Substituted dihydropyrazolones for treating cardiovascular and haematologic diseases

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

in which
R1means a heteroaryl group of the formula
or
in which
* means the connection with dihydropyrazolo cycle
And means at each separate occurrence of C-R4or N, with a maximum of two members of the cycle And at the same time mean N, and
R4in each case, independently of one another denote hydrogen or substituents selected from the group cyano, (C1-the 6)-alkyl,
C(=O)NH2where (C1-C6)-alkyl in its turn can be substituted up to three halogen atoms;
E means O or S;
R2means a heteroaryl group of the formula
or
in which # means the connection with dihydropyrazolo cycle
G, respectively, mean C-R6or N, with not more than one of the two members of the cycle G means N
R6in each case, independently of one another denote hydrogen or a Deputy selected from halogen, cyano, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, 4-10-membered geterotsiklicheskie containing 1 or 2 heteroatoms selected from N, O and S, C(=O)-OR10, -SO2R25, -OR28, -SR28and NR30R31where
(i) (C1-C6)-alkyl, in turn, can have from one to three substituents, equal or different, selected from the group comprising fluorine, chlorine, bromine, -NR18-C(=O)-OR19, -OR28and-NR30R31,
(ii) 4-10-membered heteroseksualci, in turn, may respectively have one or two identical or different substituent selected from the group (C1-C6)-alkyl, -C(=O)-R9, -C(=O)-OR10, CONHR11R22, hydroxy, (C1-C4)alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4 )-alkylamino and pyrrolidinyl,
while (C1-C6)-alkyl in its turn can be substituted by the Deputy selected from cyano, hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino and di-(C1-C4)-alkylamino;
(iii) R9, R10, R11, R19, R25and R30independently of one another for each individual occurrence denote a residue selected from the group comprising hydrogen and (C1-C6)-alkyl,
R28in each individual occurrence denotes a residue selected from hydrogen, (C1-C6)-alkyl and azetidine, and (C1-C6)-alkyl in its turn can be substituted by amino, mono-(C1-C4)-alkylamino and di-(C1-C4)-alkylamino and azetidinol, in turn, can be substituted (C1-C4-alkoxycarbonyl;
(iv) R12, R18and R31independently of one another for each individual occurrence denote a residue selected from hydrogen and (C1-C6)-alkyl;
and
J means S and
R3means hydrogen,
or its pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, in which R1means a heteroaryl group of the formula
or
where
* means the connection with dihydropyrazolo cycle
And oznachaet is at each separate occurrence of C-R 4or N, with a maximum of two members And in the loop at the same time mean N, where
R4in each case, independently of one another, mean hydrogen or a Deputy, selected from the group consisting of cyano, (C1-C6)-alkyl,
it called (C1-C6)-alkyl residue, in turn, can have up to three identical or different substituents selected from the group comprising fluorine, chlorine, bromine, and
E means O or S,
where R2means a heteroaryl group of the formula
or
where # means the connection with dihydropyrazolo cycle, G respectively mean C-R6or N, with not more than one of the two members of the cycle G means N, in which
R6in each case, independently of one another, mean hydrogen or a Deputy, selected from the group comprising fluorine, chlorine, bromine, cyano, (C1-C6)-alkyl, (C3-C6-cycloalkyl, 4-6-membered heteroseksualci containing 1 or 2 heteroatoms selected from N, O and S, -C(=O)-OR10, -OR28and-NR30R31where
(i) (C1-C6)-alkyl, in turn, can have from one to three substituents, same or different, selected from
group comprising fluorine, chlorine, bromine, -NR18-C(=O)-OR19, -OR28and-NR30R31,
(ii) 4-6-lennyreleasegoals, in turn may respectively have one or two identical or different substituent selected from the group comprising (C1-C4)-alkyl, hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino,
(iii) R10, R11, R19and R30independently of one another for each individual occurrence denote a residue selected from the group comprising hydrogen and (C1-C6)-alkyl, and
R28when each individual occurrence denote a residue selected from hydrogen, (C1-C6)-alkyl and azetidine, and (C1-C6)-alkyl in its turn can be substituted by amino, mono-(C1-C4)-alkylamino and di-(C1-C4)-alkylamino and azetidinol, in turn, can be substituted (C1-C4-alkoxycarbonyl;
(iv) R12, R18and R31independently of one another for each individual occurrence denote a residue selected from the group comprising hydrogen and (C1-C6)-alkyl,
J means S and
R3means hydrogen,
as well as its pharmaceutically acceptable salt.

