GB2046254A - Benzodiazepines - Google Patents
Benzodiazepines Download PDFInfo
- Publication number
- GB2046254A GB2046254A GB8007841A GB8007841A GB2046254A GB 2046254 A GB2046254 A GB 2046254A GB 8007841 A GB8007841 A GB 8007841A GB 8007841 A GB8007841 A GB 8007841A GB 2046254 A GB2046254 A GB 2046254A
- Authority
- GB
- United Kingdom
- Prior art keywords
- hydrochloride
- benzodiazepine
- chlorophenyl
- dihydro
- chloro
- 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.)
- Withdrawn
Links
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
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Benzodiazepine derivatives of formula (I> <IMAGE> (R1 = C4-6-cycloalkyl; R2 = H or halogen) and acid addition salts thereof are anxiolytics.
Description
SPECIFICATION
Benzodiazepine derivatives
The present invention relates to benzodiazepine derivatives, their preparation and use in therapy, especially for treatment of anxiety.
The invention provides compounds of the general formula (I)
in which R1 is a cycloalkyl radical having 4 to 6 carbon atoms and R2 is a hydrogen or halogen atom, and their pharmaceutically acceptable acid addition salts. Preferably R2 is a chlorine atom.
According to the invention, the compounds (I) can be prepared by reacting a benzodiazepine (II)
R2 as being defined above, with a compound of the formula (Ill)
R, being as defined above. The reaction usually requires sodium hydride, and is preferably carried out in a solvent, such as dimethylformamide (DMF), at a temperature ranging from 50 to 1 50on.
The compounds (11) are known and are described in French Patent 73.43341 of Synthelabo.
The compounds (III) can be obtained in accordance with the following reaction scheme:
(R, is defined above. Et = ethyl)
The following Examples illustrate the invention.
The analyses and the IR and NMR spectra confirmed the structure of the compounds.
Example 1
7-Chloro-1 -(2-cyclobutylmethoxy-ethyl)-5-(2- chlorophenyl)-2, 3-dihydro- 1 H- 1 ,4-benzodia- zepine-2-one and its hydrochloride.
0.72 g (0.015 mol) of a 50% strength suspension of sodium hydride and 20 ml of anhydrous DMF are introduced into a 100 ml
Erlenmeyer flask. A solution of 4.58 g (0.015 mol) of 5-(2-chlorophenyl)-7-chloro-2,3-dihydro-1 H-1 ,4-benzodiazepine-2-one in 20 ml of anhydrous DMF is introduced slowly. The mixture is then stirred until the evolution of hydrogen has ended. A solution of 6.1 g (0.021 mol) of 1 -(para-toluenesulphonyloxy)- 2-(cyclobutylmethoxy)-ethane in 20 ml of
DMF is then introduced slowly. The mixture is then heated for 3 hours at 60"C and left to stand overnight and 1 litre of water is poured in. Extraction is carried out with 3 times 500
ml of chloroform and the chloroform phase is washed with water, dried over MgSO4 and evaporated to dryness.
This yields an oil which is purified by pass
ing it through a silica column, using a 95/5 chloroform/acetone mixture as the eluent.
The valuable fractions are collected and evaporated to dryness, the residue is taken up in ether, the mixture is filtered through paper and the hydrochloride is precipitated by add
ing a solution of hydrogen chloride in ether.
The mixture if evaporated to dryness. The
residue is taken up in ether and the mixture is
filtered through a frit. This yields the crude
hydrochloride. It is recrystallised from a meth
anol/ether mixture with vegetable charcoal treatment.
Melting point = 177'C.
Example 2
7-Chloro-1 -(2-cyclopentylmethoxy-ethyl)-5- (2-chlorophenyl)-2, 3-dihydro-1 H- 1 ,4-benzodia- zepine-2-one and its hydrochloride.
The procedure followed is the same as in
Example 1, 4.58 g of the starting compound (II) being reacted with 6.5 of 1-(para-toluenesu I phonyloxy)-2-(cyclopentyl-methoxy)-ethane in the presence of 0.72 g of NaH. After recrystallisation from a methanol/ether mixture, the hydrochloride of the compound, which melts at 165-1 66 C, is obtained.
The compounds of the invention were subjected to pharmacological experiments which demonstrated their anxiolytic properties.
The compounds have a low toxicity.
The anxiolytic activity of the compounds is demonstrated using the "Eating test" (reference: R. J. Stephens, Brit. J. Pharmacol.
1973, 49, 146).
At a dose of 3 mg/kg, administered orally, the % increase in the food intake is 50 to 90% for the compounds of the invention.
These results show that the compounds of the invention can be used for the treatment of the various states of anxiety.
The invention consequently includes all pharmaceutical compositions containing a compound of the present invention, in association with an excipient. They are preferably formulated with an excipient suitable for oral or parenteral administration.
The preferred methods of administration are oral and parenteral. The daily dosage will usually be from 20 to 200 mg, administered orally.
Claims (9)
1. Benzodiazepine derivatives having the general formula (I)
in which R, is a cycloalkyl radical having 4 to
6 carbon atoms and R2 is a hydrogen or
halogen atom, and their pharmaceutically ac
ceptable acid addition salts.
2. 7-Chloro-1 -(2-cyclobutylmethoxy-ethyl)- 5-(2-chlorophenyl)-2,3-dihydro-1 H-1 ,4-benzo- diazepine-2-one and its hydrochloride.
3. 7-chloro- 1 -(2-cyclopentylmethoxy-ethyl)
5-(2-chlorophenyl)-2, 3-dihydro-1 H-1.4-benzo- diazepine-2-one and its hydrochloride.
4. A process for the preparation of a com
pound claimed in Claim 1, which process
comprises reacting a bezodiazepine of general
formula (II)
R2 being as defined in Claim 1, with a compound of the formula (III)
R, being as defined in Claim 1, and when the product is obtained in free base form, if desired converting the free base into a pharmaceutically acceptable acid addition salt.
5. A process according to Claim 4, carried out in sodium hydride and at a temperature of from 50 to 1 50"C.
6. A process according to Claim 4 substantially as described in Example 1 or 2.
7. A benzodiazepine derivative claimed in
Claim 1 when obtained by a process claimed in Claim 4, 5 or 6.
8. Benzodiazepine derivatives claimed in
Claim 1, 2, 3 or 7 for use in therapy.
9. A pharmaceutical composition comprising a benzodiazepine derivative claimed in
Claim 1, 2, 3 or 7 in association with a pharmaceutically acceptable excipient.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7906056A FR2450825A1 (en) | 1979-03-09 | 1979-03-09 | BENZODIAZEPINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
Publication Number | Publication Date |
---|---|
GB2046254A true GB2046254A (en) | 1980-11-12 |
Family
ID=9222942
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8007841A Withdrawn GB2046254A (en) | 1979-03-09 | 1980-03-07 | Benzodiazepines |
Country Status (4)
Country | Link |
---|---|
JP (1) | JPS55122770A (en) |
DE (1) | DE3008852A1 (en) |
FR (1) | FR2450825A1 (en) |
GB (1) | GB2046254A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5043115A (en) * | 1988-03-10 | 1991-08-27 | Sumitomo Chemical Company, Limited | Heat-shrinkable, tubular foam |
US5071886A (en) * | 1988-03-10 | 1991-12-10 | Sumitomo Chemical Company, Limited | Heat-shrinkable, tubular foam |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2491926A1 (en) * | 1980-10-10 | 1982-04-16 | Synthelabo | Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE794536A (en) * | 1972-01-31 | 1973-07-25 | Fujisawa Pharmaceutical Co | 1,4-BENZODIAZEPINES 1-SUBSTITUTES AND THEIR PREPARATION |
FR2253501A1 (en) * | 1973-12-05 | 1975-07-04 | Synthelabo | 2,3-Dihydro-1H-benzodiazepine-2-ones - as tranquillisers with an improved therapeutic index |
JPS50116485A (en) * | 1974-02-27 | 1975-09-11 |
-
1979
- 1979-03-09 FR FR7906056A patent/FR2450825A1/en active Granted
-
1980
- 1980-03-07 DE DE19803008852 patent/DE3008852A1/en active Pending
- 1980-03-07 GB GB8007841A patent/GB2046254A/en not_active Withdrawn
- 1980-03-08 JP JP2971580A patent/JPS55122770A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5043115A (en) * | 1988-03-10 | 1991-08-27 | Sumitomo Chemical Company, Limited | Heat-shrinkable, tubular foam |
US5071886A (en) * | 1988-03-10 | 1991-12-10 | Sumitomo Chemical Company, Limited | Heat-shrinkable, tubular foam |
Also Published As
Publication number | Publication date |
---|---|
FR2450825B1 (en) | 1982-01-29 |
FR2450825A1 (en) | 1980-10-03 |
JPS55122770A (en) | 1980-09-20 |
DE3008852A1 (en) | 1980-09-18 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |