CS246100B2 - Method of imidazobenzodiazepines production - Google Patents
Method of imidazobenzodiazepines production Download PDFInfo
- Publication number
- CS246100B2 CS246100B2 CS853682A CS368285A CS246100B2 CS 246100 B2 CS246100 B2 CS 246100B2 CS 853682 A CS853682 A CS 853682A CS 368285 A CS368285 A CS 368285A CS 246100 B2 CS246100 B2 CS 246100B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- benzodiazepine
- carboxylate
- oxo
- imidazo
- formulas
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 31
- KLNFAMGHSZQYHR-UHFFFAOYSA-N imidazo[4,5-i][1,2]benzodiazepine Chemical class C1=CC=NN=C2C3=NC=NC3=CC=C21 KLNFAMGHSZQYHR-UHFFFAOYSA-N 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 78
- -1 tetrahydro-2H-pyran-4-yl Chemical group 0.000 claims description 34
- CEHKKWWXELBNPS-UHFFFAOYSA-N 1,4-benzodiazepine-1-carboxylic acid Chemical compound OC(=O)N1C=CN=CC2=CC=CC=C12 CEHKKWWXELBNPS-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- OFWFBJVJXBLXOP-UHFFFAOYSA-N 9h-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylic acid Chemical compound C1=C2C=CC=CC2=NC=C2C(C(=O)O)=CCN21 OFWFBJVJXBLXOP-UHFFFAOYSA-N 0.000 claims description 16
- 239000007858 starting material Substances 0.000 claims description 16
- WXBBGXSCFXZZSI-UHFFFAOYSA-N 1h-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid Chemical compound N1=CC2=CC=CC=C2N2C(C(=O)O)N=CC2=C1 WXBBGXSCFXZZSI-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000006410 propenylene group Chemical group 0.000 claims description 6
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- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- CFMIOXCGQIHWJP-UHFFFAOYSA-N 1,2-benzodiazepine-1-carboxylic acid Chemical compound OC(=O)N1N=CC=CC2=CC=CC=C12 CFMIOXCGQIHWJP-UHFFFAOYSA-N 0.000 description 8
- 102000004300 GABA-A Receptors Human genes 0.000 description 7
- 108090000839 GABA-A Receptors Proteins 0.000 description 7
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- 239000002775 capsule Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 229960003529 diazepam Drugs 0.000 description 6
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- 239000004480 active ingredient Substances 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
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- 229940099112 cornstarch Drugs 0.000 description 4
- JDFHMNHZTKPJLV-INIZCTEOSA-N cyclohexyl (s)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9h-imidazo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate Chemical compound C1([C@@H]2CCCN2C(=O)C2=C(N1C=N1)C=CC=C2Br)=C1C(=O)OC1CCCCC1 JDFHMNHZTKPJLV-INIZCTEOSA-N 0.000 description 4
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- IADUEWIQBXOCDZ-VKHMYHEASA-N (S)-azetidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
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- 206010010904 Convulsion Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- HFTSPQUXYIMHAN-ZDUSSCGKSA-N ac1l3sqn Chemical compound C1([C@@H]2CCN2C(=O)C2=C(N1C=N1)C=CC=C2Cl)=C1C(=O)OCC1CC1 HFTSPQUXYIMHAN-ZDUSSCGKSA-N 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- RUPPUSVKQLILDN-INIZCTEOSA-N cyclopentylmethyl (7S)-14-chloro-12-oxo-2,4,11-triazatetracyclo[11.4.0.02,6.07,11]heptadeca-1(17),3,5,13,15-pentaene-5-carboxylate Chemical compound C1([C@@H]2CCCN2C(=O)C2=C(N1C=N1)C=CC=C2Cl)=C1C(=O)OCC1CCCC1 RUPPUSVKQLILDN-INIZCTEOSA-N 0.000 description 2
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 230000004973 motor coordination Effects 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
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- IADUEWIQBXOCDZ-UHFFFAOYSA-N (2S)-azetidine-2-carboxylic acid Natural products OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- WKNFCUFYGJKWGJ-JTQLQIEISA-N (s)-7-fluoro-12,12a-dihydro-9-oxo-9h,11h-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylic acid Chemical compound O=C1C2=CC(F)=CC=C2N2C=NC(C(=O)O)=C2[C@@H]2CCN21 WKNFCUFYGJKWGJ-JTQLQIEISA-N 0.000 description 1
- CUZHFFMELKJWLE-JTQLQIEISA-N (s)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9h-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid Chemical compound O=C1C2=C(Cl)C=CC=C2N2C=NC(C(=O)O)=C2[C@@H]2CCCN21 CUZHFFMELKJWLE-JTQLQIEISA-N 0.000 description 1
- QSAWTMJOFURZMK-UHFFFAOYSA-N 1-methyl-cyclopentyl 8-chloro-11,12,13,13a-tetrahydro-9-oxo-9h-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate Chemical compound N1=CN(C2=CC=CC(Cl)=C2C(=O)N2CCCC22)C2=C1C(=O)OC1(C)CCCC1 QSAWTMJOFURZMK-UHFFFAOYSA-N 0.000 description 1
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- ZOHWBYDBTLSCDE-HNNXBMFYSA-N 2-cyclopropylethyl (s)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9h-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate Chemical compound C1([C@@H]2CCCN2C(=O)C2=C(N1C=N1)C=CC=C2Cl)=C1C(=O)OCCC1CC1 ZOHWBYDBTLSCDE-HNNXBMFYSA-N 0.000 description 1
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- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Předložený vynález se týká způsobu výroby nových imidazobenzodiazepinů, které mají cenné farmakologické vlastnosti.The present invention relates to a process for the production of novel imidazobenzodiazepines having valuable pharmacological properties.
Zvláště pak se vynález týká způsobu výroby nových tri- a tetracyklických imidazobenzodiazepinů obecného vzorce IIn particular, the invention relates to a process for the preparation of novel tri- and tetracyclic imidazobenzodiazepines of the general formula I
v němžin which
A znamená alkylencvou skupinu s 1 až 7 atomy uhlíku, n znamená číslo 0 nebo 1,A is C 1 -C 7 alkylene, n is 0 or 1,
R1 znamená alkinylovou skupinu se 2 až atomy uhlíku, alkenylovou skupinu se 2 až 7 atomy uhlíku, fenylovou skupinu, která je popřípadě substituována halogenem nebo alkoxyskupinou s 1 až 7 atomy uhlíku, vždy popřípadě alkylovou skupinou s 1 až 7 atomy uhlíku substituovanou cykloalkylovou skupinu se 3 až 8 atomy uhlíku nebo cykloalkenylovou skupinu s 5 až 8 atomy uhlíku, nebo popřípadě alkylovou skupinou s 1 až 7 atomy uhlíku substituovanou tetrahydro-2H-pyran-4-ylovou skupinu,R 1 represents alkinyl having 2 to carbon atoms, alkenyl having 2-7 carbon atoms, phenyl which is optionally substituted by halogen or alkoxy having 1-7 carbon atoms each or an alkyl group having 1-7 carbon atoms substituted cycloalkyl (C až-C 8) alkyl or (C až-C 8) cycloalkenyl group, or optionally a (C až-C tetra) alkyl group substituted with tetrahydro-2H-pyran-4-yl,
R4 a R5 znamenají atom vodíku, atom halogenu, trifluormethylovou skupinu, kyanoskupínu, nítroskupinu, aminoskupinu nebo alkylovou skupinu s 1 až 7 atomy uhlíku a budR 4 and R 5 represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a cyano group, an nitro group, an amino group or an alkyl group having 1 to 7 carbon atoms and either
R2 znamená atom vodíku aR 2 is hydrogen and
R3 znamená alkylovou skupinu s 1 až 7 atomy uhlíku, neboR 3 represents an alkyl group having 1 to 7 carbon atoms, or
R2 a R3 znamenají společně dimethylenovou skupinu, trimethylenovou skupinu nebo propenylenovou skupinu, přičemž sloučeniny vzorce I, v němž R2 a R3 zamenají společně dimethylenovou skupinu, trimethylenovou skupinu nebo propenylenovou skupinu, mají s ohledem na atom uhlíku, který je označen písmenem χ, (S)- nebo (R,S)-konfiguraci, a jejich farmaceuticky přijatelných adičních solí s kyselinami.R 2 and R 3 together represent a dimethylene group, a trimethylene group or a propenylene group, the compounds of formula I in which R 2 and R 3 together denote a dimethylene group, a trimethylene group or a propenylene group, with respect to the carbon atom designated by the χ, (S) - or (R, S) -configuration, and their pharmaceutically acceptable acid addition salts.
Uvedené sloučeniny jsou nové a vyznačují se cennými farmakodynamickými vlast* nostmi. Mohou se používat k léčení chorob, popřípadě k profylaxi chorob.The compounds are novel and possess valuable pharmacodynamic properties. They can be used for the treatment of diseases or for the prophylaxis of diseases.
Dále v popisované části popřípadě používaný výraz „nižší“ v kombinacích, jako „nižší alkyl“, „nižší alkylové skupiny“, nižší alkylen“, „nižší alkyloxy“, „nižší alkinyl“, .nižší alkenyl“ apod., znamená, že takto označené zbytky obsahují nejvýše 7 atomů uhlíku, výhodně však nejvýše 4 atomy uhlíku.Hereinafter, the term " lower " optionally used in combinations such as " lower alkyl, " lower alkyl, " lower alkylene, " lower alkyloxy, " lower alkynyl, " lower alkenyl " the labeled residues contain at most 7 carbon atoms, but preferably at most 4 carbon atoms.
Alkylová skupina s 1 až 7 atomy uhlíku může mít řetězec přímý nebo rozvětvený a je představována například methylovou skupinou, ethylovou skupinou, n-propylovou skupinou, isopropylovou skupinou, n-butylovou skupinou, sek.butylovou skupinou, terc.butylovou skupinou apod.The C 1 -C 7 alkyl group may be straight or branched chain and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.
