DE2141443C3 - U-Dihydro-S-phenyl ^ H-M-benzodiazepin-2-ones, their salts, process for their preparation and pharmaceuticals - Google Patents
U-Dihydro-S-phenyl ^ H-M-benzodiazepin-2-ones, their salts, process for their preparation and pharmaceuticalsInfo
- Publication number
- DE2141443C3 DE2141443C3 DE19712141443 DE2141443A DE2141443C3 DE 2141443 C3 DE2141443 C3 DE 2141443C3 DE 19712141443 DE19712141443 DE 19712141443 DE 2141443 A DE2141443 A DE 2141443A DE 2141443 C3 DE2141443 C3 DE 2141443C3
- Authority
- DE
- Germany
- Prior art keywords
- dihydro
- benzodiazepin
- salts
- acid
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 title claims description 7
- 239000011780 sodium chloride Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 4
- 239000003814 drug Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1H-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 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 3
- ADIMAYPTOBDMTL-UHFFFAOYSA-N Oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000001773 anti-convulsant Effects 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001557 benzodiazepines Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960003529 diazepam Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960004535 oxazepam Drugs 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- ANTSCNMPPGJYLG-UHFFFAOYSA-N Chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 2
- 229960004782 Chlordiazepoxide Drugs 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- SRTHRWZAMDZJOS-UHFFFAOYSA-N Lithium hydride Chemical compound [H-].[Li+] SRTHRWZAMDZJOS-UHFFFAOYSA-N 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- -1 alkali metal amides Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000001624 sedative Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- AUAGRMVWKUSEBX-UHFFFAOYSA-N 1,3-dihydro-2$l^{6},1,3-benzothiadiazole 2,2-dioxide Chemical compound C1=CC=C2NS(=O)(=O)NC2=C1 AUAGRMVWKUSEBX-UHFFFAOYSA-N 0.000 description 1
- VOHILFSOWRNVJJ-UHFFFAOYSA-N 2-(bromomethyl)oxolane Chemical compound BrCC1CCCO1 VOHILFSOWRNVJJ-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N Diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N Diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- ZQHQZZHRRUPGSL-UHFFFAOYSA-N FC1=C(C=CC=C1)C1=NCC(=O)N(CC2CCCO2)C2=CC=C(Cl)C=C12 Chemical compound FC1=C(C=CC=C1)C1=NCC(=O)N(CC2CCCO2)C2=CC=C(Cl)C=C12 ZQHQZZHRRUPGSL-UHFFFAOYSA-N 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N Lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FEMRXDWBWXQOGV-UHFFFAOYSA-N Potassium amide Chemical compound [NH2-].[K+] FEMRXDWBWXQOGV-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N Sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VYGSFTVYZHNGBU-UHFFFAOYSA-M trichloromethanesulfonate Chemical compound [O-]S(=O)(=O)C(Cl)(Cl)Cl VYGSFTVYZHNGBU-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
(H)(H)
3535
in der Ri und R2 die in Anspruch 1 angegebene Bedeutung haben, mit einem reaktionsfähigen Estei eines Alkohols der allgemeinen Formel IIIin the Ri and R2 specified in claim 1 Have meaning with a reactive ester of an alcohol of the general formula III
4040
H O C H2 R-3H O C H2 R-3
(III)(III)
in der R3 die in Anspruch 1 angegebene Bedeutung hat, alkyliert und gegebenenfalls die erhaltene Verbindung durch Umsetzen mit einer Säure in ein Salz überführt.in which R 3 has the meaning given in claim 1, alkylated and, if appropriate, the compound obtained is converted into a salt by reaction with an acid.
3. Arzneimittel mit sedierender und antikonvulsiver Wirkung, enthaltend eine Verbindung gemäß Anspruch 1 als Wirkstoff.3. Medicaments with sedating and anticonvulsant effects, containing a compound according to Claim 1 as an active ingredient.
5555
Die Erfindung betrit'ft den in den Ansprüchen gekennzeichneten Gegenstand.The invention relates to the subject matter characterized in the claims.
Von den Halogenatomen sind Fluor- und Chloratome bevorzugt.Of the halogen atoms, fluorine and chlorine atoms are preferred.
Die Salze der Benzodiazepine der allgemeinen Formel I können sich von anorganischen oder organischen Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Salpetersäure, Essigsäure. Maleinsäure, Fumarsäure, Weinsäure, Bernsteinsäure, Citronensäure, Kampfersulfonsäure, Äthansulfonsäure. Ascorbinsäure und Milchsäure, ableiten.The salts of the benzodiazepines of the general formula I can be inorganic or organic Acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid. Maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, camphor sulfonic acid, ethanesulfonic acid. Ascorbic acid and lactic acid.
Beispiele für erfindungsgemäß verwendbare reaktionsfähige Ester sind die Halogenwasserstoffsäureester, wie die Chloride, Bromide und Jodide, sowie die Sulfonsäureester, wie das Methansulfonat, p-Toluolsulfonat, jJ-Naphthalinsulfonat und Trichlormethansulfonat. Das erfindungsgemäße Verfahren kann entweder in Gegenwart einer Base durchgeführt werden, oder zunächst wird die Verbindung der allgemeinen Formel Il mit einer Base unter Bildung des Metallsalzes umgesetzt und anschließend wird dieses mit dem reaktionsfähigen Ester des Alkohols der allgemeinen Formel III zur Umsetzung gebracht. Beispiele für verwendbare Basen sind Alkalimetallhydride, wie Natriumhydrid und Lithiumhydrid, Alkalimetallhydroxide, wie Kaliumhydroxid, Alkalimeitallamide, wie Natriumamid, Kaliumamid und Lithiumamid, Alkylalkaliverbindungen, wie Butyllithium, Phenylalkaliverbindungen, wie Phenyilithium sowie Alkalimetallalkoholate, wie Natriummethylat, Natriumäthylat und K.alium-ten.-butylat. Die Umsetzung wird im allgemeinen in Gegenwart eines organischen Lösungsmittels oder Lösungsmittelgemisches durchgeführt. Beispiele für geeignete Lösungsmittel sind Benzol, Toluol, Xylol, Dimethylformamid, Dimethylacetamid, Diphenyläther, Diäthylenglykoldimethyläther, Dimethylsulfoxid, Methyläthylketon und N-Methylpyrrolidon sowie deren Gemische. Die Umsetzung kann bei Temperaturen von etwa Raumtemperatur bis zum Siedepunkt des verwendeten Lösungsmittels durchgeführt werden.Examples of reactive which can be used according to the invention Esters are the hydrohalic acid esters, such as the chlorides, bromides and iodides, as well as the Sulfonic acid esters, such as methanesulfonate, p-toluenesulfonate, jJ-naphthalene sulfonate and trichloromethanesulfonate. The process according to the invention can either be carried out in the presence of a base, or First, the compound of the general formula II is treated with a base to form the metal salt implemented and then this is with the reactive ester of the alcohol of the general Formula III brought to implementation. Examples of bases that can be used are alkali metal hydrides, such as Sodium hydride and lithium hydride, alkali metal hydroxides such as potassium hydroxide, alkali metal amides such as sodium amide, Potassium amide and lithium amide, alkyl alkali compounds such as butyllithium, phenyl alkali compounds, such as phenylithium and alkali metal alcoholates such as sodium methylate, sodium ethylate and potassium-ten-butylate. The reaction is generally carried out in the presence of an organic solvent or solvent mixture accomplished. Examples of suitable solvents are benzene, toluene, xylene, dimethylformamide, Dimethylacetamide, diphenyl ether, diethylene glycol dimethyl ether, dimethyl sulfoxide, methyl ethyl ketone and N-methylpyrrolidone and mixtures thereof. the Reaction can be used at temperatures from about room temperature to the boiling point Solvent are carried out.
