Heterocycle-cyclic derivatives of amines or their pharmaceutically acceptable salts, intermediate compounds, pharmaceutical composition, method of inhibiting cholinesterase, the method of obtaining compounds
(57) Abstract:
Use in the chemistry of heterocyclic compounds with inhibition of cholinesterase activity. Disclosed heterocycle-cyclic derivatives of amines of the formula I, where X, M, L, R1, R2, R7, R8presented on pages 121-124 descriptions, or their salts, intermediate compounds, pharmaceutical composition and method of inhibiting cholinesterase-based compounds of the formula I, the method of obtaining these compounds. 6 C. and 4 h.p. f-crystals, 1 table. The present invention relates to heterocycle-cyclic amine derivative of the formula I and their pharmaceutically acceptable salts. The compounds of formula I are inhibitors of cholinesterase and can be used to improve memory in patients with dementia and Alzheimer's.Alzheimer's disease is caused by degeneration of cholinergic neurons in the basal fore brain, which play a fundamental role in the cognitive brain, including memory. See, Becker and others, Drug Development Research, 12, 163-195 (1988). As a result of this degeneration, patients suffering from the disease, reveals a noticeable reduction in the synthesis of acetylcholine, cholineacetyltransferase linestart are an effective means to increase cholinergic activity and can be used to improve memory in patients suffering from Alzheimer's disease. By inhibiting acetylcholinesterase these compounds contribute to the high levels of the neurotransmitter acetylcholine in the brain and thus help to improve memory. In the above-mentioned work of Becker and others indicate that behavioral changes after inhibition of cholinesterase, obviously, correspond to predicted peak levels of acetylcholine in the brain. In this work also discusses the effectiveness of three known acetylcholinesterase inhibitors, namely physostigmine, metrifonate and tetrahydroaminoacridine.European patent application EP A 0229391 refers to piperidinium derived formulasR1-X-A-R2.European patent application EP A 296560 refers to a cyclic amine compound of the formula
< / BR>Brief description of the invention
The present invention relates to compounds of the formula
< / BR>where
R1and R2independently selected from hydrogen, (C1-C6)-alkoxy, benzyloxy, phenoxy, hydroxy, phenyl, benzyl, halogen, nitro, cyano, COR5, -COOR5, -CONHR5, -NR5COR6, -OCONR5R6, -NR5R6, -NHCOOR5, (C1-C6-alkyl, where p=0, 1, or 2; pyridylmethylene or thienylmethyl; 2-oxazolyl, 2-thiazolyl and benzosulfimide; where the phenyl part of these phenoxy-, benzyloxy-, phenyl, benzyl and benzosulfimide groups; peredelnye and thienyl part of these pyridylmethylene or titillations groups; and oxazolidine and thiazole part of the above mentioned 2-oxazolines and 2-thiazolines groups may be optional substituted by 1 or 2 substituents, independently selected from halogeno-, (C1-C4)-alkyl, trifloromethyl, (C1-C4)-alkoxy, cyano, nitro and hydroxy;
or R1and R2if they are linked to adjacent carbon atoms and when X is oxygen, sulfur or NR4where R4is hydrogen or (C1-C4)-alkyl, can form together with the carbon atoms to which they are linked, a group of the formula
< / BR>where
J is oxygen, sulfur or NR4;
a = 1 or 2, R3is hydrogen or (C1-C6)-alkyl;
Q is oxygen, sulfur, NH, CHCH3C(CH3)2, -CH=CH - or - (CH2)1, where L is an integer from 1 to 3;
X represents oxygen, sulfur, CH=CH-, -CH=N-, -N=N - or-NR4where R4>n-, -NR4(CH2)m- or-O(CH2)m- where R4defined above, n is an integer from 0 to 3, and m is an integer from 1 to 3;
R5and R6independently selected from hydrogen, (C1-C6)-alkyl, phenyl or benzyl, where the phenyl part of the above mentioned phenyl and benzyl groups may be optional substituted by one or two substituents, independently selected from the fluorescent-, chloro-, bromo-, iodo-, (C1-C4)-alkyl, trifloromethyl, (C1-C4)-alkoxy, cyano, and hydroxy; or NR5R6together form a ring with 4 to 6 members, where one atom is nitrogen, and other atoms are carbon atoms, oxygen or nitrogen (e.g., pyrrolidinyl, piperidinyl, morpholino, piperazinil or N-methylpiperazine) or NR5COR6together form a cyclic laktamovogo ring with 4 to 8 members;
M is-CH - or nitrogen;
L represents phenyl, phenyl-(C1-C6)-alkyl, cinnamyl or pyridylmethyl, where the phenyl part of the above mentioned phenyl and phenyl-(C1-C6)-alkyl groups may be optional substituted by 1-3 substituents, independently selected from (C1-C6)-alkyl, (C1-C6>or galactography; or L is a group of the formula
< / BR>where
b is an integer from 1 to 4;
R13and R14independently selected from hydrogen, (C1-C4)-alkyl, galactography and phenyl;
E and F are independently chosen from CH and nitrogen;
G represents oxygen, sulfur or NR4where R4defined above, provided that if E and F are both nitrogen, then one of R13and R14no;
R7and R8independently selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylsulphonyl and (C1-C6)-(C1-C6)-alkoxy, provided that the specified (C1-C6-alkoxygroup is not associated with carbon, which is the atom adjacent to the nitrogen atom.The present invention also relates to pharmaceutically acceptable acid additive salts of compounds of formula I. Examples are the salt of the acid, p-toluensulfonate acid, maleic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, Hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-Dalwallinu key is, prednaznachennoi for inhibition of cholinesterase and containing t formula I or its pharmaceutically acceptable acid additive salt and a pharmaceutically acceptable carrier.The present invention also relates to a method of inhibiting cholinesterase in mammals, namely, that the mammal is administered a certain amount of the compounds of formula I or its pharmaceutically acceptable acid salt additive which is effective for inhibition of cholinesterase.The present invention also relates to a method for improving memory or the treatment or prevention of Alzheimer's disease in mammals, namely, that the mammal is administered a certain amount of the compounds of formula I or its pharmaceutically acceptable acid salt additive which is effective to improve memory, or for the treatment or prevention of Alzheimer's disease.The present invention also relates to compounds of the formula
< / BR>where
W is a leaving group; j is an integer from 0 to 2; R10is the nitrogen blocking group; and R7and R8independently selected from hydrogen, (C1-C6)-alkyl, (C1-C61-C6)-alkoxy group is not linked to a carbon atom adjacent to the carbon atom which is adjacent to the nitrogen atom. These compounds can be used as intermediates in the synthesis of compounds of formula I.The present invention also relates to compounds of the formula
< / BR>where
R1, R2, R7, R8, X, and Y and M are defined above, and R11is hydrogen or a nitrogen protecting group. These compounds can be used as intermediates in the synthesis of compounds of formula I.The present invention also relates to compounds of the formula:
< / BR>where
R1, R2, R7, R8and L are defined above;
Y' is-CH=CH-(CH2)n- or -(CH2)m-.These compounds can be used as intermediates in the synthesis of compounds of formula I.Used in the present description, the term "mammal" includes humans.Used in the present invention, the term "halogen" means chloro, bromo, iodo or fluorescent.The term "alkyl" used in the present description, means, unless otherwise specified particularly, recombinatio.The term "(C1-C4-alkylaryl" refers to the Deputy formula
< / BR>where
R15is (C1-C4-alkyl).The term "C1-C4-alkoxycarbonyl" refers to the Deputy of the formula V, above, where R15is (C1-C4-alkoxygroup.The term "(C1-C6-alkoxycarbonyl" refers to the Deputy of the formula V, above, where R15is (C1-C6-alkoxygroup.The term "(C1-C6-alkylaryl" refers to the Deputy of the formula V, above, where R15is (C1-C6)-alkyl.Preferred compounds of the present invention are the compounds of formula I in which X is oxygen or sulfur, Y is-CH2-, -CH2-CH2-; M is-CH is benzyl; R1and R2are (C1-C6)-alkyl, (C1-C6)-alkoxy; NR5R6or NR5COR6; R3is hydrogen or (C1-C6)-alkyl; J is oxygen or sulfur; and Q is CH(CH3), CH(CH3)2, -CH=CH or (CH2)1and their pharmaceutically acceptable salts:
3-[2-[1-(phenylmethyl)-4-piperidinyl]ettermetol)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
5-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
6-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
7-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
6-acetamido-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
6-benzamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
6-benzosulfimide-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2 - benzisoxazol;
6-(4-morpholinyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl] -ethyl] -1,2 - benzisoxazol;
5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-6H-pyrrolo [4,5-f] -1,2-benzisoxazol-6-he;
1-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]isoquinoline;
3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisothiazol;
4-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,3-hinzelin;
6-hydroxy-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazol;
6-bromo-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazol;
6-cyano-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazol;
6-carboxamido-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazol;
3-[(1-phenylmethyl-4-piperidyl)methoxy]-1,2-benzisoxazol;
3-[1-phenylmethyl-4-piperidyl)methylamino]-1,2 who yl]propyl]-1,2-benzisoxazol;
TRANS-3-[2-[1-(phenylmethyl)-4-piperidyl]ethynyl]-1,2-benzisoxazol;
3-[2-[1-(phenylmethyl)-4-piperazinil]ethyl]-1,2-benzisoxazol;
5,7-dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] -ethyl] -6H - pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-7-ethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6H-pyrrolo [4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-3-[2-[1-(1-(2-chloro-5-thiophenemethyl)-4-piperidinyl] ethyl] -6H - pyrrolo-[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-3-[2-[1-(2-methyl-4-thiazolyl)-4-piperidinyl] ethyl] -6H-pyrrolo-[4,5-f]-1,2-benzisoxazol-6-he;
3-[2-[1-(3-bromophenyl)-4-piperidinyl]5,7-dihydro-6H - pyrrolo[4,5-f] -1,2-benzisoxazol-6-he;
3-[2-[1-(4-bromophenyl)-4-piperidinyl] ethyl] -5,7-dihydro-6H - pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl] propyl] -6H - pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -5,6,8-trihydro-7H - isoxazole[4,5-q]quinoline-7-he;
6,8-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-7H - pyrrolo[5,4-q] -1,2-benzisoxazol-7-he;
5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethylene] -6H - pyrrolo[5,4-f]-1,2-benzisoxazol-6-he;
3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1H-indazol
and pharmaceutically acceptable salts of these compounds.Examples of other with whom(2-thiazolyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol;
6-(2-oxazolyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2 - benzisoxazol;
6-pyrrolidinyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazoles;
6-piperidinyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2 - benzisoxazol;
5,7-dihydro-5,5-dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2 - benzisoxazol-6-he;
5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -7 - n-propyl-6H-pyrrolo-[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -7 - propyl-6H-pyrrolo-[4,5-f]-1,2-benzisoxazol-6-he;
5,6-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H - pyrrolo-[4,5-f] -1,2-benzisoxazol-6-he;
3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6-phenylmethylsulfonyl - 1,2-benzisoxazol;
1-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1H-indazol and
3-[1-phenylmethyl-4-piperidinyl)methyl] - 1.2 benzisoxazol.The compounds of formula I may have optical centers and therefore may exist in different isomeric forms. In the scope of the present invention includes all stereoisomers of the compounds of formula I, including their mixtures.Detailed description of the invention
Obtaining compounds of formula I and some of the source materials used for the synthesis of these compounds, pollastri the R2, R3, R4, R5, R6, R7, R8, R13, R14, E, G, X, Y, M, L, a, b, I, m, n, p and structure I, A, B, and K are the same as defined above, if it is not specifically mentioned.All articles, monographs, patents, and patent applications cited in the following discussion, introduced in the present description by reference. Scheme 1 - 6 listed at the end of the text.Obtaining compounds of formula I in which Y is -(CH2)mand M is-CH-, illustrated in figure 1. These connections are depicted in figure 1 and designated as compounds of formula I-A (where L represents a phenyl-(C1-C6)-alkyl, pyridylmethyl or a group of formula (K) and as the compounds of formula I-B (where a represents a phenyl or cinnamyl).In scheme 1 the compounds of formula I-A can be obtained by deprotonation of compounds of formula II using a base in the presence of or followed by addition of an alkylating agent of the formula III, where R10represents azatadine group, and W represents a leaving group. If R10is asutamisega group, this reaction produces an intermediate compound of formula IV. This intermediate with the warping or salt of the free base, then the specified free base or its salt alkylate using the compounds of formula WL, where W is defined above, and L represents phenyl(C1-C6)-alkyl, pyridylmethyl or a group of the formula K.Examples of suitable leaving groups (W) are mesilate, tosylate, chloride, iodide or bromide. Examples of suitable azatadine groups (R10are amides, such as N-formyl and N-acetyl, and carbamates such as t-butoxycarbonyl (VOS). Preferred azatadine groups are VOS. Suitable bases used to produce compounds of formula IV are strong bases, such as diisopropylamide lithium (LDA), n-utility, s-utility, and hexamethyldisilazide lithium or sodium, or potassium (LiHMDS, NaHMDS or KHMDS). Preferred are LDA and s-utility.The reaction of the compound of formula II with the compound of the formula III in the main, carried out in a polar aprotic solvent such as diethyl ether, 1,2-dimethoxyethane or tetrahydrofuran (THF). The reaction temperature can vary from about -70 to about 30oC. Preferably, if the above reaction is carried out in THF at about -70oC.Basically, the compounds of formula II is subjected to the depot is on proton acid, it is preferable to first carry out phase deprotonation and subsequent immediate and rapid addition of an alkylating agent of the formula III.Protective group (R10) can be removed from compounds of formula IV with the formation of the corresponding compounds of formula VI by conventional methods well known in the art. For example, if R10is the SUN or other carbamato, this group can be removed using acids, such as bromovalerate (gaseous or liquid), hydrogen chloride (gaseous or liquid) or triperoxonane acid. In the case of triperoxonane acid may be added to the acceptor t-butyl cations, such as thioanisole. If razblokirovka agent acid is used, the result will be produced not free base of compounds of formula VI and its acid additive salt. Suitable solvents are non-polar solvents, such as methylene chloride, and also polar solvents, such as diethyl ether, ethyl acetate, dioxane, alcohols, such as methanol or ethanol, and water. Temperatures can vary from about -20oC and arr. to the temperature of distillation. Predpochtite the Colo 0oC.Alternatively, if R10is VOS, it can be removed using triallylisocyanurate derivative, such as (trimethylsilyl) -, triethylsilyl - or t-butyldimethylsilyl-triftorbyenzola, in the presence of aromatic or tertiary amine base, such as 2,6-lutidine or triethylamine. Suitable solvents for this reaction are non-polar solvents, such as methylene chloride, and polar solvents such as THF, diethyl ether or DMF. Temperatures can vary from about -20oC to room temperature. For this reaction it is preferable to use trimethylsilyltrifluoromethane-sulfonate and 2,6-lutidine in methylene chloride at a temperature of from about 0oC and approximately to room temperature.Intermediate secondary piperidine of the formula VI obtained in the form of free base or salt, as described above, is subjected to reaction with 2-10 equivalents of the base, and then with an alkylating agent of the formula WL, where W is the group defined above, and L is phenyl-(C1-C6)-alkyl, pyridylmethyl or a group of the formula K. Suitable bases are tretinoinretin; and metal carbonates, such as sodium bicarbonate, or carbonate of sodium, potassium or cesium. If W is chloride, the catalyst may be added iodide (iodide or potassium iodide, Tetra-n-butylamine). Suitable solvents are non-polar solvents, such as methylene chloride, and polar solvents such as dimethylformamide, THF, acetonitrile, acetone, dioxane, and alcohols, such as methanol or ethanol. The alkylation reaction is preferably carried out in the presence of triethylamine in methylene chloride at room temperature or in the presence of sodium carbonate in dimethyl formamide at room temperature.Alternatively, the intermediate secondary piperidine of formula VI, if it was obtained in the form of a salt after removal of the protective group may be subjected to deprotonation to obtain the free amine by dissolution or suspension in an appropriate solvent (e.g. methylene chloride or etiennette), mixing with aqueous sodium bicarbonate or aqueous sodium hydroxide or potassium and allocate the free amine from the organic layer using standard extraction techniques. Obtained the free amine can be plugged into the sled above, and with 1-2 equivalents of the appropriate base.Starting materials of formula II can be obtained by methods well known in the art. If X is oxygen, the original 3-methyl-1,2-benzisoxazole can be obtained by methods similar to those described Wunsch and others, Adv. Heterocycl. Chem., 1967, 8, 277; Smalley P. K., Adv. Heterocycl. Chem. 1981, 29, 2, and