(dl)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro [4,5] decane-2-he and the method of its production

 

(57) Abstract:

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1). Also described is a method of obtaining this compound by treating DL-lenigeriamovies acid, ketone, characterized in that the ketone used aminoketone-2,2,6,6-tetramethylpiperidine-4-one and the process is carried out in an environment of benzene at a molar ratio of reagents: b-aminohexanoate acid - aminoketone 1:1,1, followed by separation of the target product.

The technical result is obtained a new connection, which can be used in medicine as a non-toxic antimitoticescoe medicines. 2 N. C.p. f-crystals.

(1)

The invention relates to DL-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula

It is known that cisplatin (cisdiamminedichloroplatinum) is used in chemotherapy for cancer patients inhibition of primary tumor, and the process of metastasis. However, a significant drawback of cisplatin is its high toxicity (LD50 (lethal dose 50) is equal to 12.5 mg/kg).

The present invention is developed is latausha low toxicity relative to caloric animals and high antimetastatic activity. Another objective of the present invention is to develop a method of obtaining the claimed product.

Known way to obtain DL-3-hydroxy-2,2,5-trimethylpyrazole-4-it is by the influence of racemic 2-aminopropiophenone acid acetone under conditions of a large excess of this ketone that is used both as a reaction medium. The reaction product yield amounted to 83.5% (I. C. Westrop, Z. G. Aliev, N. Y. Andreeva, L. O. atovmian and B. S. Fedorov. WPI. Academy of Sciences, Ser.chem., 2000, 181). However, the resulting product showed antimetastatic activity.

This object is achieved in that in the proposed method of processing DL-lenigeriamovies acid as ketone use aminoketone - 2,2,6,6 - tetramethylpiperidine - 4-one, and the treatment is carried out in an environment of benzene at a molar ratio of reagents: -aminohexanoate acid - aminoketone equal to 1:1.1 and distillation of the reaction water (in the form of an azeotropic mixture with benzene) to trap Dean-stark followed by separation of the target product.

There are no restrictions for the parameters of the proposed method. For carrying out the process of obtaining the target product can be used in the molar ratio aminohexanoate kisley condensation of the target product. The temperature of the reaction (80°C) is determined by the environment of the reaction (benzene), and time of the reaction (4 h) is chosen in order to achieve maximum output.

The invention is characterized by the following example. Example. The mixture 1,041 g (10 mmol) of DL-lenigeriamovies acid, 1,707 g (11 mmol) of 2,2,6,6-tetramethylpiperidine-4-it and 50 ml of absolute benzene was boiled with trap Dean-stark, equipped with a reflux condenser for 4 hours Then the reaction mixture was filtered through filter SCHOTT, the filtrate was evaporated on a rotary evaporator under reduced pressure and a bath temperature of 20-25°C. Selected oily residue was recrystallized from absolute dioxane. Received DL-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro [4.5]decane-2-he is so pl. 115-117°C in the form of Polysorbate with dioxane. The weight of 2.54 g, yield 89%. Found (%): 58,84, N 9,80, N OF 14.46; C28H54N6ABOUT6. Calculated (%):58,92, N 9,54, N 14,72. IR spectrum (KBr, , cm-1): 3274 (NH), 3039 (NH), 2962, 2934, 2869 (CH3CH2, CH), 1680 (PL), 1670 (C=0), 1660 (PL). NMR spectrum1H (400 MHz, CD3OD, , ppm, J, Hz): 1,19 (s, 3H, Me), 1,22 (s, 3H, Me), is 1.31 (d, 3H, Snme,3J=7,1 Hz), 1,45 (s, 3H, Me) to 1.48 (s, 3H, Me), to 1.61 (s, 2H, CH2), of 1.62 (d, 1H, CHAHB,2J=13,0 Hz), 1,90 (d, 1,32 MHz, CD3OD, , ppm): 17,41 (Snma), 28,55 (Me), 28,84 (Me), 34,74 (Me), 34,89 (Me), 40,77 (CH2), 45,31 (SS, 52,99 (Snma), 53,19 (2C, Cme2), 68,37 (CH2, dioxane), 80,28 (NCN), 174,37 (C=0).

Thus the proposed method for obtaining permits to achieve the objectives of the invention and to obtain previously unknown connection DL-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-it, which can be used in medical practice as a non-toxic anti-metastatic drugs instead of highly toxic cisplatin.

Tests on acute toxicity were performed in the laboratory of experimental cancer chemotherapy IPCP RAS by intraperitoneal administration of the drug in water to mice weighing 22-24, the test Results showed that the synthesized compound is not toxic at a dose of 1000 mg/kg This data allows us to include the claimed connection to discharge toxic compounds in relation to warm-blooded animals an Index of inhibition of metastasis (MRI) for melanoma B16 is 81%, which is comparable to IMM from cisplatin, equal to 89%.

