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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton

Definitions

• This invention relates to a novel method of producing skeletal muscle relaxation and relates more particularly N 0 Drawing.
• R represents a cycloalkylmethyl group such as cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl and R represents hydrogen, lower alkyl, lower alkoxy or halogen such as chlorine or bromine, and the corresponding medicinally acceptable acid addition salts thereof.
• the invention also includes within its scope novel pharmaceutical compositions containing the above compounds.
• the therapeutic basis for the use of a muscle relaxant is the release of muscle spasms and spasticity resulting from various neuro-muscular and musculo-skeletal disorders which may result from dire-ct trauma to muscle, multiple sclerosis, arthritis, bursitis, sciatica, etc., or may result in low back pain.
• drugs for the relief of these conditions there are several available drugs for the relief of these conditions and they can be classified according to their site of activity in the neuro-m-uscular system.
• true muscle relaxant such as quinine which acts directly on the muscle to achieve relaxation.
• myoneuro junction type of drug such as curare, gallamine and the like which achieves muscle relaxation by blocking the myoneuro transmission of impulses and there is a miscellaneous group of drugs which act by a variety of complex mechanisms on the interneuronal systems such as meprobamate, carisoprodol, metaxolone and the like.
• Another object of this invention is to provide muscle relaxation by administration of a drug composition which is effective orally.
• clinically desirable and effective muscle relaxation may be produced by the administration of a composition containing as active ingredient a compound corresponding to structure (-1) above or its corresponding acid addition salt.
• useful acid addition salts include, for example, the hydrochlorides, the nitrates, the phosphates, the sulfates and the like The preparation of these compounds (I) is fully described in aforesaid copending application Ser. No. 262,846.
• compositions of the present invention comprise as active ingredient a compound of the structure (I) in combination with a nontoxic pharmaceutical carrier adapted for human or veterinary medication; the selected active ingredient being present in an amount from about 10 to about 100 mg. per dosage unit.
• oral dosage forms include, for example, solid compositions such as tablets and pills; dispersible powders or granules; or semisolid and liquid formulations in the form of syrups, solutions, suspensions or dispersions.
• compositions may also include other known therapeutic agents such as, for example, analgesics, antiinfiammatory agents, cardiovascular agents, sedatives, steroids, tranquilizers, antacids, and the like.
• analgesics include, for example, aspirin, namol xenyrate, N-acetayl-p-aminophenol and the like.
• the anti-inflammatory agents in these compositions may include, for example, prednisolone, cortisone, N- methyl-yohimbane and the like.
• Cardiovascular agents includes, for example, quindonium bromide, pentaerythritol tetranitrate and the like.
• Sedatives include, for example, phenobarbital, butylbarbital, and the like.
• the steroids may include, for example, estrogen, testosterone, and the like.
• Tranquilizers which may be included are, for example, the phenothiazines such as mep-azine, the rauwolfia alkaloids such as reserpine, and the like.
• tranquilization may also be achieved accompanied by the desired muscle relaxation by administering the active ingredient at higher doses, that is to say, the separation of the muscle relaxant activity from the tranquilizing activity of the compounds of this invention is achieved by suitably modifying the dos-age thereby giving the prescriber a choice, which, of course, is a great advantage.
• a dosage of to 25 mg. administered several times daily is sufiicient to maintain adequate muscle relaxation; a higher dose such as 50 mg. several times daily producing, in addition, a tranquilizing action.
• Example 1 In order to demonstrate the muscle relaxant effect of 7 chloro-l-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H- l,4-benzodiazenpine-2-one, graded doses of this drug are administered orally to a series of unanesthetized adult mice divided into groups of ten.
• the pharmacological test employed consists in placing the treated mice on an inclined screen having a mesh size of 1. Muscle relaxant activity in the mouse is observed as the inability of the treated animals to remain on the screen inclined at 30. The treated mice are observed at hourly intervals for about six hours. Untreated mice are included in the test as controls.
• Approximate effective dose 50 is that dose at which 50% of the treated animals are unable to remain on the screen.
• the effective oral dose of this compound has been found to be 74 mg./kg. whereas that of meprobamate is found to be 282 mg./kg.
• the same compound is also administered to cats at graded doses.
• the treated animals are observed for muscle relaxant activity by noting the ability of the drug to produce alterations in gait and palpitation of muscle tone.
• the ED of this compound is found to be 5 mg./ kg. whereas the ED of meprobamate is found to be at 25 mg./kg.
• Example 2 The lack of central depressant effect of 7-chloro-1- cyclopropylmethyl 1,3 dihydro-5-phenyl-2H-1,4-benzodiazepine-2-0ne is noted by its failure to produce hypnosis as demonstrated in the following test procedure.
• mice weighing about 18 to 2 4 grams are given orally a 1% by weight solution of the above compound in polyethylene glycol at graded doses.
• Example 5 A mixture of 25 parts of 7-chloro-1-cyclopropylmethyl- 1,3 dihydro 6 phenyl-ZH-1,4-benZodiazepine-2-one and parts of milk sugar are intimately blended together. 200 mg. of this mixture is filled into hard gelatin capsules each of which will contain 25 mg. of the active ingredient.
• Example 6 Illustrative of the muscle relaxant activity of 7-chloro- 1 cyclopropylmethyl 1,3 dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-one in human beings is the following clinical case:
• a method of producing skeletal muscle relaxation in warm-blooded mammals which comprises administer- 5 ing orally to said mammals an effective amount of a compound of the formula:
• R is cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl and R is a member of the group con- 20 sisting of hydrogen, halogen, lower alkyl and lower alkoxy and the medicinally acceptable acid addition salts.
• a method of producing skeletal muscle relaxation in warm-blooded mammals which comprises administering orally to said mammals about 5 to 25 mg. of a member of the group consisting of 7-chloro-l-cyclopropylmethyl- 1,3-dihydro 5 phenyl-2H4,4-benzodiazepine-2-one and 0 the medicinally acceptable acid addition salts several times daily.
• composition for oral administration consisting essentially of about 5 to 25 mg. of a compound of the formula:

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (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)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=26949494

Family Applications (1)

Country Status (8)

Cited By (2)

• 1964
  • 1964-02-24 DE DE19641470422 patent/DE1470422A1/de active Pending
  • 1964-02-27 GB GB8156/64A patent/GB1029741A/en not_active Expired
  • 1964-02-28 CH CH249164A patent/CH427830A/de unknown
  • 1964-03-02 BR BR157243/64A patent/BR6457243D0/pt unknown
  • 1964-03-04 BE BE644705A patent/BE644705A/xx unknown
  • 1964-03-04 FR FR966091A patent/FR3452M/fr active Active
  • 1964-03-05 SE SE2730/64A patent/SE309779B/xx unknown
  • 1964-11-12 US US410790A patent/US3326757A/en not_active Expired - Lifetime

Non-Patent Citations (1)

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