US3520920A - Amine salts of nopinic acid - Google Patents

Amine salts of nopinic acid Download PDF

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Publication number
US3520920A
US3520920A US467712A US3520920DA US3520920A US 3520920 A US3520920 A US 3520920A US 467712 A US467712 A US 467712A US 3520920D A US3520920D A US 3520920DA US 3520920 A US3520920 A US 3520920A
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US
United States
Prior art keywords
acid
nopinic
nopinic acid
compounds
nopinate
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.)
Expired - Lifetime
Application number
US467712A
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English (en)
Inventor
Leon Gillo
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Pharmatic Inc
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Pharmatic Inc
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Publication date
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Publication of US3520920A publication Critical patent/US3520920A/en
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Expired - Lifetime legal-status Critical Current

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/12—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/02—Saturated compounds containing hydroxy or O-metal groups
    • C07C62/06—Saturated compounds containing hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S585/00—Chemistry of hydrocarbon compounds
    • Y10S585/929—Special chemical considerations
    • Y10S585/947—Terpene manufacture or recovery

Definitions

  • This invention relates to new pharmaceutical compositions and particularly to compositions suitable for the prevention and control of ulcers and/or of the pain due to ulcers, particularly ulcers of the digestive tract, such as the ulcers of the gastro-duodenal tract, as well as the skin ulcers.
  • compositions according to this invention contain, as active ingredient, at least one compound of the following general formula:
  • R and R' which may be similar or different, represent a lower alkyl radical, or a group of the formula in which n, R and R have the above indicated meaning.
  • p-pinene or nopinene is a known compound of the formula:
  • compositions may also contain, as active ingredient, compounds of the general formula I which are new compounds.
  • compounds of the general formula I which are new compounds. These new compounds may be represented by the following general formulae:
  • This invention includes as new compounds the esters and salts of nopinic acid of the Formula IV and V, as well as the acid addition salts, such as the hydrochlorides of the compounds of the Formula IV.
  • compositions according to the present invention are generally intended for peroral, topical or parenteral administration.
  • Therapeutical compositions to be administered perorally may, for example, be in the form of tablets, dragees, capsules, in which at least one compound selected among the compounds of the general Formula I is mixed with a solid pharmaceutically acceptable vehicle or excipient.
  • the therapeutical compositions may also be used in the form of ointments or creams for the treatment of skin ulcers, said ointments or creams containing at least one compound selected among the compounds of the Formula I mixed to an usual pharmaceutical cream or ointment base.
  • compositions can also be used in the form of liquid preparations for oral administration, especially syrups, elixirs, aqueous dispersions or solutions.
  • compositions according to the present invention can also be used in the form of solution to be administered parenterally.
  • Solutions or suspensions for injection purpose can be prepared by using, for example, distilled water of sterile a pyrogenic water, in which at least one compound of the aforementioned Formula I is dissolved or suspended, if desired in the presence of a dissolving or stabilizing agent, such as propylene glycol.
  • a compound selected among the compounds of general Formula I can be administered rectally, by incorporating it in a composition for suppositories, for example in cocoa butter.
  • B-pinene and the compounds of the general Formulae III, IV and II can be administered in varying doses, depending on the particular compound being used, the condition of the patient and the method of administration.
  • the compounds in question can be administered in doses from 50 to 600 mg. per day, in the form of several doses taken throughout the day.
  • the invention relates also to processes for the preparation of the new compounds represented by the Formulae 1V and V.
  • alkyl esters as well as the aminoalkyl esters of nopinic acid of the Formula IV may be prepared by the usual esterification methods, such as:
  • the aminoalkanol salts of nopinic acid of the Formula V may be prepared by dissolving nopinic acid in an anhydrous organic solvent, by neutralizing the solution with a stoichiometric quantity of the suitable aminoalcohol dissolved in the same solvent and by concentratin to dryness.
  • EXAMPLE 1 Preparation of nopinic acid This acid may be prepared by oxidation of fi-pinene by means of potassium permanganate or another oxidizing agent, the reaction being carried out in an aqueous alkaline medium, by the following procedure:
  • the crude sodium nopinate is dissolved in 5-6 times its weight of boiling water.
  • the obtained solution is filtered and cooled during one night in a refrigerator.
  • the purified sodium nopinate is then filtered, washed with ice water and dried at low temperature.
  • the purified sonium nopinate is suspended into 5 times its weight of water and 7 times its weight of methylene chloride. Hydrochloric acid is added to the mixture until it is strongly acid and the sodium nopinate disappears.
