EP0000716A2 - Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant - Google Patents
Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant Download PDFInfo
- Publication number
- EP0000716A2 EP0000716A2 EP78100454A EP78100454A EP0000716A2 EP 0000716 A2 EP0000716 A2 EP 0000716A2 EP 78100454 A EP78100454 A EP 78100454A EP 78100454 A EP78100454 A EP 78100454A EP 0000716 A2 EP0000716 A2 EP 0000716A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- hydrogen
- pharmaceutically acceptable
- acceptable salt
- cyano
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- SCHRRVXSPNLRMS-UHFFFAOYSA-N 3h-pyrrolo[2,1-b][3]benzazepine Chemical class C1=CN2CC=CC2=CC2=CC=CC=C21 SCHRRVXSPNLRMS-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 13
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims abstract 6
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 229960001340 histamine Drugs 0.000 claims description 3
- 229940076279 serotonin Drugs 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- -1 piperidinyl magnesium halide Chemical class 0.000 abstract description 6
- 230000000794 anti-serotonin Effects 0.000 abstract description 5
- 239000003420 antiserotonin agent Substances 0.000 abstract description 5
- 230000001387 anti-histamine Effects 0.000 abstract description 4
- 230000018044 dehydration Effects 0.000 abstract description 4
- 238000006297 dehydration reaction Methods 0.000 abstract description 4
- 239000000164 antipsychotic agent Substances 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract 1
- MVNSDNLKXSKZPJ-UHFFFAOYSA-N pyrrolo[2,1-b][3]benzazepin-11-one Chemical compound C1=CC2=CC=CC=C2C(=O)C2=CC=CN21 MVNSDNLKXSKZPJ-UHFFFAOYSA-N 0.000 abstract 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000000561 anti-psychotic effect Effects 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- CYXNUEOUKUMAIF-UHFFFAOYSA-N 11-(1-methylpiperidin-4-yl)-5,6-dihydropyrrolo[2,1-b][3]benzazepin-11-ol Chemical compound C1CN(C)CCC1C1(O)C2=CC=CC=C2CCN2C=CC=C21 CYXNUEOUKUMAIF-UHFFFAOYSA-N 0.000 description 2
- GLILMEKKDFAGIW-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)-5,6-dihydropyrrolo[2,1-b][3]benzazepine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCN2C=CC=C21 GLILMEKKDFAGIW-UHFFFAOYSA-N 0.000 description 2
- HVUHGANPHHJBTO-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)pyrrolo[2,1-b][3]benzazepine-9-carbonitrile Chemical compound C1CN(C)CCC1=C1C2=CC(C#N)=CC=C2C=CN2C=CC=C21 HVUHGANPHHJBTO-UHFFFAOYSA-N 0.000 description 2
- WFEMZZIWWBHTKO-UHFFFAOYSA-N 5,6-dihydropyrrolo[1,2-c][3]benzazepin-11-one Chemical compound C1CC2=CC=CC=C2C(=O)C2=CC=CN21 WFEMZZIWWBHTKO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 235000011147 magnesium chloride Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- PLDCWFRDWHUWHR-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)pyrrolo[2,1-b][3]benzazepine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CN2C=CC=C21 PLDCWFRDWHUWHR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PSJCYCLXEVGEAI-UHFFFAOYSA-N 9-bromo-11-(1-methylpiperidin-4-ylidene)pyrrolo[2,1-b][3]benzazepine Chemical compound C1CN(C)CCC1=C1C2=CC(Br)=CC=C2C=CN2C=CC=C21 PSJCYCLXEVGEAI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- PTSSXLQWBTWOPU-UHFFFAOYSA-M [Cl-].CN1CCC([Mg+])CC1 Chemical compound [Cl-].CN1CCC([Mg+])CC1 PTSSXLQWBTWOPU-UHFFFAOYSA-M 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000008038 benzoazepines Chemical class 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- YHLAXQQNQYQQBC-UHFFFAOYSA-N ethanol;2,2,2-trichloroacetic acid Chemical compound CCO.OC(=O)C(Cl)(Cl)Cl YHLAXQQNQYQQBC-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- UZJBOHHDWXQTEF-UHFFFAOYSA-N pocl3 pyridine Chemical compound ClP(Cl)(Cl)=O.C1=CC=NC=C1 UZJBOHHDWXQTEF-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- PLKKXWBJOVTVEU-UHFFFAOYSA-N pyrrolo[2,3-i][1]benzazepine Chemical class C1=CC=NC2=C3C=CN=C3C=CC2=C1 PLKKXWBJOVTVEU-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical class [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention is concerned with novel pyrrolo[2,lb][3]benzazepines with a piperidinylidene group in the 11-position which are active as antipsychotic, antiserotonin, and antihistaminic agents.
