Derivatives substituted hintline and their use as inhibitors of tyrosine kinases

 

The present invention provides compounds of formula 1:

or their pharmaceutically acceptable salts, where X represents a phenyl ring substituted with halogen or dimethylaminopropoxy, Z represents-NH-, R1, R3and R4,each represents hydrogen, R2choose them different unsaturated acyl groups listed in paragraph 1, provided that when R2selected from the group consisting of:

R5represents, independently and exclusively of hydrogen, alkyl containing 1-6 carbon atoms or carboxy; X is not a phenyl ring, exclusively substituted by one or more Halogens. The compounds are inhibitors of tyrosine kinases and can be used for the treatment of cancer and certain kidney diseases such as polycystic kidney disease. The invention also relates to a method of inhibiting the biological effect of having violated the regulation of protein-tyrosine kinases in a mammal, the treatment or inhibition of growth of tumors in a mammal, the pharmaceutical composition inhibiting the receptor protein-tyrosine-kinase epidermalnog the

Description text in facsimile form (see graphic part).

Claims

1. The compound of formula 1 having the structure

where X represents phenyl, substituted Deputy represents halogen or dimethylaminopropyl;

Z represents-NH-;

R1, R3and R4each represents hydrogen;

R2selected from the group consisting of

and

where R5is independently hydrogen, alkyl containing 1-6 carbon atoms, carboxy, R7-(C(R6)2)s-, R7- ((R6)2)p-M-(C(R6)2)r-, Het-W-(C(R6)2)r-;

R7is-NR6R6or6;

M is >NR6, -O - or >N-((R6)2)

Het represents morpholinyl or piperazinil, optionally substituted on the nitrogen atom by alkyl containing 1-6 carbon atoms;

R6represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, which is linked to an atom of oxygen or nitrogen through a saturated carbon atom;

n = 0;

p= 2-4;

r = 1-4;

s = 1-6;

u = 0-4, v = 0-4, where the sum u+v is equal to 2-4, and, when M is-O - and R7is-OR6then p = 1-4,

or its pharmaceutically acceptable salt,

provided that, when

R2selected from the group consisting of

and

R5is independently and exclusively of hydrogen, alkyl containing 1-6 carbon atoms or carboxy;

X is not a phenyl ring, exclusively substituted by one or more Halogens.

2. Connection on p. 1, which is [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-dimethylamino-2-ene acid or its pharmaceutically acceptable salt.

3. Connection on p. 1, which is [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-morpholine-4-albut-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-dimethyl-aminobut is)hinzelin-6-yl]amide of 4-(4-ethylpiperazin-1-yl)but-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-(4-methylpiperazin-1-yl)but-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-[bis(2-methoxyethyl)amino]but-2-invoi acid, [4-(3-brompheniramine)-hinzelin-6-yl]amide (2-methoxyethyl)methylamino-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of isopropylethylene-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of diisopropylamino-2-invoi acid or [4-(3-brompheniramine) hinzelin-6-yl]amide of allylmethylamine-2-invoi acid or its pharmaceutically acceptable salt.

4. Connection on p. 1, which is [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-methoxybutyl-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-(2-methoxyethoxy)but-2-invoi acid or [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-methoxyethoxy-2-invoi acid, or its pharmaceutically acceptable salt.

5. Connection on p. 1, which is 3-[4-(3-brompheniramine)hinzelin-6-ylamino]-4-amoxicillinum-3-ene-1,2-dione, 3-[4-(3-brompheniramine)hinzelin-6-ylamino]-4-dimethylaminoethanol-3-ene-1,2-dione, 3-[4-(3-brompheniramine)hinzelin-6-ylamino]-4-methylimidazolium-3-ene-1,2-dione, 3-amino-4-[4-(3-brompheniramine)hinzelin-6-ylamino]cyclobuta-3-ene-1,2-dione, or 3-[4-(3-bromophenyl-hameentie under item 1, which is [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-methoxybutyl-2-ene acid or [4-(3-brompheniramine)hinzelin-6-yl]amide 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid, or its pharmaceutically acceptable salt.

