WO1993001195A1 - DIBENZ[b,e]AZEPINE DERIVATIVES AND DRUGS CONTAINING THEM - Google Patents
DIBENZ[b,e]AZEPINE DERIVATIVES AND DRUGS CONTAINING THEM Download PDFInfo
- Publication number
- WO1993001195A1 WO1993001195A1 PCT/EP1992/001465 EP9201465W WO9301195A1 WO 1993001195 A1 WO1993001195 A1 WO 1993001195A1 EP 9201465 W EP9201465 W EP 9201465W WO 9301195 A1 WO9301195 A1 WO 9301195A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- dibenz
- compound
- dihydro
- group
- Prior art date
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- 150000001538 azepines Chemical class 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 229940079593 drug Drugs 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- -1 methylene, carbonyl Chemical group 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 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 abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 241000700605 Viruses Species 0.000 claims description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 241001430294 unidentified retrovirus Species 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical group S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000004448 titration Methods 0.000 claims description 2
- 239000012050 conventional carrier Substances 0.000 claims 1
- 208000036142 Viral infection Diseases 0.000 abstract description 5
- 230000009385 viral infection Effects 0.000 abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- QAYPFHIZJSDUSF-UHFFFAOYSA-N azepin-3-one Chemical compound O=C1C=CC=CN=C1 QAYPFHIZJSDUSF-UHFFFAOYSA-N 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 3
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- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- DUAJIKVIRGATIW-UHFFFAOYSA-N trinitrogen(.) Chemical compound [N]=[N+]=[N-] DUAJIKVIRGATIW-UHFFFAOYSA-N 0.000 description 1
- 235000019871 vegetable fat Nutrition 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
- 229960002555 zidovudine Drugs 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to
- Dibenz [b, e] azepine derivatives processes for their preparation and medicaments containing these compounds.
- the invention relates to dibenz [b, e] azepine derivatives of the general formula I
- A is a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulfonyl group
- X is a valence bond or an oxygen or sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or an NH group,
- n is an integer from 1 to 3 and
- R 1 to R 3 which can be the same or different independently of one another, are each a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C-ato or C -C 6 -alkoxy, Cx-Cg-alkylmercapto, C 1 -Cs-alkylsulfinyl, Ci-Cg-alkylsulfonyl, A ino, C 1 -Cg-alkylamino, di- Ci-Cs-alkylamino, sulfonamido, C ⁇ -Cg alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy and
- R 4 is hydrogen or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms
- the object of the present invention was to provide new dibenz [b, e] azepine derivatives. These compounds are used in particular for the production of medicaments.
- the compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr-Vl üs or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and -2.
- DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr-Vl üs or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodefic
- the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
- PDL generalized lymphadenopathy
- ARC advanced stage of the AIDS-related complex
- the compounds of general formula I according to the invention have a pronounced antiviral effect and are particularly suitable for the treatment of viral or retro-viral infections.
- Viral infections in mammals, especially humans, are common.
- Che otherapeutics which cause causally or symptomatically to interfere with the viral or retroviral-related illness with evidently substantial success.
- AIDS Acquired Immune Deficiency Syndro
- ARC AIDS-related complex
- CMV cytomegalovirus
- influenza influenza and other viral infections to heal or to chemically influence the symptoms favorably.
- 3 '-azido-3' deoxythymidine (AZT) known as Zidovudine or Retrovir R
- Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
- AZT 3 '-azido-3' deoxythymidine
- Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
- Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
- AZT 3 '-azido-3' deoxythymidine
- Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
- AZT 3 '-azido-3' deoxythy
- the mentioned compounds are advantageously used prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.
- the separation of the race ate into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases with common eluents.
- Suitable optically active phases are, for example, optically active polyacrylamides or polyethacrylamides, some also on silica gel (e.g. ChiraSpher (R) from Merck, Chiralpak (R) OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel (R ) OB / OY from Baker / Daicel), phases based on cyclodextrin or crown ether (for example Crownpak (R) from Daicel) or microcrystalline cellulose triacetate (Merck).
- silica gel e.g. ChiraSpher (R) from Merck, Chiralpak (R) OT / OP from Baker
- cellulose esters / carbamates e.g. Chiracel (R ) OB / OY from Baker / Daicel
- phases based on cyclodextrin or crown ether for example Crownpak (R) from Daicel
- Merck microcrystalline cellulose tria
- A denotes in particular a carbonyl, methylene or thiocarbonyl group, the carbonyl group being preferred.
- X represents in particular an oxygen or sulfur atom or a sulfinyl or sulfonyl group.
- n is preferably the number 1 or 2.
- R 1 to R 3 are hydrogen, C] _- C3-alkyl, C2-C4-alkenyl, C2-C -alkynyl, C ⁇ ⁇ C3-alkoxy, C_-C 3 -alkylmercapto, C ⁇ ⁇ C 3 -alkylamino , C ] _-C 3 alkoxycarbonyl, amino, halogen, hydroxy, cyano and azido preferred.
- the ring system can be substituted in the 7-, 8-, 9- or 10-position by R 1 , the 8- and 9-position being preferred.
- R 1 represents a halogen atom or a Ci-Cg-alkyl group.
- R 2 and R 3 can be in the 1-, 2-, 3- or 4- position of the ring system, the 3- and 4-position are preferred.
- R 2 represents a hydrogen atom and R 3 represents a hydrogen or halogen atom, a Ci-Cg-alkyl or Ci-Cg-alkoxy group.
- R 3 is in particular a chlorine atom, or a methyl or methoxy group.
- radical R 4 hydrogen, C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl and C 2 -C 4 -alkynyl are preferred.
- R 1 to R 3 independently of one another, hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methyl ercapto, ethyl mercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, with chlorine and bromine are preferred for halogen.
- R 4 hydrogen, methyl, ethyl, isopropyl and allyl are particularly preferred.
- the aliphatic radical in the definition of R 1 -R 4 can be straight-chain or branched, saturated or unsaturated and contain a total of up to six carbon atoms.
- Ci-Cg-alkyl groups are possible as saturated residues, such as. B. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
- Unsaturated radicals are in particular C2-Cg-alkenyl and C2-C 6 -alkynyl groups, which can also be branched, such as. As allyl, vinyl, 2-butenyl or propargyl.
- the medicaments containing at least one compound of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form.
- the usual forms of application come into question, such as tablets, capsules, dragees, syrups, solutions or suspensions.
- Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers.
- additives are tartrate and Citrate buffer, ethanol, complexing agents such as ethylene diamine tetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
- Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
- Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers, such as polyethylene glycols, etc.
- suitable for applications can, if desired, contain flavorings or sweeteners.
- Pharmacologically acceptable salts are the acid addition salts with inorganic or organic acids, such as. B. halogen acids (HC1, HBr, etc.), sulfuric acid, phosphoric acid, tartaric acid, succinic acid, oxalic acid, acetic acid.
- B. halogen acids HC1, HBr, etc.
- sulfuric acid phosphoric acid
- tartaric acid tartaric acid
- succinic acid oxalic acid
- acetic acid acetic acid
- the dosage can depend on various factors, such as the mode of application, species, age or individual condition.
- the compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 applications with an active ingredient content of 0.5-500 mg being administered for each application.
- the tablets can also be delayed, which reduces the number of applications per day to 1-3.
- the ⁇ content of active substance of the retarded tablets can be 2 - mg 1000th
- the active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day being normally sufficient.
- n has the meaning given above and Y 'and Y ", which are the same or different, have the meaning of Y,
- A, X, n and R 1 to R 4 have the meaning given above and Z represents a reactive radical, cyclizes or
- Racemates can be separated into the antipodes, for example, by chromatography on suitable optically active phases such as cellulose triacetate.
- reactive residues X, Y, Y 1 and Y ".
- the groups HY, HY 1 and HY" are advantageously eliminated in a solvent in the presence of a base such as for example an alkali alcoholate in the corresponding alcohol, potassium carbonate in acetone or butanone, sodium hydride in toluene or dimethylformamide.
- a base such as for example an alkali alcoholate in the corresponding alcohol, potassium carbonate in acetone or butanone, sodium hydride in toluene or dimethylformamide.
- reactive radicals Z can also be lower alkoxy groups, optionally substituted phenoxy groups or the azide radical.
- the reduction of a carbonyl group to a CH2 group is advantageously carried out using complex metal hydrides such as lithium aluminum hydride or sodium borohydride or using catalytically excited hydrogen.
- the test system contains the purified RT from HIV-1, which was expressed by genetic engineering methods in E. coli, as well as the components of the initiation complex, such as the in vitro transcripts of the HIV-LTR with the neighboring primer binding site as a template and one for Primer binding site complementary 18mer oligonucleotide as a primer.