Thakar, etc., Indian J. Chem. 1977, 15B, 1058. The corresponding b-hydroxyacetophenone can be converted into the corresponding oximes via reaction with hydroxylamine hydrochloride in the presence of an appropriate base, such as potassium hydroxide or sodium, sodium acetate or pyridine, preferably aqueous potassium hydroxide or aqueous sodium acetate, in a polar solvent such as methanol, ethanol or water, and preferably ethanol, at a temperature from about room temperature to about 120oC. Then the reaction is transformed into the corresponding oxiracetam by acetylation with suitable acetylides agent such as acetic anhydride. This reaction can be conducted at temperatures from about room temperature to the temperature of distillation of the solvent. Preferred are temperatures 80-130oC.Reago of oxiracetam at a temperature of about 125 - 200oC at atmospheric pressure or reduced pressure, for example from about 0.01 mm RT.article (1,33 10-5bar) to about 760 mm RT.article (1,01 bar). The reaction ring closure preferably by heating oxiracetam when the distillation temperature in the appropriate base, such as pyridine, or by heating oxiracetam at a temperature of about 130oC in a polar solvent such as DMF or DMSO (dimethylsulfoxide) in the presence of several equivalents of the appropriate base, such as pyridine or 2,6-lutidine.Alternatively, the ring closure may be effected directly from the oxime using its reaction with acyl - or sulphonylchloride, such as oxalyl or thionyl chloride, in the presence of an aromatic amine, such as pyridine (see , Kalkote and others, Aust, J. Chem., 1977, 30, 1847). Suitable solvents are polar solvents, such as diethyl ether or THF. Temperatures can vary from about 0oC and approximately to room temperature. Another way to ring closure is the treatment of the oxime one or less equivalents of base, such as potassium hydroxide, in a polar solvent such as methanol, at temperatures in the limit of which is sulfur, the original 3-methyl-1,2-benzisothiazole can be obtained from o-methylthiazolidine in accordance with the procedures described above for benzisoxazole (see, McLinnon and others, Can. J. Chem., 1988, 66, 1405 and works cited in the present description). b-Methylthiazolidine converted into the corresponding oximes and ring closure is carried out directly by reaction with the corresponding allermuir agent such as acetic anhydride in the base, such as pyridine. The reaction temperature may be from about room temperature to about 130oC, and preferably about 120oC.If X is NR4where R4is hydrogen, the original 3-methyl-1H-indazols can be obtained in accordance with the methods described Behr and other "Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Ring, Heterocyclic Compounds, R. H. Wiley, Ed., 1967, 289; Barch, etc., J. Heterocycl. Chem., 1984, 21, 1063; Hannig and others, Pharmazie 1976, 31, 534; Barton and others, J. Chem. Soc. Chem. Comm., 1982, 450; Ruechardtn and others, Liebigs Ann. Chem. , 1980, 908 and Rees and others, J. Chem. Soc. D, 1971, 827. N-alkylation of 3-methyl-1H-indazols (X= NR4, R4= (C1-C4)-alkyl) can be carried out in accordance with the description Behr and others, "Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings, Heterocyclic Compounds, R. H. Wiley, Ed., 1967, 309; Palmer and others, J. Chem. Soc. Perkin Trans. II, 1975, 1695 and Claramunt and others, Heteror-Napieralksi or Pictet spengler (see, "Organic Reactions", vol VI, Chapter 2, m 3, C., 74 - 190, John Wiley & Sons, new York, 1951).If the-N=CH-, the original 4-methylpyrazole can be obtained by the methods described goes wrong and others, Indian J. Chem., 1988, 27B, 396; Higashino, T., Chem Pharm. Bull. , 1962, 10, 1043; and Uff, etc., J. Chem. Soc., Perkin Trans I, 1986, 2295.If X is-CH=N-, the original 1-methylphthalic can be obtained by the methods described by Kant and others, J. Heterocycl. Chem., 1985, 22, 1065 and works cited in the present description; Acheson. and others, J. Chem. Soc. C, 1966, 2218 and Gabriel and others, Chem. Ber. 1987, 30, 3022.If X is-N=N-, the original 4-methyl-1,2,3-benzotriazine can be obtained by the methods described Adger and others, J. Chem. Soc. Perkin Trans I, 1975, 31; Boulton and others, Ibid, 1988, 1509 and Rees and others, J. Chem. Soc. D, 1971, 828.If R1and R2both are NH2the source material of the formula II can be obtained from the corresponding NHAc-predecessor (Ac=acetyl) using acid hydrolysis. Acid hydrolysis can be carried out using hydrochloric acid at temperatures of from about 50 to about 120oC. However, it is preferable temperatures of distillation (about 120oC) 1 N. HCl. Appropriate connections NHBZ (BZ=benzoyl) or NHSO2C6H5can be obtained from the corresponding amino derivative t is min, pyridine or dimethylaminopyridine. Suitable solvents are methylene chloride, THF, diethyl ether or dimethylformamide. The reaction temperature can be from about -20 to about 80oC. If one or both of R1and R2are NHBZ, it is preferable to use the triethylamine/dimethylaminopyridine in methylene chloride at room temperature. If one or both of R1and R2are NHSO2Ph, it is preferable to use pyridine in methylene chloride at 0oC.Cyclic dialkylamino-the compounds of formula II (i.e., compounds in which one or both R1and R2are NR5R6where NR5R6together form a ring) can also be obtained from the corresponding amino derivative by alkylation, using the appropriate bis-halide reagent of the formula
< / BR>where each A is independently a bromide or chloride;
B is oxygen or (CH2)qwhere q = 0, 1, or 2,
in the presence of an appropriate base, such as triethylamine or diisopropylethylamine (base Hunosa), in a suitable nonpolar solvent such as toluene or xylene. The alkylation is usually carried out at temperature is under the base Hunga in toluene at about 120oC (distillation temperature) (see Verboom, etc., J. Org. Chem. 1984, 49, 269).Alternatively, these cyclic dialkylamino-derivatives can be obtained by nucleophilic substitution of aromatic fluoride appropriate cyclic amine. Suitable for this reaction solvents are polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, pyridine and hexamethylphosphoramide. Preferred are acetonitrile and pyridine. The reaction may proceed in the presence of a base, such as tertiary or aromatic amines (e.g. triethylamine, diisopropylethylamine, pyridine or dimethylaminopyridine), and preferably pyridine or triethylamine. The reaction can be carried out at a temperature of approximately from room temperature and up to about 160oC, and preferably from about 80 to about 160oC.If R1and R2together with the carbon atoms to which they are linked, form a group of the formula
< / BR>and
X is oxygen or sulfur, the source compound of formula II can be obtained by using the procedure shown below and is illustrated only for cases where R1and R2form a group of the formula A
< / BR>
< / BR>a) 1,4-Piperidinylcarbonyl acid, 1-(1,1-dimethylethyl)ester, 4-ethyl ester
The solution utilisedictated (20,0 g, to 0.127 M) and triethylamine (17,8 ml, to 0.127 M) in 1:1-mixture of dioxane and H2O (1.2 l) was cooled to 0oC. After 15 min was added t-BOC-anhydride (35.2 g, 0,161 M) and the resulting mixture was left overnight to warm to room temperature. Then the mixture was extracted with ethyl acetate (4 times) and the combined organic layers washed with 1 N. hydrochloric acid, water and light orange oily substance, and after Kugelrohr distillation (0,5 Torr (6,67 bar), 80 - 90oC) received target carbamate (30,69 g, 94%) as a colorless oily product.1H-NMR (CDCl3) : 4,11 (sq. 2H, J = 7.2 Hz); 3,97 - of 4.05 (m, 2H); 2,80 (Shir. , t, 2H, J = 11,6 Hz); 2.40 a (TT, 1H, J = 22,0 Hz, J = 3,9 Hz); 1,81 is 1.86 (m, 2H); 1,52 - of 1.66 (m, 2H); USD 1.43 (s, 9H); of 1.23 (t, 3H, J = 7.2 Hz).b) 4-Hydroxymethyl-1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
Alumoweld lithium (4.3 g, 0,114 M) was added to a cold (0oC) the solution carbamate obtained in stage a) (26,57 g, 0,103 M) in tetrahydrofuran (THF) (1 l). After 30 min the ice bath was removed and the reaction mixture stirred over night at room temperature. Then to the mixture was carefully added swiftdecoder sodium as long as you do not stop the gas. After 1 hour stirring, the mixture was filtered through a layer of CeliteTMand the filtrate was concentrated. After recrystallization from ethyl acetate/hexane) received target alcohol (20,67 g, 93%) as a white solid product.1H-NMR (CDCl3) : Android 4.04 - 4.26 deaths (m, 2H); 3,49 (d, 2H, J = 6.4 Hz); 2,70 (Shir. with, 2H, J = 12.0 Hz); 1,6 - of 1.73 (m, 3H); to 1.47 (s, 9H); 1,15 (DDD, 2H, J = 23,2 Hz, J = 12.0 Hz, J = 4.3 Hz).c) 4-Iodomethyl-1-piperidinylcarbonyl acid, 1-(1,1-dimethylethyl)ester
18,5 ml, 0,228 M), and then the alcohol obtained in stage (b) (20.5 g, 0,095 M). The resulting mixture was heated under reflux for 1.5 hours Then the mixture was cooled, filtered, and the filtrate was washed with saturated sodium thiosulfate (Na2S2O3) and brine, dried with magnesium sulfate, filtered and concentrated. After purification by chromatography on silica gel (10% ___ 20% ethyl acetate/hexane) received target iodide (28.5 g, 92%) as a transparent oily product. This product was cooled and received a white solid. So pl. 58 - 59oC.1H-NMR (CDCl3) 4.09 to (Shir. d, 2H, J = 13.1 Hz); is 3.08 (d, 2H, J = 6.5 Hz); 2,66 (Shir. t; 2H, J = 13.1 Hz); 1,80 (Shir. D., 2H, J = 12.9 Hz); 1,52 - of 1.64 (m, 1H); USD 1.43 (s, 9H); 1,11 (DDD, 2H, J = 24,7 Hz); J = a 12.7 Hz, J = 4.3 Hz).d) 4-[2-[1,2-Benzisoxazol-3-yl] ethyl] -1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
A mixture of 3-methyl-1,2-benzisoxazole (0,410 g is 3.08 mm) and iodide obtained in stage (c) (1,05 g, 3,23 mm) in dry THF (3.2 ml), cooled to -78oC. Then drop by drop) was added a freshly prepared 1M diisopropylamide lithium (LDA) (3.1 ml, 3.1 mm) and the resulting yellow-orange solution stirred 25 min at -78oC. then was added a saturated ammonium chloride and the mixture was extracted 3 times those who trevali and concentrated. After purification using flash chromatography on silica gel (10% ___ 20% ethyl acetate/hexane) received target connection (0,430 g, 42%) as a colorless oily substance.1H-NMR (CDCl3) a 7.62 (d, 1H, J = 8.0 Hz); 7,49 - of 7.55 (m, 2H); 7,25 - 7,31 (m, 1H); 4.09 to (m, 2H); 3,00 (t, 2H, J = 7.8 Hz); 2,66 (Shir. t, 2H, J = 13,0 Hz); 1,71 - of 1.84 (m, 4H); 1,47 - of 1.53 (m, 1H); USD 1.43 (s, 9H); 1,14 (DDD, 2H, J = 24.5 Hz, J = 12.1 Hz, J = 4,1 Hz).e) 3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol-maleat
Triperoxonane acid (TFA) (7 ml) drop by drop) was added to a cold (0oC) solution of piperidine obtained in stage (d) (0.50 g, 1,51 mm) in methylene chloride (7 ml). The resulting solution was stirred 30 min at 0oC. Volatiles were removed under reduced pressure, and excess TFE was removed by concentration (2 times from toluene. The crude product was again dissolved in methylene chloride (10 ml) and then was added triethylamine (0,42 ml, 3,01 mm) and benzylbromide (0,18 ml and 1.51 mm). The resulting mixture was stirred overnight (15 h) at room temperature. The mixture was washed with water and brine, and then dried with magnesium sulfate, filtered and concentrated. After flash chromatography on silica gel (50% ethyl acetate/hexane) received target compound free base (0,350 g, 73%) as bestv what the notes (to 0.108 g, 0,930 mm) in ethyl ether (20 ml) to a solution of free base (0,297 g, 0,926 mm) in ethyl ether (20 ml). The obtained white solid was collected and washed with ethyl ether. Yield: 0.35 g, 87%. So pl. 146,4 - 147,6oC
EIMS (emission mass spectroscopy) (not the original) 319,1; 303,1; 185,2; 172,1; 91,1.1H-NMR (CDCl3) 7,60 (d, J = 8, 1H); 7,51 - 7,52 (m, 2H); 7,37-7,49 (m, 5H); 7,25-7,32 (m, 1H); 6.30-in (s, 2H); 4.16 the (s, 2H); 3,45-3,51 (m, 2H); 2,98 (t, J=7,4); (2H); 2,60-2,70 (m, 2H); 1,84-of 1.95 (m, 4H); 1.60-to is 1.82 (m, 3H).13C-NMR 169,5; 163,0; 157,7; 135,8; 131,1; 130,1; 130,0; 129,3; 128,5; 123,5; 121,3; 121,1; 110,0; 60,6; 52,1; 32,8; 28,8; 22,1.IR (KBr): 2944, 2927, 2921, 2499-2518 (Shir.), 2329-2388 (Shir.), 1583, 1517, 1473, 1458, 1445, 1438, 1383, 1360, 782 cm-1< / BR>Analysis for C21H24N2O C4H4O4:
Calculated: C 68,79; H 6,47; N, 6.42 Per.Found: C 68,80; H 6,35; N 6,27.Example 2.5-Methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]1,2-benzisoxazole
< / BR>4-[2-[-5--Methyl-1,2-benzisoxazol-3-yl] ethyl] -2-piperidinecarbonitrile acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 1d, using 3,5-dimethyl-1,2-benzisoxazole (0,500 g, 3,40 mm), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl)-complex ester (1.20 g, 3,74 mm) and 1M of diisopropylamide lithium (LDA) (3,74 ml, 3,74 mm) in the A.1H-NMR (CDCl3) 7,28-7,40 (m, 3H); 4.04 the-4,11 (m, 2H); to 2.94 (t, 2H, J= 7.8 Hz); 2,64 (Shir.t, 2H, J=12.3 Hz); 2,43 (s, 3H); 1.70 to 1,99 (m, 4H); of 1.42 (s, 9H); 1.41 to 1.55V (m, 1H); 1,13 (DDD, 2H, J=24,4 Hz); J=12.0 Hz); J= 4,1 Hz).a) 5-Methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazole
Repeating the procedure described in example Ie, using piperidine, obtained in stage (a) (0.910 g, 2.64 mm), and TFA (13 ml) in methylene chloride (CH2Cl2) (13 ml), and triethylamine (3,7 ml of 26.4 mm), and benzylbromide (0,32 ml, 2,69 mm) in methylene chloride (CH2Cl2) (20 ml). After cleaning has been the target compound free base as a transparent oily product (0.56 g, 63%).Maleate (salt) was obtained by adding a solution of maleic acid (0.20 g, 1,72 mm) in ethyl ether (Et2O) (10 ml) to a solution of free base (0.56 g, 1,67 mm) Et2O (40 ml). The resulting white solid was collected and washed with ethyl ether. Output: 0,70 g, 93%. So pl. 149-151oC.1H-NMR (CDCl3) 7,27-the 7.43 (m, H8); 6,32 (s, 2H); to 4.17 (s, 2H); 3,51 (Shir.d, J=11,6 Hz, 2H); 2,96 (t, J=7,3 Hz, 2H); 2,66 (Shir.t, J=10,8 Hz, 2H); of 2.45 (s, 3H); 1.60-to of 1.97 (m, 7H).13C-NMR: 169,4; 161,6; 157,3; 135,7; 133,2; 131,6; 131,0; 130,1; 129,3; 128,4; 121,4; 120,2; 60,6; 52,0; 32,8; 32,7; 28,7; 22,0; 21,1.IR (KBr) 2934; 2848; 2499; 2362; 1701; 1617; 1572; 1487; 1454; 1357 UB>2
Calculated: C 69,32; H Of 6.71; N 6,22.Found: C 69,18; H 6,48; N Between 6.08.Example 3.5,6-Dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2 - benzisoxazole
< / BR>a) 4-[2-[5,6-Dimethyl-1,2-benzisoxazol-3-yl]ethyl]-1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 1d, using 3,5,6-trimethyl-1,2-benzisoxazole (0,600 g of 3.73 mm), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) of ester (1,30, 4,10 mm)) and 1M LDA (4,10 ml, 4,10 mm) in dry THF (10 ml). After cleaning has been the target connected (1.04 g, 78%) as a transparent oily substance.1H-NMR (CDCl3) to 7.32 (s, 1H); 7,27 (s, 1H); 4.04 the-4,10 (m, 2H); of 2.93 (t , 2H, J= 7.8 Hz); 2,64 (Shir.T. 2H, J=11.8 Hz); 2,35 (s, 3H); 2,32 (s, 3H); 1,70-1,80 (m, 4H); USD 1.43 (s, 9H); 1,43-is 1.51 (m, 1H); 1,13 (DDD, 2H, J= 24.3 Hz); J=12.3 Hz; J= 4,2 Hz).a) 5,6-Dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2 - benzisoxazole
Repeating the procedure described in example 1e using piperidine, obtained in stage (A) (1.04 g, 2,90 mm), and TFA (16 ml) in CH2Cl2(16 ml), and triethylamine (4,2 ml, 29,0 mm), and benzylbromide (0,36 ml, 3,03 mm) in CH2Cl2(20 ml). After cleaning has been the target connection (free osnovaniya maleic acid (0.18 g, 1,55 mm) Et2O (10 ml) to a solution of free base (0,53 g, 1.52 mm) Et2O (25 ml). The resulting white solid was collected and washed with ethyl ether.Yield: 0.65 g, 92%. So pl. 182-183,5oC.1H-NMR (CDCl3) 7,30-7,41 (m, 7H); 6,32 (s, 2H); to 4.17 (s, 2H); 3,51 (Shir. d, J=11.8 Hz; 2H); 2.95 points (t, J=7,2, 2H); 2,65 (Shir. t, J= 11.7 Hz, 2H); of 2.38 (s, 3H); of 2.34 (s, 3H); 1,59 is 1.96 (m, 7H).13C-NMR 169,4; 162,3; 157,1; 140,2; 135,7; 132,6; 131,1; 130,1; 129,3; 128,3; 120,3; 119,2; 110,0; 60,6; 52,0; 32,7; 28,7; 22,0; 20,9; 29,9.EIMS 347,2; 331,1; 185,1; 172,1; 91,1 (base)
IR (KBr) 2949; 2914; 2512; 2420; 1580; 1476; 1456; 1449; 1358 cm-1.Analysis for C23H28N2O C4H4O41/4H2O:
Calculated: C 69,14; H 6,93; N 5,97.Found: C 69,27; H 6,83; N 5,91.Example 4.5-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2 - benzisoxazole
< / BR>a) 4-[2-[5-Methoxy-1,2-benzisoxazol-3-yl] ethyl] -1-piperidinecarboxylate acid. 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 1d, using 5-methoxy-3-methyl-1,2-benzisoxazole (0.32 g, 1,96 mm) 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl)of ester (0,70 g, 2,15 mm) and IM LDA (2.0 ml, 2.0 mm) in dry THF (2 ml). After cleaning has been the target connection (0,62 g, 87%) in the J = 2.5 Hz); of 6.96 (d, 1H, J = 2.4 Hz); 4.09 to to 4.16 (m, 2H), a 3.87 (c, 3H); 2,99 (t, 2H, J = 7.8 Hz); 2,68 (Shir. t, 2H, J = 12.3 Hz); 1,74-of 1.85 (m, 4H); 1,46-of 1.64 (m, 1H); 1,46 (c, 9H); 1,17 (DDD, 2H, J = 22,3 Hz, J = 12,2 Hz; J = 4,2 Hz).a) 5-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2 - benzisoxazole
Repeating the procedure described in example Ie, using piperidine, obtained in stage (a) (0,58 g, 1,61 mm), and TFA (7 ml) in CH2Cl2(7 ml), and triethylamine (and 0.50 ml, 3.6 mm), and benzylbromide (of € 0.195 ml, 1,64 mm) in CH2Cl2(10 ml). After cleaning has been the target compound (free base) (0.27 g, 48%) as a transparent oily product.Maleate (salt) was obtained by adding a solution of maleic acid (0,080 g, 0,69 mm) Et2O (10 ml) to a solution of free base (0.24 g, 0.68 mm) Et2O (20 ml). The resulting white solid was collected and washed with ethyl ether. Output: 0.29 grams, 91%, so pl. 143,5-145oC.1H-NMR (CDCl3) 7,35-7,42 (m, 6H); 7,13 (DD, J1= 9,1, J2= 2,5, 1H); 6,92 (d, J = 2,4, 2H); 6.30-in (c, 2H); 4,17 (c, 2H); 3,83 (c, 3H); 3.46 in-3,51 (m, 2H); to 2.94 (t, J = 7,3, 2H); 2,60 is 2.80 (m, 2H); 1.60-to a 1.96 (m, 7H).13C-NMR 169,4; 158,4; 157,6; 156,3; 135,8; 131,0; 130,0; 129,2; 128,4; 121,5; 120,3; 110,6; 101,1; 60,5; 56,0; 52,0; 32,7; 32,5; 28,7; 22,0.IR (KBr) 2942, 2927, 2916, 2518, 2366, 1616, 1572, 1544, 1521, 1480, 1454, 1443, 1384, 1357, 1220 cm-1.