- Cyproheptadine and several derivatives are known tricyclic compounds with antiserotonin and antihistamine activity as described in U.S. Patent 3,014,911. It is also known that the cyano-and trifluoromethylthio- derivatives of cyproheptadine, as described in U.S. Patents 3,988,342 and 4,031,222 are antipsychotic agents.
- the compounds of the present invention have the following structural formula: or pharmaceutically acceptable salt thereof, wherein the dotted line represents saturation or
- a preferred embodiment of the nowel compounds of this invention is the compourd of structural formula: or pharmaceutically acceptable salt thereof, wherein X, Y, and R are as defined above.
- a still more preferred embodiment is where one of X and Y is hydrogen, and the other is hydrogen, chloro, cyano, or trifluoromethylthio.
- compositions prepared by conventional means, include the hydrochloride, maleate, sulfate, phosphate, citrate, tartrate, succinate, and the like.
- novel processes of this invention comprise treatment of a pyrrolobenzazepinllone, II, with a lRpiperidin4ylmagnesium chloride, followed by dehydration of the resulting carbinol compound, III, to the final product, I, as illustrated below.
- the ketone starting material (II) is treated with the Grignard reagent in a solvent such as tetrahydrofuran, ether, or the like at a temperature of from about -10°C. to reflux for from about 10 minutes to about 10 hours to provide the 11-hydroxy intermediate, (III), which species is then dehydrated by treatment with an acid such as hydrochloric, oxalic, trifluoroacetic, formic, acetic, trifluoroacetic anhydride, trichloroacetic acid, phosphorous oxychloride with a tertiary amine, or the like at a temperature of from about 0 to about 100°C.
- a solvent such as tetrahydrofuran, ether, or the like
- an acid such as hydrochloric, oxalic, trifluoroacetic, formic, acetic, trifluoroacetic anhydride, trichloroacetic acid, phosphorous oxychloride with a ter
- novel compounds of this invention of structure I or a pharmaceutically acceptable salt thereof possess antipsychotic, antiserotonin and antihistaminic activity and may be administered to patients requiring antipsychotic, antiserotonin and/or antihistamine treatment in any of the usual pharmaceutical forms such as powders, capsules, tablets, elixirs, and aqueous suspension, in the amount of from about 1 to about 750 mgms per day, preferably in divided doses taken 2 to 4 times daily. Sterile solutions for injection purposes would be administered in amounts of from 0.1 to 150 mgms per day.
- 6,11-Dihydro-5H-pyrrolo[2,1-b][3]benza- zepin-11-one (7 g., 35.6 mmol) is dissolved in 100 ml. of tetrahydrofuran and to it is added with stirring 200 ml. of tetrahydrofuran containing 0.425 mmoles/ml. of 1-methyl-piperidin-4-ylmagnesium chloride. After a few minutes of stirring, 40 ml. of water is added and after another few minutes the mixture is diluted with methylene chloride. The organic phase is separated, dried over magnesium sulfate, filtered, and concentrated to dryness.
- Step B there may be substituted for the oxalic acid in ethanol dehydration system (1) used therein, trifluoroacetic anhydridechloroform (2), trifluoroacetic acid (3), hydrogen chloride in chloroform (4), phosphorus oxychloride-pyridine (5), trichloroacetic acid-ethanol (6), acetic acid (7), or formic acid (8).