7. Connection on p. 1, which is N-[4-(3-brompheniramine)hinzelin-6-yl]-2-morpholine-4-iletilerini, or [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-diethylamino-2-ene acid, or its pharmaceutically acceptable salt.

8. Connection on p. 1, which is N-[4-(3-brompheniramine)hinzelin-6-yl]-2-metilsulfonilmetane, N-[4-(3-brompheniramine)hinzelin-6-yl]-3-metilsulfonilmetane, N-[4-(3-brompheniramine)hinzelin-6-yl]-2-methyldichlorosilane, N-[4-(3-brompheniramine)hinzelin-6-yl]-2-tert-butyldiethanolamine, N-[4-(3-brompheniramine)hinzelin-6-yl]-2-isobutylpyrazine, or N-[4-(3-brompheniramine)hinzelin-6-yl]-2-isopropylpyrazine, or its pharmaceutically acceptable salt.

9. Connection on p. 1, which is a methyl ester of 2-{[4-(3-brompheniramine)hinzelin-6-ylamino]methyl}acrylic acid or methyl ester (E)-4-[4-(3-brompheniramine)-hinzelin-6-ylamino]methyl}but-2-ene acid, or its pharmaceutical 4-harbut-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of 4-hydroxyben-2-invoi acid, [4-(3-brompheniramine)hinzelin-6-yl]amide of oxiran-2-carboxylic acid, [4-(3-brompheniramine)hinzelin-6-yl]amide atenololbuy acid, or its pharmaceutically acceptable salt.

11. A method of inhibiting the biological effect of having violated the regulation of protein-tyrosine kinases in a mammal, in need thereof, which comprises introducing said mammal an effective amount of the compounds of formula 1 having the structure

where X represents phenyl, substituted Deputy represents halogen or dimethylaminopropyl;

Z represents-NH-;

R1, R3and R4each represents hydrogen;

R2selected from the group consisting of

and6)2)s-, R7- ((R6)2)p-M-(C(R6)2)r-, Het-W-(C(R6)2)r-;

R7is-NR6R6or6;

M is >NR6, -O - or >N-((R6)2)p-OR6;

W represents a bond;

J represents chlorine;

Q is alkyl containing 1-6 carbon atoms;

Het represents morpholinyl or piperazinil, optionally substituted on the nitrogen atom by alkyl containing 1-6 carbon atoms;

R6represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, which is linked to an atom of oxygen or nitrogen through a saturated carbon atom;

n = 0;

p = 2-4;

r = 1-4;

s = 1-6;

u = 0-4, v = 0-4, where the sum u+v is equal to 2-4, and, when M is-O - and R7is-OR6then p = 1-4;

or its pharmaceutically acceptable salt,

provided that when R2selected from the group consisting of

and

R5is independently and exclusively of hydrogen, alkyl containing 1-6 carbon atoms or carboxy;

X is not a phenyl ring, exclusively replaced by

one or bore the same time, which includes the introduction of the specified mammal an effective amount of the compounds of formula 1 having the structure

where X represents phenyl, substituted Deputy represents halogen or dimethylaminopropyl;

Z represents-NH-;

R1, R3and R4each represents hydrogen;

R2selected from the group consisting of

and

where R5is independently hydrogen, alkyl containing 1-6 carbon atoms, carboxy, R7-(C(R6)2)s-, R7- ((R6)2)p-M-(C(R6)2)r-, Het-W-(C(R6)2)r-;

R7is-NR6R6or6;

M is >NR6, -O - or >N-((R6)2)p-OR6;

W is folini or piperazinil, optionally substituted on the nitrogen atom by alkyl containing 1-6 carbon atoms;

R6represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, which is linked to an atom of oxygen or nitrogen through a saturated carbon atom;

n = 0;

p = 2-4;

r = 1-4;

s = 1-6;

u = 0-4, v= 0-4, where the sum u+v is equal to 2-4, and, when M is-O - and R7is-OR6then p = 1-4;

or its pharmaceutically acceptable salt,

provided that when R2selected from the group consisting of

and

R5is independently and exclusively of hydrogen, alkyl containing 1-6 carbon atoms or carboxy;

X is not a phenyl ring, exclusively substituted by one or more Halogens.

