Classifications

• • 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
  • C07D401/04—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • 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
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
• • 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
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4

Definitions

• the present invention relates to new phenoxypropanolamines, pharmaceutical compositions containing them, a process for their preparation and intermediates in this process.
• BE 902897 describes aryloxypropanolamines carrying a 4-piperidininyl-1-group substituted on amine, these compounds having beta-1-blocking and alpha-blocking activity.
• the beta-3 adrenergic receptor has been the subject of numerous studies aimed at synthesizing agonist compounds with respect to this receptor, these compounds exerting an important anti-obesity and anti-diabetic effect in humans, as described by example by Weyer, C et al, Diabetes Metab., 1999, 25 (1): 11-21.
• the present invention relates, according to one of its aspects, to phenoxypropanolamines of formula (I)
• Ri represents a hydrogen or halogen atom, a group -S (0) z - (C * - C 4 ) alkyl, -S (O) z - (C, -C 4 ) R 3 , -SO 2 -NH- (C I -C 4 ) alkyl, -NHCO (C, - C 4 ) alkyl, -CO (C ⁇ -C 4 ) alkyl or -NHSO 2 - (C ⁇ -C 4 ) alkyl; m and n independently represent 0, 1 or 2;
• A represents a group of formula (a) or (b):
• R represents a group -SO 2 -R 3 , -CO-R 3 or -CO- (C ⁇ -C 4 ) alkyl;
• R 3 represents a phenyl group, optionally substituted by a group
• R 4 represents a hydrogen or halogen atom, a group (C--
• (C ⁇ -C) alkyl and "(C ⁇ -C 6 ) alkyl” denote monovalent radicals of a hydrocarbon respectively C 1 -C 4 and C [-C 6 straight saturated chain or branched.
• halogen denotes an atom chosen from chlorine, bromine, iodine and fluorine
• the salts of the compounds of formula (I) according to the present invention also include the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, 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), such as picrate, oxalate or addition salts with optically active acids, for example camphosulphonic acids and mandalic or substituted mandalic acids.
• pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalen
• the salts also include the salts with mineral bases, preferably those with alkali metals such as sodium or potassium, or with organic bases
• mineral bases preferably those with alkali metals such as sodium or potassium
• organic bases preferably those with alkali metals such as sodium or potassium
• Preferred compounds are those in which the (C ⁇ -C 4 ) alkyl group is a methyl or ethyl group.
• Preferred compounds of the present invention include the compounds of formula (I) where A is a group (a), X is N and the NHR 2 group is in the 5 position of pyridine.
• Other preferred compounds of the present invention include the compounds of formula (I) where A is a group (b) and the group R 4 is in the 4 position of benzene.
• R 4 is chosen from - COOH, -COO (C, -C 4 ) alkyl, -CN, -NO 2 , -CONR 2 R 3 , -NHS0 2 - (C, -C 4 ) alkyl, -SO 2 NR 5 R 6 .
• the compounds of formula (I) can be prepared by treating a compound of formula (II)
• Gp is a leaving group such as tosylate, mesylate or a halogen atom, with an amine of formula (IH)
• reaction between the compounds of formula (H) and (HI) is carried out in an organic solvent, such as a lower alcohol such as methanol, ethanol and isopropanol; dimethylsulfoxide; 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.
• organic solvent such as a lower alcohol such as methanol, ethanol and isopropanol
• dimethylsulfoxide such as methanol, ethanol and isopropanol
• a linear or cyclic ether such as an amide such as dimethylformamide or dimethylacetamide
• amide such as dimethylformamide or dimethylacetamide
• protecting groups P ′ it is possible to use the usual protecting groups for hydroxy groups such as for example methoxyethoxymethyl (MEM), benzyl, benzoyl or silyl ethers such as for example tert-butyldimethylsilylether (TBDMS).
• MEM methoxyethoxymethyl
• benzyl benzoyl
• silyl ethers such as for example tert-butyldimethylsilylether (TBDMS).
• cleavage of these protective groups is carried out according to the usual methods according to the protective group chosen and according to the reactivity of the other groups present, 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 MEM or TBDMS, an acid such as trifluoroacetic acid can also be used; in the case of benzoyl, a transesterification reaction can be carried out with an alkanol in basic medium.