- aqueous phase is extracted two times with benzene, once with ether and the combined- benzene-ether extracts are washed successively with dilute sodium cyanide, water, dilute ammonium hydroxide, and water. Upon drying over sodium sulfate the solvents are evaporated in vacuo to give 1-methyl-4-[9-cyano-11H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine as an oil (5.0 g., 94%). Trituration with acetonitrile gives a solid (3.6 g., m.p. 156-159°C.). An analytical sample is obtained after one recrystallization from acetonitrile, m.p. 158-161°C.
- a typical tablet containing 10 mg. 1-methyl,-4-[9-cyano-11H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine per tablet is prepared by mixing together with the active ingredient calcium phosphate, lactose and starch in the amounts shown in the tables below. After these ingredients are thoroughly mixed, the dry mixture is blended for an additional three minutes. This mixture is then compressed into tablets weighing approximately 134 mg. each.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US819739 | 1977-07-28 | ||
| US05/819,739 US4148903A (en) | 1977-07-28 | 1977-07-28 | Antipsychotic, antiserotonin and antihistaminic pyrrolo[2,1-b][3]benzazepines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP0000716A2 true EP0000716A2 (fr) | 1979-02-21 |
| EP0000716A3 EP0000716A3 (en) | 1979-05-16 |
| EP0000716B1 EP0000716B1 (fr) | 1983-03-09 |
Family
ID=25228916
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100454A Expired EP0000716B1 (fr) | 1977-07-28 | 1978-07-20 | Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4148903A (fr) |
| EP (1) | EP0000716B1 (fr) |
| JP (1) | JPS5427597A (fr) |
| DE (1) | DE2862196D1 (fr) |
| DK (1) | DK328478A (fr) |
| IE (1) | IE47146B1 (fr) |
| IT (1) | IT1107463B (fr) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992006981A1 (fr) * | 1990-10-10 | 1992-04-30 | Schering Corporation | Imidazobenzazepines substituees et imidazopyridazepines |
| EP0518434A1 (fr) * | 1991-06-13 | 1992-12-16 | Janssen Pharmaceutica N.V. | Dérivés d'imidazo(1,2-a)(pyrrolo, thieno ou furano)(3,2-d)azépine, compositions et méthodes d'utilisation |
| EP0518435A1 (fr) * | 1991-06-13 | 1992-12-16 | Janssen Pharmaceutica N.V. | Dérivés d'imidazo[2,1-b][3]benzazépine, compositions et méthode d'utilisation |
| US10617695B2 (en) | 2006-03-31 | 2020-04-14 | Vistakon Pharmaceuticals, Llc | Ophthalmic compositions containing alcaftadine |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4242349A (en) * | 1979-10-01 | 1980-12-30 | Merck & Co., Inc. | Orexigenic use of pyrrolo[2,1-b][3]benzazepines |
| ITRM20040178A1 (it) * | 2004-04-07 | 2004-07-07 | Sigma Tau Ind Farmaceuti | Composti ad attivita' antipsicotica atipica. |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3014911A (en) * | 1958-09-29 | 1961-12-26 | Merck & Co Inc | Derivatives of dibenzo[a, e]cycloheptatriene |
| US3988342A (en) * | 1972-08-14 | 1976-10-26 | Merck & Co., Inc. | Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene |
| FR2315935A1 (fr) * | 1975-07-02 | 1977-01-28 | Merck & Co Inc | Pyrrolo(2,1-b |
| US4031222A (en) * | 1975-12-22 | 1977-06-21 | Merck & Co., Inc. | Trifluoromethylthio (and sulfonyl) derivatives of cyproheptadine analogs |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA746508A (en) * | 1966-11-15 | D. Marcus Arnold | Dibenzocycloheptenes | |
| US3458522A (en) * | 1967-05-17 | 1969-07-29 | Sandoz Ag | 4-piperidine substituted benzocycloheptaoxazoles and benzocycloheptathiazoles |
| US4056536A (en) * | 1976-06-29 | 1977-11-01 | Merck & Co., Inc. | Pyrrolo[2,1-b][3]benzazepines |
-
1977
- 1977-07-28 US US05/819,739 patent/US4148903A/en not_active Expired - Lifetime
-
1978
- 1978-07-20 EP EP78100454A patent/EP0000716B1/fr not_active Expired