Alkyloxyskupina s 1 až 7 atomy uhlíku označuje alkylové skupiny vázané přes atom kyslíku, jako je například methoxyskupina, ethoxyskupina, isopropoxyskupina apod.C1-C7alkyloxy refers to alkyl groups bonded via an oxygen atom, such as methoxy, ethoxy, isopropoxy and the like.
Výraz „alkylenová skupina“ označuje dvojvazné, přímé nebo rozvětvené, nasycené uhlovodíkové skupiny s 1 až 7 atomy uhlíku, jako je methylenová skupina, 1,2-ethylenová skupina, ethylidenová skupina apod.The term "alkylene" refers to divalent, straight or branched, saturated hydrocarbon groups having 1 to 7 carbon atoms, such as methylene, 1,2-ethylene, ethylidene and the like.
Výraz „alkinylová skupina“ ozančuje přímé nebo rozvětvené uhlovodíkové skupiny s jednou trojnou vazbou, obsahující 2 až 7 atomů uhlíku, jako je propargylová skupina a podobně.The term "alkynyl" denotes straight or branched chain hydrocarbon groups having one triple bond containing from 2 to 7 carbon atoms such as a propargyl group and the like.
Výraz „alkenylová skupina“ označuje přímé nebo rozvětvené uhlovodíkové skupiny s jednou dvojnou vazbou, které obsahují 2 až 7 atomů uhlíku, jako je allylová skupina a podobně.The term "alkenyl" refers to straight or branched hydrocarbon groups having one double bond containing 2 to 7 carbon atoms, such as an allyl group and the like.
Výraz „cykloalkylová skupina se 3 až 8 atomy uhlíku“ označuje cyklické uhlovodíkové skupiny se 3 až 8 členy v kruhu, jako je cyklopropylová skupina, cyklobutylová skupina, cyklopentylová skupina, cyklohexylová skupina, cykloheptylová skupina a cyklooktylová skupina.The term "C 3 -C 8 cycloalkyl" refers to cyclic C 3 -C 8 ring hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Výraz „cykloalkenylová skupina s 5 až 8 atomy uhlíku“ označuje nenasycené cyklické uhlovodíkové skupiny s 5 až 8 členy v kruhu, jako je 2-cyklohexen-l-ylová skupina a podobně.The term "C 5 -C 8 cycloalkenyl" refers to unsaturated cyclic C 5 -C 8 ring hydrocarbon groups such as 2-cyclohexen-1-yl and the like.
jako fenylová skupina, která je popřípadě substituována halogenem nebo alkoxyskupinou s 1 až 7 atomy uhlíku přichází v úvahu výhodně monosubstituovaná fenylová skupina, jako je fenylová skupina, o-chlorfenylová skupina, m-chlorfenylová skupina, p-chlorfenylová skupina, o-methoxyfenylová skupina, m-methoxyfenylová skupina, p-methoxyfenylová skupina apod.as phenyl optionally substituted by halogen or alkoxy having 1 to 7 carbon atoms, preferably a monosubstituted phenyl group such as phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl and the like.
Výraz „halogen“ znamená fluor, chlor, brom nebo jod.The term "halogen" means fluorine, chlorine, bromine or iodine.
Výhodně se připravují sloučeniny obecného vzorce I, v němž buď n znamená číslo 0 nebo n znamená číslo 1 a potom A znamená popřípadě alkýlovou skupinu s 1 až 6, popřípadě až 5 atomy uhlíku substituovanou methylenovou skupinu nebo 1,2-ethylenovou skupinu, R1 znamená výhodně alkinylovou skupinu se 2 až 7 atomy uhlíku, fenylovou skupinu nebo vždy popřípadě alkýlovou skupinou s 1 až 7 atomy uhlíku substituovanou cykloalkylovou skupinu se 3 až 8 atomy uhlíku nebo cykloalkenylovou skupinu s 5 až 8 atomy uhlíku, přičemž zvláště výhodnou je cykloalkylová skupina se 3 až 6 atomu uhlíku.Preferably, compounds of formula (I) are prepared wherein either n is 0 or n is 1 and then A is optionally an alkyl group having 1 to 6, optionally up to 5 carbon atoms substituted methylene or 1,2-ethylene groups, R 1 is preferably C 2 -C 7 alkynyl, phenyl or C 1 -C 7 alkyl optionally substituted C 3 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl, with cycloalkyl being particularly preferred. C 3 -C 6 carbon atoms.
Při zcela zvláště výhodném provedení znamená skupina —(Ajn-Rx cyklohexylovou skupinu, 2-cyklohexen-l-ylovou skupinu, cyklopropylmethylovou skupinu, 1-cyklopropylethylovou skupinu nebo 2-cyklopropylethylovou skupinu.In a particularly preferred embodiment, the group is - (A n -R x cyclohexyl, 2-cyclohexen-1-yl, cyclopropylmethyl, 1-cyclopropylethyl or 2-cyclopropylethyl).
R2 a R3 znamenají výhodně společně dimethylenovou skupinu, trimethylenovou skupinu nebo propenylenovou skupinu, přičemž odpovídající sloučeniny vzorce I mají, pokud jde o atom uhlíku označený písmenem y, výhodně (Sj-konfiguraci.R @ 2 and R @ 3 are preferably together a dimethylene group, a trimethylene group or a propenylene group, the corresponding compounds of formula I having, preferably with respect to the carbon atom designated by the letter y, preferably (Sj configuration).
R4 znamená výhodně atom vodíku, halogenu, trifluormethylovou skupinu, nitroskupinu, kyanoskupinu nebo alkýlovou skupinu s 1 až 7 atomy uhlíku.R 4 is preferably a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group, a cyano group or an alkyl group having 1 to 7 carbon atoms.
R5 znamená výhodně atom vodíku nebo atom halogenu.R 5 is preferably hydrogen or halogen.
Zcela zvláště výhodnou sloučeninou v rámci předloženého vynálezu je cyklopropylmethyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo [ 1,5-a ] [ 1,4 ] benzodiazepin-l-karboxylát.A particularly preferred compound of the present invention is cyclopropylmethyl- (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [ 1,4] benzodiazepine-1-carboxylate.
Dalšími zcela zvláště výhodnými sloučeninami jsou:Other particularly preferred compounds are:
cyklohexyl-(S)-8-brom-ll,12,13,13a-tetrahydr o-9-oxo-9H-imidazo [ 1,5-a] pyrrolo [2,1-c][ 1,4 ] benzodiazepin-l-karboxylát, (R,S) -2-cyklohexen-l-yl- (S) -8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-1-karboxylát, cyklohexyl- (S j -8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeta[ 2,1-c ] imidazo [1,5-a ] [ 1,4 ] benzodiazepin-l-karboxylát, cyklohexyl-(S)-7-fluor-12,12a-dihydro-9-oxo-9H,HH-azeto [ 2,1-c ] imidazo [1,5-a][ 1,4] benzodiazepin-l-karboxylát, cyklohexyl-(S J-8-chlor-7-fluor-ll,12,13,13a-tetrahydr o-9-oxo-9H-imidazo[ 1,5-a ] pyrrolo[ 2,1-a ] [ 1,4- ] benzodiazepin-l-karboxylát, (R,S )-l-cyklopropylethyl- (S )-8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo[ 2,5-a ] [ 1,4- ] benzodlazepin-l-karboxylát, cyklohexyl-(S )-12,12a-dihydro-8-jod-9-oxo-9H,llH-azetoi[ 2,1-c ] imidazo [ 1,5-ař] [ 1,4] benzodiazepin-l-karboxylát, cyklopropylraethyl-(S)-7-fluor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a ]pyrrolo [ 2, Ι-c·] [ 1,4] benzodiazepin-l-karboxylát, (R,S) -1-cyklopropylethyl- (S )-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [ 2,1-c 1,4] benzodiazepin-1-karboxylát, cyklopropylmethyl-(S)-7-fluor-12,12a-dihydro-9-oxo-9H,llH-azetci [ 2,1-c ] imidazo] 1,5-a ] [1,4] benzodiazepin-l-karboxylát, acyclohexyl- (S) -8-bromo-11,12,13,13a-tetrahydr o-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine- 1-carboxylate, (R, S) -2-cyclohexen-1-yl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S, -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeta [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -7-fluoro-12,12a-dihydro-9-oxo-9H, HH-azeto [2,1- c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclohexyl (S-8-chloro-7-fluoro-11, 12,13,13a-tetrahydr o-9-oxo) 9H-imidazo [1,5-a] pyrrolo [2,1-a] [1,4-] benzodiazepine-1-carboxylate, (R, S) -1-cyclopropylethyl (S) -8-chloro-12, 12a-Dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [2,5-a] [1,4-] benzodlazepine-1-carboxylate, cyclohexyl (S) -12,12a- dihydro-8-iodo-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclopropylraethyl (S) -7-fluoro -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2, [c]] [1,4] benzodiazepine-1-carboxylate, (R, S) -1-cyclopropylethyl (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c 1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl (S) -7-fluoro-12,12a-dihydro-9-oxo-9H, 11H-azetec [ 2,1-c] imidazo] 1,5-a] [1,4] benzodiazepine-1-carboxylate, and
cyklohexyl-(S)-11,12,13,13a-tetrahydro-9-oxo-8- [trifluormethyl) -9H-imidazo [ 1,5-a ] pyrrolo] 2,1-c ]í[ 1,4] benzodiazepin-l-karboxylát.cyclohexyl- (S) -11,12,13,13a-tetrahydro-9-oxo-8- [trifluoromethyl] -9H-imidazo [1,5-a] pyrrolo] 2,1-c] [1,4] benzodiazepine-1-carboxylate.
Dalšími výhodnými sloučeninami, které spadají pod rozsah obecného vzorce I, jsou následující sloučeniny:Other preferred compounds within the scope of Formula I are the following:
cyklohexyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imid.azo [1,5-a ] pyrr olo[ 2,1-c ] benzodiazepin-l-karboxylát,cyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] benzodiazepine-1-carboxylate ,
2-propinyl- (S) -8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a ] pyrrolo [ 2,1-c ] [ 1.4] benzodiazepin-l-karboxylát, cyklopropylmethyl-8-chlor-ll,13a-dihydro-9-oxo-9H-imidazo] 1,5-a] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, cyklopropylmethyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a Jpyrrolo[ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, cyklopropylmethyl- (S) -8-brom-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [2, l-d]j[ 1,4] benzodiazepin-l-karboxylát, cyklopropylmethyl- (S) -11,12,13,13a-tetrahydro-8-jod-9-oxo-9H-imidazo [ 1,5-a] pyrrolo [ 2,1-Q ]![ 1,4] benzodiazepin-l-karboxylát,2-propynyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, cyclopropylmethyl-8-chloro-11,13a-dihydro-9-oxo-9H-imidazo] 1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-d] [1,4] benzodiazepine-1- carboxylate, cyclopropylmethyl- (S) -11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-Q] [1,4] benzodiazepine-1-carboxylate,
2-cyklopropylethyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo;[ 1,5-a] pyrrolo [ 2,l-q]l[ 1,4] benzodiazepin-l-karboxylát, cyklohexyl- (S) -12,12a-dihydro-8-methyl-9-oxo-9I-I,lH-azeto [ 2,1-c ] imidazo] 1,5-a ]'[ 1,4 ] benzodiazepin-l-karboxylát, rac.-cis-3-methylcyklohexyl- (S) -8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a) pyrrolo} 2,1-a ] [ 1,4 ] benzodiazepin-1-karboxylát, cyklopentyl-(S)-12,12a-dihydro-8-jod-9-oxo-9H,llH-azetd[ 2,1-c ] imidazo [ 1,5-a] [ 1,4] benzodiazepin-l-karboxylát, cykloheptyl- (S) -8-chlor-ll,12,13,13a-tetrahy dro-9-oxo-9H-imidazo [1,5-a ] pyrrolo [ 2,1-c) [ 1,4] benzodiazepin-l-karboxylát, benzyl- (S) -8-chlor-12,12a-dihydro-9-oxoS2-cyclopropylethyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-a] [1,4] benzodiazepine -1-carboxylate, cyclohexyl- (S) -12,12a-dihydro-8-methyl-9-oxo-9I-1,1H-azeto [2,1-c] imidazo] 1,5-a] - [1] 4] benzodiazepine-1-carboxylate, rac.-cis-3-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a) pyrrolo} 2,1-a] [1,4] benzodiazepine-1-carboxylate, cyclopentyl (S) -12,12a-dihydro-8-iodo-9-oxo-9H, 11H-azetd [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cycloheptyl (S) -8-chloro-11, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [1] 5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, benzyl (S) -8-chloro-12,12a-dihydro-9-oxoS
-9H,llH-azetof[ 2,1-c ] imidazo [ 1,5-a)] [1,4]henzodiazepin-l-karboxylát, cyklopropylmethyl-(S)-12,12a-dihydro-8-jod-9-oxo-9H,llH-azeto[2,l-c]ímidazo[ 1,5-a ]·[ 1,4| ] benzodiazepin-l-karboxylát, cyklohexyl- (S) -8-br om-12,12a-dihydro-9-0X0-9H,HH-azeto[ 2,1-c] imidazo [1,5-a ][1,4] benzodiazepin-l-karboxylát, cyklopropylmethyl-(S)-8-brom-12,12a-dihydro-9-oxo-9H,llH-azeto]2,l-c]imidazo]l,5-a][1,4] benzodiazepin-l-karboxylát, cyklohexyl-(S )-11,12,13,13n-tetrahydro-8-nitro-9-oxo-9H-imidazo [1,5-a ] pyrrolo[2,1-0] [1,4]benzodiazepin-l-karboxylát a cyklohexyl- (S) -8-kyan-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karb oxylát.-9H, 11H-azetof [2,1-c] imidazo [1,5-a]] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl (S) -12,12a-dihydro-8-iodo-9 -oxo-9H, 11H-azeto [2,1c] imidazo [1,5-a] · [1,4 | benzodiazepine-1-carboxylate, cyclohexyl- (S) -8-bromo-12,12a-dihydro-9-0X0-9H, HH-azeto [2,1-c] imidazo [1,5-a] [1] 4] benzodiazepine-1-carboxylate, cyclopropylmethyl- (S) -8-bromo-12,12a-dihydro-9-oxo-9H, 11H-azeto] 2,1c] imidazo] 1,5-a] [1, 4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -11,12,13,13n-tetrahydro-8-nitro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-O] [1,4] benzodiazepine-1-carboxylate and cyclohexyl- (S) -8-cyano-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-a] -c] [1,4] benzodiazepine-1-carboxylate.
Dalšími reprezentativními zástupci této skupiny sloučenin podle vynálezu jsou následující sloučeniny:Further representative representatives of this class of compounds of the invention are the following compounds:
cyklopropylmethyl-(S j-11,12.13,13a-tetrahydro-9-oxo-8-( trifluormethyl )-9H-imidazo[ 1,5-ai] pyrrolo} 2,1-c ]j [ 1,4 ] benzodiazepin-1-karboxylát, cyklohexyl-(S )-12,12a-dihvdro-9-oxo-8-(trifluormethyl )-9H,llH-azeto[ 2,1-c Jimidazo[l,5-a']'[ 1,4] benzodiazepin-l-karboxylát, cyklopropylmethyl- (S) -12,12a-dihydro-9-oxo-8- (trifluormethyl) -9H,llH-azeto] 2,1-c ] imidazo[ 1,5-aí] [ 1,4] benzodiazepin-l-karboxylát, cyklopropylmethyl- (S )-8-chlor-7-fluor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ l,5-a,]pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-1-karboxylát, cyklohexyl- (S) -8-chlor-7-f luor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo[ l,5-ai]’[ 1,4] benzodiazepin-l-karboxylát, cyklopropylmethyl-(S )-8-chlor-7-fluor-12,12a-dihydro-9-oxo-9H,llH-azeto[ 2,1-c ] imidazo} 1,5-a }} 1,4] benzodiazepin-l-karboxylát, cyklohexyl- (S )-8-fluor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a ] pyrrolo[2,l-c(]j[ 1,4] benzodiazepin-l-karboxylát, cyklopropylmethyl- (S) -8-f luor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo[ 2,1-d ]} 1,4] benzodiazepin-l-karboxylát, cyklohexyl- (S) -8-f luor-12,12a-dihydro-9-oxo-9H,llH-azeto [2,1-c ] imidazo [ 1,5-a ] [1,4] benzodiazepin-l-karboxylát, a cyklopropylmethyl- (S) -8-fluor-12,12a-dihydro-9-oxo-9H,HH-azeto [ 2,1-c ] imidazo[l,5-aj]'[l,4]benzodiazepi.n-l-karboxylát.cyclopropylmethyl- (5,6,1,12,12,13a-tetrahydro-9-oxo-8- (trifluoromethyl) -9H-imidazo [1,5-a] pyrrolo} 2,1-c] [1,4] benzodiazepine- 1-carboxylate, cyclohexyl (S) -12,12a-dihydro-9-oxo-8- (trifluoromethyl) -9H, 11H-azeto [2,1-c] imidazo [1,5-a]] - [1, 4] benzodiazepine-1-carboxylate, cyclopropylmethyl- (S) -12,12a-dihydro-9-oxo-8- (trifluoromethyl) -9H, 11H-azeto] 2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl (S) -8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a , ] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H, 11H-azeto [ 2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl (S) -8-chloro-7-fluoro-12,12a-dihydro-9-oxo 9H, 11H-azeto [2,1-c] imidazo} 1,5-a}} 1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -8-fluoro-11,12,13,13a-tetrahydro -9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl (S) -8-fluoro-11,12,13 , 1 3α-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-d]} 1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -8-fluoro-12, 12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, and cyclopropylmethyl (S) -8-fluoro- 12,12a-Dihydro-9-oxo-9H, HH-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate.
Imidazobenzodiazepiny shora uvedeného obecného vzorce I a jejich farmacenticky použitelné adiční soli s kyselinami se podle tohoto vynálezu připravují tím, že se na sloučeninu obecného vzorce VThe imidazobenzodiazepines of the above general formula (I) and their pharmaceutically acceptable acid addition salts are prepared according to the invention by preparing a compound of the general formula V
v němžin which
X znamená odštěpitelnou skupinu aX represents a leaving group and
R2, R3, R4 a R5 mají shora uvedený význam, působí v přítomnosti báze esterem isokyanoctové kyseliny obecného vzorce VIR 2, R 3, R 4 and R 5 are as defined above, operating in the presence of a base isocyanoacetate ester of formula VI
CN—CH2-COO—(A)„—R1 (VI) v němžCN-CH2-COO- (A) "- R 1 (VI) in which
A, n a R1 mají shora uvedený význam, a získané sloučeniny vzorce I se popřípadě převedou na farmaceuticky použitelné adiční soli s kyselinami.A, R 1 is as defined above, and the compounds of formula I obtained are optionally converted into pharmaceutically usable acid addition salts.
