New derivatives of solidilin, the retrieval method (variants), the pharmaceutical compositions based on them, the method of prevention or treatment, a way of reducing glucose and intermediate connection

 

(57) Abstract:

The invention relates to a new derivative of solidilin formula (I) where one of X, Y and Z represents C=O or C=S, and one of the remaining X, Y and Z denotes a group With=, and the other group C=S; R1, R2and R3are Deputy or X, Y and Z, or nitrogen atom and may be the same or different and denote hydrogen, halogen, hydroxy, nitro, etc., the group -(CH2)n-O - and may be joined through the nitrogen atom, or X, Y, Z, n is 1-4, Ar denotes a phenylene or naftilan, R4denotes hydrogen or forms a bond with group a, And denotes nitrogen or CR5, R5denotes hydrogen, halogen or forms a bond with R4In means O or S, when a is CR5and means that, when a is N, its tautomeric forms, stereoisomers, polymorphic forms, pharmaceutically acceptable salt and solvate. The method of obtaining the compounds of formula (I) by reacting the compounds of formula (VIII) with the compound of the formula (XII), etc., a Pharmaceutical composition having anti-diabetic activity containing a compound of the formula (I) and a pharmaceutically acceptable carrier, diluent, filler or MES. The way to prevent elisma, including the introduction of the compounds of formula (I) to the needy in this patient. A method of reducing blood glucose, triglyceride levels as well as or free fatty acids in plasma, including the introduction of the compounds of formula (I) to the needy in this patient. The intermediate compound of formula (III), where G represents-Cho, -NH2, -CH=NOH, etc., J denotes a hydroxy-group, halogen, R represents hydrogen, lower alkyl, one of X, Y and Z represents C=O or C=S, and one of the remaining X, Y and Z denotes a group With=, and the other group C=S; R1, R2and R3are Deputy or X, Y and Z, or nitrogen atom and may be the same or different and denote hydrogen, halogen, hydroxy, nitro, etc., or any two of1, R2, R3together with the adjacent atoms to which they are attached, may form a substituted or unsubstituted cycle from 4-7 atoms with one or more double bonds, and so on, the group -(CH2)n-O - and may be joined through the nitrogen atom, or X, Y, Z, n is 1-4, Ar denotes a phenylene or naftilan, R4denotes hydrogen or forms a bond with group a, And denotes nitrogen or CR5, R5denotes hydrogen, halogen or forms a bond with R4In means O or S, when a is CR5and SS="ptx">

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Description text in facsimile form (see table). T T

1. The compound of General formula (I)

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its tautomeric forms, stereoisomers, polymorphic modifications, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, where one of X or Z represents C= O or C= S, and one of the remaining X, Y and Z denotes a group With= , and the other group C= S; R1, R2and R3are Deputy or X, Y or Z, or a nitrogen atom, and may be the same or different and denote hydrogen, halogen, hydroxy, or nitro or CF3C1-6alkyl, alkoxy, phenyl, phenyl-C1-6-alkyl, acyl, acyloxy, amino, C1-6acylamino, aminoalkyl, aryloxy, alkylamino or alkoxyalkyl, provided that when R1, R2, R3are substituents on the nitrogen atom, they do not signify hydrogen, halogen, nitro, or any two of R1, R2, R3together with the adjacent atoms to which they are attached, can also form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, which may be carbocyclic and may contain one or two heteroatoms selected from kislota nitrogen or through X, Y, or Z, where n is an integer in the range from 1 to 4; AG denotes a phenylene or naftilan optionally substituted1-3alkoxygroup; R4denotes hydrogen, or forms a bond with the adjacent group; And a denotes a nitrogen atom or a group CR5where R5denotes hydrogen, halogen or R5forms a link with R4; In denotes an oxygen atom or a sulfur atom when a is CR5; and In denotes an oxygen atom when a is a nitrogen atom.

2. Connection on p. 1, in which X is C= O or C= S, and Y and Z, is selected from = C and C= C.

3. Connection on p. 1, in which Y is C= O or C= S, and X and Z is selected from = C and C= C.

4. Connection on p. 1, in which Z is C= O or C= S, and X and Y are selected from = C and C= C.

5. Connection on p. 1, in which one of R1, R2or R3is Deputy on the nitrogen atom and is selected from (C1-C6)alkyl, phenyl, substituted or unsubstituted phenyl(C1-6)alkyl; amino(C1-C6)alkyl; and acyl groups.

6. Connection on p. 1, in which the cyclic structure formed by any two of R1, R2or R3together with the adjacent atoms to which they are attached, is replaced, and eroticly, heteroaryl, heteroalkyl, hydroxy, acyl, acyloxy, hydroxyalkyl, amino, acyl, acyloxy, acylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, carboxylic acid or its derivatives, or sulfonic acids or its derivatives.