3. The compound of formula (I) according to claim 1, in which R1means a heteroaryl group of the formula
or
where
* means the connection with dihydropyrazolo CEC is om, And means at each separate occurrence of C-R4or N, with a maximum of one of the members of the cycle And is equal to N, where
R4in each case, independently of one another, mean hydrogen or a Deputy, selected from the group consisting of cyano, (C1-C6)-alkyl,
it called (C1-C6)-alkyl residue, in turn, can have up to three substituents, such as fluorine, and
E means O or S,
R2means a heteroaryl group of the formula
or
where
# means the connection with dihydropyrazolo cycle
G, respectively, mean C-R6or N, with not more than one of the two members of the cycle G means N, where
R6in each case, independently of one another, mean hydrogen or a Deputy, selected from the group comprising fluorine, chlorine, bromine, cyano, (C1-C6)-alkyl, (C3-C6-cycloalkyl, 4-6-membered heteroseksualci containing 1 or 2 heteroatoms selected from N, O and S, -C(=O)-OR10, -OR28and-NR30R31where
(i) (C1-C6)-alkyl, in turn, can have from one to three substituents, same or different, selected from the group comprising fluorine, -NR18-C(=O)-OR19, -OR28and-NR30R31,
(ii) 4-6-membered heteroseksualci, in turn, can which respectively have one or two identical or different substituent, selected from the group comprising (C1-C6)-alkyl, hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, while (C1-C6)-alkyl in its turn can be substituted by the Deputy selected from hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino,
(iii) R10, R11, R19and R30independently of one another for each individual occurrence denote a residue selected from the group comprising hydrogen and (C1-C6)-alkyl,
R28when each individual occurrence denote a residue selected from hydrogen, (C1-C6)-alkyl and azetidine, and (C1-C6)-alkyl in its turn can be substituted by amino, mono-(C1-C4)-alkylamino and di-(C1-C4)-alkylamino and azetidinol, in turn, can be substituted (C1-C4-alkoxycarbonyl;
(iv) R12, R18and R31independently of one another for each individual occurrence denote a residue selected from the group comprising hydrogen and (C1-C6)-alkyl,
J means S and
R3means hydrogen,
as well as its pharmaceutically acceptable salt.

4. The compound of formula (I) according to any one of claims 1 to 3, in which
R1means a heteroaryl group form the s
or
where
* means the connection with dihydropyrazolo cycle
and R4means hydrogen, cyano, (C1-C4)-alkyl and trifluoromethyl,
R2means a heteroaryl group of the formula
or
where
# means the connection with dihydropyrazolo cycle, and
R6, R6Aand R6Bare the same or different and independently of one another denote hydrogen or Deputy, selected from the group comprising fluorine, chlorine, bromine, cyano, (C1-C6)-alkyl, 4-6-membered heteroseksualci containing 1 or 2 heteroatoms selected from N, O and S, and
(C1-C6)-alkyl, in turn, may have a Deputy, such as hydroxy, (C1-C4)-alkoxy or amino,
and
4-6-membered heteroseksualci, in turn, may respectively have one or two substituent, identical or different, such as (C1-C4)-alkyl, hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, and
R3means hydrogen,
as well as its pharmaceutically acceptable salt.

5. The compound of formula (I) according to any one of claims 1 to 3, in which
R1means a heteroaryl group of the formula
where
* means the connection with dihydropyrazolo cycle
and
R4means hydrogen, cyano or (C1-C4)-alkyl,
R2means a heteroaryl group of the formula
or
where
# means the connection with dihydropyrazolo cycle
and
R6, R6Aand R6Bare the same or different and independently of one another denote hydrogen or Deputy, selected from the group comprising fluorine, chlorine, bromine, cyano, (C1-C6)-alkyl, 4-6-membered heteroseksualci containing 1 or 2 heteroatoms selected from N, O and S, and
(C1-C6)-alkyl, in turn, may have a Deputy, such as hydroxy, (C1-C4)-alkoxy or amino,
and
4-6-membered heteroseksualci, in turn, may respectively have one or two substituent, identical or different, such as (C1-C4)-alkyl, hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, and
R3means hydrogen,
as well as its pharmaceutically acceptable salt.

6. 2-(6-Morpholine-4-Yeremey-4-yl)-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one according to claim 1, having the following formula:

and its pharmaceutically acceptable salts.

7. Hydrochloride of 2-(morpholin-4-Yeremey-4-yl)-4-(1H-1,2,3-triazole-1-yl)-1,2-dihydro-3H-pyrazole-3-one according to claim 1, having the following formula:

8. 2-[5-(Hydroxymethyl)pyridine-2-yl]-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]-1,2-dihydro-3H-pyrazole-3-one according to claim 1, having the following formula:

and its pharmaceutically acceptable salts.