Postupem podle vynálezu se sloučeniny obecného vzorce I připravují ze sloučenin obecného vzorce V a esterů isokyanoctové kyseliny obecného vzorce VI. Odštěpitelnou skupinou, která je ve vzorci V označena symbolem X, je například snadno odštěpitelná fosfinylová skupina, například skupina vzorceAccording to the process of the invention, the compounds of formula I are prepared from compounds of formula V and isocyanic acid esters of formula VI. For example, a leaving group which is indicated by the symbol X in the formula V is an easily cleavable phosphinyl group, for example a group of the formula
OO
II 7 —OP(OR7)2 nebo O —OP(NR8R9)2, kdeII 7 —OOP (OR 7 ) 2 or O —OOP (NR 8 R 9 ) 2, where
R7 znamená nižší alkylovou skupinu aR 7 represents a lower alkyl group and
R8 a R9 znamenají nižší alkylovou skupinu, allylovou skupinu, fenylovou skupinu nebo substituovanou fenylovou skupinu nebo společně s atomem dusíku znamenají nesubstituovaný nebo substituovaný heterocyklický kruh se 3 až 8 členy, jako například morfolinový kruh, dále atom halogenu, alkylthioskupina, aralkylthioskupina, N-nitrosoalkylaminoskupina, alkoxyskupina, merkaptoskupina apod. (jestliže X znamená merkaptoskupinu, pak se jedná u odpovídající sloučeniny vzorce V o iminothiolovou formu odpovídajícího thiolaktamu). Reakce sloučenin obecných vzorců V a VI se provádí v inertním rozpouštědle, jako v dimethylformamidu, hexamethyltriamidu fosforečné kyseliny, dimethylsulfoxidu, tetrahydrofuranu nebo nějakém dalším vhodném organickém rozpouštědle a v přítomnosti báze, která je dostatečně silně bázická, aby vytvořila z esteru isokyanoctové kyseliny vzorce VI aniont. Jako báze jsou vhodné alkoxidy alkulických kovů, jako methoxid sodný, nebo terc.butoxid draselný, hydridy alkalických kovů, jako hydrid sodný, amidy alkalických kovů, jako amid lithný, nebo lithiumdiisopropylamid, terciární aminy, jako triethylamin apod. Reakční teplota se účelně pohybuje mezi asi — 40 °C a asi teplotou místnosti.R 8 and R 9 represent a lower alkyl group, an allyl group, a phenyl group or a substituted phenyl group or together with a nitrogen atom represent an unsubstituted or substituted 3 to 8 membered heterocyclic ring such as a morpholino ring, halo, alkylthio, aralkylthio, N nitrosoalkylamino, alkoxy, mercapto and the like (when X is mercapto, the corresponding compound of formula V is the iminothiol form of the corresponding thiolactam). The reaction of the compounds of formulas V and VI is carried out in an inert solvent such as dimethylformamide, hexamethylphosphoric triamide, dimethylsulfoxide, tetrahydrofuran or some other suitable organic solvent and in the presence of a base sufficiently strong to form an isocyanic acid ester of formula VI . Suitable bases are alkali metal alkoxides such as sodium methoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride, alkali metal amides such as lithium amide or lithium diisopropylamide, tertiary amines such as triethylamine and the like. about -40 ° C and about room temperature.
Postupem podle vynálezu se mohou sloučeniny vzorce I převádět na farmaceuticky použitelné adiční soli s kyselinami. Výroba takovýchto farmaceuticky použitelných adičních solí s kyselinami se provádí podle obecně obvyklých metod. V úvahu přitom přicházejí jak soli s anorganickými kyselinami, tak i soli s organickými kyselinami, například hydrochloridy, hydrobromidy, sírany, methansulfonáty, p-toluensulfonáty, oxaláty apod.According to the process of the invention, the compounds of formula I can be converted into pharmaceutically usable acid addition salts. The preparation of such pharmaceutically usable acid addition salts is carried out according to generally conventional methods. Both inorganic acid salts and organic acid salts such as hydrochlorides, hydrobromides, sulfates, methanesulfonates, p-toluenesulfonates, oxalates and the like are suitable.
Výchozí sloučeniny obecného vzorce V náleží k o sobě známé skupině látek a mohou se vyrábět ze sloučenin obecného vzorce VIIIThe starting compounds of the formula V belong to a group of substances known per se and can be prepared from the compounds of the formula VIII
tVUl] v němžtVUl] in which
R2, R3, R4 a R5 mají shora uvedený význam, a to o sobě známými metodami (srov. například belgické patentové spisy č. 802 233, 833 249 a 865 653, americký patentový spis č. 3 681 341 a J. Org. hemistry 29, 231 (1961)1.R 2 , R 3 , R 4 and R 5 are as defined above by known methods (cf., for example, Belgian Patent Nos. 802 233, 833 249 and 865 653, US Patent Nos. 3,681,341 and J). Org Hemistry 29, 231 (1961) 1.
Sloučeniny obecného vzorce VIII jsou rovněž známými sloučeninami, nebo se dají snadno připravit o sobě známými metodami. Tak se mohou připravovat například reakcí odpovídajícího anhydridu karboxylové kyseliny obecného vzorce IXThe compounds of formula (VIII) are also known compounds or can be readily prepared by methods known per se. Thus, they can be prepared, for example, by reacting the corresponding carboxylic anhydride of the formula IX
y (IX v němžy (IX in which
R4 a R5 mají shora uvedený význam, s aminokyselinou obecného vzorce XR 4 and R 5 are as defined above, with an amino acid of formula X
HOOCHOOC
R' (XI v němžR '(XI in which
R2 a R3 mají shora uvedené významy. Sloučeniny obecného vzorce VIII, v němž jeden ze zbytků R’ a R5 znamená atom halogenu, a druhý znamená atom vodíku, trifluormethylovou skupinu, aminoskupinu, nitroskupinu, kyanoskupinu nebo nižší alkylovou skupinu, se mohou převádět působením kyanidu měďnatého na odpovídající kyanderlváty. Další možnost přeměny sloučenin obecného vzorce VIII spočívá v tom, že se taková sloučenina, ve které jeden ze zbytků R4 a R5 znamená aminoskupinu a druhý znamená atom vodíku, halogenuje v «-poloze k aininoskupině. Dále je možno ve sloučenině obecného vzorce VIII, v němž jeden ze zbytků R4 a R5 znamená aminoskupinu a druhý znamená atom vodíku, halogen, trifluormethylovou skupinu, nitroskupinu, kyanoskupinu nebo nižší alkylovou skupinu, odštěpit aminoskupinu například redukci odpovídající diazoniové soli, nebo nahradit aminoskupinu přes příslušnou diazoniovou sůl atomem halogenu nebo kyanoskupinou nebo nitroskupinou, nebo oxidovat aminoskupinu na nitroskupinu. Konečně lze také sloučeninu obecného vzorce VIII, v němž R4 a R5 znamenají vodík, nitrovat, přičemž se získá odpovídající sloučenina obecného vzorce VIII, v němž R5 znamená nitroskupinu a R4 znamená atom vodíku, nebo je možno odpovídající sloučeninu, ve které jeden ze zbytků R4 a R5 znamená nitroskupinu, redukovat na odpovídající aminosloučeninu.R 2 and R 3 have the abovementioned meanings. Compounds of formula VIII wherein one of R 1 and R 5 is halogen, and the other is hydrogen, trifluoromethyl, amino, nitro, cyano or lower alkyl may be converted by treatment with copper (I) cyanide to the corresponding cyanates. A further possibility for the conversion of compounds of formula VIII is that such a compound in which one of the radicals R 4 and R 5 is an amino group and the other one is a hydrogen atom is halogenated at the n-position to the amino group. Further, in a compound of formula VIII wherein one of R 4 and R 5 is amino and the other is hydrogen, halogen, trifluoromethyl, nitro, cyano or lower alkyl, the amino may be cleaved by, for example, reduction of the corresponding diazonium salt, or replaced amino via an appropriate diazonium salt with a halogen atom or a cyano or nitro group, or oxidize the amino group to a nitro group. Finally, a compound of formula VIII in which R 4 and R 5 are hydrogen may also be nitrated to give the corresponding compound of formula VIII in which R 5 is nitro and R 4 is hydrogen or a corresponding compound in which one of R 4 and R 5 is nitro, reduced to the corresponding amino compound.
Jak již bylo na začátku uvedeno, jsou sloučeniny vzorce I nové. Tyto sloučeniny mají mimořádně cenné farmakologické vlastnosti a mají jen nepatrnou toxicitu.As mentioned at the outset, the compounds of formula I are novel. These compounds have extremely valuable pharmacological properties and have little toxicity.
Tyto sloučeniny mají jako společný znak výraznou afinitu k centrálním benzodiazepinovým receptorům a mají buď výrazné anxiolytické, antikonvulsivní, svalově relaxační a sedativně-hypnotické vlastnosti, nebo/a antagonizují selektivně částečně nebo úplně některé nebo všechny účinky, které rozvíjejí trankvilizačně účinné 1,4-benzodiazepiny nebo další látky prostřednictvím centrálních benzodiazepinových receptorů.As a common feature, these compounds have a pronounced affinity for central benzodiazepine receptors and have either pronounced anxiolytic, anticonvulsive, muscle relaxant and sedative-hypnotic properties, or / and antagonize selectively partially or completely some or all of the effects that develop transquillising 1,4-benzodiazepines or other agents via central benzodiazepine receptors.
Afinita sloučenin obecného vzorce I k centrálním benzodiazepinovým receptorům byla zjišťována metodou popsanou v Life Science 29, 2101 až 2110 (1977) a Science 198, 849 až 851 (1977). Podle této metody se zjišťuje potlačení vazby tritiem značeného diazepamu na specifické benzodiazepinové receptory v kůře mozkové příslušnými testovanými sloučeninami. Jako ICso (50% inhibiční koncentrace) se označuje ta koncentrace příslušné testované látky, která způsobuje 50% potlačení specifické vazby tritiem značeného diazepamu na specifické benzodiazepinové receptory v kůře mozkové.The affinity of the compounds of formula I for central benzodiazepine receptors was determined by the method described in Life Science 29, 2101-2110 (1977) and Science 198: 849-851 (1977). According to this method, suppression of tritium-labeled diazepam binding to specific benzodiazepine receptors in the cortex is determined by the respective test compounds. IC 50 (50% inhibitory concentration) refers to the concentration of the test substance that causes 50% suppression of specific binding of tritium-labeled diazepam to specific benzodiazepine receptors in the cerebral cortex.
Centrální vlastnosti sloučenin obecného vzorce I, které se vyrábějí postupem podle předloženého vynálezu, se mohou prokázat například v dále popsaném antipentetrazolovém testu, který je obecně uznáván pro zjišťování antikonvulsivních vlastností.The central properties of the compounds of formula (I) produced by the process of the present invention can be demonstrated, for example, in the antipentetrazole assay described below, which is generally recognized for detecting anticonvulsant properties.