Another important property of the synthesized compounds yavlyaetsya that this substance amphiphile that allows it to carry membranotropic connections.



 

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The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

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The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: chemical industry, organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel spiropyrazole compounds of the general formula (I): wherein W means hydrogen atom, (C1-C10)-alkyl, (C3-C7)-cycloalkyl, cyano-(C1-C10)-alkyl, -(C1-C4)-alkyl-COOV1 wherein V1 means hydrogen atom (H) or (C1-C6)-alkyl, -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-group, or -(C1-C5)-alkyl-NHS(=O)2-W1 wherein W1 means -(C1-C10)-alkyl; Q means phenyl; n mean a whole number 0 or 1; A, B and C mean hydrogen atom; Z means a simple bond, methylene or ethylene group; R1 means (C3-C12)-cycloalkyl substituted optionally with (C1-C10)-alkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl, norbornyl, dibenzocycloheptyl, 9-acenaphthyl, phenyl substituted optionally with benzyloxy-group, biphenyl or (C1-C10)-alkyl substituted optionally with 1-3 substitutes chosen from phenyl, cyano-group, -COOV1 wherein V1 means (C1-C6)-alkyl and -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-, (C1-C4)-alkylamino- or di-(C1-C4)-alkylamino-group; R2 means (C1-C10)-alkyl, (C3-C7)-cycloalkyl or halogen atom. Also, invention to their pharmaceutically acceptable salts, solvates, pharmaceutical composition containing thereof, a method for treatment of pain and a method for modulation of pharmacological response of described ORL-1- or μ-receptors. Invention can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

EFFECT: improved method of treatment, valuable medicinal properties of compounds.

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of class quinoxalin-2-spiropyrroles of the general formula (I): wherein R1 = R2 mean hydrogen atom (H) (I); R1 means H; R2 means CH3 (II); R1 = R2 mean CH3 (III). Compound can be used as parent substances for synthesis of novel heterocyclic systems, and in medicine as antibacterial agents. Also, invention describes a method for synthesis of these compounds.

EFFECT: improved method of synthesis, valuable properties of compounds.

3 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula where A-B stands for CH2-CH2, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -N(R4)-CH2- or -CH2-N(R4)-; R1 stands for (lower)alkyl, (lower)alkenyl, cycloalkyl or stands for aryl, optionally substituted with one or two substitutes chosen from the group consisting of haloid, cyano, (lower)alkyl, CF3, OCF3 or (lower)alkoxy, or stands for heteroaryl representing cyclic aromatic hydrocarbon radical containing one or two heteroatoms chosen of the group consisting of sulphur or nitrogen, e.g. thiazolyl or thienyl, optionally substituted with one or two substitutes chosen from (lower)alkyl; R2 stands for (lower)alkyl, cycloalkyl or stands for aryl, optionally substituted with one or two substitutes chosen from the group consisting of haloid, (lower)alkyl, CF3, (lower)alkoxy, or stands for heteroaryl representing cyclic aromatic hydrocarbon radical containing one sulphur heteroatom, e.g. thienyl; R3 stands for hydrogen; R4 stands for hydrogen or benzyl; n stands for 0, 1 or 2; and to their pharmaceutically acceptable salts. Besides, the invention concerns a medical product.

EFFECT: production of new biologically active compounds inhibiting glycine carrier 1 (GlyT-1).

19 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (1) where: R1 represents hydrogen atom, halogen, CP3, (1-3C)alkoxy group, m is an integer within 1 to 4, provided when m is equal to 2, 3 or 4, R1 substitutes can be either identical or different, R2 represents hydrogen atom, alkyl (1-6C) group optionally substituted with alkoxy group, cycloalkyl (3-6C) group, -CH2OH, -CH2OCH3, acetyl group, benzyl group optionally substituted with amino group, or group Q of the following composition (2): were: [ ]n symbolically represents -(CH2)n-, where n is an integer within 0 to 7, R3 represents hydrogen atom or alkyl (1-3C) group, R4 represents hydrogen atom, alkyl (1-6C) group optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkoxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, amido group dialkyl, carboxyl group, saturated, unsaturated or partially saturated mono- or dicyclic 5-10-meroud ring optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or alkyl (1-3C) group substituted with saturated, unsaturated or partially saturated five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen from alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or (R3+R4) together with nitrogen atom, they are attached to, represent saturated, unsaturated or partially saturated mono- or dicyclic five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl groups, as well as to all stereoisomers, to pharmaceutically acceptable salts. Additionally, the invention concerns pharmaceutical compositions and application of compounds.

EFFECT: production of new biologically active compounds with agonist activity to ORL1 receptors.

9 cl, 488 ex, 2 tbl

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