US3038835A - Method for the production of lowtoxic surface anaesthetics - Google Patents

Method for the production of lowtoxic surface anaesthetics Download PDF

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US3038835A
US3038835A US39211A US3921160A US3038835A US 3038835 A US3038835 A US 3038835A US 39211 A US39211 A US 39211A US 3921160 A US3921160 A US 3921160A US 3038835 A US3038835 A US 3038835A
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carbon atoms
duration
anaesthetic
anaesthetics
dimethyl
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Endres Gunther
Soehring Klaus
Henn Fritz
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Saab Bofors AB
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    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic 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
    • C07D211/36—Heterocyclic 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the purpose of the present invention is to create a new surface anaesthetic which has a low toxicity.
  • injectable local anaesthetics as surface anaesthetics.
  • examples of such are procaine, tetracaine, hostacaine, lidocaine and carbocaine.
  • the last-mentioned compound has the following formula:
  • R designates hydrogen or a hydrocarbon chain with a maximum of two carbon atoms
  • R designates hydrogen or a hydrocarbon chain with a maximum of two carbon atoms, R and R, then together having not more than three carbon atoms, and
  • R R are chosen among hydrogen groups, alkyl groups with a maximum of two carbon atoms, R R then together having not more than four carbon atoms.
  • a common characteristic. for the said injectable local anaesthetics is that they are toxic to a certain extent. When they are to be used as surface anaesthetics on for instance skin and mucous membranes, it can sometimes occur that they are to be used on large surfaces, and large quantities will then be required. It is then desirable that the concentration of the local anaesthetic is kept as low as possible with consideration to the toxicity. This involves that the duration is reduced considerably and in many cases does not attain the value required. It is thus a desire to be able to increase the duration while maintaining a low toxicity. It is, consequently, the toxicity which sets the upper limit for the duration of the injectable local anaesthetic. It is not advisable to use concentrations of more than 4% with consideration to the toxicity.
  • n has a value lying between 4 and 16 or preferably between 6 and 14.
  • the said compound has very little toxicity but iias the disadvantage that the depth of this anaesthetic is not satisfactory.
  • the compound should not be used in concentrations higher than 6%, as otherwise dermatological secondary etfects can occur. In most cases it is recommendable not to use concentrations lower than 2%. It is not advisable to exceed a molecular weight of 800 and not even to set a lower limit for the molecular weight than 500.
  • An appropriate relation between the number of carbon atoms in the group R and the number of oxyethyl groups is about 4-3.
  • Tests have now shown that if, when using surface anaesthetics, an injectable local anaesthetic or its salt are combined in a concentration which keeps the toxicity within permissible limits with a surface anaesthetic according to the last-mentioned formula and in a concentration which does not give rise to any secondary effects, a surface anaesthetic is obtained with an effect which exceeds the total effect of the two preparations. Tests have also shown that if an injectable local anaesthetic is chosen in a concentration which does not cause surface anaesthesia and this is combined with a surface anaesthetic of the abovementioned formula, the combination preparation obtains an effect which as regards the toxicity is considerably higher than that of the said surface anaesthetic.
  • the combination preparation formed is to be regarded as a mixture of the said injectable local anaesthetic and the said surface anaesthetic.
  • the two parts which have been mixed can be dissolved in an appropriate solvent, for instance water, or can be mixed into an appropriate carrier so that an ointment, a gel or a tablet is obtained.
  • Concentrations of the components of the combination preparation can of course be varied within wide limits on the condition that the toxicity of the combination preparation does not amount to such values that the preparation is not appropriate as a surface anaesthetic.
  • Example 1 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6- dimethyl anilide in a pulverized form and 0.25 g. of hydroxy ethoxy polyethoxy dodecane in the form of an oil and with a molecular weight of approx. 600 are dissolved in g. of distilled water with an isotonic addition of salt.
  • the said mixture has the character of a liquid. If 0.25 ml. of the said liquid is placed on a rabbit cornea a duration of approx. 20 minutes is obtained.