13. The method according to p. 12, where the tumor expresses EGFR.

14. The method according to p. 12, where the tumor is selected from the group consisting of tumors of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary and lung.

15. The pharmaceutical composition inhibiting the receptor protein-tyrosine kinase epidermal growth factor cells containing the compound of formula 1,which represents a halogen or dimethylaminopropyl;

Z represents-NH-;

R1, R3and R4each represents hydrogen;

R2selected from the group consisting of

and

where R5is independently hydrogen, alkyl containing 1-6 carbon atoms, carboxy, R7-(C(R6)2)s-, R7- ((R6)2)p-M-(C(R6)2)r-, Het-W-(C(R6)2)r-;

R7is-NR6R6or6;

M is >NR6, -O - or >N-((R6)2)p-OR6;

W represents a bond;

J represents chlorine;

Q is alkyl containing 1-6 carbon atoms;

Het represents morpholinyl or piperazinil, optionally substituted on the nitrogen atom by alkyl containing 1-6 carbon atoms;

R6represents hydrogen, alkyl containing the C saturated carbon atom;

n = 0;

p = 2-4;

r = 1-4;

s = 1-6;

u = 0-4, v = 0-4, where the sum u+v is equal to 2-4, and, when M is-O - and R7is-OR6then p = 1-4;

or its pharmaceutically acceptable salt,

provided that when R2selected from the group consisting of

and

R5is independently and exclusively of hydrogen, alkyl containing 1-6 carbon atoms or carboxy;

X is not a phenyl ring, exclusively substituted by one or more Halogens,

and pharmaceutically acceptable carrier.

16. The compound according to any one of paragraphs.1-10 for use in inhibition of the biological actions have violated the regulation of protein-tyrosine kinases in a mammal, in need thereof.

17. The method of obtaining the compounds of formula 1 having the structure

where X represents phenyl, substituted Deputy represents halogen or dimethylaminopropyl;

Z represents-NH-;

R1, R3and R4each represents hydrogen;

R2selected from the group consisting of

where R5is independently hydrogen, alkyl containing 1-6 carbon atoms, carboxy, R7-(C(R6)2)s-, R7- ((R6)2)p-M-(C(R6)2)r-, Het-W-(C(R6)2)r-;

R7is-NR6R6or6;

M is >NR6, -O - or >N-((R6)2)p-OR6;

W represents a bond;

J represents chlorine;

Q is alkyl containing 1-6 carbon atoms;

Het represents morpholinyl or piperazinil, optionally substituted on the nitrogen atom by alkyl containing 1-6 carbon atoms;

R6represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, which is linked to an atom of oxygen or nitrogen through a saturated carbon atom;

n = 0;

p = 2-4;

r = 1-4;

s = 1-6;

u = 0-4, v = 0-4, where the sum u+v is equal to 2-4, and, when M is-O - and R7is-OR6then p = 1-4;

or its pharmaceutically acceptable salts, provided that when R2selected from the group consisting of

and

R5is independently and exclusively of hydrogen, alkyl containing 1 likemy Halogens,

which involves the reaction of compounds of the formula

where R1, R3, R4and X are such as defined above,

c compound of the formula:

where R2is

where R5, J, s, r, u, v such as defined above,

in an inert solvent and in the presence of an organic base, and, optionally, the formation of pharmaceutically acceptable salts are obtained the compounds of formula 1.

18. The method according to p. 17 where the compound of the formula

where R1, R3, R4and X are such as defined in paragraph 17,

produced by interaction of the compounds of formula

with regenerating agent.

19. The method according to p. 18,where the compound of the formula

where R1, R3, R4and X are such as defined in paragraph 18,

produced by interaction of the corresponding compounds of the formula

with >/p>with an aniline of the formula

X-NH2,

where X is as defined in paragraph 18.

20. The method according to any of paragraphs.17-19, which includes protected primary or secondary amino or hydroxyl group contained in the group R2’ protective group prior to the sequencing reaction, and then removing the protective group.