  • the organic phase contains the nopinic acid.
  • EXAMPLE 2 Preparation of alkaline metal and ammonium salts of nopinic acid These salts may be prepared by dissolving nopinic acid in methanol or another solvent. The solution is neutralized by the stoichiometric quantity of a suitable base dissolved in methanol. The methanol is removed under vacuum.
  • ammonium nopinate for example, 1.8 g. of pure nopinic acid are dissolved into 20 m1. of methanol and the alcoholic solution is exactly neutralized with a titrated solution of gaseous ammonia in methanol. The methanol is removed under vacuum. The obtained ammonium nopinate is soluble in water.
  • EXAMPLE 3 Preparation of methylnopinate 10 g. of sodium nopinate are refluxed during 18 hours with 20 g. of methyl iodide dissolved in ml. of methanol. The mixture is then concentrated to dryness. 25 ml. of water are added to the residue and the aqueous solution is extracted several times with 20 ml. of methylene chloride. The combined extracts are dried on anhydrous sodium sulphate and the methylene chloride is evaporated. The methyl nopinate is distilled under reduced pressure. Yield: 76%. This product is a liquid which is not miscible with water, but may be dissolved in organic solvents.
  • EXAMPLE 4 Preparation of the dirnethylaminoethyl ester of nopinic acidand the hydrochloride thereof 7 g. of methyl nopinate prepared as described in Example 3 are heated during 12 hours at 100 C. in the presence of 50 ml. of dimethylaminoethanol and 1 g. of sodium. The excess of dimethylaminoethanol is removed by concentration to dryness. The solid residue is suspended in 100 ml. of ether. 50 ml. of water are added, whereafter methanol is added in a sufficient quantity for dissolving again the precipitate. The organic (ether) phase is collected and the aqueous phase is extracted three times with 50 ml. of ether.
  • the ether extracts are combined and washed 5 times with 25 ml. of water.
  • the ether solutions are dried on anhydrous magnesium sulphate. After distillation of the ether, a solid residue of dimethylaminoethyl nopinate is obtained.
  • hydrochloride of this base gaseous hydrochloric acid is bubbled into an ether solution of said base until saturation is reached.
  • the hydrochloride precipitates: M.P. 226 C.
  • This salt may be recrystallized from a mixture (1:3) of methanol and isopropanol. Fine white needles melting at 230-231" C. are obtained.
  • This product is soluble in water and methanol, insoluble in ether, benzene and hexane.
  • EXAMPLE 6 Preparation of the monomethylaminoethyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Example 4 from methyl nopinate, monomethylaminoethanol and sodium.
  • the ester melts at 144-145 C.
  • the hydrochloride melts at 141143 C. after recrystallization from acetone.
  • EXAMPLE 7 Preparation of the diisopropylaminoethyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Example 4 from methyl nopinate, diisopropylaminoethanol and sodium. The hydrochloride melts at 179-180 C. after recrystallization from a mixture of benzene and acetone.
  • EXAMPLE 8 Preparation of the di-n-butylaminoethyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Example 4 from methyl nopinate, di-n-butylaminoethanol and sodium. The hydrochloride cannot be crystallized.
  • EXAMPLE 9 Preparation of the dimethylaminopropyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Examples 4 from methyl nopinate, dimethylaminopropanol and sodium. The hydrochloride melts at 90-91 C.
  • EXAMPLE 10 Preparation of the dimethylaminoethanol salt of nopinic acid 18.4 g. of nopinic acid are dissolved in 100 ml. of methylene chloride and 8.9 g. of dimethylaminoethanol
  • EXAMPLE 11 Preparation of the aminoethyl salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and aminoethanol. After recrystallization from a mixture of ethanol and benzene, the compound melts at 155 C.
  • EXAMPLE 12 Preparation of the monomethylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and monoethylaminoethanol. This compound melts at 99-100 C. after recrystallization from benzene.
  • EXAMPLE 13 Preparation of the diethylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and diethylaminoethanol. This compound melts at 6667 C. (benzene).
  • EXAMPLE 14 Preparation of the diisopropylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and diisopropylaminoethanol. The compound melts at 7273 C. after recrystallization from ethanol.
  • EXAMPLE 15 Preparation of the di-n-butylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and di-n-butylaminoethanol. The white glasey compound cannot be recrystallized.
  • EXAMPLE 16 Preparation of the dimethylaminopropanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and dimethylaminopropanol. The pasty white product obtained by this process cannot be recrystallized.
  • EXAMPLE 17 Tablets of nopinic acid derivative Mg. Nopinic acid derivative 100 Starch 100 Talc 50 Magnesium stearate 5 EXAMPLE 18 Vial for intramuscular injection Nopinic acid derivative100 mg. Buffering phosphate to pH7.5 Apyrogenic water q.s. ad.-1 m1.
  • EXAMPLE 19 Suppositories Nopinic acid derivative-100 mg. Cocoa butter q.s. ad.-1 suppository 7
  • EXAMPLE 20 Ointment G.
  • Nopinic acid derivative 10 Ointment base (sodium lauryl sulfate, cetyl alcohol,
  • the nopinic acid derivative is preferably the dimethylaminoethanol salt of nopinic acid or the hydrochloric of dimethylaminoethyl nopinate.
  • esters and salts of nopinic acid of the Formulae IV and V are especially active, the compounds wherein R and R represent identical methyl, ethyl, or propyl groups being the most active compounds, The best compound seems to be the dimethyl-aminoethanol salt of nopinic acid (called S.N.D.).

