Sulfoaluminate that inhibit decomposing matrix metalloproteinases

 

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2. The method of obtaining the compounds of formula I by reacting the compounds of formula IV with a compound of formula V to obtain the compounds of formula VI, which is converted into the compound of formula I. the Pharmaceutical composition inhibiting razlika pharmaceutically acceptable carriers. The technical result - the creation of new sulfoaluminate, inhibition razlagaemoi the matrix metalloproteinases. 4 C. and 5 C.p. f-crystals, 2 PL.

Description text in facsimile form (see graphic part). T

Claims

1. Derivative sulfonylamino acid and sulphoniumhydroxide acid of the formula Iwhere W denotes-IT or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl, dihydroisoquinolyl, tetrahydroquinazoline, tetrahydroimidazo[1,5-b]ethenolysis, each of which may be substituted by 1-5 substituents, represents an alkyl or oxoprop, b) -NR1SO2R2where R1denotes a hydrogen atom, and R2denotes phenyl substituted by alkyl, in) heterophilically where heterocyclyl means 1,1,3-trioxo-2,3-dihydrobenzofuran, g) -CONR2R3where R2and R3together with the nitrogen atom to which they are attached, form morpholinyl or piperidineacetate substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy and-NR'1COR'2where R'1denotes a hydrogen atom, and R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted by the group-CF3;
m denotes an integer from 1 to 4;
n denotes an integer of 1 or 2,
or their pharmaceutically acceptable salts.

2. Connection on p. 1, where W denotes-IT or-NHOH, X denotes (a) 1,1,3-trioxo-2,3-dihydrobenzofuran, 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin, 4,4-dimethyl-2,5-dioxoimidazolidin-1-yl, (1,3-dioxo-1,5,10, (10S)tetrahydroimidazo- [1,5-b] ethenolysis), b) -NR1SO2R2where R1denotes a hydrogen atom, and R2denotes phenyl substituted by alkyl, in) heterocyclisation where heterocyclyl means 1,1,3-trioxo-2,3-dihydrobenzofuran, g) -NR2R3where R2and R3together with the nitrogen atom to which they are attached, form morpholinyl or piperidinyl, symbols and radicals have indicated in paragraph 1 of values, or its pharmaceutically acceptable salt.

3. Connection on p. 1, representing
(2R)-(4'-chlorobiphenyl-4-samino)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin-3-yl)pentane acid,
(2R)-(4-biphenylmethanol)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxygenation-3-yl) pentane acid
(2R)-(4'-chlorobiphenyl-4-sulfonylamino)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) pentane acid,
(2R)-(4'-chlorobiphenyl-4-sulfonylamino)-5-(4-methylbenzenesulfonamide) pentane acid,
hydroxyamide (2R)-(4'-chlorobiphenyl-4-sulfonylamino)-5-(1,1,3-trioxo-2,3-dehydrobenzperidol-2-yl) pentanol acid,
hydroxyamide (2R)-(4'-chlorobiphenyl-4-sulfonylamino)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxygenation-3-yl) pentanol acid,
hydroxyamide (2R)-(4-biphenylmethanol)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxygenation-3-yl)pentanol acid,
(2R, S)-(4'-chlorobiphenyl-4-sulfonylamino)-6-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin-3-yl) hexanoic acid,
(2R, S)-(4'-chlorobiphenyl-4-sulfonylamino)-6-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) hexanoic acid,
(2R)-(4'-chlorobiphenyl-4-sulfonylamino)-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) butyric acid,
(2R)-(4'-chlorobiphenyl-4-sulfonylamino)-4-[(1,3-dioxo-1,5,10, (10aS)-tetrahydroimidazo [1,5-b]isoquinoline-2-yl) butyric acid,
(2R)-(4'-chlorobiphenyl-4-sulfonylamino)-4-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin-3-yl)butyric acid,
hydroxyamide (2R)-(4'-chlorobiphenyl-4-Sul is about)-3-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid,
(2R, S)-(4'-chlorobiphenyl-4-sulfonylamino)-3-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin-3-yl) propanoic acid,
hydroxyamide (2R, S)-(4'-chlorobiphenyl-4-sulfonylamino)-3-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid,
(2R)-(4-phenoxybenzenesulfonyl)-4-morpholine-4-yl-4-oxomethane acid,
(2R)-(4'-chlorobiphenyl-4-sulfonylamino)-4-morpholine-4-yl-4-oxomethane acid,
hydroxamic (2R)-(4-phenoxybenzenesulfonyl)-4-morpholine-4-yl-4-oxomalonate acid, or
hydroxyamide (2R)-(4'-chlorobiphenyl-4-sulfonylamino)-4-morpholine-4-yl-4-oxomalonate acid, or a pharmaceutically acceptable salt of any of these compounds.