Die Benzodiazepine der allgemeinen Formel I und ihre Salze mit Säuren sind wertvolle Arzneistoffe. Sie haben eine ausgezeichnete sedierende und antikonvulsive Wirkung bei sehr niedriger akuter Toxizität. In dieser Hinsicht sind sie CMordiazepoxid, Oxazepam und Diazepam überlegen.The benzodiazepines of the general formula I and their salts with acids are valuable medicinal substances. she have excellent sedative and anticonvulsant effects with very low acute toxicity. In this In this respect they are superior to CMordiazepoxide, Oxazepam and Diazepam.
Dies geht aus folgenden pharmakologischen Versuchen hervor:This is evident from the following pharmacological tests:
1. Untersuchte Verbindungen1. Connections examined
»A«: l-(j3,j<-Epoxypropyl)-5-(o-fluorphenyl)-7-chlor-l,3-dihydro-2 H-l,4-benzo-"A": 1- (j3, j <-epoxypropyl) -5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2 H-1,4-benzo-
diazepin-2-on,diazepin-2-one,
»B«: 1 -Tetrahydrofurfuryl-5-(o-fluorphenyl)-"B": 1 -Tetrahydrofurfuryl-5- (o-fluorophenyl) -
7-chlor-1,3-dihydro-2 H-1,4-benzo-7-chloro-1,3-dihydro-2 H-1,4-benzo-
diazepin-2-on,diazepin-2-one,
]>C«: l-Tetrahydrofurfuryl-5-^D-chlorphenyl)-]> C ": l-tetrahydrofurfuryl-5- ^ D-chlorophenyl) -
7-chlor-1,3-dihydro-2 H-1,4-benzo-7-chloro-1,3-dihydro-2 H-1,4-benzo-
diazepin-2-on,diazepin-2-one,
»Chlordiazepoxid«:2-Methylamino-5-phenyl-"Chlordiazepoxide": 2-methylamino-5-phenyl-
7-ch!or-3 H-1,4-benzodiazepin-4-oxid,7-ch! Or-3 H-1,4-benzodiazepine-4-oxide,
!■>Oxazepam«:3-Hydroxy-5-phenyl-7-chlor-! ■> Oxazepam «: 3-hydroxy-5-phenyl-7-chloro
l,3-dihydro-2 H-l,4-benzodia/epin-2-on,l, 3-dihydro-2 H-l, 4-benzodia / epin-2-one,
»Diazepam«: l-Methyl-S-phenyl-T-chlor-"Diazepam": l-methyl-S-phenyl-T-chloro-
l,3-dihydro-2 H-l,4-benzodia;?epin-2-on.1,3-dihydro-2 H-1,4-benzodia;? epin-2-one.
2. Versuchsmethoden2. Experimental methods
a) Anti-Pentamethylentetrazolschocktest; E. A. Swinyard, J. Am. Pharm. Assoc. (Sei. Ed.) Bd. 38 (1949), S. 201. Dieser Test erfaßt die Sedierung und antikonvulsive Wirkung.a) anti-pentamethylene tetrazole shock test; E. A. Swinyard, J. Am. Pharm. Assoc. (Sei. Ed.) Vol. 38 (1949), p. 201. This test records the sedation and anticonvulsant effect.
VersuchsmethodikExperimental methodology
Die Unterdrückung der durch Pentamethylentetrazol hervorgerufenen Krämpfe wird am Gruppen von jeweils 10 männlichen Albino-Mäusen mit einem Körpergewicht von 20 + 2 g bestimmt. 30 Minuten nach oraler Verabfolgung der zu untersuchenden Verbindung wird den Mäusen Pentamethylentetrazol in einer Dosis vonThe suppression of convulsions induced by pentamethylenetetrazole is performed on groups of each 10 male albino mice with a body weight of 20 + 2 g were determined. 30 minutes after oral Administration of the test compound will give the mice pentamethylenetetrazole at a dose of
65 mg/kg Körpergewicht intravenös gespritzt. Die ED5Q wird durch Probitanalyse berechnet, wobei sowohl die Unterdrückung der Krämpfe als auch Todesfälle berücksichtigt werden.65 mg / kg body weight injected intravenously. The ED 5 Q is calculated by probit analysis, taking into account both suppression of convulsions and deaths.