Při tomto testu na zvířatech se orálně podává samičím exemplářům krys o hmotnosti 60 až 80 g testovaná sloučenina a o 30 minut později se intraperitoneálně aplikuje 120 mg/kg pentetrazolu, který u nechráněných pokusných zvířat způsobuje 1 až 4 minuty po injekci emprosthotonus a tonické napětí předních nebo/a zadních končetin. Na jednu dávku testované látky se používá 10 pokusných zvířat. Po spočítání chráněných pokusných zvířat se zjišťuje hodnota ED50 metodou probitů. EDso znamená takovou dávku, která chrání 50 % pokusných zvířat před záchvaty křečí způsobených pentetrazolem.In this animal test, 60 to 80 g of female rats are orally administered to the test compound and 30 minutes later 120 mg / kg of pentetrazole is administered intraperitoneally, causing unprotected experimental animals 1 to 4 minutes after injection of emprosthotonus and anterior tonic tension; / and hind limbs. 10 test animals are used per dose of test substance. After counting the protected test animals, the ED50 value was determined by the probit method. ED 50 is a dose that protects 50% of the test animals from seizures caused by pentetrazole.
Antagonistické vlastnosti sloučenin vzorce I, tj. jejich schopnost antagonizovat účinky, které rozvíjejí trankvilizačně účinné 1,4-benzodiazepiny nebo další látky prostřednictvím centrálních benzodiazepinových receptorů, se mohou prokázat například dále popsaným, známým trakčním testem. Při tomto testu na zvířatech se zjišťuje schopost testovaných látek antagonizovat sedativní, svalově relaxační účinek narušující motorickou koordinaci, který je vyvolán vyššími dávkami diazepamu.The antagonistic properties of the compounds of formula I, i.e. their ability to antagonize the effects that develop transquilizing 1,4-benzodiazepines or other agents via central benzodiazepine receptors, can be demonstrated, for example, by the known traction test described below. In this animal test, the ability of the test substances to antagonize the sedative, muscle-relaxing effect of disrupting motor coordination, which is induced by higher doses of diazepam, is investigated.
Myši o hmotnosti 17 až 29 g se pověsí za ocásek tak, aby se předními tlapkami dotýkaly horizontálně napnutého drátu (délka cm, výška 20 cm, průměr 1 mm), načež se pokusné zvířata uvolní. Neošetřená kon11The mice weighing 17-29 g are hung by the tail so that they touch the horizontal tensioned wire (length cm, height 20 cm, diameter 1 mm) with the front paws and the test animals are released. Untreated con11
46 10 0 trolní zvířata jsou schopna zachytit se během 3 sekund oběma předními tlapkami alespoň jednou zadní tlapkou trátu. Aplikuje-li se pokusným zvířatům 3 mg/kg i. p. diazepamu, pak ztrácejí tato zvířata své shora uvedené schopnosti, tzn., že nejsou schopna zachytit se během 3 sekund oběma předními tlapkami a alespoň jednou zadní tlapkou horizontálně napnutého drátu. 15 minut po aplikaci diazepamu se pokusným zvířatům aplikuje testovaná sloučenina (perorálně), načež se spočítají ta zvířata, která znovu nabyla shora zmíněné schopnosti, jako EDso se označuje ta dávka, která antagonizuje u 50 % pokusných zvířat účinek diazepamu, tj. tento účinek ruší.Troll animals are capable of being captured by both front paws in at least one back paw within 3 seconds. When treated with 3 mg / kg i.p. of diazepam, the animals lose their abovementioned abilities, i.e., they are unable to get hold of both the front paws and the at least one back paw of the horizontally stretched wire within 3 seconds. 15 minutes after diazepam administration, the test compound (orally) is administered to the test animals and the animals that have regained the abovementioned abilities are counted, and the ED50 is the dose that antagonizes the effect of diazepam in 50% of the test animals. .
V následující tabulce jsou shrnuty výsledky, kterých bylo dosaženo s vybranými zástupci sloučenin definovaných obecným vzorcem I. Kromě toho obsahuje tato tabulka údaje akutní toxicity některých těchto sloučenin (DLso v mg/kg při jednorázové perorální aplikaci krysám).The following table summarizes the results obtained with selected representatives of the compounds of formula (I). In addition, this table contains the acute toxicity data of some of these compounds (DL 50 in mg / kg for a single oral administration to rats).
Sloučenina vzorce I, v němž znamená — (A)n—R1 R2 R3 R4 R5 konfi- ICso antipentetra- trakční toxicita gurace v μΜ/l zolový test, test DLsoCompound of formula (I) in which - (A) n — R 1 R 2 R 3 R 4 R 5 confi-antipentetra-traction toxicity guration in μΜ / l zole test, DLso test
EDso EDso v mg/kg p.ED 50 ED 50 in mg / kg p.
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Selektivní antagonistická složka, jak ji lze prokázat u četných sloučenin vzorce I, má značný terapeutický význam tím, že dovoluje využití žádoucích vlastností (například antioxyolytického nebo antikonvulsivního účinkuj sloučenin vyráběných podle vynálezu, za potlačení přídavných vlastností, které jsou v určitém případě aplikace nežádoucí (například sedativních účinků, svalově relaxačních účinků a účinků narušujících motorickou koordinaci}.The selective antagonist component, as evidenced by the numerous compounds of Formula I, is of considerable therapeutic importance by allowing the desired properties (e.g., antioxyolytic or anticonvulsive effect) of the compounds of the invention to be utilized while suppressing additional properties that are undesirable in a particular application (e.g. {\ f4. sedative effects, muscle relaxant effects and motor coordination disrupting effects}.
Sloučeniny vzorce I a jejich farmaceuticky použitelné adiční soli s kyselinami se mohou používat jako léčiva, například ve formě farmaceutických přípravků. Farmaceutické přípravky se mohou aplikovat orálně, například ve formě tablet, lakovaných tablet, dražé, tvrdých a měkkých želatinových kapslí, roztoků, emulzí nebo suspenzi. Aplikace se však může provádět také rektálně, například ve formě čípků, nebo parenterálně, například ve formě injekčních roztoků.The compounds of formula I and their pharmaceutically usable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injectable solutions.
Za účelem výroby farmaceutických přípravků se mohou látky podle vynálezu aplikovat společně s farmaceuticky inertními, anorganickými nebo organickými nosnými látkami. Jako takovéto nosné látky lze pro tablety, lakované tablety, dražé a tvrdé želatinové kapsle použít například laktózy, kukuřičného škrobu nebo jeho derivátů, mastku, stearové kyseliny nebo jejich solí apod. Pro měkké želatinové kapsle se hodí jako nosné látky například rostlinné oleje, vosky, tuky, polopevné a kapalné polyoly a podobné látky; podle skupenství účinné látky nejsou však u měkkých želatinových kapslí zapotřebí vůbec žádné nosné látky. Pro výrobu roztoků a sirupů se jako nosné látky hodí například voda, polyoly, sacharóza, invertní cukr, glukóza a podobné látky. Pro injekční roztoky se hodí jako nosné látky například voda, alkoholy, polyoly, glycerin, rostlinné oleje a podobné látky. Pro čípky se hodí jako nosné látky například přírodní nebo ztužené oleje, vosky, tuky, polokapalné nebo kapalné polyoly a podobné látky.For the manufacture of pharmaceutical preparations, the compounds according to the invention can be administered together with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. For soft gelatine capsules, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the state of the active substance, however, no carriers are required at all for soft gelatine capsules. Water, polyols, sucrose, invert sugar, glucose and the like are suitable carriers for the preparation of solutions and syrups. For injectable solutions, for example, water, alcohols, polyols, glycerin, vegetable oils and the like are suitable as carriers. For suppositories, suitable carriers are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
Farmaceutické přípravky mohou vedle toho obsahovat ještě konzervační prostředky, pomocná rozpouštědla, stabilizátory, smáčedla, emulgátory, sladidla, barviva, aromatizující prostředky, soli k ovlivňování osmotického tlaku, pufry, povlaky nebo antioxidační prostředky. Dále mohou obsahovat také ještě další terapenticky cenné látky.The pharmaceutical preparations may additionally contain preservatives, co-solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for influencing the osmotic pressure, buffers, coatings or antioxidants. They may also contain other therapeutically valuable substances.
Léčiva, která obsahují sloučeninu vzorce I nebo její farmaceuticky použitelnou adiční sůl s kyselinou, se mohou připravovat tím, že se jedna nebo několik sloučenin vzorce I nebo jejich farmaceuticky použitelných adičních solí a popřípadě jedna nebo několik dalších terapeuticky cenných látek převede na galenickou aplikační formu.Medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof can be prepared by converting one or more compounds of formula I or pharmaceutically acceptable addition salts thereof and optionally one or more other therapeutically valuable substances into a galenic dosage form.
Jak již bylo shora uvedeno, mohou se sloučeniny vzorce I a jejich farmaceuticky použitelné adiční soli používat k léčení chorob a popřípadě k profylaxi chorob, a to zejména k léčení křečí a stavů strachu nebo/ /a při částečném nebo úplném antagonizování něktených nebo všech účinků, které mají trankvilizačně účinné 1,4-benzodiazepiny nebo další látky a které se uplatňují pomocí centrálních benzodiazepinových receptorů. Dávka se může měnit v širokých mezích a lze ji přirozeně v každém individuálním případě přizpůsobit daným podmínkám. Obecně smí při orální aplikaci činit denní dávka asi 0,1 mg až 100 mg.As mentioned above, the compounds of formula I and their pharmaceutically usable addition salts can be used for the treatment of diseases and, optionally, for the prophylaxis of diseases, in particular for the treatment of convulsions and states of fear and / / and to partially or completely antagonize some or all effects. which have transquilizing activity 1,4-benzodiazepines or other substances and which are exerted by central benzodiazepine receptors. The dosage may vary within wide limits and may, of course, be tailored to the circumstances in each individual case. In general, for oral administration, the daily dose may be about 0.1 mg to 100 mg.