antisocial-maleate
Calculated: C 66,94; H 6,48; N 6,00.Found: C 67,21; H Of 6.52; N 5,94.Example 5.6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol
< / BR>a) 4-[2-[6-Methoxy-1,2-benzisoxazol-3-yl] ethyl] -1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 1d, using 6-methoxy-3-methyl-1,2-benzisoxazol (0.32 g, 1,96 mm), 4-iodomethyl-1-piperidinecarboxylic acid 1-(1,1-dimethylethyl)of ester (0,70 g, 2,15 mm) and IM LDA (2.0 ml, 2.0 mm) in dry THF (3 ml). After cleaning has been the target connection (or 0.57 g, 80%) as a white solid product. So pl. 95-96oC.1H-NMR (CDCl3) 7,47 (d, 1H, J = 8.7 Hz); 6,99 (d, 1H, J = 2.1 Hz); 6,91 (DD, 1H, J = 8.6 Hz, J = 2.1 Hz); 4,08-4,11 (m, 2H); 3,89 (c, 3H); of 2.97 (t, 2H, J = 7.8 Hz); 2,68 (Shir.T., 2H, J = a 12.7 Hz); 1,72-of 1.84 (m, 4H); 1,46 is 1.60 (m, 1H); 1,46 (c, 9H); to 1.16 (DDD, 2H, J = 24.6 Hz, J = 12.3 Hz, J = 4.3 Hz).b) 6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol
Repeating the procedure described in example 1e using piperidine, obtained in stage (a) (0,49 g, 1,36 mm), and TFA (7 ml) in CH2Cl2(7 ml), and triethylamine (of 0.85 ml, 6.1 mm), and benzylbromide (0,165 ml, 1,39 mm) in CH2Cl2(8 ml). After cleaning has been the target connection (0,265 g, 55%) as a white solid was = 8,7, J2= 2,0, 1H); 3,88 (c, 3H); 3,50 (c, 2H); 2,88 are 2.98 (m, 4H); 1,96 (Shir.t, J = 10,6, 2H); 1,74 of-1.83 (m, 4H); of 1.27 to 1.34 (m, 3H).13NMR 164,8; 162,0; 158,3; 138,4; 129,3; 128,1; 126,9; 121,4; 115,0; 113,8; 92,6; 63,4; 55,7; 53,7; 35,3; 34,3; 32,6; 22,6.IR (KBr) 2924, 2913, 2797, 2758, 1625, 1608, 1276, 1196, 1154, 734 cm-1.EIMS 349,2; 333,6; 259,1; 185,1; 172,1; 91,0 (the basis).Analysis for C22H26N2O2:
Calculated: C 75,40; H 7,8; N 7,99.Found: C 75,52; H 7,63; N 7,94.Example 6.7-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2 - benzisoxazole
< / BR>a) 4-[2-[7-Methoxy-1,2-benzisoxazol-3-yl] ethyl-1-piperidinylcarbonyl acid. 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example Id, using 7-methoxy-3-methyl-1,2-benzisoxazol (0,30 g, 1,84 mm), 4-iodomethyl-1-piperidinecarboxylic acid 1-(1,1-dimethylethyl)ester (0,60 g of 1.85 mm) and 1M LDA (1.9 ml, 1.9 mm) in dry THF (2 ml). After cleaning has been the target connection (0,41 g, 62%) as a pale yellow oily substance.1H-NMR (CDCl3) 7,12-7,10 (m, 2H); 6,91(DD, 1H, J=6,5 Hz, J=2.2 Hz); 3,98-4,07 (m, 2H); 3,98 (s, 3H); 2.95 and (t, 2H, J=7.8 Hz); 2,62 (Shir.t, 2H, J= 12,2 Hz); 1,67-of 1.78 (m, 4H); of 1.40 to 1.48 (m, 1H); of 1.40 (s, 9H); 1,10 (DDD, 2H, J=24.5 Hz, J=12,5 Hz, J=4.3 Hz).b) 7-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazol,11 mm), and TFA (6 ml) in CH2Cl2(6 ml), and triethylamine (0,34 ml, 2,44 mm), and benzylchloride (0,14 ml of 1.18 mm) in CH2Cl2(140 ml). After cleaning has been the target compound (free base) (0,080 g, 21%) as a transparent oily product.Fumaric salt was obtained by addition of a solution of fumaric acid (0.025 g, 0,213 mm) in ethanol EtOH (2 ml) to a solution of free base (0,071 g, 0,203 mm) in ethyl ether (10 ml). After concentration to a final volume of 4-5 ml was formed whitish-pink precipitate. This solid precipitate was collected and washed with ethyl ether. Output: 0,065 g, 69%.So pl. 138-139oC.1H-NMR (CDCl3) 7,27-7,41 (m, 7H); 7,19 (d, J=7,7, 1H); 6,59 (s, 2H); of 3.97 (s, 3H); 3,65 (C. 2H); 2,90-a 3.01 (m, 4H); 2,18 (Shir.t, J=10,8, 2H); 1,67-to 1.77 (m, 4H); 1.26 in-1,32 (m, 3H).13C-NMR 166,6; 158,8; 152,4; 144,0; 136,5; 134,4; 129,4; 128,3; 127,5; 124,9; 122,9; 113,2; 111,4; 61,5; 56,2; 52,6; 34,3; 33,4; 30,7; 22,0.VRMS: calculated (free base) 350,1992. Found: 350,1984.IR (KBr) 1705, 1531, 1266, 756, 642 cm-1.Analysis for C22H26N2C4H4O4:
Calculated: C 66,94; H 6,48; N 6,00.Found: C 66,76; H Of 6.31; N 5,61.Example 7.6-Ndimethylacetamide-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2 - benzisoxazol-hemifumarate the th ether
Freshly prepared 1M LDA (of 11.0 ml, 11.0 mm) drop by drop and quickly added to a cooled (-78oC) a solution of 6-N-acetyl-3-methylbenzoate (1.0 g, 5,26 M) in THF (50 ml). Immediately after adding one portion was added a solution of 1-(1,1-dimethylethanol) of ester 4-iodomethyl-1-piperidinecarboxylic acid (1,71 g, 5,26 mm) in THF (8 ml). Then added saturated ammonium chloride (NH4Cl) and the resulting mixture was extracted with ethyl acetate (EtOAc) (3 times). The combined organic layer was washed with saline, dried with magnesium sulfate, filtered and concentrated.After purification using flash chromatography on silica gel (20% ___ 50% EtOAc/CH2Cl2) received target compound (1.56 g, 76%) as a white solid product. So pl. 142-143oC.1H-NMR (CDCl3) (CH2Cl2____ 10% 8,76 (s, 1H); with 8.05 (s, 1H); of 7.48 (d, 1H) J= 8.5 Hz); to 7.32 (DD, 1H, J=8.6 Hz, J=1.5 Hz); 4,06 (Shir. d, 2H, J=11.5 Hz); to 2.94 (t, 2H, J= 7.8 Hz); 2,66 (Shir.t, 2H, J=11.8 Hz); of 2.20 (s, 3H); was 1.69 and 1.80 (m, 4H); of 1.41 to 1.47 (m, 1H); 1.44MB (c, 9H); 1,12 (DDD, 2H, J=23,8 Hz; J=12.0 Hz, J=3,9 Hz).b) 6-Acetamido-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]- 1,2-benzisoxazol-fumarate
Triperoxonane acid (TFA) (4 ml) drop by drop) was added to a cold (0oC) solution of piperidine obtained in stage (a) (Yali under reduced pressure, and excess TFA was removed by concentration (2 times from toluene. The crude product was again dissolved in methylene chloride (10 ml) was added triethylamine (1,44 ml of 10.3 mm) and benzylbromide (0,184 ml of 1.55 mm). The resulting mixture was placed 6 h at room temperature. The mixture is then washed with water and brine and was dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel, MeOH/CH2Cl2) received target compound (free base) (0,270 g, 69%) as a white solid.Fumaric salt was obtained by addition of a solution of fumaric acid (0,091 g, 0,788 mm) in ethanol (EtOH) (5 ml) to a solution of free base (0,270 g, 0,716 mm) in CH2Cl2(20 ml). After concentrating the obtained solid product was recrystallized from ethanol and obtained white needle crystals.Yield: 0.17 g, 48%. So pl. 225-226oC.1H-NMR (DCO-d6) 10,37 (s, 1H); 8,13 (c, 1H); 7,76 (d, 1H, J=8,5); 7,25 was 7.36 (m, 6H); 6,59 (c, 2H); 3,54 (c, 2H); 2,83-2,96 (m, 4H); 2,10 (c, 3H); 2,01 (Shir.t, 2H, J=11,1); 1,69-of 1.73 (m, 4H); 1,20 of 1.28 (m, 3H).Analysis for C23H27N3O21/2 C4H4O41/4H2O:
Calculated: C 68,24; H 6,76; N Of 9.55.Found: C 68,35; H 6,63; N 9,35.Manumaleuna Sol was obtained by adding a solution of maleic acid (0,099 g, 0.85 mm) in EtOH (5 ml) to a solution of free base (0.26 g, 0.77 mm) in CH2Cl2(3 ml). After concentration the residue is triturated with ethyl ether and was obtained a white powder. Output: 0.29 grams, 64%. So pl. 173, 0mm-173.5 metricoC
1H-NMR (DMCO-d6) 7,41-7,47 (m, 6H); 6,58-6,63 (m, 2H); 6,06 (c, 2H); by 5.87 (Shir.s, 2H); 4.26 deaths (c, 2H); 3,29-to 3.38 (m, 2H); 2,80-2,95 (m, 4H); 1,90 (Shir.d, J=12,5, 2H); 1,25-of 1.80 (m, 5H).13C-NMR (DMCO-d6) 167,4; 164,8; 157,4; 151,9; 136,0; 131,2; 130,1; 129,5; 128,9; 121,9; 112,8; 110,7; 90,9; 59,3; 51,5; 32,6; 32,6; 28,6; 21,6.EIMS (not source.) 289, 268, 218, 190 (the basis).IR (KBr) 3483, 3384, 2929, 2526, 1633, 1619, 1582, 1515, 1474, 1459, 1438, 1389, 1379, 1359, 977, 702 cm-1.Analysis for C21H25N2O C4H4O4:
Calculated: C 66,50; H 6,47; N 9,31.
< / BR>6-Benzamide-3-methyl-1,2-benzisoxazol
The benzoyl chloride high (0.56 ml, 4,82 mm) was added to a solution of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0,70 g, 4,72 mm, triethylamine (1,35, RS 9.69 mm) and 4-dimethylaminopyridine (0.07 g, 0,57 mm) in CH2Cl2(30 ml). The resulting mixture was stirred at room temperature overnight. This heterogeneous mixture was concentrated, and the obtained solid residue was collected, washed with water and ether, and dried by air, resulting in a received target connection (1,02 g, 86%) as a whitish solid. A small sample was purified by recrystallization from ethanol and received net flocculent product.
