic ring
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/10—Radicals substituted by halogen atoms or nitro radicals
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
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- C07D261/14—Nitrogen atoms
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
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- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
Definitions
- the present invention relates to an amine derivative, which is useful as an active ingredient of pharmaceutical preparations.
- the amine derivatives of the present invention have vanilloid receptor 1 (VRl) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with VRl activity, in particular for the treatment of urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and/or inflammatory disorders.
- VRl vanilloid receptor 1
- Vanilloid compounds are characterized by the presence of vanillyl group or a functionally equivalent group.
- vanilloid compounds or vanilloid receptor modulators are vanillin (4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2- methoxy-phenol), zingerone (4-/4-hydroxy-3-methoxyphenyl/-2-butanon), eugenol
- capsaicin the main pungent ingredient in "hot” chili peppers
- capsaicin is a specific neurotoxin that desensitizes C-fiber afferent neurons.
- Capsaicin and its analogues such as resiniferatoxin, are shown to be effective in the treatment of urological disorder e.g., urinary incontinence and overactive bladder, due to the desensitization of C-fiber afferent neurons [(Michael B Chancellor and William C. de Groat, The Journal of Urology Vol. 162, 3-11, 1999) and (K.E. Andersson et al., BJU International, 84, 923-947, 1999)].
- the mechanism in which capsaicin and other analogues cause the desensitization of C-fiber afferent neurons is very complicated.
- Vanilloid receptor is a specific neuronal membrane recognition site for capsaicin. It is expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation. The VR functions as a cation-selective ion channel with a preference for calcium. Capsaicin interacts with VRl, which is a functional subtype of the VR and predominantly expressed in cell bodies of dorsal root ganglia (DRG) or nerve endings of afferent sensory fibers including C-fiber nerve endings [Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H,
- VRl can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit neuronal signals in a pathological conditions or diseases.
- antagonists of the VRl can be used for prophylaxis and treatment of the condition and diseases including urology disorder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and inflammatory disorders.
- Urology disorder used herein refers to e.g., urinary incontinence and overactive bladder.
- Urinary incontinence and overactive bladder encompass detrusor hyper-reflexia, detrusor instability and urgency/- frequency syndrome, such as urge urinary incontinence and the like.
- WO 00/50387 discloses the compounds having a vanilloid receptor agonist activity represented by the general formula:
- X p is an oxygen or sulfur atom
- a p is -NHCH 2 - or -CH 2 -;
- R a is a substituted or unsubstituted C 1-4 alkyl group, or R aI CO-;
- R al is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or substituted or unsubstituted aryl group having 6 to 10 carbon atoms;
- R b is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom;
- R is a hydrogen atom, an alkyl group having 1 to 4 carbon atom, an aminoalkyl, a diacid monoester or ⁇ -alkyl acid;
- the asteric mark * indicates a chiral carbon atom, and their pharmaceutically acceptable salts.