b) Akute Toxizität; Die akute Toxizität wird an Gruppen von jeweils 10 männlichen Albino-Mäusen mit
einem Körpergewicht von 20±2g in drei verschiedenen Dosen bestimmt. Die LDm ist die Dosis einer
Verbindung, die 50 Prozent der Versuchstiere innerhalb 10 Tagen nach oraler Verabreichung tötet.
In der Tabelle sind die Ergebnisse zusammengefaßt:b) acute toxicity; The acute toxicity is determined in groups of 10 male albino mice each with a body weight of 20 ± 2 g in three different doses. The LDm is the dose of a compound that will kill 50 percent of the test animals within 10 days of oral administration.
The results are summarized in the table:
Die Benzodiazepine und ihre Salze mit Säuren der allgemeinen Formel I können parenteral oder oral in üblichen Dosierungsformen, z. B. als Tabletten, Dragees, Kapseln, Suspensionen, Lösungen und Elixieren, verabfolgt werden.The benzodiazepines and their salts with acids of the general formula I can be administered parenterally or orally in common dosage forms, e.g. B. as tablets, coated tablets, capsules, suspensions, solutions and elixirs administered will.
Die Beispiele erläutern die Erfindung.The examples illustrate the invention.
Eine Lösung von 5 g 5-(o-Fluorphenyl)-7-chlor-l,3-dihydro-2 H-l,4-benzodiazepin-2-on in 40 ml Dimethylformamid wird zu einer Suspension von 1,25 g Natriummethylat in 40 ml Dimethylformamid gegeben und 1 Stunde auf 50 bis 60°C erwärmt. Nach dem Abkühlen wird das Gemisch mit 2,4 g Epichlorhydrin in 20 ml wasserfreiem Toluol bei einer Temperatur unterhalb 100C versetzt. Danach wird das Gemisch 1 Stunde bei Raumtemperatur und hierauf 3 Stunden bei 60 bis 700C gerührt. Nach dem Abkühlen wird das Reaktionsgemisch in Eiswasser gegossen und mehrmals mit Methylenchlorid extrahiert. Die vereinigten Methyienchloridextrakte werden mit gesättigter Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und zur A solution of 5 g of 5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2 Hl, 4-benzodiazepin-2-one in 40 ml of dimethylformamide becomes a suspension of 1.25 g of sodium methylate in 40 ml Given dimethylformamide and heated to 50 to 60 ° C for 1 hour. After cooling, the mixture is treated with 2.4 g of epichlorohydrin in 20 ml of anhydrous toluene at a temperature below 10 ° C. The mixture is then stirred at room temperature for 1 hour and then at 60 to 70 ° C. for 3 hours. After cooling, the reaction mixture is poured into ice water and extracted several times with methylene chloride. The combined Methyienchloridextrakte are washed with saturated sodium chloride solution, dried over sodium sulfate and used for
Trockene eingedampft. Der Rückstand wird in Chloroform gelöst, an Kieselgel Chromatographien und mit Chloroform eluiert. Das Eluat wird eingedampft und der sirupöse Rückstand aus Diisopropyläther umkristallisiert. Nach nochmaliger Umkristallisation aus einer Evaporated dry. The residue is dissolved in chloroform , chromatographed on silica gel and eluted with chloroform. The eluate is evaporated and the syrupy residue is recrystallized from diisopropyl ether. After another recrystallization from a
Mischung von Diisopropyläther und Methylenchlorid wird das l-(ß,y-Epoxypropyl)-5-(o-fluorphenyl)-7-chlorl,3-dihydro-2 H-l,4-benzodiazepin-2-on in Form farbloser Prismen vom F. 118 bis 119° C erhalten.Mixture of diisopropyl ether and methylene chloride is the 1- (ß, γ-epoxypropyl) -5- (o-fluorophenyl) -7-chlorl, 3-dihydro-2 H-1,4-benzodiazepin-2-one obtained in the form of colorless prisms with a temperature of 118 to 119 ° C.