Repeating the procedure described in example 7a using benzamide obtained in stage (a) (1.0 g, 3,96 mm), IM (LDA to 7.95 ml, 7.95 mm) and 4-iodomethyl-1-piperidinecarboxylic acid 1-(1,1-dimethylethyl)ester (of 1.30 g, 4.00 mm) in dry THF (50 ml), except that after adding the reagent mixture R is the group (1.54 g, 87%) as a pale yellow solid. A small sample was purified by recrystallization (CH2Cl2/Et2O) and received a white solid. Etc., 177-178,5oC.1H-NMR (CDCl3) 8,61 (c, 1H); 8,15 (c, 1H); 7,86 (d, 2H, J=7.4 Hz); 7,39-7,53 (m, 5H); 4,03 (Shir.d, 2H, J=a 12.7 Hz); of 2.92 (t, 2H, J= 8.0 Hz); 2,50-by 2.73 (m, 2H); 1,60-1,80 (m, 4H); 1,40-1,45 (m, 1H); 1,41 (c, 9H); 1,13 (DDD, 2H, J=24,0 Hz); J=and 12.2 Hz, J=3.8 Hz).c) 6 - Benzamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl] -1,2-benzisoxazole Triperoxonane acid (TFA) (8,4 ml) drop by drop) was added to a cold solution (0oC) piperidine obtained in stage (b) (0,70 g, 1,56 mm) in CH2Cl2(10 ml). The resulting solution was stirred 30 min at 0oC. Volatiles were removed under reduced pressure, and excess TFA was removed by concentration (2 times from toluene. The crude product was dissolved in THF 10 ml was added triethylamine (2.1 ml, 15.1 mm), and then benzylbromide (of 0.21 ml, 1,77 mm). The resulting mixture was diluted with ethyl acetate and stirred at room temperature overnight. The mixture is then washed with water and brine, dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (30% EtOAc/CH2Cl2100% EtOAc) received target compounds by adding a solution of maleic acid (of 0.081 g, 0,702 mm) in EtOH (5 ml) to a solution of free base (0,280 g, 0,638 mm) in CH2Cl2(20 ml). After concentrating the obtained solid product was recrystallized from EtOH/CH2Cl2and got a white solid. Output: 0,208 g, 59%. So pl. 181,5-USD 183.0oC.1H-NMR (DMCO-d6) 10,65 (s, 1H); 8,31 (s, 1H); 7,98 (d, J=7,2, 2H); a 7.85 (d, J= 8,6, 1H); of 7.48-7,71 (m, 9H); 6,03 (c, 2H); 4.25 in (lat.s, 2H); 3,20-of 3.60 (m, 4H); 2,89-to 3.02 (t, 2,99 J=7.5 and m, 4H); 1,40-of 1.97 (m, 7H).13C-NMR (DMCO-d6167,2; 166,2; 163,0; 158,1; 141,5; 135,9; 134,6; 132,0; 131,2; 129,5; 128,9; 128,5; 127,8; 121,9; 117,01; 116,8; 99,9; 59,5; 51,7; 32,8; 32,5; 28,8; 21,7.EIMS 439,2; 422,2; 100; 383; 348; 293; 185.IR (KBr): 2934, 2919, 1657, 1610, 1579, 1536, 1499, 1491, 1462, 1453, 1352 cm-1.Analysis for C28H29N3O2C4H4O4:
Calculated: C 69,17; H Of 5.99; N 7,56.Found: C 68,81; H 5,90; N 7,49.Example 10.6-Benzosulfimide-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] - 1,2-benzisoxazol-fumarate
< / BR>a) 6-Benzosulfimide-3-methyl-1,2-benzisoxazol
Benzosulphochloride (0,528 ml, 4,14 mm) was added to a cold (0oC) a solution of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2-benzisoxazole (0,613 g, 4,14 mm) and pyridine (0,670 ml of 8.28 mm) in CH2Cl2(30 ml). After 1.3 h was added saturated bicar the second layer was separated and washed with water and brine, was dried by magnesium sulfate, filtered and concentrated. After purification on a flash chromatography on silica gel (5% EtOAc/CH2Cl2) received target connection (0,867 g, 83%) as a white solid. So pl. 183-184oC.1H-NMR (CDCl3) (20% ___ 40% 10,9 (Shir.s, 1H); to 7.84 (d, 2H, J=6,7 Hz); to 7.68(d, 1H, J=8.5 Hz); 7,52-7,63 (m, 3H); 7,34 (d, 1H, J=1.5 Hz); 7,11 (DD, 1H, J=8.5 Hz, J=1.7 Hz); 2,52 (s, 3H).(b) 4-2-6-Benzosulfimide-1,2-benzisoxazol-3-yl-ethyl-1 - piperidinylcarbonyl acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 7a using benzosulfimide obtained in stage (a) (0,60 g, 2,08 mm), IM (LDA 4,58 ml, 4,58 mm) and 1-(1-dimethylethyl) ester 4-iodomethyl-1-piperidinecarboxylic acid (0,813 g, 2.50 mm) in dry THF (70 ml), except that after addition of the reagents, the mixture is stirred at -78oC for 10-15 minutes After purification by chromatography using EtOAc/hexane) received target connection (0,997 g, 99%) as a white foamy substance. So pl. 66-67oC.1H-NMR (CDCl3) (CH2Cl2____ 5% of 7.85 (DD, 2H, J=8,3 Hz, J=1.6 Hz); 7,35 (-7,57 (m, 6H); 7,02 (DD, 1H, J=8.5 Hz, J=1.6 Hz); 4,11 (Shir.d, 2H, J=13,2 Hz); to 2.94 (t, 2H, J=7.4 Hz); 2,68 (Shir.t, 2H, J=12,8 Hz); 1,71-to 1.77 (m, 4H); 1,46 (c, 9H); 1,46-of 1.55 (m, 1H); 1,15 (DDD, 2H, J=23,6 Hz, J=11.7 Hz, J=3,9 Hz).c) 6-Be consultant (1,30 ml, 6,76 mm) drop by drop) was added to a cold (0oC) solution of piperidine obtained in stage (b) (0,819 g, 1,69 mm) and 2,6-lutidine (0,590 ml 5,07 mm) in CH2Cl2(17 ml). An hour and a half was added saturated sodium bicarbonate (NaHCO3) and the resulting mixture was stirred 15 min at room temperature. The resulting white precipitate was collected by filtration and again dissolved in water at pH 2. This acidic aqueous layer was extracted 2 times with methylene chloride and 1 times with ethyl acetate. All organic layers were combined, dried with magnesium sulfate, filtered and concentrated. The obtained white residue suspended in THF (30 ml) and FMD (50 ml) was added triethylamine (and 0.40 ml of 2.86 mm) and benzylbromide (0,22 ml of 1.86 mm). Received a heterogeneous mixture stirred at room temperature for 24 h (time, more homogeneous mixture). The mixture was concentrated and to the residue was added CH2Cl2. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel, MeOH/CH2Cl2) received target connection (loose coupling) (0,334 g, 49%) as a white foamy substance.Fumarate (Sol) has received the mm) in CH2Cl2(6 ml). After concentration the residue is triturated with ethyl ether and obtained white solid. Output: 0,151 g, 81%.1H-NMR (DMCO-d6) of 7.82 (d, 1H, J= 7,0); of 7.70 (d, 1H, J = 8,6); 7,51 - of 7.60 (m, 3H); 7,27 - to 7.32 (m, 6H); 7,07 (DD, 1H, J= 8,6, J=1,6); 6,59 (s, 2H); of 5.55 (s, 2H); 2,82 - 2,90 (m, 4H); 20,3 (W, T. 2H, J=11,5); 1,61 is 1.70 (m, 4H); a 1.20 - 1.25 (m, 3H).Example 11.6-(4-morpholinyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2-benzisoxazol
,,
a) 3-Methyl-6-(4-morpholinyl)-1,2-benzisoxazol
A mixture of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]1,2-benzisoxazole (0,230 g 1,55 mm) dibromomethane ether (0,397 g, 171 mm) and diisopropylethylamine (base Hunya, 0,648 ml, 3,71 mm) in toluene (2.5 ml) was heated for 15 h at 120oC. the Cooled mixture was diluted with ethyl acetate and washed with water m saline, then was dried with magnesium sulfate, filtered and concentrated. After this was carried out in the same way two separate reactions using 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2 - benzisoxazole (0,050 g 0,34 mm and 0.150 g, 1,01 mm). The crude product obtained from the three reactions were combined and purified using flash chromatographie on silica gel (1% MeOH/CH2Cl2), resulting in a received target connection (0,499 g, 79%) full the tOAc/hexane) and received a white solid. So pl. 138,5 - 139,5oC.1H-NMR (CDCl3) (5% ___ 40% 7,46 (d, 1H, J=8.7 Hz); to 6.95 (DD, 1H, J=8.7 Hz, J=2.0 Hz); 6.90 to (d, 1H, J=1.9 Hz); 3,88 (so-4H, J=4.9 Hz); of 3.27 (t, 4H, J=4,8 Hz); 2,52 (s, 3H).b) 4[2-[6-(4-Morpholinyl)-1,2-benzisoxazol-3-yl] ethyl]-1 - piperidinecarboxylate acid. 1-(1,1-dimethylethyl) ester
Repeating the procedure described in example 7a using morpholino-derivative obtained in stage (a) (0369 g, 1,69 mm), 1M LDA (of 1.86 ml of 1.86 mm), and 4-iodomethyl-1-piperidinecarboxylic acid 1-(1,1-dimethylethyl) ester (0,605 g, 1,86 mm) in dry THF (8 ml). Also acted in another reaction with the above morpholino-derived (0,100 g, 0.46 mm). The crude product obtained from these two reactions were combined and after purification by chromatography EtOAc/hexane) received target connection (0,477 g, 53%) as a white solid product. Then a small sample was purified by recrystallization (EtOAc/hexane) and received a white solid.So pl. 164 - 165oC.1H-NMR (CDCl3) 7,46 (d, 1H, J=8.6 Hz); 6,92 - 6,97 (m, 2H); as 4.02 - to 4.15 (m, 1H); to 3.89 (t, 4H, J=4.9 Hz); of 3.27 (t, 4H, J=4.9 Hz); 2.95 and (t, 2H, J=7.8 Hz); 2,7 (Shir. t, 2H, J=12.1 Hz); 1,74 and 1.80 (m, 4H); 1,46 - of 1.56 (m, 1H); of 1.46 (s, 9H); 1,10 - 1,22 (m, 2H).c) 6-(4-Morpholinyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl-1,2-benzisoxazol
Triperoxonane of kyanite (1.13 ml, 9,60 mm) in CH2Cl2(10 ml). The resulting mixture was stirred 30 min at 0oC. Volatiles were removed under reduced pressure and to the residue was added 1N. NaOH. The aqueous layer was extracted with ethyl acetate ( 2 times) and the combined organic layer was washed with water and brine, dried with magnesium sulfate, filtered and concentrated. The obtained yellow oily substance was again dissolved in methylene chloride (10 ml) and to the solution was added triethylamine (0,267 ml of 1.92 mm) and benzylbromide (0,148 ml, 11,25 mm). The resulting mixture was stirred at room temperature overnight. After that, the mixture was washed with water and brine, dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (CH2Cl2____ 10% MeOH/CH2Cl2), had been the target connection (0,285 g, 73%) as a white solid product. Then a small sample was purified by recrystallization from ethanol and obtained white solid. So pl. 129 - 130oC.1H-NMR (CDCl3) 7,44 (d, J=8,7, 1H); 7.23 percent - 7,30 (m, 5H); 6,89 - 6,93 (m, 2H); a 3.87 (t, J=4,8, 4H); 3,47 (s, 2H); of 3.25 (t, J=4,8, 4H); 2,85 - to 2.94 (m, 4H); 1,92 (Shir. so J=10,8, 2H); 1,72 - to 1.79 (m, 4H); 1,21 - 14,31 (m, 3H).13C-NMR: 165, 158, 153,4; 138,8; 129,2; 128,1; 126,9; 121,3; 113,3; 94,5; 66,7;�I C25H31N3O2:
Calculated: C 74,04; H Of 7.70; N 10,36.Found: C 73,75; H Of 7.69; N 10,36.Example 12.5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6H - periodo[4-, 5-f]-1,2-benzisoxazol-6-it-maleate
a) 5-Acetyl-1,3-dihydro-6-hydroxy-2H-indol-2-he
Acetylchloride (4.09 to ml, 0,0575 M) was added to a suspension of trichloride aluminum (AlCl3) (up RUB 35.36 g, 0,265 M) in carbon disulfide (CS2) (250 ml). After 2 to 3 minutes was added 6-methoxyxanthone (7,22 g, 0,0442 M). The resulting mixture was heated under reflux for 2.5 hours (from the time the mixture became black tar). The excess solvent decantation, and the residue was carefully added to ice water. The resulting mixture was stirred over night. The obtained solid pale yellow product was collected, washed with water, and dried in high vacuum and got the target connection (to 7.32 g, 87%).1H-NMR (DMCO-d6) 13,0 (s, 1H); to 10.8 (s, 1H); of 7.70 (s, 1H); 6.30-in (s, 1H); 3.40 in (s, 2H); to 2.54 (s, 3H).b) 5-Acetyl-1,3-dihydro-6-hydroxy-2H-indol-2-it, 5-oxime
An aqueous solution of hydroxylamine hydrochloride (compared to 8.26 g, 0,119 M) and the trihydrate of sodium acetate (16,9 g, 0,124 M) was added to a mixture of the ketone obtained in stage (a) (9.88 g, 0,0517 M) in EtOH(600 ml). The resulting mixture was heated with reverse cold which After drying has been the target connection (10,11 g, 95%) as a pale yellow substance.1H-NMR (DMCO-d6) to 12.0 (s, 1H); 11.4 in (s, 1H); to 10.5 (s, 1H); 7.29 trend (s, 1H); 6,35 (s, 1H); to 3.38 (s, 2H); of 2.20 (s, 3H).c) 5-Acetyl-1,3-dihydro-6-hydroxy-2-indole-2-it, 5-oxiracetam
A heterogeneous mixture of oxime, obtained in stage (b) (7,15 g, 34,7 mm) in acetic anhydride (55 ml) was heated for 2 h at 80oC. the Cooled reaction mixture was filtered and the collected solid washed with water. After drying of the received target connection (4,67 g, 54%) as a pale yellow solid.1H-NMR (DMCO-d6) to 11.3 (S, 1H); to 10.6 (s, 1H); to 7.35 (s, 1H); 6,44 (s, 1H); to 3.41 (s, 2H); is 2.37 (s, 3H), of 2.21 (s, 3H).d) 5,7-Dihydro-3-methyl-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he
A mixture of oxiracetam obtained in stage (4,48 g, 18,0 mm), and pyridine (14.6 ml, 180 mm) in dimethylformamide (DMF) (660 ml) was heated for 4 h at 125 - 130oC. the Cooled reaction mixture was poured into water and was extracted 4 times with ethyl acetate. The combined organic layer was washed with water and brine, dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (50% EtOAc/ hexane____ 100% EtOAc) received target compound (2.20 g, 65%) as pale yellow-orange solid product. So the tx2">
Repeating the procedure described in example 7a using benzisoxazol obtained in stage d (2,33 g, 12,4 mm), IM (LDA 40,9 ml of 40.9 mm), and 4-iodomethyl-1-piperidine-carboxylic acid 1-(1,1-dimethylethyl) ester (4.42 g, 13,6 mm) in dry THF (500 ml), except that after addition of the reagents, the mixture is stirred 4 h at -78oC. After purification by chromatography ( 20%____ 30% EtOAc/CH2Cl2) received source material (0,210 g, 9%) and the target connection (2,75 g, 58%) as a whitish solid.1H-NMR (CDCl3) 8,48 (s, 1H); 7,44 (s, 1H); 7.03 is (s, 1H); 4,08-to 4.14 (m, 2H); 3,63 (s, 2H); of 2.97 (t, 2H, J=7.8 Hz); 2,69 (Shir.t, 2H, J=12,8 Hz); 1,74-of 1.84 (m, 4H); 1,46-of 1.55 (m, 1H); of 1.46 (s, 9H); 1.18 to (DDD, 2H, J=24,4 Hz; J=12.1 Hz, J=4.3 Hz).f) 5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] - 6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-it-maleate
Triperoxonane acid (TFA) (3,3 ml) drop by drop) was added to a cold solution (0oC) piperidine obtained in stage (e) (0.50 g, 1,30 mm) in CH2Cl2(13 ml). After 30 min the mixture was concentrated and the excess TFA was removed by concentration from toluene (2-3 times). The crude residue was dissolved in DMF (12.5 ml) Merivale 4 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was dissolved in methylene chloride, washed with saline, dried with magnesium sulfate, filtered and concentrated. After purification by chromatography on silica gel (CH2Cl210% MeOH/CH2Cl2) received target compound (free base) (0,343 g, 70%) as a white solid.Maleate (salt) was obtained by adding a solution of maleic acid (0,061, 0,528 mm) in ethanol (EtOH) (1 ml) to a solution of free base (0,180 g, 0.48 mm) in CH2Cl2(10 ml). After concentration of the salt was purified by recrystallization from isopropanol, the resulting received a whitish solid. Output: 0,173 g, 73% So pl. 194-195oC.1H-NMR (DMCO-d6) was 10.82 (s, 1H); the 7.65 (s, 1H); of 7.48 (s, 5H); 7,00 (s, 1H); 6,03 (s, 1H); 4,24 (Shir.s, 2H); to 3.58 (s, 2H); 3.25 to to 3.38 (m, 2H); to 2.94 (t, 2H, J=7,6 Hz); 2,82-of 2.97 (m, 2H); 1,86 is 1.96 (m, 2H); 1,62=1,76 (m, 2H); 1,30-1,60 (m, 3H).Analysis for C23H25N3O2C4H4O4:
Calculated: C 65,97; H 5,95; N 8,55.Found: C 65,98; H 6,04; N 8,54.Example 13.1-[2-[1-(phenylmethyl)-4-piperidinyl]ethanolinduced
< / BR>a) 4-[2-[1-Sonnoli] ethyl] -1-piperidinecarboxylate acid. 1-(1,1-D49 mm), 1M LDA (of 4.2 ml, 4.2 mm) and 1-(1,1-dimethylethyl)ester 4-iodomethyl-1-piperidinecarboxylic acid (1.2 g, of 3.84 mm) in dry THF (45 ml), except that after addition of the reagents, the mixture is stirred 1.75 h at -78oC. After purification by chromatography ( 30%____ EtOAc/toluene) was obtained target compound (0,784 g, 66%) as a yellow oily substance.1H-NMR (CDCl3) scored 8.38 (d, 1H, J=5.8 Hz); 8,08 (d, 1H, J=8,3 Hz); to 7.77 (d, 1H, J=8.0 Hz); a 7.62 (t, 1H, J=7,1 Hz); rate of 7.54 (t, 1H, J=7,1 Hz); 7,46 (d, 1H, J=5.7 Hz); 4,08 (Shir.s, 2H); 3.25 to 3.30 is (m, 2H); 2,67 (Shir.t, 2H, J=12.3 Hz); 1,73-of 1.81 (m, 4H); 1,49-to 1.63 (m, 1H); of 1.42 (s, 9H); 1,17 (DDD, 2H, J= 24.6 Hz, J=12.1 Hz, J=3.8 Hz).b) 1-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]ethanolinduced
Repeating the procedure described in example 1e using piperidine, obtained in stage (a) (0,713 g, 2,10 mm), and TFA (7 ml) in CH2Cl2(14 ml), and triethylamine (2.9 ml, 21,0 mm), and benzylbromide (0,275 ml, 2,31 mm) in CH2Cl2(60 ml). After cleaning ( CH2Cl2_____ 5% MeOH/CH2Cl2) received target compound (free base) (0.26 g, 38%) as a pale yellow oily substance.Maleate (salt) was obtained by adding a solution of maleic acid (0.10 g, 0,867 mm) in EtOH (3 ml) to a solution of free base (0.26 g, 0,788 mm) in CH2Cl2(7 ml). Poshlovatoe solid.Output: of € 0.195 g, 56%.1H-NMR (DMCO-d6) 8,39 (d, 1H, J=5.7 Hz); compared to 8.26 (d, 1H, J=8,3 Hz); of 7.97 (d, 1H, J=8,1 Hz); to 7.77 (t, 1H, J=7.4 Hz); 7,66-7,71 (m, 2H); 7,49 (s, 5H); 6,05 (s, 2H); 4,28 (Shir. s, 2H); 3.27 to of 3.32 (m, 2H); 2,87-2,90 (m, 2H); 1,76-2,03 (m, 6H), 1,55 was 1.69 (m, 1H); 1,33 of 1.46 (m, 2H).Example 14.3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]- 1,2-benzisothiazolin
