NO326158B1 - Nye benzazepiner og beslektede heterocykliske derivater, farmasoytiske preparater inneholdende slike og fremgangsmate for fremstilling av slike samt slike forbindelser for anvendelse som medikament - Google Patents
Nye benzazepiner og beslektede heterocykliske derivater, farmasoytiske preparater inneholdende slike og fremgangsmate for fremstilling av slike samt slike forbindelser for anvendelse som medikament Download PDFInfo
- Publication number
- NO326158B1 NO326158B1 NO20032905A NO20032905A NO326158B1 NO 326158 B1 NO326158 B1 NO 326158B1 NO 20032905 A NO20032905 A NO 20032905A NO 20032905 A NO20032905 A NO 20032905A NO 326158 B1 NO326158 B1 NO 326158B1
- Authority
- NO
- Norway
- Prior art keywords
- dimethoxy
- benzyl
- benzo
- tetrahydro
- azepin
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 title claims description 6
- 150000008038 benzoazepines Chemical class 0.000 title abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 3
- 239000004480 active ingredient Substances 0.000 claims abstract 3
- 125000004321 azepin-2-yl group Chemical group [H]N1C([H])=C([H])C([H])=C([H])C([H])=C1* 0.000 claims description 150
- 239000000203 mixture Substances 0.000 claims description 61
- -1 for example Chemical class 0.000 claims description 48
- ZRJOKIUEJIOAPR-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetic acid Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C(O)=O)C1=CC=CC=C1 ZRJOKIUEJIOAPR-UHFFFAOYSA-N 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 102000002512 Orexin Human genes 0.000 claims description 16
- 108060005714 orexin Proteins 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 13
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- 208000008589 Obesity Diseases 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 235000020824 obesity Nutrition 0.000 claims description 7
- 229940080818 propionamide Drugs 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000005493 quinolyl group Chemical group 0.000 claims description 7
- 208000019116 sleep disease Diseases 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- LSBDFXRDZJMBSC-UHFFFAOYSA-N Amide-Phenylacetic acid Natural products NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 5
- ZDGREJASPPCBKV-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenyl-n-(pyrazin-2-ylmethyl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=CN=CC=N1 ZDGREJASPPCBKV-UHFFFAOYSA-N 0.000 claims description 5
- OODOKBUERXZTEM-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-(3-ethoxypropyl)-2-phenylacetamide Chemical compound C=1C=CC=CC=1C(C(=O)NCCCOCC)N1CCCC2=CC(OC)=C(OC)C=C2C1CC1=CC=C(OC)C(OC)=C1 OODOKBUERXZTEM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- RXOMTHSWBRHWFB-UHFFFAOYSA-N ethyl 2-[[2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetyl]amino]acetate Chemical compound C=1C=CC=CC=1C(C(=O)NCC(=O)OCC)N1CCCC2=CC(OC)=C(OC)C=C2C1CC1=CC=C(OC)C(OC)=C1 RXOMTHSWBRHWFB-UHFFFAOYSA-N 0.000 claims description 5
- KUSBLETVJOWRFU-UHFFFAOYSA-N methyl 3-[[2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetyl]amino]propanoate Chemical compound C=1C=CC=CC=1C(C(=O)NCCC(=O)OC)N1CCCC2=CC(OC)=C(OC)C=C2C1CC1=CC=C(OC)C(OC)=C1 KUSBLETVJOWRFU-UHFFFAOYSA-N 0.000 claims description 5
- UHKAJLSKXBADFT-UHFFFAOYSA-N 1,3-indandione Chemical compound C1=CC=C2C(=O)CC(=O)C2=C1 UHKAJLSKXBADFT-UHFFFAOYSA-N 0.000 claims description 4
- UDQSXTNTGLMCLG-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenyl-n-(pyridin-3-ylmethyl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=CC=CN=C1 UDQSXTNTGLMCLG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- HKQKTAMBBMTGDD-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-1-yl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1CC(=O)NC1C2=CC=CC=C2CC1 HKQKTAMBBMTGDD-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- MPFLOPTYHIWHPE-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenyl-n-(quinolin-2-ylmethyl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=CC=C(C=CC=C2)C2=N1 MPFLOPTYHIWHPE-UHFFFAOYSA-N 0.000 claims description 3
- UKXTXTNECPGUOU-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C(N)=O)C1=CC=CC=C1 UKXTXTNECPGUOU-UHFFFAOYSA-N 0.000 claims description 3
- GLKGMBLBUXTRNS-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-(furan-2-ylmethyl)-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=CC=CO1 GLKGMBLBUXTRNS-UHFFFAOYSA-N 0.000 claims description 3
- UFYDEPGYHVIHIO-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-[(1-methylindazol-3-yl)methyl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=NN(C)C2=CC=CC=C12 UFYDEPGYHVIHIO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- POSPYQBWALZTKG-UHFFFAOYSA-N methyl 2-[[2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetyl]amino]-3-hydroxypropanoate Chemical compound C=1C=CC=CC=1C(C(=O)NC(CO)C(=O)OC)N1CCCC2=CC(OC)=C(OC)C=C2C1CC1=CC=C(OC)C(OC)=C1 POSPYQBWALZTKG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- QUWWIIRDEGPVPH-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-1-yl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7-methoxy-8-propan-2-yloxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC(C)C)=C(OC)C=C2CCCN1CC(=O)NC1C2=CC=CC=C2CC1 QUWWIIRDEGPVPH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 3
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 2
- UXSNPWRWHWVTBA-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-(3-hydroxypropyl)-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C(=O)NCCCO)C1=CC=CC=C1 UXSNPWRWHWVTBA-UHFFFAOYSA-N 0.000 claims description 2
- RJJZERINOZZCMV-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-(3-phenyl-2,3-dihydro-1h-inden-1-yl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1CC(=O)NC1C2=CC=CC=C2C(C=2C=CC=CC=2)C1 RJJZERINOZZCMV-UHFFFAOYSA-N 0.000 claims description 2
- BETUUILLOVSEAL-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-(naphthalen-1-ylmethyl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1CC(=O)NCC1=CC=CC2=CC=CC=C12 BETUUILLOVSEAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- LKLCKJXNZVHPQW-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1CC(=O)NC1CC2=CC=CC=C2C1 LKLCKJXNZVHPQW-UHFFFAOYSA-N 0.000 claims description 2
- QKODOALLIMEFAQ-UHFFFAOYSA-N n-(cyanomethyl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C(=O)NCC#N)C1=CC=CC=C1 QKODOALLIMEFAQ-UHFFFAOYSA-N 0.000 claims description 2
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 claims 3
- NQKCJVGYQMQDNT-UHFFFAOYSA-N n-cyclopentyl-2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NC1CCCC1 NQKCJVGYQMQDNT-UHFFFAOYSA-N 0.000 claims 2
- BNUAZZNLMVATQP-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenyl-n-prop-2-ynylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C(=O)NCC#C)C1=CC=CC=C1 BNUAZZNLMVATQP-UHFFFAOYSA-N 0.000 claims 1
- ZSRYAVUNNADOFU-UHFFFAOYSA-N 2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-n-[(1-methylbenzimidazol-2-yl)methyl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=NC2=CC=CC=C2N1C ZSRYAVUNNADOFU-UHFFFAOYSA-N 0.000 claims 1
- 239000012876 carrier material Substances 0.000 claims 1
- MBTRBDRYULFSCA-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=CC=C(OCO2)C2=C1 MBTRBDRYULFSCA-UHFFFAOYSA-N 0.000 claims 1
- MEFSKYLTPHEZTC-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-[8-(2,2-difluoroethoxy)-1-[(3,4-dimethoxyphenyl)methyl]-7-methoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OCC(F)F)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NCC1=CC=C(OCO2)C2=C1 MEFSKYLTPHEZTC-UHFFFAOYSA-N 0.000 claims 1
- CIKPTGFKVJUBIX-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-1-yl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]-2-phenylacetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCCN1C(C=1C=CC=CC=1)C(=O)NC1C2=CC=CC=C2CC1 CIKPTGFKVJUBIX-UHFFFAOYSA-N 0.000 claims 1
- BTDLTVCMYAYRDQ-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-1-yl)-2-[1-[(3,4-dimethoxyphenyl)methyl]-7-methoxy-8-phenylmethoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]acetamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OCC=3C=CC=CC=3)=C(OC)C=C2CCCN1CC(=O)NC1C2=CC=CC=C2CC1 BTDLTVCMYAYRDQ-UHFFFAOYSA-N 0.000 claims 1
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- 208000030062 persistent idiopathic facial pain Diseases 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 208000020351 pituitary gland basophil adenoma Diseases 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 208000026961 psychosexual disease Diseases 0.000 description 1
- FVGCPPSBZHDZPC-UHFFFAOYSA-N pyrazin-2-ylmethanamine;hydrochloride Chemical compound Cl.NCC1=CN=CC=N1 FVGCPPSBZHDZPC-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- XPAZBFLKFMBGMF-UHFFFAOYSA-N quinolin-2-ylmethanamine;dihydrochloride Chemical compound Cl.Cl.C1=CC=CC2=NC(CN)=CC=C21 XPAZBFLKFMBGMF-UHFFFAOYSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical class NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
Foreliggende oppfinnelse angår nye benzazepiner og beslektede heterocykliske derivater med den generelle formel (I) og anvendelse av disse som farmasøytiske midler. Oppfinnelsen angår også beslektede aspekter som omfatter fremgangsmåter for fremstilling av forbindelsene, farmasøytiske preparater som inneholder én eller flere forbindelser med formel (I) og spesielt anvendelse av disse som orexin-reseptorantagonister.
Orexiner (hypocretiner) omfatter to nevropeptider som produseres i hypotalamus: orexin A (OX-A) (et peptid av 33 aminosyrer) og orexin B (OX-B) (et peptid av 28 aminosyrer). Det er funnet at orexiner stimulerer matinntak hos rotter, hvilket indikerer at disse peptidene har en fysiologisk rolle som mediatorer av den sentrale feedback-mekanisme som regulerer spiseadferd (Sakurai T. et al, Cell 1998, 92, 573-585). På den annen side ble det også foreslått at orexiner regulerer nivåer av søvn og våkenhet, noe som åpner for potensielle, nye terapeutiske måter å behandle narkolepsi-pasienter (Chemelli R.M. et al, Cell 1999, 98,437-451). To orexin-reseptorer er klonet og karakterisert hos pattedyr. De tilhører superfamilien G-protein-koblet reseptor (Sakurai T. et al, Cell 1998, 92, 573-585). Orexin-1-reseptoren (OXO er selektiv for OX-A og orexin-2-reseptoren (OX2) kan bindes til OX-A, så vel som OX-B.
Orexin-reseptorer er funnet hos pattedyr og kan være ansvarlige for mange biologiske funksjoner så som patologiske tilstander som omfatter, men ikke er begrenset til, depresjon; angst; avhengighet; obsessiv-kompulsiv lidelse; affektiv nevrose; depressiv nevrose; angstnevrose; dystymisk lidelse; adferdsforstyrrelse; forstyrrelse i stemningsleie; seksuell dysfunksjon; psykoseksuell dysfunksjon; kjønnsforstyrrelse; schizofreni; manisk depresjon; delirium; demens; alvorlig mental retardasjon og dyskinesier som Huntingtons sykdom og Tourettes syndrom; spiseforstyrrelser som anoreksi, bulimi, kakeksi og fedme; diabetes; appetitt-/smaks-forstyrrelser; oppkast/kvalme; astma; kreft; Parkinsons sykdom; Cushings syndrom/sykdom; basofilt adenom; prolaktinom; hyperprolaktinemi; hypopituitarisme; hypofysetumor/-adenom; sykdommer i hypotalamus; inflammatorisk tarmsykdom; gastrisk diskinesi; gastrisk ulcus; Froehlichs syndrom; adreno-hypofyse-sykdom; hypofyse-sykdom; pituitært veksthormon; hypofunksjon av adreno-hypofyse; hyperfunksjon av adreno-hypofyse; hypotalamisk hypogonadisme; Kallmans syndrom (anosmi, hyposmi); funksjonell eller psykogen amenorré; hypopituitarisme; hypotalamisk hypotyreoidisme; hypotalamisk-adrenal dysfunksjon; idiopatisk hyperprolaktinemi; hypotalamisk forstyrrelse på grunn av mangel på veksthormon; idiopatisk veksthemming; dvergvekst; gigantisme; akromegali; forstyrrede biologiske og sirkadianske rytmer; søvnforstyrrelser relatert til sykdommer som nevrologiske lidelser, nevropatisk smerte og restless leg-syndrom; hjerte- og lungesykdommer, akutt og kongestiv hjertesvikt; hypotensjon; hypertensjon; urinretensjon; osteoporose; angina pektoris; myokardinfarkt; iskemisk eller hemoragisk slag; subaraknoidalblødning; mavesår; allergier; godartet prostatahypertrofi; kronisk nyresvikt; nyresykdom; redusert glukosetoleranse; migrene; hyperalgesi; smerte; øket eller overdrevet sensitivitet overfor smerte så som hyperalgesi, kausalgi og allodyni; akutt smerte; forbrenningssmerte; atypisk ansiktssmerte; nevropatisk smerte; ryggsmerte; komplekst regionalt smertesyndrom I og II; artrittsmerte; sportsskadesmerte; smerte relatert til infeksjon f.eks. av HIV, smerte etter kjemoterapi; smerte etter slag; postoperativ smerte; nevralgi; lidelser relatert til visceral smerte, så som irritabel tarm-syndrom, migrene og angina; urininkontinens f.eks. urgeinkontinens; avhengighet ("tolerance") av narkotika eller avvenning fra narkotika; søvnforstyrrelser; søvnapné; narkolepsi; søvnløshet; parasomni; jetlag-syndrom; og nevrodegenerative lidelser som omfatter nosologiske tilstander, så som desinhibering ("disinhibation")-demens-parkinsonisme-amyotrofi-kompleks; pallido-ponto-nigral degenerasjon epilepsi; krampelidelser og andre sykdommer relatert til orexin.
Foreliggende oppfinnelse tilveiebringer benzazepiner og beslektede heterocykliske derivater som er ikke-peptidiske antagonister av humane orexin-reseptorer, spesielt OXi- og OX2-reseptorer. Spesielt er disse forbindelsene potensiellt nyttige ved behandling av fedme og/eller søvnforstyrrelser.
Ennå vet man lite om lavmolekylære forbindelser som er potensielle antagonister, enten spesifikt for OXi eller OX2, eller begge reseptorer samtidig. I de nylig publiserte WO 99/09024, WO 99/58533, WO 00/47577 og WO 00/47580 er fenyl-urinstoff- og fenyl-tiourinstoff-derivater oppgitt å være fortrinnsvis OXi-reseptorantagonister. Også i den ganske nylig publiserte WO 00/47576 er cinnamid-derivater beskrevet som OXi-reseptorantagonister. De nye forbindelsene ifølge foreliggende oppfinnelse tilhører en helt annen klasse lavmolekylære forbindelser enn alle tidligere orexin-reseptorantagonister som hittil er beskrevet i litteraturen.