Eine Lösung von 1 g5-(o-Fluorphenyl)-7-chlor-l,3-dihydro-2 H-l,4-benzodiazepin-2-on in 15 m! Toluol und 15 ml Dimethylformamid wird zu 0,15 g einer 63prozentigen Dispersion von Natriumhydrid in Mineralöl gegeben, und das Gemisch wird 30 Minuten auf 50 bis 6O0C erwärmt. Danach wird das Gemisch mit 0,69 g Tetrahydrofurfurylbromid versetzt und 3 Stunden auf 90 bis 95°C erhitzt. Nach dem Abkühlen wird das Reaktionsgetaisch in Wasser gegossen und mehrmals mit Chloroform extrahiert. Die vereinigten Chloroformextrakte werden mit gesättigter Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und zur Trockene eingedampft. Der Rückstand wird in Chloroform gelöst,A solution of 1 g of 5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2 Hl, 4-benzodiazepin-2-one in 15 m! Of toluene and 15 ml of dimethylformamide to 0.15 g of a 63prozentigen dispersion of sodium hydride in mineral oil, and the mixture is heated for 30 minutes at 50 to 6O 0 C. The mixture is then mixed with 0.69 g of tetrahydrofurfuryl bromide and heated to 90 to 95 ° C. for 3 hours. After cooling, the reaction table is poured into water and extracted several times with chloroform. The combined chloroform extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is dissolved in chloroform,
an Kieselgel Chromatographie« und mit einem Gemisch aus Chloroform und Äthylacetat (1 :1) eluiert. Das Eluat wird eingedampft. Es hinterbleibt 1 -Tetrahydrofurfuryl-5-(o-fluorphenyl)-7-chlor-1,3-dihydro-2 H-1,4-benzodiazepin-2-on als hellgelbes viskoses öl. Die Verbindungon silica gel chromatography and eluted with a mixture of chloroform and ethyl acetate (1: 1). The eluate is evaporated. What remains is 1-tetrahydrofurfuryl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2 H-1,4-benzodiazepin-2-one as a light yellow viscous oil. The connection
hat im IR-Absorptionsspektrum eine Bande bei 1665 cm-1. Das Hydrochlorid schmilzt bei 87 bis 9TC (Zers.).has a band at 1665 cm- 1 in the IR absorption spectrum. The hydrochloride melts at 87 to 9TC (dec.).
In ähnlicher Weise wird das l-Tetrahydrofurfuryl-5-(o-chlorphenyl)-7-chlor-l,3-dihydro-2H-l,4-benzodia- In a similar way, the l-tetrahydrofurfuryl-5- (o-chlorophenyl) -7-chloro-l, 3-dihydro-2H-l, 4-benzodia-
zepin-2-on als hellgelbes viskoses öl erhalten, das im IR-Absorptionsspektrum eine Bande bei 1665 cm1 aufweist. Das Hydrochlorid schmilzt bei 90 bis 95°C (Zers.).zepin-2-one obtained as a pale yellow viscous oil which has a band at 1665 cm 1 in the IR absorption spectrum. The hydrochloride melts at 90 to 95 ° C (decomp.).
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7441070 | 1970-08-24 | ||
| JP45074410A JPS4835273B1 (en) | 1970-08-24 | 1970-08-24 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2141443A1 DE2141443A1 (en) | 1972-03-02 |
| DE2141443B2 DE2141443B2 (en) | 1977-01-13 |
| DE2141443C3 true DE2141443C3 (en) | 1977-08-25 |
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