Následující příklady předložený vynález blíže objasňují, avšak jeho rozsah v žádném případě neomezují.The following examples illustrate the invention in more detail, but do not limit it in any way.
PříkladExample
a)and)
Směs 23,7 g (0,131 mol) anhydridů 5-íluorisatonové kyseliny, 13,23 g (0,131 mol) L-azetidin-2-karboxylové kyseliny a 150 ml dimethylsulfoxidu se zahřívá po dobu 3 hodin na teplotu 90 °C, potom se odpaří ve vysokém vakuu a zbytek se zahřívá 17 hodin ve vysokém vakuu. Překrystalováním z methanolu se získá (S)-6-fluor-l,10a-dihydroazeto [ 2,1-c] [ 1,4'J benzodiazepin-4,10 (2H,9H) -dion o teplotě tání 216 až 217 °C.A mixture of 5-fluoroisatonic acid anhydrides (23.7 g, 0.131 mol), L-azetidine-2-carboxylic acid (13.23 g, 0.131 mol) and dimethylsulfoxide (150 ml) was heated at 90 ° C for 3 hours. under high vacuum and the residue was heated under high vacuum for 17 hours. Recrystallization from methanol gave (S) -6-fluoro-l, 10a-dihydroazeto [2,1-c] [1,4'J benzodiazepine-4,10 (2H, 9H) -dione, m.p. 216-217 °. C.
b)(b)
K suspenzi 5,5 g (125 mmol J hydridu sodného (55% olejová disperze) ve 100 ml absolutního dimethylformamidu se při teplotě —20 až —10 °C za míchání přidá 25 g (113,5 mmolj (SJ-6-fluor-l,10a-dihydroazeto [ 2,1-c ] [ 1,4] benzodiazepin-4,10 (2H,9H)-dionu, směs se míchá ještě 45 minut při shora uvedené teplotě a potom se přikape při teplotě — 40 °C 18,1 ml (125 mmol) diethylchlorfosfátu.To a suspension of 5.5 g (125 mmol) of sodium hydride (55% oil dispersion) in 100 ml of absolute dimethylformamide was added 25 g (113.5 mmol) of (S-6-fluoro-) at -20 DEG to -10 DEG C. with stirring. 1,10a-dihydroazeto [2,1-c] [1,4] benzodiazepine-4,10 (2H, 9H) -dione, stirred for 45 minutes at the above temperature and then added dropwise at -40 ° C 18.1 mL (125 mmol) of diethyl chlorophosphate.
Mezitím se rozpustí 14,1 g (125 mmolj terc.butoxidu draselného ve 40 ml absolutního dimethylformamidu, roztok se ochladí v lázni acetonu a pevného oxidu uhličitého, k roztoku se přidá 20,9 g (125 mmolj cyklohexylesteru isokyanoctové kyseliny a získaný roztok se přikape při teplotě —20 až —15 °C ke shora uvedené reakční směsi. Potom se reakční směs nechá zahrát na teplotu 20 °C, zneutralizuje se přidáním 7,1 ml ledové kyseliny octové, vylije se na 600 ml ledové vody a směs se třikrát extrahuje methylenchloridem. Organické extrakty se postupně promyjí jednou vodou a jednou nasyceným roztokem chloridu sodného, vysuší se síranem hořečnatým a odpaří se. Zbytek se chromatografuje na silikagelu za vymývání směsí ethylacetátu a n-hexanu (3:2). Překrystalováním z ethylacetátu se získá cyklohexyl- (S) -7-f luor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c j imidazo [ 1,5-a ] [l,4]benzodiazepin-l-karboxylát o teplotě tání 231 až 232 °C.Meanwhile, 14.1 g (125 mmol) of potassium tert-butoxide are dissolved in 40 ml of absolute dimethylformamide, the solution is cooled in an acetone / solid carbon dioxide bath, 20.9 g (125 mmol) of cyclohexyl isocyanate are added dropwise. The reaction mixture was then allowed to warm to 20 ° C, neutralized by the addition of 7.1 ml of glacial acetic acid, poured into 600 ml of ice water and extracted three times. The organic extracts were washed successively with water and once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated, and the residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and n-hexane (3: 2). (S) -7-Fluoro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate at temperature melting 231 to 232 DEG.
240100240100
Analogickým postupem jako je popsán shora se rovněž připraví následující sloučeniny:The following compounds were also prepared in an analogous manner to that described above:
cyklopropylmethyl-(S)-8-chlor-ll,12,13,13a-te trahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [ 2,1c ] [ 1,4] benzodiazepin-l-karboxylát, teplota táni 195 až 196 °C;cyclopropylmethyl- (S) -8-chloro-11,12,13,13-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1c] [1,4] benzodiazepine-1- carboxylate, m.p. 195-196 ° C;
cyklopropylmethyl-(S)-8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c jimídazo[ 1,5-aJ [ 1,4 ] benzodiazepin-l-karboxylát, t. t. 183 až 185 °C (rozklad) (parciálně racemizovaný produkt);cyclopropylmethyl (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-cimidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, mp 183 DEG-185 DEG C. (decomposition) (partially racemized product);
cyklohexyl- (S) -8-brom-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepin-l-karboxylát, teplota tání 167 až 168 °C;cyclohexyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 167-168 ° C;
cyklohexyl- (S) -8-brom-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a Jpyrrolo[2,1-c] [1,4]benzodiazepin-l-karboxylát, teplota tání 167 až 168 °G;cyclohexyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1- carboxylate, m.p. 167-168 ° C;
cyklopropy]methyl-(S)-8-brom-li,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a ] pyrrolo[ 2,1-c )(1,4] benzodiazepin-l-karboxylát; teplota tání 135 až 136 CC;cyclopropylmethyl- (S) -8-bromo-1β, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] (1,4) benzodiazepine m.p. 135 DEG- 136 DEG C .;
cyklopropylmethyl-(S )-8-brom-ll,12,13,13a-tetrahydro-9-oxo-91I-imidazo[ 1,5-a jpyrrolo[ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát; teplota tání 135 až 136 CC;cyclopropylmethyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-91I-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1- carboxylate; mp 135-136 ° C;
cyklopropylmethyl-(S)-12,12a-dihydro-8-jod-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo[1,5-0(] [1,4] benzodiazepin-l-karboxylát, teplota tání 190 až 191 °C;cyclopropylmethyl- (S) -12,12a-dihydro-8-iodo-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1- carboxylate, m.p. 190-191 ° C;
cyklohexyl-(S )-11,12,13,13a-tetrahydro-8- jod-9-oxo-9H-imidazo [1,5-a ] pyrrolo [ 2,1-c ] [ 1,4) benzodlazepin-l-karboxylát, teplota tání 181 až 182 °C;cyclohexyl- (S) -11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodlazepine-1 -carboxylate, m.p. 181-182 ° C;
cyklohexyl- (S) -12,12a-dihydro-8-jod-9-oxo-9H,llH-azeto [ 2,1-c | imidazo [ 1,5-a ]·[ 1,4] benzodiazepin-l-karboxylát, teplota tání 124 až 125 °C;cyclohexyl- (S) -12,12a-dihydro-8-iodo-9-oxo-9H, 11H-azeto [2,1-c | imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, m.p. 124-125 ° C;
cyklopropylmethyl- (S )-11,12,13,13a-tetrahydro-8-jod-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 164 až 165 °C;cyclopropylmethyl- (S) -11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 164-165 ° C;
cyklopropylmethyl-8-chlor-ll,13a-dihydro-9-oxo-9H-imidazo [ 1,5-a J pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 189 až 190 C;cyclopropylmethyl-8-chloro-11,13a-dihydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 189-190 C;
cyklobutylmethyl- (S )-12,12a-dihydro-8-jod-9-oxo-9H,llH-azeío[2,l-c]imidazo[l,5-a][1,4] benzodiazepin-l-karboxylát, teplota tání 169 až 170 °C;cyclobutylmethyl (S) -12,12a-dihydro-8-iodo-9-oxo-9H, 11H-azeolo [2,1c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, temperature mp 169-170 ° C;
cyklopentyl-(S)-12,12a-dihydro-8-jod-9-oxo-9H,llH-azeto[ 2,1-c]imidazo [1,5-a] [1,4] benzodiazepin-l-karboxylát, teplota tání 184 až 185 °C;cyclopentyl (S) -12,12a-dihydro-8-iodo-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 184-185 ° C;
cyklohexyl- (S ] -8-brom-12,12a-dihydro-9-oxo-9H,llH-azeto'[ 2,1-c ] imidazo [ 1,5-a ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 203 až 204 °C;cyclohexyl- (S) -8-bromo-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1- carboxylate, m.p. 203-204 ° C;
cyklopropylmethyl-(S)-8-brom-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo[ 1,5-a ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 212 až 213 °C;cyclopropylmethyl (S) -8-bromo-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 212-213 ° C;
cyklohexyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,llH-ezeto [ 2,1-c ] imidazo [ 1,5-a ] [1,4] benzodiazepin-l-karboxylát, teplota tání 223 až 224 °C;cyclohexyl (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-ezeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 223-224 ° C;
cyklohexyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a jpyrrolo[ 2,1-c)[ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 166 až 167 C;cyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1- carboxylate, m.p. 166 DEG-167 DEG C .;
cyklohexyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-iinidazo [ 1,5-a ] pyrrolo[ 2,1-c j [ 1,4] benzodiazepin-l-karboxylát, teplota tání 210,5 až 212 °C;cyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-cj [1,4] benzodiazepine-1- carboxylate, m.p. 210.5-212 ° C;
cyklobutylmethyl-(S)-9-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c J [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 204 až 205 °C;cyclobutylmethyl- (S) -9-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 204-205 ° C;
tenyl- (S) -8-chlor-ll,12,13,13a-tetrahydro-9 -oxo-9H-iniidazo[ 1,5-a] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 211 až 212°C;thenyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, mp 211-212 ° C;
cyklopropylmethyl-(S)-7-fluor-ll,12,13,13a -tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c 1 [ 1,4] benzodlazepln-l-karboxylát, teplota tání 140 až 142 °C;cyclopropylmethyl- (S) -7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodlazepine-1 -carboxylate, m.p. 140-142 ° C;
cyklohexyl-(S)-12,12a-dihydro-8-methyl-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo [ 1,5-a ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 199 až 200 °C;cyclohexyl- (S) -12,12a-dihydro-8-methyl-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 199-200 ° C;
benzyl-(S)-8-chlor-ll,12,13,13a-tetrahyd.ro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [1,4] benzodiazepin-l-karboxylát, teplota tání 141 až 142 °C;benzyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 141-142 ° C;