- 1978-07-20 DE DE7878100454T patent/DE2862196D1/de not_active Expired
- 1978-07-20 IT IT50403/78A patent/IT1107463B/it active
- 1978-07-24 DK DK328478A patent/DK328478A/da not_active Application Discontinuation
- 1978-07-27 IE IE1517/78A patent/IE47146B1/en unknown
- 1978-07-28 JP JP9167378A patent/JPS5427597A/ja active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3014911A (en) * | 1958-09-29 | 1961-12-26 | Merck & Co Inc | Derivatives of dibenzo[a, e]cycloheptatriene |
| US3988342A (en) * | 1972-08-14 | 1976-10-26 | Merck & Co., Inc. | Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene |
| FR2315935A1 (fr) * | 1975-07-02 | 1977-01-28 | Merck & Co Inc | Pyrrolo(2,1-b |
| US4031222A (en) * | 1975-12-22 | 1977-06-21 | Merck & Co., Inc. | Trifluoromethylthio (and sulfonyl) derivatives of cyproheptadine analogs |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992006981A1 (fr) * | 1990-10-10 | 1992-04-30 | Schering Corporation | Imidazobenzazepines substituees et imidazopyridazepines |
| US5393753A (en) * | 1990-10-10 | 1995-02-28 | Schering Corporation | Substituted imidazobenzazepines |
| EP0518434A1 (fr) * | 1991-06-13 | 1992-12-16 | Janssen Pharmaceutica N.V. | Dérivés d'imidazo(1,2-a)(pyrrolo, thieno ou furano)(3,2-d)azépine, compositions et méthodes d'utilisation |
| EP0518435A1 (fr) * | 1991-06-13 | 1992-12-16 | Janssen Pharmaceutica N.V. | Dérivés d'imidazo[2,1-b][3]benzazépine, compositions et méthode d'utilisation |
| WO1992022551A1 (fr) * | 1991-06-13 | 1992-12-23 | Janssen Pharmaceutica N.V. | DERIVES D'IMIDAZO[2,1-b][3]BENZAZEPINE, COMPOSITIONS ET METHODE D'UTILISATION |
| WO1992022553A1 (fr) * | 1991-06-13 | 1992-12-23 | Janssen Pharmaceutica N.V. | DERIVES D'IMIDAZO[1,2-a](PYRROLO, THIENO OU FURANO)[3,2-d]AZEPINE, COMPOSITIONS ET METHODES D'UTILISATION |
| US5461050A (en) * | 1991-06-13 | 1995-10-24 | Janssen Pharmaceutica N.V. | Imidazo[1,2-a](pyrrolo, thieno or furano) [3,2a-d]azepine derivatives, compositions and methods of use |
| US5468743A (en) * | 1991-06-13 | 1995-11-21 | Janssen Pharmaceutica N.V. | Imidazo[2,1-b]benzazepine derivatives, compositions and method of use |
| CN1070368C (zh) * | 1991-06-13 | 2001-09-05 | 詹森药业有限公司 | 含咪唑并[2,1－b][3]苯并吖庚因衍生物的药物组合物的制备方法 |
| US10617695B2 (en) | 2006-03-31 | 2020-04-14 | Vistakon Pharmaceuticals, Llc | Ophthalmic compositions containing alcaftadine |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2862196D1 (en) | 1983-04-14 |
| US4148903A (en) | 1979-04-10 |
| IT7850403A0 (it) | 1978-07-20 |
| IT1107463B (it) | 1985-11-25 |
| IE781517L (en) | 1979-01-28 |
| DK328478A (da) | 1979-01-29 |
| EP0000716B1 (fr) | 1983-03-09 |
| IE47146B1 (en) | 1983-12-28 |
| JPS5427597A (en) | 1979-03-01 |
| EP0000716A3 (en) | 1979-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE60020994T2 (de) | Neue verwendung sowie neue n-azabicycloamid-verbindungen | |
| US4210648A (en) | II-Aminoacyl-5,11-dihydro-6H-pyrido(2,3-B) (1,4)benzodiazepin-6-ones and salts thereof | |
| DE19636769A1 (de) | 3-Substituierte Pyrido [4',3':4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung | |
| EP0167901A2 (fr) | Composés actifs | |
| US4808718A (en) | Fused polycyclic and bridged compounds useful as calcium channel blockers | |
| EP0000716B1 (fr) | Dérivés de la pyrrolo(2,1-b)(3)benzazépine, procédé pour leur préparation et compositions pharmaceutiques les contenant | |
| EP0085899B1 (fr) | Pyridobenzodiazépinones, procédé pour leur préparation et compositions pharmaceutiques les contenant | |
| DE60204582T2 (de) | Neue heteroaromatische amidderivate von 3beta aminoazabicyclooctanen, verfahren zu ihrer herstellung und ihre therapeutische verwendung | |
| EP0288048A2 (fr) | Dérivés de benzo- et thiéno-3,4-dihydropyridine, procédés pour leur préparation et médicaments les contenant | |
