US3422203A - Treatment of depression with diphenyl prop-2-enylamine derivatives - Google Patents

Treatment of depression with diphenyl prop-2-enylamine derivatives Download PDF

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Publication number
US3422203A
US3422203A US615327A US3422203DA US3422203A US 3422203 A US3422203 A US 3422203A US 615327 A US615327 A US 615327A US 3422203D A US3422203D A US 3422203DA US 3422203 A US3422203 A US 3422203A
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United States
Prior art keywords
enylamine
dimethyl
prop
diphenylprop
methyl
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Expired - Lifetime
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US615327A
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English (en)
Inventor
Roy Frederick Maisey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GEISTLICH ED SOHNE AG fur CHEM
GEISTLICH ED SOHNE AG fur CHEMISCHE IND
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GEISTLICH ED SOHNE AG fur CHEM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Definitions

  • compositions for example, tablets, containing a diphenylpropQ-enylamine derivative, for example, N,N-dimethyl-3,3-diphenylprop-2-enylamine hydrochloride. Useful as antidepressants.
  • This invention relates to new pharmaceutical compositions and more particularly it relates to new pharmaceutical compositions having antidepressant activity.
  • compositions comprising at least one alkene derivative of the formula:
  • R and R which may be the same or different, stand for hydrogen atoms or alkyl or aralkyl radicals, and one or both of the phenyl radicals A and B may optionally be substituted with one or two substituents selected from halogen atoms and trifiuoromethyl, alkyl and alkoxy radicals, or a pharmaceutically-acceptable acid-addition salt thereof, and a pharmaceutically-acceptable diluent or carrier.
  • alkene derivatives includes all stereoisomeric forms thereof, for example the cisand trans-isomers, and mixtures thereof.
  • R or R when it stands for an alkyl or aralkyl radical there may be mentioned, for example, an alkyl radical of not more than 6 carbon atoms, and more particularly an alkyl radical of not more than 2 carbon atoms, for example the methyl or ethyl radical, or a phenylalkyl radical of not more than 11 carbon atoms, and more particularly a phenylalkyl radical of not more than 9 carbon atoms, for example the benzyl radical.
  • the substituent(s) which may optionally be present in one or both of the phenyl radicals A and B may be selected from fluorine, chlorine and bromine atoms, and the trifluoromethyl radical, and alkyl and alkoxy radicals of "ice not more than 6 carbon atoms, and more particularly alkyl and alkoxy radicals of not more than 2 carbon atoms, for example the methyl and methoxy radical.
  • a preferred group of active ingredients for use in the compositions of the invention consists of alkene derivatives of the above formula wherein R stands for a hydrogen atom or the methyl radical, R stands for the methyl or ethyl radical, and one or both of the phenyl radicals A and B is or are optionally substituted with a halogen atom, and pharmaceutically-acceptable acid-addition salts thereof.
  • alkene derivatives which may be used as active ingredients in the pharmaceutical compositions of the invention there my be mentioned, for example,
  • Preferred compounds are N,N-dimethyl-3,3-diphenylprop- 2-enylamine and pharmaceutically-acceptable acid-addition salts thereof, for example the hydrochloride.
  • salts derived from inorganic or organic acids affording pharmaceutically-acceptable anions, for example hydrochlorides. oxalates, citrates, maleates or tartrates.
  • Suitable pharmaceutically-acceptable diluents or carriers for use as excipients in the compositions of the invention are those known to the art and used in the preparation of pharamecutical formulations for human and veterinary medication.
  • compositions which are suitable for oral administration include, for example, solid compositions, for example tablets, pills, capsules, dispersible powders and granules, which may optionally be coated, for example, with a sweetening agent and/or a protective material designed to modify the distribution and absorption of the active ingredient or ingredients in the digestive tract.
  • solid compositions for example tablets, pills, capsules, dispersible powders and granules, which may optionally be coated, for example, with a sweetening agent and/or a protective material designed to modify the distribution and absorption of the active ingredient or ingredients in the digestive tract.
  • sweetening agent and/or a protective material designed to modify the distribution and absorption of the active ingredient or ingredients in the digestive tract.
  • protective material designed to modify the distribution and absorption of the active ingredient or ingredients in the digestive tract.
  • orally-administrable semi-solid or liquid formulations for example pharmaceutically-acceptable emulsions, syrups, dispersions and solutions, either for administering per se with or Without flavouring agents or
  • compositions of the invention also include liquid compositions which are sterile aqueous solutions, suspensions or emulsions, or sterile non-aqueous solutions or suspensions which can be administered by injection, for example intravenously, subcutaneously or intramuscularly.