1- methylcyklopentyl-8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 190 až 191 °C;1-methylcyclopentyl-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate mp 190-191 ° C;
cyklopentyl-7-chlor-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [ 1,5-a] [ 1,4] benzodiazepin-3-karboxylát, teplota tání 162 až 163 °C;cyclopentyl-7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 162-163 ° C;
2- propinyl- (S) -8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo[ 2,1-q] [1,4] benzodiazepin-l-karboxylát, teplota tání 213 až 214 °C;2-propynyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-q] [1,4] benzodiazepine -1-carboxylate, m.p. 213-214 ° C;
cyklopentylmethyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a ]pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 123 až 124 °C;cyclopentylmethyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 123-124 ° C;
cyklopentylmethyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 112 až 114 °C;cyclopentylmethyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 112-114 ° C;
trans-2-methylcyklohexyl- (S) -8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a ] pyrrolo [ 2,1-c,'] [ 1,4 ] benzodiazepin-1-karboxylát, teplota tání 213 až 215 °C (směs obou diastereomerů v poměru 1:1);trans-2-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c,]] 4] benzodiazepine-1-carboxylate, m.p. 213-215 ° C (1: 1 mixture of both diastereomers);
tetrahydro-2H-pyran-4-yl- (S) -8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-1-karboxylát, teplota tání 226 až 227 °C;tetrahydro-2H-pyran-4-yl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 226-227 ° C;
2-propinyl-7-chlor-5,6-dihydro-5-methyl-6-oxo-4H-imldazo [1,5-a ] [ 1,4 ] benzodiazepin-3-karboxylát, teplota tání 198 až 200 °C;2-propynyl-7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imldazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 198-200 ° C ;
2-propinyl-8-fluor-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a] [l,4]benzodiazepin-3-karboxylát, teplota tání 220 až 222 °C;2-propynyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 220-222 ° C ;
cyklopropylmethyl-7-chlor-5,6-dlhydro-5-methyl-6-oxo-4H-imidazo [ 1,5-a] [ 1,4 ] benzodiazepin-3-karboxylát, teplota tání 194 až 195 °C;cyclopropylmethyl-7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 194-195 ° C;
cyklopropylmethyl-(S)-7,8-dichlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ l,4]benzodiazepin-l-karboxylát, teplota tání 185 až 186 °C;cyclopropylmethyl- (S) -7,8-dichloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 185-186 ° C;
cyklopropylmethyl- (S) -7-chlor-ll,12,13,13a-tetraliydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 146 až 148 °C;cyclopropylmethyl- (S) -7-chloro-11,12,13,13a-tetraliydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 146-148 ° C;
rac.-trans-3-methylcyklohexyl- (S )-8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo(1,5-a,] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-1-karboxylát, teplota tání 130 až 142 °C (směs obou diastereomerů v poměru 1:1);rac.-trans-3-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo (1,5-a,] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 130-142 ° C (1: 1 mixture of both diastereomers);
rac.-cis-3-methylcyklohexyl- (S)-8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo] 2,1-c ] [ 1,4] benzodiazepin-1-karboxylát, teplota tání 142 až 160 °C (směs obou diastereomerů v poměru 1:1);rac.-cis-3-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo] 2,1-c] [ 1,4] benzodiazepine-1-carboxylate, m.p. 142-160 ° C (1: 1 mixture of both diastereomers);
(R,S)-2-cyklohexen-l-yl-(S)-8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a,] pyrrolo] 2, l-o] (1,4] benzodiazepin-1-karboxylát, teplota tání 179 až 180 °C;(R, S) -2-Cyclohexen-1-yl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a,] pyrrolo] 2 mp] (1,4) benzodiazepine-1-carboxylate, m.p. 179-180 ° C;
cykloheptyl- (S) -8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo[ 2,1-c ] [ 1,4)]benzodiazepin-l-karboxylát, teplota tání 179 až 180 °C;cycloheptyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4)] benzodiazepine- 1-carboxylate, m.p. 179-180 ° C;
cyklooktyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a] pyrrolo[ 2,1-c,] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 183 až 184 °C;cyclooctyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine- 1-carboxylate, m.p. 183-184 ° C;
2-cyklohexylethyl- (S) -8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5a ] pyrrolo[ 2,1-c ][ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 131 až 132 °C;2-Cyclohexylethyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 131-132 ° C;
cyklohexyl-7-chlor-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [ 1,5-a] [ 1,4] benzodiazepin -3-karboxylát, teplota tání 208 až 209 °C;cyclohexyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 208-209 ° C;
o-chlorbenzyl- (S) -8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ]pyrrolo[ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 192 až 193 °C;o-chlorobenzyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 192-193 ° C;
m-chlorbenzyl- (S )-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 114 až 116 °C;m-chlorobenzyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 114-116 ° C;
p-chlorbenzyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 183 až 184 °C;p-chlorobenzyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 183-184 ° C;
o-methoxybenzyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 178 až 179 °C;o-Methoxybenzyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 178-179 ° C;
m-methoxybenzyl- (S) -8-chlor-ll,12,13,13a-tetrahydr o-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 131 až 133 °C;m-methoxybenzyl- (S) -8-chloro-11,12,13,13a-tetrahydr o-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 131-133 ° C;
p-methoxybenzyl- (S) -8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 185 až 186 °C;p-methoxybenzyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 185-186 ° C;
benzyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto[ 2,1-c ] imidazo [ 1,5-á] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 180 až 182 °C;benzyl (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 180-182 ° C;
cyklohexyl-[S)-8-amino-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a ]pyrrolo[ 2,1-c] [l,4]benzodiazepin-l-karboxylát, teplota tání 211 až 212 °C;cyclohexyl- [S] -8-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, mp 211-212 ° C;
p-methoxyfenyl-(S)-8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a ] pyrrolo[ 2,1-c] [ l,4i]benzodiazepin-l-karboxylát, teplota tání 210 až 211 °C;p-methoxyphenyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4i] benzodiazepine -1-carboxylate, m.p. 210-211 ° C;
p-chlorf eny 1- (S )-8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a jpyrrolo[ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 241 až 242 °C;p-chlorophenyl 1- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 241-242 ° C;
o-chlorfenyl-(S )-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo[ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 214 až 215 °C;o-chlorophenyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 214-215 ° C;
m-chlorfenyl-(S )-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo[ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 194 až 195 °C;m-chlorophenyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 194-195 ° C;
o-methoxyf enyl- (S)-8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H imidazo [1,5-a jpyrrolo[ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 205 až 206 °C;o-methoxyphenyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine- 1-carboxylate, m.p. 205-206 ° C;
m-methoxyfenyl-(S)-8-chlor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 184 až 185 °C;m-methoxyphenyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 184-185 ° C;
cis-4-methylcyklohexyl- (S) -8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a Jpyrrolo [ 2,1-c ] [1,4 J benzodiazepin-1-karboxylát, teplota tání 176 až 177 °C;cis-4-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 176-177 ° C;
cis-2-methylcyklohexyl- (S) - 8-chlor-ll,12,13,13a-íetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [2,1-c] [1.4] benzodiazepin-1-karboxylát, teplota tání 178 až 180 C (směs obou diastereomerů v poměru 1:1};cis-2-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate, m.p. 178-180 ° C (1: 1 mixture of both diastereomers);
trans-4-methylcyklohexyl- (S) -8-chlor-11,12,13,13a-tetrabydro-9-oxo-9H-imidazo[ 1,5-a ]pyrrolo [ 2,1-c ] [ 1,4j benzodiazepin-1-karboxylát, teplota tání 220 až 221 °C;trans-4-methylcyclohexyl- (S) -8-chloro-11,12,13,13a-tetrabydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 220-221 ° C;
cyklobutylmethyl- [ S) -8-brom-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [2,1-c ] [ 1,4 j benzodiazepin-3-karboxylát, teplota tání 170 až 172 °C;cyclobutylmethyl- [S] -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-3 -carboxylate, m.p. 170-172 ° C;
[R,S )-l-cyklopropylethyl-(S }-8-chlor-,[R, S] -1-cyclopropylethyl- (S) -8-chloro,
-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a)pyrrolo[2,1-c] [ 1,4]benzodiazepin-1-karboxylát, teplota tání 157 až 158 CC;-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, m.p. 157-158 ° C C;
cyklohexyl-(S )-l 1,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ]pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-l-karboxylát, teplota tání 212 až 213 °C;cyclohexyl (S) -1,1,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, mp 212-213 ° C;
cyklobutylmethyl-7-chlor-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [ 1,5-a ] [ 1,4] benzodiazepin-3-karboxylát, teplota tání 181 až 182 °C;cyclobutylmethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 181-182 ° C;