4. Connection on p. 1, representing
(2R)-(4-phenoxybenzenesulfonyl)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin-3-yl) pentane acid,
(2R)-[4-(4-pertenece)benzosulfimide] -5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoimidazolidin-3-yl) pentane acid,
(2R)-[4-(4-pertenece)benzosulfimide] -5-(1,1,3-trioxo-2,3-dehydrobenzperidol-2-yl) pentane acid,
(2R)-(4-phenoxybenzenesulfonyl)-5-(1,1,3-trioxo-2,3-dehydrobenzperidol-2-yl) pentane acid,
or pharmaceutically acceptable salt of any of these compounds.

5. The connection p is anew acid or its pharmaceutically acceptable salt.

6. Connection on p. 1, representing (2R)-(4-phenoxybenzenesulfonyl)-5-(1,1,3-trioxo-2,3-dehydrobenzperidol-2-yl) pentane acid or its pharmaceutically acceptable salt,
7. The pharmaceutical composition inhibiting razlagaemoi the matrix metalloproteinase containing a pharmacologically active compound and one or more pharmaceutically acceptable carriers, characterized in that the pharmacologically active compound contains a compound according to any one of paragraphs.1-6.

8. A method of treating warm-blooded animals, including humans, for the introduction of such a warm-blooded animal suffering from a tumor, effective as an antitumor agent, the dose of the compounds of formula I according to any one of paragraphs. 1-13, or a pharmaceutically acceptable salt.

9. The method of obtaining sulfoaluminate or sulphoniumhydroxide acid of the formula I

where W denotes-IT or-NHOH;
X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl, dihydroisoquinolyl, tetrahydroquinazoline, tetrahydroimidazo[1,5-b]ethenolysis, each of which may be substituted by 1-5 substituents, before the R2denotes phenyl substituted by alkyl, in) heterocyclisation where heterocyclyl means 1,1,3-trioxo-2,3-dihydrobenzofuran, g) -NR2R3where R2and R3together with the nitrogen atom to which they are attached, form morpholinyl or piperidinyl;
Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is 2,
Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenyloxazolyl, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy and-NR'1COR'2where R'1denotes a hydrogen atom, and R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted by the group-CF3;
m denotes an integer from 1 to 4;
n denotes an integer of 1 or 2,
or its salt,
including the interaction of the compounds of formula IV

where X has the values specified above for compounds of formula I,
with sulphonylchloride formula V

obtaining the compounds of formula VI

and optionally after processing the compounds of formula VI anhydrous acid with the AET hydroxyl, with a protected hydroxylamine and removing the protective group to obtain the compounds of formula I, where W denotes hydroxylamine.

 

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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>
< / BR>
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< / BR>
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< / BR>
< / BR>
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in which the substituents have the following meanings: L, M denote hydrogen, alkyl, alkyloxy, alkylthio, chlorine, cyano, methylsulphonyl, nitro or trifluoromethyl, J denotes hydrogen, alkyl, cycloalkyl, alkenyl, quinil, acyl, phenyl, optionally substituted with halogen or alkyl, benzyl, means connected in position 2 optional substituted cyclohexane-1,3-diNovo ring of formula II

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and they are usually used in agriculture salt
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