IL27360A - 1,alpha,alpha-trimethyl-2-piperidylcarbinol diphenylacetate,process for the preparation thereof and its use as topical anesthetic - Google Patents

1,alpha,alpha-trimethyl-2-piperidylcarbinol diphenylacetate,process for the preparation thereof and its use as topical anesthetic

Info

Publication number
IL27360A
IL27360A IL2736067A IL2736067A IL27360A IL 27360 A IL27360 A IL 27360A IL 2736067 A IL2736067 A IL 2736067A IL 2736067 A IL2736067 A IL 2736067A IL 27360 A IL27360 A IL 27360A
Authority
IL
Israel
Prior art keywords
diphenylacetate
alpha
acid addition
piperidylcarbinol
process according
Prior art date
Application number
IL2736067A
Original Assignee
Farmaceutici Italia
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Farmaceutici Italia filed Critical Farmaceutici Italia
Publication of IL27360A publication Critical patent/IL27360A/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/04Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent
    • C08J9/06Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent by a chemical blowing agent
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02Preparation by ring-closure or hydrogenation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2327/00Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers
    • C08J2327/02Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment
    • C08J2327/04Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment containing chlorine atoms
    • C08J2327/06Homopolymers or copolymers of vinyl chloride

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

C O H E N Z E D E K & S P I S B A C H R E G D. PA TE NT A TT O R N E YS 24, LEVONTIN SIR., P. O. B. 1169 T E L - A V I V Ί 3 P A T E N T S & D E S I G N S O R D I N A N C E 1615V67 SPECIFICATION 1 · tt-TRIMETHYL-2—PIPERIDULCARBINOL DIPHENYLACETATE , PROCESS FOR THE PREPARATION THEREOF AND ITS USE AS TOPICAL ANAESTHETIC ¾?n o Tain Tina ia SOCIETA' FABfi-ACEUTICI ITALIA, an Italian Joint Stock Company, of 1/2, largo Guido Donegani, Milano, Italy, HEREBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement: The invention relates to a new 2-piperidylcarbinol which has proved useful in therapy as a topical anaesthetic and to a process of preparing it.
The new compound of the invention is the diphenylacetate of l,ck , k -trimethyl-2-piperidylcarbinol and the process of preparation starts from k ,<λ -dimethyl-2-pyr idylcarbinol and comprises hydrogenating to the corresponding piperidylcarbinol, treating this compound with formaldehyde and hydrogen in the presence of a hydrogenat ion catalyst, and esterifying the oroduct to form the diphenylacetate. The non-toxic pharmaceutically acceptable acid addition salts of the new compounds of the invention are also active. These may be obtained by treatment with an acid in the usual manner. The invention includes pharmaceutical compositions containing one or more active compounds according to the invention in admixture with a pharmaceutically acceptable diluent.
This process is illustrated by the following reaction scheme: CH- H n- I II esterify The new compound of the invention shows an interesting topical anaesthetic activity which has been tested in comparison with that of Lidocaine (2-diet hyl-amino-2' ,6' -aceto-xylidMe ) , which is a most effective product used in the field. It has been demonstrated that at the same toxicity level a clearly higher anaesthetic activity is shown by the new compound of the invention. Because of its major pharmacological activity the new compound of the invention can be classified among those substances capable of blocking the transmission of the nervous centripetal impulses in nerve fibres. Such an activity has been tested by the following methods; a) Sur ac e ..anae. st he s ia : The technique of anaesthesia of the conjunctival mucosa in the rabbit based on the b) Infiltration anaesthesia : The technique of intradermic anaesthesia in the Guinea-pig based upon the disappearance of the horripilation reflex (Btilbring E., Wa^da J.: J.
Pharmacol, exp. Ther., 19^ , 8>, 78) was used. c) Conduction anaesthesia : The technique of anaesthesia of the lumbar plexus of the frog based on the disappearance of the defence reflex of the lower limbs (Bulbring E., Wajda ubl supra) was used.
In all cases adequate gradual concentrations of l,dt > <λ -trimethyl-2-piperidylcarbinol dipheylacetate , dissolved in a physiological sodium chloride solution (NaCl 9°/Q0 τ 7°/00 for amphibians) were used. The symbol °/Q0 means per thousand. Determinations were repeated on at least 6-10 animals in order to obtain statistically valid and valuable data. The statistic evaluation of the activity ratio was calculated by the method of "6-point biological essay" according to the 1st supplement to the Farmacopea Ufficiale Italiana, 7th edition 1965. In Table 1 are reported the effective concentrations (A) of 1,<λ ,ελ -trimethyl-2-piperidylcarbinol dipheaylacetate and the activity ratio (B) in comparison to Lidocaine taken as unity. The effective concentration of a substance is that necessary to produce total anaesthesia for at least 30 minutes in the subject under examination.
TABLS 1 From the above data the new compound of the invention appears active even at very low concentrations. In intradermic anaesthesia it is at least three times more ative than Lidocaine while in surface anaesthesia this ratio rises to about forty.
Acute o icity determined in the albino mouse by a single treatment by various admi istration routes is practicall; the same as that of Lidocaine subcutaneously administered.
The test has been carried out on groups of a least 10 subjects for each dosage and the relevant statistical calculation of LD^Q and of limits of utility has been carried out by the probits method (Burn J.H.: Biological Standardization - Oxford 1950). In Table 2 LD^0 (acute toxicity) data after subcutaneous and intravenous administratio of 1,· , The following Example illustrates the invention: EXAMPLE 1Τ Λ ,<Λ -trimethyl-2-pineridylc^arbiniOl, diphenylacetate 39.75 g of ck -dimethyl-2-pyridylcarbinol (prepared according to Chem. Ber., 1908, ίϋ, page LH03) are dissolved in 60 cc of ethanol. 1 g of Adams platinum is added and hydrogenat ion is carried out in an autoclave at 90°C under 60 atmospheres s h u caustic soda and extracted with diethyl ether. After evaporation of the ether 25 g of t -dimethyl-2-piperidylcarbinol are distilled in vacuo. The boiling point is 78-80°C under a pressure of 5 mm Hg.
To 9.7 g of this compound dissolved in 100 cc of ethanol 11 cc of 30 aqueous formaldehyde solution and 0.7 g of 10$ palladium on charcoal are added and hydrogenat ion is carried out at 110°C under a pressure of 60 atmospheres. After 20 hours the reaction mass is filtered, the alcohol is removed, and the remainder is distilled in vacuo, The fraction which distills between 70 and 75°C under a pressure of 2 mm Hg is collected. 6.5 g of 1,<Λ^ -trimethyl-2-piperidylcarbinol are obtained.
To 2 g of this last compound dissolved in 10 cc of pyridine 3 g of diphenylacetyl chloride are added. After 2 days the pyridine is evaporated off in vacuo, taken up with benzene and washed with a 10$ aqueous sodium hydroxide solution. The benzene solution is dried and chromatographed over a column of 60 g of silica gel. By elution 2.5 g of 1, c jck -trimethyl-2-piperidylcarbinol diphenylacetate are obtained, which on treatment with hydrochloric acid gives the corresponding hydrochloride in the form of a white crystalline powder, soluble in water and ethanol. Melting point: 177°C.

