WO1995017894A1 - Application des derives de la pyridone a titre de medicaments anesthesiques - Google Patents
Application des derives de la pyridone a titre de medicaments anesthesiques Download PDFInfo
- Publication number
- WO1995017894A1 WO1995017894A1 PCT/FR1994/001507 FR9401507W WO9517894A1 WO 1995017894 A1 WO1995017894 A1 WO 1995017894A1 FR 9401507 W FR9401507 W FR 9401507W WO 9517894 A1 WO9517894 A1 WO 9517894A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- alkyl
- pharmaceutically acceptable
- anesthetic
- Prior art date
Links
- KGUFNCBGEVQYMJ-UHFFFAOYSA-N CC(CCCN1C(CN2CCCC2)c2ccccc2)(c(cc2)cc(Cl)c2Cl)C1=O Chemical compound CC(CCCN1C(CN2CCCC2)c2ccccc2)(c(cc2)cc(Cl)c2Cl)C1=O KGUFNCBGEVQYMJ-UHFFFAOYSA-N 0.000 description 1
- HHUHVTVIAZMEIX-UHFFFAOYSA-N CCN(CC(Nc1c(C)cccc1C)=O)C(C)C Chemical compound CCN(CC(Nc1c(C)cccc1C)=O)C(C)C HHUHVTVIAZMEIX-UHFFFAOYSA-N 0.000 description 1
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.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95904582A EP0735873A1 (fr) | 1993-12-24 | 1994-12-21 | Application des derives de la pyridone a titre de medicaments anesthesiques |
AU13201/95A AU1320195A (en) | 1993-12-24 | 1994-12-21 | Use of pyridone derivatives as anesthetic drugs |
JP7517806A JPH09507220A (ja) | 1993-12-24 | 1994-12-21 | 麻酔薬としてのピリドン誘導体の用途 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9315629A FR2714291B1 (fr) | 1993-12-24 | 1993-12-24 | Application des dérivés de la pyridone à titre de médicaments anesthésiques. |
FR93/15629 | 1993-12-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995017894A1 true WO1995017894A1 (fr) | 1995-07-06 |
Family
ID=9454380
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1994/001507 WO1995017894A1 (fr) | 1993-12-24 | 1994-12-21 | Application des derives de la pyridone a titre de medicaments anesthesiques |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0735873A1 (fr) |
JP (1) | JPH09507220A (fr) |
AU (1) | AU1320195A (fr) |
FR (1) | FR2714291B1 (fr) |
WO (1) | WO1995017894A1 (fr) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9012494B2 (en) * | 2004-05-07 | 2015-04-21 | Janssen Pharmaceutica N.V. | Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
ES2334246T3 (es) | 2004-08-30 | 2010-03-08 | Janssen Pharmaceutica Nv | Derivados triciclos de adamantilamida como inhibidores de la 11-beta-hidroxiesteroide-deshidrogenasa. |
MX2007002449A (es) | 2004-08-30 | 2007-10-10 | Janssen Pharmaceutica Nv | Derivados de n-2 adamantanil-2-fenoxi-acetamida como inhibidores de deshidrogenasa 11-beta hidroxiesteroide. |
DE602005017159D1 (de) | 2004-08-30 | 2009-11-26 | Janssen Pharmaceutica Nv | Oxysteroid-dehydrogenase-inhibitoren |
FR2889065B1 (fr) * | 2005-07-26 | 2009-06-26 | Inst Evaluation Dermatophysiqu | Nouvelle methode de chirurgie laser oculaire lasek |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0437120A1 (fr) * | 1989-10-17 | 1991-07-17 | Roussel Uclaf | Nouveaux dérivés de la pyridone, leur procédé de préparation, les nouveaux intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant |
-
1993
- 1993-12-24 FR FR9315629A patent/FR2714291B1/fr not_active Expired - Fee Related
-
1994
- 1994-12-21 WO PCT/FR1994/001507 patent/WO1995017894A1/fr not_active Application Discontinuation
- 1994-12-21 AU AU13201/95A patent/AU1320195A/en not_active Abandoned
- 1994-12-21 EP EP95904582A patent/EP0735873A1/fr not_active Withdrawn
- 1994-12-21 JP JP7517806A patent/JPH09507220A/ja not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0437120A1 (fr) * | 1989-10-17 | 1991-07-17 | Roussel Uclaf | Nouveaux dérivés de la pyridone, leur procédé de préparation, les nouveaux intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant |
Also Published As
Publication number | Publication date |
---|---|
FR2714291B1 (fr) | 1996-03-01 |
EP0735873A1 (fr) | 1996-10-09 |
FR2714291A1 (fr) | 1995-06-30 |
JPH09507220A (ja) | 1997-07-22 |
AU1320195A (en) | 1995-07-17 |
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