cyklopropylmethyl-(S j-7-fluor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c ] imidazo[ 1,5-a] [1,4]benzodiazepin-l-karboxylát, teplota tání 171 až 172 °C;cyclopropylmethyl- (S, 7-fluoro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 171-172 ° C;
cyklohexyl-(S)-8-kyan-ll,12,13,13a-tetrahyd ro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 246 až 247 °C;cyclohexyl- (S) -8-cyano-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine- 1-carboxylate, m.p. 246-247 ° C;
cyklohexyl- (S} -11,12,13,13a-tetrahydro-8-nitro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo[ 2,l-c ] [1,4 ] ben.zodiazepin-1-karboxylát, teplota tání 204 °C (rozklad);cyclohexyl- (S) -11,12,13,13a-tetrahydro-8-nitro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, mp 204 ° C (dec.);
cyklopropylmelhyl- (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo[2,1-c] [ 1,4]benzodiazepin-l-karboxylát, teplota tání 189 až 190 °C;cyclopropylmethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, temperature mp 189-190 ° C;
cyklopropylmelhyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,llH-ázeto [ 2,1-c ] imidazo[ 1,5-a ] [ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 193 až 194 °C;cyclopropylmethyl (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate mp 193-194 ° C;
cyklopropylmethyl-8-fluor-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [ 1,5-a ][ 1,4 ] benzodiazepin-3-karboxylát, teplota tání 156 až 157 °C;cyclopropylmethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 156-157 ° C;
allyl- (S) -8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo (2,1-c ] [ 1,4]benzodiazepin-l-karboxylát, teplota tání 122 až 123 °C;allyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo (2,1-c] [1,4] benzodiazepine-1 -carboxylate, m.p. 122-123 ° C;
cyklohexyl- (3)-11,12,13,13a-íetrahydro-9-oxo-9- (trif luormethyl )-9H-imidazo [ 1,5- ] pyrrolo[2,l-c] [l,4]benzodiazepin-l-karboxylát, teplota tání 193 až 194 °C;cyclohexyl- (3) -11,12,13,13a-tetrahydro-9-oxo-9- (trifluoromethyl) -9H-imidazo [1,5-] pyrrolo [2,1-c] [1,4] benzodiazepine-1 -carboxylate, mp 193-194 ° C;
cyklohexyl- (S) -8-chlor-7-fluor-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo[ 2,1-c ][ 1,4 ] benzodiazepin-l-karboxylát, teplota tání 163 až 166 °C;cyclohexyl- (S) -8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] ] benzodiazepine-1-carboxylate, m.p. 163-166 ° C;
ro-metboxybenzyl- (S) -8-chlor-12,12a-dihydro -9-oxo-9H,llH-azeto [ 2,1-c ] imidazo [ 1,5,-a ] [1,4] benzodiazepin-l-karboxylát, teplota tátní 126 až 127 °C;? -methoxybenzyl- (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo [1,5, -a] [1,4] benzodiazepine- 1-carboxylate, m.p. 126-127 ° C;
2-cyklopropylethyl- (S) -8-chlor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [ 2,1-c} [ 1,4] benzodiazepin-l-karboxylát, teplota tání 163 až 164 °C;2-cyclopropylethyl- (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c} [1,4] benzodiazepine -1-carboxylate, m.p. 163-164 ° C;
(R,S) -1-cyklopropylethyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,HH-azeto [ 2,1-c ]-imidazo [1,5-a] [l,4]benzodiazepin-l-karboxylát, teplota tání 187 až 188 °C (směs obou diastereomerů).(R, S) -1-Cyclopropylethyl- (S) -8-chloro-12,12a-dihydro-9-oxo-9H, HH-azeto [2,1-c] imidazo [1,5-a] [ 1,4] benzodiazepine-1-carboxylate, m.p. 187-188 ° C (mixture of both diastereomers).
Cyklohexyl-(S)-8-brom-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a ] pyrr olo[2,1-c] [l,4]benzodiazepin-l-karboxylát je možno používat jako účinnou látku k výro bě farmaceutických přípravků, jak je uve děno v následujících příkladech A až C:Cyclohexyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine- The 1-carboxylate can be used as an active ingredient in the manufacture of pharmaceutical preparations as outlined in Examples A to C below:
Příklad AExample A
Obvyklým způsobeni se připravují tablety následujícího složení:Tablets of the following composition are prepared as usual:
mg/tabletamg / tablet
hmotnost náplně kapsle 200weight of capsule filling 200
Účinná látka, laktóza a kukuřičný škrob so nejprve smísí v mísící a potom se rozmělní v rozmělňováním stroji. Směs se poté opět vrátí do inísiče, přidá se mastek a vše se důkladně promísí. Směs se potom pomocí stroje plní do tvrdých želatinových kapslí.The active ingredient, lactose and corn starch are first mixed in a blender and then comminuted in a comminution machine. The mixture is then returned to the mixer, talc is added and mixed thoroughly. The mixture is then filled into hard gelatin capsules by machine.
P ř í k 1 a d CExample 1 a d C
Příprava čípků následujícího složení:Preparations of suppositories of the following composition:
mg/čípek účinná látka 15 základová limota pro přípravu čípků 1 285 celkem 1 300mg / suppository active substance 15 base limit for suppository preparation 1 285 total 1 300
Základová hmota pro přípravu čípků se roztaví ve skleněné nebo v ocelové nádobě, důkladně se promísí a potom se ochladí na teplotu 45 °C. Poté se přidá jemně práškovaná účinná látka a směs se míchá až do stavu, kdy je účinná látka dokonale dispergována. Směs se potom lije do forem ve tvaru čípků vhodné velikosti, potom se čípky vyjmou z forem a jednotlivě se balí do voskovaného papíru nebo do kovové fólie.The suppository base is melted in a glass or steel vessel, mixed thoroughly, and then cooled to 45 ° C. The finely powdered active ingredient is then added and the mixture is stirred until the active ingredient is completely dispersed. The mixture is then poured into molds in the form of suppositories of appropriate size, then the suppositories are removed from the molds and individually wrapped in waxed paper or metal foil.
Místo cyklohexyl-(S)-8-brom-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a jpyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylátu se mohou jako účinné látky uvedené v pří kladech A až C používat dále uvedené slou čeniny vzorce I:Instead of cyclohexyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1 The following compounds of formula I may be used as the active compounds of Examples A to C as follows:
cyklopropylmethyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto[ 2,1-c jimidazo[ 1,5-a] [ 1,4] benzodiazepin-l-karboxylát, cyklohexyl- (S )-8-chlor-7-fluor-ll, 12,13,13a-tetrahydro-9-oxo-9H-imidazo [ 1,5-a ] pyrrolo [2,1-c ] [ 1,4] benzodlazepin-l-karboxylát, cyklopropylmethyl-(Sj-7-fluor-ll,12,13,13a-tetrahydro-9-oxo-9H-imldazo [ 1,5-a ] pyrrolo [ 2,1-c ][ 1,4 ] benzodiazepin-l-karboxylát, cyklohexyl- (S) -8-brom-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a jpyrrolo[ 2,1-c ][ 1,4 ] benzodiazepin-l-karboxylát, (R,S) -1-cyklopr opylethyl- (S) -8-chlor-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a ] pyrrolo [ 2,1-c ] [ 1,4] benzodiazepin-1-karboxylát, cyklohexyl- (S j-7-fluor-12,12a-dihydro-9-oxo-9H,llH-azeto [ 2,1-c j imidazo [1,5-a][1,4] benzodiazepin-l-karboxylát, (R,S) -2-cyklohexen-l-yl- (S) -8-chior-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[ 1,5-a] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-1-karboxylát, (R,S ] -1-cyklopropyletliyl- (S )-8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto[2,l-c]imidazo[ 1,5-a] [1,4]benzodiazepin-l-karboxylát, cyklohexyl- (S j -12,12a-dihydro-8-jod-9-oxo-9H,llH-azeto[2,1-c ]imidazo] 1,5-a] [ 1,4]benzodiazepin-l-karboxylát, cyklopropylmethyl- (S) -7-f luor-12,12a-dihydro-9-oxo-9H-imidazo [ 1,5-a j pyrrolo [ 2,1-c J [ 1,4] benzodiazepin-l-karboxylát, cyklohexyl-(S )-11,12,13,13a-tetrahydro-9-oxo-8-(trif luormethyl ]-9H-imidazo[l, 5-a] pyrrolo [ 2,1-c ] [ 1,4 ] benzodiazepin-l-karboxylát, a cyklohexyl- (S) -8-chlor-12,12a-dihydro-9-oxo-9H,llH-azeto (2,1-c ] imidazo [ 1,5-a ] [ 1,4 ] benzodiazepin-l-karboxylát.cyclopropylmethyl (S) -8-chloro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2,1-cimidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodlazepine-1-carboxylate, cyclopropylmethyl- (S, 7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imldazo [1,5-a] pyrrolo [2,1-c] [1] 4] benzodiazepine-1-carboxylate, cyclohexyl- (S) -8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, (R, S) -1-cyclopropylethyl (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1, 5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclohexyl- (S-7-fluoro-12,12a-dihydro-9-oxo-9H, 11H-azeto [2] 1,1-cis imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, (R, S) -2-cyclohexen-1-yl- (S) -8-chloro-11,12,13 13a-Tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, (R, S) -1-cyclopropyletliyl- (S) -8-Chloro-12,12a-dihydro-9-oxo-9H, 11 H-azeto [2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclohexyl (S-12,12a-dihydro-8-iodo-9-oxo-9H, 11H) -azeto [2,1-c] imidazo] 1,5-a] [1,4] benzodiazepine-1-carboxylate, cyclopropylmethyl (S) -7-fluoro-12,12a-dihydro-9-oxo-9H imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, cyclohexyl (S) -11,12,13,13a-tetrahydro-9-oxo-8- ( trifluoromethyl] -9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate, and cyclohexyl (S) -8-chloro-12,12a-dihydro- 9-oxo-9H, 11H-azeto (2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxylate.
Claims (20)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH446082 | 1982-07-21 | ||
| CS835419A CS246063B2 (en) | 1982-07-21 | 1983-07-19 | Method of imidazobenzodiazepines production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS368285A2 CS368285A2 (en) | 1985-12-16 |
| CS246100B2 true CS246100B2 (en) | 1986-10-16 |
Family
ID=25695524
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS853682A CS246100B2 (en) | 1982-07-21 | 1985-05-22 | Method of imidazobenzodiazepines production |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS246100B2 (en) |
-
1985
- 1985-05-22 CS CS853682A patent/CS246100B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS368285A2 (en) | 1985-12-16 |
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