9. Hydrochloride of 2-[5-(hydroxymethyl)pyridine-2-yl]-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]-1,2-dihydro-3H-pyrazole-3-one according to claim 1, having the following formula:

10. The method of obtaining compounds of formula (I)as defined in claims 1 to 5, in which R3means hydrogen, characterized in that the first connection of the formula (V)

in which R1is specified in claims 1 to 5 values and
Z1means methyl or ethyl,
is condensed with the compound of the formula (VI)

in which
Z2means methyl or ethyl,
with the formation of the compounds of formula (VII)

in which Z1and R1have the above values,
and then in the presence of acid interacts with the compound of the formula (III)

in which R2is specified in claims 1 to 5 value,
with the formation of compounds of the formula (IV-A)

in which Z1, R1and R2have the above values, which are already under these conditions, the Prov is possible reactions or in a subsequent reaction stage under the influence of reason cyclists with the formation of compounds of formula (I), in which R3means hydrogen.



 

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SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

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15 cl, 227 ex

FIELD: chemistry.

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22 cl, 90 ex, 4 tbl

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24 cl, 1195 ex, 215 tbl

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11 cl, 279 ex, 1 tbl, 10 dwg

FIELD: chemistry.

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16 cl, 479 ex

FIELD: chemistry.

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25 cl, 3 dwg, 4 ex

Indole derivative // 2454415

FIELD: medicine, pharmaceutics.

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16 cl, 536 ex, 1 tbl, 9 dwg

FIELD: medicine, pharmaceutics.

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12 cl, 1 ex

FIELD: chemistry.

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14 cl, 20 dwg, 284 ex

FIELD: chemistry.

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7 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

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7 cl, 3 tbl, 106 ex

FIELD: medicine.

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67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

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20 cl, 13 ex, 1 dwg

FIELD: chemistry.

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9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

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12 cl, 95 tbl, 55 ex

FIELD: chemistry.

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13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: medicine, pharmaceutics.

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13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel cyanoisoquinoline derivatives of formula I , where R is selected from a group comprising hydrogen and C1-C10 alkyl, R1, R2, R3 and R4 are independently selected from a group comprising hydrogen, halogen, hydroxy, C1-C10 alkyl, substituted with 1-3 halogen atoms or C6-C14 acryl, C6-C14 aryl, -OR7, -SR7 and -SO2R7, where R7 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14 aryl, C3-C10 cycloalkyl, C6-C14 aryl and C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are optionally substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino and C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, and R5 and R6 are independently selected from a group comprising hydrogen and C1-C3 alkyl, or pharmaceutically acceptable salts thereof. The invention also relates to novel cyanoquinoline derivatives of formula II , where R31, R32, R33 and R34 are independently selected from a group comprising hydrogen, hydroxy, halogen, C1-C10 alkyl substituted with 1-3 halogen atoms or with C6-C14 aryl, C6-C14 aryl, -OR37, -SR37 and -SO2R37, where R37 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14aryl, C3-C10 aryl, C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, R35 denotes hydrogen or methyl, or pharmaceutically acceptable salts thereof. The invention also relates to specific cyanoisoquinoline compounds, a pharmaceutical composition based on the compound of formula I, a hypoxia-inducible factor (HIF) hydroxylase inhibiting method, a method of treating, preventing or slowing down development of a condition associated with hypoxia-inducible factor (HIF), a condition associated with erythropoietin (EPO), anaemia, based on use of the compound of formula I.

EFFECT: obtaining novel cyanoisoquinoline compounds having useful biological properties.

42 cl, 1 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I): wherein n means 1 or 2, X means an oxygen atom, a sulphur atom or NH, R1 means a side group of natural α-amino acid or its homologues or isomers specified in hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methyl-propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxy-ethyl, carboxymethyl, 2-carboxyethyl, carbamoyl-methyl, 2-carbamoyl ethyl a, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl, R2 means hydrogen or methyl, R3 means hydrogen, or R1 and R3 are coupled together by the group (CH2)3- or (CH2)4- and together with nitrogen and carbon atoms whereto attached form a five- or six-member ring, as well to their salts, solvates and salt solvates.

EFFECT: preparing compounds for treating and/or preventing the diseases, first of all thromboembolic diseases.

2 cl, 2 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel dihydroindolone derivatives of formula I or its pharmaceutically acceptable salts: Formula I, where values of R1-R9,R16,R17,n1,n2,n3, m, are given in 1 of the formula. Described are methods of obtaining compounds.

EFFECT: compounds demonstrate anti-tumour activity, which makes it possible to use them in pharmaceutical compositions for treatment and/or prevention of diseases, associated with protein tyrosine kinases in organism, in particular for treatment and/or prevention of tumours and diseases, associated with proliferation of fibroblasts.

13 cl, 1 dwg, 5 tbl, 37 ex

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