Aromatic heterocyclic compounds with activity against hiv integrase

 

The invention relates to pharmaceutical compositions for inhibiting integrase, which contains as active substance a compound of the formula (I)

where X denotes a hydroxy-group; Y represents a group-COORAin which RArepresents hydrogen or ester residue, or denotes a group-CONRInRCin which RInand RCeach independently of one another denotes hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl, and1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or And1denote optionally substituted indol-3-yl, or contains its tautomer, prodrug, pharmaceutically acceptable salt or hydrate, compounds of formulas I, II

where X, Y described above, And1- optional replaced heteroaryl; Z1and Z2indicate the relationship; Z2means a connection, (ness.)alkylene, -CH(OH)-, -S-, -SO2-, -O - or-CO; Z4means a connection, (ness.)alkylene, (ness.)albaniles or-CO-; R1denotes optionally substituted aryl, the optional is 2 denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (ness.)allyloxycarbonyl, optionally substituted aryl, optionally substituted by alloctype, carboxy or halogen; R=0 or 1, with the exception of compounds in which (1) Y and/or And1denotes optionally substituted indol-3-yl and (2) X denotes a hydroxy-group, Y represents 2-thienyl, And1denotes a 1H-1,2,4-triazole-3-yl, Z1and Z3each denotes a bond, Z2denotes-NH-, R1denotes phenyl or para-tolyl and p=0; (3) X denotes a hydroxy-group, Y represents 4-methoxyphenyl, or 4-chlorophenyl, And1means thiazol-5-yl, Z1, Z2, Z3and Z4each represents a bond, R1denotes phenyl, 4-methoxyphenyl or 4-chlorophenyl, R2denotes methyl and p=1; (4) X denotes hydroxyl, Y represents phenyl, 4-were, 4-bromophenyl or 4-chlorophenyl, And1signifies imidazol-2-yl, Z1and Z3each denotes a bond, Z2denotes methylene, R1denotes phenyl, Z4denotes a bond, R2denotes 4-dimethylaminophenyl or 4-methoxyphenyl, and p=1; (5) X denotes hydroxyl, Y represents phenyl, 4-were-or 4-methoxyphenacyl phenyl and p=0; (6) X denotes hydroxyl, Y represents-COORAwhere RAdenotes hydrogen or ethyl, And1signifies 3-indolyl, imidazo[1,2-a]pyridine-3-yl or imidazo[2,1-b] thiazole-5-yl, Z1, Z2and Z3each represents a bond, R1denotes optionally substituted phenyl, and tautomer, prodrug, pharmaceutically acceptable salt or hydrate; various farmkompanijam, comprising as active ingredient the compound II, the drug compound having anti-HIV activity; the method of obtaining compounds of formula III

as well as the intermediate products of the formula

where Z2denotes a bond, -CO-, -O-, -CH2- or -(CH2)2and R1denotes phenyl, substituted with fluorine, and

where And denotes C-W, where W denotes hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N, Q denotes trail and L denotes ethoxypropan. 17 C. and 11 C.p. f-crystals, 3 tables.

Description text in facsimile form (see graphic part).

Claims

1. Pharmaceutical composition https://img.russianpatents.com/img_data/75/753706.gif">

where X denotes a hydroxy-group;

Y denotes a group-COORAndin which RAndrepresents hydrogen or ester residue, or denotes a group-CONRInRWithin which RInand RWitheach independently of one another denotes hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl;

And1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or And1denote optionally substituted indol-3-yl,

or contains its tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

2. The compound of formula (I)

where X denotes a hydroxy-group;

Y denotes a group-CONRInRWithwhere RInand RWitheach independently from each other represents hydrogen or amide residue, or denotes optionally substituted heteroaryl;

And1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or And1denote optionally substituted indol-3-yl,