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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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US467712A 1964-07-06 1965-06-28 Amine salts of nopinic acid Expired - Lifetime US3520920A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB27788/64A GB1117782A (en) 1964-07-06 1964-07-06 Nopinic acid derivatives, their preparation and pharmaceutical compositions containing them

Publications (1)

Publication Number Publication Date
US3520920A true US3520920A (en) 1970-07-21

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US467712A Expired - Lifetime US3520920A (en) 1964-07-06 1965-06-28 Amine salts of nopinic acid

Country Status (9)

Country Link
US (1) US3520920A (fr)
BE (1) BE666352A (fr)
CY (1) CY616A (fr)
DE (1) DE1235310B (fr)
ES (1) ES314976A1 (fr)
FR (2) FR1439597A (fr)
GB (1) GB1117782A (fr)
MY (1) MY7100219A (fr)
NL (1) NL6508625A (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1319931C (zh) * 2005-08-05 2007-06-06 中国科学院广州化学研究所 一种制备4－异丙基环己烷甲酸的方法
CN1331837C (zh) * 2005-09-01 2007-08-15 中国科学院广州化学研究所 一种制备诺蒎酸的方法
CN100436396C (zh) * 2006-09-11 2008-11-26 浙江树人大学 一种合成对异丙基苯甲酸的新方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1319931C (zh) * 2005-08-05 2007-06-06 中国科学院广州化学研究所 一种制备4－异丙基环己烷甲酸的方法
CN1331837C (zh) * 2005-09-01 2007-08-15 中国科学院广州化学研究所 一种制备诺蒎酸的方法
CN100436396C (zh) * 2006-09-11 2008-11-26 浙江树人大学 一种合成对异丙基苯甲酸的新方法

Also Published As

Publication number Publication date
MY7100219A (en) 1971-12-31
GB1117782A (en) 1968-06-26
DE1235310B (de) 1967-03-02
ES314976A1 (es) 1966-04-01
FR4687M (fr) 1966-12-19
CY616A (en) 1971-10-20
BE666352A (fr) 1966-01-03
NL6508625A (fr) 1966-01-07
FR1439597A (fr) 1966-05-20

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