Claims (2)

1. particularly and ascertained the our and is to be that what A process of preparing carbinol diphenylacetate a acceptable acid addition salt thereof in which is hydrogenated to the corresponding this compound with formaldehyde and hydrogen in the presence of a hydrogenation esterifying the product to form the he ylacet and where appropriate treating with an acid to obtain a pharmaceutically acceptable acid addition A process according to Claim 1 in which the initial hydrogenation is carried out in the presence of Adams A process according to Claim 1 or
2. Claim 2 in which the treatment with formaldehyde and hydrogen is carried out in the oresence of palladium on A process according to any of the preceding claims in which esterificat ion is carried out with diphenylacetyl chloride A process of preparing carbinol diphenylacetate or a pharmaceutically of acceptable acid addition salt substant ially as hereinbefore described in the 1 carbinol diphenylacetate or a pharmaceutically acceptable acid addition salt thereof prepared by a process according to any of the preceding 1 diphenylacetate hydrochloride A pharmaceutical composition containing 1 diphenylacetate or a acid addition salt thereof in admixture with a tically acceptable Dated this 9th day of Box Attorneys for Applicants insufficientOCRQuality
IL2736067A 1966-02-03 1967-01-30 1,alpha,alpha-trimethyl-2-piperidylcarbinol diphenylacetate,process for the preparation thereof and its use as topical anesthetic IL27360A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT1408166 1966-02-03
IT228666 1966-02-03

Publications (1)

Publication Number Publication Date
IL27360A true IL27360A (en) 1971-01-28

Family

ID=26325232

Family Applications (1)

Application Number Title Priority Date Filing Date
IL2736067A IL27360A (en) 1966-02-03 1967-01-30 1,alpha,alpha-trimethyl-2-piperidylcarbinol diphenylacetate,process for the preparation thereof and its use as topical anesthetic

Country Status (11)

Country Link
BE (1) BE693587A (en)
CH (1) CH484905A (en)
DK (1) DK118186B (en)
ES (1) ES336375A1 (en)
FR (1) FR6135M (en)
GB (1) GB1110637A (en)
IL (1) IL27360A (en)
NL (1) NL6701022A (en)
NO (1) NO122068B (en)
SE (1) SE321474B (en)
YU (1) YU32140B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE7607114L (en) 1976-06-22 1977-12-23 Bofors Ab METHOD OF PREPARING THE HYDROCHLORIDE OF N-METHYLPIPERIDINE-2-CARBONIC ACID-2,6-XYLLIDIDE

Also Published As

Publication number Publication date
BE693587A (en) 1967-08-02
FR6135M (en) 1968-06-24
DK118186B (en) 1970-07-20
ES336375A1 (en) 1968-04-01
YU32140B (en) 1974-04-30
YU18367A (en) 1973-08-31
NL6701022A (en) 1967-08-04
SE321474B (en) 1970-03-09
CH484905A (en) 1970-01-31
GB1110637A (en) 1968-04-24
NO122068B (en) 1971-05-18

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