| US3470179A (en) | 4-substituted-3,4-dihydroquinazolines | |
| EP1379234B1 (fr) | Aminobenzophenones et aminobenzoylpyridines halogenees en tant qu'inhibiteurs de l'il-1 et du tnf | |
| EP0233483B1 (fr) | Pyrrolo[1,2-a][4,1]benzoxazépines, procédé pour leur préparation, compositions pharmaceutiques contenant ces composés et application therapeutique | |
| US3981877A (en) | Piperidylidene derivatives of carboxy-5H-dibenzo[a,d]cycloheptene | |
| CS244107B2 (en) | Method of substituted pyrdoido-(1,2-a)pyrimidines production | |
| US4616023A (en) | Pharmaceutical compositions of 4-(dibenzo-[a,d]cycloalkenyl)piperazine compounds and methods | |
| US4977176A (en) | Pilocarpine compounds which are used as pharmaceutical agents | |
| US4032640A (en) | 4H-Benzo[4,5]cyclohepta[1,2-b]thiophenes | |
| EP0270692A1 (fr) | Agent antiarythmique | |
| CA1113091A (fr) | Pyrrolo [2,1-b][3] benzazepines ayant un groupe piperidinylidene en position 11 | |
| DE2233682A1 (de) | 2- eckige klammer auf 3-(subst. aminomethyl)-4-h-1,2,4-triazol-4-yl eckige klammer zu -benzophenone, ein verfahren zu ihrer herstellung sowie diese enthaltende arzneimittel | |
| US4195091A (en) | Appetite stimulating pyrrolo[2,1-b][3]benzazepines | |
| US4659707A (en) | Aminoacyl derivatives of 4,9-dihydro-10H-pyrido[3,2-b]thieno[3,2-e][1,4]diazepinone and of 4,9-dihydro-10H-pyrido[3,2-b]thieno[3,4-e][1,4]diazepinone, their preparation and pharmaceutical compositions containing them | |
| EP0264232A1 (fr) | Dérivés de l'azétidinone-2 | |
| US4835174A (en) | Pilocarpine derivatives | |
| US5451584A (en) | N-alkynyl carboxamides as sertonergic agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL SE |
|
| PUAL | Search report despatched |
Free format text: ORIGINAL CODE: 0009013 |
|
| AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL SE |
|
| 17P | Request for examination filed | ||
| GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
| AK | Designated contracting states |
Designated state(s): BE CH DE FR GB LU NL SE |
|
| REF | Corresponds to: |
Ref document number: 2862196 Country of ref document: DE Date of ref document: 19830414 |
|
| ET | Fr: translation filed | ||
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 19830720 Year of fee payment: 6 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19830731 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19840430 Year of fee payment: 7 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19840601 Year of fee payment: 7 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 19840630 Year of fee payment: 7 Ref country code: SE Payment date: 19840630 Year of fee payment: 7 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 19840830 Year of fee payment: 7 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Effective date: 19850721 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Effective date: 19850731 |
|
| BERE | Be: lapsed |
Owner name: MERCK & CO. INC. Effective date: 19850731 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19870731 Year of fee payment: 10 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19880720 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Effective date: 19880731 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19890201 |
|
| NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
| GBPC | Gb: european patent ceased through non-payment of renewal fee | ||
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19890331 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19890401 |
|
| REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
| EUG | Se: european patent has lapsed |
Ref document number: 78100454.4 Effective date: 19860729 |
|
| PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |