US3712925A - Acenaphthene derivatives - Google Patents

Acenaphthene derivatives Download PDF

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Publication number
US3712925A
US3712925A US00101161A US3712925DA US3712925A US 3712925 A US3712925 A US 3712925A US 00101161 A US00101161 A US 00101161A US 3712925D A US3712925D A US 3712925DA US 3712925 A US3712925 A US 3712925A
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ether
compounds
percent
isopropyl
acenaphtheneacetonitrile
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US00101161A
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S Levine
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups

Definitions

  • the present invention relates to acenaphthene derivatives and more particularly to acenaphthene nitriles and amides having anti-inflammatory activity and to intermediates for the preparation of these new compounds.
  • the compounds of this invention are useful as antiinfiarnmatory agents and are effective in the prevention and inhibition of granuloma tissue formation in warm blooded animals, for example, in a manner similar to indomethacin. They may be used to decrease joint swelling tenderness, pain and stiffness, in mammalian species, e.g., in conditions such as rheumatoid arthritis.
  • a compound of Formula I or a physiologically acceptable salt (when applicable) of the character described hereinafter may be compounded according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg. to 2 gm. per day, preferably 100 mg. to 1 gm. per day in two to four divided doses. For example, about 150 mg./kg./day is effective in reducing paw swelling in rats.
  • acenaphthene derivatives of the invention have the general formula l-C-NH:
  • R and R are the same or dilferent and at least one must be alkyl having from one to about eight carbon atoms and preferably from about one to about three carbon atoms, or substituted aminoalkyl and the other can be hydrogen.
  • R and R can be the same or different and can be hydrogen or a hydrocarbon radical including alkyl having from one to about eight and preferably from one to about six carbon atoms, alkenyl having from two to about eight and preferably from two to about five carbon atoms, phenyl and alkylphenyl or phenylalkyl having from seven to about fifteen and preferably from seven to about ten carbon atoms, and A is alkylene having from one to about six and preferably from one to about four carbon atoms in the linking group.
  • alkyl radicals included in the compounds of the invention are straight, branched chain or cyclic radicals containing from about one to about eight carbon atoms and preferably from about three to about eight carbon ,atoms, and include, for example, methyl, ethyl, propyl,
  • alkenyl radicals examples include ethenyl, l-butenyl, 2-propenyl and B-pentenyl.
  • alkylphenyl radicals examples include all isomers of tolyl, xylyl, mesityl, and butylphenyl.
  • the phenylalkyl radicals are preferably phenyl lower alkyl radicals, wherein the lower alkyl group contains up to about six carbon atoms, such as benzyl, phenethyl, and phenylbutyl.
  • alkylene radicals (A) include methylene, ethylene, trimethylene, and tetramethylene as well as any of these containing alkyl side chains.
  • R is dimethylaminoethyl or dimethylaminopropyl and R is isopropyl.
  • Acids useful for preparing these acidaddition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids, such as maleic, methane sulfonic, cyclohexane sultamic, tartaric, citric, acetic and succinic acids.
  • inorganic acids such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as maleic, methane sulfonic, cyclohexane sultamic, tartaric, citric, acetic and succinic acids.
  • Examples of compounds falling within the present invention include, but are not limited to, the following:
  • nitrile of the structure R-iH-CN and finally hydrolyzing the nitrile IV by reacting it with an acid such as polyphosphoric acid, a mineral acid such as sulfuric acid, or an organic acid such as acetic acid or mixtures of such acids or an alkali metal al koxide such as potassium-t-butoxide to form a compound of the structure R I -CNH: H ll Nitrile IV