Foreliggende oppfinnelse angår nye benzazepiner og beslektede heterocykliske derivater med den generelle formel (I).
hvor:
R<2> og R<3> representerer uavhengig hydroksy, C|-C4-alkoksy, C2-Cs-alkenyloksy eller fenyl-C i -C4-alkoksy; R<5> representerer fenyl-C i-Q-alkoksy eventuelt substituert på fenylringen med C1-C4-alkoksy eller halogen; R 7 og R 8 representerer uavhengig hydrogen eller fenyl; R<9> og R<10> representerer uavhengig hydrogen; indanyl, eventuelt substituert med C1-C4-alkyl eller Ci-C4-alkoksy; tetrahydronaftyl; fenyl-Ci-C4-alkyl, eventuelt substituert med C|-C4-alkoksy; naftyl-Ci-C4-alkyl; Ci-C6-alkyl; C2-C5-alkenyl; C2-C5-alkinyl; C3-C6-cykloalkyl; heterocyklyl eller heterocyklyl-Ci-C4-alkyl, hvor heterocyklylen er valgt fra gruppen bestående av benzodioksolyl, furyl, pyridyl, benzimidazolyl, indolyl, isoksazolyl, isokinolyl, indazolyl, kinolyl og pyrazinyl, hvor heterocyklylen eventuelt er substituert med Ci-C4-alkyl; eller Ci-C4-alkyl hvor én eller to hydrogenatomer er erstattet med hydroksy, cyano, trifluormetyl, -0-Ci-C4-alkyl, -NH-Ci-C4-alkyl, -N(Ci-C4-alkyl)2, -S-Ci-C4-alkyl, -COO-Ci-C4-alkyl, -CONH-Ci-C4-alkyl, -CON(Ci-C4-alkyl)2, eller
-NHCO-C,-C4-alkyl; og
-X-Y- uavhengig representerer -CH2-CH2-, -0-CH2-, -S-CH2-, -S02-CH2- og -NH-CO-;
og optisk rene enantiomerer, blandinger av enantiomerer som for eksempel racemater, optisk rene diastereoisomerer, blandinger av diastereoisomerer, diastereoisomere racemater, blandinger av diastereoisomere racemater eller mesoformer og farmasøytisk akseptable salter derav.
Følgende definisjoner gjelder om ikke på annen måte definert i kravene:
I foreliggende beskrivelse betyr betegnelsen "lavere alkyl", alene eller i kombinasjon, en rettkjedet eller forgrenet alkylgruppe med 1 til 8 karbonatomer, fortrinnsvis en lineær eller forgrenet alkylgruppe med 1-4 karbonatomer. Eksempler på rettkjedede og forgrenede Ci-Cs alkylgrupper er metyl, etyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-heksyl, n-heptyl, n-oktyl, isobutyl, tert-butyl, isomer pentyl, isomer heksyl, isomer heptyl og isomer oktyl, fortrinnsvis metyl, etyl, n-propyl, isopropyl, n-butyl, 2-butyl og ferf-butyl.
Betegnelsen "lavere alkenyl", alene eller i kombinasjon, betyr, om ikke annet er angitt, en rettkjedet eller forgrenet alkenylgruppe med 2 til 5 karbonatomer, fortrinnsvis allyl og vinyl.
Betegnelsen "lavere alkinyl", alene eller i kombinasjon, betyr en rettkjedet eller forgrenet alkinylgruppe med 2 til 5 karbonatomer, fortrinnsvis propargyl og n-butinyl.
Betegnelsen "lavere alkoksy", alene eller i kombinasjon, betyr en gruppe med formelen lavere alkyl-O-, hvor betegnelsen "lavere alkyl" har samme betydning som tidligere angitt, så som metoksy, etoksy, n-propoksy, isopropoksy, n-butoksy, isobutoksy, sek-butoksy og tert-butoksy, fortrinnsvis metoksy og etoksy.
Lavere alkenyloksygrupper er fortrinnsvis vinyloksy og allyloksy.
Betegnelsen "cykloalkyl", alene eller i kombinasjon, betyr en cykloalkylring med 3 til 8 karbonatomer og fortrinnsvis en cykloalkylring med 3 til 6 karbonatomer. Eksempler på C3-C8 cykloalkylgrupper er cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl og cyklooktyl, fortrinnsvis cyklopropyl, cyklopentyl, cykloheksyl og spesielt cykloheksyl eller cykloalkyl som fortrinnsvis kan være substituert med lavere alkyl, så som metyl-cyklopropyl, dimetyl-cyklopropyl, metyl-cyklobutyl, metyl-cyklopentyl, metyl-cykloheksyl, dimetyl-cykloheksyl.
Betegnelsen "aryl", alene eller i kombinasjon, betyr en fenyl- eller naftylgruppe som eventuelt har én eller flere substituenter, fortrinnsvis én eller to substituenter, som, uavhengige av hverandre, er valgt fra cyano, halogen, hydroksy, lavere alkyl, lavere alkenyl, lavere alkoksy, lavere alkenyloksy, nitro, trifluormetyl, trifluormetoksy, amino, karboksy og lignende, så som fenyl, p-tolyl, 4-metoksyfenyl, 4-tert-butoksyfenyl, 4-fluorfenyl, 2-klorfenyl, 4-hydroksyfenyl, 1-naftyl og 2-naftyl. Foretrukket er karboksyfenyl, lavere alkoksy-fenyl, hydroksyfenyl og spesielt fenyl.
Betegnelsen "aralkyl", alene eller i kombinasjon, betyr en lavere alkyl- eller cykloalkylgruppe som tidligere definert, hvor ett hydrogenatom er erstattet av en arylgruppe som tidligere definert. Foretrukket er benzyl og benzyl som er substituert på fenylringen med hydroksy, lavere alkyl, lavere alkoksy eller halogen, fortrinnsvis klor. Spesielt foretrukket er benzyl.
Betegnelsen "arylcykloalkyl", alene eller i kombinasjon, betyr en aryl cykloalkylgruppe hvor cykloalkyl gruppen består av 4 til 7 karbonatomer f.eks. indanyl, tetrahydronaftyl, benzocykloheptyl og benzocyklobutyl. Den aromatiske gruppen kan være substituert med én eller flere substituenter, fortrinnsvis én eller to substituenter, som, uavhengige av hverandre, er valgt fra cyano, halogen, hydroksy, lavere alkyl, lavere alkenyl, lavere alkoksy, lavere alkenyloksy, nitro, trifluormetyl, trifluormetoksy, amino og karboksy.
I betegnelsene "heterocyklyl" og "heterocyklyl-lavere alkyl", er fortrinnsvis heterocyklylgruppen en 5- til 10-leddet, monocyklisk eller bicyklisk ring som kan være mettet, delvis umettet eller aromatisk og som inneholder for eksempel 1, 2 eller 3 heteroatomer valgt fra oksygen, nitrogen og svovel, som kan være like eller forskjellige. Eksempler på slike heterocyklylgrupper er pyrrolidinyl, piperidinyl, piperazinyl, morfolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, kinolyl, isokinolyl, tienyl, tiazolyl, isotiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoksazolyl, oksazolyl, kinoksalinyl, ftalazinyl, cinnolinyl, dihydropyrrolyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. Heterocyklylgruppen kan eventuelt ha opptil 5, fortrinnsvis 1, 2 eller 3, substituenter. Eksempler på egnede substituenter omfatter halogen, lavere alkyl, amino, nitro, cyano, hydroksy, lavere alkoksy, karboksy og lavere alkyloksy-karbonyl.
Betegnelsen "halogen" betyr fluor, klor, brom eller jod og fortrinnsvis fluor og klor.
Betegnelsen "karboksy", alene eller i kombinasjon, betyr en -COOH-gruppe.
En gruppe foretrukne forbindelser ifølge foreliggende oppfinnelse er forbindelser med formel (II)
hvor:
R 2 og R 3 uavhengig representerer hydroksy, Ci-C4-alkoksy, C2-Cs-alkenyloksy eller fenyl-C i -C4-alkoksy; R<5> representerer fenyl-C i-C4-alkoksy eventuelt substituert på fenylringen med C1-C4-alkoksy eller halogen; R<7> og R8 representerer uavhengig hydrogen eller fenyl; R<9> og R<10> representerer uavhengig hydrogen; fenyl-C i-C4-alkyl, eventuelt substituert med C|-C4-alkoksy; naftyl-Ci-C4-alkyl; C|-C6-alkyl; C2-C5-alkenyl; C3-C6-cykloalkyl; eller heterocyklyl eller heterocyklyl-Ci-C4-alkyl, hvor heterocyklylen er valgt fra gruppen bestående av benzodioksolyl, furyl, pyridyl, benzimidazolyl, indolyl, isoksazolyl, isokinolyl, indazolyl, kinolyl og pyrazinyl, hvor heterocyklylen eventuelt er substituert med Ci-C4-alkyl; og -X-Y- uavhengig representerer -CH2-CH2-, -0-CH2-, -S-CH2-, -S02-CH2- og -NH-CO-;
og optisk rene enantiomerer, blandinger av enantiomerer som for eksempel racemater, optisk rene diastereoisomerer, blandinger av diastereoisomerer, diastereoisomere racemater, blandinger av diastereoisome racemater eller mesoformer og farmasøytisk akseptable salter derav.
En annen gruppe foretrukne forbindelser ifølge foreliggende oppfinnelse er forbindelser med formel (III)
hvor:
R'<1> og R'<2> uavhengig representerer hydroksy, Ci-C4-alkoksy eller C2-Cs-alkenyloksy; R'<3> representerer fenyl-C i-C4-alkoksy eventuelt substituert på fenylringen med C1-C4-alkoksy eller halogen; R'4 representerer hydrogen eller fenyl; R'<5> representerer hydrogen; fenyl-C i-C4-alkyl, eventuelt substituert med Ci-C4-alkoksy; naftyl-Ci-C4-alkyl; Ci-C6-alkyl; C2-Cs-alkenyl; C3-C6-cykloalkyl; heterocyklyl eller heterocyklyl-Ci-C4-alkyl, hvor heterocyklylen er valgt fra gruppen bestående av benzodioksolyl, furyl, pyridyl, benzimidazolyl, indolyl, isoksazolyl, isokinolyl, indazolyl, kinolyl og pyrazinyl, hvor heterocyklylen eventuelt er substituert med Ci-C4-alkyl; -X-Y- uavhengig representerer -CH2-CH2-, -0-CH2-, -S-CH2-, -S02-CH2- og -NH-CO-;
og optiske rene enantiomerer, blandinger av enantiomerer som for eksempel racemater, optisk rene diastereoisomerer, blandinger av diastereoisomerer, diastereoisomere racemater, blandinger av diastereoisomere racemater eller mesoformer og farmasøytisk akseptable salter derav.
Eksempler på foretrukne forbindelser er: 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-naftalen-1 -ylmetyl-acetamid
N-benzo[ 1,3]dioksol-5-ylmetyl-2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-indan-2-yl-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f] [ 1,4]oksazepin-4-yl]-AT-indan-2-yl-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dirnetoksy-2,3-dihydro-5H-benzo[fJ[l,4]oksazepin-4-yl]-AT-indan-l-yl-acetamid
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] - N-indan-1 -yl-acetamid
2-[9-(3,4-dimetoksy-benzyl)-2,3-dirnetoksy-5,5-diokso-5,6,7,9-tetrahydro-5X-tia-8-aza-benzocyklohepten-8-yl]-AMndan-2-yl-acetamid
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9-tetrahydro-5X,-tia-8-aza-benzocyklohepten-8-yl] -N-indan-1 -yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->indan-1 -yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-indan-2-yl-2-fenyl-acetamid
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-N-naftalen-l-ylmetyl-acetamid
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-A7-(2-etoksy-benzyl)-acetamid
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-AMndan-l-yl-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[fJ[l,4]oksazepin-4-yl]-AK 1,2,3,4-tetrahydro-naftalen-1 -yl)-acetamid
Ar<->benzyl-2-[9-(3,4-dimetoksy-benzyl)-23-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[fJ[l,4]oksazepin-4-yl] -N-indan-1 -yl-acetamid
Af-butyl-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-indan-1 -yl-2-fenyl-acetamid
Ar-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
Af-cyklopentyl-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -2-fenyl-acetamid
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-N-furan-2-ylmetyl-2-fenyl-acetamid
{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -eddiksyre-etylester
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -2-fenyl-N-pyridin-4-ylmetyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyridin-3-ylmetyl-acetamid
Ar<->cyklopropyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -2-fenyl-acetamid 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahyo^o-benzo[c]azepin-2-yl]-A<7->
(2-okso-tetrahydro-furan-3-yl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AA-(4-metoksy-indan-1 -yl)-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(3-fenyl-indan- l-yl)-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-(4-metyl-indan-1 -yl)-acetamid
2- {2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -3-hydroksy-propionsyre-metylester
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-etylkarbamoylmetyl-2-fenyl-acetamid
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-Af-[(etyl-metyl-karbamoyl)-metyl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl] -Af-indan-1 -yl-acetamid
2-[8-benzyloksy-1 -(3,4-dimetoksy-benzyl)-7-metoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2- yl]-Af-indan-l-yl-acetamid
3- {2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -propionsyre-metylester
Ar-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
N-( lH-benzoimidazol-2-ylmetyl)-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
3 - {2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoks y-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl] - 2- fenyl-acetylamino} -Ar,Af-dimetyl-propionamid
3- {2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -Acetyl-N-metyl-propionamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(1 -metyl-1 H-indol-3 -ylmetyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->isoksazol-5-ylmetyl-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->
(lH-indol-3-ylmetyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A</->
(1 -metyl-1 H-benzoimidazol-2-ylmetyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A?-isokinolin-l-ylmetyl-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-AT-(4-[l,2,3]tiadiazol-4-yl-benzyl)-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->
(l-metyl-lH-indazol-3-ylmetyl)-2-fenyl-acetamid
Af-cyanometyl-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
A7-(2-acetylamino-etyl)-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-2-fenyl-Ar-(2,2,2-trifluor-etyl)-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-(2-metylsulfanyl-etyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-kinolin-2-ylmetyl-acetamid
Af-(2-cyano-etyl)-2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->
(3-metoksy-propyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-etoksy-propyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyrazin-2-ylmetyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Af-prop-2-ynyl-acetamid
AT-tert-butyl-2-t 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid 2-[l-(3,4-dimetoksy-benzyl)-7,8-dm (3 -metyl-butyl)-2-fenyl-acetamid
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -N-(3,3-dimetyl-butyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->
(l-etyl-propyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A7-(2-etylsulfanyl-etyl)-2-fenyl-acetamid
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-(2-hydroksy-etyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->
(3-hydroksy-propyl)-2-fenyl-acetamid
[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre-A^AT-dimetyl-hydrazid
2-[8-allyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-ylj-AMndan-l-yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7-metoksy-8-propoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af-indan-l-yl-acetamid
2-[ 1 -(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->indan-l-yl-acetamid
2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzotclazepin-2-ylj-A^-indan-l-yl-acetamid
A^-benzo[l,3]dioksol-5-ylmetyl-2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzy0 metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
Ar<->benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[5-(3,4-diklor-benzyl)-7,8-dimetoksy-2-okso-1,2,3,5-tetrahydro-benzo[e] [ 1,4]diazepin-4-ylJ-AMndan-l-yl-acetamid
2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af-indan-1 -yl-acetamid
2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-indan-2-yl-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f] [ 1,4]oksazepin-4-yll-Af-naftalen-l-ylmetyl-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-Af-(2-etoksy-benzyl)-acetamid
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-AT-( 1,2,3,4-tetrahydro-naftalen-1 -yl)-acetamid.
