US3867388A - 3{8 4-(2-thienoyl)-piperazino{9 -4,5-dihydro-1h-2,4-benzodiazepines - Google Patents

3{8 4-(2-thienoyl)-piperazino{9 -4,5-dihydro-1h-2,4-benzodiazepines Download PDF

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US3867388A
US3867388A US317799A US31779972A US3867388A US 3867388 A US3867388 A US 3867388A US 317799 A US317799 A US 317799A US 31779972 A US31779972 A US 31779972A US 3867388 A US3867388 A US 3867388A
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dihydro
benzodiazepine
hydroiodide
benzodiazepine hydroiodide
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Richard A Schnettler
John T Suh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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  • the compounds of the present invention are readily prepared from 3-methylmercapto-4,5-dihydro-1-H- 2,4-benzodiazepines of the formula
  • Thevcompounds of the invention are conveniently prepared by dissolving the corresponding 3- methylmercapto-4,5-dihydrol H-2,4-benzodiazepine hydroiodide and a suitable amine in anhydrous acetonitrile and heating the mixture under reflux conditions until the reaction is complete.
  • Acid addition salts of the compounds of the present invention may be conveniently produced by contacting the free base with a suitable acid such as sulfuric acid, hydrochloric acid, succinic, acid, tartaric acid, benzoic acid or fumaric acid.
  • a suitable acid such as sulfuric acid, hydrochloric acid, succinic, acid, tartaric acid, benzoic acid or fumaric acid.
  • the thiocyanic acid addition salts of the compounds when condensed with formaldehyde form resinous materials useful as pickling agents according to U.S. Pat. Nos. 2,425,320 and 2.606,l55.
  • the compounds also form fluosilicic acid addition salts which are useful as mothproofing agents according to US. Pat. Nos. 1,915,334 and 2,075,359.
  • the compounds of the invention are pharmacologically active.
  • the compounds 3-[N-(N'-2- thienoylpiperazino)]-4,5-dihydro-lH-2,4- benzodiazepine hydroiodide when evaluated in mouse behavioral studies at intraperitoneal doses of 30 to 100 mg/kg, was found to produce a central nervous system depression characterized by sedation.
  • the mouse behavioral studies also indicated that the compound was relatively safe and possessed an LD in excess of 175 mg/kg of body weight.
  • the behavioral studies were conducted essentially in accordance with the procedure outlined by S. Irwin in Animal and Clinical Pharmacologic Techniques in Drug Evaluation, J. H. Nodine and P. E. Siegler, Ed., Year Book Medical Publishers, Inc. (1964).
  • the compounds When intended for pharmaceutical use, the compounds are preferably combined with one or more suitable pharmaceutical diluents and additives and formed into unit dosage forms for oral or parenteral administration such as tablets, capsules and solutions.
  • suitable pharmaceutical diluents and additives such as tablets, capsules and solutions.
  • EXAMPLE 5 and pharmaceutically acceptable salts thereof, in which X and Y are hydrogen, hydroxy, halogen, CR, or lower alkoxy of l to 4 carbon atoms.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The 3-substituted-2,4-dihydrobenzodiazepines and their pharmaceutically acceptable acid addition salts are central nervous system depressants. A compound disclosed is 3-(N-(N''-2thienoylpiperazino))-4,5-dihydro-1H-2,4-benzodiazepine hydroiodide.

Description

United States Patent [191 Schnettler et al.
{22] Filed: Dec. 22, 1972 [21] Appl. No.: 317,799
[52] US. Cl 260/268 BC, 424/250 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268 B, 268 C [56] References Cited UNITED STATES PATENTS 3,696,093 10/1972 Rodriguez et al. 260/268 BC Feb. 18, 1975 Primary Examiner-Donald G. Daus Assistant Examiner]ose Tovar Attorney, Agent, or FirmM. L. Youngs; T. F. Kryshak [57] ABSTRACT The 3-substituted-2,4-dihydrobenzodiazepines and their pharmaceutically acceptable acid addition salts are central nervous system depressants. A compound disclosed is 3-[N-(N-2-thienoylpiperazino)]-4,5- dihydro-lH-2,4-benzodiazepine hydroiodide.
2 Claims, N0 Drawings 3[4-(2-THIENOYL)-PIPERAZINO]-4,5-D]HYDRO- lH-2,4-BENZODIAZEPINES DETAILED DESCRIPTION The compounds of the present invention have the following formula of l to 4 carbon atoms. especially methoxy or ethoxy, and R is 4 O CH2-\;| 5 aim Q I in which R, is an alkyl of l to 4 carbons.
BACKGROUND OF THE INVENTION U.S. Pat. Nos. 3,496,179 and 3,609,l52 disclose 2- amin0-3,4-dihydroquinazolines which are antihypertensive agents. An article by H. R. Rodriquez, et al., J. Org. Chem, 33, 670 (1968), discloses the compound 2-amino-4,5-dihydro-lH-2,4-benzodiazepine, and related compounds are disclosed in U.S. Pat. No. 3.696.093.
PREPARATION OF THE COMPOUNDS The compounds of the present invention are readily prepared from 3-methylmercapto-4,5-dihydro-1-H- 2,4-benzodiazepines of the formula Thevcompounds of the invention are conveniently prepared by dissolving the corresponding 3- methylmercapto-4,5-dihydrol H-2,4-benzodiazepine hydroiodide and a suitable amine in anhydrous acetonitrile and heating the mixture under reflux conditions until the reaction is complete.
The described process may be illustrated as follows:
H x N -sca a; Y
III
in which R, X and Y are as previously defined.
Among the compounds which may be prepared by the described process are .the following:
3-[N-(N'-2-thienoylpiperazino)]-4,5-dihydro-lH 2,4-benzodiazepine hydroiodide,
3-[N-(N-2-thienoylpiperazino)]-7,8-dimethoxy-4,5- dihydro-l H-2,4-benzodiazepine hydroiodide,
3-[N-(N-2-thienoylpiperazino)]-7,8-dichloro 4,5- dihydro-l H-2,4-benzodiazepine hydroiodide,
3-[N-(N-piperonoylpiperazino)]-4,5-dihydro-lH- 2,4-benzodiazepine hydroiodide hydrate,
3-[N-(N-piperonoylpiperazino)]-7,8-dimethoxy- 4,5-dihydro-lH-2,4-benzodiazepine hydroiodide hydrate,
3-[N-(N-piperonoylpiperazino)]-7,8-dichloro-4,5- dihydro-l H-2,4-benzodiazepine hydroiodide hydrate,
3-[N-(N-carboethoxypiperazino)]-4,5-dihydro-l H- 2,4-benzodiazepine hydroiodide,
3-[N-(N-carboethoxypiperazino)1-7.8-dimethoxy- 4,5-dihydro-lH-2,4-benzodiazepine hydroiodide,
3-[N-(N'-carboethoxypiperazino)]-7,8-dichloro-4,S- dihydro-l H-2,4-benzodiazepine hydroiodide,
3-[N-(N'-2-thienylmethylpiperazino)]-4,5-dihydrolH-2,4-benzodiazepine hydroiodide,
3-[N-(N-2-thienylmethylpiperazino)]-7,8- dimethoxy-4,5-dihydro- 1 H-2,4-benzodiazepine hydroiodide,
3-[N-(N-2-thienylmethylpiperazino)]-7,8-dichloro- 4,5-dihydro-lH-2,4-benzodiazepine hydroiodide,
3-[N-(N-piperonylpiperazino)]-4,5-dihydro-l H- 2,4-benzodiazepine hydroiodide,
3-[N-(N-piperonylpipera2ino)]-7,8-dimethoxy-4,5- dihydro-l H-2,4-benzodiazepine hydroiodide, and
3-[N-(N'-piperonylpiperazino)]-7,8-dichloro-4,5- dihydrol H-2,4-benzodiazepine hydroiodide.
The compounds in which X and/or Y are hydroxy may be readily prepared from the corresponding compounds in which X and Y are aralkoxy or alkoxy by conventional procedures.
Acid addition salts of the compounds of the present invention may be conveniently produced by contacting the free base with a suitable acid such as sulfuric acid, hydrochloric acid, succinic, acid, tartaric acid, benzoic acid or fumaric acid.
The thiocyanic acid addition salts of the compounds when condensed with formaldehyde form resinous materials useful as pickling agents according to U.S. Pat. Nos. 2,425,320 and 2.606,l55. The compounds also form fluosilicic acid addition salts which are useful as mothproofing agents according to US. Pat. Nos. 1,915,334 and 2,075,359.
The compounds of the invention are pharmacologically active. For example, the compounds 3-[N-(N'-2- thienoylpiperazino)]-4,5-dihydro-lH-2,4- benzodiazepine hydroiodide, when evaluated in mouse behavioral studies at intraperitoneal doses of 30 to 100 mg/kg, was found to produce a central nervous system depression characterized by sedation. The mouse behavioral studies also indicated that the compound was relatively safe and possessed an LD in excess of 175 mg/kg of body weight. The behavioral studies were conducted essentially in accordance with the procedure outlined by S. Irwin in Animal and Clinical Pharmacologic Techniques in Drug Evaluation, J. H. Nodine and P. E. Siegler, Ed., Year Book Medical Publishers, Inc. (1964).
When intended for pharmaceutical use, the compounds are preferably combined with one or more suitable pharmaceutical diluents and additives and formed into unit dosage forms for oral or parenteral administration such as tablets, capsules and solutions. The following examples are presented to illustrate this inventron:
EXAMPLE 1 3-[N-(N'-2-Thienoylpiperazino)]-4,5-dihydro-lH-2,4- benzodiazepine hydroiodide A mixture of 7.5 g. (0.023 mole) of 3- methylmercapto-4,5-dihydro-1H-2,4-benzodiazepine hydroiodide and 8.8 g. (0.046 mole) of N-2-thienoylpiperazine in 100 ml. of dry acetonitrile is refluxed for hours. The solvent is evaporated and the residual glass dissolved in ethyl alcohol, treated with activated charcoal, filtered and cooled. The resulting solids are recrystallized from absolute ethyl alcohol to afford 3- [N-(N-2-thienoylpiperazino)]-4,S-dihydr0-1H-2,4- benzodiazepine hydroiodide, m.p. 192l93.5, in the form of a white crystalline solid.
Anal. Calcd. for C H ,IN.,OS: C, 46.16; H, 4.52; N,
11.97. Found: C, 45.88; H, 5.04; N, 11.87.
EXAMPLE 2 3-[N-(N-Piperonoylpiperazino)]-4,5-dihydro-1H-2,4- benzodiazepine hydroiodide hydrate A mixture of 9.4 g. (0.04 mole) of N-piperonoylpiperazine and 6.4 g. (0.02 mole) of 3-methylmercapto- 4,5-dihydro-lH-2,4-benzodiazepine hydroiodide -.in 150 ml. of dry acetonitrile is refluxed 16 hours, cooled, the solids filtered and recrystallized from ethanol to afford 3-[N-(N-piperonoylpiperazino)]-4,5-dihydro- 1H-2,4-benzodiazepine hydroiodide hydrate as a white powder, m.p. 17918l.5.
Anal. Calcd. for C H, ',lN O C, 48.10; H, 4.81; N,
10.68. Found: C, 48.09; H, 4.53; N, 10.96.
EXAMPLE 3 3-[N-(N -Carboethoxypiperazino)]-4,5-dihydro- 1H- 2,4-benzodiazepine hydroiodide ln ml. dry acetonitrile is suspended 8 g. (0.025
mole) 3-methy1mercapto-4,5-dihydro- 1 H-2,4- benzodiazepine hydroiodide and 7.9 g. (0.050 mole) ethyl N-piperazinocarboxylate. The mixture is refluxed 22 hours, cooled, and the solvent evaporated. The residue is triturated with isopropanol and the solid collected. Recrystallization from isopropanol gives 3-[N- (N' carboethoxypiperazino ]-4,5-dihydrol H-2 ,4- benzodiazepine hydroiodide as a white solid. m.p. 200202.
Anal. Calcd. for C H N O l: C, 44.66; H. 5.39; N,
13.02. Found: C, 44.51; H, 5.09; N, 12.80.
EXAMPLE 4 3-[ N-(N2-Thienylmethylpiperazino) ]-4,5-dihydrolH-2,4-benzodiazepine hydroiodide A mixture of 5.4 g. (0.017 mole) of 3- methylmercapto-4,5-dihydro-1H-2,4-benzodiazepine hydroiodide and 6.2 g. (0.034 mole) of N-2-thienylmethylpiperazine in 50 ml. of dry acetonitrile is refluxed for 23 hours. The solvent is evaporated and the residual oil dissolved in hot isopropyl alcohol. The solids are filtered and dried to afford 3-[N-(N'-2- thienylmethylpiperazino ]-4,5-dihydrol H-2,4- benzodiazepine hydroiodide as a beige powder, m.p. 194-196.
Anal. Calcd. for C H lN S: C, 47.58; H, 5.10; N,
12.33. Found: C, 47.13; H, 5.05; N, 12.12.
EXAMPLE 5 and pharmaceutically acceptable salts thereof, in which X and Y are hydrogen, hydroxy, halogen, CR, or lower alkoxy of l to 4 carbon atoms.
2. The compound of claim 1 which is 3-[N-(N-2- thienoylpiperazino)]-4,5-dihydro-1l-l-2,4-
benzodiazepine hydroiodide.
* 1 v k I

Claims (2)

1. A COMPOUND SELECTED FORM A COMPOUND OF THE FORMULA:
2. The compound of claim 1 which is 3-(N-(N''-2-thienoylpiperazino))-4,5-dihydro-1H-2,4-benzodiazepine hydroiodide.
US317799A 1972-12-22 1972-12-22 3{8 4-(2-thienoyl)-piperazino{9 -4,5-dihydro-1h-2,4-benzodiazepines Expired - Lifetime US3867388A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013536873A (en) * 2010-09-06 2013-09-26 グアンジョウ インスティテュート オブ バイオメディスン アンド ヘルス，チャイニーズ アカデミー オブ サイエンスィズ Amide compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3696093A (en) * 1970-09-30 1972-10-03 Ciba Geigy Corp 2,4-benzodiazepines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3696093A (en) * 1970-09-30 1972-10-03 Ciba Geigy Corp 2,4-benzodiazepines

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013536873A (en) * 2010-09-06 2013-09-26 グアンジョウ インスティテュート オブ バイオメディスン アンド ヘルス，チャイニーズ アカデミー オブ サイエンスィズ Amide compounds
US9238643B2 (en) 2010-09-06 2016-01-19 Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences Amide compounds

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