  • a 0.25% solution of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide gives a duration of 0 when applied to a rabbit cornea in a quantity of 0.25
  • a concentration of 0.25% hydroxy ethoxy polyethoxy dodecane when applied to a rabbit cornea and in a quantity of 0.25 ml. gives a duration of 10 minutes.
  • Example 2 If in Example 1, 0.25 g. of 1-methyl-2-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.50 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide a combination preparation is obtained which in a rabbit cornea gives a duration of 21.2 minutes. A 0.50% solution of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide gives a duration of 0 in a rabbit cornea.
  • Example 3 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.25 g. of w-diethyl amino-2,6-dimethyl acetanilide, a combination preparation is obtained which in a rabbit cornea gives a duration of 18.9 minutes. A 0.25% solution of w-diethyl amino-2,6-dimethyl acetanilide gives a duration of 0 in a rabbit cornea test.
  • Example 4 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.10 g. of 2-diethyl aminoethyl ester of p-aminobenzoic acid a combination preparation is obtainedwhich in a rabbit cornea test gives a duration of 18.4 minutes. A 0.1% solution of the said ester gives a duration of in a rabbit cornea test.
  • Example 5 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecane is replaced by 0.25 g. of hydroxy ethoxy polyethoxy benzene a combination preparation is obtained which in a rabbit cornea test gives a duration of 14.5 minutes. A potentiation is obtained as the anaesthetics alone only give durations of 0 and 6.5 minutes, respectively.
  • Example 6 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecane is replaced by 0.25 g. of hydroxy ethoxy polyethoxy octenyl dirnethyl benzene, a combination preparation is obtained which in a rabbit cornea test gives a duration of 15.3 minutes. A concentration of 0.25% of hydroxy ethoxy polyethoxy octenyl dimethyl benzene gives a duration of only 4.5 minutes in the same test.
  • Example 7 If in Example 1 the injectable local anaesthetic is replaced by 01 g. of (1-cyclopentyl-2-piperidine carboxylic acid)2,6-dimethyl anilide a combination preparation is obtained which in a rabbit cornea test gives a duration of 23.5 minutes. A potentiation is obtained as the anaesthetics individually give durations of only 3.0 and 6.5 minutes, respectively.
  • Example 8 If in Example 1 the injectable local anaesthetic is replaced by 0.1 g. of (1-methyl-5-ethyl-2-piperidine carboxylic acid)2,4,6-trimethyl anilide, a combination preparation is obtained which in a cornea test gives a duration of 21.0 minutes. A potentiation is obtained, as the an aesthetics individually only give durations of 0 and 6.5 minutes, respectively.
  • a surface active anesthetic composition comprising a member of the group consisting of injectable local anesthetics and salts thereof and a compound having the formula wherein R designates a member of the group consisting of alkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is a whole number ranging from 4 to 16.
  • R designates a saturated hydrocarbon radical having a maximum of 8 carbon atoms
  • R and R designate a member of the group consisting of hydrogen and an alkyl group having a maximum of 2 carbon atoms, provided that R plus R does not exceed 3 carbon atoms;
  • R R R R and R are members of the group consisting of hydrogen and alkyl radicals having a maximum of 2 carbon atoms, provided that the total carbon atoms in R plus R plus R plus R does not exceed 4 carbon atoms.
  • Method of producing surface active anmthetic compositions of low toxicity which comprises mixing a member of the group consisting of injectable local anesthetics and salts thereof with a compound having the formula wherein R designates a member of the group consisting of alkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is a whole number ranging from 4 to 16.
  • the local anesthetic is a member of the group consisting of lmethyLZ-Piperidine carboxylic acid-2,6-dimethyl anilide, (l-cyclo-pentyl-Z- iperidine car-boxylic acid)2,6-dimethyl anilide, (1-methyl-5-ethyl-2-piperidine carboxylic acid)- 2,4,6-trirnethyl anilide, w-diethyl amino-2,6-dimethyl acetanilide and Z-diethyl aminoethyl ester of p-amino benzoic acid.
  • R designates a saturated hydrocarbon radical having a maximum of 8 carbon atoms
  • R and R designate a member of the group consisting of hydrogen and an alkyl group having a maximum of 2 carbon atoms, provided that R plus R does not exceed 3 carbon atoms;
  • R R R R and R are members of the group consisting of hydrogen and alkyl radicals having a maximum of 2 carbon atoms, provided that the total carbon atoms in R plus R plus R plus R does not exceed 4 carbon atoms.

Description

United States Patent 3,038,835 METHOD FOR THE PRODUCTION OF LGW- TOXIC SURFACE ANAESTHETICS Giinther Endres and Klaus Seehring, Hamburg, Germany,
and Fritz Henn, Bofors, Sweden, assignors to Aktiebolaget Bofors, Bofors, Sweden, a company of Sweden No Drawing. Filed June 28, 1960, Ser. No. 39,211
Claims priority, application Sweden July 1, 1959 8 Claims. (Cl. 167-52) The purpose of the present invention is to create a new surface anaesthetic which has a low toxicity.
It is previously known to use injectable local anaesthetics as surface anaesthetics. Examples of such are procaine, tetracaine, hostacaine, lidocaine and carbocaine. The last-mentioned compound has the following formula:
(II) R4 O -NH in which R designates a straight branched or cyclic hydrocarbon chain with a maximum of eight carbon atoms,
in which R designates hydrogen or a hydrocarbon chain with a maximum of two carbon atoms,
in which R, designates hydrogen or a hydrocarbon chain with a maximum of two carbon atoms, R and R, then together having not more than three carbon atoms, and
in which R R are chosen among hydrogen groups, alkyl groups with a maximum of two carbon atoms, R R then together having not more than four carbon atoms.
A common characteristic. for the said injectable local anaesthetics is that they are toxic to a certain extent. When they are to be used as surface anaesthetics on for instance skin and mucous membranes, it can sometimes occur that they are to be used on large surfaces, and large quantities will then be required. It is then desirable that the concentration of the local anaesthetic is kept as low as possible with consideration to the toxicity. This involves that the duration is reduced considerably and in many cases does not attain the value required. It is thus a desire to be able to increase the duration while maintaining a low toxicity. It is, consequently, the toxicity which sets the upper limit for the duration of the injectable local anaesthetic. It is not advisable to use concentrations of more than 4% with consideration to the toxicity. It is known to use as a surface anaesthetic a compound called Thesit (hydroxy-polyethoxy-dodecane) and with the general formula R-(OCH CH ),,OCH CH OH in which R designates an alkyl, an aryl or an alkyl aryl group with a maximum of 20 carbon atoms and a minimum of 6 carbon atoms or preferably with a maximum of 16 carbon atoms and a minimum of 8 carbon atoms, in which n has a value lying between 4 and 16 or preferably between 6 and 14. The said compound has very little toxicity but iias the disadvantage that the depth of this anaesthetic is not satisfactory. The compound should not be used in concentrations higher than 6%, as otherwise dermatological secondary etfects can occur. In most cases it is recommendable not to use concentrations lower than 2%. It is not advisable to exceed a molecular weight of 800 and not even to set a lower limit for the molecular weight than 500. An appropriate relation between the number of carbon atoms in the group R and the number of oxyethyl groups is about 4-3.
At the production of a compound according to the 3,038,835 Patented June 12, 1962 general formula it proves that a mixture is obtained in a which the different components have values of n lying within the said limits. It is, of course, possible to separate a compound with the desired value of n but as a rule the mixture is accepted in its existing state.
Tests have now shown that if, when using surface anaesthetics, an injectable local anaesthetic or its salt are combined in a concentration which keeps the toxicity within permissible limits with a surface anaesthetic according to the last-mentioned formula and in a concentration which does not give rise to any secondary effects, a surface anaesthetic is obtained with an effect which exceeds the total effect of the two preparations. Tests have also shown that if an injectable local anaesthetic is chosen in a concentration which does not cause surface anaesthesia and this is combined with a surface anaesthetic of the abovementioned formula, the combination preparation obtains an effect which as regards the toxicity is considerably higher than that of the said surface anaesthetic.
The combination preparation formed is to be regarded as a mixture of the said injectable local anaesthetic and the said surface anaesthetic. The two parts which have been mixed can be dissolved in an appropriate solvent, for instance water, or can be mixed into an appropriate carrier so that an ointment, a gel or a tablet is obtained.
As the injectable local anaesthetics are very expensive and surface anaesthetics according to the formula are cheap to manufacture, a cheap and useful surface anaesthetic is obtained.
Concentrations of the components of the combination preparation can of course be varied within wide limits on the condition that the toxicity of the combination preparation does not amount to such values that the preparation is not appropriate as a surface anaesthetic.
The procedure according to the present invention will be illustrated through the following examples:
Example 1 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6- dimethyl anilide in a pulverized form and 0.25 g. of hydroxy ethoxy polyethoxy dodecane in the form of an oil and with a molecular weight of approx. 600 are dissolved in g. of distilled water with an isotonic addition of salt. The said mixture has the character of a liquid. If 0.25 ml. of the said liquid is placed on a rabbit cornea a duration of approx. 20 minutes is obtained. A 0.25% solution of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide gives a duration of 0 when applied to a rabbit cornea in a quantity of 0.25 A concentration of 0.25% hydroxy ethoxy polyethoxy dodecane when applied to a rabbit cornea and in a quantity of 0.25 ml. gives a duration of 10 minutes.
Example 2 If in Example 1, 0.25 g. of 1-methyl-2-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.50 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide a combination preparation is obtained which in a rabbit cornea gives a duration of 21.2 minutes. A 0.50% solution of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide gives a duration of 0 in a rabbit cornea.
Example 3 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.25 g. of w-diethyl amino-2,6-dimethyl acetanilide, a combination preparation is obtained which in a rabbit cornea gives a duration of 18.9 minutes. A 0.25% solution of w-diethyl amino-2,6-dimethyl acetanilide gives a duration of 0 in a rabbit cornea test.
aoaasse Example 4 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide is replaced by 0.10 g. of 2-diethyl aminoethyl ester of p-aminobenzoic acid a combination preparation is obtainedwhich in a rabbit cornea test gives a duration of 18.4 minutes. A 0.1% solution of the said ester gives a duration of in a rabbit cornea test.
Example 5 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecane is replaced by 0.25 g. of hydroxy ethoxy polyethoxy benzene a combination preparation is obtained which in a rabbit cornea test gives a duration of 14.5 minutes. A potentiation is obtained as the anaesthetics alone only give durations of 0 and 6.5 minutes, respectively.
Example 6 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecane is replaced by 0.25 g. of hydroxy ethoxy polyethoxy octenyl dirnethyl benzene, a combination preparation is obtained which in a rabbit cornea test gives a duration of 15.3 minutes. A concentration of 0.25% of hydroxy ethoxy polyethoxy octenyl dimethyl benzene gives a duration of only 4.5 minutes in the same test.
Example 7 If in Example 1 the injectable local anaesthetic is replaced by 01 g. of (1-cyclopentyl-2-piperidine carboxylic acid)2,6-dimethyl anilide a combination preparation is obtained which in a rabbit cornea test gives a duration of 23.5 minutes. A potentiation is obtained as the anaesthetics individually give durations of only 3.0 and 6.5 minutes, respectively.
Example 8 If in Example 1 the injectable local anaesthetic is replaced by 0.1 g. of (1-methyl-5-ethyl-2-piperidine carboxylic acid)2,4,6-trimethyl anilide, a combination preparation is obtained which in a cornea test gives a duration of 21.0 minutes. A potentiation is obtained, as the an aesthetics individually only give durations of 0 and 6.5 minutes, respectively.
Tests have also shown that a 0.3% solution of hydroxy ethoxy polyethoxy tetradecane can be combined with either 0.1% p-butyl aminobenzoyl-dimethyl aminoethanol or with 0.2% n-butyl amino2-methyl-6-chloroacetanilide, and a usable surface anaesthetic is then obtained, the effect of which is approximately twice the effect of the hydroxy ethoxy polyethoxy tetradecane.
We claim:
1. A surface active anesthetic composition comprising a member of the group consisting of injectable local anesthetics and salts thereof and a compound having the formula wherein R designates a member of the group consisting of alkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is a whole number ranging from 4 to 16.
2. A surface active anesthetic composition in accordance with claim 1, wherein the local anesthetic is a member of the group consisting of l-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide, (l-cyclo-pentyl-Z-piperidine carboxylic acid)2,6-dimethyl anilide, (l-methyl-S- ethyl Z-piperidine carboxylic acid)2,4,6-trimethyl anilide, 'w-diethyl amino-2,6-dimethyl acetanilide and Z-diethyl aminoethyl ester of p-amino benzoic acid.
3. A surface active anesthetic composition in accordance with claim 1, wherein the compound has a molecular weight'of about 500 to 800.
4. A surface active anesthetic composition in accordiance with claim 1, wherein the local anesthetic has the formula R R l H C-NHQ-Ru l Rz If Rs R1 wherein:
R designates a saturated hydrocarbon radical having a maximum of 8 carbon atoms;
R and R designate a member of the group consisting of hydrogen and an alkyl group having a maximum of 2 carbon atoms, provided that R plus R does not exceed 3 carbon atoms; and
R R R R and R are members of the group consisting of hydrogen and alkyl radicals having a maximum of 2 carbon atoms, provided that the total carbon atoms in R plus R plus R plus R plus R does not exceed 4 carbon atoms.
5. Method of producing surface active anmthetic compositions of low toxicity which comprises mixing a member of the group consisting of injectable local anesthetics and salts thereof with a compound having the formula wherein R designates a member of the group consisting of alkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is a whole number ranging from 4 to 16.
6. Method as defined in claim 5, wherein the local anesthetic is a member of the group consisting of lmethyLZ-Piperidine carboxylic acid-2,6-dimethyl anilide, (l-cyclo-pentyl-Z- iperidine car-boxylic acid)2,6-dimethyl anilide, (1-methyl-5-ethyl-2-piperidine carboxylic acid)- 2,4,6-trirnethyl anilide, w-diethyl amino-2,6-dimethyl acetanilide and Z-diethyl aminoethyl ester of p-amino benzoic acid.
7. Method as defined in claim 5, wherein the compound has a molecular weight of about 500 to 800v 8. Method as defined in claim 5, wherein the local anesthetic has the formula R4 R5 i H C-NH Rn I R2 Rs R1 wherein:
R designates a saturated hydrocarbon radical having a maximum of 8 carbon atoms;
R and R designate a member of the group consisting of hydrogen and an alkyl group having a maximum of 2 carbon atoms, provided that R plus R does not exceed 3 carbon atoms; and
R R R R and R are members of the group consisting of hydrogen and alkyl radicals having a maximum of 2 carbon atoms, provided that the total carbon atoms in R plus R plus R plus R plus R does not exceed 4 carbon atoms.
References Cited in the file of this patent FOREIGN PATENTS 799,779 Great Britain Aug. 13, 1958 799,780 Great Britain Aug. 13, 1958 805,523 Great Britain Dec. 10, 1958 91,086 Norway Mar. 3, 1958 OTHER REFERENCES Monash: Arch. Dermatol, 1957, pp. 752-756.
Ellin et al.: J. Am. Pharm. Ass. Pract. Ed., 1955, pp. 747-9 Utsumi et al.: Chem. Abst., 51, 1957, 5831(c).

Claims (1)

  1. 5. METHOD OF PRODUCING SURFACE ACTIVE ANESTHETIC COMPOSITIONS OF LOW TOXICITY WHICH COMPRISES MIXING A MEMBER OF THE GROUP CONSISTING OF INJEECTABLE LOCAL ANESTHETICS AND SALTS THEREOF WITH A COMPOUND HAVING THE FORMULA
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879401A (en) * 1972-09-01 1975-04-22 Wyeth John & Brother Ltd Piperidines
US4344965A (en) * 1978-10-13 1982-08-17 Raymond Stone Anesthetic compositions containing benzocaine
WO1997018813A1 (en) * 1995-11-22 1997-05-29 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5817678A (en) * 1995-11-22 1998-10-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6127366A (en) * 1995-11-22 2000-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

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SE7713618L (en) * 1977-12-01 1979-06-02 Astra Laekemedel Ab LOCAL ANESTHETIC MIXTURE
SE431092B (en) * 1979-07-10 1984-01-16 Thuresson Af Ekenstam Bo THERAPEUTICALLY ACTIVE, SUBSTITUTED PIPERIDINKARBOXIANILIDES
EP0031603A1 (en) * 1979-12-31 1981-07-08 American Cyanamid Company Pharmaceutical composition of matter
FR2528834B1 (en) * 1982-06-16 1986-03-07 Sanofi Sa AMMONIUM SALTS QUATERNARY OF CYCLIC AMINES DISUBSTITUTED IN A AND A 'BY PHENYLCARBAMOYLE GROUPS POTENTIALLY SUBSTITUTED ON PHENYL, AND ANTIARRHYTHMIC ACTS COMPRISING SAID SALTS
US5834490A (en) * 1993-11-04 1998-11-10 Instituto De Investigacion Y Desarrolo Quimico Biologico, S.A. Cyclopropyl derivatives, preparation method there-of and applications
ES2082703B1 (en) * 1993-11-04 1996-12-16 Inst Investigacion Desarrollo NEW DERIVATIVES OF CYCLOPROPIL, PROCEDURES FOR ITS PREPARATION AND APPLICATIONS.
US5715572A (en) * 1994-01-04 1998-02-10 Amiram Steinberg & Dalia Lapidot Hinge
US5776859A (en) * 1995-11-15 1998-07-07 Nickel; Alfred A. Sodium channel active novel compounds and related processes and bioassay techniques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB799779A (en) * 1956-02-22 1958-08-13 Bofors Ab Method of producing n-alkyl-alkyl-piperidine monocarboxylic acid amides and n-alkyl-alkyl-pyrrolidine monocarboxylic acid amides
GB799780A (en) * 1956-02-22 1958-08-13 Bofors Ab New n-alkyl-alkyl-piperidine-ª‡-monocarboxylic acid amides and n-alkyl-alkyl-pyrrolidine-ª‡-monocarboxylic acid amides
GB805523A (en) * 1955-08-08 1958-12-10 Cook Waite Lab Inc Local anesthetic composition and preparation thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB805523A (en) * 1955-08-08 1958-12-10 Cook Waite Lab Inc Local anesthetic composition and preparation thereof
GB799779A (en) * 1956-02-22 1958-08-13 Bofors Ab Method of producing n-alkyl-alkyl-piperidine monocarboxylic acid amides and n-alkyl-alkyl-pyrrolidine monocarboxylic acid amides
GB799780A (en) * 1956-02-22 1958-08-13 Bofors Ab New n-alkyl-alkyl-piperidine-ª‡-monocarboxylic acid amides and n-alkyl-alkyl-pyrrolidine-ª‡-monocarboxylic acid amides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879401A (en) * 1972-09-01 1975-04-22 Wyeth John & Brother Ltd Piperidines
US4344965A (en) * 1978-10-13 1982-08-17 Raymond Stone Anesthetic compositions containing benzocaine
WO1997018813A1 (en) * 1995-11-22 1997-05-29 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5817678A (en) * 1995-11-22 1998-10-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6127366A (en) * 1995-11-22 2000-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

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