- /61581 discloses amine derivatives represented by the general formula:
- R R represent (F, F), (CF 3 , H), or (iPr, iPr)
- R 90 is hydrogen, C 1-12 alkyl, C 3-8 cycloalkyl, or the like, and R 91 is amino-C 1-6 alkyl, aminocarbonyl-C 1-6 alkyl, or hydroxyamino- carbonyl C 1-6 alkyl; and
- R 90 and R 91 are independently selected from the group consisting of H, C ⁇ - 6 alkyl, C ⁇ -6 alkylthio, C ⁇ -6 alkoxy, fluoro, chloro, bromo, iodo, and nitro;
- This invention is to provide the following general formula (I), its tautomeric or stereoisomeric form, and the salts thereof:
- X represents C 3-8 cycloalkyl optionally fused by benzene, t ienyl, thienyl straight alkyl, quinolyl, 1,2-oxazolyl substituted by R 1 , naphthyl optionally substituted by R 4 and R 5 , phenyl fused by C 4-8 cycloalkyl, phenyl fused by saturated C 4-8 heterocycle having one or two O atoms, carbazolyl of which N-H is substituted by N-R 1 , phenyl fused by indanone, phenyl fused by indan, phenyl fused by cyclohexanone, phenyl fused by dihydrofuranone, phenyl substituted by R 1 , R 2 and R 3 , phenyl C 1-6 straight alkyl of which phenyl is substituted by R 1 , R 2 and
- R 3 phenyl fused by unsaturated 5-6 membered hetero ring having one or two hetero atoms selected from the group consisting of N, O, S, and SO , wherein the hetero ring is optionally substituted by R 1 ,
- R 1 , R 2 and R 3 are identical or different and represent hydrogen, halogen, straight-chain or branched C ⁇ -6 alkyl, straight-chain or branched Cj -6 alkylcarbamoyl, carbamoyl, straight-chain or branched Cj -6 alkoxy, carboxyl, nitro, amino, straight-chain or branched C ⁇ -6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, morpholino, straight-chain or branched C 1-6 alkoxycarbonyl, benzyl, phenoxy, halogen substituted phenoxy, straight-chain or branched C 1-6 alkylthio, straight-chain or branched C 1-6 alkanoyl, straight-chain or branched C 1-6 alkanoylamino, hydroxy substituted straight-chain or branched C 1-6 alkyl, mono-, di- or tri- halogen substituted straight-chain or branched C
- the substituents are each identical or different and selected from the group consisting of hydrogen, halogen, straight-chain or branched C ⁇ - 6 alkoxy, straight-chain or branched C 1-6 alkyl, straight-chain or branched C 1-6 alkanoyl, and carboxy;
- R represents hydrogen, hydroxy, or straight-chain or branched C 1-6 alkoxy
- R 5 represents hydrogen, hydroxy, or straight-chain or branched C 1-6 alkoxy
- Q represents CH or N
- R 6 represents hydrogen or methyl
- R 7 represents hydrogen or methyl
- R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3- cycloalkyl- methoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, straight-chain or branched C 1-6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, C 1-6 alkylsulfonamino, or the group represented by the formula
- R and R 81 are each identical or different and represent hydrogen, halogen, or straight-chain or branched C 1-6 alkoxy;
- R 8a represents hydrogen or halogen
- R 9 and R ⁇ are each identical or different and represent hydrogen, halogen, or nitro
- R 10 represents hydrogen, halogen, carboxy, carbamoyl, cyano, or straight-chain or branched C 1-6 alkyl optionally substituted by the substituent, which substituent is selected from the group consisting of hydroxy, amino, di(straight-chain or branched C 1-6 alkyl)amino, piperidino, morpholino, and methyl- piperazino.
- the compounds of the present invention suprisingly show excellent VRl antagonistic activity. They are, therefore, suitable especially as VRl antagonists and in particular for the production of medicament or medical composition, which may be useful to treat urological disorder. Since the amine derivatives of the present invention antagonize VRl activity, they are useful for treatment and prophylaxis of diseases as follows: urology disorder (e.g., urinary incontinence and overactive bladder), chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and/or inflammatory disorders.