- the [ 3 H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter.
- the table below shows the ICsoth for the compounds examined. This value corresponds to the concentration of the test substance which causes an inhibition of the reverse transcriptase activity by 50%.
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- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Medicines Containing Plant Substances (AREA)
Abstract
The invention relates to dibenz[b,e]azepine derivatives of formula (I), in which A is a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulphonyl group; X is a valency bond or an oxygen or sulphur atom, a sulphinyl or sulphonyl group, a CH2?S group or an NH group; n is a whole number from 1 to 3; and R?1 to R?4, which can be the same or different, are, independently of each other, a hydrogen atom or an aliphatic group with 1-6 C-atoms, as well as their tautomers, enantiomers, diastereomers and their physiologically tolerated salts. In addition, the invention concerns drugs containing compounds of formula (I), in particular drugs for use in treating viral infections.
Description
Dibenzrb.elazepinderivate und diese enthaltende ArzneimittelDibenzrb.elazepine derivatives and medicinal products containing them
Gegenstand der vorliegenden Erfindung sindThe present invention relates to
Dibenz[b,e]azepinderivate, Verfahren zu deren Herstellung und Arzneimittel, die diese Verbindungen enthalten.Dibenz [b, e] azepine derivatives, processes for their preparation and medicaments containing these compounds.
Die Erfindung betrifft Dibenz[b,e]azepinderivate der all¬ gemeinen Formel IThe invention relates to dibenz [b, e] azepine derivatives of the general formula I
in derin the
A eine Methylen-, Carbonyl-, Thiocarbonyl-, Carbimino-, N- Hydroxycarbimino- oder Sulfonylgruppe,A is a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulfonyl group,
X eine Valenzbindung oder ein Sauerstoff- oder Schwefelatom, eine Sulfinyl- oder Sulfonylgruppe, eine Gruppe CH2S oder eine Gruppe NH,X is a valence bond or an oxygen or sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or an NH group,
n eine ganze Zahl von 1 bis 3 undn is an integer from 1 to 3 and
R1 bis R3, die unabhängig voneinander gleich oder verschie¬ den sein können, je ein Wasserstoffatom, einen geradkettigen oder verzweigten, gesättigten oder
ungesättigten aliphatischen Rest mit 1-6 C- Ato en oder C -C6-Alkoxy, Cx-Cg-Alkylmercapto, C1-Cs-Alkylsulfinyl, Ci-Cg-Alkylsulfonyl, A ino, C1-Cg-Alkylamino, Di-Ci-Cs-Alkylamino, Sulfonamido, C^-Cg-Alkoxycarbonyl, Carboxy, Halogen, Hydroxy, Nitro, Cyano, Azido, Phenyl oder Benzyloxy undR 1 to R 3 , which can be the same or different independently of one another, are each a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C-ato or C -C 6 -alkoxy, Cx-Cg-alkylmercapto, C 1 -Cs-alkylsulfinyl, Ci-Cg-alkylsulfonyl, A ino, C 1 -Cg-alkylamino, di- Ci-Cs-alkylamino, sulfonamido, C ^ -Cg alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy and
R4 Wasserstoff oder einen geradkettigen oder verzweigten, gesättigten oder ungesättigten aliphatischen Rest mit 1-6 C-AtomenR 4 is hydrogen or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms
bedeuten,mean,
deren Tautomere, Enantio ere, Diastereomere und physiologisch verträgliche Salze.their tautomers, enantiomers, diastereomers and physiologically acceptable salts.
Der vorliegenden Erfindung lag die Aufgabe zugrunde, neue Dibenz[b,e]azepinderivate zur Verfügung zu stellen. Diese Verbindungen werden insbesondere zur Herstellung von Arznei¬ mitteln verwendet.The object of the present invention was to provide new dibenz [b, e] azepine derivatives. These compounds are used in particular for the production of medicaments.
Die Verbindungen der vorliegenden Erfindung weisen wertvolle pharmakologische Eigenschaften auf. Insbesondere eignen sie sich zur Therapie und Prophylaxe von Infektionen, die durch DNA-Viren wie z.B. das Herpes-Simplex-Virus, das Zytomegalie- Virus, Papilloma-Viren, das Varicella-Zoster-Virus oder Epstein-Barr-Vl üs oder RNA-Viren wie Toga-Viren oder insbeson¬ dere Retroviren wie die Onko-Viren HTLV-I und II, sowie die Lentiviren Visna und Humanes-Immunschwäche-Virus HIV-1 und -2, verursacht werden.The compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr-Vl üs or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and -2.
Besonders geeignet erscheinen die Verbindungen der Formel I zur Behandlung der klinischen Manifestationen der retroviralen HIV- Infektion beim Menschen, wie der anhaltenden, generalisierten Lymphadenopathie (PGL) , dem fortgeschrittenen Stadium des AIDS- verwandten Komplex (ARC) und dem klinischen Vollbild von AIDS.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I besitzen eine ausgeprägte antivirale Wirkung und eignen sich insbesondere zur Behandlung von viralen bzw. retro-viralen Infektionen. Virale Infektionen von Säugern, insbesondere des Menschen, sind weit verbreitet. Trotz intensiver Bemühungen ist es bisher nicht gelungen, Che otherapeutika bereitzustellen, die ursächlich oder symptomatisch mit dem viral oder retroviral bedingten Krankheitsgeschehen mit erkennbar substantiellem Erfolg interferieren. Es ist heutzutage nicht möglich, bestimmte Viruserkrankungen, wie zum Beispiel das Acquired Immune Deficiency Syndro (AIDS) , den AIDS-related-complex (ARC) und deren Vorstadien, Herpes-, Cytomegalie-Virus (CMV)-, Influenza- und andere Virusinfektionen zu heilen oder chemo¬ therapeutisch deren Symptome günstig zu beeinflussen. Derzeit steht beispielsweise für die Behandlung von AIDS fast aus¬ schließlich das 3 '-Azido-3 '-deoxy-thymidin (AZT) , bekannt als Zidovudine oder RetrovirR, zur Verfügung. AZT ist jedoch durch eine sehr enge therapeutische Breite bzw. durch bereits im therapeutischen Bereich auftretende, sehr schwere Toxizitäten charakterisiert (Hirsch, M.S. (1988) J.Infec.Dis. 157, 427- 431) . Die Verbindungen der allgemeinen Formel I besitzen diese Nachteile nicht. Sie wirken antiviral, ohne in pharmakologisch relevanten Dosen cytotoxisch zu sein.The compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS. The compounds of general formula I according to the invention have a pronounced antiviral effect and are particularly suitable for the treatment of viral or retro-viral infections. Viral infections in mammals, especially humans, are common. Despite intensive efforts, it has so far not been possible to provide Che otherapeutics which cause causally or symptomatically to interfere with the viral or retroviral-related illness with evidently substantial success. It is not possible today to diagnose certain viral diseases such as Acquired Immune Deficiency Syndro (AIDS), the AIDS-related complex (ARC) and its pre-stages, herpes, cytomegalovirus (CMV), influenza and other viral infections to heal or to chemically influence the symptoms favorably. For the treatment of AIDS, for example, 3 '-azido-3' deoxythymidine (AZT), known as Zidovudine or Retrovir R , is available almost exclusively. However, AZT is characterized by a very narrow therapeutic range or by very severe toxicities already occurring in the therapeutic area (Hirsch, MS (1988) J.Infec.Dis. 157, 427-431). The compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.
Es konnte nun nachgewiesen werden, daß Verbindungen der allge¬ meinen Formel I die Vermehrung von DNA- bzw. RNA-Viren auf der Stufe der virusspezifischen DNA- bzw. RNA-Transkription hemmen. Die Substanzen können über die Inhibierung des Enzyms Reverse Transkriptase die Vermehrung von Retroviren beeinflussen (vgl. Proc. Natl. Acad. Sei. USA 81, 1911, 1986 bzw. Nature 325. 773 1987) .It has now been shown that compounds of general formula I inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription. The substances can influence the multiplication of retroviruses by inhibiting the enzyme reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA 81, 1911, 1986 and Nature 325, 773 1987).