7. Connection on p. 1, in which the cyclic structure formed by any two of R1, R2or R3is phenyl, pyridinium, thienyl or pyrazol ring, optionally substituted C1-6-alkyl or C1-6the alkoxy group.

8. The method of obtaining the compounds of formula (I)

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its tautomeric forms, stereoisomers, polymorphic forms and their pharmaceutically acceptable salts, pharmaceutically acceptable solvate, where one of X, Y and Z represents C= O or C= S, and one of the remaining X, Y and Z represent a group With a= , and the other group C= S; R1, R2and R3are Deputy or X, Y or Z, or nitrogen atom and may be the same or different, and denote hydrogen, halogen, hydroxy or nitro CF3C1-6alkyl, alkoxy, phenyl, phenyl WITH1-6alkyl, acyl, acyloxy, amino, C1-6acylamino, aminoalkyl, aryloxy, alkylamino, alkoxyalkyl, provided that when R1, R2, R3I have UP>, R3together with the adjacent atoms to which they are attached, can also form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, the cyclic structure may be carbocyclic or may contain one or two heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH2)n-O-, can join via the nitrogen atom or through X, Y, Z, where n is an integer in the range from 1 to 4; Ar denotes fenelonov or Neftyanoy group, optionally substituted C1-3-alkoxygroup; R4denotes hydrogen, or forms a bond together with the adjacent group; And a denotes a nitrogen atom or CR5where R5denotes hydrogen, halogen or R5forms a link with R4; and In denotes an oxygen atom or sulfur, in the case when a is CR5; and is On when a is nitrogen, including: the interaction of compounds of formula (VIII)

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where R1, R2, R3X, Y, Z and n are previously defined and L1is a halogen atom or a leaving group, with a compound of formula (XII)

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where R4And, and Ar is defined previously and R6is hydrogen in formula (I)

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their tautomeric forms, stereoisomers, polymorphic forms, pharmaceutically acceptable salts, or pharmaceutically acceptable solvate, where one of X, Y and Z represents C= O or C= S, and one of the remaining X, Y and Z represent a group With a= , and the other group C= S; R1, R2and R3are Deputy or X, Y or Z, or nitrogen atom and may be the same or different, and denote hydrogen, halogen, hydroxy or nitro, CF3C1-6alkyl, alkoxy, phenyl, panels1-4alkyl, acyl, acyloxy, amino, C1-6acylamino, aminoalkyl, aryloxy, alkylamino, alkoxyalkyl, provided that when R1, R2, R3are substituents on the nitrogen atom, they do not signify hydrogen, halogen, nitro, or any two of R1, R2, R3together with the adjacent atoms to which they are attached, form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, the cyclic structure may be carbocyclic or may contain one or two heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH2)n-O-, can join via the nitrogen atom or through X, Y, Z, n is an integer Chi is UB>alkoxygroup; R4represents hydrogen; represents a group CR5where R5represents hydrogen; represents an oxygen atom or sulfur,

a) interaction of the compounds of formula (IV)

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where X, Y, Z, R1, R2and R3previously defined, and the atom H is attached to one of the nitrogen atoms of the ring, with a compound of formula (V)

L1(CH2)n-O-Ar-G (V)

where AG and n are as previously defined, and L1is a halogen atom or a leaving group, and G is a Cho group, to obtain compounds of formula (III)

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where G denotes-SNO group, and X, Y, Z, R1, R2, R3n and AG, as previously defined,

(b) coordination compounds of General formula (III) obtained in step a), above, with thiazolidin-2,4-dione, or oxazolidin-2,4-dione, to obtain the compounds of formula (X)

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where R1, R2, R3X, Y, Z, n, Ar, defined previously, and represents a sulfur atom or oxygen, and removing water formed during the reaction, and

(C) recovering the compound of formula (X) obtained in step (b), to obtain the compounds of formula (XI)

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in which R1, R2, R3X, Y, Z, n, AG previously defined, and represents a sulfur atom or oxygen.

Orme pharmaceutically acceptable salt or pharmaceutically acceptable solvate, where one of X, Y and Z represents C= O or C= S, and one of the remaining X, Y and Z denote the group= other - group= S; R1, R2and R3are Deputy or X, Y or Z, or nitrogen atom and may be the same or different, and denote hydrogen, halogen, hydroxy or nitro, CF3C1-6alkyl, alkoxy, phenyl, panels1-6alkyl, acyl, acyloxy, amino, C1-6acylamino, aminoalkyl, aryloxy, alkylamino, alkoxyalkyl, provided that when R1, R2, R3are substituents on the nitrogen atom, they do not signify hydrogen, halogen, nitro, or any two of R1, R2, R3together with the adjacent atoms to which they are attached, can also form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, the cyclic structure may be carbocyclic or may contain one or two heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH2)n-O-, may join or through nitrogen atom or through X, Y or Z, where n is an integer in the range from 1 to 4; AG indicates fenelonov or Neftyanoy group, optionally substituted C1-3alkoxygroup where R5denotes hydrogen, halogen or R5forms a link with R4; In denotes an oxygen atom or sulfur, in the case when a is CR5; and In denotes an oxygen atom when a is a nitrogen atom, including:

a) interaction of the compounds of formula (XVII)

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where R1, R2and R3defined previously, X is C= O or C= S and Y represents C= S; or R2and R3together with Y form a cyclic structure, as mentioned previously, where X represents C= O or C= S, Y represents C= C and R1was indicated earlier, with a compound of formula (XVIII),

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where Ar, R4And, In and n are previously defined, D can be-CN or-C(OR7)3where R7is (C1-C4)alkyl, or-C(= O)-R8where R8can be selected from HE, Cl, Br, I, -NH2-The other, OR, where R is lower alkyl; or R8can be O-(C= O)-R9where R9can be linear or branched (C1-C5)alkyl group.

11. The method according to p. 10, characterized in that the compound of formula XVII and formula XVIII to form a compound of formula 1 through the formation of intermediate compounds of formula (XIX)

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where X, Y, R1, R2, R3, n, Ar, R4And and is defined as the Oia, the compounds of formula (I)

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where And denotes CR5where R5is hydrogen, and In denotes an oxygen atom or sulfur, and X, Y, Z, R1, R2, R3, Ar and n are defined in any one of paragraphs. 1-7, including the interaction of the compounds of formula (XIV)

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where R1, R2, R3X, Y, Z, n, and Ar are defined above, J is a halogen atom or hydroxy-group and R is lower alkyl, with urea, in the case when J is a hydroxy-group, or with thiourea, when J is a halogen atom, and treatment with an acid.

13. The method of obtaining the compounds of formula (I)

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its tautomeric forms, stereoisomers, polymorphic modifications, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, where one of X or Z represents C= O or C= S, and one of the remaining X, Y and Z denotes a group With= , and the other group C= S; R1, R2and R3are Deputy or X, Y or Z, or a nitrogen atom, and may be the same or different and denote hydrogen, halogen, hydroxy, or nitro or CF3C1-6alkyl, alkoxy, phenyl, panels1-6alkyl, acyl, acyloxy, amino, C1-6acylamino, aminoalkyl, aryloxy, alkylamino or alkoxyalkyl, provided that when R1, R2R<1, R2, R3together with the adjacent atoms to which they are attached, can also form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, the cyclic structure may be carbocyclic or may contain one or two heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH2)n-O-, can join through nitrogen atom or through X, Y and Z, where n denotes an integer in the range from 1 to 4; AG denotes a phenylene or naftilan, optionally substituted C1-3alkoxygroup; R4denotes a hydrogen atom or forms a bond together with the adjacent A; a is nitrogen or CR5where R5is hydrogen, halogen or R5forms a bond together with R4; In denotes oxygen, sulfur atom when a is CR5; and In denotes an oxygen atom when a represents nitrogen, including:

a) interaction of the compounds of formula (III)

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where G denotes the SNO group, and other symbols previously defined, with hydroxylamine hydrochloride, followed by reduction with alkali metal borohydride to obtain the compounds of formula (XVI)

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where all si is oxycarbonyl the isocyanate or potassium isocyanate, followed by treatment carbonyliron reagent to obtain compounds of General formula (I), where R1, R2, R3X, Y, Z, n and ar are defined above and a denotes a nitrogen atom, and oxygen atom.

14. The method of obtaining compounds of General formula (I), where X represents C= O, Y represents C= C, Z denotes a = C, n denotes an integer of 1, R1denotes a methyl group, A represents a sulfur atom, R2and R3together with Y form a phenyl ring, given by the formula (XX)

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including:

a) restoring the compounds of formula (XXI),

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where R10is lower alkyl, using standard terms of recovery, obtaining the compounds of formula (XXII)

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where R10defined above,

b) hydrolysis of compounds of formula (XXII) using conventional conditions to obtain compounds of formula (XXIII),

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(C) the interaction of the compounds of formula (XXIII) with halogenerator or halogenation reagent to obtain the compounds of formula (XXIV)

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where D denotes l, COBr or-C(= O)-O-(C= O)-R9where R9denotes methyl or tert-butyl,

d) the interaction of the compounds of formula (XXIV) with a compound of formula (XXV)
Oia formula (XXVI)

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e) and optional conversion of the compounds of formula (XX) into its pharmaceutically acceptable salt, polymorph modifications, solvate.

15. The method according to p. 14, characterized in that the compound of formula (XXVI)

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cyclized with the formation of the compounds of formula (XX).