- urology disorder e.g., urinary incontinence and overactive bladder
- chronic pain e.g., neuropathic pain, postoperative pain, rheumatoid arthritic pain
- neuralgia e.g., nerve injury, ischaemia, neurodegeneration, stroke,
- the amine derivative of the formula (I) is those wherein;
- R , R and R are different or identical and represent hydrogen, halogen, straight-chain or branched d- 6 alkyl, straight-chain or branched C 1-6 alkylcarbamoyl, carbamoyl, straight-chain or branched C 1-6 alkoxy, carboxyl, nitro, amino, straight-chain or branched C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, morpholino, straight-chain or branched C 1-6 alkoxycarbonyl, benzyl, phenoxy, halogen substituted phenoxy, straight-chain or branched C 1-6 alkylthio, straight-chain or branched C 1-6 alkanoyl, straight-chain or branched C 1-6 alkanoylamino, hydroxy substituted straight-chain or branched C 1-6 alkyl, mono-, di- or tri- halogen substituted straight-chain or branched C 1-6 alkyl,
- the substituents are each different or identical and selected from the group consisting of hydrogen, halogen, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C ⁇ -6 alkyl, straight-chain or branched C 1-6 alkanoyl, and carboxy;
- R 4 represents hydrogen, hydroxy, or straight-chain or branched C 1-6 alkoxy;
- R 5 represents hydrogen, hydroxy, or straight-chain or branched C ⁇ -6 alkoxy
- R .6 represents hydrogen or methyl
- R 7 represents hydrogen or methyl
- R 8 represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 C 3-6 cycloalkylmethoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, straight-chain or branched Cj -6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C ⁇ -6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, straight-chain or branched C ⁇ -6 alkylsulfonamino, or the group represented by the formula wherein
- R 80 and R 81 are each identical or different and represent hydrogen, halogen, or straight-chain or branched Cj_ 6 alkoxy;
- R 8a represents hydrogen or halogen
- R 9 represents hydrogen or halogen
- R 10 represents hydrogen, halogen, or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
- R u represents hydrogen, halogen, or nitro
- the amine derivative of the formula (I) is those wherem;
- R 6 represents hydrogen
- R represents hydrogen
- R 8 represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight- chain or branched C ⁇ -6 alkanoyloxy, C 3- C 3-6 cycloalkylmethoxy, straight-chain or branched C -6 alkenyloxy, benzoyloxy, amino, straight-chain or branched C 1-6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, or C 1-6 alkylsulfonamino;
- R , 8a represents hydrogen, chloro, or fluoro
- R represents hydrogen or halogen
- R .10 represents hydrogen, halogen or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
- R l represents hydrogen or halogen
- the amine derivative of the formula (I) is those wherein;
- R represents hydrogen
- R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 C 3-6 cycloalkylmethoxy, straight-chain or branched C -6 alkenyloxy, benzoyloxy, amino, straight-chain or branched C 1-6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, or straight-chain or branched C 1-6 alkylsulfonamino;
- R a represents hydrogen
- R represents hydrogen, bromo, chloro, or fluoro
- R 10 represents hydrogen,halogen or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
- R 1 ' represents hydrogen, chloro, or fluoro
- the amine derivative of the fo ⁇ nula (I) is those wherein;
- R ) 6 represents hydrogen
- R 7 represents hydrogen
- R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 cyclo- alkylmethoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, or straight-chain or branched C 1-6 alkylamino;
- R a represents hydrogen
- R ,9 represents bromo or chloro
- R , 10 represents bromo, chloro, or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
- R , ⁇ represents hydrogen
- the amine derivative of the formula (I) is those wherein;
- R > 6 represents hydrogen
- R 7 represents hydrogen
- R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 cycloalkyl- methoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, or straight-chain or branched C 1-6 alkylamino;
- R ,8a represents hydrogen
- R represents chloro
- R , 10 represents chloro
- R 11 represents hydrogen
- the present invention further provides the medicament having one of the compounds mentioned-above and one or more pharmaceutically acceptable excipients.
- the compound of the formula (I) of the present invention can be, but not limited to be, prepared by the general methods [A]-[K] below.
- one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3 rd Edition, John Wiley, New York, 1999)" by Greene and Wuts.
- the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, tetrahydrofuran (
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
- the substituted naphthylamine and isocyanate are commercially available or can be prepared by the use of known techniques.
- the compound [I-b] and the compound [I-b ], wherein R 6 , R 7 , R 8a , R 8 ', R 9 , R 10 , R 11 , and X are the same as defined above, can be prepared by (1) reacting a substituted naphthylamine and phenylchloroformate, and (2) adding amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) to the reaction mixture.