• a catalyst such as Pd / C in a suitable solvent
• an acid such as trifluoroacetic acid
• benzoyl a transesterification reaction can be carried out with an alkanol in basic medium.
• the epoxides of formula (II) are compounds known in the literature or they can be prepared by methods analogous to those described in the literature.
• amines of formula (III) are novel compounds and constitute another aspect of the present invention.
• the present invention relates to amines of formula (ffl ')
• P " is a protective group such as tert-butoxycarbonyl or carbobenzyloxy with a radical Cl-R 2 where R 2 is as described above and Hal is a halogen atom, in a suitable solvent, such as by for example pyridine, dimethylformamide or dimethylsulfoxide and by elimination of the group P "by hydrogenation or by treatment in an acid medium such as hydrochloric acid in ethyl acetate or in ethanol.
• a suitable solvent such as by for example pyridine, dimethylformamide or dimethylsulfoxide
• the starting amines of formula (IV) can be prepared by reaction of the suitable py ⁇ dmes of formula (V)
• n is as defined above and P "represents a protective group, in an organic solvent in the presence of a base.
• reaction solvent it is possible, for example, to use dimethylformamide, py ⁇ dine, dimethylsulfoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.
• an alkali hydroxide As a base, it is possible to use, for example, an alkali hydroxide, an alkali carbonate such as potassium carbonate or a tertiary amine such as t ⁇ ethylamme.
• the reaction temperature is composed between room temperature and the reflux temperature of the chosen solvent.
• protecting groups P it is possible to use, for example, the protecting groups indicated for the products of formula (IV).
• cleavage of these protective groups is carried out according to the usual methods to haircut the chosen protective group; in the case of tert-butoxycarbonyl for example, the cleavage is normally carried out by acid hydrolysis.
• P ° is a tert-butoxycarbonyl group; n and m are 0, 1 or 2;
• R ° 4 is a group chosen from -COOH, -COO (C * -C 4 ) alkyl, -CONR ° 5 R ° 6 and -NHSO 2 (C, -C 4 ) alkyl; R ° 5 and R ° 6 independently represent a hydrogen atom or a group (C--)
• Particularly preferred compounds of formula (m ") are those where n is 0, m is 0 or 1 and R 4 is -COO (CC 4 ) alkyl.
• the compounds of formula (HI") can be prepared analogously to compounds (IV) above.
• the compounds of formula (I) have shown a very potent affinity for beta-3 receptors.
• the compounds of formula (I) are not very toxic, in particular, their acute toxicity is compatible with their use as medicaments for the treatment of diseases in which the compounds having an affinity for the beta-3 receptor find their application.
• formula (I), as well as their pharmaceutically acceptable salts can therefore be indicated for example in the treatment of gastrointestinal diseases such as irotable colon syndrome (EBD), as modulators of intestinal motility, such as hpolytics, anti- obesity, anti-diabetic, psychotropic, anti-glaucomatous, scarring, anti-depressive, tocolytic.
• mammals which require such treatment are administered an effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt and solvate thereof.
• the compounds of formula (I) 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 daily doses of 0, 1 to 10 mg / kg.
• the dose may preferably range 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) are generally administered in dosage units of 0.1 to 500 mg, preferably 0.5 to 100 mg of active poncipe, one to five times a day.
• Said dosage units are preferably formulated in pharmaceutical compositions in which the active poncipe is mixed with a pharmaceutical excipient.
• the present invention relates to pharmaceutical compositions containing, as active poncipe, a compound of formula (I) above or one of its pharmaceutically acceptable salts and solvates.
• the active ingredients of formula (I) above, their pharmaceutically acceptable salts and solvates can be administered in unit administration forms , mixed with conventional pharmaceutical carriers, animals and humans, for the treatment of the above conditions.