16. Compound which is selected from the group comprising the following compounds:

5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethyl] thiazolidine-2,4-dione and its salts and polymorphic modifications

5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-hintline] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,
/BR>5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] oxazolidin-2,4-dione and its salts,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] oxazolidin-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethyl] oxazolidin-2,4-dione and its salts,

2-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -1,2,4-oxadiazolidine-3,5-dione and its salts,

2-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -1,2,4-oxadiazolidine-3,5-dione and its salts,

2-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethyl] -1,2,4-oxadiazolidine-3,5-dione and its salts,

5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-Hina is ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-hintline] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] -3-methoxyphenylacetic] thiazolidin-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt and its poly-form modification,

5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-hintline] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt,

5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-hintline] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethyl] thiazolidine-2,4-dione potassium salt,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-hintline] methoxy] phenylmethylene] thiazolidine-2,4-dione, sodium salt.

17. Pharmaceutical composition having anti-diabetic activity, including active compound, pharmaceutically acceptable carrier, diluent, filler or MES, characterized in that it contains as the active connection of the formula I

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as defined in any of items 1 to 5, or 14.

18. Pharmaceutical composition having anti-diabetic activity, including active Sona contains as the active connection of the formula I

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as defined in any of paragraphs. 1-7, or 16.

19. The pharmaceutical composition under item 17 or 18 in the form of tablets, capsules, powder, syrup, solution or suspension.

20. The method of prevention or treatment of diseases in which insulin resistance that underlies their pathophysiological mechanism involving the introduction of the compounds of formula (I) PP. 1-7 or 16, as well as pharmaceutically acceptable carrier, diluent or excipient to the needy in this patient.

21. The method according to p. 20, in which the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary artery disease, cardiovascular disturbance, atherosclerosis, insulin resistance associated with obesity and psoriasis, a complication of diabetes mellitus, polycystic ovary syndrome (PCOS), renal disease, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, late stage renal disease, microalbuminuria, nutritional disturbance.

22. A method of reducing blood glucose, triglyceride or free fatty acids in plasma, comprising the administration to a patient in need this, connection /P> 23. The intermediate compound of formula (III)

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where G represents-Cho, -NH2, -CH= NOH, -CH2NHOH, -CH2N(OH)CONH2or CH2CH(J)-COOR, J denotes a hydroxy group, a halogen atom, R denotes hydrogen or lower alkyl; one of X, Y and Z represents C= O or C= S, and one of the remaining X, Y and Z represent a group With a= and other= S; R1, R2and R3are Deputy or X, Y or Z, or nitrogen atom and may be the same or different, and denote hydrogen, halogen, hydroxy or nitro, CF3C1-6alkyl, alkoxy, phenyl, panels1-6alkyl, acyl, acyloxy, amino, C1-6acylamino, aminoalkyl, aryloxy, alkylamino, alkoxyalkyl, provided that when R1, R2, R3are substituents on the nitrogen atom, they may not be hydrogen, halogen, nitro groups; or any two of R1, R2, R3together with the adjacent atoms to which they are attached, can also form a substituted or unsubstituted cyclic structure containing from 4 to 7 atoms with one or more double bonds, which may be carbocyclic or may contain one or two heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH21-3alkoxygroup; R4is hydrogen or forms a bond together with the adjacent group A; a is nitrogen or a group of CR5where R5is hydrogen, halogen or R5forms a bond together with R4; Is oxygen or sulfur, And when is CR5and is oxygen, when a is nitrogen.

24. The method according to any one of paragraphs. 8-14, characterized in that it further includes the transformation of the compounds of formula I, its pharmaceutically acceptable salts, polymorphic form or a solvate.

 

Same patents:

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to the derivatives of pyrrolidine formula I

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where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHCОСН2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl,< / BR>
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R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of chemical bonding;displays a CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHCО-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate of the compound

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

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The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

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The invention relates to the field of organic chemistry, namely to new derivatives of amides heterylamine butenova acids that have anti-inflammatory activity

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to new isoxazol derivative of formula 1, where D represents hydrogen; one of a and b is a group (1) -E-N= C(NR25R26)NR27R28; E represents a direct link or alkilinity group; R25and R26each represents, independently, hydrogen; C1-4-alkyl; -(CH2)n-CO2R32, n is an integer of 1-3, and R32represents hydrogen, C1-4-alkyl; -(CH2)m-CO2R35m is 2 or 3 and R35represents hydrogen, C1-4-alkyl; -(CH2)mHE, m defined above, or -(CH2)n-C(O)R36n is defined above and R3represents hydrogen, C1-4-alkyl; and t

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to new derivatives of kalaidjieva, fungicides, method of combating fungal diseases of crops and intermediate compounds for obtaining

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts
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