| 3-spiroindolin-2-one derivatives, preparation and therapeutic use thereof -> Monitor Keywords |
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3-spiroindolin-2-one derivatives, preparation and therapeutic use thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Oxygen As Ring Hetero Atoms (e.g., Monocyclic 1,2- And 1,3-oxazines, Etc.), Chalcogen Bonded Directly To Ring Carbon Of 1,4-oxazine Ring3-spiroindolin-2-one derivatives, preparation and therapeutic use thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070191359, 3-spiroindolin-2-one derivatives, preparation and therapeutic use thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to 3-spiroindolin-2-one derivatives, to the process for preparing them and to the therapeutic use thereof. [0002] A subject of the present invention is compounds of formula (I): in the base, hydrate or solvate state, in the form of cis/trans isomers or of mixtures thereof. [0003] The compounds of formula (I) contain one or more rings. They can therefore exist in the form of cis/trans isomers. These isomers and mixtures thereof are part of the invention. [0004] The compounds of formula (I) can also exist in hydrate and/or solvate form, i.e. in the form of an association or of a combination with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention. [0005] The compounds of the invention can be prepared according to scheme 1 which follows. [0006] According to scheme 1, the compound of formula (V) is obtained by means of a step consisting of displacement of the tosylate group present in the compound of formula (VI), by an ethanolamine group, in the presence of a protic solvent such as ethanol or methanol. The synthesis of the compound for formula (VI) is described in document EP 0 873 309 (preparation 4, compound (III.4)). The compound of formula (V) is subsequently converted to the compound of formula (IV) by means of a reaction consisting of acylation of the amine function with 2-bromoacetyl bromide or bromoacetyl chloride, in the presence of triethylamine and of an aprotic solvent such as dichloromethane (CH.sub.2Cl.sub.2) or tetrahydrofuran (THF). The compound of formula (IV) is then converted to the compound of formula (III) by means of a cyclization reaction in a basic medium, in the presence of a polar aprotic solvent such as THF, dimethyl-formamide or dimethyl sulfoxide. The compound of formula (III) thus obtained is added to the compound of formula (II), in a basic medium and in the presence of benzyltriethylammonium chloride and in an aprotic solvent such as CH.sub.2Cl.sub.2 or THF, so as to obtain the compound of formula (I). The synthesis of the compound of formula (II) is described in document EP 0 873 309 (preparation 13, reactant (2).2). [0007] When the method of preparing the reactants is not described, they are commercially available or are described in the literature, or else they can be prepared according to methods which are described therein or which are known to those skilled in the art. [0008] The example which follows describes a method of preparing a compound in accordance with the invention. This example is not limiting and merely illustrates the present invention. [0009] In the example of preparation of a compound of formula (I) which follows, the following definitions are used: [0010] DMSO=dimethyl sulfoxide, [0011] LC/MS=liquid chromatography/mass spectrometry, [0012] Mp=melting point, [0013] eq.=molar equivalent, [0014] s=singlet, [0015] m=multiplet, [0016] t=triplet. [0017] The .sup.1H and .sup.13C NMR spectra were realized on two Bruker devices: AC 200 and Avance 600. [0018] The chromatography/mass spectrometry procedures were carried out on a Micromass.RTM. "TOF" (time of flight) mass spectrometer, model LCT. [0019] The melting points were measured on a Buchi melting point B-545 device. EXAMPLE Stage a): Displacement of the Tosylate by Ethanolamine Preparation of the Compound of Formula (V) [0020] 6 ml of ethanolamine (6.1 g; 100 mmol; 5 eq.), 20 ml of methanol, and then 9.19 g of the compound of formula (VI) (20 mmol; 1 eq.), the synthesis of which is described in document EP 0 873 309 (preparation 4, compound (III.4)), are introduced into a 100 ml round-bottomed flask under an argon atmosphere. The reaction mixture is heated to reflux for 10 hours. After cooling, the reaction medium is concentrated under vacuum, and the residue is washed with water and extracted several times with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and concentrated. [0021] In the subsequent step, the crude product obtained is used without purification. [0022] The proton NMR spectrum is compatible with the desired structure. [0023] The LC/MS analysis confirms the predominant formation of the product: M+H.sup.+=349.5. Stage b): Acylation of the Amine Function with 2-bromo-acetyl Bromide Preparation of the Compound of Formula (IV) [0024] 7.45 g of the aminated derivative of formula (V) obtained in stage a) (19.24 mmol; 1 eq.), 19.5 ml of anhydrous dichloromethane and 2.68 ml of triethylamine (1.94 g; 19.24 mmol; 1 eq.) are introduced into a 100 ml round-bottomed flask under an argon atmosphere. After cooling of the reaction medium to -15.degree. C. (methanol/ice bath), 1.71 ml of 2-bromoacetyl bromide (3.96 g; 19.24 mmol; 1 eq.) are added in 30 minutes. The temperature of the medium is brought back up to ambient temperature and the reaction is stirred for 2 hours. The mixture is subsequently washed with water and the aqueous phase is extracted several times with dichloromethane. The organic phases are combined, subsequently dried over magnesium sulfate, filtered, and concentrated. The crude product (8.26 g) is purified on silica gel (320 g; 40-63 .mu.m particles; the eluent used is a gradient: pure CH.sub.2Cl.sub.2 to a 95/5 CH.sub.2Cl.sub.2/methanol mixture). The fractions containing the desired derivative are combined and concentrated under vacuum. [0025] The proton NMR spectrum is compatible with the desired structure. [0026] The LC/MS analysis confirms the structure of the desired product: M+H.sup.+ in the form of a doublet in a ratio 1/1=469.3/471.3. Stage c): Formation of the Morpholinone Ring Continue reading about 3-spiroindolin-2-one derivatives, preparation and therapeutic use thereof... 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