- the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chlorofo ⁇ n and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chlorofo ⁇ n and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, te
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 50°C.
- the reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.
- the reaction can be advantageously carried out in the presence of a base including, for instance, an alkali metal hydride such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N- diisopropylethylamine, and others.
- a base including, for instance, an alkali metal hydride such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N- diisopropylethylamine, and others.
- the reaction (2) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N- dimethylaceta ide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 120°C.
- the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
- substituted naphthylamine, phenylchloroformate and amine are commercially available or can be prepared by the use of known techniques.
- X are the same as defined above, can be prepared by the reaction of a substituted naphthylamine carbamate and amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above).
- the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloro- form and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran
- THF 1,2-dimethoxyethane
- aromatic hydrocarbons such as benzene, toluene and xylene
- ketones such as acetone
- nitriles such as acetonitrile
- amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone
- sulfoxides such as dimethylsulfoxide (DMSO); and others.
- two or more of the solvents selected from the listed above can be mixed and used.
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 120°C.
- the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
- the compound [I-d] and the compound [I-d ' ] 5 wherein R 6 , R 7 , R 8a , R 9 , R 10 , R ⁇ , and X are the same as defined above, can be prepared by (1) reacting a substituted naphthylamine carbamate and amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above), and (2) adding base to the reaction mixture.
- the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF)
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 120°C.
- the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
- the reaction (2) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); alcohol such as tert-butanol, methanol and ethanol; water, and others.
- halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
- ethers such as diethylether, dioxan
- two or more of the solvents selected from the listed above can be mixed and used.
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 30°C to 100°C.
- the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
- the base used in the reaction (2) can be, for instance, alkali metal alkoxide such as sodium methoxide and sodium ethoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, and others.
- the compound [I-e] and the compound [I-e ' ], wherein R 7 , R 8' , R 8a , R 9 , R 10 , R 11 , and X are the same as defined above, can be prepared by (1) reacting amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) and 1,1'- carbonyldi(l,2,4-triazole) (CDT) and (2) adding substituted naphthylamine to the reaction mixture.
- amine represented by the formula X-NH-R 6 wherein R 6 and X are the same as defined above
- CDT 1,1'- carbonyldi(l,2,4-triazole)
- the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 40 hours and preferably 1 to 24 hours.
- the reaction (2) may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide
- halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
- ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 30°C to 100°C.
- the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
- the compound [I-fJ and the compound [l-f ], wherein R 6 , R 7 , R 8' R 8a , R 9 , R 10 , R 11 and X is the same as defined above, can be prepared by (1) reacting a substituted naphthylamine and l,l '-carbonyldi(l,2,4-triazole) (CDT), and (2) adding amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) to the reaction mixture.
- the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydro- furan (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydro- furan (
- the reaction temperature can be optionally set depending on The reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.
- the reaction (2) may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 100°C.
- the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
- the substituted naphthylamine, l,l'-carbonyldi(l,2,4-triazole) (CDT) and amine are commercially available or can be prepared by the use of known techniques.
- the reaction may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 20°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 40 hours and preferably 1 to 24 hours.
- the reaction can be advantageously conducted in the presence of substance having catalytic activity.
- substances include, but not limited to, copper salts, such as copper (II) acetate, or the like.
- the reaction can also be advantageously carried out in the presence of a base including, for instance, organic amines such as triethylamine and N,N-diiso- propylethylamine, and the others.
- arylboronic acid and coper salts are commercially available or can be prepared by the use of known techniques.
- the compound [I-h] and the compound [I-h'], wherein R 82 is hydrogen, or straight- chain or branched C 1-6 alkyl, R 83 is hydrogen, straight-chain or branched C 1-6 alkyl, or phenyl Cj -6 alkyl, R 8a is halogen, R 9 , R 10 and X are the same as defined above, can be prepared by reacting a substituted naphthylamine and suitable halogenating agents, for instance, N-halosuccinimides such as N-chlorosuccinimide and N-bromo- succinimide; and N-fluoro-pyridium salts such as N-fluoro-4-methylpyridinium-2- sulfonate, and others.