 

Same patents:

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where And denotes the radical

in which R1, R2and R3mean hydrogen, halogen, HE, alkyl or alkoxy and the other,

or radical

in which R8means hydrogen, x is the radical -(CH2)m-Q, m is an integer from 0 to 6, Y represents alkyl, alkenylphenol or alkenylphenol chain or other, R10is hydrogen or alkyl, or their salts

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to new derivatives chromane General formula I,

,

where R is hydrogen, halide or NR1R1group; R1means hydrogen or alkyl group with 1-10 carbon atoms; R2means R1or NR1R1; R3means hydrogen or CO2R1; Ar1means a phenyl group or a 5-or 6-membered heterocyclic ring containing as the heteroatom atom N; m = 1, 2, or 3; n = 1, when this symbol is the group -(CO)nand n is 0, 1 or 2, when this symbol is the group (X); X is alkyl group with 1-4 carbon atoms; R4means hydroxyl or CNS group with 1-10 carbon atoms; and their pharmaceutically acceptable salts, having agonistic activity against beta-3-adrenergic receptor

The invention relates to 4-oxocyclohexyl the urea compounds of General formula (I), where X, Y, R, R1, R2, R3, R4, R5And L, such as defined in the claims

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new optically active proizvodnim of benzopyran formula

< / BR>
where R and R are independently selected from the group consisting of hydroxyl and a moiety that can be converted in vivo in hydroxyl, such as acyloxy, -OR4, -OC(O)R7or-OC(O)OR4(where R4represents alkyl, alkenyl, quinil or aryl; and R7represents amino, alkylamino, aminoalkyl and alkylsulfonyl); and R3represents-CH2- or-CH2CH2-; or its pharmaceutically acceptable salt, where the specified compound or salt is optically active because they contain more than 50% (by weight relative to all stereoisomers) 2S stereoisomers

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to the derivatives of hintline formula I, where X represents phenyl, which is optionally substituted with halogen; R, R1and R2represent hydrogen, Y represents a radical selected from the group comprising groups of formula (a-f); R3independently represents hydrogen, alkyl with 1-6 carbon atoms, carboxy, carbalkoxy with 1-6 carbon atoms or phenyl; n=2-4; or their pharmaceutically acceptable salts, provided that each of R3the group Y may be the same or different

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

The invention relates to the derivatives of hintline formula (I), where n = 2 and each R2independently halogen; R3- (1-4C)alkoxy; R1di-[(1-4C)alkyl]amino(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)-alkoxy-(2-4C)alkyl] amino-(2-4C)alkoxy, and any R1containing methylene group, which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy, or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of inhibitory activity of compounds to inhibit the receptor tyrosinekinase in the treatment of proliferative diseases, such as cancer

The invention relates to new derivatives of 2-amino-7-(CH2R2R3)-3H,5H-pyrrolo[3,2-d] pyrimidines having the properties of a selective inhibitor of T-lymphocytes, methods for their preparation and to a method of selective inhibition of proliferation of T-lymphocytes of a mammal and does not impact B-lymphocytes

The invention relates to a LHRH antagonists - compounds of General formula Iin which a represents acetyl or 3-(4-forfinal)propionyloxy group Xxx1mean D-Nal(1) or D-Nal(2), Xxx2-Xxx3mean D-Cpa-D-Pal(3) or a simple link, Xxx4means Ser, Xxx5means N-Me-Tyr, Xxx6mean D-Hci or a residue of D-amino acids of General formula (II)

where n means the number 3 or 4, a R1means a group of the General formula IIIwhere R denotes an integer from 1 to 4, R2means hydrogen or alkyl group, and R3means unsubstituted or substituted aryl group or heteroaryl group, or R1mean 3-amino-1,2,4-triazole-5-carbonyl group,Xxx7means Leu or Nle, Xxx8means Arg or Lys(iPr), Xxx9means Pro and Xxx10means A1A or Sar, and their salts with pharmaceutically acceptable acids: process for the preparation of these compounds, pharmaceutical compositions having the properties of an LHRH antagonist, comprising as an active narushenie compounds according to the invention has a high solubility in water
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