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  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
  • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
  • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/06—Antiabortive agents; Labour repressants
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/40—Radicals substituted by oxygen atoms
  • C07D307/42—Singly bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention relates to new phenoxvpropanolamines, the pharmaceutical compositions containing them, a process for their preparation and intermediates in this process.
• BE 902897 describes aryloxypropanolamines carrying a 4-piperidininyl-1-substituted group on the amine, these compounds having ⁇ i-blocking and -blocking activity.
• J. Org. Chem., 1988, 63: 889: 894 describes other aryloxypropanolamines carrying a 4-piperidinyl-1-group substituted on the amine.
• the present invention relates, according to one of its aspects, to phenoxypropanolamines of formula (la)
• R represents hydrogen, a group -S (O) z- (C ⁇ -C4) Alk group, a -CO (C ⁇ - -C 4) Alk group, an -NHSO 2 - (C 1 -C 4) Alk, an NHCO group (C ⁇ -C 4 ) Alk, a 2-furyl group or a halogen;
• R 2 represents hydrogen or a group a (Ci-C) alkoxyl group, a halogen, -COOH, -COO (C 1 -C 4 ) Alk, -CN, -CONR ⁇ , -NO 2 , -SO 2 NH 2 , -NHSO 2 (C, - C 4 ) Alk; m and n independently 0, 1 or 2;
• R 3 and R 4 independently represent hydrogen or a group (C ⁇ -C 4 ) Alk; Z is 1 or 2; and their salts or solvates.
• the invention relates to compounds of formula (I): or
• Ri represents hydrogen, a group -S (O) z - (C ⁇ -C 4 ) Alk, a group -CO (C r C) Alk or a group -NHSO 2 - (CC 4 ) Alk; • R 2 represents hydrogen or a group (CC) Alk, a group (C 1 -C 4 ) alkoxyl, a halogen, -COOH, -COO (C, -C 4 ) Alk, -CN, -CONR 3 R . -NO 2 , -SO 2 NH 2 , - NHSO 2 (CC 4 ) Alk; m and n independently 0, 1 or 2;
• R 3 and R4 independently represent hydrogen or a group (C ⁇ -C) Alk; Z is 1 or 2; and their salts or solvates.
• (Ci-G Alk) denotes a monovalent radical of a saturated straight or branched chain Cj-C hydrocarbon.
• the salts of the compounds of formula (I) and (la) according to the present invention include both the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the bromohydrate, the sulphate, the hydrogen sulphate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., as addition salts which allow proper separation or crystallization of the compounds of formula (I) or (la) such as picrate, oxalate or addition salts with optically active acids, for example camphorsulfonic acids and mandelic or substituted mandelic acids.
• pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the bromohydrate, the sulphate, the hydrogen sulphate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-
• the salts also include the salts with mineral bases, preferably those with alkali metals such as sodium or potassium, or with bases organic.
• optically pure stereoisomers, and mixtures of isomers of compounds of formula (I) and (Ia), due to asymmetric carbons or the sulfinyl group in the meaning of R a or R, in any proportion, are part of the present invention.
• Preferred compounds of the present invention include the compounds of formula (I) or (la) where the group R 2 is in the 5 position of pyridine.
• Other preferred compounds include the compounds of formula (I) or (la) where the group R 2 is in position 6 of pyridine.
• R 2 is a halogen, in particular chlorine.
• Still other preferred compounds are those where n and m are zero.
• the compounds of formula (I) or (la) can be prepared by treating a compound of formula (II):
• Rb is the R or R as indicated above, P 'is a protecting group and X is a group of formula (a) or (b)
• Gp is a leaving group such as tosylate, mesylate or a halogen, with an amine of formula (III)
• the reaction between the compounds of formula (II) and (HT) is carried out in an organic solvent, such as a lower alcohol such as methanol, ethanol and isopropanol; dimethyl sulfoxide; a linear or cyclic ether; an amide such as dimethylformamide or dimethylacetamide; using at least equimolecular amounts of the reactants, possibly in small excess of amine.
• an organic solvent such as a lower alcohol such as methanol, ethanol and isopropanol
• dimethyl sulfoxide such as methanol, ethanol and isopropanol
• a linear or cyclic ether such as an amide such as dimethylformamide or dimethylacetamide
• the reaction temperature is between room temperature and the reflux temperature of the chosen solvent.
• protecting groups P ′ it is possible to use the usual protecting groups for hydroxy groups such as for example methoxyethoxymethyl (MEM) or benzyl.
• cleavage of these protecting groups is carried out according to the usual methods for the chosen protecting group; in the case of the benzyl group, for example by hydrogenation in the presence of a catalyst such as Pd / C in a suitable solvent; in the case of methoxyethoxymethyl (MEM) one can on the other hand use an acid such as trifluoroacetic acid.