Da ein sehr großer Bedarf an Chemotherapeutica besteht, die möglichst spezifisch mit retroviral bedingten Erkrankungen oder deren Symptomen interferieren, ohne die normal ablaufenden natürlichen Körperfunktionen zu beeinflussen, könnten die
genannten Verbindungen vorteilhaft prophylaktisch oder thera¬ peutisch bei der Behandlung von Krankheiten eingesetzt werden, bei denen eine retrovirale Infektion von pathophysiologischer, symptomatischer oder klinischer Relevanz ist.Since there is a very great need for chemotherapeutics that interfere as specifically as possible with retroviral-related diseases or their symptoms without affecting the normal natural body functions, the mentioned compounds are advantageously used prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.
Die Trennung der Race ate in die Enantiomeren kann analytisch, semipräparativ und präparativ chromatographisch auf geeigneten optisch aktiven Phasen mit gängigen Elutionsmitteln durch¬ geführt werden.The separation of the race ate into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases with common eluents.
Als optisch aktive Phasen eignen sich beispielsweise optisch aktive Polyacrylamide oder Poly ethacrylamide, z.T. auch an Kieselgel (z.B. ChiraSpher (R) von Merck, Chiralpak (R) OT/OP von Baker), Celluloseester/-carbamate (z.B. Chiracel (R) OB/OY von Baker/Daicel) , Phasen auf Cyclodextrin- oder Kronenether¬ basis (z.B. Crownpak (R) von Daicel) oder mikrokristallines Cellulosetriacetat (Merck) .Suitable optically active phases are, for example, optically active polyacrylamides or polyethacrylamides, some also on silica gel (e.g. ChiraSpher (R) from Merck, Chiralpak (R) OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel (R ) OB / OY from Baker / Daicel), phases based on cyclodextrin or crown ether (for example Crownpak (R) from Daicel) or microcrystalline cellulose triacetate (Merck).
In der allgemeinen Formel I bedeutet A insbesondere eine Carbonyl-, Methylen- oder Thiocarbonylgruppe, wobei die Carbonylgruppe bevorzugt in Frage kommt.In the general formula I, A denotes in particular a carbonyl, methylene or thiocarbonyl group, the carbonyl group being preferred.
X stellt insbesondere ein Sauerstoff- oder Schwefelatom oder eine Sulfinyl- oder Sulfonylgruppe dar.X represents in particular an oxygen or sulfur atom or a sulfinyl or sulfonyl group.
n bedeutet bevorzugt die Zahl 1 oder 2.n is preferably the number 1 or 2.
Für die Reste R1 bis R3 sind Wasserstoff, C]_-C3-Alkyl, C2-C4- Alkenyl, C2-C -Alkinyl, Cι~C3-Alkoxy, C_-C3-Alkylmercapto, Cι~ C3-Alkylamino, C]_-C3-Alkoxycarbonyl, Amino, Halogen, Hydroxy, Cyano und Azido bevorzugt. Das Ringsystem kann in 7-, 8-, 9- oder 10-Stellung durch R1 substituiert sein, wobei die 8- und 9-Stellung bevorzugt sind. Insbesondere bedeutet R1 ein Halogenatom oder eine Ci-Cg-Alkylgruppe.For the radicals R 1 to R 3 are hydrogen, C] _- C3-alkyl, C2-C4-alkenyl, C2-C -alkynyl, Cι ~ C3-alkoxy, C_-C 3 -alkylmercapto, Cι ~ C 3 -alkylamino , C ] _-C 3 alkoxycarbonyl, amino, halogen, hydroxy, cyano and azido preferred. The ring system can be substituted in the 7-, 8-, 9- or 10-position by R 1 , the 8- and 9-position being preferred. In particular, R 1 represents a halogen atom or a Ci-Cg-alkyl group.
Die Substituenten R2 und R3 können in 1-, 2-, 3- oder 4- Stellung des Ringsystems stehen, wobei die 3- und 4-Stellung
bevorzugt sind. Insbesondere bedeutet R2 ein Wasserstoffatom und R3 ein Wasserstoff- oder Halogenatom, eine Ci-Cg-Alkyl- oder Ci-Cg-Alkoxygruppe. In diesem Sinne ist R3 insbesondere ein Chloratom, oder eine Methyl- oder Methoxygruppe.The substituents R 2 and R 3 can be in the 1-, 2-, 3- or 4- position of the ring system, the 3- and 4-position are preferred. In particular, R 2 represents a hydrogen atom and R 3 represents a hydrogen or halogen atom, a Ci-Cg-alkyl or Ci-Cg-alkoxy group. In this sense, R 3 is in particular a chlorine atom, or a methyl or methoxy group.
Für den Rest R4 sind Wasserstoff, C]_-C3-Alkyl, C2~C4-Alkenyl und C2~C4-Alkinyl bevorzugt.For the radical R 4 , hydrogen, C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl and C 2 -C 4 -alkynyl are preferred.
Für R1 bis R3 sind unabhängig voneinander besonders bevorzugt Wasserstoff, Methyl, Ethyl, Isopropyl, Allyl, Methoxy, Ethoxy, Methyl ercapto, Ethylmercapto, Methylamino, Methoxycarbonyl, Ethoxycarbonyl, Amino, Azido, Cyano, Hydroxy und Halogen, wobei Chlor und Brom für Halogen bevorzugt sind. Für R4 sind besonders bevorzugt Wasserstoff, Methyl, Ethyl, Isopropyl und Allyl.For R 1 to R 3 , independently of one another, hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methyl ercapto, ethyl mercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, with chlorine and bromine are preferred for halogen. For R 4 , hydrogen, methyl, ethyl, isopropyl and allyl are particularly preferred.
Der aliphatische Rest in der Definition von R1-R4 kann gerad- kettig oder verzweigt, gesättigt oder ungesättigt sein und insgesamt bis zu sechs C-Atome enthalten. Als gesättigte Reste kommen Ci-Cg-Alkylgruppen in Frage, wie z. B. Methyl, Ethyl, n- Propyl, i-Propyl, n-Butyl, i-Butyl oder t-Butyl. Ungesättigte Reste sind insbesondere C2-Cg-Alkenyl- und C2-C6-Alkinyl- gruppen, die auch verzweigt sein können, wie z. B. Allyl, Vinyl, 2-Butenyl oder Propargyl.The aliphatic radical in the definition of R 1 -R 4 can be straight-chain or branched, saturated or unsaturated and contain a total of up to six carbon atoms. Ci-Cg-alkyl groups are possible as saturated residues, such as. B. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. Unsaturated radicals are in particular C2-Cg-alkenyl and C2-C 6 -alkynyl groups, which can also be branched, such as. As allyl, vinyl, 2-butenyl or propargyl.
Die Arzneimittel enthaltend mindestens eine Verbindung der Formel I zur Behandlung von viralen Infektionen können in flüssiger oder fester Form enteral oder parenteral appliziert werden. Hierbei kommen die üblichen Applikationsformen in Frage, wie beispielsweise Tabletten, Kapseln, Dragees, Sirupe, Lösungen oder Suspensionen. Als Injektionsmedium kommt vorzugs¬ weise Wasser zur Anwendung, das die bei Injektionslösungen üblichen Zusätze wie Stabilisierungsmittel, Lösungsvermittler und Puffer enthält. Derartige Zusätze sind z.B. Tartrat- und
Zitratpuffer, Ethanol, Komplexbildner, wie Ethylen-diamintetra- essigsäure und deren nichttoxischen Salze, hochmolekulare Polymere, wie flüssiges Polyethylenoxid zur Viskositätsregu- lierung. Flüssige Trägerstoffe für Injektionslösungen müssen steril sein und werden vorzugsweise in Ampullen abgefüllt. Feste Trägerstoffe sind beispielsweise Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, höher molekulare Fettsäuren, wie Stearinsäure, Gelatine, Agar-Agar, Calziumphosphat, Magnesiumstearat, tierische und pflanzliche Fette, feste hochmolekulare Polymere, wie Polyethylenglykole, etc. Für orale Applikationen geeignete Zubereitungen können gewünschtenfalls Geschmacks- oder Süßstoffe enthalten.The medicaments containing at least one compound of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. Here, the usual forms of application come into question, such as tablets, capsules, dragees, syrups, solutions or suspensions. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers. Such additives are tartrate and Citrate buffer, ethanol, complexing agents such as ethylene diamine tetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers, such as polyethylene glycols, etc. For oral Preparations suitable for applications can, if desired, contain flavorings or sweeteners.
Pharmakologisch verträgliche Salze sind die S ureadditionssalze mit anorganischen oder organischen Säuren, wie z. B. Halogen- sauren (HC1, HBr, etc.), Schwefelsäure, Phosphorsäure, Wein¬ säure, Bernsteinsäure, Oxalsäure, Essigsäure.Pharmacologically acceptable salts are the acid addition salts with inorganic or organic acids, such as. B. halogen acids (HC1, HBr, etc.), sulfuric acid, phosphoric acid, tartaric acid, succinic acid, oxalic acid, acetic acid.
Die Dosierung kann von verschiedenen Faktoren, wie Applika¬ tionsweise, Spezies, Alter oder individuellem Zustand abhängen. Die erfindungsgemäßen Verbindungen werden üblicherweise in Mengen von 0,1 - 100 mg, vorzugsweise 0,2 - 80 mg pro Tag und pro kg Körpergewicht appliziert. Bevorzugt ist es, die Tages- dosis auf 2-5 Applikationen zu verteilen, wobei bei jeder Applikation 1-2 Tabletten mit einem Wirkstoffgehalt von 0,5 - 500 mg verabreicht werden. Die Tabletten können auch retardiert sein, wodurch sich die Anzahl der Applikationen pro Tag auf 1-3 vermindert. Der~Wirkstoffgehalt der retardierten Tabletten kann 2 - 1000 mg betragen. Der Wirkstoff kann auch durch Dauer¬ infusion gegeben werden, wobei die Mengen von 5 - 1000 mg pro Tag normalerweise ausreichen.The dosage can depend on various factors, such as the mode of application, species, age or individual condition. The compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 applications with an active ingredient content of 0.5-500 mg being administered for each application. The tablets can also be delayed, which reduces the number of applications per day to 1-3. The ~ content of active substance of the retarded tablets can be 2 - mg 1000th The active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day being normally sufficient.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I werden nach an sich bekannten Verfahren hergestellt, indem man entweder
a) eine Verbindung der Formel IIThe compounds of general formula I according to the invention are prepared by processes known per se by either a) a compound of formula II
in der A, X, n und R1 bis R4 die oben angegebene Bedeutung haben und Y einen reaktiven Rest darstellt, oderin which A, X, n and R 1 to R 4 have the meaning given above and Y represents a reactive radical, or
b) eine Verbindung der Formel IIIb) a compound of formula III
in der A, X, n, R1 bis R4 und Y die vorstehend genannte Bedeutung haben.in which A, X, n, R 1 to R 4 and Y have the meaning given above.
unter Abspaltung von HY cyclisiert, oder
c) eine Verbindung der Formel IVcyclized with elimination of HY, or c) a compound of formula IV
in der A, X und R1 bis R4 die oben angegebenen Bedeutung haben, mit einer Verbindung der Formel (V) ,in which A, X and R 1 to R 4 have the meaning given above, with a compound of the formula (V),
ϊ,-(CH2)n-Y" (V),ϊ , - ( CH 2 ) nY "(V),
worin n die oben genannte Bedeutung hat und Y' und Y", die gleich oder verschieden sind, die Bedeutung von Y haben,wherein n has the meaning given above and Y 'and Y ", which are the same or different, have the meaning of Y,
unter Abspaltung von HY1 und HY" umsetzt, oderwith the splitting off of HY 1 and HY ", or
d) eine Verbindung der Formel VId) a compound of formula VI
in der A, X, n und R1 bis R4 die oben angegebene Bedeutung haben und Z einen reaktiven Rest darstellt, cyclisiert
oderin which A, X, n and R 1 to R 4 have the meaning given above and Z represents a reactive radical, cyclizes or
e) eine Verbindung der Formel (I) , in der eine oder mehrere der n CH2-Gruppen durch CO oder ein Derivat davon ersetzt sind, durch Reduktion in eine Verbindung der Formel I überführt,e) converting a compound of formula (I) in which one or more of the n CH2 groups has been replaced by CO or a derivative thereof by reduction into a compound of formula I,
und gegebenenfalls anschließend Verbindungen der Formel I in andere, durch den Anspruch umfaßte Verbindungen der Formel I umwandelt und gewünschtenfalls durch Titration mit pharmako- logisch verträglichen Säuren oder Basen in Salze überführt. Racemate können beispielsweise durch Chromatographie an geeigneten optisch aktiven Phasen wie Cellulosetriacetat in die Antipoden getrennt werden.and, if appropriate, then subsequently converting compounds of the formula I into other compounds of the formula I and, if desired, converting them into salts by titration with pharmacologically acceptable acids or bases. Racemates can be separated into the antipodes, for example, by chromatography on suitable optically active phases such as cellulose triacetate.
Als reaktive Reste, X, Y, Y1 und Y" kommen leicht abspaltbare Reste, insbesondere Halogenatome sowie die Mesyloxy- und Tosyloxygruppe in Frage. Die Abspaltung der Gruppen HY, HY1 und HY" erfolgt zweckmäßig in einem Lösungsmittel in Gegenwart einer Base wie beispielsweise einem Alkalialkoholat im entsprechenden Alkohol, Kaliumcarbonat in Aceton oder Butanon, Natriumhydrid in Toluol oder Dimethylformamid. Für reaktive Reste Z können neben den für Y genannten auch niedere Alkoxy- gruppen, gegebenenfalls substituierte Phenoxygruppen oder der Azidrest stehen.Easily removable residues, in particular halogen atoms and the mesyloxy and tosyloxy group, are suitable as reactive residues, X, Y, Y 1 and Y ". The groups HY, HY 1 and HY" are advantageously eliminated in a solvent in the presence of a base such as for example an alkali alcoholate in the corresponding alcohol, potassium carbonate in acetone or butanone, sodium hydride in toluene or dimethylformamide. In addition to those mentioned for Y, reactive radicals Z can also be lower alkoxy groups, optionally substituted phenoxy groups or the azide radical.
Die Reduktion einer Carbonylgruppe zu einer CH2-Gruppe erfolgt zweckmäßig mit komplexen Metallhydriden wie Lithiumaluminium¬ hydrid oder Natriumborhydrid oder mit katalytisch erregtem Wasserstoff.The reduction of a carbonyl group to a CH2 group is advantageously carried out using complex metal hydrides such as lithium aluminum hydride or sodium borohydride or using catalytically excited hydrogen.
Die Ausgangsstoffe der Formeln II bis VI sind literaturbekannt oder können nach bekannten Verfahren aus beschriebenen Stoffen herstellt werden.The starting materials of the formulas II to VI are known from the literature or can be prepared from the substances described by known processes.