• Appropriate unit administration forms include oral forms such as compomés, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous administration forms , intramuscular or intravenous, forms of local administration and forms of rectal administration.
• the poncipal active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the compomés 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 amount of active poncipe
• 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 syrup or exir may contain the active ingredient together with a sweetener, preferably alcoholic, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable 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 poncipe 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.
• 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 stolen and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
• the active poncipe can also be formulated in the form of microcapsules, optionally with one or more supports or additives.
• the present invention relates to a method of treatment of pathologies which are improved by a beta-3-agon ⁇ ste action, which comprises administering a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates .
• the compounds of formula (I), in particular the compounds (I) labeled with an isotope, can also be used as laboratory tools in biochemical tests.
• the compounds of formula (I) bind to the beta-3-adrenergic receptor We can therefore use these compounds in an ordinary binding test, in which an organic tissue is used where this receptor is particularly abundant, and we measures the amount of compound (I) displaced by a test compound, 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) suitably labeled
• PREPARATION 1 4-tert-Butoxycarbonylamino-piperidine. 25 g (0.13 mole) of 4-ammo-1-benzylp ⁇ regardsnd ⁇ ne, 36.2 ml (0.26 mole) of toethylamme and 31.2 g (0.143 mole) of d ⁇ - are mixed at ambient temperature for 2 hours. tert-butyl-d ⁇ carbonate in 200 ml of dimethylformamide. The mixture is poured into water, extracted with ethyl acetate, washed with water and the product thus obtained is costallized in 200 ml of isopropyl ether.
• the product obtained by Preparation 2 is heated at reflux for 5 hours in a solution containing 15 ml of ethyl acetate and 15 ml of hydrochloric acid in ethyl acetate (approximately 3N). After cooling, it is filtered, washed with acetone and the product is dried under reduced pressure.
• the title product is obtained in the form of hydrochloride dihydrate by costalhsation in an ethanol solution
• TBDMSC1 tert-butyldimethylsilyl chloride
• DBU 8-d ⁇ azab ⁇ cyclo [5.4.0] undec-7-ene
• Preparation 14 an hour of the product of Preparation 7 and the product of
• EXAMPLE 14 14a 5 - [((4-Isopropylphenyl) sulfonyl) amino] -2- (4 - ((3- (4- (benzyloxy) -3- (methylsulfinyl) phenoxy) -2-hydroxypropyl) amino) piperidino) -pyridine Heated at reflux overnight 0.27 g (0.00084 mole) of 4-benzyloxy-3-methylsulfinyl-1 - [(2,3-epoxypropoxy)] - benzene (prepared according to US
• Example 13c (methylsuIfinyl) phenoxy) -2-hydroxypropyl) amino) piperidino) -pyridine
• the product from the preceding stage is deprotected.
• 1.2 g of this product, 1.12 ml of toethylamine, 0.738 g of 4-benzyloxy-3-methylsulftnyl-1 - [(2,3-epoxypropoxy)] - benzene (heated according to US 4,396,629) are heated under reflux for 12 hours. / example 3) in 100 ml of ethanol.
• a mixture containing 680 mg of the product thus obtained and 30 ml of CF 3 COOH is heated at 55 ° C. for 5 hours.
• the solvent is evaporated off and treated with a saturated sodium bicarbonate solution. Extraction is carried out with ethyl acetate, drying and the solvent are evaporated off.
• the title compound is obtained in the base form. Mp 147 ° C.

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• 2000
  • 2000-12-14 AU AU25258/01A patent/AU2525801A/en not_active Abandoned
  • 2000-12-14 EP EP00988915A patent/EP1242083B1/fr not_active Expired - Lifetime
  • 2000-12-14 US US10/149,497 patent/US6867220B2/en not_active Expired - Fee Related
  • 2000-12-14 JP JP2001544882A patent/JP4782342B2/ja not_active Expired - Fee Related
  • 2000-12-14 DE DE60033964T patent/DE60033964T2/de not_active Expired - Lifetime
  • 2000-12-14 WO PCT/FR2000/003535 patent/WO2001043744A1/fr not_active Ceased
  • 2000-12-14 AT AT00988915T patent/ATE356624T1/de not_active IP Right Cessation

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