EP0735873A1 - Verwendung von pyridon-derivaten als anästhetische arzneimittel - Google Patents

Verwendung von pyridon-derivaten als anästhetische arzneimittel

Info

Publication number
EP0735873A1
EP0735873A1 EP95904582A EP95904582A EP0735873A1 EP 0735873 A1 EP0735873 A1 EP 0735873A1 EP 95904582 A EP95904582 A EP 95904582A EP 95904582 A EP95904582 A EP 95904582A EP 0735873 A1 EP0735873 A1 EP 0735873A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
alkyl
pharmaceutically acceptable
anesthetic
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.)
Withdrawn
Application number
EP95904582A
Other languages
English (en)
French (fr)
Inventor
Denis Guedin
Gilles Hamon
Francis Petit
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.)
Sanofi Aventis France
Original Assignee
Roussel Uclaf SA
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 Roussel Uclaf SA filed Critical Roussel Uclaf SA
Publication of EP0735873A1 publication Critical patent/EP0735873A1/de
Withdrawn legal-status Critical Current

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the subject of the present invention is the application as medicaments, of pyridone derivatives, having a local anesthetic activity of long duration of action.
  • compositions in accordance with the present invention contain as active principle a compound of formula (I) exerting a local anesthetic activity of contact and infiltration of long duration. This activity has been verified by several methods commonly used in pharmacology. Several of the compounds of formula (I) have already been described in EP-A 437 120 for the treatment of diseases such as pancreatitis or colic nephretic or biliary.
  • RL represents a fluorine, chlorine or bromine atom, or a nitro or -0- (C 1 -C 6 ) -alkyl group, preferably a halogen atom
  • R 2 represents a fluorine, chlorine or bromine atom, or a nitro or -0- (C 1 -C 8 ) -alkyl group, preferably a halogen atom
  • R 3 represents a (C 1 -C 6 ) -alkyl, (C ⁇ C g ) -alkenyl or benzyl radical, preferably a (C 1 -C 8 ) -alkyl radical;
  • X represents an oxygen or sulfur atom or a group
  • n 1, 2 or 3; to obtain a medicine for use as an anesthetic.
  • a compound of formula (I) or one of its pharmaceutically acceptable salts is used as active principle, in which R 3 represents a radical (C- j ⁇ -Cg) - alkyl, X represents a group -CH 2 -, m represents 2 and n represents 1.
  • the star in the general formula indicates a center of chirality, which can have the configuration (R) or (S).
  • the compound of formula (I) reacts with an equivalent of organic or mineral acid to form the corresponding acid addition salt.
  • These acid addition salts and the free base naturally form the same structural entity.
  • the acid addition salts are the equivalent of the free bases and the compound of formula (I) includes both the free base and its acid addition salts.
  • acids to form pharmaceu ⁇ tically acceptable salts include the following acids: formic, acetic, isobutyric, sulfonic, hydrochloric, alpha-mercaptopropionic, trifluoroacetic, malic, fumaric, succinic, succinamic, glutamic, tartaric , oxalic, citric, lactic and glycolic.
  • the fumaric and sulfonic salts are preferred.
  • the acid addition salts are prepared in the usual manner, for example by direct mixing of the acid and the base or, when this process is not suitable, by dissolving the acid and / or the base separately in water or in an organic solvent and by mixing the two solutions or by dissolving the acid and the base together in a solvent.
  • the resulting acid addition salt is isolated by filtration if it is insoluble in the reaction medium or by evaporation of the reaction medium to leave the acid addition salt in the form of a residue.
  • R 1 and R 2 represent a chlorine atom; R 3 represents a methyl radical; X represents a group -CH 2 -; m represents 2 and n represents 1.
  • fumarate is more particularly used such as for example the fumarate of S- (3) - (3,4-dichlorophenyl) 3-methyl l- (l-phenyl 2- (1-pyrrolidinyl) ethyl) 2-piperidinone.
  • the center of chirality of the atom linked to the radical R 3 (marked by a star) can have the R or S configuration.
  • the center of chirality of the atom linked to the phenyl group is preferably of R configuration, but the compounds of configuration S are also active.
  • the various methods for the preparation of the compounds of formula (I) are well known, described for example in EP-A 437 120.
  • the subject of the invention is also the application of a compound of formula (I) or of its pharmaceutically acceptable salts to obtain a local anesthetic drug for contact or infiltration.
  • the dosage of the anesthetic drug varies in particular depending on the route of administration, the condition treated and the subject concerned.
  • the dose of active ingredient is variable.
  • the invention extends to pharmaceutical compositions containing as active ingredient the compounds defined above.
  • compositions can be administered locally, applied topically to the skin and mucous membranes. Such presentations are packaged, as the case may be, in jars or tubes, in a glass or plastic bottle or possibly in a dosing bottle or in ampoules.
  • These compositions can be solid in the form of a gel, or liquid and can be in several pharmaceutical forms commonly used in human medicine, such as, for example, solutions, injections, emulsions, ointments, milks, creams, gels and preparations in the form of aerosols or liposomes; they are prepared according to the usual methods.
  • the active compound is prepared as described in Example 37 of European patent application EP-A 437 120, having a melting point of 175 ° C.
  • Solutions are prepared which contain: a) 0.5 g of the active principle in 100 g of a 50% aqueous solution of glycerol formai, b) 1.0 g of the active principle in 100 g of a 50% aqueous solution of glycerol formai, c) 0.1 g of the active principle in 100 g of a 12% aqueous solution of glycerol formai, d) 0.2 g of the active principle in 100 g of a 12% aqueous solution of glycerol formai.
  • glycerol formai Sanderson DM, "A note of glycerol formai as a solvent in toxicity testing", J. Pharm. Pharmacol (1959); 11, 150-156) at 50% with concentrations of 0.5% and 1% (solutions a) and b) of Example 1).
  • the test is carried out on guinea pigs according to the method of M.R.A. Chance and H.J. Lobstein, "The value of the guinea-pig corneal reflex for tests of surface anaesthesia", J. Pharma ⁇ col (1944); 82, 203.
  • the anesthetic activity is highlighted by the disappearance of the corneal reflex following 5 successive stimulations carried out on the cornea by means of a horsehair.
  • the active compound is instilled into the lacrimal sac of the eye in a volume of 50 ⁇ l; the eyelid is maintained for 30 seconds to allow good contact of the product with the eye.
  • the solvent is administered in the same way to the other eye.
  • the eye is then stimulated 5, 10, 15, 30 and 60 minutes after the administration of the product and then optionally every 30 minutes until the anesthetic effect disappears.
  • the results are expressed by the time (in minutes) during which the product induces a 100% suppression of the corneal reflex.
  • the test is carried out on immobilized guinea pigs placed in the prone position, the backs of the animals being largely shaved.
  • the active product is injected intradermally in a volume of 0.1 ml on one side of the spine. On the other side the solvent is injected in the same way.
  • the local anesthetic activity is highlighted by the disappearance of the paucier reflex following 6 successive stimulations carried out using a needle.
  • the stimulations were carried out 5, 10, 15, 30, 60 minutes after the injection and then every 30 minutes until the anesthetic effect disappeared.
  • the results are expressed by the time (in minutes) during which the product induces a 100% suppression of the paucier reflex.
  • Lidocaine (solubilized in HC1 0.05 N) is used as a reference product.
  • RESULTS a) Local contact anesthesia: corneal reflex
  • the active compound has a local anesthetic contact activity greater than that of bupivacaine. At a concentration of 1%, the activity of the active principle is 100% for 90 minutes while bupivacaine gives such activity only for 15 minutes. At a concentration of 0.5% the total anesthesia of all animals lasts 45 minutes.
  • the local anesthetic activity of the new active ingredient lasts 15 minutes.
  • the anesthesia is complete for 5 minutes.
  • the compounds according to this invention are less arrhythmogenic than known anesthetic drugs.
  • the products also have better hemodynamic tolerance than the known compounds.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP95904582A 1993-12-24 1994-12-21 Verwendung von pyridon-derivaten als anästhetische arzneimittel Withdrawn EP0735873A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9315629 1993-12-24
FR9315629A FR2714291B1 (fr) 1993-12-24 1993-12-24 Application des dérivés de la pyridone à titre de médicaments anesthésiques.
PCT/FR1994/001507 WO1995017894A1 (fr) 1993-12-24 1994-12-21 Application des derives de la pyridone a titre de medicaments anesthesiques

Publications (1)

Publication Number Publication Date
EP0735873A1 true EP0735873A1 (de) 1996-10-09

Family

ID=9454380

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95904582A Withdrawn EP0735873A1 (de) 1993-12-24 1994-12-21 Verwendung von pyridon-derivaten als anästhetische arzneimittel

Country Status (5)

Country Link
EP (1) EP0735873A1 (de)
JP (1) JPH09507220A (de)
AU (1) AU1320195A (de)
FR (1) FR2714291B1 (de)
WO (1) WO1995017894A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ551077A (en) 2004-05-07 2009-05-31 Janssen Pharmaceutica Nv Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
DE602005017159D1 (de) 2004-08-30 2009-11-26 Janssen Pharmaceutica Nv Oxysteroid-dehydrogenase-inhibitoren
MY141198A (en) 2004-08-30 2010-03-31 Janssen Pharmaceutica Nv Tricyclic adamantylamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
BRPI0515121A (pt) 2004-08-30 2008-07-08 Janssen Pharmaceutica Nv derivados da n-2 adamantil-2-fenóxi acetamida como inibidores da 11-beta hidroxiesteróide desidrogenase
FR2889065B1 (fr) * 2005-07-26 2009-06-26 Inst Evaluation Dermatophysiqu Nouvelle methode de chirurgie laser oculaire lasek

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2653123B1 (fr) * 1989-10-17 1992-01-17 Roussel Uclaf Nouveaux derives de la pyridone, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9517894A1 *

Also Published As

Publication number Publication date
WO1995017894A1 (fr) 1995-07-06
JPH09507220A (ja) 1997-07-22
AU1320195A (en) 1995-07-17
FR2714291B1 (fr) 1996-03-01
FR2714291A1 (fr) 1995-06-30

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