- suitable halogenating agents for instance, N-halosuccinimides such as N-chlorosuccinimide and N-bromo- succinimide; and N-fluoro-pyridium salts such as N-fluor
- the reaction may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, and others.
- halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
- ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane
- aromatic hydrocarbons such as benzene, and others.
- two or more of the solvents selected from the listed above can be mixed and used.
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 0°C to 60°C.
- the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
- substituted naphthylamine and halogenating agents are commercially available or can be prepared by the use of known techniques.
- the compound [I-i] and the compound [I-i'], wherein R 85 represents hydrogen or straight-chain or branched C 1-6 alkyl and R 6 , R 7 , R 8a , R 9 , R 10 , R 11 and X is the same as defined above, can be prepared by reacting a substituted naphthylamine and suitable acylating agents, for instance, carboxylic anhydrides such as formic anhydride, and acetic anhydride; acyl halides such as acetyl chloride, and others.
- suitable acylating agents for instance, carboxylic anhydrides such as formic anhydride, and acetic anhydride; acyl halides such as acetyl chloride, and others.
- the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF)
- the reaction can be advantageously ca ⁇ ied out in the presence of a base including, for instance, alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
- a base including, for instance, alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 0°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 10 hours.
- substituted naphthylamine and acylating agents are commercially available or can be prepared by the use of known techniques.
- the compound [I-j]and the compound [I-j'], wherein R 86 is straight-chain or branched C ⁇ -6 alkyl and R 6 , R 7 , R 8a , R 9 , R 10 , R 11 and X is the same as defined above, can be prepared by reacting a substituted naphthylamine and alkylsulfonyl chloride such as methanesulfonyl chloride, ethanesulfonyl chloride and others.
- the reaction may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
- a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
- the reaction can be advantageously carried out in the presence of a base including, for instance, alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
- a base including, for instance, alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 0°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
- substituted naphthylamine and alkylsulfonyl chlorides are commercially available or can be prepared by the use of known techniques.
- the compound [I-k] and the compound [I-k'], wherein R 6 , R 7 , R 9 , R 10 , R 11 , and X are the same as defined above, can be prepared by (l)the reacting a substituted naphthalene and amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) (2) adding fluoride salts, such as tetrabutylamonium fluoride to the reaction mixture.
- the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxy ethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide
- DMSO dimethylethyl-N-(2-amino- ⁇ ropyl)-3-ethylcarbodiimide
- coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and l-(3-dimethylamino- ⁇ ropyl)-3-ethylcarbodiimide, and others.
- the reaction may be advantageously ca ⁇ ied out in the presence of a base including, for instance, organic amines such as pyridine, 4-dimethlyaminopyridine, triethylamine and N,N-diisopropylethylamine, and others.
- a base including, for instance, organic amines such as pyridine, 4-dimethlyaminopyridine, triethylamine and N,N-diisopropylethylamine, and others.
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 0°C to 60°C.
- the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
- the reaction (2) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide
- halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
- ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane
- the reaction temperature can be optionally set depending on the compounds to be reacted.
- the reaction temperature is usually, but not limited to, about 0°C to 100°C.
- the reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.
- substituted naphthalene, amine, and fluoride salt are commercially available or can be prepared by the use of known techniques.
- compound shown by the formula (I) or a salt thereof has tautomeric isomers and/or stereoisomers (e.g., geometrical isomers and conformational isomers), each of their separated isomer and mixtures are also included in the scope of the present invention.
- Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
- Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like
- organic acids such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
- inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
- the compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
- the compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
- the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
- the dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
- the compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.
- Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
- compositions of the present invention are pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore.
- the active ingredient may be mixed with a diluent, or enclosed within a ca ⁇ ier, which may be in the form of a capsule, sachet, paper, or other container.
- the ca ⁇ ier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
- a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
- the active ingredient may be combined with an oral, and nontoxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium
- the ca ⁇ ier may be a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
- the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
- Suitable solid ca ⁇ iers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.
- Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
- the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
- a suitable organic solvent for example, aqueous propylene glycol.
- Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.
- the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
- a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
- a "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
- the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more accordmg to the particular treatment involved.
- Typical oral dosages of the present invention when used for the indicated effects, will range from about 0.0 lmg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
- parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to lOOmg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
- the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
- Fig. 1 presents charts showing bladder capacity and voiding frequency in normal rats, cyclophosphamide treated rats (vehicle) and CYP-VR1 antagonist treated rats.
- Fig. 2 presents graphs which shows the bladder capacity in normal rats, cyclophosphamide treated rats (vehicle), and CYP-VR1 antagonist treated rats.
- Fig. 3 presents graphs which shows the micturition frequency in normal rats, cyclophosphamide treated rats (vehicle), and CYP-VR1 antagonist treated rats.
- Human vanilloid receptor (hVRl) cDNA was cloned from libraries of axotomized dorsal root ganglia (WO2000/29577). The cloned hVRl cDNA was constructed with pcDNA3 vector and transfected into a CHOluc9aeq cell line. The cell line contains aequorin and CRE-luciferase reporter genes as read-out signals.
- the transfectants were cloned by limiting dilution in selection medium (DMEM/F12 medium (Gibco BRL) supplemented with 10% FCS, 1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg/ml G418). Ca 2+ influx was examined in the capsaicin-stimulated clones. A high responder clone was selected and used for further experiments in the project.
- the human VRl-CHOluc9aeq cells were maintained in the selection medium and passaged every 3-4 days at l-2.5xl0 5 cells/flask (75 mm 2 ).
- Human VRl-CHOluc9aeq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1,000 cells per well into 384-well plates (black walled clear-base / Nalge
- DRG dorsal root ganglia
- DRG was incubated with 0.1% trypsin (Gibco BRL) in PBS(-) (Gibco BRL) for 30 min at 37°C, then a half volume of fetal calf serum (FCS) was added and the cells were spun down.
- FCS fetal calf serum
- the DRG neuron cells were resuspended in Ham F12/5% FCS/5% horse serum (Gibco BRL) and dispersed by repeated pipetting and passing through 70 ⁇ m mesh (Falcon). The culture plate was incubated for 3 hours at 37°C to remove contaminating Schwann cells.
- Non-adherent cells were recovered and further cultured in laminin-coated 384 well plates (Nunc) at lxlO 4 cells/50 ⁇ l/well for 2 days in the presence of 50 ng/ml recombinant rat NGF (Sigma) and 50 ⁇ M 5- fluorodeoxyuridine (Sigma).
- Bladder strips were equilibrated for 60 min before each stimulation. Contractile response to 80 mM KCl was determined at 15 min intervals until reproducible responses were obtained. The response to KCl was used as an internal standard to evaluate the maximal response to capsaicin. The effects of the compounds were investigated by incubating the strips with compounds for 30 min prior to the stimulation with 1 ⁇ M of capsaicin (Nacalai Tesque) (vehicle: 80% saline, 10% EtOH, and 10% Tween 80). One of the preparations made from the same animal was served as a control while the others were used for evaluating compounds. Ratio of each capsaicin-induced contraction to the internal standard (i.e. KCl-induced contraction) was calculated and the effects of the test compounds on the capsaicin-induced contraction were evaluated.
- capsaicin Nacalai Tesque
- Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.2 g/kg.
- the abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder tlirough the dome.
- a polyethylene catheter (Hibiki, size 5) filled with 2 IU / ml of heparin (Novo Heparin, Aventis Pharma, France) in saline (Otsuka) was inserted into a femoral vein.
- the bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinj ection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 3.6 ml/hr. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, conesponding to a 20-minute period, were recorded before a test compound administration and used as baseline values. (4) Administration of test compounds and stimulation of bladder with capsaicin
- the saline infusion was stopped before administrating compounds.
- a testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1 : 1 : 8, v/v/v) was administered intraarterially at 3mg/kg or
- saline including 30 ⁇ M of capsaicin (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml/hr.
- capsaicin-induced intravesical pressure were analyzed from the cystometry data.
- the capsaicin-induced bladder pressures were compared with the maximum bladder pressure during micturition without the capsaicin stimulation.
- the testing compounds-mediated inhibition of the increased bladder pressures was evaluated using Student's t- test. A probability level less than 5% was accepted as significant difference.
- Cyclophosphamide (CYP) dissolved in saline was administered intra- peritoneally at 150 mg/kg 48 hours before experiment.
- Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg. The abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. In parallel, the inguinal region was incised, and a polyethylene catheter (BECTON DICKINSON, PE50) filled with saline (Otsuka) was inserted into a femoral vein. After the bladder was emptied, the rats were left for 1 hour for recovery from the operation.
- urethane Sigma
- the bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinj ection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 3.6 ml/hr for 20 min. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, conesponding to a 20-minute period, were recorded before a test compound administration.
- a testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1 : 1 : 8, v/v/v) was administered intravenously at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg. 3min after the administration of the compound, saline (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml/hr.
- the cystometry parameters were analyzed as described previously [ Lecci A et al: Eur. J. Pharmacol. 259: 129-135, 1994].
- the micturition frequency calculated from micturition interval and the bladder capacity calculated from a volume of infused saline until the first micturition were analyzed from the cystometry data.
- the testing compounds-mediated inhibition of the frequency and the testing compounds-mediated increase of bladder capacity were evaluated using unpaired Student's t-test. A probability levels less than 5% was accepted as significant difference. Data were analyzed as the mean + SEM from 4 - 7 rats.
- Human P2X1 -transfected CHOluc9aeq cell line was established and maintained in Dulbecco's modified Eagle's medium (DMEM/F12) supplemented with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM sodium pyruvate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine (Gibco BRL) and 0.5 Units/ml apyrase (grade I, Sigma).
- the suspended cells were seeded in each well of 384-well optical bottom black plates (Nalge Nunc International) at 3 x IO 3 / 50 ⁇ l / well. The cells were cultured for following 48 hrs to adhere to the plates.
- P2X1 receptor agonist-mediated increases in cytosolic Ca levels were measured using a fluorescent Ca 2+ chelating dye, Fluo-3 AM (Molecular Probes).
- the plate-attached cells were washed twice with washing buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units/ml apyrase), and incubated in 40 ⁇ l of loading buffer (1 ⁇ M Fluo-3 AM, 1 mM probenecid, 1 ⁇ M cyclosporin A, 0.01% pluronic (Molecular Probes)in washing buffer) for 1 hour in a dark place.
- IC 50 value of equal to or below 10 nM.
- the compounds of the present invention also show excellent selectivity, and strong activity in other assays (2)-(4) described above.
- N,N-dimethylformamide 100 mL
- Phosphorus oxychloride 61.2 g, 399.2 mmol
- N,N-dibenzyl-7-(benzyloxy)-l-naphthalenamine 49.0 g, 114.1 mmol
- the mixture was stined at room temperature for 16 hours, and then poured into ice- water.
- the product mixture was extracted with dichloromethane, and the organic layer was washed with water, aqueous sodium bicarbonate, and brine.
- N,N-dimethylformamide 100 mL
- Phosphorus oxychloride 61.2 g, 399.2 mmol
- N,N-dibenzyl-7-(benzyloxy)-l-naphthalenamine 49.0 g, 114.1 mmol
- the mixture was stined at room temperature for 16 hours, and then poured into ice- water.