< / BR>a) 4-[2-[1,2-Benzisothiazol-3-yl] ethyl] -1-piperidinecarboxylate acid. 1-(1,1-dimethylethyl) ester
Repeating the procedure described in example 1o, using 3-methyl-1,2-benzisothiazol (0.50 g, 3,35 mm), 1-(1,1-dimethylethyl) ester 4-iodomethyl-2-piperidinecarboxylic acid (1.20 g, 3,69 mm) and 1M diisopropylamide lithium (LDA) (3,35 ml, 3,35 mm) in dry THF (100 ml). After cleaning has been the target connection (0,582 g, 50%) as a yellowish oily substance.1H-NMR (CDCl3) to $ 7.91-of 7.96 (m, 2H); 7,43-7,52 (m, 2H); 4,05-to 4.14 (m, 2H); 3.15 in (t, 2H, J=7.9 Hz); 2,69 (Shir.t, 2H, J=12.1 Hz); 1,74-of 1.88 (m, 4H); 1,46 is 1.60 (m, 1H); of 1.46 (s, 9H); 1,29-1,10 (m, 2H).b) 3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisothiazol-maleate
Repeating the procedure described in example 1e using piperidine, obtained in stage (a) (is 0.102 g, 0,29 mm), and triperoxonane acid (TFA) (0.75 ml) in methylene chloride (3 ml), and triethylamine (0,202 mg, 1,45 mm), and benzylbromide (0,038 ml, 0.32 mm) in methylene chloride is the main ingredient.Maleate (salt) was obtained by adding a solution of maleic acid (0,020 g, 0.17 mm) in ethanol (3 ml) to a solution of free base (0,058 g, 0.17 mm) in methylene chloride (3 ml). The mixture was concentrated and the residue triturated with Et2O. the Obtained white solid was filtered and the filtrate was collected, resulting in a received target connection (0,077 g, 96%). So pl. 175-176oC.1H-NMR (CDCl3) 8,14-8,21 (m, 2H); 7,63 (t, J=7,4, 1H); 7,50-of 7.55 (m, 6H); 6,04 (s, 2H); 4.26 deaths (Shir.s, 2H); 3,35 (Shir.s, 2H); 3.15 in (t, J=7,6, 2H); 2,80 of 2.92 (m, 2H); 1,92 is 2.00 (m, 2H); 1,78-of 1.88 (m, 2H); 1,54-of 1.65 (m, 1H); 1,35-1,35 (and 2H);
13C-NMR (DMCO-d6) 167,3; 166,2; 151,6; 136,0; 134,2; 131,3; 130,1; 129,5; 128,9; 127,9; 124,9; 123,6; 120,6; 59,4; 51,6; 32,5; 33,5; 28,9; 27,8.IR (KBr) 3030, 2910, 2350, 1700, 1575, 1445, 1350 cm-1.HIMS: 336,2 (M+free base); 319,1; 245,1; 185,1; 172,1; 91,0 (the basis).Analysis for C21H24N2S C4H4O4:
Calculated: C 66,35; H 6,24; N Is 6.19.Found: C 66,21; H To 5.93; N 6,03.Example 15.4-[2-[1-(Phenylmethyl)-4-piperidyl]ethyl]-1,3-chinazolinei
< / BR>a) 4-[2-[1,3-Gynazol-4-yl]ethyl]-1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl) ester
Freshly prepared 1M LDA (of 4.2 ml, 4.2 mm) was added to a solution of 4-methyl-1,3-hintline (0,60 g, 4.2 mm) in TG ice bath was removed and the reaction mixture is stirred 3 minutes After that, the mixture was again cooled to 0oC and added a second equivalent of 1M LDA (of 4.2 ml, 4.2 mm). Then was added a solution of 1-(1,1-dimethylethyl)ester 4-iodomethyl-1-piperidinecarboxylic acid (1,49 g, 4.6 mm) in THF (10 ml) and stirred for 1 h at 0oC. then was added dilute HCl (1 BC) and the mixture stirred at room temperature for 30 minutes and Then the reaction mixture was podslushivaet by adding 1 N. NaOH and was extracted with ethylacetate. The organic layer was washed with saline, dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (20%____ 50% EtOAc-hexane) received target connection (0,466 g, 33%) as an oily substance.1H-NMR (CDCl3) of 9.21 (s, 1H); to 8.12 (d, 1H, J = 7,7 Hz); with 8.05 (d, 1H, J = 8,4 Hz); of 7.90 (t, 1H, J = 7.8 Hz); the 7.65 (t, 1H, J = 7,7 Hz); 4,08 - 4,17 (m, 2H); of 3.32 (t, 2H, J = 8,3 Hz); 2,72 (Shir.t, 2H, J = 12.1 Hz); of 1.78 - 1.90 (m, 4H); 1,57 - to 1.59 (m, 1H); to 1.47 (s, 9H); 1.18 to of 1.29 (m, 2H).b) 4-[2-[1-(Phenylmethyl)-4-piperidyl]ethyl]-1,3 - chinazolinei
Repeating the procedure described in example 1e using piperidine, obtained in stage (a) (0,429 g, 1,26 mm), and TFA (3.5 ml) in CH2Cl2(13 ml), and triethylamine (from 0.88 ml, 6.3 mm), and benzylbromide (0.17 ml, 1,39 mm) in CH2Cl2(22 ml). After cleaning e) (0,179 g, 13%) as a colorless oily product.Maleate (salt) was obtained by adding a solution of maleic acid (0,052 g, 0.45 mm) in ethyl ether (10 ml) to a solution of free base (is 0.135 g, 0,41 mm) Et2O (200 ml). The obtained white solid was collected by filtration, resulting in a received target connection (0,103 g, 56%). So pl. 121 - 122oC.1H-NMR (DMCO-d6) 9,16 (s, 1H); with 8.33 (d, 1H, J = 8,4 Hz); 7,98 shed 8.01 (m, 2H); 7,72 for 7.78 (m, 1H); the 7.43 (s, 5H); of 6.02 (s, 2H); 4,08 (Shir.s, 2H); of 3.32 (t, 2H, J = 7,7 Hz); 3,15 - to 3.35 (m, 2H); 2,60 is 2.80 (m, 2H); 1,89 - of 1.94 (m, 2H); 1,76 - to 1.79 (m, 2H); 1,30 - 1,60 (m, 3H).IR (KBr): 3037, 2923, 1705, 1571, 1386 cm-1.EIMS 331 (M+free base); 318, 248, 143, 77 (the basis).Analysis for C22H25N3C4H4O4:
Calculated: C 69,78; H 6,53; N 9,39.Found: C 69,46; H Is 6.61; N 9,26.Example 16.6-Hydroxy-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2 - benzisoxazol
< / BR>A mixture of 6-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] - 1,2-benzisoxazol (0.11 g, in 0.288 mm) in 48% aqueous HBr (10 ml) was heated for 16 h at 110oC. Then the mixture was podslushivaet by adding saturated NaHCO3and were extracted with methylene chloride. The organic layer was dried with magnesium sulfate, filter, the SUB>) received target connection (to 0.055 g, 57%) as a white solid. So pl. 148 - 149oC.1H-NMR (CDCl3) 7,70 (Shir.s, 1H); 7,27 - 7,37 (m, 6H); 6,74 - to 6.80 (m, 2H); 3,63 (s, 2H); 3.04 from (Shir.d, 2H, J = 10,8 Hz); is 2.88 (t, 2H, J = 7,7 Hz); 2,05 - of 2.20 (m, 2H); 1,65 - of 1.95 (m, 4H); 1,30 - 1,60 (m, 3H).IR (KBr): 3080, 3040, 2945, 1624, 1437, 1384 cm-1.EIMS: 336,2 (M+), 319,2; 255,0; 185,1; 91,1 (the basis).VRMS (high slit. mass spectrometry (MS) for C21H24N2O2:
Calculated: 336,18382.Found: 336,18187.Example 17.6-Bromo-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2 - benzisoxazole
< / BR>a) 4-[2-[6-Bromo-1,2-benzisoxazol-3-yl] ethyl] - piperidinylcarbonyl acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 1d, using 6-bromo-3-methyl-1,2-benzisoxazol (1,02 g, 4,81 mm), 4-iodomethyl-1-piperidinecarboxylic acid 1-(1,1-dimethylethyl)ester (1,72 g of 5.29 mm) and 1M LDA (and 5.30 ml, 5,30 mm) in dry THF (40 ml), except that after addition of the reagents, the mixture is stirred for one and a half hours at -78oC. After purification was obtained target compound (0,697 g, 35%) as a pale yellow solid.1H-NMR (CDCl3) to 7.77 (s, 2H); 7,52 (d, 1H, J = 7.2 Hz); was 7.45 (d, 1H, J = 7.2 Hz); 4,11 (Shir.d, 2H, J = 1 (m, 1H); 1,09 - 1,29 (and 2H).b) 6-Bromo-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2 - benzisoxazole
Repeating the procedure described in example 1e using piperidine, obtained in stage (a) (0,398 g, 0,972 mm), and TFA (4 ml) with CH2Cl2(26 ml), and triethylamine (1.6 ml, 11.8 mm), and benzylbromide (0,155 ml, 1.3 mm) in CH2Cl2(12 ml). Also acted in another reaction with the above piperidine (is 0.102 g, 0,249 mm). The crude product obtained from these two reactions were combined and after treatment were obtained target compound (free base) (0,021 g, 4%) in the form of hard yellow-brown product.Maleate (salt) was obtained by adding a solution of maleic acid (0,023 g, 0,198 mm) in ethanol (5 ml) to a solution of free base (0,072 g, 0.18 mm) in methylene chloride (6 ml). After concentration the residue was recrystallized from ethanol and obtained target compound (0.035 g, 38%) as a white solid product. So pl. 156,8-157,5oC.1H-NMR (DMCO-d6) 8,08 (s, 1H); 7,87 (d, 1H, J=8,4 Hz); 7,58 (d, 1H, J= 8.5 Hz); 7,47 (s, 5H); 6,03 (s, 2H); 4,23 (Shir. s, 2H); 3.25 to 3.40 in (m, 2H); to 3.02 (t, 2H, J=7.5 Hz); 2,80-2,95 (m, 2H); 1,88 is 2.00 (m, 2H); 1,70-1,80 (m, 2H); 1,30-1,60 (m, 3H).13C-NMR (DMCO-d6) 167,2; 162,8; 158,6; 136,0; 131,1; 129,5; 128,9; 127,0; 124,0; 123,7; 120,6; 113,1; 59,6; 51,9; 32,7; 28,9; 21,6;
EIMS: 398 (M+), 381 Found: 398,0941.Example 18.6-Cyano-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2 - benzisoxazol
< / BR>A solution of NaNO2(0,112 g, 1,62 mm) in water (4 ml) was added to a solution of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazole (0.534 g, 1,59 Mm) in 28% HCl (20 ml), aged at 0oC. the resulting mixture was neutralized to pH 7 by careful addition of solid Na2CO3. Then the neutral mixture portions was added to a well stirred mixture of toluene (75 ml), ice and a freshly prepared solution of CuCN (Organic Synthesis, Coll. Vol. 1, S. 514; CuSO4: 0,318 g 1,99 mm). The resulting mixture was stirred for 30 min at 0oC and then 2 h at room temperature, and then heated for 5 min at 50oC. thereafter, the mixture was extracted with ethyl acetate, and the organic phase is washed with water, brine, dried magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (3% MeOH-CH2Cl2) received target connection (0,236 g, 43%) as a pale orange solid product. After recrystallization of a small sample (ethanol-hexane) was obtained target compound in the form of a whitish solid. So pl. 113-144,5oC.1H-NMR (CDCl3) 7,89 (s, 1H); to 7.77 (d, 1H, J = 8,4 Hz); 7, 3H).1C-NMR (CDCl3) 161,7; 158,8; 129,2; 128,2; 127,0; 126,3; 125,1; 122,5; 118,1; 114,5; 113,2; 63,4; 53,6; 35,2; 34,0; 32,0; 22,6.IR (CHCl3): 2830, 2720, 2160, 1600, 1425, 1385 cm-1.FAB-MS (mass spectroscopy by fast atom bombardment): 346 (M++ 1), 309, 275, 239, 155, 119 (the basis).VRMS for C22H23N3O:
Calculated 345, 1842.Found: 345,1836.Example 19.6-Carboxamido-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]1,2 - benzisoxazol
< / BR>Powdered potassium hydroxide (KOH) (0,150 g, 2,68 mm) was added to a mixture of 6-cyano-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2 - benzisoxazole (0,250 g, 0,724 mm) in t-BuOH (10 ml). The resulting mixture was heated for 20 min at 85oC. Then kaliden the reaction mixture was poured over brine and was extracted with methylene chloride. The organic phase was washed with 10% NaOH, brine, dried magnesium sulfate, filtered and concentrated. The crude product was purified by recrystallization (EtOAc-hexane) and received the target connection (0,114 g, 43%) as a white solid.So pl. 181-182oC.1H-NMR (DMCO-d6) 8,20 (Shir.s, 1H, -NH); 8,15 (s, 1H); of 7.97 (d, 1H, J = 8,4 Hz); 7,87 (d, 1H, J=8,1 Hz); to 7.64 (Shir.s, 1H,-NH), 7,22-7,31 (m, 5H); of 3.42 (s, 2H); to 3.02 (t, 2H, J = 7.8 Hz); 2,78 (W is 136,3; 128,7; 126,8; 126,8; 123,3; 122,0; 108,7; 62,5; 53,2; 34,9; 33,7; 31,6; 22,0.FAB-MS: 346 (M++ 1), (base), 321, 272, 185, 172.Example 20.3-[(1-Phenylmethyl-4-piperidyl)methoxy)-1,2-benzisoxazole
< / BR>a) 4-[(1,2-Benzisoxazol-3-yl)oxymethyl] -1-piperidyl - carboxylic acid, 1-(1,1-dimethylethyl)ester
NaH (60% dispersion in mineral oil, 0,941 g, 23,53 mm) was added in portions to a solution of 1-(1,1 dimethylethyl)of ester 4-hydroxymethyl-1-piperidinecarboxylic acid (4,82 g, 22,41 mm) in DMF (220 ml) at 0oC. After 10 min the reaction mixture was heated to room temperature and was added 3-chloro-1,2-benzisoxazol (3,44 g, 22,41 mm). The resulting mixture was heated for 16 h at 115oC. Then the reaction mixture was diluted with ethyl acetate and washed with water (4x), brine, dried magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (10% EtOAc-hexane) was obtained target compound (4,16 g, 56%) as a white solid. So pl. 103-104,5oC.1H-NMR (CDCl3) to 7.61 (d, 1H, J=7,0 Hz); of 7.48-rate of 7.54 (m, 1H); 7,41 (d, 1H, J= 8.5 Hz); 7,22-7,27 (m, 1H); to 4.28 (d, 2H, J=6.5 Hz); 4,16 (Shir.d, 2H, J= 13.3 Hz); 2,75 (dt, 2H, J=13,2 Hz); J= 2,6 Hz); 2,04 and 2.13 (m, 1H); 1,83 (Shir. d, 2H, J=13,7 Hz); 1,45 (s, 9H); 1.30 on (DDD, 2H, J=24,9 Hz, J=12,5 Hz, J=4, 2 Hz).b) 3-[(1 is obavljale to a solution of piperidine obtained in stage (a) (0,827 g, 2,49 mm) in CH2Cl2(25 ml) at 0oC. the resulting mixture was stirred 20 min at 0oC. Then the mixture was concentrated and the excess TFA was removed by concentration of toluene. The residue was distributed between methylene chloride and saturated MaHCO3. The organic layer was dried with magnesium sulfate, filtered and koncentrirebuli. The crude product (0,192 g, 0,827 mm) was dissolved ethylthiourea (8 ml) was added triethylamine (of 0.58 ml, 4,13 mm), and then benzylbromide (0,128 ml of 1.07 mm). The resulting mixture was stirred overnight (18 h) at room temperature. Then the reaction mixture was washed with water, brine, dried magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (5% MeOHCH2Cl2) received target compound (free base) (0,199 g, 25%) in the form of a whitish solid.Fumarate (salt) was obtained by adding fumaric acid (0,074 g, 0,633 mm), dissolved in minimum amount of EtOH, to a solution of free base (0,186 g, 0.58 mm) in methylene chloride (6 ml). After concentration, the crude salt was purified by recrystallization (EtOH-Et2O), received the target connection (0,134 g, 53%) in the form of a whitish solid ve is, 2H, J=6.4 Hz); the 3.65 (s, 2H); 2,07 (Shir. d, 2H, J= 11,4 Hz); 2,20 (Shir. t, 2H, J=11.7 Hz); 1,90 - 2,05 (m, 1H); 1,81 (Shir. d, 2H, J=12,8 Hz); 1,38 - 1,49 (m, 2H).13C-NMR (DMCO-d6) 166,5; 166,1; 163,3; 137,0; 134,3; 131,1; 129,3; 128,3; 127,3; 123,6; 120,8; 113,5; 110,3; 74,2; 61,7; 52,2; 34,7; 27,6.IR (KBr) 2980, 2550, 1706, 1650, 1616, 1573, 1447, 1374 cv-1< / BR>EIMC: 305, 185, 172, 90 (base).BPMC for C20H22N2O2(free base):
Calculated: 322,1682.Found: 322,1719.Analysis for C20H22N2O2C4H4O40,75 H2O:
Calculated: C 63,78; H 6,13; N 6,20.Found: C 63,88; H Of 5.85; N 6,14.Example 21.3-[(1-Phenylmethyl-4-piperidyl)methylamino] - 1.2 benzisoxazol
< / BR>A mixture of 3-chloro-1,5-benzisoxazole (0,238 g 1,55 mm), 4-aminomethyl-1-phenylethylhpiperidinyl (0,316 g 1,55 mm) and K2CO3(0,214 g of 1.55 mm) in DMCO (10 ml) was heated at 150oC for 20 h the Cooled reaction mixture was diluted with ethyl acetate (75 ml) and poured into water (200 ml). The organic phase was separated and washed with saline, dried with magnesium sulfate, filtered and concentrated. The obtained brown oily product was purified using flash chromatography on silica gel (4% MeOH-CH2Cl2) and received the target connection (0,08 7,16 - 7,31 (m, 6H); 4,35 was 4.42 (m, 1H, -NH-); 3,51(s, 2H); to 3.33 (t, 2H, J=6.2 Hz); 2,92 (Shir. d, 2H, J=11.5 Hz); 1,99 (t, 2H, J=11,6 Hz); 1.77 in (lat. d, 2H, J=a 12.7 Hz); 1,75 - 1,80 (m, 1H); 1,33 - of 1.45 (m, 2H).13C-NMR (CDCl3) 162,8; 158,6; 137,8; 129,8; 128,2; 127,2; 122,1; 119,7; 116,2; 110,1; 63,2; 53,3; 49,4; 35,2; 29,9; 29,7.IR (KBr) 3290, 2924, 2852, 1614, 1564, 1450, 1365 cm-1.EIMS: 321 (M+), 230, 201, 185, 172, 91 (the basis).BPMC for C20H23N3O.Calculated: 321,1842.Found: 321,1825.Example 22.3-[2-[(Phenylmethyl)-4-piperidyl)ethylamine] - 1.2 benzisoxazol
< / BR>Repeating the procedure described in example 21 using 3-chloro-1,2-benzisoxazol (0,682 g of 4.44 mm), 4-amino-ethyl-1 - phenylmaleimide (0,970 g of 4.44 mm) and K2CO3(0,614 g of 4.44 mm) in DCO (30 ml). After cleaning has been the target connection (0,231 g, 15%) as a pale yellow oily product.1H-NMR (CDCl3) 7,45 - rate of 7.54 (m, 2H); 7.24 to 7,40 (m, 6H); 7,19 (t, 1H, J= 7.8 Hz); 4,40 (Shir. t, 1H, J=5.5 Hz); to 3.52 (s, 2H); of 3.45 (dt, 2H, J=7,4 Hz, J= 6.0 Hz); 2.91 in (lat. d, 2H, J=11.8 Hz); 1,99 (Shir. t, 2H, J=11.2 Hz) 1,62 - of 1.73 (m, 4H); 1,37 - of 1.52 (m, 3H).13C-NMR (CDCl3) 162,7; 158,6; 137,8; 129,8; 129,4; 128,2; 127,1; 122,1; 119,8; 116,3; 110,0; 63,3; 53,6; 41,5; 36,1; 33,4; 32,0.EIMC: 335 (M+), 244, 199, 186, 172, 91 (the basis).BPMC for C21H25N3O:
Calculated 335,1998.