Eksempler på spesielt foretrukne forbindelser er: 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->indan-2-yl-acetamid
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl] -Af-indan-1 -yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-indan-1 -yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetr^ indan-1 -yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3.4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->indan-2-yl-2-fenyl-acetamid
A^-butyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->indan-1 -yl-2-fenyl-acetamid
AT-benzo[ 1,3]dioksol-5-ylmetyl-2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
Af-cyklopentyl-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5 -tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af<->furan-2-ylmetyl-2-fenyl-acetamid
{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -eddiksyre etylester
2- [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyridin-3-ylmetyl-acetamid
3- {2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -propionsyre-metylester
Ar<->(lH-benzoimidazol-2-ylmetyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-13,4,5-tetrah<y>dro-benzo[c]aze<p>in-2-yl]-A7-(1 -metyl-1 H-indol-3-ylmetyl)-2-fenyl-acetamid
2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-isoksazol-5-ylmetyl-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-(lH-indol-3-ylmetyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->isokinolin-1 -ylmetyl-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Ar-(4-[ 1,2,3]tiadiazol-4-yl-benzyl)-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(l-metyl-lH-indazol-3-ylmetyl)-2-fenyl-acetamid
A^-cyanometyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-A<7->(2,2,2-trifluor-etyl)-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af<->
(2-metylsulfanyl-etyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-kinolin-2-ylmetyl-acetamid
Ar<->(2-cyano-etyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid 2-[l-(3,4-dimetoksy-benzyl)-7,8-dm^
(3-metoksy-propyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-etoksy-propyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyrazin-2-ylmetyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dirnetoksy-l,3,4,5-tetxahydro-benzo[c]azepin-2-yl]-2-fenyl-Af-prop-2-ynyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->
(3-metyl-butyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->
(3,3-dimetyl-butyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->
(1 -etyl-propyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-(2-etylsulfanyl-etyl)-2-fenyl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(2-hydroksy-etyl)-2-fenyl-acetamid
2-[8-allyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-l-yl-acetamid
2-[l-(3,4-dimetoksy-benzyl)-7-metoksy-8-propoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl] -N-indan-1 -yl-acetamid
2-[ 1 -(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-l-yl-acetamid
2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af-indan-l-yl-acetamid
AT-benzo[ 1,3]dioksol-5-ylmetyl-2-[8-(2,2-difluor-etoksy)-1 -(3,4-dimetoksy-benzyl)-7-metoksy-1,3,4,5 -tetrahydro-benzo [c] azepin-2-yl] -2-fenyl-acetamid
Ar<->benzori,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid
2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af-indan-1 -yl-acetamid
2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-2-yl-acetamid
Eksempler på fysiologisk anvendelige eller farmasøytisk akseptable salter av forbindelsene med den generelle formel (I), er salter med fysiologisk forenlige mineralsyrer så som saltsyre, svovelsyre eller fosforsyre, eller med organiske syrer så som metansulfonsyre, eddiksyre, trifluoreddiksyre, sitronsyre, fumarsyre, maleinsyre, vinsyre, ravsyre eller salicylsyre. Forbindelser med formel (I) som har sure grupper, kan også danne salter med fysiologisk forenlige baser. Eksempler på slike salter er alkalimetall-, jordalkalimetall-, ammonium- og alkylammonium-salter så som Na-, K-, Ca- eller tetraalkylammonium-salter. Forbindelsene med den generelle formel (I) kan også foreligge i form av et zwitterion.
Foretrukne forbindelser som beskrevet ovenfor, har IC50 -verdier under 1000 nM; spesielt foretrukne forbindelser har ICso-verdier under 100 nM, som er bestemt ved hjelp av FLIPR-metoden (Plateavlesning for fluorescens-avbildning) som er beskrevet i begynnelsen av avsnittet som vedrører forsøk.
Forbindelsene med den generelle formel (I) og deres farmasøytisk anvendelige salter kan anvendes ved behandling av sykdommer eller lidelser hvor en antagonist av en human orexin-reseptor er påkrevet, så som fedme, diabetes, kardiovaskulære lidelser, kreft, prolaktinom, smerte, narkolepsi, søvnløshet, søvnapné, parasomni, depresjon, angst, avhengighet, schizofreni, nevrodegenerative lidelser og demens.
Forbindelsene med den generelle formel (I) og deres farmasøytisk anvendelige salter er spesielt anvendelige ved behandling av fedme og søvnforstyrrelser.
Forbindelsene med den generelle formel (I) og deres farmasøytisk anvendelige salter kan anvendes som medikament (f.eks. i form av farmasøytiske preparater). De farmasøytiske preparater kan administreres enteralt eller oralt (f.eks. i form av tabletter, overtrukne tabletter, dragéer, harde og myke gelatinkapsler, løsninger, emulsjoner eller suspensjoner), nasalt (f.eks. i form av nesespray-preparater) eller rektalt (f.eks. i form av suppositorier). Administreringen kan imidlertid også utføres parenteralt så som intramuskulært eller intravenøst (f.eks. i form av injeksjonsløsninger).
Forbindelsene med den generelle formel (I) og deres farmasøytisk anvendelige salter kan være formulert med farmasøytisk inerte, uorganiske eller organiske tilsetningsmidler for fremstilling av tabletter, overtrukne tabletter, dragéer og harde gelatinkapsler. Laktose, maisstivelse eller derivater derav, talkum, stearinsyre eller salter derav etc. kan anvendes, for eksempel som slike tilsetningsmidler for tabletter, dragéer og harde gelatinkapsler.
Egnede tilsetningsmidler for myke gelatinkapsler er for eksempel vegetabilske oljer, vokser, fett, halvfaste substanser og flytende polyoler, etc.
Egnede tilsetningsmidler for fremstilling av løsninger og siruper er for eksempel vann, polyoler, sakkarose, invertsukker, glukose, etc.
Egnede tilsetningsmidler for injeksjonsløsninger er for eksempel vann, alkoholer, polyoler, glycerol, vegetabilske oljer, etc.
Egnede tilsetningsmidler for suppositorier er for eksempel naturlige eller herdede oljer, vokser, fett, halvfaste eller flytende polyoler, etc.
Videre kan de farmasøytiske preparatene inneholde konserveringsmidler, solubiliseringsmidler, viskositetsøkende substanser, stabiliseringsmidler, fuktemidler, emulgeringsmidler, søtningsmidler, fargemidler, smaksmidler, salter for å endre det osmotiske trykket, buffere, smaksmaskeringsmidler eller antioksydasjonsmidler. De kan også inneholde andre substanser av terapeutisk nytte. Oppfinnelsen angår også fremgangsmåter for fremstilling av forbindelser med den generelle formel (I).
Forbindelsene med den generelle formel (I) ifølge foreliggende oppfinnelse, blir fremstilt i henhold til den generelle reaksjonssekvens som er beskrevet i skjemaene nedenfor, hvor R<2>, R<3>, R5, R7, R8, R<9> og R<10> er definert som for den generelle formel (I) ovenfor. I tilfeller hvor hvilken som helst av de fremstilte forbindelser har ett eller flere optisk aktive karbonatomer, kan den isoleres som rene enantiomerer eller diastereomerer, blandinger av enantiomerer eller diastereomerer, diastereomere racemater og mesoformer, på måter som er kjent per se.
De fremstilte forbindelser kan også omdannes til et farmasøytisk akseptabelt salt på måter som er kjent per se.
Forbindelsene med den generelle formel (I) kan fremstilles ved hjelp av standard prosedyrer { Prosedyre A hvor R<7> og R8 er hydrogenatomer og Prosedyre B hvor R<7 >og/eller R Q er forskjellig fra hydrogen) vist i Skjema 1, ved anvendelse av syntetisert benzazepin og beslektede heterocykliske derivater.
Benzazepin-derivater hvor X og Y er CH2, kan fremstilles fra det tilsvarende fenylpropylamin ved kobling med den ønskede karboksylsyre eller det ønskede acylklorid, etterfulgt av behandling med POCI3 og til slutt NaBFLt (Bischler-Napieralski-reaksjon) som vist i Skjema 2a (S. Kano et al., Chem. Pharm. Bull. 1977, 25, 10, 2510-2515).
Benzazepiner med forskjellige substituenter i 8-stilling kan fremstilles ved hydrogenolyse av de tilsvarende 8-benzyloksy-l,3,4,5-tetrahydro-benzazepiner, etterfulgt av O-alkylering med en passende elektrofil ( Skjema 2b, -OR'<11> omfattes av definisjonen av R<3>). Benzyleterne kan fremstilles ved hjelp av den forrige prosedyren ( Skjema 2a), anvendt på 3-(4-benzyloksy-fenyl)-propionsyre-derivater.
Benzotiazepin- og benzoksazepin-derivater hvor X er O eller S, Y er CH2 og, kan fremstilles fra det tilsvarende arylamin ved kobling med den ønskede karboksylsyre eller det ønskede acylklorid, etterfulgt av behandling med POCI3 og til slutt NaBH; (Bischler-Napieralskis reaksjon) som vist i Skjema 3.
l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-on-derivater hvor X er NR<15>, Y er CO, kan fremstilles ved Friedel-Crafts-acylering av et passende acetylert anilin med det respektive acylklorid (Sternbach L.H. et al, J. Org. Chem. 1962, 27, 3781-3788), etterfulgt av N-avbeskyttelse, cyklisering ved behandling med metylestere av a-aminosyrer (Sternbach L.H. et al, J. Org. Chem. 1962, 27, 3788-3796) og til slutt hydrogenolyse av dihydro-forbindelsen (Fryer R.I. et al, J. Med. Chem. 1964, 386-389) ( Skjema 4a). En alternativ syntese av slike l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-on-derivater er beskrevet i Skjema 4b. I henhold til denne metoden blir et arylketon-derivat fremstilt ved Friedel-Crafts-acylering, og påfølgende nitrering og hydrogenering gir anilin-derivatet. 1,3-dihydro-benzo[e][l,4]diazepin-2-on-skjelettet blir deretter fremstilt i henhold til en veldokumentert cykliserings-prosedyre som omfatter bromacetylbromid og ammoniakk (Bock M.G. et al, J. Org. Chem. 1987, 3232-3239; Zhang W. et al, J. Med. Chem. 1994, 745-757).
De tidligere prosedyrer som er basert på Bischler-Napieralski-reaksjonen, er uforenlige med fremstilling av benzazepin-derivater som har elektrontiltrekkende substituenter på fenylringen. Det kan derfor innføres cyanogrupper ved omsetning av et triflat med cyanid-ioner i nærvær av palladium(O) (Austin N.E. et al, Bioorg. Med. Chem. Lett. 2000, 10, 2553-2555; Ritter K. et al., Syntese 1993, 735; Selnick H.G. et al., Synth. Commun. 1995, 25, 20, 3255-3262) ( Skjema 5).
Karboksylatgrupper kan også innføres ved omsetning av et triflat med karbonmonoksyd og en alkohol i nærvær av palladium(O) (Roth G.P. et al, Tetrahedron Lett. 1992, 33, 1959; Ma D. et al, Bioorg. Med. Chem. Lett. 1998, 8, 18, 2447-2450; Fisher M.J. et al, J. Med. Chem. 1997, 40, 2085-2101; Kraus G.A. et al, Tetrahedron Lett. 1994, 35, 9189-9190). Disse karboksylat-funksjonene kan deretter omdannes til amino-funksjoner ved hydrolyse, etterfulgt av Curtius-reaksjon ( Skjema 6).
Halogenholdige 2-benzazepiner kan fremstilles ved å behandle en halogenen tetralon-oksimer med POCI3/DMF, og det resulterende l,3,4,5-tetrahydro-l-okso-2#-2-benzazepin-2-karboksaldehyd kan deretter deformyleres og reduseres (Majo V.J. et al, Synth. Commun. 1995,25, 23, 3863-3868) ( Skjema 7). 8-nitro-2,3,4,5-tetrahydro-l//-2-benzazepin kan fremstilles ved regioselektiv nitrering av 2,3,4,5-tetrahydro-l//-2-benzazepin-l-on ved anvendelse av kaliumnitrat og svovelsyre (Grunewald G.L. et al., J. Heterocyklisk Chem. 1994, 31,1609-1617) ( Skjema 8). Fremstilling av rene enantiomerer av l-substituert-2-tetrahydrobenzazepin-derivater ( Skjema 9) er basert på en beskrevet metode for syntetisering av optisk rene 1-substituerte tetrahydroisokinoliner (Polniaszek R.P. et al., J. Am. Chem. Soc. 1989, 111,4859-4863). Hovedtrinnet i denne asymmetriske syntesen er stereoselektiv hydrid-reduksjon av et kiralt imminium-ion som er fremstilt ved Bischler-Napieralskis reaksjon. Substratets kiralitet vil være avledet fra det kommersielt tilgjengelig (5)-(-)-a-fenetylamin.
Eksperimenter
Forkortelser:
AcOEt Etylacetat
Bn Benzyl
Boe 7erf-butoksykarbonyl
BSA Bovint serumalbumin
CHO Eggstokk fra kinesisk hamster (Chinese hamster ovary) DMF Dimetylformamid
DMSO Dimetylsulfoksyd
ES Elektronspray
FCS Kalvefoster-serum (Foetal calf serum) FLIPR Plateleser for fluorescens-avbildning (Fluorescent imaging plate reader) HB SS Hank's balanserte saltløsning
HEPES 4-(2-hydroksyetyl)-piperazin-1 -etansulfonsyre HV Høyvakuum
MeOH Metanol
Min Minutt(er)
MS Massespektroskopi
LC Væskekromatografi
PyBOP Benzotriazol-l-yl-oksy-tris-pyrrolidino-fosfoniumheksafluorfosfat
Rf Retensjonsfront
rt Retensjonstid
RT Romtemperatur
TE Trietylamin
TFA Trifluoreddiksyre
Tf CF3SO2-
THF Tetrahydrofuran
TLC Tynnsjiktskromatografi
I. Biologi
Bestemmelse av effekten av OXi- og OX2-reseptorantagonister
Den antagonisteffekt som forbindelsene med den generelle formel (I) hadde på OXi- og OX2-reseptorer, ble bestemt i henhold til følgende eksperimentelle metode.
Eksperimentell metode:
Måling av intracellulær kalsium
Eggstokkceller fra kinesisk hamster (CHO-celler) som uttrykker henholdsvis den humane orexin-1-reseptor og den humane orexin-2-reseptor, ble dyrket i dyrkningsmedium (Ham F-12 med 1-glutamin) som inneholdt 300 |ig/ml G418,100 U/ml penicillin, 100 ug/ml streptomycin og 10 % inaktivert kalvefoster-serum (FCS).
Cellene ble podet med 80'000 celler / brønn i 96-brønners, sorte, sterile plater (Costar) med gjennomsiktig bunn som var belagt med 1% gelatin i Hanks' balanserte saltløsning (HBSS). Alle reagenser var fra Gibco BRL.
De podete platene ble inkubert natten over ved 37°C i 5% CO2.
Human orexin-A i form av agonist, ble fremstilt som 1 mM stamløsning i metanol:vann (1:1), fortynnet i HBSS som inneholdt 0,1 % BSA og 2 mM HEPES, for å anvendes i forsøket i en totalkonsentrasjon på 10 nM.
Antagonister ble fremstilt som 10 mM stamløsning i DMSO, ble deretter fortynnet i 96-brønners plater, først i DMSO, deretter i HBSS som inneholdt 0,1 % bovint serumalbumin (BSA) og 2 mM HEPES.
På forsøksdagen ble hver brønn tilsatt 100 ul påsettingsmedium (HBSS som inneholdt 1% FCS, 2 mM HEPES, 5 mM probenecid (Sigma) og 3 uM fluorescerende kalsium-indikator Fluo-3 AM (1 mM stamløsning i DMSO med 10% pluronsyre Molecular Probes).
96-brønns-platene ble inkubert i 60 min ved 37° C i 5% CO2. Påsettingsløsningen ble deretter sugd opp og cellene ble vasket 3 ganger med 200 ul HBSS som inneholdt 2,5
mM probenecid, 0,1% BSA, 2 mM HEPES. 100 ul av den samme bufferen ble fylt i hver brønn.
Før platelesing for fluorescens-avbildning (FLIPR) ble utført (Molecular Devices) ble antagonister satt til platen i et volum på 50 ul, inkubert i 20 min og til slutt ble 100 ul agonist tilsatt. Fluorescens ble målt for hver brønn i intervaller på ett sekund, høyden av hver fluorescens-topp ble sammenlignet med høyden av den fluorescens-toppen som ble oppnådd for 10 nM orexin-A med buffer istedenfor antagonist. IC50-verdien (den konsentrasjon av forbindelse som er nødvendig for å hemme 50 % av agonistresponsen) for hver antagonist ble bestemt. Verdier for utvalgte forbindelser er oppgitt i Tabell 1.
II. Kjemi
De følgende eksempler illustrerer fremstillingen av farmakologisk aktive forbindelser ifølge foreliggende oppfinnelse, men begrenser på ingen måte omfanget av den. Alle temperaturer er oppgitt som °C. Alle hydrokloridsalter ble fremstilt ved å oppløse den frie basen i diklormetan og behandle den resulterende løsning med overskudd HC1 i 2-propanol (5-6 M).
A. Utgangsmaterialer: Syntese av tetrahydrobenzazepin og beslektede
heterocykliske derivater:
3-(3,4-dimetoksy-fenyl)-propionamid
En omrørt løsning av 3-(3,4-dimetoksy-fenyl)-propionsyre (10,0 g, 47,56 mmol) i tørr THF (175 ml), ble under nitrogen tilsatt TEA (7,3 ml, 52,44 mmol), og den resulterende blanding ble avkjølt til -10°C før etylklorformiat (5 ml, 52,47 mmol) ble tilsatt dråpevis. Etter omrøring ved -10°C (20 min) ble ammoniumhydroksyd (25% i vann, 105 ml) i THF (105 ml) tilsatt, og blandingen ble omrørt ved -15°C i 30 min og deretter ved RT i 1,5 timer. Reaksjonsblandingen ble inndampet under vakuum, ekstrahert tre ganger med CH2CI2 og de samlede organiske ekstrakter ble vasket med mettet, vandig NaHCC«3 og saltløsning. Den organiske fasen ble tørket over vannfri MgSC<4, filtrert og inndampet, hvilket ga tittelforbindelsen (9,73 g, 46,50 mmol, 97%) i form av et fargeløst, fast stoff. Ingen ytterligere rensning av rå-amidet var nødvendig.
LC-MS: rt = 2,94 min, 210 (M+l, ES+).
3-(3,4-dimetoksy-fenyl)-propylamin
En løsning av 3-(3,4-dimetoksy-fenyl)-propionamid (11,09 g, 53,00 mmol) i vannfri THF (400 ml) ble langsomt satt til en omrørt, isavkjølt suspensjon av UAIH4 (4,02 g, 106,00 mmol) i vannfri THF (170 ml). Etter fullført tilsetning ble blandingen omrørt ved tilbakeløp i 2 timer. Etter avkjøling til 0°C ble H20 (5 ml) og NaOH IN (5 ml) tilsatt dråpevis for å nedbryte overskudd av hydrid. Suspensjonen ble deretter filtrert og residuet ble etter inndampning fordelt mellom H20 (40 ml) og CH2C12 (100 ml). Det organiske sjiktet ble vasket med mettet, vandig NaHCC<3 og saltløsning, tørket over vannfri MgSC«4 og inndampet under redusert trykk, hvilket ga rå-aminet (7,00 g, 35,84 mmol, 68%) i form av en gul olje.
'H-NMR (300 MHz, CDC13) a: 6,9-6,6 (3H, m), 3,9-3,8 (6H, d), 2,9-2,7 (2H, m), 2,65-2,55 (2H, m), 1,9-1,75 (2H, m).
2-(3,4-dimetoksy-fenyl)-N-[3-(3,4-dimetoksy-fenyl)-propyl]-acetamid
En løsning av 3-(3,4-dimetoksy-fenyl)-propylamin (12,51 g, 64,06 mmol) og TEA (10 ml, 71,84 mmol) i vannfri THF (70 ml), ble avkjølt til 0°C og (3,4-dimetoksy-fenyl)-acetylklorid (13,75 g, 64,07 mmol) i THF (28 ml) ble tilsatt dråpevis. Etter omrøring under nitrogen i 13 timer ved RT, ble en mettet, vandig NaHCC«3-løsning tilsatt og reaksjonsblandingen ble ekstrahert tre ganger med AcOEt. Den organiske fasen ble tørket over vannfri MgSC«4, filtrert og løsningsmidlet ble fjernet under vakuum. Påfølgende vasking av det rå faste stoffet med toluen, ga tittelforbindelsen (12,81 g, 34,30 mmol, 53%) i form av et beige, fast stoff.
LC-MS: rt = 4,00 min, 374 (M+l, ES+).
l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-Lff-benzo[c]azepin
En blanding av 2-(3,4-dimetoksy-fenyl)-Ar<->[3-(3,4-dimetoksy-fenyl)-propyl]-acetamid (6,16 g, 16,49 mmol) og POCI3 (4,95 ml, 54,07 mmol) i vannfri acetonitril (185 ml), ble omrørt ved tilbakeløp i 4 timer under nitrogen. Etter avkjøling ble reaksjonsblandingen inndampet under vakuum og residuet ble oppløst i MeOH (125 ml). Løsningen ble avkjølt til 0°C og NaBHU (4,31 g, 113,93 mmol) ble tilsatt porsjonsvis. Etter omrøring ved 0°C i 2 timer under nitrogen, ble reaksjonsblandingen hellet i H2O og ekstrahert tre ganger med CH2CI2. De samlede organiske ekstrakter ble vasket med saltløsning, tørket over vannfri MgSCU, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (CHjCVMeOH: 9/1) ga tittelforbindelsen i form av en racemisk blanding (2,29 g, 6,40 mmol, 39%, gul olje).
LC-MS: rt = 3,02 min, 358 (M+l, ES+).
[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre-metylester
En blanding av l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l//- benzo[c]azepin (1,10 g, 3,08 mmol), TEA (1,3 ml, 9,33 mmol) og metyl-a-bromfenylacetat (487 ul, 3,09 mmol) i vannfri toluen (13 ml), ble omrørt ved tilbakeløp i 17 timer under nitrogen. Etter avkjøling ble reaksjonsblandingen oppløst i CH2CI2 (40 ml), vasket med H2O (15 ml) og den vandige fasen ble ekstrahert to ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgSC«4, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (AcOEt/heksan: 1/1) ga tittelforbindelsen i form av en blanding av stereoisomerer (1,34 g, 2,65 mmol, 86%, gul olje).
LC-MS: rt = 3,99 min. og rt = 4,24 min (diastereoisomerer), 506 (M+l, ES+).
[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre
Til en løsning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre-metylester (1,17 g, 2,31 mmol) i MeOH (9 ml) og dioksan (12 ml), ble vandig 2N NaOH (11 ml, 22 mmol) tilsatt dråpevis. Den resulterende gule, homogene blanding ble deretter omrørt ved 45 °C i 8 timer. Reaksjonsblandingen ble deretter inndampet under vakuum og vasket med Et20 (5 ml). Den vandige fasen ble surgjort (pH = 1) med 2N HC1 og ekstrahert tre ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgSCv, filtrert og inndampet, hvilket ga tittel-karboksylsyren (1,14 g, 2,31 mmol, 100%) i form av et beige, fast stoff (blanding av diastereoisomerer).
LC-MS: rt = 3,58 min, 492 (M+l, ES+).
3-(4-benzyloksy-3-metoksy-fenyl)-propionsyre-benzylester
En blanding av 3-(4-hydroksy-3-metoksy-fenyl)-propionsyre (5,1 g, 25,99 mmol), vannfri K2CO3 (25 g, 180,88 mmol) og benzylbromid (7,5 ml, 63,14 mmol) i vannfri aceton (100 ml), ble omrørt ved tilbakeløp i 7,5 timer under nitrogen. Etter avkjøling ble reaksjonsblandingen filtrert og inndampet under vakuum. Flash-kromatografi (CH2CI2) ga tittelforbindelsen (8,83 g, 23,45 mmol, 90%).
LC-MS: rt = 5,65 min, 377 (M+l, ES+).
3-(4-benzyloksy-3-metoksy-fenyl)-propionsyre
En løsning av 3-(4-benzyloksy-3-metoksy-fenyl)-propionsyre-benzylester (11,03 g, 29,30 mmol) i MeOH (110 ml) og dioksan (145 ml), ble tilsatt vandig 2N NaOH (139 ml, 278 mmol) dråpevis. Den resulterende gule, homogene blanding ble deretter omrørt ved 50°C i 17 timer. Reaksjonsblandingen ble deretter inndampet under vakuum og vasket med Et20 (100 ml). Den vandige fasen ble surgjort (pH = 1) med 2N HC1 og ekstrahert tre ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgSCv, filtrert og inndampet, hvilket ga tittel-karboksylsyren (8,4 g, 29,30 mmol, 100%) i form av et fargeløst, fast stoff.
LC-MS: rt = 4,53 min, 285 (M-l, ES-).
3-(4-benzyloksy-3-metoksy-fenyl)-propionamid
En omrørt løsning av 3-(4-benzyloksy-3-metoksy-fenyl)-propionsyre (8,38 g, 29,30 mmol) i tørr THF (110 ml), ble under nitrogen tilsatt TEA (4,5 ml, 32,33 mmol), og den resulterende blanding ble avkjølt til -10°C før etylklorformiat (3,1 ml, 32,53 mmol) ble tilsatt dråpevis. Etter omrøring ved -10°C (20 min) ble ammoniumhydroksyd (25% i vann, 65 ml) i THF (65 ml) tilsatt, og blandingen ble omrørt ved -15°C i 30 min og deretter ved RT i 1,5 timer. Reaksjonsblandingen ble inndampet under vakuum, ekstrahert tre ganger med CH2Cl2 og de samlede organiske ekstrakter ble vasket med mettet, vandig NaHCC«3 og saltløsning. Den organiske fasen ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga tittelforbindelsen (8,40 g, 29,30 mmol, 100%) i form av et fargeløst, fast stoff. Ingen ytterligere rensning av rå-amidet var nødvendig. LC-MS: rt = 4,08 min, 286 (M+l, ES+).
3-(4-benzyloksy-3-metoksy-fenyl)-propylamin
En løsning av 3-(4-benzyloksy-3-metoksy-fenyl)-propionamid (7,85 g, 27,53 mmol) i vannfri THF (210 ml) ble langsomt satt til en omrørt, isavkjølt suspensjon av LiAlH*
(2,09 g, 55,07 mmol) i vannfri THF (90 ml). Etter fullført tilsetning ble blandingen omrørt ved tilbakeløp i 1 time. Etter avkjøling til 0°C ble H2O (15 ml) tilsatt dråpevis for å nedbryte overskudd av hydrid, og den resulterende suspensjon ble deretter filtrert. Residuet ble etter inndampning fordelt mellom H2O (50 ml) og CH2CI2 (100 ml). Det organiske sjiktet ble vasket med NaHCC«3 og saltløsning, tørket over vannfri MgSC>4 og inndampet under redusert trykk, hvilket ga rå-aminet (6,03 g, 22,22 mmol, 81%) i form av en gul olje.
LC-MS: rt = 3,20 min, 272 (M+l, ES+).
A7-[3-(4-benzyloksy-3-metoksy-fenyl)-propyl]-2-(3,4-dimetoksy-fenyl)-acetamid
En løsning av 3-(4-benzyloksy-3-metoksy-fenyl)-propylamin (6,06 g, 22,36 mmol) og TEA (3,5 ml, 25,14 mmol) i vannfri THF (25 ml), ble avkjølt til 0°C og (3,4-dimetoksy-fenyl)-acetylklorid (4,80 g, 22,36 mmol) i THF (10 ml) ble tilsatt dråpevis. Etter omrøring ved RT i 28 timer under nitrogen, ble en mettet, vandig NaHCC>3-løsning tilsatt og reaksjonsblandingen ble ekstrahert tre ganger med AcOEt. Den organiske fasen ble tørket over vannfri MgSO^, filtrert og løsningsmidlet ble fjernet under vakuum. Påfølgende vasking av det rå, faste stoffet med toluen ga tittelforbindelsen (6,57 g, 14,61 mmol, 65%) i form av et beige, fast stoff.
LC-MS: rt = 4,90 min, 450 (M+l, ES+).
8-benzyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-2,3,4,54etrahydro-l// benzo[c]azepin
En blanding av Af<->[3-(4-benzyloksy-3-metoksy-fenyl)-propyl]-2-(3,4-dimetoksy-fenyl)-acetamid (6,04 g, 13,43 mmol) og POCI3 (4,1 ml, 44,78 mmol) i vannfri acetonitril (350 ml), ble omrørt ved tilbakeløp i 5 timer under nitrogen. Etter avkjøling ble reaksjonsblandingen inndampet under vakuum og residuet ble oppløst i MeOH (120 ml). Løsningen ble avkjølt til 0°C og NaBFU (3,50 g, 92,70 mmol) ble tilsatt porsjonsvis. Etter omrøring ved 0°C i 2 timer under nitrogen, ble reaksjonsblandingen hellet i H2O og ekstrahert tre ganger med CH2Cl2. De samlede organiske ekstrakter ble vasket med saltløsning, tørket over vannfri MgSC<4, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (C^Cb/MeOH: 9/1) ga tittelforbindelsen i form av en racemisk blanding (2,44 g, 5,62 mmol, 42%, gul olje).
LC-MS: rt = 3,52 min, 434 (M+l, ES+).
(3,4-dimetoksy-fenoksy)-acetonitril
En løsning av 3,4-dimetoksyfenol (5,0 g, 32,4 mmol) i tørr aceton (160 ml), ble tilsatt kloracetonitril (2,05 ml, 32,4 mmol) og vannfri K2CO3 (6,72 g, 48,6 mmol). Reaksjonsblandingen ble omrørt ved tilbakeløp i 20 timer under nitrogen. Etter avkjøling ble blandingen filtrert og inndampet under vakuum. Residuet ble kombinert med H2O, ekstrahert med CH2CI2 og de samlede organiske faser ble tørket over vannfri MgSCu, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (AcOEt/ heksan: 3/7) ga tittelforbindelsen (4,5 g, 68%).
'H-NMR (300 MHz, CDCI3) a: 6,8 (1H, d), 6,6 (1H, d), 6,5 (1H, dd), 4,75 (2H, s), 3,85 (6H, d).
2-(3,4-dimetoksy-fenoksy)-etylamin
En kald (0°C) suspensjon av LiAIRt (1,73 g, 45,6 mmol) i vannfri THF (72 ml), ble dråpevis tilsatt en løsning av (3,4-dimetoksy-fenoksy)-acetonitril (5,88 g, 30,4 mmol) i vannfri THF (42 ml). Den resulterende blanding fikk nå RT og ble omrørt ved RT i 20 timer under nitrogen. Reaksjonsblandingen ble kombinert med en blanding av H2O/2N NaOH (vandig) (4/1) for å nedbryte overskudd av LiAltL;. Den hvite suspensjonen ble filtrert og det faste stoffet ble vasket med CH2CI2. De samlede organiske faser ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (CH2C12/ MeOH: 9/1) ga tittelforbindelsen (4,65 g, 77%).
'H-NMR (300 MHz, CDCI3) a: 6,78 (1H, d), 6,55 (1H, d), 6,4 (1H, dd), 3,95 (2H, t), 3,80 (6H, d), 3,05 (2H, t), 1,92 (2H, br.s.).
Ar<->[2-(3,4-dimetoksy-fenoksy)-etyl]-2-(3,4-dimetoksy-fenyl)-acetamid
En kald (0°C) løsning av 2-(3,4-dimetoksy-fenoksy)-etylamin (2,3 g, 11,8 mmol) i vannfri THF (21 ml), ble tilsatt TEA (1,4 ml, 19,2 mmol) og 3,4-dimetoksyfenylacetylklorid (2,49 g, 11,6 mmol) porsjonsvis. Den resulterende blanding ble omrørt ved RT i 20 timer under nitrogen. Blandingen ble kombinert med H20 og ekstrahert tre ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgSC>4, filtrert og inndampet, hvilket ga et fast råprodukt. Omkrystallisering fra dietyleter ga tittelforbindelsen (3,59 g, 80%) i form av et hvitt, fast stoff.
'H-NMR (300 MHz, CDCI3) a: 6,8 (3H, m), 6,4 (1H, d), 6,35 (1H, dd), 5,95 (1H, br.s) 3,95 (2H, t), 3,80 (12H, k), 3,6 (2H, m), 3,55 (2H, s).
LC-MS: rt = 3,84 min, 376 (M+l, ES+).
5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[f][l,4]oksazepin
En omrørt løsning av N-[2-(3,4-dimetoksy-fenoksy)-etyl]-2-(3,4-dimetoksy-fenyl)-acetamid (3,6 g, 9,56 mmol) i tørr CH3CN (20 ml), ble tilsatt POCl3 (2,62 ml, 28,6 mmol). Den resulterende blanding ble omrørt ved tilbakeløp i 3 timer under nitrogen. Etter avkjøling ble reaksjonsblandingen inndampet under vakuum og residuet ble oppløst i MeOH (80 ml). Løsningen ble avkjølt til 0°C og NaBH4 (2,53 g, 67,0 mmol) ble tilsatt porsjons vis. Den resulterende blekgule suspensjon ble omrørt ved RT i 16 timer under nitrogen. Reaksjonsblandingen ble hellet i H20 og ekstrahert tre ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (CH2C12/ MeOH: 9/1) ga tittelforbindelsen (1,14 g, 33%) i form av en viskøs, brun olje.
'H-NMR (300 MHz, CDCI3) a: 6,8-6,6 (5H, m), 6,45 (1H, s), 4,15 (1H, m), 3,80 (12H, k), 3,55-2,95 (6H, m).
LC-MS: rt = 2,99 min, 360 (M+l, ES+).
(3,4-dimetoksy-fenylsulfanyl)-acetonitril
En løsning av 3,4-dimetoksytiofenol (5,0 g, 29,4 mmol) i tørr DMF (150 ml), ble tilsatt kloracetonitril (1,85 ml, 29,4 mmol), vannfri K2C03 (6,09 g, 44,1 mmol) og DMAP (358 mg, 2,9 mmol). Reaksjonsblandingen ble omrørt ved 80°C i 20 timer under nitrogen. Etter avkjøling ble blandingen filtrert og inndampet under vakuum. Residuet ble kombinert med H2O, ekstrahert med CH2CI2, og de samlede organiske faser ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (AcOEt) ga tittelforbindelsen (5,16 g, 84%).
'H-NMR (300 MHz, CDCI3) a: 7,2 (1H, d), 7,15 (1H, d), 6,9 (1H, d), 3,85 (6H, d), 3,5
(2H, s).
2-(3,4-dimetoksy-fenylsulfanyl)-etylamin
En kald (0°C) løsning av (3,4-dimetoksy-fenylsulfanyl)-acetonitril (7,53 g, 36,0 mmol) i vannfri THF (41 ml), ble tilsatt NaBtU (1,22 g, 32,0 mmol) porsjonsvis og en løsning av BF3OEt2 (5,37 ml, 20,0 mmol) i vannfri THF (13,4 ml) dråpevis i løpet av 30 min. Den resulterende blanding ble omrørt ved RT i 3 timer under nitrogen. Blandingen ble inndampet under vakuum, residuet ble oppløst i CH2CI2 og vasket med HC1 37%. Den vandige fasen ble nøytralisert med NaOH 30% og ekstrahert med CH2CI2. De samlede organiske faser ble tørket over vannfri MgSC«4, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (CH2C12/ MeOH: 9/1) ga tittelforbindelsen (3,6 g, 46%).
'H-NMR (300 MHz, CDCI3) a: 7,05 (2H, m), 6,85 (1H, d), 3,80 (6H, d), 2,95 (2H, m), 1,7 (2H, br.s.).
2-(3,4-dimetoksy-fenyl)-Ar<->[2-(3,4-dimetoksy-fenylsulfanyl)-etyl]-acetamid
En kald (0°C) løsning av 2-(3,4-dimetoksy-fenylsulfanyl)-etylamin (3,97 g, 18,6 mmol) i vannfri THF (49 ml), ble tilsatt TEA (3,11 ml, 18,6 mmol) og 3,4-dimetoksyfenylacetylklorid (4,0 g, 18,6 mmol) porsjonsvis. Den resulterende blanding ble omrørt ved RT i 20 timer under nitrogen. Blandingen ble kombinert med H2O og ekstrahert tre ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga et fast råprodukt. Flash-kromatografi (AcOEt) ga tittelforbindelsen (7,08 g, 97%).
'H-NMR (300 MHz, CDCI3) a: 6,95-6,7 (6H,m), 5,95 (lH.br.s), 3,95 (12H,k), 3,5 (2H,s), 3,55 (2H,k), 2,95 (2H,t).
LC-MS: rt = 3,87 min, 392 (M+l, ES+).
9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9-tetrahydro-5-tia-8-aza-benzocyklohepten
En omrørt løsning av 2-(3,4-dimetoksy-fenyl)-Af-[2-(3,4-dimetoksy-fenylsulfanyl)-etyl]-acetamid (4,0 g, 10,0 mmol) i tørr CH3CN (21 ml), ble tilsatt POCl3 (2,80 ml, 30,0 mmol). Den resulterende blanding ble omrørt ved tilbakeløp i 3 timer under nitrogen. Etter avkjøling ble reaksjonsblandingen inndampet under vakuum og residuet ble oppløst i MeOH (85 ml). Løsningen ble avkjølt til 0°C og NaBHj (2,7 g, 69,0 mmol) ble tilsatt porsjonsvis, den resulterende blekgule suspensjon ble omrørt ved RT i 16 timer under nitrogen. Reaksjonsblandingen ble hellet i H2O og ekstrahert tre ganger med CH2CI2. De samlede organiske faser ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (CH2C12/ MeOH: 9/1) ga tittelforbindelsen (1,14 g, 27%) i form av en viskøs, brun olje.
'H-NMR (300 MHz, CDC13) a: 7,1 (1H, s), 6,8 (4H, s), 4,6 (1H, m), 4,15, 3,80 (12H, q), 3,45-2,75 (6H, m).
LC-MS: rt = 4,39 min, 376 (M+l, ES+).
9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6/7-dihydro-9/7-5-tia-8-aza-benzocyklohepten-8-karboksylsyreterf-butylester
En kald (0°C) omrørt løsning av 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9 tetrahydro-5-tia-8-aza-benzocyklohepten (417 mg, 1,11 mmol) i tørr CH2CI2 (5 ml), ble tilsatt TEA (168 uL, 1,2 mmol) og di-fert-butyl-dikarbonat (262 mg, 1,2 mmol). Den resulterende blanding fikk nå RT og ble omrørt ved RT i 20 timer under nitrogen. Reaksjonsblandingen ble kombinert med vann, ekstrahert to ganger med CH2CI2, de samlede organiske faser ble tørket over vannfri MgS04, filtrert og inndampet, hvilket ga en rå, gul olje. Flash-kromatografi (AcOEt) ga tittelforbindelsen i form av en blekgul olje (486 mg, 91%).
'H-NMR (300 MHz, CDC13) 5: 7,15 (1H, d); 6,6-6,8 (4H, m); 5,05 (1H, m); 3,85 (12H, d); 3,65 (2H, m); 3,45 (2H, m); 2,75 (2H, m); 1,45 (9H, d).
9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9-tetrahydro-5X<6->tia-8-aza-benzocyklohepten-8-karboksylsyre-tørf-butylester
En kald (0°C), omrørt løsning av 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro 9//-5-tia-8-aza-benzocyklohepten-8-karboksylsyre-ferf-butylester (100 mg, 0,21 mmol) i tørr CH2CI2 (1 ml), ble tilsatt 3-klorperbenzosyre (106 mg, 0,614 mmol). Den resulterende blanding ble omrørt ved 0°C i 2 timer, fikk nå RT og ble omrørt ved RT natten over. Reaksjonsblandingen ble kombinert med vann, ekstrahert to ganger med CH2CI2, de samlede organiske faser ble tørket over vannfri MgSC>4, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (AcOEt/ heksan: 1/1) ga tittelforbindelsen i form av etblekgult, fast stoff (76 mg, 71%).
'H-NMR (300 MHz, CDCI3) 6: 7,15 (1H, d); 6,6-6,8 (4H, m); 5,25 (1H, m); 3,85 (12H, d); 3,65 (2H, m); 3,35 (2H, m); 2,75 (2H, m); 1,35 (9H, d).
9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9-tetrahydro-5-tia-8-aza-benzocyklohepten-5,5-dioksyd.
En omrørt løsning av 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9 tetrahydro-5A,<6->tia-8-aza-benzocyklohepten-8-karboksylsyre-ferf-butylester (310 mg, 0,61 mmol) i tørr CH2C12 (3 ml), ble tilsatt trifluoreddiksyre (372 uL, 4,86 mmol). Den resulterende blanding ble omrørt ved RT i 20 timer under nitrogen. Reaksjonsblandingen ble kombinert med vann/ 2N NaOH, ekstrahert to ganger med CH2C12> og de samlede organiske faser ble tørket over vannfri MgSC«4, filtrert og inndampet, hvilket ga en rå olje. Flash-kromatografi (CH2CI2/ MeOH: 9/1) ga tittelforbindelsen i form av en blekgul olje (118 mg, 47%).
'H-NMR (300 MHz, CDCI3) 8: 7,6 (1H, d); 6,85 (4H, m); 4,95 (1H, m); 3,95-3,81 (12H, m); 3,45 (4H, m); 3,25 (2H, m).
2-(3,4-diklor-fenyl)-l-(3,4-dimetoksy-fenyl)-etanon
En blanding av (3,4-diklor-fenyl)-eddiksyre (11,14 g, 54,33 mmol) og vannfri DMF (1,45 ml) i tionylklorid (137 ml), ble omrørt ved RT under nitrogen i 17 timer. Overskudd av tionylklorid ble fjernet under vakuum. Vannfri toluen ble satt til residuet som igjen ble inndampet under vakuum (gjentatt to ganger til). Pulverisert, vannfri aluminiumklorid (11,57 g, 86,72 mmol) ble satt porsjonsvis (eksoterm reaksjon) til en omrørt blanding av 1,2-dimetoksy-benzen (6,92 ml, 54,34 mmol) og det ovennevnte acylklorid i vannfri diklormetan (120 ml). En eksoterm reaksjon skjedde og reaksjonsblandingen ble oppvarmet ved tilbakeløp i 2 timer. Reaksjonsblandingen fikk nå romtemperatur og ble deretter hellet i en blanding av is (67 g) og vandig 7,5 N HC1 (64 ml). Sjiktene ble separert og det vandige sjiktet ble ekstrahert med diklormetan. De samlede organiske ekstrakter ble vasket med saltløsning, tørket over magnesiumsulfat, filtrert og inndampet til tørrhet, hvilket ga en brun rest (olje og fast stoff). Etter ytterligere tørking (HV) ble vannfri dietyleter tilsatt og et beige, fast stoff ble utfelt. Det beige, faste stoffet ble frafiltrert og ytterligere tørket (8,33 g, 47%).
LC-MS: rt = 5,25 min, 326 (M+l, ES+).
2-(3,4-diklor-fenyl)-l-(4,5-dimetoksy-2-nitro-fenyl)-etanon
En heterogen blanding av 2-(3,4-diklor-fenyl)-l-(3,4-dimetoksy-fenyl)-etanon (8,33 g, 25,6 mmol) i eddiksyreanhydrid (65 ml), ble satt dråpevis til en avkjølt (0°C) løsning av 65% salpetersyre (140 ml) og eddiksyreanhydrid (21,3 ml). Den resulterende blanding ble omrørt ved 0°C i 2 timer. Vann ble tilsatt dråpevis og den resulterende heterogene blanding ble omrørt og langsomt oppvarmet. Råproduktet ble deretter frafiltrert og det beige, faste stoffet ble vasket flere ganger med destillert vann og tørket under HV (6,98 g, 74%).
LC-MS: rt = 5,43 min, 370 (M+l, ES+).
l-(2-amino-4,5-dimetoksy-fenyl)-2-(3,4-diklor-fenyl)-etanon
En blanding av 2-(3,4-diklor-fenyl)-l-(4,5-dimetoksy-2-nitro-fenyl)-etanon (9,62 g, 25,98 mmol) og palladium på trekull (2,88 g, 30% av massen) ble tilsatt metanol (500 ml) dråpevis, og den resulterende heterogene blanding ble hydrogenen (latm) ved RT i 4 dager. Reaksjonsblandingen ble filtrert over Celite og Celite-kakene ble vasket flere ganger med vannfri metanol. Filtratet ble deretter inndampet til tørrhet og den rå brune oljen ble renset med flash-kromatografi (diklormetan/metanol, 360/1), hvilket ga det forventede anilinderivat i form av en brun olje (5,04 g, 57%).
LC-MS: rt = 5,12 min, 341 (M+l, ES+).
2-brom-Ar-{2-[2-(3,4-diklor-fenyl)-acetyl]-4,5-dimetoksy-fenyl}-acetamid
1- (2-amino-4,5-dimetoksy-fenyl)-2-(3,4-diklor-fenyl)-etanon (5,52 g, 16,24 mmol) ble oppløst i diklormetan (20 ml), destillert vann ble deretter tilsatt (2 ml) og den resulterende løsning ble avkjølt til -5°C under nitrogen. Bromacetylbromid (1,63 ml, 18,68 mmol) ble oppløst i diklormetan (10 ml) og satt dråpevis til den ovennevnte løsning; temperaturen fikk ikke overstige +5°C. Reaksjonsblandingen ble omrørt ved 0°C i 15 min og fikk deretter nå RT før ytterligere omrøring i 2,5 timer. Diklormetan ble tilsatt (30 ml) og det organiske sjiktet ble vasket med destillert vann, mettet NaHCC>3-løsning og saltløsning. Det ble tørket over magnesiumsulfat, filtrert og løsningsmidlet ble fjernet under vakuum. Denne rå blandingen ble renset med flash-kromatografi (diklormetan/metanol, 360/1), hvilket ga produktet i form av et gult, fast stoff (5,25 g, 70%).
LC-MS: rt = 5,65 min, 462 (M+l, ES+).
5-(3,4-diklor-benzyl)-7,8-dimetoksy-l,3-dihydro-benzo[e][l,4]diazepin-2-on
2- brom-Ar-{2-[2-(3,4-diklor-fenyl)-acetyl]-4,5-dimetoksy-fenyl}-acetamid (5,25 g, 11,39 mmol) ble plassert under nitrogen ved -10°C. Ammoniakk i metanol (7N, 55 ml) ble tilsatt dråpevis ved -10°C, og reaksjonsblandingen ble oppvarmet ved 40°C i 2,5 timer og deretter ved tilbakeløp (75°C) i 1 time. Løsningsmidlet ble avdampet under vakuum, hvilket ga et gult, fast stoff som ble oppløst i diklormetan og vasket med vann. Den organiske fasen ble tørket over magnesiumsulfat, filtrert og inndampet til tørrhet. Flash-kromatografi (diklormetan/metanol, 18/1) ga det forventede produkt i form av et gult, fast stoff (1,5 g, 35%).
LC-MS: rt = 3,15 min, 380 (M+l, ES+).
5-(3,4-diklor-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[e][l,4]diazepin-2-on
En løsning av 5-(3,4-diklor-benzyl)-7,8-dimetoksy-l,3-dihydro-benzo[e][l,4]-diazepin-2-on (0,48 g, 1,17 mmol) i iseddik (1,67 ml) og metanol (9,4 ml), ble omrørt ved 0°C under nitrogen. Natriumcyanoborhydrid (0,148 g, 2,23 mmol) ble tilsatt porsjonsvis, og reaksjonsblandingen ble omrørt ved 0°C i 30 min og deretter ved RT i 2 timer. Vann (17 ml) ble tilsatt dråpevis, og produktet ble ekstrahert med diklormetan og vasket med vandig IN ammoniakk. Den organiske fasen ble tørket over magnesiumsulfat og filtrert, og løsningsmidlet ble fjernet under vakuum. Den resulterende gule olje utkrystalliserte under HV (0,19 g, 41%).
LC-MS: rt = 3,55 min, 382 (M+l, ES+).
B. Generell prosedyre A:
Ved -15°C ble en løsning av det respektive amin R<9>R<10>NH (1 ekvivalent) i THF (0,40 M) satt dråpevis til en løsning av 2-bromacetylbromid (1 ekvivalent) i THF (0,20 M). Reaksjonsblandingen ble deretter behandlet dråpevis med en løsning av diisopropyletylamin (4 ekvivalenter) i THF (2,0 M), fikk langsomt nå RT (i løpet av 30 min) og ble omrørt ved RT i 30 min. En løsning av det respektive benzazepin (1 ekvivalent) i THF (0,20 M) ble tilsatt, og blandingen ble omrørt ved 75°C i 15 timer. Etter avkjøling ble AcOEt og H2O tilsatt og den vandige fasen ble ekstrahert to ganger med AcOEt. De samlede organiske ekstrakter ble vasket med saltløsning, tørket over vannfri MgS04, filtrert og inndampet under vakuum. Flash-kromatografi ga det forventede benzazepin-derivat. Eksempel 1 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-naftalen- 1-ylmetyl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med 1-naphtalenemetylamin og l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-lH-benzo[c]azepin.
LC-MS: rt = 3,95 min, 555 (M+l, ES+).
Eksempel 2
A^-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyI)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med piperonylamin og l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l//-benzo[c]azepin.
LC-MS: rt = 3,67 min, 549 (M+l, ES+).
Eksempel 3
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-2-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med 2-aminoindan-hydroklorid og 1-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-lH-benzo[c]azepin.
LC-MS: rt = 3,83 min, 531 (M+l, ES+).
Eksempel 4
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-AMndan-2-yl-acetamid:
fremstilt ved omsetning av 2-bromacetylbromid med 2-aminoindan-hydroklorid og 5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[fJ[l,4]oksazepin. LC-MS: rt = 4,34 min, 533 (M+l, ES+). Eksempel 5 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-A^-indan-l-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-l-aminoindan og 5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[f][l,4]oksazepin.
LC-MS: rt = 4,62 min, 533 (M+l, ES+).
Eksempel 6
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-l-aminoindan og l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l/f-benzo[c]azepin.
LC-MS: rt = 3,90 min, 531 (M+l, ES+).
Eksempel 7
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9-tetrahydro-5X,6-tia-8-aza-benzocyklohepten-8-yl]-iV-indan-2-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med 2-aminoindan-hydroklorid og 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9-tetrahydro-5-tia-8-aza-benzocyklohepten-5,5-dioksyd.
LC-MS: rt = 3,81 min, 581 (M+l, ES+).
Eksempel 8
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9-tetrahydro-5X.<6->tia-8-aza-benzocyklohepten-8-yl]-AMndan-l-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-l-aminoindan og 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9-tetrahydro-5-tia-8-aza-benzocyklohepten-5,5-dioksyd.
LC-MS: rt = 4,49 min, 581 (M+l, ES+).
Eksempel 9
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-JV-indan-l-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med S(+)-l-aminoindan og l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l/f-benzo[c]azepin.
LC-MS: rt = 3,80 min, 531 (M+l, ES+).
Eksempel 10
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-iV-naftalen-l-ylmetyl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med 1-naphtalenemetylamin og 5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[f][l,4]oksazepin.
LC-MS: rt = 4,39 min, 557 (M+l, ES+).
Eksempel 11
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-iV-(2-etoksy-benzyl)-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med 2-etoksy-benzylamin og 5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[fJ[l,4]oksazepin.
LC-MS: rt = 4,34 min, 551 (M+l, ES+).
Eksempel 12
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-A7-in dan- 1-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med S(+)-l-aminoindan og 5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[f] [ 1,4]oksazepin.
LC-MS: rt = 4,32 min, 533 (M+l, ES+).
Eksempel 13
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-Ar<->(l,2,3,4-tetrahydro-naftalen-l-yl)-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-1,2,3,4-tetrahydro-naftalen-l-ylamin og 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9-tetrahydro-5-tia-8-aza-benzocyklohepten.
LC-MS: rt = 5,01 min, 563 (M+l, ES+).
Eksempel 14
A7-benzyl-2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med benzylamin og 5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-benzo[f][l,4]oksazepin.
LC-MS: rt = 4,05 min, 507 (M+l, ES+).
Eksempel 15
2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-AMndan-l-yl-acetamid:
fremstilt ved omsetning av 2-bromacetylbromid med S(+)-l-aminoindan og 9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7,8,9-tetrahydro-5-tia-8-aza-benzocyklohepten. LC-MS: rt = 4,85 min, 549 (M+l, ES+). Eksempel 16 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(4-metoksy-indan-l-yl)-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-4-metoksy-indan-l-ylamin og 1-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l^-benzo[c]azepin.
LC-MS: rt = 3,83 min, 561 (M+l, ES+).
Eksempel 17
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-jV-(3-fenyl-indan-l-yl)-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-3-fenyl-indan-l-ylamin og 1-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l//-benzo[c]azepin.
LC-MS: rt = 4,42 min, 607 (M+l, ES+).
Eksempel 18
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(4-metyl-indan-l-yl)-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med rac-4-metyl-indan-l-ylamin og 1-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l//-benzo[c]azepin.
LC-MS: rt = 4,02 min, 545(M+1, ES+).
Eksempel 19 2-[8-benzyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-acetamid: fremstilt ved omsetning av 2-bromacetylbromid med S(+)-l-aminoindan og l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l^-benzo[c]azepin.
LC-MS: rt = 4,39 min, 607 (M+l, ES+).
C. Generell prosedyre B:
En løsning av det respektive [l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre (1 ekvivalent) i vannfri DMF (0,04 M), ble suksessivt tilsatt PyBOP (1,1 ekvivalenter), det respektive amin (1 ekvivalent) og A^Af-diisopropyletylamin (2,3 ekvivalenter). Den resulterende blanding ble omrørt ved RT i 15 timer under nitrogen. Etter fullført reaksjon ble AcOEt tilsatt, og den organiske fasen ble vasket med saltløsning, tørket over vannfri MgS04, filtrert og inndampet under vakuum. Flash-kromatografi ga det tilsvarende benzazepin-derivat. Eksempel 20 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yI]-AMndan-2-yl-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2-aminoindan-hydroklorid.
LC-MS: rt = 4,26 min, 607 (M+l, ES+).
Eksempel 21
A7-butyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med n-butylamin.
LC-MS: rt = 3,91 min, 547 (M+l, ES+).
Eksempel 22
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med S(+)-l-aminoindan.
LC-MS: rt = 4,09 min og rt = 4,39 min (diastereoisomerer), 607 (M+l, ES+).
Eksempel 23
Ar-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med piperonylamin.
LC-MS: rt = 3,88 min og rt = 3,98 min (diastereoisomerer), 625 (M+l, ES+).
Eksempel 24
Ar<->cyklopentyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med cyklopentylamin.
LC-MS: rt = 3,79 min og rt = 3,92 min (diastereoisomerer), 559 (M+l, ES+).
Eksempel 25 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-furan-2-ylmetyl-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med furfurylamin.
LC-MS: rt = 3,72 min og rt = 3,85 min (diastereoisomerer), 571 (M+l, ES+).
Eksempel 26
{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-eddiksyre-etylester: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med glycin-etylester-hydroklorid.
LC-MS: rt = 3,72 min, 577 (M+l, ES+).
Eksempel 27
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Ar<->pyridin-4-ylmetyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 4-pikolylamin.
LC-MS: rt = 3,09 min, 582 (M+l, ES+).
Eksempel 28
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyridin-3-ylmetyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-pikolylamin.
LC-MS: rt = 3,20 min, 582 (M+l, ES+).
Eksempel 29
Ar-cyklopropyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med cyklopropylamin.
LC-MS: rt = 3,59 min, 531 (M+l, ES+).
Eksempel 30
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4^-tetrahydro-benzo[c]azepin-2-yl]-Ar-(2-okso-tetrahydro-furan-3-yl)-2-fenyl-acetamid:
fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2-amino-4-butyrolakton-hydrobromid. LC-MS: rt = 3,46 min, 575 (M+l, ES+). Eksempel 31 2-{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-3-hydroksy-propionsyre-metylester: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -fenyl-eddiksyre med L-serin-metylester-hydroklorid.
LC-MS: rt = 3,40 min, 593 (M+l, ES+).
Eksempel 32
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-etylkarbamoylmetyl-2-fenyl-acetainid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2-amino-Af-etyl-acetamid.
LC-MS: rt = 3,37 min, 576 (M+l, ES+).
Eksempel 33
2- [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^(etyl-metyl-karbamoyl)-metyl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c] azepin-2-yl] -fenyl-eddiksyre med 2-amino-AT-etyl-A^-metyl-acetamid.
LC-MS: rt = 3,42 min, 590 (M+l, ES+).
Eksempel 34
3- {2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-propionsyre-metylester: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-amino-propionsyre-metylester.
LC-MS: rt = 3,52 min, 577 (M+l, ES+).
Eksempel 35
A<7->(lH-benzoimidazol-2-ylmetyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2-aminometyl-benzimidazol-dihydroklorid-hydrat.
LC-MS: rt = 3,36 min, 621 (M+l, ES+).
Eksempel 36
3-{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-AyV-dimetyl-propionamid:
fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-amino-A^N-dimetyl-propionamid. LC-MS: rt = 3,42 min, 590 (M+l, ES+). Eksempel 37 3-{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetyIamino}-A^-etyl-Ar-metyl-propionamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-amino-N-etyl-Af-metyl-propionamid. LC-MS: rt = 3,40 min, 604 (M+l, ES+). Eksempel 38 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(l-metyl-lH-indol-3-ylmetyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyremed C-(l-metyl-lH-indol-3-yl)-metylamin. LC-MS: rt = 3,99 min og rt = 4,12 min (diastereoisomerer), 634 (M+l, ES+). Eksempel 39 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-isoksazol-5-ylmetyl-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med C-isoksazol-5-yl-metylamin-hydroklorid. LC-MS: rt = 3,65 min, 572 (M+l, ES+). Eksempel 40 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(lH-indol-3-ylmetyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyremed C-(lH-indol-3-yl)-metylamin-dihydroklorid. LC-MS: rt = 3,82 min og rt = 3,96 min (diastereoisomerer), 620 (M+l, ES+). Eksempel 41 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A7-(l-metyl-lH-benzoimidazol-2-ylmetyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyremed C-(l-metyl-lH-benzoimidazol-2-yl)-metylamin.
LC-MS: rt = 3,50 min, 635 (M+l, ES+).
Eksempel 42
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMsokinolin-l-ylmetyl-2-fenyl-acetamid:
fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med C-isokinolin-l-yl-metylamin-dihydroklorid. LC-MS: rt = 3,88 min, 632 (M+l, ES+). Eksempel 43 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-A7-(4-[l,2,3]tiadiazol-4-yl-benzyl)-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 4-(l,2,3-tiadiazol-4-yl)benzylamin-hydroklorid.
LC-MS: rt = 4,09 min, 665 (M+l, ES+).
Eksempel 44
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(l-metyl-lH-indazol-3-ylmetyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med C-(l-metyl-lH-indazol-3-yl)-metylamin-hydroklorid.
LC-MS: rt = 3,83 min, 635 (M+l, ES+).
Eksempel 45
iV-cyanometyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med amino-acetonitril-hydroklorid.
LC-MS: rt = 3,42 min og rt = 3,58 min (diastereoisomerer), 530 (M+l, ES+).
Eksempel 46
Ar<->(2-acetylamino-etyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med iV-acetyletylendiamin.
LC-MS: rt = 3,13 min, 576 (M+l, ES+).
Eksempel 47
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Ar<->(2,2,2-trifluor-etyl)-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2,2,2-trifluoretylamin.
LC-MS: rt = 4,11 min, 573 (M+l, ES+).
Eksempel 48
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->(2-metylsulfanyl-etyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2-(metyltio)-etylamin.
LC-MS: rt = 3,63 min, 565 (M+l, ES+).
Eksempel 49
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-JV-kinolin-2-ylmetyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med C-kinolin-2-yl-metylamin-dihydroklorid. LC-MS: rt = 3,91 min, 632 (M+l, ES+).
Eksempel 50
A^-(2-cyano-etyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-aminopropionitril.
LC-MS: rt = 3,30 min, 544 (M+l, ES+).
Eksempel 51
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(3-metoksy-propyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-metoksypropylamin.
LC-MS: rt = 3,32 min, 563 (M+l, ES+).
Eksempel 52
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-etoksy-propyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-etoksypropylamin.
LC-MS: rt = 3,51 min, 577 (M+l, ES+).
Eksempel 53
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yI]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med ammoniumklorid.
LC-MS: rt = 3,15 min, 491 (M+l, ES+).
Eksempel 54
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyrazin-2-ylmetyl-acetamid:
fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med C-pyrazin-2-yl-metylamin-hydroklorid. LC-MS: rt = 3,33 min, 583 (M+l, ES+). Eksempel 55 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-iV-prop-2-ynyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med propargylamin.
LC-MS: rt = 3,36 min og rt = 3,51 min (diastereoisomerer), 529 (M+l, ES+).
Eksempel 56
A^-tert-butyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med ferf-butylamin.
LC-MS: rt = 3,69 min, 547 (M+l, ES+).
Eksempel 57
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(3-metyl-butyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med l-amino-3-metylbutan.
LC-MS: rt = 3,89 min, 561 (M+l, ES+).
Eksempel 58
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2V-(3,3-dimetyl-butyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3,3-dimetylbutylamin.
LC-MS: rt = 4,20 min, 575 (M+l, ES+).
Eksempel 59
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(l-etyl-propyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 1-etylpropylamin.
LC-MS: rt = 3,77 min, 561 (M+l, ES+).
Eksempel 60
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(2-etylsulfanyl-etyl)-2-fenyI-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 2-(etyltio)etylamin-hydroklorid.
LC-MS: rt = 3,72 min, 579 (M+l, ES+).
Eksempel 61
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A7-(2-hydroksy-etyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med etanolamin.
LC-MS: rt = 3,19 min, 535 (M+l, ES+).
Eksempel 62
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-(3-hydroksy-propyl)-2-fenyl-acetamid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med 3-amino-l-propanol.
LC-MS: rt = 3,13 min, 549 (M+l, ES+).
Eksempel 63
[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre iV^-dimetyl-hydrazid: fremstilt ved omsetning av [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre med AVV-dimetylhydrazin.
LC-MS: rt = 3,20 min, 534 (M+l, ES+).
D. Variasjon av substituenter i 8-stilling:
Generell prosedyre:
En løsning av det respektive 8-benzyloksy-l,3,4,5-tetrahydro-benzazepin i metanol (0,07 M), ble tilsatt palladium (10 vekt% på aktivert trekull; 10 % av vekten av benzyleteren), og den resulterende heterogene blanding ble kraftig omrørt under hydrogenatmosfære ved RT inntil benzyleteren var borte (TLC). Etter fullstendig omdanning ble blandingen filtrert gjennom Celite og inndampet under vakuum. Flash-kromatografi ga det rene fenol-derivatet. En løsning av dette fenol-derivatet (1 ekvivalent) i vannfri DMF (0,04 M), ble suksessivt tilsatt vannfri kaliumkarbonat (5 ekvivalenter) og den respektive elektrofil (1,2 ekvivalenter). Den resulterende heterogene blanding ble omrørt ved 50°C i opptil 15 timer. Etter reaksjonen ble blandingen oppløst i AcOEt og vasket med en mettet, vandig løsning av NaHC03. Den organiske fasen ble tørket over vannfri MgS04, filtrert og inndampet under vakuum. Flash-kromatografi ga det rene benzazepin-derivatet. Eksempel 64 2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-acetamid: fremstilt ved hydrogenolyse av 2-[8-benzyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-AMndan-1 -yl-acetamid.
LC-MS: rt = 3,64 min, 517 (M+l, ES+).
Eksempel 65
Ar-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved hydrogenolyse av Ar-benzo[l,3]dioksol-5-ylmetyl-2-[8-benzyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid. LC-MS: rt = 3,77 min, 611 (M+l, ES+). Eksempel 66 2-[8-allyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-JV-indan-l-yl-acetaniid: fremstilt ved omsetning av 2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-acetamid med allylbromid.
LC-MS: rt = 4,05 min, 557 (M+l, ES+).
Eksempel 67
2-[l-(3,4-dimetoksy-benzyl)-7-metoksy-8-propoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-indan-l-yl-acetamid: fremstilt ved omsetning av 2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af-indan-l-yl-acetamid med 1-brompropan.
LC-MS: rt = 4,13 min, 559 (M+l, ES+).
Eksempel 68
2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV-indan-l-yl-acetamid: fremstilt ved omsetning av 2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c] azepin-2-ylJ-AMndan-1 -yl-acetamid med 2-brompropan.
LC-MS: rt = 4,07 min, 559 (M+l, ES+).
Eksempel 69
2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-acetamid: fremstilt ved omsetning av 2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzofcjazepin^-ylJ-Af-indan-1 -yl-acetamid med 2-brom-1,1 -difluoretan. LC-MS: rt = 4,14 min, 581 (M+l, ES+).
Eksempel 70
A7-benzo[l,3]dioksol-5-ylmetyl-2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3>4,5-tetrahydro-benzo[c]azepin-2-yI]-2-fenyl-acetamid: fremstilt ved omsetning av A<7->benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid med 2-brom-1,1 -difluoretan.
LC-MS: rt = 4,20 min og rt = 4,37 min (diastereoisomerer), 675 (M+l, ES+).
Eksempel 71
A7-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid: fremstilt ved omsetning av Ar<->benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid med 2-brompropan.
LC-MS: rt = 3,96 min, 653 (M+l, ES+).
E. l,4-benzodiazepin-2-oner:
Eksempel 72
2-[5-(3,4-diklor-benzyl)-7,8-dimetoksy-2-okso-l,2,3,5-tetrahydro benzo[e][l,4]diazepin-4-yl]-AMndan-l-yl-acetamid: fremstilt i henhold til den generelle prosedyre A, ved omsetning av 2-bromacetylbromid med S(+)-l-aminoindan og 5-(3,4-diklor-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[e] [ 1,4]diazepin-2-on.
LC-MS: rt = 5,18 min, 554,47 (M+l, ES+).
F. Optisk rene benzazepiner:
Fremstillingen av rene enantiomerer av l-substituert-2-tetrahydrobenzazepin-derivater ble basert på metoden som er beskrevet av Polniaszek, i tilfellet med optisk rene 1-substituerte tetrahydroisokinoliner (Polniaszek R.P. et al, J. Am. Chem. Soc. 1989,111, 4859-4863). I Bischler-Napieralski-reaksjonen ble det benyttet de samme forsøksbetingelser som beskrevet av Kano (S. Kano et al., Chem. Pharm. Bull. 1977, 25, 10, 2510-2515).
1- (5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-lJy benzo[c]azepin.
2- (3,4-dimetoksy-fenyl)-A7-[3-(3,4-dimetoksy-fenyl)-propyl]-Ar-(l-(5)-fenyl-etyl)-acetamid ble fremstilt i henhold til de beskrevne prosedyrer (Polniaszek R.P. et al., J. Am. Chem. Soc. 1989, 111,4859-4863).
En blanding av 2-(3,4-dimetoksy-fenyl)-Af<->[3-(3,4-dimetoksy-fenyl)-propyl]-A<7->(l-(5)-fenyl-etyl)-acetamid (7,0 g, 14,65 mmol) og fosforoksyd-klorid (13,4 ml, 146,5 mmol) i vannfri acetonitril (160 ml), ble oppvarmet ved tilbakeløp i 6,5 timer under nitrogen. Etter avkjøling til romtemperatur ble de flyktige stoffene fjernet under vakuum, og den resulterende oljen ble oppløst i vannfri metanol før inndampning til tørrhet (gjentatt to ganger). Den resulterende brune oljen ble igjen oppløst i vannfri metanol (122 ml) og avkjølt til -78 °C under nitrogen. Deretter ble natrium-borhydrid (3,02 g, 79,99 mmol) tilsatt porsjonsvis i løpet av 5 timer til reaksjonsblandingen holdt -78 °C. Reaksjonen ble stanset ved dråpevis tilsetning av vandig IN HC1 (8 ml), og blandingen fikk nå romtemperatur før løsningsmidlet ble fjernet under vakuum og vann (175 ml) ble tilsatt. Etter ekstraksjon med CH2CI2 (4 x 150 ml) ble det organiske sjiktet tørket over vannfritt magnesiumsulfat, og løsningsmidlet ble fjernet under vakuum. Den resulterende rå oljen ble renset med flash-kromatografi (CH2CI2/CH3OH : 36/1), hvilket ga den rene diastereoisomer l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2-(l-(5)-fenyl-etyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin i form av en gul olje (1,36 g, 20%). Denne forbindelsen (225 mg, 0,49 mmol) ble deretter oppløst i metanol (8 ml), og 10% palladium på trekull (225 mg) og trifluoreddiksyre (0,05 ml, 0,65 mmol) ble tilsatt. Den resulterende blanding ble omrørt under hydrogen (1 atm) ved RT i 13 timer. Etter filtrering over Celite og inndampning til tørrhet, ble vann (10 ml) og vandig 2N NaOH (0,35 ml, 0,70 mmol) tilsatt. Blandingen ble ekstrahert med CH2CI2 (3 x 15 ml) og det organiske ekstraktet ble tørket over vannfri MgSC<4, filtrert og inndampet under vakuum. Det optisk rene l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l/f-benzo[c]azepinble oppnådd i form av en gul olje (152 mg, 88%).
LC-MS: rt = 3,04 min, 358 (M+l, ES+).
Eksempel 73
2-[l-(S)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-indan-(5)-l-yl-acetamid: fremstilt i henhold til den generelle prosedyre A ved omsetning av 2-bromacetylbromid med S(+)-l-aminoindan og l-(S)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro-l//-benzo[c]azepin.
LC-MS: rt = 3,76 min, 531 (M+l, ES+).
Eksempel 74
2-[l-(S)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-2-yI-acetamid: fremstilt i henhold til den generelle prosedyre A ved omsetning av 2-bromacetylbromid med 2-aminoindan-hydroklorid og l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3,4,5-tetrahydro- l/J-benzo[c]azepin.
LC-MS: rt = 3,70 min, 531 (M+l, ES+).
Claims (8)
1. Forbindelse med den generelle formel (I)
hvor: R<2> og R<3> representerer uavhengig hydroksy, C)-C4-alkoksy, C2-Cs-alkenyloksy eller fenyl-C i -C4-alkoksy; R<5> representerer fenyl-C i-C4-alkoksy eventuelt substituert på fenylringen med C1-C4-alkoksy eller halogen; R<7> og R<8> representerer uavhengig hydrogen eller fenyl; R<9> og R<10> representerer uavhengig hydrogen; indanyl, eventuelt substituert med C1-C4-alkyl eller Ci-C4-alkoksy; tetrahydronaftyl; fenyl-Ci-C4-alkyl, eventuelt substituert med Ci-Q-alkoksy; naftyl-Ci-C4-alkyl; CrC6-alkyl; C2-C5-alkenyl; C2-C5-alkinyl; C3-C6-cykloalkyl; heterocyklyl eller heterocyklyl-Ci-C4-alkyl, hvor heterocyklylen er valgt fra gruppen bestående av benzodioksolyl, furyl, pyridyl, benzimidazolyl, indolyl, isoksazolyl, isokinolyl, indazolyl, kinolyl og pyrazinyl, hvor heterocyklylen eventuelt er substituert med Ci-C4-alkyl; eller Ci-C4-alkyl hvor én eller to hydrogenatomer er erstattet med hydroksy, cyano, trifluormetyl, -0-Ci-C4-alkyl, -NH-Ci-C4-alkyl, -N(Ci-C4-alkyl)2, -S-Ci-C4-alkyl, -COO-C,-C4-alkyl, -CONH-Ci-C4-alkyl, -CON(Ci-C4-alkyl)2, eller - NHCO-C,-C4-alkyl; og -X-Y- uavhengig representerer -CH2-CH2-, -0-CH2-, -S-CH2-, -S02-CH2- og -NH-CO-; eller en optisk ren enantiomer, en blanding av enantiomerer slik som for eksempel en racemat, en optisk ren diastereoisomer, en blanding av diastereoisomerer, en diastereoisomer racemat, en blanding av diastereoisomere racemater, eller en mesoform; eller et farmasøytisk akseptabelt salt derav.
2. Forbindelse med formel (II) ifølge krav 1
hvor: R 2 og R 3 uavhengig representerer hydroksy, Ci-d-alkoksy, C2-Cs-alkenyloksy eller fenyl-C i -C4-alkoksy; R<5> representerer fenyl-C i-C4-alkoksy eventuelt substituert på fenylringen med C1-C4-alkoksy eller halogen; R7 og R8 representerer uavhengig hydrogen eller fenyl; R9 og R<10> representerer uavhengig hydrogen; fenyl-C i-C4-alkyl, eventuelt substituert med Ci-C4-alkoksy; naftyl-Ci-C4-alkyl; Ci-C6-alkyl; C2-C5-alkenyl; C3-C6-cykloalkyl; eller heterocyklyl eller heterocyklyl-C|-C4-alkyl, hvor heterocyklylen er valgt fra gruppen bestående av benzodioksolyl, furyl, pyridyl, benzimidazolyl, indolyl, isoksazolyl, isokinolyl, indazolyl, kinolyl og pyrazinyl, hvor heterocyklylen eventuelt er substituert med Ci-C4-alkyl; og -X-Y- uavhengig representerer -CH2-CH2-, -0-CH2-, -S-CH2-, -S02-CH2- og -NH-CO-; eller en optisk ren enantiomer, en blanding av enantiomerer slik som for eksempel en racemat, en optisk ren diastereoisomer, en blanding av diastereoisomerer, en diastereoisomer racemat, en blanding av diastereoisomere racemater, eller en mesoform; eller et farmasøytisk akseptabelt salt derav.
3. Forbindelse med formel (III) ifølge krav 1 eller 2
hvor:
R'<1> og R'<2> uavhengig representerer hydroksy, Ci-Q-alkoksy eller C2-Cs-alkenyloksy;
R'<3> representerer fenyl-C i-C4-alkoksy eventuelt substituert på fenylringen med C1-C4-alkoksy eller halogen;
R'<4> representerer hydrogen eller fenyl;
R'<5> representerer hydrogen; fenyl-C i-C4-alkyl, eventuelt substituert med Ci-C4-alkoksy; naftyl-Ci-C4-alkyl; Ci-C6-alkyl; C2-C5-alkenyl; C3-C6-cykloalkyl; heterocyklyl eller heterocyklyl-Ci-C4-alkyl, hvor heterocyklylen er valgt fra gruppen bestående av benzodioksolyl, furyl, pyridyl, benzimidazolyl, indolyl, isoksazolyl, isokinolyl, indazolyl, kinolyl og pyrazinyl, hvor heterocyklylen eventuelt er substituert med Ci-C4-alkyl; -X-Y- uavhengig representerer -CH2-CH2-, -0-CH2-, -S-CH2-, -S02-CH2- og -NH-CO-;
eller en optisk ren enantiomer, en blanding av enantiomerer slik som for eksempel en racemat, en optisk ren diastereoisomer, en blanding av diastereoisomerer, en diastereoisomer racemat, en blanding av diastereoisomere racemater, eller en mesoform; eller et farmasøytisk akseptabelt salt derav.
4. Forbindelse ifølge hvilket som helst av kravene 1 til 3, valgt fra gruppen bestående av 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-naftalen-1 -ylmetyl-acetamid; Af-benzo[ 1,3]dioksol-5-ylmetyl-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->indan-2-yl-acetamid; 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-AMndan-2-yl-acetamid;
2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dmyd^o-5H-benzo[f][l,4]oksazepin-4-yl]-AMndan-1 -yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->indan-1 -yl-acetamid; 2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9-tetrahydro-5A,-tia-8-aza-benzocyklohepten-8-yl]-Ar-indan-2-yl-acetamid; 2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-5,5-diokso-5,6,7,9-tetrahydro-5X-tia-8-aza-benzocyklohepten-8-yl]-N-indan-l-yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-indan-1 -yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-indan-2-yl-2-fenyl-acetamid; 2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yll-A^-naftalen-1 -ylmetyl-acetamid; 2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-A/-(2-etoksy-benzyl)-acetamid; 2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-ylj-N-indan-l-yl-acetamid; 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-iV-(l ,2,3,4-tetrahydro-naftalen-1 -yl)-acetamid; Ar-benzyl-2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl]-acetamid; 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-iV-indan-l-yl-acetamid; A7-butyl-2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-2-fenyl-acetamid;
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl] - N-indan-1 -yl-2-fenyl-acetamid; N-benzo[ 1,3]dioksol-5-ylmetyl-2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; A^-Cyklopentyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;
2-[ 1-(3,4-dimetoksy-benzyl)-7,8-&^ furan-2-ylmetyl-2-fenyl-acetamid; {2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-eddiksyre syre etylester; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-AT-pyridin-4-ylmetyl-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyridin-3-ylmetyl-acetamid; iV-Cyklopropyl-2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7)8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A?<->(2-okso-tetrahydro-furan-3-yl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-(4-metoksy-indan-1 -yl)-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(3-fenyl-indan-1 -yl)-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(4-metyl-indan-l-yl)-acetamid;
2- {2-[ l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-3-hydroksy-propionsyre syre metylester; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->etylkarbamoylmetyl-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->[(etyl-metyl-karbamoyl)-metyl]-2-fenyl-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-AMndan-l-yl-acetamid; 2-[8-benzyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-indan-l-yl-acetamid;
3- {2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-propionsyre syre metylester; Ar<->benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-hydroksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;
Ar-(lH-benzoimidazol-2-ylmetyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;3-{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-13.4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-A<7>^V-dimetyl-propionamid; 3-{2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino} -Af-etyl-Af-metyl-propionamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dirnetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-(l-metyl-lH-indol-3-ylmetyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->isoksazol-5-ylmetyl-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(1 H-indol-3-ylmetyl)-2-fenyl-acetamid;
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoks y-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] - N-(1 -metyl-1 H-benzoimidazol-2-ylmetyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->isokinolin-1 -ylmetyl-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Ar-(4-[ 1,2,3]tiadiazol-4-yl-benzyl)-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl] - N-(1 -metyl- lH-indazol-3-ylmetyl)-2-fenyl-acetamid; A<7->cyanometyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c] azepin-2-yl] -2-fenyl- acetamid; Ar<->(2-acetylamino-etyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-A<7->(2,2,2-trifluor-etyl)-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->(2-metylsulfanyl-etyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-AMcinolin-2-ylmetyl-acetamid; Ar<->(2-cyano-etyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(3-metoksy-propyl)-2-fenyl-acetamid;
2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-etoksy-propyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyrazin-2-ylmetyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-A^-prop-2-ynyl-acetamid; N-tert-butyl-2-f l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(3-metyl-butyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(3,3-dimetyl-butyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(1 -etyl-propyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A7-(2-etylsulfanyl-etyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-(2-hydroksy-etyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A^-(3-hydroksy-propyl)-2-fenyl-acetamid; [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-fenyl-eddiksyre syre A^AT-dimetyl-hydrazid; 2-[8-allyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AT-indan-1 -yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7-metoksy-8-propoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-ylJ-N-indan-l-yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-l-yl-acetamid; 2-[8-(2,2-difluor-etoksy)-1-(3,4-dimetoksy-benzyl)-7-metoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-indan-l-yl-acetamid; N-benzo[ 1,3]dioksol-5-ylmetyl-2-[8-(2,2-difluor-etoksy)-1 -(3,4-dimetoksy-benzyl)-7-metoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl] -2-fenyl-acetamid;
A<7->benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[5-(3,4-diklor-benzyl)-7,8-dimetoksy-2-okso-l,2,3,5-tetrahydro-benzo[e][l,4]diazepin-4-yl]-A7-indan- 1-yl-acetamid; 2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-l-yl-acetamid; 2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-2-yl-acetamid; 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[fJ[l,4]oksazepin-4-yl] -Af-naftalen-1 -ylmetyl-acetamid; 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f][l,4]oksazepin-4-yl]-Af-(2-etoksy-benzyl)-acetamid; og 2-[9-(3,4-dimetoksy-benzyl)-2,3-dimetoksy-6,7-dihydro-9H-5-tia-8-aza-benzocyklohepten-8-yl] -Af-( 1,2,3,4-tetrahydro-naftalen-1 -yl)-acetamid.
5. Forbindelse ifølge hvilket som helst av kravene 1 til 4, valgt fra gruppen bestående av 2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl] - N-indan-2-yl-acetamid; 2-[5-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-2,3-dihydro-5H-benzo[f] [ 1,4]oksazepin-4-ylJ-AMndan-1-yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-indan- 1-yl-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]- N-indan-1 -yl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-indan-2-yl-2-fenyl-acetamid; Ar<->butyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A</->indan- l-yl-2-fenyl-acetamid; AT-benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;
A^-Cyklopentyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;
2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl] - N-furan-2-ylmetyl-2-fenyl-acetamid; {2-[l-(3,4-dimetoksy-benzyl)-7,8-dirnetoksy-l,3.4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-eddiksyre syre etylester;
2- [l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-berizo[c]azepin-2-yl]-2-fenyl-A^pyridin-3-ylmetyl-acetamid;
3- {2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetylamino}-propionsyre syre metylester; A</->(lH-benzoimidazol-2-ylmetyl)-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->(l-metyl-lH-indol-3-ylmetyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-isoksazol-5-ylmetyl-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Af<->(lH-indol-3-ylmetyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->isokinolin-1 -ylmetyl-2-fenyl-acetamid;
2- r 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -2-fenyl-Ar-(4-[ 1,2,3]tiadiazol-4-yl-benzyl)-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(l-metyl-lH-indazol-3-ylmetyl)-2-fenyl-acetamid; A^-cyanometyl-2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Ar-(2,2,2-trifluor-etyl)-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->(2-metylsulfanyl-etyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-kinolin-2-ylmetyl-acetamid;
AT-(2-cyano-etyl)-2- [ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A<7->(3-metoksy-propyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3-etoksy-propyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-N-pyrazin-2-ylmetyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-Af-prop-2-ynyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-A</->(3-metyl-butyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(3,3-dimetyl-butyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar<->(1 -etyl-propyl)-2-fenyl-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-7,8-dimetoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl] - N-(2-etylsulfanyl-etyl)-2-fenyl-acetamid; 2-[l-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Ar-(2-hydroksy-etyl)-2-fenyl-acetamid; 2-[8-allyloksy-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-1 -yl-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-7-metoksy-8-propoksy-1,3,4,5-tetrahydro-benzo[c] azepin-2-yl]-A^indan-l-yl-acetamid;
2-[ 1 -(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-1,3,4,5-tetrahydro-benzo[c]azepm-2-yl]-AMndan-l-yl-acetamid; 2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -AT-indan-1 -yl-acetamid; Af<->benzo[l,3]dioksol-5-ylmetyl-2-[8-(2,2-difluor-etoksy)-l-(3,4-dimetoksy-benzyl)-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid; Af<->benzo[l,3]dioksol-5-ylmetyl-2-[l-(3,4-dimetoksy-benzyl)-8-isopropoksy-7-metoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-fenyl-acetamid;
2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-AT-indan-1 -yl-acetamid; 2-[l-(5)-(3,4-dimetoksy-benzyl)-7,8-dimetoksy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-AMndan-2-yl-acetamid.
6. Farmasøytisk preparat for behandling av lidelser som er relatert til orexins rolle, spesielt lidelser som fedme og søvnforstyrrelser, som inneholder én eller flere forbindelser ifølge hvilket som helst av kravene 1 til 5, eller et farmasøytisk akseptabelt salt derav, og vanlige bærermaterialer og tilsetningsmidler.
7. Forbindelse ifølge hvilket som helst av kravene 1 til 5, eller et farmasøytisk akseptabelt salt derav, for anvendelse som medikament for behandling av lidelser som er relatert til en av orexins roller, spesielt fedme og søvnforstyrrelser.
8. Fremgangsmåte for fremstilling av farmasøytiske preparater for behandling av lidelser relatert til orexins rolle, spesielt fedme og søvnforstyrrelser, som inneholder én eller flere forbindelser som krevet i hvilket som helst av kravene 1 til 5, eller et farmasøytisk akseptabelt salt eller salter derav, som aktive bestanddeler, hvor fremgangsmåten omfatter å blande én eller flere aktive bestanddeler med farmasøytisk akseptable tilsetningsmidler og hjelpestoffer på en måte som er kjent per se.
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US3236838A (en) | 1964-06-09 | 1966-02-22 | Hoffmann La Roche | Certain 1-substituted-benzodiazepin-2-one compounds |
US3480714A (en) * | 1966-02-07 | 1969-11-25 | Ciba Geigy Corp | N-substituted isoquinolines as antiprotozoal agents |
JP2002527433A (ja) | 1998-10-08 | 2002-08-27 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | ドーパミンd3受容体のモジュレーター(抗精神病薬)として有用なテトラヒドロベンズアゼピン誘導体 |
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CA2431982C (en) | 2010-07-20 |
ZA200303697B (en) | 2004-08-13 |
HUP0301665A3 (en) | 2008-12-29 |
KR20030069199A (ko) | 2003-08-25 |
KR100849569B1 (ko) | 2008-07-31 |
NO20032905L (no) | 2003-06-24 |
WO2002051838A1 (en) | 2002-07-04 |
DE60132017D1 (de) | 2008-01-31 |
ATE381560T1 (de) | 2008-01-15 |
JP2004516324A (ja) | 2004-06-03 |
CN1261430C (zh) | 2006-06-28 |
HUP0301665A2 (en) | 2008-07-28 |
EP1347967A1 (en) | 2003-10-01 |
CA2431982A1 (en) | 2002-07-04 |
NO20032905D0 (no) | 2003-06-24 |
US20040058912A1 (en) | 2004-03-25 |
JP4219166B2 (ja) | 2009-02-04 |
EP1347967B1 (en) | 2007-12-19 |
US7192950B2 (en) | 2007-03-20 |
AU2002240855B2 (en) | 2006-08-17 |
BR0116505A (pt) | 2004-02-03 |
NZ525613A (en) | 2005-01-28 |
MXPA03004779A (es) | 2003-09-25 |
ES2296825T3 (es) | 2008-05-01 |
IL155806A0 (en) | 2003-12-23 |
WO2002051232A2 (en) | 2002-07-04 |
DE60132017T2 (de) | 2008-12-04 |
IL155806A (en) | 2008-03-20 |
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