  • an acid such as polyphosphoric acid, a mineral acid such as sulfuric acid, or an organic acid such as acetic acid or mixtures of such acids or an alkali metal al koxide such as potassium-t-butoxide
  • R I -CNH: H ll Nitrile IV can be further alkylated by reacting it in the presence of a base such as sodium amide with an alkylating agent of the structure wherein R and X are as defined above in a molar ratio of IV:IV of within the range of from about 4:1 to about 1:1 to form a nitrile of the
  • EXAMPLE 2 a-Isopropy1-5-acenaphtheneacetonitrile A solution of 500 mg. of S-acenaphtheneacetonitrile in ml. of dimethylformarnide is cooled in an ice bath and treated with 111 mg. of sodium hydride and stirred for 0.5 hr. The mixture is treated with 0.44 ml. of isopropyl iodide and stirred at room temperature overnight. The mixture is poured into water and extracted with ether. The ether extracts are washed with water, 8% salt solution, dried (Na SO and evaporated.
  • EXAMPLE 3 a-[2- (dimethylamino)ethylJl-S-acenaphtheneacetonitrile, hydrochloride
  • a solution of 4.13 g. of 5-acenaphtheneacetonitrile in ml. of dimethylformamide is cooled in an ice bath and treated with 1.0 g. of sodium hydride and stirred for 45 min.
  • the mixture is treated with 2.3 g. of dimethylaminoethylbromide and stirred at room temperature overnight.
  • the mixture is diluted with water and extracted with ether.
  • the ether extracts are washed with 8% salt solution and then extracted with 2 N HCl.
  • the acidic fraction is made alkaline and extracted with ether.
  • the ether extracts are washed with 8% salt solution, dried (Na SO and evaporated. The residue is distilled to give 3.5 g. of an oil which is dissolved in ether and converted to a hydrochloride salt with I-ICl in methanol. The product is crystallized from ethanol-ether to give the title compound (3.72 g., M.P. 171-173").
  • the analytical sample is prepared by recrystallization from ethanol-ether: M.P. 171- 173;
  • EXAMPLE 4 a- [Z-(dimethylamino) ethyl]-a-isopropyl-5- acenaphtheneacetonitrile
  • the suspension is cooled and treated with 3.5 ml. of isopropyl bromide and stirred and refluxed for three days.
  • the mixture is treated with water and ether and the ether layer is separated.
  • the aqueous layer is extracted with additional ether.
  • EXAMPLE 5 a-[2-(dimethylamino)ethyl]-5-acenaphtheneacetamide A suspension of 250 mg. of a-[Z-(dimethyIamino) ethyl]-5-acenaphtheneacetonitrile, hydrochloride in 5 ml. of polyphosphoric acid is. stirred at ,for 1.5 hrs. The mixture is poured into ice water and stirred until solution is achieved. The aqueous fraction is extracted with ether and then made alkaline. The alkaline fraction is extracted with chloroform and the chloroform extracts washed (1:1) and evaporated to give 121 mg.
  • a compound according to claim 1 having the for- References Cited mula UNITED STATES PATENTS 3,282,964 11/1966 Szarvasi et a1. 260-558 5 3,257,420 6/1966 Szarvasi et a1. 260-558 0 3,573,304 3/1971 Eberle et a1. 260-558 O OTHER REFERENCES B Ianczewsl-u et 211., Chemical Abstracts, vol. 62, col. wherein R is 10 49697 (1965) R3 Smith, Open-Chain Nitrogen Compounds, v01. 1, p. 143 (1965). --AN 4 HENRY R. JILES, Primary Examiner I 3.
  • a compound of claim 1 having the name oc[2- H. I. MOATZ, Assistant Examiner (dimethylamino)ethyl]-u-isopropy1 5 acenaphtheneacetamide. US. Cl. X.R.
  • a compound of claim 1 having the name oz[Z-(di- 26O 465 R 465 E 5 methy1amino)propy1]-a-isopropyl 5 acenaphtheneacet- 20 amide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00101161A 1970-12-23 1970-12-23 Acenaphthene derivatives Expired - Lifetime US3712925A (en)

Applications Claiming Priority (1)

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US10116170A 1970-12-23 1970-12-23

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US (1) US3712925A (OSRAM)
CA (1) CA937941A (OSRAM)
CH (1) CH546216A (OSRAM)
DE (1) DE2163316A1 (OSRAM)
FR (1) FR2119034B1 (OSRAM)
GB (1) GB1380429A (OSRAM)
HU (1) HU163790B (OSRAM)

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Publication number Publication date
CA937941A (en) 1973-12-04
GB1380429A (en) 1975-01-15
HU163790B (OSRAM) 1973-10-27
FR2119034A1 (OSRAM) 1972-08-04
FR2119034B1 (OSRAM) 1975-11-28
CH546216A (fr) 1974-02-28
DE2163316A1 (de) 1972-07-13

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