The
< / BR>a) 4-[2-Ethoxy-2-oxoethylidene] -1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
The solution triethylphosphate (3.1 ml, 15,69 mm) in freshly distilled 1,2-dimethoxyethane (DME, 12.5 ml) was added to a suspension of NaH (60% dispersion in mineral oil, 0.75 g, 18,18 mm) in DME (6.5 ml). The resulting mixture was stirred for 1 h at room temperature and the solution was added 1-(1,1-dimethylethyl)of ester 4-keto-1-piperidinecarboxylic acid (2.5 g, 12,55 mm) in DME (12.5 ml). After stirring overnight (15 h). the mixture was concentrated. The residue was purified using flash chromatography on silica gel (5____ 20% EtOAc-hexane) and received the target connection (a 3.06 g, 91%) as a white solid.
The mixture of olefin, obtained in stage (a) (3,05 g of 11.3 mm) and 10% Pd/C (1.2 g, 1,13 mm) in EtOH (50 ml) was first made in a Parr shaker at a pressure of 50 psi (3.45 bar) within one and a half hours. The resulting mixture was filtered through a pad of CeliteTMand the filtrate was concentrated, resulting in a received Clevo (CDCl3) 4,14 (square, 2H, J=7.0 Hz); 4,05 - 4,12 (m, 2H); 2,72 (Shir. dt, 2H, J=12.1 Hz, J=2,8 Hz); of 2.23 (d, 2H, J=7.2 Hz); 1.85 to 1,95 (m, 1H); 1,61 - of 1.66 (m, 2H); 1,45 (s, 9H); 1.26 in (t, 3H, J=7.0 Hz); of 1.05 to 1.23 (m, 2H).c) 4-Hydroxyethyl-1-piperidinylcarbonyl acid. 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 1b, using the ester obtained in stage (b) (a 3.06 g of 11.3 mm), and alumoweld lithium (0,47 g, 12,4 mm) in THF (105 ml). After purification using flash chromatography on silica gel (50% EtOAc-hexane) received unreacted starting material (0.73 g, 24%) and the target connection (1,74 g, 68%) as a colorless oily product.1H-NMR (CDCl3) 4,07 (Shir.D. 2H, J=14.1 Hz); 3,71 (t, 2H, J=6.5 Hz); 2,69 (Shir.T. 2H, J=12,5 Hz); 1,50-1,70 (m, 6H); 1,45 (s, 9H); 1,=5-1,15 (m, 2H).d) 4-Iodomethyl-1-piperidinylcarbonyl acid, 1-(1-1-dimethylethyl)ester
Repeating the procedure described in example 1c, using the alcohol obtained in stage (c) (1,74 g, to 7.59 mm), triphenylphosphine (2,49 g, 9,49 mm), iodine (2,31 g, 9,11 mm) and pyridine (1.5 ml, 18.2 mm) in benzene (50 ml). After cleaning has been the target connection of 2.27 g, 98%) as a colorless oily product.1H-NMR (CDCl3) 4.09 to (Shir.d, 2H, J=11,4 Hz); up 3.22 (t, 2H, J=7,3 Hz); 2,70 (Shir. t, 2H, J=12,5 Hz); 1,78 (square, 2H, J=6.9 Hz); 1,47 by 1.68 (m, 3H); of 1.46 (s, 9H); 1,12 (DDD, 2H, J=24,2 Hz);false air of
Repeating the procedure described in example 1d, using 3-methyl-1,2-benzisoxazol (0,412 g, to 3.09 mm), iodide obtained in stage (1,15 g, 3.4 mm), and 1M LDA (3.4 ml, 3.4 mm) in THF (8 ml). After cleaning has been the target connection (0,694 g, 65%) as a pale yellow oily product.1H-NMR (CDCl3) 7,65 (D. 1H, J=8.0 Hz); 7,54-EUR 7.57 (m, 2H); 7,27-7,34 (m, 1H); 4,08 (Shir.d, 2H, J=12,5 Hz); 2,99 (t, 2H, J= 7,6 Hz); 2,66 (Shir.t, 2H, J= 12.0 Hz); 1,86-of 1.92 (m, 2H); 1,63 by 1.68 (m, 4H); 1,45 (s, 9H); 1,36-of 1.45 (m, 1H); 1,06 by 1.12 (m, 2H).f) 3-[3-[1-(Phenylmethyl)-4-piperidyl]propyl]-1,2-benzisoxazol-maleate
Repeating the procedure described in example 1e using piperidine, obtained in stage (e) (0,544 g, 1,58 mm), and TFA (4 ml) in methylene chloride (16 ml), and triethylamine (1.1 ml, 7.9 mm), and benzylbromide (of 0.21 ml, 1,74 mm) in methylene chloride (10 ml). After purification by chromatography (2 -____ 5% MeOH-CH2Cl2) received target compound (free base) (0,285 g, 54%) as a pale yellow oily product.Maleate (salt) was obtained by adding maleic acid (0,109 g 0,94 mm), dissolved in minimum amount of ethanol, to the solution of free base (0,285 g, 0.85 mm) in methylene chloride (10 ml). After concentration the residue was purified by recrystallization (EtOFc) and received target Sedina-d6) of 7.90 (D. 1H, J=7.9 Hz); to 7.61-7,72 (m, 2H); 7,47 (s, 5H); 7,38 (t, 1H, J=7,3 Hz); 6,04 (s, 2H); 4.26 deaths (Shir.s, 2H); 3,22/of 3.45 (m, 2H); 2,99 (t, 2H, J=7.4 Hz); 2,70-2,96 (m, 2H); 1,70-1,90 (m, 4H); 1,40-of 1.65 (m, 1H); 1,20-1,40 (m, 4H).13C-NMR (DMCO-d6) 167,2; 162,2; 158,4; 135,8; 131,2; 130,3; 129,5; 128,9; 123,5; 122,1; 121,2; 109,7; 59,3; 51,7; 34,8; 32,6; 28,9; 24,5; 24,1.IR (KBR): 2942, 1705, 1581, 1460, 1359 cm-1..EIMS: 334 (M+, free base), 243, 202, 173 (base), 91.Analysis for C22H26N2O C4H4O4:
Calculated: C 69,31; H Of 6.71; N 6,22.Found: C 69,11; H 6,64; N 6,46.Example 24.TRANS-3-[2-[-1-(phenylmethyl-4-piperidyl]ethynyl]-1,2-benzisoxazole
< / BR>NaH (60% dispersion in mineral oil, 0.10 g, of 2.51 mm) was added to a mixture of 3-triphenylphosphonium-1,2-benzisoxazole (1.19 g, of 2.51 mm) in THF (10 ml). After 1 hour stirring at room temperature was added a solution of 4-carboxaldehyde-1-phenylethylhpiperidinyl (0.51 g, of 2.51 mm) in THF (2 ml). The resulting mixture was stirred 4 h and filtered. The filtrate was concentrated, and the residue was distributed between diethyl ether and water. The separated organic layer was dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (40% EtOAc-hexane) received target connection which were given by adding maleic acid (0,194 g, 1,67 mm), dissolved in minimum amount of ethanol, to the solution of free base (0,483 g, 1.52 mm) Et2O (25 ml). The obtained white solid was collected by filtration and received the target connection (0,581 g, 88%).So pl. 174-175oC
1H-NMR (DMCO-d6) 8,16 (D. 1H, J=7.8 Hz); of 7.75 (d, 1H, J=8,4 Hz); to 7.67 (i.e 1H, J= 8,2 Hz); 7,41-of 7.55 (m, 6H); of 6.96 (Shir.DD, 1H, J=16.5 Hz); J=5.6 Hz); is 6.78 (d, 1H, J=16.5 Hz); between 6.08 (s, 2H); to 4.33 (s, 2H); 3,32-3,39 (m, 2H); 2.95 and is 3.15 (m, 2H); 2,50-2,70 (m, 1H); 2.06 to (Shir.d, 2H, J=12,6 Hz); 1.60-to 1,90 (m, 2H).13C-NMR (DMCO-d6) : 167,3; 162,7; 154,9; 142,7; 135,9; 131,2; 130,4; 130,2; 129,5; 128,9; 124,2; 122,7; 119,4; 116,5; 109,9; 59,2; 51,0; 36,2; 27,8.IR (KBr) 3035, 2944, 1708, 1588, 1472, 1360 cm-1.EIMS : 3,18 (M+, free base), 201, 227, 172, 91 (the basis).Analysis for C21H22N2O C4H4O4:
Calculated: C 69,11; H 6,03; N 6,45.Found: C EUR 69.04; H 6,27; N 6,38.Example 25.3-[2-[1-(phenylmethyl)-4-piperazinil] ethyl] -1,2-benzisoxazol, dihydrochloride salt
< / BR>A mixture of 3-[2-chloroethyl] -1,2-benzisoxazole (0.55 g, 3,03 mm) and N-benzylpiperazine (of 1.06 ml, the 6.06 mm) in xylene (4 ml) was heated in a period of 4.75 hours at 150oC. the Cooled mixture was diluted with ethylenchloride and washed with water. The organic layer was dried with magnesium sulfate, filtered and to the second connection (free base) (of 0.337 g, 35%) as a pale yellow oily product.Dihydrochloride salt was obtained by ozonation of excess hydrogen chloride through a solution of the free base (of 0.337 g of 1.05 mm) in ethyl ether (50 ml). The resulting white solid was collected by filtration and received the target connection (0,259 g, 63%). So pl. 233-234oC.H1NMR (D2O) : 7,79 (d, 1H, J=8.0 Hz); 7,53-of 7.69 (m, 2H); to 7.50 (s, 5H); 7,40 (DDD, 1H, J=7.9 Hz, J=6,6 Hz, J=1.3 Hz) 4,47 (s, 2H); 3,82 (t, 2H, J= 7.5 Hz); 3,60-of 3.80 (m, 8H); 3,55 (t, 2H, J=7.5 Hz).13C-NMR (D2O) 165,5; 158,0; 134,2; 133,6; 132,4; 130,3; 127,1; 124,4; 123,2; 112,8; 63,4; 56,6; 51,8; 51,0; 23,2.IR (KBr) 2989, 1608, 1436, 1375 cm-1.EIMS : 312 (M+, free base), 256, 189, 91 (base).Analysis for C20H23N3O2HCl:
Calculated: C 60,92; H To 6.39; N 10,66.Found: C 60,64; H To 6.57; N 10,42.Example 26.5,7-Dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-it-mesilate
< / BR>NaH (60% dispersion in mineral oil, 0,048 g, 1.2 mm) was added to a solution of 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6H-pyrrolo[4,5-f] -1,2-benzisoxazol-6-she (0,374 g, 1.0 mm) with DMF (10 ml) at room temperature. After the termination of allocation of gaseous hydrogen was added and water (> 50 ml). The reaction mixture was extracted with methylene chloride, and the organic layer was dried with magnesium sulfate, filtered and concentrated. After purification using flash-chromatography on silica gel ( CH2Cl2____ 3% MeOH-CH2Cl2) received target compound (free base( (0,056 g, 14%) in the form of whitish foamy product.Mesilate (salt) was obtained by adding methanesulfonic acid (0,009 ml, 0,144 mm) to a solution of free base (0,056 g 0,044 mm) in methylene chloride (5 ml). After concentration the residue is triturated with ethyl ether and was obtained target compound (0,049 g, 70%) in the form of a whitish solid. So pl. 164-165oC (Razlog.).1H-NMR (DMCO-d6) of 7.69 (s, 1H); 7,49 (s, 5H); to 7.32 (s, 1H); to 4.28 (s, 2H); to 3.64 (s, 2H); 3,35 (Shir.d, 2H. J=11,6 Hz); 3,18 (s, 3H); 2,85-to 2.99 (m, 4H); 2,30 (s, 3H); 1,95 (Shir.d, 2H, J=12.9 Hz); 1,66 and 1.80 (m, 2H); 1,45-to 1.60 (m, 1H); 1,35-of 1.44 (m, 2H).EIMS : 389 (M+, free base), 298, 217, 200, 185 (base), 172.BPMC for C24H27N3O2CH3SO3H:
Calculated 389, 2104.Found: 389,2075.Example 27.5,7-Dihydro-7-ethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6H - pyrrolo[4,5-f]-1,2-benzisoxazol-6-he mesilate
< / BR>Repeating the procedure described in the,0 mm), NaH (0,068 g, 1.7 mm) and ethyliodide (0.16 ml, 2.0 mm) in DMF (10 ml). After cleaning has been the target compound (free base) (0,076 g, 19%) as a pale yellow oily product.Mesilate (salt) was obtained by adding methanesulfonic acid (0,007 ml, 0,112 mm) to a solution of free base (0,045 g, 0,112 mm) in CH2Cl2(5 ml). After concentration the residue is triturated with Et2O and got the target connection (0,042 g, 75%) as a whitish solid (hygroscopic). So pl. 162oC (decomp. when >60oC).1H-NMR (DMCO-d6) of 7.69 (s, 1H); of 7.48 (s, 5H); 7,39 (s, 1H); 4,27 (c, 2H); of 3.77 (Shir. square, 2H, J=7,1 Hz); 3,64 (c, 2H); 3,34-3,39 (m, 2H); 2,92 are 2.98 (m, 4H); 2,30 (s, 3H); 1,94 (Shir.d, 2H, J=12,8); 1,66-of 1.78 (m, 2H); 1,30-1,60 (m, 3H); to 1.16 (t, 3H, J=7,1 Hz).13C-NMR (DMCO-d6) 174,5; 163,2; 158,1; 147,0; 131,4; 131,0; 129,8; 129,6; 128,9; 121,2; 117,0; 115,2; 90,0; 59,3; 51,6; 34,5; 34,4; 33,0; 32,6; 28,5; 21,6; 12,3.IR (KBr) 2934, 1716, 1630, 1605, 1466, 1330 cm-1.EIMS 403 (M+, free base), 386, 312, 185 (base), 172.BPMC for C25H29N3O2CH3SO3H:
Calculated: 403,22605.Found: 403,22761.Example 28.< / BR>5,7-Dihydro-3-[2-[1-(2-chloro-5-thiophenemethyl)-4-piperidinyl] ethyl] -6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he
Repeated preincarnate acid 1-(1; 1-dimethylethyl) ester (0,328 g, 0,851 mm) and TFA (2 ml) in CH2Cl2(8 ml). Under alkylation used only a portion of the crude salt: Na2CO3(0,175 g of 1.66 mm) and 2-chloro-5-chloromethylstyrene (0,048 ml, 0.40 mm) in DMF (3 ml). After cleaning (2-4% MeOH-CH2Cl2) received target connection (0,0514 g, 43%) as a white solid. So pl. 202-204oC (Razlog).1H-NMR (DMCO-d6) to 10.8 (s, 1H); a 7.62 (s, 1H); 6,79 (s, 1H); 6,92 (d, 1H, J=3,7 Hz); to 6.80 (d, 1H, J=3,7 Hz); of 3.57 (s, 2H); 3,55 (s, 2H); 2,81-of 2.93 (m, 4H); 1.91 a (Shir.t, 2H, J=10,7 Hz); 1,61-1,71 (m, 4H); 1,11-of 1.23 (m, 3H).13C-YOKES (DMCO-d6) : : 176,7; 162,9; 158,3; 146,5; 142,8; 127,0; 126,1; 125,1; 123,2; 117,1; 115,1; 90,1; 57,0; 53,0; 35,0; 34,8; 33,9; 31,6; 21,9.IR (KBr) 3174, 2950, 1702, 1631, 1453, 1330 cm-1.EIMS: 398, 382, 350, 322, 236, 172, 91, 81 (the basis).BPMC for C21H22ClN3O2S:
Calculated: 415,1122.Found: 415,1085.Analysis for C21H22ClN3O2S 0,5 H2O:
Calculated: C 59,36; H 5,46; N 9,89.Found: C 59,21; H 5,12; N 9,65.Example 29.5,7-Dihydro-3-[2-[1-(2-methyl-4-titlemeta)-4-piperidinyl] ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he
< / BR>Repeating the procedure described in example 12f, using 4-[2-[5,7-dihydro-6H-pyrrolo[4,5-f] -1,2-benzisoxazol-6-he-3 is e (10 ml), and Na2CO3(1.01 g, 9,52 mm), and 4-chloromethyl-2-methylthiazole cleaners containing hydrochloride salt (0,210 g 1,142 mm) in DMF (10 ml). After purification by chromatography (4% MeOH-EtOAc) followed by recrystallization (EtOAc-hexane) was obtained target compound (0,074 g, 20%) as a white solid. So pl. 172-173oC (Razlog.).1H-NMR (CDCl3) 9,40 (Shir.s, 1H); 7,41 (s, 1H); 7,05 (s, 1H); 7,02 (s, 1H); and 3.72 (s, 2H); 3,61 (s, 2H); 3,07 (Shir.d, 2H, J=11.3 Hz); at 2.93 (t, 2H, J= 7.8 Hz); 2,69 (s, 3H); 2,15 (Shir.t, 2H, J=10,8 Hz); 1,76-1,85 (and, 4H); 1,42-of 1.55 (m, 3H).13C-YOKES (CDCl3) : : 177,4; 166,0; 163,6; 158,3; 151,7; 145,1; 122,2; 116,8; 116,3; 91,5; 57,9; 53,4; 35,4; 34,8; 34,0; 31,2; 22,5; 19,2.IR (KBr) 3101, 3015, 2938, 2924, 1713, 1633, 1456, 1328 cm-1.EIMS: 396 (M+), 379, 284, 267, 206 (the basis).BPMC for C21H24N4O2S:
Calculated 396,1621.Found: 396,1631.Example 30.3-[2-[1-(3-Brompheniramine)-4-piperidinyl] ethyl] -5,7-dihydro-6H-pyrrolo [4,5-f]-1,2-benzisoxazol-6-he
< / BR>Repeating the procedure described in example 12f, using 1-[1,1-dimethylethyl)ester 4-[2-[5,7-dihydro-6H-pyrrolo-[4,5-f] - 1,2-benzisoxazol-6-one-3-yl]ethyl]-1-piperidinecarboxylic acid (0.50 g, 1,30 mm) and TFA (3 ml) in methylene chloride (12 ml), and Na2CO3(0,689 g, 6.5 mm) and 3-bromobenzylamine (0,46 g, 1,84 mm) in DMF (20 ml). Th the 14 g, 53%) as a pale yellow solid. After recrystallization (EtOAc twice) was obtained white solid product (0,076 g, 13%). So pl. 173-174oC.1H-Yarm (CDCl3) 8,77 (s, 1H); 7,47 (s, 1H); 7,41 (s, 1H); of 7.36 (d, 1H, J 7.7 Hz); 7.23 percent (d, 1H, J=7.9 Hz); 7,16 (t, 1H), J=7,7 Hz); 7,00 (s, 1H); 3,61 (s, 2H); 3.46 in (s, 2H); 2,86-2,96 (m, 4H); 1,90-2,02 (m, 2H); 1,70-of 1.85 (m, 4H); 1,30-of 1.42 (m, 3H).13C-YOKES (CDCl3) : 177,1; 163,5; 158,4; 144,7; 132,0; 130,1; 129,8; 127,8; 122,3; 122,0; 116,5; 91,5; 62,6; 53,6; 35,3; 35,2; 34,3; 31,9; 22,6.Example 31.3-[2-[1-(4-Brompheniramine)-4-piperidinyl] ethyl] -5,7-dihydro-6H-pyrrolo [4,5-f]-1,2-benzisoxazol-6-he
< / BR>Repeating the procedure described in example 12f, using 4-[2-[5,7-dihydro-6H-pyrrolo[4,5-f] -1,2-benzisoxazol-6-one-3-yl] ethyl]- 1-piperidinecarboxylic acid 1-(1,1-dimethylethyl)ester (0.50 g, 1.3 mm) and TFA (3 ml) in CH2Cl2(12 ml), and Na2CO3(0,689 g, 6.5 mm), and 4-bromobenzylamine (0.39 g, 1,56 mm) in DMF (15 ml). After purification using chromatography (CH2Cl2____ 5% MeOH-CH2Cl2) received target connection (0,415 g, 70%) in the form of a whitish solid.So pl. 177-178oC.1H-NMR (CDCl3) 9,98 (Shir.s, 1H); 7,37-7,40 (m, 3H); 7,16 (d, 2H, J = 8,2 Hz); 6,99 (s, 1H); of 3.60 (s, 2H); 3.42 points (s, 2H); 2,87-to 2.94 (m, 4H); 1,94 (Shir.t, 2H, J = 10.5 Hz); of 1.65 and 1.80 (m, 4H); of 1.20 and 1.35 (m, 3H).5,7-Dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl] propyl] - 6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he
< / BR>and) 4-[3-[5-, 7-Dihydro-6H-pyrrolo[4,5-f] -1,2-benzisoxazol - 6-one-3-yl] propyl]-1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 7a using 5,7-dihydro-3-methyl-6H-pyrrolo[4,5-f] -1,2-benzisoxazol-6-he (0,13 g, 0,69 mm), IM LDA (2.8 ml, 2.8 mm) and 4-deatil-1-piperidinecarboxylic acid 1-(1,1-dimethylethyl)ester (0,233 g, 0,69 mm) in dry THF (14 ml), except that after addition of the reagents, the mixture is stirred at -78oC for 4 h After purification using chromatography(10% _____ 50% EtOAc-CH2Cl2) has been restored to its original material (0,031 g, 24%) and the target connection (0,129 g, 47%) as a colorless oily product.1H-NMR (CDCl3) : 9,50 (s, 1H); 7,42 (s, 1H);? 7.04 baby mortality (s, 1H); 4,06 (Shir.d, 2H, J = 14,5 Hz); 3,62 (s, 2H); 2.91 in (t, 2H, J = 7.5 Hz); 2,66 (dt, 2H, J = 13,0 Hz, J = 2.0 Hz); 1,81-to 1.87 (m, 2H); 1,65 (Shir.d, 2H, J = 12.3 Hz); the 1.44 (s, 9H); 1,34 was 1.43 (m, 3H); 1,09 is 1.20 (M, 2H).a) 5,7-Dihydro-3-[3-[3-[1-(phenylmethyl)-4-piperidyl] propyl] - 6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he
Repeating the procedure described in example 12f, using piperidine, obtained in stage (a) (0,114 g, 0,29 mm), and TFA (1.5 ml) in CH2Cl2(6 ml), and Na2Cl2____ 5% MeOH-CH2Cl2) received target connection (0,70 g, 62%) as a white foamy solid. This product was recrystallized (CH2Cl2) and received a white solid (0,054 g, 48%).So pl. 164-166oC.1H-NMR (CDCl3) : 9,73 (Shir.s, 1H); 7,41 (s, 1H); 7.24 to 7,34 (m, 5H); 6,99 (s, 1H); 3,61 (s, 2H); of 3.56 (s, 2H); 2,86-of 2.97 (m, 4H); 1,97-of 1.05 (m, 2H); 1,76-of 1.88 (m, 2H); 1,65-1,70 (m, 2H); 1.26 in-to 1.38 (m, 5H).13C-NMR (CDCl3) 177,7; 163,6; 158,3; 145,2; 129,5; 128,3; 127,3; 122,2; 116,8; 116,4; 91,6; 63,2; 53,6; 36,1; 35,5; 35,3; 31,9; 25,4; 25,0.IR (KBr) 3150, 3096, 2930, 1705, 1634, 1495, 1345 cm-1.EIMS: 389 (M+), 372, 298, 202, 172, 108, 91 (the basis).BPMC for C24H27N3O:
Calculated: 389,2104.Found: 389,2107.Example 33.3-[2-[1-(Phenylmethyl)-4-piperidine] ethyl] -5,6,8-trihydro-7H - isoxazole[4,5-g]quinoline-7-he
< / BR>a) 6-Acetyl-3,4-dihydro-7-hydroxy-2H-quinoline-2-he
Acetylchloride (2.0 ml, 28,1 ml) was added to a mixture of 3,4-dihydro - 7-methoxy-2H-quinoline-2-it (1,99 g, 11.2 mm) in 1,2-dichloroethane (30 ml). The resulting mixture was cooled to 0oC and portions were added AlCl3(6.0 g, 44,98 mm). The reaction mixture was heated under reflux for 2 hours then the reaction mixture was carefully poured into ice water, razmeri the Loy was washed with saline, was dried by magnesium sulfate, filtered and concentrated, resulting in a received target compound (1.89 g, 82%) as a whitish solid product.1H-NMR (DMCO-d6) : : 12,4 (S, 1H); 10,4 (s, 1H); 7,74 (s, 1H); 6,38 (s, 1H); of 2.86 (t, 2H, J = 7.4 Hz); of 2.56 (s, 3H); 2,46-of 2.56 (m, 1H).o) 6-Acetyl-3,4-dihydro-7-hydroxy-2H-quinoline-2-it, 6-oxime
An aqueous solution of the hydrochloride hydroxyamine (1.47 g, 21,2 mm) and three-hydrate sodium acetate (3.0 g, 22,1 mm) was added to a mixture of the ketone obtained in stage (A) (1.89 g, 9.2 mm) in EtOH (100 ml). The resulting mixture was heated under reflux for 4 hours Then the reaction mixture was concentrated, and the residue is stirred with water. The obtained solid substance was collected by filtration and washed with ethanol and ethyl ether, resulting in the received target connection (1,67 g, 82%) as a whitish solid.So pl. 286,5-287,7oC (Razlog.).1H-NMR (DMCO-d6) to 11.7 (S, 1H) and 11.3 (s, 1H); from 10.1 (s, 1H); 7,28 (s, 1H); 6,37 (s, 1H); of 2.81 (t, 2H, J = 7.5 Hz); 2,43 (t, 2H, J = 7.5 Hz); of 2.21 (s, 3H).c) 6-Acetyl-3,4-dihydro-7-hydroxy-2H-quinoline-2-it, 6-oxiracetam
A heterogeneous mixture of oxime, obtained in stage b (1,67 g, EUR 7.57 mm) in acetic anhydride (13 ml) was heated at 80oC for one and a half hours. Reactio the drying was obtained target compound (1.7 g, 86%) in the form of a whitish solid product.1H-NMR (DMCO-d6) 11,0 (s, 1H); to 10.2 (s, 1H); of 7.36 (s, 1H); 6,44 (s, 1H); 2,82 (t, 2H, J=7.5 Hz); of 2.45 (t, 2H, J=7.5 Hz); of 2.38 (s, 3H); 2,22 (s, 3H).o) 5,6,8-Trihydro-7H-isoxazole-[4,5-g]quinoline-7-he
A mixture of oxiracetam obtained in stage (c) (1,58 g of 6.02 mm), and pyridine (4.8 ml, 60,2 mm) in DMF (75 ml) was heated at 125-130oC for 2 h, the Reaction mixture was concentrated in vacuo, and the residue was purified by recrystallization EtOAc, resulting in a received target connection (0,80 g, 66%) as a pale-yellow solid product.So pl. 309-311oC (Razlog.).1H-NMR (DMCO-d6) to 10.4 (s, 1H); a 7.62 (s, 1H); 7,02 (s, 1H); 2,99 (t, 2H, J=7.4 Hz); 2,49 of $ 2.53 (m, 2H); 2,47 (s, 3H).e) 4-[2-[5,6,8-Trihydro-7H-isoxazole[4,5-g] quinoline-7-one-3-yl - ethyl]-1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 7a using benzisoxazol obtained in stage d (of 0.47 g, 2.3 mm), 1M LDA (8.1 ml, 8,1 mm) and 1-(1,1-dimethylethyl)ester 4-iodomethyl-1-piperidinecarboxylic acid (0.75 g, 2.3 mm) in dry THF (150 ml), except that after addition of the reagents, the mixture is stirred 3.5 h at -78oC. Then spent another reaction, which was carried out in a similar way using the and and was purified by chromatography (EtOAc), received target connection (0,72 g, 54%) as a white solid.1H-NMR (DMCO-d6) : of 10.4 (s, 1H); to 7.67 (s, 1H); 7,02 (s, 1H); 3,93 (Shir. d, 2H, J=13,4 Hz); 2,89-of 3.31 (m, 4H); 2.57 m-2,75 (Shir.m, 2H); 2.49 USD of $ 2.53 (m, 2H); 1,64-1,72 (m, 4H); to 1.38 (s, 9H); 1,36 of 1.50 (m, 1H); 1,01-of 1.16 (m, 2H).f) 3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-5,6,8-trihydro-7H - isoxazole[4,5-g]quinoline-7-he
Repeating the procedure described in example 12f, using piperidine, obtained in stage (e) (0.55 g, 13,37 mm), and TFA (3.5 ml) in CH2Cl2(14 ml), and Na2CO3(0,758 g, 7,14 mm), and benzylbromide (0,23 ml of 1.93 mm) in DMF (14 ml). After purification by chromatography (5 --> 30% MeOH - CH2Cl2) received target compound in the form of a white solid product. A sample was recrystallized from EtOAc-MeOH.So pl.: 164,4-165,9oC.1H-NMR (CDCl3) 9,37 (c, 1H); 7,38 (c, 1H); 7,22 and 7.36 (m, 5H); 7,01 (s, 1H); 3,55 (s, 2H); to 3.09 (t, 2H, J=7.4 Hz); 2.91 in-of 2.97 (m, 4H); 2,70 (t, 2H, J=7.4 Hz); 2,01 (Shir.t, 2H, J=10,3); 1,75-1,80 (m, 4H); 1,39 of 1.50 (m, 3H).1C-NMR (CDCl3) 170,6; 162,0; 158,2; 141,1; 140,9; 128,7; 128,2; 126,8; 121,2; 120,3; 115,7; 94,6; 62,5; 53,2; 34,9; 33,8; 31,6; 30,2; 24,8; 21,9.IR (KBr) 3172, 3088, 2821, 1694, 1631, 1447, 1381 cm-1.EIMS 389 (M+), 388, 372, 298, 185, 172, 91 (the basis).BPMC for C24H27N3O2:
Calculated: 389, 2104.Found: oxazol-7-he
< / BR>a) 5-Acetyl-1,3-dihydro-4-hydroxy-2H-indol-2-he
A well stirred mixture of 4-atomic charges-1,3-dihydro-2H-indol-2-it (0,876 g, 4,58 mm) and AlCl3(1,83 g, 13,7 mm) were placed in a flask-shaped tears, and the flask was immersed in an oil bath, preheated to 190oC, and then heated for 1 h Then cooled reaction mixture was carefully added to ice water and stirred for 1.5 h and Then was added conc. HCl and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated. After purification using flash chromatography on silica gel (I ___ 3% MeOH-CH2Cl2) received target connection (0,441 g, 50%) in the form of a whitish solid product.1H-NMR (DMCO-d6) : 12,6 (s, 1H); to 10.8 (s, 1H); a 7.85 (d, 1H, J = 8,4 Hz); of 6.49 (d, 1H, J=8,4 Hz); to 3.41 (s, 2H); 2.57 m (s, 3H).o) 5-Acetyl-1,3-dihydro-4-hydroxy-2H-indol-2-it, 5-oxime)
Repeating the procedure described in example 33b, using the ketone obtained in stage (a), (0.40 g, of 2.09 mm), an aqueous solution of the hydrochloride NH2OH (0.29 grams, 4,18 mm) and NaOAc trihydrate (0,569 g, 4,18 mm) in EtOH (32 ml). After 3 h the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated in financial p is.1H-NMR (DMCO-d6) : 12,0 (s, 1H); 11.4 in (s, 1H); 10,4 (s, 1H); to 7.35 (d, 1H, J=8,2 Hz); 6,41 (9D, 1H, J=8,3 Hz); 3,34 (s, 2H); 2,22 (s, 3H).c) 5-Acetyl-1,3-dihydro-4-hydroxy-2H-indol-2-it, 5-oxiracetam
Repeating the procedure described in example 33c, using the oxime obtained in stage (b) (0,392 g, 1.9 mm) Ac2O (10 ml). The obtained solid substance was recovered from any inorganic salts obtained in the previous phase, by mixing in the H2O. After filtration and drying was obtained target compound (0,417 g, 88%) as a reddish-pinkish solid.1H-NMR (DMCO-d6) of 11.45 (s, 1H); to 10.6 (s, 1H); 7,50 (d, 1H, J=8,2 Hz); of 6.49 (d, 1H, J=8,2 Hz); 3.40 in (s, 2H); to 2.41 (s, 3H), of 2.23 (s, 3H).d) 6,8-Dihydro-3-methyl-7H-pyrrolo[5,4-g]-1,2-benzisoxazol-7-he
Repeating the procedure described in example 33b, using oxiracetam obtained in stage (c) (0,334 g, 1.35mm), and pyridine (0,55 ml of 6.75 mm) in DMF (25 ml). After processing, the residue was purified using flash chromatography on silica gel (50 ___ 75% EtOAc-hexane) and received the target connection (0,086 g, 34%) as a white solid product.So pl. 259-260oC (Razlog.).1H-NMR (DMCO-d6) : 10,79 (s, 1H); to 7.67 (d, 1H, J=8.5 Hz); 6,92 (d, 1H, J=8,3 Hz); of 3.73 (s, 2H); 2.49 USD (s, 3H).e) 4-[2-[6,8-Dihydro-7H-pyrrolo-[5,4-g] -1,2-bengre, described in example 7a using benzisoxazol obtained in stage (d) (0,040 g, 0,213 mm), 1M LDA (of 0.85 ml, 0.85 mm) and 1-(1,1-dimethylethyl)ester 4-iodomethyl-1-piperidinecarboxylic acid (0,078 g, 1,234 mm) in dry THF (20 ml), except that after addition of the reagents, the mixture is stirred for 4 h at -78oC. After purification by chromatography (25 ___ 45% EtOAc-CH2Cl2) received target connection (0,042 g, 51%) as a pale-yellow solid product.1H-NMR (CDCl3) : cent to 8.85 (s, 1H); 7,53 (d, 1H, J= 8,1 Hz); to 6.95 (d, 1H, J= 8,3 Hz); 4,08-to 4.14 (m, 2H); of 3.78 (s, 2H); 2,99 (t, 2H, J=7.8 Hz); 2,68 (Shir. t, 2H, J=12.1 Hz); 1,73-of 1.84 (m, 4H); 1,46 is 1.60 (m, 1H); of 1.46 (s, 9H); 1,17 (DDD, 2H, J=23,2 Hz; J=12.1 Hz, J=4.3 Hz).f) 6,8-Dihydro-3-[2-[1-(phenylmethyl-4-piperidinyl] ethyl] - 7H-pyrrolo[5,4-g]-1,2-benzisoxazol-7-he
Repeating the procedure described in example 12f, using piperidine, obtained in stage (e) (0,042 g, 0,109 mm), TFA (1.5 ml) in CH2Cl2(6 ml), Na2CO3(0,058 g, 0,545 mm) and benzylbromide (0,016 ml, 0,131 mm) in DMF (6 ml). After purification using chromatography (I ___ 10% MeOH-CH2Cl2) received target connection (0,018 g, 44%) in the form of a whitish solid product. So pl. 188-189oC.1H-NMR (CDCl3) 9,59 (s, 1H); 7,51 (d, 1H, J= 8,1 Hz); 7.23 percent-7,33 (m, 5H); 6,94 (d, 1H, J=8,2 Hz); of 3.77 (s, 2H); 3,56 ( 129,4; 128,3; 127,2; 121,5; 117,9; 107,1; 105,1; 63,2; 53,5; 35,1; 34,1; 33,8; 31,7; 29,7; 22,5.Example 35.5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl - 6H-pyrrolo-[5,4-f] -1,2-benzisoxazol-6-he
< / BR>a) 6-Acetyl-1,3-dihydro-5-hydroxy-2H-indol-2-he
Repeating the procedure described in example 33a, using 1,3-dihydro-5-methoxy-2H-indol-2-he (4.4 g, 26,96 mm), acetylchloride (4.8 ml, 67,41 mm) and AlCl3(14.4 g, to 107.8 mm) in 1,2-dichloroethane (210 ml) for 6 hours After treatment with water and mixing during the night had been precipitate. The yellow solid precipitate was collected by filtration and dried, resulting in a received target compound (2.7 g, 52%).1H-NMR (DMCO-d6) : 12,0 (s, 1H); 10,4 (s, 1H); for 7.12 (s, 1H); 6.89 in (s, 1H); of 3.54 (s, 2H); 2,61 (s, 3H).o) 6-Acetyl-1,3-dihydro-5-hydroxy-2H-indol-2-it, 6-oxime
Repeating the procedure described in example 33b, using the ketone obtained in stage (a) (2.7 g, 14.4 mm), aqueous solution of NH2OH hydrochloride (of 2.26 g, 32.5 mm) and NaOAc-trihydrate (4.6 g, 33,9 mm) in EtOH (155 ml), and received the target compound (2.7 g, 93%) as a whitish solid.1H-NMR (LMCO-d6) : 11,5 (s, 1H) and 11.3 (s, 1H); to 10.2 (s, 1H); for 6.81 (s, 1H); is 6.78 (s, 1H); 43,44 (s, 2H); 2,22 (s, 3H).c) 6-Acetyl-1,3-dihydro-5-hydroxy-2H-indol-2-it, 6-oxiracetam
Repeated the procedure,Uchali target connection (with 2.93 g, 90%) in the form of a whitish solid product.1H-NMR (DMCO-d6) : of 10.4 (s, 1H); to 10.2 (s, 1H); 6,86 (s, 1H); for 6.81 (s, 1H); of 3.48 (s, 2H); is 2.37 (s, 3H); 2,22 (s, 3H).d) 5,7-Dihydro-3-methyl-6H-pyrrolo[5,4-f]-1,2-benzisoxazol-6-he
Repeating the procedure described in example 33d using oxiracetam obtained in stage (c) (2,75 g, 10,97 mm), and pyridine (8,9 ml, 109,7 mm) in DMF (110 ml). After concentration in vacuo the residue was purified using flash chromatography on silica gel (2% MeOH-CH2Cl2) and received (0,245 g, 12%) as a light yellow solid product.1H-NMR (DMCO-d6) to 10.6 (s, 1H); 7,58 (s, 1H); 7.03 is (s, 21H); 3,63 (s, 2H); 2.50 each (s, 3H).e) 4-[2-[5,7-Dihydro-6H-pyrrolo[5,4-f] -1,2-benzisoxazol - 6-one-3-yl] ethyl]-1-piperidinecarboxylate acid, 1-(1,1-dimethylethyl)ester
Repeating the procedure described in example 7a using benzisoxazol obtained in stage (d) (0.152 g, 0,808 mm), 1M LDA (3.2 ml, 3.2 mm) and 1-(1,1-dimethylethyl)ester 4-iodomethyl-1-piperidinecarboxylic acid (is 0.135 g, 0,970 mm) in dry THF (30 ml), except that after addition of the reagents, the mixture is stirred for 4.5 h at -78oC. After purification by chromatography (50% ___ EtOAc-CH2Cl2were inseparable mixture (0,153 g of 1.6:1) the source material and the target with the separately get the best ratio of source material to the target compound, namely 1:3.1H-NMR (CDCl3) : 9,84 (s, 1H); 7,45 (s, 1H); 7,05 (s, 1H); 4,05-to 4.15 (m, 2H); of 3.69 (s, 2H); 2,96 (t, 2H, J=7.8 Hz); 2,68 (Shir.t, 2H, J=11.8 Hz); 1,72-to 1.82 (m, 4H); 1,45 (s, 9H); 1,43-of 1.53 (m, 1H); 1,15 (DDD, 2H, J=23,6 Hz, J=12.1 Hz, J=4.0 Hz).f) 5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -6H - pyrrolo[5,4-f]-1,1-benzisoxazol-6-he
Repeating the procedure described in example 12f, using the mixture obtained in stage (a) (0,153), and TFA (1.5 ml) in methylene chloride (6 ml). Under alkylation used only a portion of the crude salt mixture (of 0.081 g): Na2CO3level (0.041 g, 0,388 mm) and benzylbromide (0,012 ml, 0,101 mm) in DMF (6 ml). Note: for stage alkylation solvent (DMF) was carefully degirolami using silver and processing of saturated NaHCO3not performed (instead was used saline solution). After cleaning (2____ 6% MeOH-CH2Cl2) received target connection (0,018 g, 60%) as compared to the desired source material in the form of a light yellow solid product.So pl. 204,5-205,5oC (Razlog.).1H-NMR (CDCl3) : of 8.09 (s, 1H); 7,46 (s, 1H); 7,27-7,33 (m, 5H); 6,99 (s, 1H); 3,68 (s, 2H); 3,50-to 3.52 (m, 2H); 2,90-to 2.99 (m, 4H); 1,92-2,05 (m, 2H); 1,70-1,80 (m, 4H); 1,30-1,40 (m, 4H).Example 36.Part of the mixture obtained above (0,661 g), and PtO2(0,070 g, 0,31 mm) in EtOH was subjected to hydrogenation in a Parr shaker at a pressure of 48 psi (3,31 bar) for 2 hours Then the mixture was filtered through a pad of Celite and the filtrate was concentrated. Then osushestvljali and was purified using flash chromatography (I ___ 3% MeOH-CH2Cl2), and then 30% EtOAc-hexane), resulting in a received target connection (0,192 g, 5.3 per cent) (full) as a colorless oily product.1H-NMR (CDCl3) a 7.85 (dt, 1H, J=7,6 Hz, J=1.8 Hz); 7,47-7,56 (m, 1H); 7,09-7,33 (m, 7H); 43,49 (s, 2H); 2.95 and-3,03 (m, 2H); 2,89 (Shir.d, 2H, J=11,4 Hz); 1,94 (Shir.t, 2H, J=11,1 Hz); and 1.63-1.77 in (m, 4H); 1,24-of 1.39 (m, 3H).EIMS 325 (M+), 202, 188, 172, 91, 66 (the basis).b) 3-[2-[1-Phenylmethyl)-4-piperidinyl]ethyl]-1H-indtalled
A mixture of the ketone obtained in stage (b) (0,178 g, 0.55 mm) in anhydrous hydrazine (10 ml) was heated under reflux for 3 h Then the reaction mixture was cooled, added water, and the mixture was extracted with ethylenchloride. The organic layer was dried with magnesium sulfate, filtered and concentrated. After purification using radial chromatography on silica gel (CH2Cl2___ 10% MeOH-CH2Cl2) received target compound free base (0,047 g, 27%) as a colorless oily product.Maleate (salt) was obtained by adding a solution of maleic acid (0,010 g of 0.085 mm) Et2O (5 ml) to a solution of free base (0,027 g of 0.085 mm) Et2O (75 ml). The obtained white solid substance was collected by filtration and received the target connection (0,014 g, 38%t, 1H, J= 7,3 Hz); 7,06 (t, 1H, J=7.4 Hz); of 6.02 (s, 2H); 4,24 (Shir. s, 2H); of 2.93 (t, 2H, J=7,6 Hz); 1,9-2,00 (m, 2H); 1,60-1,80 (m, 3H); 1,30-1,50 (m, 4H).With respect to biological data.The data presented in table indicate the ability of compounds to inhibit acetylcholinesterase. The values of the IC50were obtained by the method mentioned in the description and described in the article Ellman et al., Biochem. Pharm., 1, 88 (1961).Example 37.The drug 1 (pill)
(1) Compound of example 4 (maleate) - 50 g
(2) Lactose - 100 g
(3) Corn starch 15 g
(4) Calcium carboxymethylcellulose - 44 g
(5) magnesium Stearate 1 g
1000 tablets - 210 g
Components (1), (2) and (3) and 30 g of the component (4) was mixed with water, was dried under vacuum and was granulated. The obtained granulated powder was mixed with 14 g of the component (4) and 1 g of the component (5) and the mixture was loaded into tabletiruemuju machine. Received 1000 tablets containing 50 mg of the component (1) in each tablet.Example 38.Drug 2
(1) Compound of example 9 (maleate) 10 grams
(2) Lactose - 4.5 g
(3) Corn starch - 4.5 g
(4) magnesium Stearate 1 g
100 capsules - 20 g
All components are thoroughly mixed, and the mixture was filled gelatin capsules. Received 100 capsules this formula I
< / BR>where R1and R2independently selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, cyano-, amino-, amido-, hydroxy-group, halogen, acetamido, benzamido, benzosulfimide, morpholinopropan, R1and R2taken together may form a pyrrolidone, which may be substituted (C1-C6)-alkyl, and piperidino ring and hinaningyou;
R7and R8is hydrogen;
X represents oxygen, sulfur, -NH, -CH=CH-, -CH-N-group;
Y represents a (C1-C6)-alkyl, (C1-C6)-alkoxy, (C2-C6-alkylene, (C1-C6)- alkylamino;
M is nitrogen or-CH-group;
L represents a phenyl-(C1-C6)-alkyl, phenyl group which may be substituted, but not necessarily, halogen, or halogentated-(C1-C6)-alkyl, or (C1-C6)-alkylthio-(C1-C6)-alkyl,
or their pharmaceutically acceptable salts.2. Connection on p. 1, where X represents sulfur or oxygen, Y represents-CH2-CH2- or-CH2-, M represents-CH-, and L represents a benzyl, R1and R2represents a C1-C63-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
5-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]- 1,2-benzisoxazol;
5,5-dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -1,2-benzisoxazol;
5-methoxy-3-[2-[1-phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
6-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
7-methoxy-3-[2-[1-(phenylmethyl) -4-piperidinyl]ethyl]-1,2-benzisoxazol;
6-acetamido-3-[2-[1- (phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
6-amino-3-[2-1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
6-benzamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
6-benzosulfimide-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl] 1,2-benzisoxazol;
6-(4-morpholinyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2-benzisoxazol;
5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]- 6N-pyrrolo[4,5-f] -1,2-benzisoxazol-6-he;
3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol;
6-hydroxy-3-[2-[1-(phenylmethyl) -4-piperidyl]ethyl]-1,2-benzisoxazol;
6-bromo-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazol;
6-cyano-3-[2-[1- (phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazol;
6-carboxamido-3- [2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-gasoline]-1,2-benzisoxazol;
3-[1-[(1-phenylmethyl)-4-piperidyl]ethylamino]-1,2-benzisoxazol;
3-[3-[(1-(phenylmethyl)-4-piperidyl]propyl]-1,2-benzisoxazol;
TRANS-3-[2-[1-(phenylmethyl)-4-piperidyl]ethynyl]-1,2-benzisoxazol;
3-[2-[1-(phenylmethyl)-4-piperazinil]ethyl]-1,2-benzisoxazol;
5,7-dihydro-7-methyl-3-[2-[1-(phenylmethyl) -4-piperidinyl]ethyl]-6N-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-7-ethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-6N-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-3-[2-[1-(2-chloro-5-thiophenemethyl)-4-piperidyl] ethyl]-6N-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
5,7-dihydro-3-[2-[1-(2-methyl-4-thiazolyl)-4-piperidinyl] ethyl] -6N - pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
3-[2-[1-(3-bromophenyl)-4-piperidinyl] ethyl] -5,7 - dihydro-6N-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
3-[2-[1-(4- bromophenyl)-4-piperidinyl] ethyl]-5,7-dihydro-6N-pyrrolo[4,5-f] -16-benzisoxazol-6-he;
5,7-dihydro-3-[3-[1-(phenylmethyl)-4 - piperidinyl] propyl] -6N-pyrrolo[4,5-f]-1,2-benzisoxazol-6-he;
3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl] -5,6,8-trihydro-7H - isoxazole[4,5-g]quinoline-7-he;
6,8-dihydro-3-[2-[1- (phenylmethyl)-4-piperidinyl]ethyl]-7H-pyrrolo[5,4-g] -1,2-benzisoxazol-7-he;
5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-6N-pyrrolo[5,4-f] -1,2-benzisoxazol-6-he;
3-[2-[1-(phenylmethyl) -inania by p. 1, which is chosen from the group comprising:
3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazol Aleut;
5,6-dimethyl-3-[2-[1-(phenylmethyl)-4 - piperidinyl] ethyl] -1,2-benzisoxazole;
5-methoxy-3- [2-[1-(phenylmethyl)-4-piperidinyl] ethyl]-1,2-benzisoxazole;
7-methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2 - benzisoxazole;
6-benzamide-3-[2-[1-(phenylmethyl)-4 - piperidinyl] ethyl] -1,2-benzisoxazole; and
6-benzosulfimide-3- [2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole.5. The compound of General formula II
< / BR>where R7and R8is hydrogen;
R10has the values defined for L in paragraph 1;
W is a leaving group;
j is an integer from 1 to 2.6. Connection on p. 1 of formula IV
< / BR>where R1, R2, R7, R8X, Y, M defined in paragraph 1;
R11has the values defined for L in paragraph 1.7. The compounds of formula III
< / BR>where R1, R2, R7, R8and L are defined in paragraph 1;
Y' represents-CH=CH-(CH2)nor -(CH2)mwhere n = 1 to 3, m = 1 - 3.8. The pharmaceutical composition inhibiting cholinesterase in mammals containing the active substance of the formula I according to p. 1 in an effective amount.9. Method of inhibiting cholinesterase in mammals by introduction of the active substance, characterized in that the injected compound of formula I under item 1 in a daily dose of 1 to 300 mg/kg of body weight.10. A method of obtaining a heterocyclic derivatives of amines of the formula Ia,
< / BR>where R1, R2, R7, R8, X, L have the meanings given in paragraph 1;
m = 1 - 3,
or their pharmaceutically acceptable salts, characterized in that the compound of formula VI
< / BR>where R1, R2, R7, R8, X, and m have the above values,
subjected to interaction with the compound of the formula
WL,
where L is the specified value;
W - tsepliaeva group,
with subsequent isolation of the target product in free form or in the form of pharmaceutically acceptable salts.
Same patents:
The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals
The invention relates to androidiani carboxanilides, compositions based on them and the way to deal with arteriotomy and can be used in agriculture
The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I
< / BR>where X is oxygen or sulfur;
Y is carbon or nitrogen;
Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;
R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;
R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;
R5and R6independent from each other and denote hydrogen or methyl;
n is 0,1 or 2,
Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,
in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis
< / BR>where X is oxygen or sulfur;Y is carbon or nitrogen;
Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;
R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;
R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;
R5and R6independent from each other and denote hydrogen or methyl;
n is 0,1 or 2,
Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,
in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis
The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions
The invention relates to methods of optical separation pornoencaricaturas compounds, which are important intermediate product in the synthesis of optically active derivative of pianolasociety, useful in the treatment of hypertension (hypertension) and asthma
The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity
The invention relates to a derivative of thiazolidinedione formula
,
where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5
,where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5
The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions
The invention relates to 3-/1-diazolidinyl butyl-4-piperazinil/ 1H-indazols formula I
< / BR>where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;
R3and R4independently represent hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;
R5is hydrogen or lower alkyl;
X is halogen;
m is an integer of 0 or 1, to their pharmaceutically acceptable acid additive salts, and where applicable, optical, geometric and stereoisomers and racemic mixtures
< / BR>where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;R3and R4independently represent hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;
R5is hydrogen or lower alkyl;
X is halogen;
m is an integer of 0 or 1, to their pharmaceutically acceptable acid additive salts, and where applicable, optical, geometric and stereoisomers and racemic mixtures
Derived 1,4-benzodiazepin // 2089550
The invention relates to a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate
The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/
The invention relates to organic chemistry, relates to new heterocyclic compounds 4-[(benzo-2,1,3-imidazolyl-4)amino]- 5,6,7,8,-tetrahydrothieno[2,3-d]pyrimidine of the formula 1
,
with improved anthelminthic activity, and can be used in medicine for the treatment of larval and alveolar hydatidosis of hydatid cysts
,with improved anthelminthic activity, and can be used in medicine for the treatment of larval and alveolar hydatidosis of hydatid cysts
The invention relates to a derivative of thiazolidinedione formula
,
where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5
,where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5
