IE43727B1 - Dibenzo/b,e//1,4/diazepines - Google Patents
Dibenzo/b,e//1,4/diazepinesInfo
- Publication number
- IE43727B1 IE43727B1 IE2098/76A IE209876A IE43727B1 IE 43727 B1 IE43727 B1 IE 43727B1 IE 2098/76 A IE2098/76 A IE 2098/76A IE 209876 A IE209876 A IE 209876A IE 43727 B1 IE43727 B1 IE 43727B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- chg
- carbon atoms
- electrolyte
- formula
- Prior art date
Links
- 150000004908 diazepines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000003839 salts Chemical group 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 239000003792 electrolyte Substances 0.000 abstract 8
- 239000007788 liquid Substances 0.000 abstract 3
- 239000004020 conductor Substances 0.000 abstract 1
- 238000009713 electroplating Methods 0.000 abstract 1
- 238000007747 plating Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- -1 alkoxy radical Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Electroplating Methods And Accessories (AREA)
Abstract
PURPOSE: To decrease the supply quantity of electrolyte and to simplify a device by receiving electrolyte fed from below a pair of electrodes in a trap above the electrode and transferring it to a nozzle through a communicative pipe to supply it to another pair of electrodes. CONSTITUTION: Between electrodes 5, 5' vertically arranged contrary to each other is made to travel a strip 2 through conductor rolls 3, 3' to give the strip electroplating by jetting electrolyte. In the vertical jet plating device, primary liquid supply nozzles 4 are arranged under one electrolytic cell and electrolyte is fed from below upwards between the electrodes 5. The electrolyte is received in a transit electrolyte trap 8 arranged above and further transferred through a communicative pipe (not illustrated) to a second liquid supply nozzle 9 arranged above the other electrolytic cell. From here, further the electrolyte is fed from above downwards between the electrodes 5' and discharged to a liquid receiver tank 1 through an electrolyte discharge device 10[JPS5239689A]
Description
The present invention relates to dibenzo[b,e][l,4]diazepines.
The present invention provides compounds of formula I, wherein is hydrogen, alkyl of 1 to 4 ca'rbon atoms, hydroxyalkyl of 2 to 4 carbon atoms, or alkoxyalkyl of 2 to 5 carbon atoms in the aggregate thereof, Rg is fluorine or chlorine, and Rg is alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 2 to 4 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms in the aggregate thereof, or alkenyl of 3 or 4 carbon atoms, with the proviso that when Rg is methyl, R2 is fluorine. 3727 Alkyl in has preferably 1 to 2 carbon atoms.
The alkoxy moiety in alkoxyalkyl or the hydroxy moiety in hydroxyalkyl is preferably located in the terminal position of the alkylene chain which preferably 5 has 2 or 3, especially 2, carbon atoms. The alkoxy radical in alkoxyalkyl is preferably methoxy. The double bond in alkenyl is in the 2,3 or 3,4 position. Alkenyl is preferably allyl or 2-methyl-2-propenyl.
R^ is preferably methyl. R^ is preferably alkyl 10 or alkoxyalkyl, especially alkyl. R^ especially is methyl, ethyl or n-propyl.
The present invention also provides a process for the production of a compound of formula I as defined above, which comprises reacting a compound of formula II, wherein R^ and R^ are as defined above, and X is a leaving group, with a compound of formula III, HN, v_y N-R, III - 2 wherein R^ is as defined above.
The process may be effected in conventional manner for such reactions.
In the compound of formula II X is attached by a covalent or ionic bond to the carbon atom, and signifies, for example, amino which may be substituted by one or two alkyl groups of 1 to 4 carbon atoms, especially 1 carbon atom; sulfhydryl, alkoxy or alkylthio of 1 to 4 carbon atoms, for example methoxy or methylthio, p-nitrobenzylthio or tosyloxy, or preferably halogen, especially chlorine.
The process is conveniently effected at temperatures between 50° and 170°C in an inert organic solvent, for example xylene or dioxane.
The starting materials of formula II may be prepared in known manner, e.g. as described herein, for example via the corresponding lactam, e.g. by reaction With phosphorusoxychloride.