• the amines of formula (III) can be prepared by reaction of the suitable pyridines of formula (TV)
• Hal represents a halogen and R 2 and m are as defined above, with a piperidine of formula (V) below where n is as defined above and P represents a protective group, in an organic solvent in the presence of a base, followed by cleavage of the P group of the compounds of formula (VI) thus obtained.
• reaction solvent it is possible to use, for example, dimethylformamide, pyridine, dimethyl sulfoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.
• an alkali hydroxide an alkali carbonate such as potassium carbonate or a tertiary amine such as triethylamine can be used, for example.
• the reaction temperature is between room temperature and the reflux temperature of the chosen solvent.
• protecting groups P it is possible to use the usual protecting groups for amines such as, for example, rert-butoxycarbonyl, acetyl, carbobenzyloxy.
• cleavage of these protective groups is carried out according to the usual methods described the protective group chosen; in the case of tert-butoxycaibonyl for example, the cleavage is normally carried out by acid hydrolysis.
• P ° is hydrogen or a protecting group; n ° and m ° are 0, 1 or 2;
• R 2 ° is a (CC 4 ) Alk; (dC 4 ) alkoxyl, -COOH, -COO (C ⁇ -C 4 ) Alk, -CN, NO 2 , -CONR 3 ° R4 °, -SO 2 NH 2 , -NHSO 2 (C 1 -C 4 ) Alk; R 3 ° and R 4 0 are hydrogen or a group (C ⁇ -C 4 ) Alk; provided that when n ° and m ° are zero, R 2 ° is other than methoxy in position 6 and that halogen in position 3 or 6 of pyridine; when n 3 is 1 m ° is 0, R 2 ° is other than chlorine in position 6 of pyridine and when n " is 0 m ° is 0 or 1.
• R 2 ° is other than methyl: as well as their salts, are new compounds and constitute a further object of the present invention.
• Particularly preferred compounds of formula (Nile) are those in which R 2 ° is chosen from the groups -COOH, -COO (C * -C 4 ) Alk, -C ⁇ , ⁇ O. -CONR 3 ° R 4 °, -SO 2 NH 2, and -NHSO 2 (C, -C 4 ) Alk.
• the compounds of formula (I) and (la), as well as their pharmaceutically acceptable salts, can therefore be indicated for example in the treatment of gastrointestinal diseases such as irritable bowel syndrome, as modulators of intestinal motility, as lipolytics , anti-obesity, anti-diabetic, psychotropic, anti-glaucomatous, healing, anti-depressants, as an inhibitor of uterine contractions, as tocolytics to prevent or delay early deliveries, for the treatment and / or prophylaxis of dysmenorrhea.
• the use of the compounds of formula (I) and (la) above, as well as that of their pharmaceutically acceptable salts and solvates for the preparation of the above medicaments constitutes a further aspect of the present invention.
• mammals which require such treatment are administered an effective amount of a compound of formula (I) or (la) or of a pharmaceutically acceptable salt and solvate thereof.
• the compounds of formula (I) and (la) above and their pharmaceutically acceptable salts and solvates can be used in daily doses of 0.01 to 20 mg per kg of body weight of the mammal to be treated, preferably in doses 0.1 to 10 mg / kg daily.
• the dose may preferably vary from 0.5 mg to 1500 mg per day, in particular from 2.5 to 500 mg depending on the age of the subject to be treated, the type of treatment, prophylactic or curative, and the severity of the condition.
• the compounds of formula (I) and (la) are generally administered in dosage units of 0.1 to 500 mg, preferably 0.5 to 100 mg of active principle, one to five times per day.
• Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
• the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) or (la) above or one of its pharmaceutically acceptable salts and solvates.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, the active ingredients of formula (I) or (la) above, their salts and pharmaceutically acceptable solvates can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to animals and humans, for the treatment of the above conditions.
• suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, subcutaneous administration forms , intramuscular or intravenous, forms of local administration and forms of rectal administration.
• the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the tablets can be coated with sucrose or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
• a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
• a preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
• a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
• Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.
• the active principle is mixed in an excipient for the preparation of creams or ointments or it is dissolved in a vehicle for intraocular administration, for example in the form of eye drops.
• Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
• aqueous suspensions, saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
• the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
• the present invention relates to a method of treatment of pathologies which are improved by a ### 3 -agonist action, which comprises administering a compound of formula (I) or (la) or one of its pharmaceutically acceptable salts or solvates.
• a compound of formula (I) or (la) or one of its pharmaceutically acceptable salts or solvates comprising administering a compound of formula (I) or (la) or one of its pharmaceutically acceptable salts or solvates.
• the compounds of formula (I) and (la) in particular the compounds (I) and (la) marked with an isotope, can also be used as laboratory tools in biochemical tests.
• the compounds of formula (I) and (la) bind to the ### 3 -adrenergic receptor. These compounds can therefore be used in an ordinary binding test, in which an organic tissue is used where this receptor is particularly abundant, and the quantity of compound (I) or (la) displaced by a compound is measured. test, to assess the affinity of said compound vis-à-vis the binding sites of this particular receptor.
• Another specific object of the present invention is therefore a reagent usable in biochemical tests, which comprises at least one compound of formula (I) or (la) suitably labeled.
• PREPARATION 1 4-ter ⁇ -butoxycarbonylamino-pi Southerndine. 25 g (0.13 mole) of 4-amino-1-benzylpiperidine are mixed at room temperature for 2 hours. 36.2 ml (0.26 mole) of triethylamine and 31.2 g (0.143 mole) of di-tert-butyl-dicarbonate in 200 ml of dimethylformamide. The mixture is poured into water, extracted with ethyl acetate, washed with water and the product thus obtained is crystallized from 200 ml of isopropyl ether.
• Example 2 By operating as described in Example 2 but using the product of Example 7 instead of the product of Example 1, and treating the hydrochloride salt thus obtained with an aqueous solution of NH 4 OH, the compound is obtained of the title. Mp 68-72 ° C.
• Example 9 By operating as described in Example 9 but using the product of Example 8 instead of the product of Example 2, the title compound is obtained. P.f. 160-162 ° C.
• Example 16 By operating as described in Example 2 but using the product of Example 16 instead of the product of Example 1, the title compound is obtained. P.f. 270-273 ° C.
• Example 9 By operating as described in Example 9 but using the product of Example 20 (base) instead of the product of Example 2, the title compound base is obtained.
• the hydrochloride is prepared using a hydrochloric acid solution in isopropanol.
• the title compound is obtained. P.f. 195 ° C Dec.
• Example 30 The product of Example 30 is heated for 3 hours at 40 ° C in a CH 2 C1 2 solution containing 11 ml of CF 3 COOH. The solvent is evaporated and crystallized from acetone. The title product is obtained. Mp: 173 ° -175 ° C.
• EXAMPLE 32 3- [1- (5-methoxycarbonyI-pyrid-2-ym ⁇ éthyl) -4-pi SoutherndmyIamino] -l- (4-hydroxy phenoxy) -2-propanol
• CHTRALCEL OD 390 g of ciralcel OD phase are suspended in 200 ml of propanol and are compressed to 20 bars.
• Stationary phase KROMASTL C18 100 ⁇ lO ⁇ m. 380 g of stationary phase are suspended in 560 ml of methanol and are compressed to 40 bars.
• a solution containing 1 g is heated at reflux for 6 hours under nitrogen.
• Example 48 The product of Example 48 is reacted with the product of Example 4 (base), according to the process described in Example 9a.
• the product is crystallized from isopropanol. Mp: 123-126 ° C
• EXAMPLE 50 4-benzyIoxy-3 (N ertbutoxycarbonyl-N-methylsulfonyl) -amino] -1- (2,3-epoxypropoxy) -benzene.
• EXAMPLE 51 51a 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino] -l - [(4-benzyloxy-3-methansulfonamido) -phenoxy] -2-propanol
• Example 51a The product of Example 51a is hydrogenated according to the process described in Example 9b, operating at a pressure that varies between ambient pressure and 50 psi.
• EXAMPLE 52
• EXAMPLE 58 4- a ⁇ no-l- (6-ethoxycarbonylpyrid-2-yI) -piperidine and its hydrochloride The mixture is heated at reflux for 8 hours 0.99 g (0.0025 mole) of the product of Example 56 in 6 ml of acetate and 6 ml of a HCl solution
• Example 26b 0.48 g (0.001 mole) of the product of Example 26b is mixed at room temperature 2.51 ml of IN NaOH (0.0025 mole), 2.5 ml of water and 2.5 ml of ethanol.
• Example 64a The product of Example 64a is hydrogenated according to the process described in Example 9b. The title product is obtained. Mp: 103-105 ° C.
• MMPP magnesium monoperoxyphthalate
• Example 50 The product of Example 50 is reacted with 4-amino-1- (6-chloropyrid-2yl) -piperidine (prepared as described in EP 21973) according to the method described in Example 51.
• Example 58 By operating as described in Example 58 but using 4-amino-1- (6-chloropyrid-2yl) -piperidine instead of the product of Example 57, the title product is obtained.

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