  • Those injectable compositions of the invention which are suspensions contain their particulate matter in a finely divided form, for example in a micropulverised form, and those compositions which are aqueous suspensions may optionally contain small amounts of such agents as are commonly used to facilitate the manufacture and maintain the efiicacy of aqueous suspensions, for example dispersing agents and suspending agents.
  • Suitable vehicles for the non-aqueous solutions and suspensions of the invention include, for example, watermiscible non-toxic vehicles, for example propylene glycol and polyethylene glycol, and water-immiscible non-toxic vehicles, for example injectable vegetable oils, for example arachis oil, and oil-like injectable organic esters, for example dibutyl succinate.
  • the said water-immiscible vehicles may also contain metallic soaps, for example aluminium stearate.
  • sterile injectable solutions, suspensions or emulsions of the invention may be obtained sterile by known procedures, for example by aseptic formulation, by Seitz filtration, by irradiation, by the incorporation of sterilising agents in the compositions, or by heat treatment.
  • compositions of the invention include pharmaceutical compositions which are sterile powders comprising the active ingredient or ingredients together with such non-toxic pharmaceutical excipients as are required to provide, on mixing with water, sterile aqueous solutions or suspensions suitable for parenteral administration.
  • alkene derivatives which are used as the active ingredients in the pharmaceutical compositions of this invention may be obtained by the dehydration of a propanolamine derivative of the formula:
  • Example 1 A mixture of 25 parts of N,N-dimethyl-3,S-diphenylprop-2-enylamine hydrochloride, 125 parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a 16-mesh screen. The granules so obtained are then compressed into tablets which are suitable for oral administration for therapeutic purposes.
  • Example 2 A mixture of 25 parts of N-methyl-3,3-diphenylprop-2- enylamine hydrochloride, 125 parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a l6-mesh screen. The granules so obtained are then compressed into tablets which are suitable for oral administration for therapeutic purposes.
  • N-methyl-3,3-diphenylprop-Z-enylamine hydrochlorid may be obtained as follows:
  • N-rnethyl-3,3-diphenylprop-2-enylamine hydrochloride M.P. 146l48 C.
  • N-methyl-3,3-diphenyl-3 hydroxypropylamine (M.P. l48-150 C., crystallised from n-butyl acetate) may be obtained in conventional manner by the interaction of phenyl magnesium bromide and w-methylaminopropiophenone.
  • Example 3 A mixture of 25 parts of N,N-dimethyl-3-(3-fluorophenyl)-3-phenylprop-2-enylamine hydrochloride, parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a 16-mesh screen. The granules so obtained are then compressed into tablets which are suitable for oral administration for therapeutic purposes.
  • N,N-dimethyl-3-(3-fluorophenyl) 3 phenylprop-Z- enylamine hydrochloride may be obtained as follows:
  • a mixture of 9 parts of N,N-dimethyl-3-(3-fiuorophenyl)-3-phenyl-3-hydroxypropylamine, 150 parts of acetic acid and 40 parts of 10 N-hydrochloric acid is heated at 95 C. for 2 hours, and is then kept at C. for 12 hours.
  • the solvent is then evaporated and the residue is made strongly alkaline with aqueous sodium hydroxide and is then extracted with 200 parts of ether.
  • the ethereal extract is washed with water and dried over anhydrous calcium sulphate, and the ether is then removed from the extract by evaporation.
  • the hydroxypropane derivative used as starting material may be obtained in conventional manner by the interaction of the appropriate Grignard reagent with the appropriate ketone.
  • diphenylalkenylamine derivatives listed above may be obtained in similar manner to that described for N,N-dimethyl-3-(3-fluorophenyl) 3 phenylprop-Z-enylamine hydrochloride.
  • the alkene derivatives which are used as active ingredients in the pharmaceutical compositions of this invention are active in a procedure that is standard in the art for testing for antidepressant agents. These results were obtained in standard experimental animals (mice), and they presumptively indicate utility in man. On the basis of these results obtained in standard experimental animals and data obtained in related laboratory studies, it is considered reasonable to expect that pharmaceutical compositions of this invention could be used clinically in man.
  • the total daily oral dose is expected to be in the range 30 to 300 mg. per kg. man, administered, for example, in the form of a tablet or capsule.
  • R is selected from the group consisting of hydrogen, methyl and ethyl
  • R is selected from the group consisting of hydrogen, methyl, ethyl and benzyl
  • A is selected from the group consisting of phenyl, hal-ogenophenyl, trifiuoromethylphenyl and tolyl
  • B is selected from the group consisting of phenyl, halogenophenyl, trifluoromethylphenyl, tolyl and anisyl, and pharmaceuticallyacceptable acid-addition salts thereof.
  • a method for effecting an antidepressant action comprises administering to said host an effective amount of N,N-di1nethyl-3,3-diphenylprop-2-enylamine or a pharmaceutica-lly-acceptable acid-addition salt thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US615327A 1966-02-24 1967-02-13 Treatment of depression with diphenyl prop-2-enylamine derivatives Expired - Lifetime US3422203A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB460766 1966-02-24
GB8166/66A GB1135926A (en) 1966-02-24 1966-02-24 Pharmaceutical compositions containing bisphenyl-alkenylamine derivatives
GB2627566 1966-06-13
GB4607266 1966-10-14

Publications (1)

Publication Number Publication Date
US3422203A true US3422203A (en) 1969-01-14

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US615327A Expired - Lifetime US3422203A (en) 1966-02-24 1967-02-13 Treatment of depression with diphenyl prop-2-enylamine derivatives

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US (1) US3422203A (US06299757-20011009-C00006.png)
BE (1) BE694631A (US06299757-20011009-C00006.png)
FR (1) FR7029M (US06299757-20011009-C00006.png)
GB (1) GB1135926A (US06299757-20011009-C00006.png)
NL (1) NL6702969A (US06299757-20011009-C00006.png)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6750244B2 (en) 1993-02-08 2004-06-15 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6017965A (en) * 1993-02-08 2000-01-25 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US7087765B2 (en) 1995-06-07 2006-08-08 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6071970A (en) * 1993-02-08 2000-06-06 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA525752A (en) * 1956-06-05 V. Petersen Poul Antispasmodic unsaturated tertiary amines
DE1122514B (de) * 1959-09-08 1962-01-25 Giulini Gmbh Geb Verfahren zur Herstellung von blutdrucksteigerndem 2-AEthyl-3,3-diphenyl-propen-(2)-yl-amin
DE1149002B (de) * 1961-10-19 1963-05-22 Giulini Gmbh Geb Verfahren zur Herstellung von blutdrucksteigernden Salzen von N, N-Dialkyl-2-aethyl-3, 3-diphenyl-propen-(2)-yl-aminen
DE1203247B (de) * 1961-10-10 1965-10-21 Koninklijke Pharma Fab Nv Verfahren zur Herstellung von Diphenylalkenyl-aminen sowie deren nicht-toxischen Salzen

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA525752A (en) * 1956-06-05 V. Petersen Poul Antispasmodic unsaturated tertiary amines
DE1122514B (de) * 1959-09-08 1962-01-25 Giulini Gmbh Geb Verfahren zur Herstellung von blutdrucksteigerndem 2-AEthyl-3,3-diphenyl-propen-(2)-yl-amin
DE1203247B (de) * 1961-10-10 1965-10-21 Koninklijke Pharma Fab Nv Verfahren zur Herstellung von Diphenylalkenyl-aminen sowie deren nicht-toxischen Salzen
DE1149002B (de) * 1961-10-19 1963-05-22 Giulini Gmbh Geb Verfahren zur Herstellung von blutdrucksteigernden Salzen von N, N-Dialkyl-2-aethyl-3, 3-diphenyl-propen-(2)-yl-aminen

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Publication number Publication date
FR7029M (US06299757-20011009-C00006.png) 1969-06-09
GB1135926A (en) 1968-12-11
NL6702969A (US06299757-20011009-C00006.png) 1967-08-25
BE694631A (US06299757-20011009-C00006.png) 1967-08-24

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