Free base forms of compounds of formula I may be converted into the acid addition salt forms in conventional manner and vice versa. A suitable acid is hydrochloric acid.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. 3 7.2 EXAMPLE 1: 5-n~Propyl-8-chloro-ll-(4~methyl-l-piperazinyl) .74 g of 5-n-propyl-8-chloro-10,ll-dihydro-5Hdibenzo[b,e] [l,4]diazepin-13.-one, 30 ml of phosphorusoxy5 chloride and 1 ml of Ν,Ν-dimethylaniline are boiled for 3 hours. The resulting solution of the imido-chloride of the lactam is evaporated to dryness, the residue evaporated twice more after the addition of xylene, and then boiled for 6 hours with 20 ml of dioxane and 25 ml of N-methyl10 piperazine. The resulting mixture is then concentrated as far as possible, and the residue is partitioned between aqueous ammonia and ether. The ethereal phase is washed with water, and extracted continuously with dilute acetic acid to remove the basic components. The base is ret free by the addition of sodium hydroxide and taken up in chloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulphate and concentrated to dryness. The residue is taken up in ether, filtered through basic aluminium oxide and crystallized from ether/petroleum ether to give the title compound; M.Pt. 120° - 122°C.
The starting materials may be obtained as follows :2-Nitro-4-chloro-diphenylamine-2'-carboxylic acid is converted via the acid chloride into 2-nitro-4-chlorodiphenylamine~2‘-carboxylic acid methyl ester (M.Pt. 155° 25 156°). This is reacted with n-propyl iodide in the - 4 43727 presence of sodium hydride in hexamethylphosphoric acid triamide to form N-n-propyl-2-nitro-4~chloro~diphenylamine-2'-carboxylic acid methyl ester. This is reduced in the presence of Raney nickel in ethyl acetate to form N-n-propyl-2-amino-4-chloro-diphenylamine-2’-carboxylic acid methyl ester. This is cyclized in the presence of sodium amide in boiling dioxane over Several hours to yield the starting material used in Example 1.
In analogous manner to that described in Example 1, the following compounds of formula 1 may be obtained, wherein:- IxampleR2R1R3 M.Pt.° 2 ClCH3C2H5 145-146° 3 CliCH3 CIIgCHgOCHg 160-161° 4 F ch3C2HS 133-135° 5 FCH3 n-C3H7 95-97° and 115-117° 6 FCH3nC4Hg 124-125° 7 ClCH3 CHg-CH-CHg 157-159° 8 ciCH3 CHjCHgOH 157-159° 9 Cl ch3 iso-CgH^ 152-154° 10 ClCH3 iso-C,H„ 4 9 128-131° 43737 ExampleR2 *1R3 M.Pt. 11 Cl ch3 n-C4Hg 122-124° 12 F CH3 ch3 172-174° 13 F CH2CH20H CH3 122-124° 14 F ' colir 2 5 CH 146-147° 15 F Ii ch3 147-149° 16 F i-CjH? CH3 136-137° 17 F n-C3H7 ch3 136-138° 18 1' CH2CH2OCH ch3 107-109° 19 F t-c,HO 4 9 ch3 170-171° 20 F ch3 CH2-C1P--CH2 139-140° , 1*1 Ο ιν a ( « The compounds of formula I exhibit pharmacological activity. In particular, the compounds of formula I exhibit neuroleptic activity as indicated by standard tests. For example, the compounds inhibit spontaneous locomotor activity in mice upon administration of from to 50 mg/kg p.o. animal body weight of the compounds according to the principles of Caviezel et al Pharm. Acta itelv. (1958) 33, 469-484.
Additionally the compounds, wherein It, is chlorine 10 and R^ is alkyl or alkenyl, exhibit insignificant activity in tests indicating anti-chlolinergic activity, e.g. in the mydriasis test and in tests indicating effects on blood circulation, e.g. in the infusion test in the cat.
Therefore the compounds are indicated for use as L5 neuroleptics and the compounds of formula I, wherein R2 is chlorine and R^ is alkyl or alkenyl, exhibit surprisingly beneficial activity than is expected for such compounds.
An indicated daily dose is from about 10 to 500 ’-0 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about to about 250 mg of the compound, or in sustained release form.
Compounds of formula I, wherein R2 is fluorine, additionally exhibit anti-depressant activity, as - 7 4 3 7 2 7 indicated in standard tests. For example, these compounds inhibit the ptosis and catalepsy produced by tetrabenazine on i.p. administration of from 0,1 to 10 mg/kg animal body weight of the compounds to rats.
These compounds are therefore further indicated for use as anti-depressants. An indicated daily dose is from about 5 to about 150 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1 to about 35 mg of the compounds or in sustained release form.
The compounds of formula 1' may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be made in conventional manner so as to be, for example, a solution or a tablet.
In one group of compounds is hydrogen, alkyl or hydroxyalkyl, and R^ is hydroxyalkyl or alkoxyalkyl.
In a sub-group R^ is methoxyethyl, ethoxyethyl, propoxyethyl, ethoxypropyl, methoxypropyl or methoxybutyl.
In another group of compounds R^ is alkyl and Rg is chlorine, and Rg is alkyl of 2 to 4 carbon atoms.
Claims (10)
1. Λ process for the production of a compound of formula I, wherein R 1 is hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of
2. To 4 carbon atoms, or alkoxyalkyl of 2 to 5 carbon atoms in the aggregate thereof, Rg is fluorine or chlorine, and I< 3 is alkyl of 1 to 4 carbon atoms, hydroxyalkyl or 2 to 4 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms in the aggregate thereof, or alkenyl of 3 or 4 carbon atoms, with the proviso that when Rg is methyl, Rg is fluorine, which comprises reacting a compound of formula II, - 10 4373? wherein R 2 and R^ are as defined above, and X is a leaving group, with a compound of formula XXI, r~y UN v_/ N-R x III wherein R^ is as defined above.
3. A compound of formula I, whenever produced by a process according to claim 1 or 2. .0 4. A compound of formula I, as defined in claim 1. 4.3 7 27 26. A compound of claim 4 , wherein I? lf Ι? 2 , I? 3 arc respectively t-C^Hg , F, CII^27. A compound of claim 4, wherein R 2 , R 3 are respectively CH 3 , F, CH 2 -C!I=CH . 26. A compound according to any one of claims 3 to 27 in free base form. 29. A compound according to any one of claims 3 to 27 in acid addition salt form. 30. A pharmaceutical composition comprising a
4.3 7 2 7 5. 18. A compound of claim ,. wherein R^, Rg, Rg are respectively CHg, Cl, n-C^Hg. 19. A compound of claim A - wherein R^, Rg, K 3 are respectively CHg, F,. CHg. 20. A compound of claim 4, wherein R^, R 2 , Rg are 10 respectively CHgCHgOH, F, CHg. 21. A compound of claim 4, wherein R^, R 2 , Rg are respectively Chit., F, C!I,. z t> j 22. A compound of claim 4, wherein R,, R_, R, are i z ύ respectively 1Γ, F, CHg. 15 23. A compound of claim 4, wherein R^, R 2 , Rg are respectively i-CgH^, F, CH,. 24. A compound of claim 4, wherein R^, R 2 , Rg are respectively n-CgHg, F, CHg. 25. A compound of claim 4, wherein R, R 2 , Rg are 0 respectively CHgCHgOCHg, F, CHg.
5. A compound of claim 4, wherein R^ is hydrogen, alkyl or hydroxyalkyl, and is hydroxyalkyl or alkoxyalkyl. 5 2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Example
6. A compound of claim 4, wherein is alkyl, Rg is chlorine and Rg is alkyl of 2 to 4 carbon atoms.
7. A compound of claim 4, wherein Rg is fluorine.
8. A compound of claim 4, which is 5-n-propyl-8chloro-11-(4-methyl-l-piperazinyl)-SE-dibanzo[b,e][1,4]diazopine.
9. 9. A compound of claim 4, wherein 1^, R z' Eg respectively CHg, Cl, C 2 H 5· 10. A compound of claim 4., wherein R^, Rg, K 3 are respectively CH , Cl, CH.CH.OCH... 2 2 j 11. A compound of claim 4, wherein R^, Rg, R 3 are respectively CITg, F, CgHg. 12. A compound of claim 4, wherein R l' R 3 are respectively CHg, F, n-C.J! 7 . 13. Λ compound of cla.im 4, wherein R r *2' R 3 are respectively CHg, F, n C 4 K 9· 14 . A compound of claim 4, wherein R r Rg, R 3 are respectively CHg, Cl, CHg-CH=CH 0 . 15. A compound of claim 4, wherein R l' R 2' R 3 are respectively CHg, Cl, CI^CHgOH. 12 16. Λ compound of claim 4, wherein R^, Rg, Rg are respectively CHg, Cl, iso-CgH^. 17. A compound of claim 4, wherein R^, Rg, Rg are respectively CHg, Cl, iso-C^Hg.
10. Compound according to any one of claims 3 to 27 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1241475A CH602709A5 (en) | 1975-09-24 | 1975-09-24 | (11)-Piperazinyl dibenzo-(b,e) (1,4)-diazepine derivs. |
| CH1241375A CH599196A5 (en) | 1975-09-24 | 1975-09-24 | (11)-Piperazinyl dibenzo-(b,e) (1,4)-diazepine derivs. |
| CH725076A CH602708A5 (en) | 1976-06-09 | 1976-06-09 | (11)-Piperazinyl dibenzo-(b,e) (1,4)-diazepine derivs. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE43727L IE43727L (en) | 1977-03-24 |
| IE43727B1 true IE43727B1 (en) | 1981-05-06 |
Family
ID=27175741
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2098/76A IE43727B1 (en) | 1975-09-24 | 1976-09-22 | Dibenzo/b,e//1,4/diazepines |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5239689A (en) |
| AU (1) | AU1808576A (en) |
| DE (1) | DE2641378A1 (en) |
| DK (1) | DK416476A (en) |
| ES (1) | ES451772A1 (en) |
| FI (1) | FI762646A (en) |
| FR (1) | FR2325381A1 (en) |
| GB (1) | GB1554275A (en) |
| IE (1) | IE43727B1 (en) |
| IL (1) | IL50531A0 (en) |
| NL (1) | NL7610420A (en) |
| NO (1) | NO763172L (en) |
| NZ (1) | NZ182137A (en) |
| PT (1) | PT65629B (en) |
| SE (1) | SE7610219L (en) |
| SU (1) | SU668602A3 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991010661A1 (en) * | 1990-01-11 | 1991-07-25 | Novokuznetsky Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut | DERIVATIVES OF 5-AMINO-8-CHLORINE-DIBENZO[b,e][1,4]-DIAZEPINE AND A PHARMACEUTICAL PREPARATION FOR TREATMENT OF EPILEPSY AND EPILEPTIC STATUS BASED THEREON |
| US6034078A (en) * | 1992-05-29 | 2000-03-07 | Eli Lilly And Company Limited | Thienobenzodiazepine compounds |
| NZ247703A (en) * | 1992-05-29 | 1995-07-26 | Lilly Industries Ltd | Thienobenzdiazepine derivatives and medicaments thereof |
| DE602004020263D1 (en) | 2003-12-22 | 2009-05-07 | Acadia Pharm Inc | AMINO-SUBSTITUTED DIARYLÄA, DREPTYCLEPTEN ANALOGUE AS MUSCARINAL AGONISTS AND METHOD FOR THE TREATMENT OF NEUROPSYCHIATRICAL DISEASES |
| WO2013070107A1 (en) * | 2011-11-09 | 2013-05-16 | Общество С Ограниченной Ответственностью "Валентек" | 5h-dibenzo[b,e][1,4]diazepine derivatives and use thereof |
-
1976
- 1976-09-15 FI FI762646A patent/FI762646A/fi not_active Application Discontinuation
- 1976-09-15 DE DE19762641378 patent/DE2641378A1/en not_active Withdrawn
- 1976-09-15 DK DK416476A patent/DK416476A/en unknown
- 1976-09-15 SE SE7610219A patent/SE7610219L/en unknown
- 1976-09-16 NO NO763172A patent/NO763172L/en unknown
- 1976-09-20 SU SU762402953A patent/SU668602A3/en active
- 1976-09-20 NL NL7610420A patent/NL7610420A/en not_active Application Discontinuation
- 1976-09-21 GB GB39054/76A patent/GB1554275A/en not_active Expired
- 1976-09-22 NZ NZ182137A patent/NZ182137A/en unknown
- 1976-09-22 PT PT65629A patent/PT65629B/en unknown
- 1976-09-22 IL IL50531A patent/IL50531A0/en unknown
- 1976-09-22 JP JP51113199A patent/JPS5239689A/en active Pending
- 1976-09-22 ES ES451772A patent/ES451772A1/en not_active Expired
- 1976-09-22 IE IE2098/76A patent/IE43727B1/en unknown
- 1976-09-23 FR FR7628560A patent/FR2325381A1/en active Granted
- 1976-09-23 AU AU18085/76A patent/AU1808576A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1554275A (en) | 1979-10-17 |
| IL50531A0 (en) | 1976-11-30 |
| FR2325381B1 (en) | 1978-11-17 |
| DE2641378A1 (en) | 1977-04-07 |
| AU1808576A (en) | 1978-04-06 |
| NO763172L (en) | 1977-03-25 |
| PT65629B (en) | 1978-05-10 |
| IE43727L (en) | 1977-03-24 |
| NZ182137A (en) | 1978-12-18 |
| JPS5239689A (en) | 1977-03-28 |
| NL7610420A (en) | 1977-03-28 |
| SE7610219L (en) | 1977-03-25 |
| PT65629A (en) | 1976-10-01 |
| FI762646A (en) | 1977-03-25 |
| SU668602A3 (en) | 1979-06-15 |
| FR2325381A1 (en) | 1977-04-22 |
| ES451772A1 (en) | 1978-01-01 |
| DK416476A (en) | 1977-03-25 |
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