Im Sinne der vorliegenden Erfindung kommen außer den in den Beispielen genannten Verbindungen und der durch Kombination aller in den Ansprüchen genannten Bedeutungen der Substituenten
die folgenden Verbindungen der Formel I in Frage, die als racemischen Gemische oder in optisch aktiver Form bzw. als reine R- und S-Enantiomere vorliegen können:For the purposes of the present invention, in addition to the compounds mentioned in the examples and the combination of all the meanings of the substituents mentioned in the claims the following compounds of formula I in question, which can be present as racemic mixtures or in optically active form or as pure R and S enantiomers:
1. 5,6-Dihydro-ll,5-thiomethano-llH-dibenz[b,e]azepin-6-on1. 5,6-dihydro-ll, 5-thiomethano-llH-dibenz [b, e] azepin-6-one
2. l-Methyl-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on2. l-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
3. 2-Methyl-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on3. 2-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
4. 3-Methyl-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on4. 3-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
5. 4-Methyl-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on5. 4-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
6. 3-Chlor-5,6-dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin- 6-on6. 3-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin- 6-one
7. 4-Chlor-5,6-dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin- 6-on7. 4-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin- 6-one
8. 3-Methoxy-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on8. 3-methoxy-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
9. 4-Methoxy=5",6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on9. 4-methoxy = 5 " , 6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
10. 8-Chlor-5,6-dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin- 6-on10. 8-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin- 6-one
11. 9-Chlor-5,6-dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin- 6-on
12. 9-Methyl-5,6-dihydro-ll ,5-thioethano-llH- dibenz[b,e]azepin-6-on11. 9-chloro-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one 12. 9-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
13. 9-Methoxy-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on13. 9-methoxy-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one
14. 5,6-Dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin14. 5,6-Dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepine
15. 6-Imino-5,6-dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin15. 6-imino-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepine
16. 6-Oximino-5,6-dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin16. 6-oximino-5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepine
17. 5,6-Dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin-6-thion17. 5,6-Dihydro-ll, 5-thioethano-IIH-dibenz [b, e] azepine-6-thione
18. 6,11-Dihydro-ll,6-thioethano-dibenzo[c,f] [l,2]thiazepin- 5,5-dioxid18. 6,11-Dihydro-ll, 6-thioethano-dibenzo [c, f] [1,2] thiazepine-5,5-dioxide
19. ll-Methyl-5,6-dihydro-ll,5-thioethano-llH-dibenz- [b,e]azepin-6-on19. ll-methyl-5,6-dihydro-ll, 5-thioethano-llH-dibenz- [b, e] azepin-6-one
20. 5,6-Dihydro-5,11-propano-llH-dibenz[b,e]azepin-6-on20. 5,6-Dihydro-5,11-propano-IIH-dibenz [b, e] azepin-6-one
21. 5,6-Dihydro-ll,5-epoxyethano-llH-dibenz[b,e]azepin-6-on21. 5,6-Dihydro-ll, 5-epoxyethano-llH-dibenz [b, e] azepin-6-one
22. 5,6-Dihydro-ll,5-iminoethano-llH-dibenz[b,e]azepin-6-on22. 5,6-Dihydro-ll, 5-iminoethano-llH-dibenz [b, e] azepin-6-one
23. 5,6-Dihydro-5,11-ethano-llH-dibenz[b,e]azepin-6-on23. 5,6-Dihydro-5,11-ethano-IIH-dibenz [b, e] azepin-6-one
24. 5,6-Dihydro-ll,5-thiopropano-llH-dibenz[b,e]azepin-6-on24. 5,6-Dihydro-ll, 5-thiopropano-llH-dibenz [b, e] azepin-6-one
25. 5,6-Dihydro-ll,5-methanothioethano-llH-dibenz[b,e]azepin- 6-on25. 5,6-Dihydro-ll, 5-methanothioethano-IIH-dibenz [b, e] azepin- 6-one
26. 5,6-Dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin-6-on-12- oxid
27. 5,6-Dihydro-ll,5-thioethano-llH-dibenz[b,e]azepin-6-on- 12,12-dioxid26. 5,6-Dihydro-ll, 5-thioethano-IIH-dibenz [b, e] azepin-6-one-12-oxide 27. 5,6-Dihydro-ll, 5-thioethano-IIH-dibenz [b, e] azepin-6-one, 12,12-dioxide
Beispiel 1example 1
5,6-Dihvdro-ll.5-thioethano-llH-dibenzfb,eiazepin-6-on5,6-Dihvdro-ll.5-thioethano-llH-dibenzfb, eiazepin-6-one
Zu einer Suspension von 240 mg 50proz. Natriumhydrid (Weißöl- Dispersion) in 20 ml N,N-Dimethylformamid (DMF) tropft man bei 70°C die Lösung von 1.5 g (5 mmol) ll-(2-Chlor-ethylthio)-5,6- dihydro-HH-dibenz[b,e]azepin-6-on in 10 ml DMF, rührt 1 h bei 70βC nach, engt ein, nimmt in Dichlormethan auf, wäscht mit Wasser, trocknet, engt ein und reinigt durch Chromatographie an Kieselgel RP18 (Merck) . Nach Elution mit Methanol/Wasser/ Essigsäure 40:60:1 erhält man nach Verreiben mit Ether 680 mg (51 % d.Th.) Titelverbindung vom Schmp. 201-202βC.To a suspension of 240 mg 50 percent. Sodium hydride (white oil dispersion) in 20 ml of N, N-dimethylformamide (DMF), the solution of 1.5 g (5 mmol) of ll- (2-chloroethylthio) -5,6-dihydro-HH- is dropped at 70 ° C. dibenz [b, e] azepin-6-one in 10 ml DMF, stirred for 1 h at 70 β C, concentrated, taken up in dichloromethane, washed with water, dried, concentrated and purified by chromatography on silica gel RP18 (Merck ). After elution with methanol / water / acetic acid 40: 60: 1, 680 mg (51% of theory) of the title compound of mp 201-202 β C. are obtained after trituration with ether.
Das als Ausgangsstoff verwendete ll-(2-Chlorethylthio)-5,6- dihydro-HH-dibenz[b,e]azepin-6-on kann wie folgt erhalten werden:The ll- (2-chloroethylthio) -5,6-dihydro-HH-dibenz [b, e] azepin-6-one used as starting material can be obtained as follows:
a) Eine Mischung aus 8.0 g (33 mmol) ll-Chlor-5,6-dihydro- HH-dibenz[b,e]azepin-6-on (J.Pharm.Pharmako1. 21, 520 (1969)), 75 ml Dichlormethan und 2.6 g (33 mmol) Mercapto- ethanol wird 4 h bei Raumtemp. gerührt. Man engt im Vakuum ein und setzt das erhaltene ll-(2-Hydroxy-ethylthio)-5,6- dihydro-HH-dibenz[b,e]azepin-6-on (9.5 g öl, quantitativ) als Rohprodukt weiter um.a) A mixture of 8.0 g (33 mmol) ll-chloro-5,6-dihydro-HH-dibenz [b, e] azepin-6-one (J.Pharm.Pharmako1. 21, 520 (1969)), 75 ml of dichloromethane and 2.6 g (33 mmol) of mercaptoethanol is 4 h at room temperature. touched. The mixture is concentrated in vacuo and the resulting ll- (2-hydroxyethylthio) -5,6-dihydro-HH-dibenz [b, e] azepin-6-one (9.5 g oil, quantitative) is reacted further as a crude product.
b) Eine Mischung aus 14.2 g (50 mmol) des vorstehend beschriebenen Rohprodukts, 70 ml Dichlormethan und 5.5 ml Thionylchlorid wird 2 h zum Rückfluß erhitzt. Man engt ein, verreibt mit Ether und filtriert. Es verbleiben 13.8 g ll-(2-Chlor-ethylthio)-5,6-dihydro-HH- dibenz[b,e]azepin-6-on (91 % d.Th.) vom Schmp. 170-172°C.
Beispiel 2b) A mixture of 14.2 g (50 mmol) of the crude product described above, 70 ml of dichloromethane and 5.5 ml of thionyl chloride is heated to reflux for 2 h. The mixture is concentrated, triturated with ether and filtered. There remain 13.8 g of ll- (2-chloroethylthio) -5,6-dihydro-HH-dibenz [b, e] azepin-6-one (91% of theory), mp. 170-172 ° C. Example 2
5,6-Dihydro-ll.5-thioethano-llH-dibenzrb,eiazepin-6-on5,6-dihydro-ll.5-thioethano-llH-dibenzrb, eiazepin-6-one
Zu der Lösung von 1.2 g (5 mmol) ll-Mercapto-5,6-dihydro-llH- dibenz[b,e]azepin-6-on in 20 ml DMF tropft man 0.43 ml (5 mmol) 1,2-Dibromethan, rührt 30 min bei Raumtemp., erwärmt auf 70"C, tropft eine Suspension von 0.48 g 50proz. Natriumhydrid in 20 ml DMF zu, rührt 1 h nach, engt ein, nimmt in Dichlormethan auf, wäscht mit Wasser, trocknet, engt ein und reinigt wie in Beispiel 1 beschrieben.0.43 ml (5 mmol) of 1,2-dibromoethane are added dropwise to the solution of 1.2 g (5 mmol) of II-mercapto-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one in 20 ml of DMF , stirred for 30 min at room temperature, heated to 70 ° C., a suspension of 0.48 g of 50 percent sodium hydride in 20 ml of DMF is added dropwise, the mixture is stirred for 1 h, concentrated, taken up in dichloromethane, washed with water, dried, concentrated and cleans as described in Example 1.
Man erhält 420 mg (31 % d.Th.) Titelverbindung vom Schmp. 196- 198βC.420 mg (31% of theory) of the title compound of mp 196-198 β C. are obtained.
Das als Ausgangsstoff verwendete ll-Mercapto-5,6-dihydro-llH- dibenz[b,e]azepin-6-on kann wie folgt erhalten werden:The ll-mercapto-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one used as the starting material can be obtained as follows:
Eine Mischung aus 7.2 g (30 mmol) ll-Chlor-5,6-dihydro-llH- dibenz[b,e]azepin-6-on, 2.7 g Thioharnstoff und 60 ml Ethanol wird 6 h unter Stickstoff zum Rückfluß erhitzt. Anschließend gibt man 18 ml 5 N Natronlauge zu, erwärmt 2 h zum Rückfluß, stellt mit Salzsäure sauer, engt ein, nimmt in Wasser auf, extrahiert mit Dichlormethan, trocknet und engt ein. Nach Verreiben des Rückstands mit Ether erhält man 4.5 g (62 % d.Th.) ll-Mercapto-5,6-dihydro-llH-dibenz[b,e]azepin-6-on vom Schmp. 188-190βC.
Beispiel 3A mixture of 7.2 g (30 mmol) ll-chloro-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one, 2.7 g thiourea and 60 ml ethanol is heated under reflux for 6 h under nitrogen. Then 18 ml of 5 N sodium hydroxide solution are added, the mixture is heated under reflux for 2 h, acidified with hydrochloric acid, concentrated, taken up in water, extracted with dichloromethane, dried and concentrated. After the residue has been triturated with ether, 4.5 g (62% of theory) of ll-mercapto-5,6-dihydro-IIH-dibenz [b, e] azepin-6-one, mp. 188-190 β C. Example 3
Enantiomerentrennunα von rac-5,6-Dihvdro-ll,5-thioethano-llH- dibenzfb,eiazepin-6-onEnantiomer separation of rac-5,6-dihvdro-ll, 5-thioethano-llH-dibenzfb, eiazepin-6-one
Für die Trennung der Antipoden wurden 300 mg des Racemats in 30 ml Methanol gelöst, auf eine Säule mit 50 mm Innendurchmesser und 300 mm Länge (entsprechend 250 g Cellulosetriacetat, 15-25 /um Korngröße, Merck 16326) aufgegeben und mit 80proz. wässrigem Methanol eluiert (Fluß 7.5 ml/min, ca. 1.5 bar).For the separation of the antipodes, 300 mg of the racemate were dissolved in 30 ml of methanol, placed on a column with an inner diameter of 50 mm and a length of 300 mm (corresponding to 250 g of cellulose triacetate, 15-25 / um grain size, Merck 16326) and with 80 percent. aqueous methanol eluted (flow 7.5 ml / min, approx. 1.5 bar).
Nach Einengen der entsprechenden Fraktionen und Verreiben mit Isohexan wurden erhalten:After concentration of the appropriate fractions and trituration with isohexane, the following were obtained:
a) aus Fraktion 1: 90 mg (-)-5,6-Dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on vom Schmp. 177-178"C, [OL]D20 - 121β .a) from fraction 1: 90 mg (-) - 5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one with mp. 177-178 "C, [OL] D 20 - 121 β .
b) aus Fraktion 2: 90 mg (+)-5,6-Dihydro-ll,5-thioethano-llH- dibenz[b,e]azepin-6-on vom Schmp. 178-179°C, [^]D20 + 117°C.b) from fraction 2: 90 mg (+) - 5,6-dihydro-ll, 5-thioethano-llH-dibenz [b, e] azepin-6-one, mp. 178-179 ° C, [^] D 20 + 117 ° C.
3eispiel 43Example 4
5,6-Dihvdro-ll,5-thioethano-llH-dibenzTb,eiazepin-hvdrochlorid5,6-dihvdro-ll, 5-thioethano-llH-dibenzTb, eiazepine-hvdrochloride
Zu einer Lösung-von 1.4 g (5 mmol) Verbindung des Beispiels 1 in 20 ml 1,2-Dimethoxyethan gibt man bei Raumtemperatur 2.6 g Aluminiumchlorid, rührt 30 min nach, trägt innerhalb 1 h 0.74 g Natriumborhydrid ein, rührt 3 h nach, zersetzt mit Eiswasser, stellt alkalisch, extrahiert mit Dichlormethan und reinigt an Kieselgel. Nach Elution mit Isohexan: Ethylacetat 3:1 erhält man 0.5 g der gewünschten Verbindung (40 % d. Th. ) , die mit etherischer Chlorwasserstofflösung in das Hydrochlorid vom Schmp. 220-222 °C überführt wird.
Beispiel 52.6 g of aluminum chloride are added at room temperature to a solution of 1.4 g (5 mmol) of the compound of Example 1 in 20 ml of 1,2-dimethoxyethane, the mixture is stirred for a further 30 minutes, 0.74 g of sodium borohydride is added within 1 h, and the mixture is stirred for 3 hours, decomposes with ice water, makes alkaline, extracts with dichloromethane and cleans on silica gel. After elution with isohexane: ethyl acetate 3: 1, 0.5 g of the desired compound (40% of theory) is obtained, which is converted into the hydrochloride with a melting point of 220-222 ° C. using an ethereal hydrogen chloride solution. Example 5
5,6-Dihvdro-ll.5-thioethano-llH-dibenzfb,eiazepin-thion5,6-Dihvdro-ll.5-thioethano-llH-dibenzfb, eiazepine-thione
Eine Mischung aus 2.1 g (7.9 mmol) Verbindung des Beispiels 1, 60 ml Toluol und 1.5 g Lawesson's Reagenz wird 6 h zum Rückfluß erhitzt, mit weiteren 1.5 g Lawesson's Reagenz versetzt, erneut 6 h unter Rückfluß gekocht, eingeengt und an Kieselgel gereinigt. Nach Elution mit Isohexan:Ethylacetat 3:1 isoliert man 0.6 g Titelverbindung (27 % d. Th.), die nach Verreiben mit Ether bei 192-193 °C schmelzen.A mixture of 2.1 g (7.9 mmol) of compound from Example 1, 60 ml of toluene and 1.5 g of Lawesson's reagent is heated to reflux for 6 h, a further 1.5 g of Lawesson's reagent are added, the mixture is boiled under reflux for 6 h, concentrated and purified on silica gel. After elution with isohexane: ethyl acetate 3: 1, 0.6 g of the title compound (27% of theory) is isolated, which melts at 192-193 ° C. after trituration with ether.
Beispiel 6Example 6
5,6-Dihvdro-ll.5-thiopropano-llH-dibenzTb,eiazepin-6-on5,6-Dihvdro-ll.5-thiopropano-llH-dibenzTb, eiazepin-6-one
In analoger Weise wie in Beispiel 1 beschrieben erhält man die Titelverbindung in 23 % Ausbeute vom Schmp. 222-224 °C aus 11- (3-Chlor-propylthio)5,6-dihydro-llH-dibenz[b,e]azepin-6-on und Natriu hyrid.In an analogous manner to that described in Example 1, the title compound is obtained in 23% yield, mp. 222-224 ° C. from 11- (3-chloropropylthio) 5,6-dihydro-IIH-dibenz [b, e] azepine 6-one and natriu hyrid.
Der vorstehend genannte Ausgangsstoff kann wie folgt erhalten werden:The above-mentioned starting material can be obtained as follows:
a) Eine Mischung aus 14.6 g (60 mmol) ll-Chlor-5,6-dihydro- HH-dibenz[b,e]azepin-6-on, 200 ml Dichlormethan und 5.4 ml (60 mmol) 3-Mercapto-propionsäure wird 4 h bei Raumtemperatur gerührt, mit Sodalösung extrahiert, der Extrakt angesäuert und das Produkt abfiltriert.a) A mixture of 14.6 g (60 mmol) ll-chloro-5,6-dihydro-HH-dibenz [b, e] azepin-6-one, 200 ml dichloromethane and 5.4 ml (60 mmol) 3-mercapto-propionic acid is stirred for 4 h at room temperature, extracted with soda solution, the extract acidified and the product filtered off.
Man isoliert 15.9 g 3-(5,6Dihydro-llH-dibenz[b,e]azepin-6- on-ll-yl)mercaptopropionsäure (85 % d. Th.) vom Schmp. 185-187 °C.
b) Zu einer Suspension von 2.66 g Lithiumaluminiumhydrid in 75 ml Tetrahydrofuran tropft man eine Lösung von 15.6 g (50 mmol) der vorstehend beschriebenen Säure in 125 ml Tetrahydrofuran, erwärmt 5 h zum Rückfluß, zersetzt mit Kochsalzlösung, extrahiert mit Ethylacetat und reinigt an Kieselgel. Nach Elution mit Isohexan:Ethylacetat 3:1 erhält man 8.1 g ll-(3-Hydroypropylthio)-5,6-dihydro-llH- dibenz[b,e]azepin-6-on (54 % d. Th.) vom15.9 g of 3- (5,6-dihydro-IIH-dibenz [b, e] azepin-6-on-II-yl) mercaptopropionic acid (85% of theory), mp. 185-187 ° C., are isolated. b) A solution of 15.6 g (50 mmol) of the above-described acid in 125 ml of tetrahydrofuran is added dropwise to a suspension of 2.66 g of lithium aluminum hydride in 75 ml of tetrahydrofuran, heated to reflux for 5 h, decomposed with brine, extracted with ethyl acetate and purified on silica gel . After elution with isohexane: ethyl acetate 3: 1, 8.1 g of ll- (3-hydroypropylthio) -5,6-dihydro-IIH-dibenz [b, e] azepin-6-one (54% of theory) of
Schmp. 113-135 °C.Mp 113-135 ° C.
c) In analoger Weise wie in Beispiel 1 b beschrieben erhält man aus der vorstehenden Zwischenstufe und Thionylchlorid in 68 % Ausbeute das ll-(3-Chlor-propylthio)-5,6-dihydro- HH-dibenz[b,e]azepin-6-on vom Schmp. 110-112 °C (aus Ether) .c) In a manner analogous to that described in Example 1b, the above intermediate and thionyl chloride give the ll- (3-chloropropylthio) -5,6-dihydro-HH-dibenz [b, e] azepine in 68% yield 6-one with a melting point of 110-112 ° C (from ether).
Beispiel 7Example 7
5,6-Dihvdro-ll.5-thioethano-llH-dibenzTb,eiazepin-6-on-12-oxid5,6-Dihvdro-ll.5-thioethano-llH-dibenzTb, eiazepin-6-one-12-oxide
Eine Lösung von 1.3 g (5mmol) Verbindung des Beispiels 1, 50 ml Aceton und 1.2 ml 30%igem Wasserstoffperoxid wird 2 h bei 50 °C gerührt, mit Wasser versetzt und mit Ethylacetat extrahiert. Nach Einengen des Extraktes und Verreiben mit Ether verbleiben 0.8 g Titelverbindung (53 % d. Th) vom Schmp. 108-109 °C als Monohydrat.A solution of 1.3 g (5 mmol) of compound from Example 1, 50 ml of acetone and 1.2 ml of 30% hydrogen peroxide is stirred for 2 hours at 50 ° C., mixed with water and extracted with ethyl acetate. After concentrating the extract and triturating with ether, 0.8 g of the title compound (53% of theory), mp. 108-109 ° C., remains as a monohydrate.
Beispiel 8Example 8
5,6-Dihvdro-ll,5-thioethano-llH-dibenzrb,e1azepin-6-on-12,12- dioxid5,6-Dihvdro-ll, 5-thioethano-llH-dibenzrb, e1azepin-6-one-12,12-dioxide
Eine Lösung von 1.3 g (5 mmol) Verbindung des Beispiels 1 in 30 ml Chloroform versetzt man mit einer Lösung von 2.1 g 3- Chlorperoxybenzoesäure in 30 ml Chloroform, rührt 1 h bei
Raumtemperatur, wäscht mit Natriumhydrogencarbonatlösung und engt die organische Phase ein. Nach Verreiben mit Ether verbleiben 0.9 g TitelVerbindung (60 % d. Th. ) vom Schmp. 244- 246 °C.A solution of 1.3 g (5 mmol) of the compound from Example 1 in 30 ml of chloroform is mixed with a solution of 2.1 g of 3-chloroperoxybenzoic acid in 30 ml of chloroform, and the mixture is stirred for 1 hour Room temperature, washes with sodium bicarbonate solution and concentrated the organic phase. After trituration with ether, 0.9 g of the title compound (60% of theory) of mp. 244-246 ° C. remain.
Beispiel 9Example 9
Hemmung der Reversen Transskriptase (RT) durch Derivate des DibenzTb,eiazepins.Inhibition of reverse transcriptase (RT) by derivatives of dibenzTb, eiazepine.
Das Testsystem beinhaltet die gereinigte RT aus HIV-1, die durch gentechnologische Methoden in E. coli exprimiert wurde, sowie die Komponenten des Initiationskomplexes, wie die in-vitro-Transkripte des HIV-LTR's mit der benachbarten Primer Binding Site als Template und einem zur Primer Binding Site komplementären 18mer Oligonukleotid als Primer. Gemessen wurde der [3H]-Thymidin-5'-triphosphat-Einbau durch Auszählen im ß- Counter. In der folgenden Tabelle wird für die untersuchten Verbindungen der ICso- ert angegeben. Dieser Wert entspricht derjenigen Konzentration der Testsubstanz, die eine Hemmung der Reversen Transkriptase Aktivität um 50% bewirkt.The test system contains the purified RT from HIV-1, which was expressed by genetic engineering methods in E. coli, as well as the components of the initiation complex, such as the in vitro transcripts of the HIV-LTR with the neighboring primer binding site as a template and one for Primer binding site complementary 18mer oligonucleotide as a primer. The [ 3 H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter. The table below shows the ICsoth for the compounds examined. This value corresponds to the concentration of the test substance which causes an inhibition of the reverse transcriptase activity by 50%.
ErgebnisseResults
Claims
Patentansprüche Claims
Dibenz [b , e] azepin-Derivate der Formel IDibenz [b, e] azepine derivatives of the formula I.
in derin the
A eine Methylen-, Carbonyl-, Thiocarbonyl-, Carbimino-, N-Hydroxycarbimino- oder Sulfonylgruppe,A is a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulfonyl group,
X eine Valenzbindung oder ein Sauerstoff- oderX is a valence bond or an oxygen or
Schwefelatom, eine Sulfinyl- oder Sulfonylgruppe, eine Gruppe CH2S oder eine Gruppe NH,Sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or a NH group,
n eine ganze Zahl von 1 bis 3 undn is an integer from 1 to 3 and
R1 bis R3, die unabhängig voneinander gleich oder ver¬ schieden sein können, je ein Wasserstoffatom, einen geradkettigen oder verzweigten, gesättigten oder ungesättigten aliphatischen Rest mit 1-6 C-Atomen oder Ci-Cg-Alkoxy, Ci-Cg-Alkylmercapto, C-_-CQ- Alkylsulfinyl, Ci-Cg-Alkylsulfonyl, Amino, C1-C5- Alkylamino, Di-Ci-Cg-Alkylamino, Sulfonamido, C-_-CQ- Alkoxycarbonyl, Carboxy, Halogen, Hydroxy, Nitro, Cyano, Azido, Phenyl oder Benzyloxy und
R4 Wasserstoff oder einen geradkettigen oder ver¬ zweigten, gesättigten oder ungesättigten alipha¬ tischen Rest mit 1-6 C-AtomenR 1 to R 3 , which can be the same or different independently of one another, each represent a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or Ci-Cg-alkoxy, Ci-Cg-alkyl mercapto , C -_- C Q - alkylsulfinyl, Ci-Cg-alkylsulfonyl, amino, C1-C5-alkylamino, di-Ci-Cg-alkylamino, sulfonamido, C -_- C Q - alkoxycarbonyl, carboxy, halogen, hydroxy, nitro , Cyano, azido, phenyl or benzyloxy and R 4 is hydrogen or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms
bedeuten,mean,
deren Tautomere, Enantiomere, Diastereomere und physio¬ logisch verträgliche Salze.their tautomers, enantiomers, diastereomers and physiologically compatible salts.
Dibenz[b,e]azepin-Derivate gemäß Anspruch 1, dadurch gekennzeichnet, daßDibenz [b, e] azepine derivatives according to claim 1, characterized in that
R1 bis R3 Wasserstoff, C]_-C3-Alkyl, C2"C4-Alkenyl, C2-C4- Alkinyl, C_-C3-Alkoxy, Cι-C3-Alkylmercapto, C]_-C3- Alkylamino, Cι-C3-Alkoxycarbonyl, Amino, Halogen, Hydroxy, Cyano und Azido bedeutet.R 1 to R 3 are hydrogen, C] _- C3-alkyl, C2 "C4-alkenyl, C2-C4-alkynyl, C_-C 3 -alkoxy, Cι-C 3 -alkylmercapto, C ] _-C3- alkylamino, Cι -C 3 -alkoxycarbonyl, amino, halogen, hydroxy, cyano and azido.
3. Dibenz[b,e]azepin-Derivate gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß3. dibenz [b, e] azepine derivatives according to claim 1 or 2, characterized in that
R4 Wasserstoff, C!-C3-Al yl, C2-C -Alkenyl oder C2-C - Alkinyl bedeutet.R 4 is hydrogen, C! -C3-al yl, C2-C-alkenyl or C 2 -C - alkynyl.