- the product mixture was extracted with dichloromethane, and the organic layer was washed with water, aqueous sodium bicarbonate, and brine.
- This example was performed according to the general method A.
- This example was performed according to the general method B.
- N-(l, -biphenyl-3-yl)-N'-(2-chloro-7-hydroxy-l-naphthyl)urea 102.1 mg, 87.5 %).
- This example was performed according to the general method C.
- This example was performed according to the general method D.
- This example was performed according to the general method E.
- This example was performed according to said method F.
- Methyl 3-aminobenzoate (60.5mg, 0.4mmol) was added to the suspension at room temperature. The reaction mixture was stirred at 50°C for 15hrs. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and ethanol (1:1), and it was passed through a silicagel short cartridge (lg Si / 6ml). The cartridge was washed with a mixture of ethyl acetate and ethanol (1:1). The combined filtrates were concentrated to give the dark purple solid.
- This example was performed according to the general method H.
- the compounds of the present invention inhibit the capsaicin-induced increase of intracellular calcium levels (Ca 2+ flux) in the cell line expressing human VRl in a concentration dependent manner with IC 5 o values.
- Functional activity (Ca 2+ flux) in the capsaicin-stimulated rat DRG cells is inhibited by the tested compounds.
- Significant inhibition of the capsaicin-induced rat bladder detrusor contraction is observed for most of the tested compounds.
- Selectivity over other ion channel receptors such as P2X1 and P2X3 is high - more than 100 fold.
- the effect of one of the compound of the present invention (VRl antagonist) on the capsaicin-induced overactive bladder in vivo in anesthetized rats is investigated.
- the overactive bladder is induced by intravesical infusion of capsaicin solution.
- the frequency of the micturition is compared.
- VRl antagonist inhibits the capsaicin-induced increase of micturition reflex at 3 or 10 mg/kg.
- assay 5 the effect of VRl antagonists of the present invention on cyclophosamide induced cystitis in anesthetized rats is investigated.
- Significant improvement of both bladder capacity (Fig. 1 and Fig. 2) and micturition frequency (Fig. 1 and Fig. 3) is observed at a dosage of 0.5 mg/kg, i.v. and 5 mg/kg, i.v.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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EP02758413A EP1414788A1 (en) | 2001-07-31 | 2002-07-31 | Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists |
US10/485,481 US20040259875A1 (en) | 2001-07-31 | 2002-07-31 | Amine derivatives |
CA002455754A CA2455754A1 (en) | 2001-07-31 | 2002-07-31 | Amine derivatives |
AU2002325381A AU2002325381A1 (en) | 2001-07-31 | 2002-07-31 | Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists |
JP2003524319A JP2005501873A (ja) | 2001-07-31 | 2002-07-31 | アミン誘導体 |
Applications Claiming Priority (4)
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JP232503-2001 | 2001-07-31 | ||
JP2001232503A JP2003055209A (ja) | 2001-07-31 | 2001-07-31 | フェニルナフチル尿素誘導体 |
JP392310-2001 | 2001-12-25 | ||
JP2001392310 | 2001-12-25 |
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WO2003014064A1 true WO2003014064A1 (en) | 2003-02-20 |
WO2003014064A8 WO2003014064A8 (en) | 2003-11-27 |
Family
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Family Applications (1)
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PCT/EP2002/008493 WO2003014064A1 (en) | 2001-07-31 | 2002-07-31 | Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists |
Country Status (6)
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AU2002325381A1 (en) | 2003-02-24 |
US20040259875A1 (en) | 2004-12-23 |
JP2005501873A (ja) | 2005-01-20 |
WO2003014064A8 (en) | 2003-11-27 |
EP1414788A1 (en) | 2004-05-06 |
CA2455754A1 (en) | 2003-02-20 |
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