4. Verfahren zur Herstellung von Dibenz[b,e]azepin-Derivaten der Formel I gemäß den Ansprüchen 1, 2 oder 3, dadurch gekennzeichnet, daß man
4. A process for the preparation of dibenz [b, e] azepine derivatives of the formula I according to claims 1, 2 or 3, characterized in that
a) eine Verbindung der Formel IIa) a compound of formula II
in der A, X, n und R1 bis R4 die oben angegebene Bedeutung haben und Y einen reaktiven Rest darstellt, oderin which A, X, n and R 1 to R 4 have the meaning given above and Y represents a reactive radical, or
b) eine Verbindung der Formel IIIb) a compound of formula III
in der A, X, n, R1 bis R4 und Y die vorstehend genannte Bedeutung haben,in which A, X, n, R 1 to R 4 and Y have the meaning given above,
unter Abspaltung von HY cyclisiert, oder
c) eine Verbindung der Formel IVcyclized with elimination of HY, or c) a compound of formula IV
in der A, X und R1 bis R4 die oben angegebenen Bedeutung haben, mit einer Verbindung der Formel (V) ,in which A, X and R 1 to R 4 have the meaning given above, with a compound of the formula (V),
Y,-(CH2)n-ϊ" (V),Y , - (C H 2 ) n-ϊ "(V),
worin n die oben genannte Bedeutung hat und Y' und Y", die gleich oder verschieden sind, die Bedeutung von Y haben,wherein n has the meaning given above and Y 'and Y ", which are the same or different, have the meaning of Y,
unter Abspaltung von HY' und HY" umsetzt, oderwith the splitting off of HY 'and HY ", or
d) eine Verbindung der Formel VId) a compound of formula VI
in der A, X, n und R1 bis R4 die oben angegebene Bedeutung haben und Z einen reaktiven Rest darstellt, cyclisiert
oderin which A, X, n and R 1 to R 4 have the meaning given above and Z represents a reactive radical, cyclizes or
e) eine Verbindung der Formel (I) , in der eine oder mehrere der n CH2-Gruppen durch CO oder ein Derivat davon ersetzt sind, durch Reduktion in eine Verbindung der Formel I überführt,e) converting a compound of the formula (I) in which one or more of the n CH2 groups has been replaced by CO or a derivative thereof into a compound of the formula I by reduction,
und gegebenenfalls anschließend Verbindungen der Formel I in andere, durch den Anspruch umfaßte Verbindungen der Formel I umwandelt und gewünschtenfalls durch Titration mit pharmakologisch verträglichen Säuren oder Basen in Salze überführt.and, if appropriate, then subsequently converting compounds of the formula I into other compounds of the formula I and, if desired, converting them into salts by titration with pharmacologically acceptable acids or bases.
Arzneimittel enthaltend mindestens ein Dibenz[b,e]azepin- Derivat der Formel I gemäß den Ansprüchen 1, 2 oder 3, sowie übliche Träger- oder Hilfsstoffe.Medicaments containing at least one dibenz [b, e] azepine derivative of the formula I according to Claims 1, 2 or 3, and also conventional carriers or auxiliaries.
6. Verwendung von Dibenz[b,e]azepin-Derivaten der Formel I gemäß Anspruch 1, 2 oder 3 zur Herstellung von Arznei¬ mitteln zur Behandlung von durch Viren oder Retroviren verursachten Erkrankungen.
6. Use of dibenz [b, e] azepine derivatives of the formula I according to claim 1, 2 or 3 for the preparation of medicaments for the treatment of diseases caused by viruses or retroviruses.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5501932A JPH06508840A (en) | 1991-07-05 | 1992-06-30 | Dibenzo[b,e]azepine derivatives and pharmaceutical compositions containing the same |
| EP92913494A EP0593536A1 (en) | 1991-07-05 | 1992-06-30 | DIBENZ b,e]AZEPINE DERIVATIVES AND DRUGS CONTAINING THEM |
| CA002111710A CA2111710A1 (en) | 1991-07-05 | 1992-06-30 | Dibenz[b,e]azepin derivatives and medicaments containing these |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4122240.7 | 1991-07-05 | ||
| DE4122240A DE4122240A1 (en) | 1991-07-05 | 1991-07-05 | DIBENZ (B, E) AZEPINE DERIVATIVES AND MEDICAMENTS CONTAINING THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993001195A1 true WO1993001195A1 (en) | 1993-01-21 |
Family
ID=6435479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1992/001465 WO1993001195A1 (en) | 1991-07-05 | 1992-06-30 | DIBENZ[b,e]AZEPINE DERIVATIVES AND DRUGS CONTAINING THEM |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0593536A1 (en) |
| JP (1) | JPH06508840A (en) |
| AU (1) | AU2194292A (en) |
| CA (1) | CA2111710A1 (en) |
| DE (1) | DE4122240A1 (en) |
| WO (1) | WO1993001195A1 (en) |
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| US9271967B2 (en) | 2010-11-08 | 2016-03-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
| US9708315B2 (en) | 2013-09-06 | 2017-07-18 | Janssen Pharmaceutica Nv | 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors |
| US10106542B2 (en) | 2013-06-04 | 2018-10-23 | Janssen Pharmaceutica Nv | Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors |
| US10537573B2 (en) | 2014-01-21 | 2020-01-21 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
| US11369606B2 (en) | 2014-01-21 | 2022-06-28 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0419861B1 (en) * | 1989-08-29 | 1995-11-02 | Boehringer Ingelheim Pharmaceuticals Inc. | Use of dibenz[b,f][1,4]oxazepin (and thiazepin)-11(10H)-ones and -thiones in the preparation of a pharmaceutical composition for the prevention or treatment of aids |
-
1991
- 1991-07-05 DE DE4122240A patent/DE4122240A1/en not_active Withdrawn
-
1992
- 1992-06-30 WO PCT/EP1992/001465 patent/WO1993001195A1/en not_active Application Discontinuation
- 1992-06-30 EP EP92913494A patent/EP0593536A1/en not_active Withdrawn
- 1992-06-30 AU AU21942/92A patent/AU2194292A/en not_active Abandoned
- 1992-06-30 JP JP5501932A patent/JPH06508840A/en active Pending
- 1992-06-30 CA CA002111710A patent/CA2111710A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0419861B1 (en) * | 1989-08-29 | 1995-11-02 | Boehringer Ingelheim Pharmaceuticals Inc. | Use of dibenz[b,f][1,4]oxazepin (and thiazepin)-11(10H)-ones and -thiones in the preparation of a pharmaceutical composition for the prevention or treatment of aids |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9266834B2 (en) | 2006-03-15 | 2016-02-23 | Janssen Pharmaceuticals, Inc. | 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors |
| US8841323B2 (en) | 2006-03-15 | 2014-09-23 | Janssen Pharmaceuticals, Inc. | 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors |
| US8906939B2 (en) | 2007-03-07 | 2014-12-09 | Janssen Pharmaceuticals, Inc. | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
| US9067891B2 (en) | 2007-03-07 | 2015-06-30 | Janssen Pharmaceuticals, Inc. | 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors |
| US11071729B2 (en) | 2007-09-14 | 2021-07-27 | Addex Pharmaceuticals S.A. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones |
| US9132122B2 (en) | 2007-09-14 | 2015-09-15 | Janssen Pharmaceuticals, Inc. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones |
| US9114138B2 (en) | 2007-09-14 | 2015-08-25 | Janssen Pharmaceuticals, Inc. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones |
| US8691849B2 (en) | 2008-09-02 | 2014-04-08 | Janssen Pharmaceuticals, Inc. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
| US8691813B2 (en) | 2008-11-28 | 2014-04-08 | Janssen Pharmaceuticals, Inc. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
| US9737533B2 (en) | 2009-05-12 | 2017-08-22 | Janssen Pharmaceuticals. Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
| US9085577B2 (en) | 2009-05-12 | 2015-07-21 | Janssen Pharmaceuticals, Inc. | 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
| US8946205B2 (en) | 2009-05-12 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
| US8937060B2 (en) | 2009-05-12 | 2015-01-20 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
| US9226930B2 (en) | 2009-05-12 | 2016-01-05 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
| US10071095B2 (en) | 2009-05-12 | 2018-09-11 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders |
| US8993591B2 (en) | 2010-11-08 | 2015-03-31 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors |
| US9271967B2 (en) | 2010-11-08 | 2016-03-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
| US9012448B2 (en) | 2010-11-08 | 2015-04-21 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors |
| US10106542B2 (en) | 2013-06-04 | 2018-10-23 | Janssen Pharmaceutica Nv | Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors |
| US10584129B2 (en) | 2013-06-04 | 2020-03-10 | Janssen Pharmaceuticals Nv | Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors |
| US9708315B2 (en) | 2013-09-06 | 2017-07-18 | Janssen Pharmaceutica Nv | 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors |
| US10537573B2 (en) | 2014-01-21 | 2020-01-21 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
| US11103506B2 (en) | 2014-01-21 | 2021-08-31 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
| US11369606B2 (en) | 2014-01-21 | 2022-06-28 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
| US12048696B2 (en) | 2014-01-21 | 2024-07-30 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4122240A1 (en) | 1993-01-07 |
| AU2194292A (en) | 1993-02-11 |
| CA2111710A1 (en) | 1993-01-21 |
| JPH06508840A (en) | 1994-10-06 |
| EP0593536A1 (en) | 1994-04-27 |
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