and tautomer, prodrug, pharmaceutically acceptable salt or hydrate of the compound of formula (I), except that the RUPE, Y and a1denote 2-furyl, (3) X denotes a hydroxy-group, one of Y and a1denotes 2-thienyl, and the other represents a 5-ethoxycarbonylmethyl-1H-1,2,4-triazole-3-yl, 5-Pratolino-1H-1,2,4-triazole-3-yl, 5-phenylamino-1H-1,2,4-triazole-3-yl, 5-hydrazino-1H-1,2,4-triazole-3-yl, 5-(3,6-dioxotetrahydrofuran-4-ylsulphonyl)-1H-1,2,4-triazole-3-yl, 5-[3-(3,4-dimetilfenil)-6-oxo-1-phenyl-1,4,5,6-tetrahydro-pyridazin-4-ylsulphonyl]-1H-1,2,4-triazole-3-yl, 5-(1,2-dicarboxyethyl)-1H-1,2,4-triazole-3-yl, 5-[1-carboxy-3-(3,4-dimetilfenil)-3-oxopropylidene]-1H-1,2,4-triazole-3-yl or 5-(2-cyan-2-etoxycarbonyl-1-phenylethylamines)-1H-1,2,4-triazole-3-yl, (4) X denotes a hydroxy-group, and Y And1denote [3-(2-methoxycarbonylethyl)-4-methoxycarbonylmethyl-5-methyl]-1H-pyrrol-2-yl, (5) X denotes a hydroxy-group, and Y And1denote 3-methylpyrazole-1-yl, (6) X denotes a hydroxy-group, and Y And1denote 4-chloropyridin-3-yl, (7) X denotes a hydroxy-group, one of Y and a1represents 5-bromo-2-furyl, and the other denotes a 2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl or 4,5-dibromo-2-thienyl, and (8) X denotes a hydroxy-group, one of Y and a1denotes 2-selenol or 5-nitro-2-selenol, and the other represents 2-furyl or 2-selenol, provided that also ischet 6-[3-(pyridin-2-yl)-1,3-disopropyl]pyridine-2-yl; (10) X denotes hydroxyl, and Y And1each independently from each other pyridin-2-yl or 6-methylpyridin-2-yl; and (11) X denotes hydroxyl, one of Y and a1denotes 2-thienyl, and the other is pyridyl.

3. The compound of formula (II)

where X denotes a hydroxy-group;

Y denotes a group-COORAndin which RAndrepresents hydrogen or ester residue, or denotes a group-CONRInRWithin which RInand RWitheach independently from each other represents hydrogen or amide residue, or denotes optionally substituted aryl or optionally substituted heteroaryl,

And1means optionally substituted heteroaryl,

Z1and Z3indicate the connection;

Z2means a connection, (ness.)alkylene, -CH(OH)-, -S-, -SO2-, -O - or-CO;

Z4means a connection, (ness.)alkylene, (ness.)albaniles or-CO-;

R1denotes optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycle;

R2denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (neither is halogen;

p denotes 0 or 1,

with the exception of compounds in which (1) Y and/or And1denotes optionally substituted indol-3-yl and

(2) X denotes a hydroxy-group, Y represents 2-thienyl, And1denotes a 1H-1,2,4-triazole-3-yl, Z1and Z3each denotes a bond, Z2denotes-NH, R1denotes phenyl or paratool and R represents 0; (3) X denotes a hydroxy-group, Y represents 4-methoxyphenyl, or 4-chlorophenyl, And1means thiazol-5-yl, Z1, Z2, Z3and Z4each represents a bond, R1denotes phenyl, 4-methoxyphenyl or 4-chlorophenyl, R2denotes methyl and p=1; (4) X denotes hydroxyl, Y represents phenyl, 4-were, 4-bromophenyl or 4-chlorophenyl, And1signifies imidazol-2-yl, Z1and Z3each denotes a bond, Z2denotes methylene, R1denotes phenyl, Z4denotes a bond, R2denotes 4-dimethylaminophenyl or 4-methoxyphenyl, and p=1; (5) X denotes hydroxyl, Y represents phenyl, 4-were-or 4-methoxyphenyl, And1indicates 1,2,3-triazole-4-yl, Z1, Z2and Z3each represents a bond, R1denotes phenyl and p=0; (6) X denotes hydroxyl, Y represents-COORAwhere RAdenotes hydrogen >and Z3each represents a bond, R1denotes optionally substituted phenyl,

and tautomer, prodrug, pharmaceutically acceptable salt or hydrate of the compounds of the formula (II).

4. Connection on p. 2 or 3, wherein A1denotes optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted benzofuran, optionally substituted benzothieno, optionally substituted benzimidazolyl, optionally substituted indolizinyl, optionally substituted chinoline, optionally substituted isoxazolyl, optionally substituted pyridyl, optionally substituted thiazolyl or optionally substituted oxazolyl, his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

5. Connection on p. 4, in which And1denotes optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted pyridyl, optionally substituted thiazolyl the rat.

6. Connection on p. 5, in which And1denotes optionally substituted furyl, optionally substituted pyrrolyl or optionally substituted oxazolyl, his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

7. The compound according to any one of paragraphs.3-6, in which Y denotes the group-COORAndin which RAndrepresents hydrogen or ester residue, or the group,- CONRInRWithin which RInand RWitheach independently from each other represents hydrogen or amide residue, or denotes heteroaryl, optionally substituted Deputy selected from the group comprising halogen, (ness.)alkyl, (ness.)haloalkyl, (ness.)alkyloxy-(ness.)alkyl, carboxypropyl, (ness.)allyloxycarbonyl, optionally substituted aryl(ness.)alkyl and optionally substituted arylsulfonyl, his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

8. Connection on p. 7, in which Y represents-COOH, tetrazolyl, triazolyl, optionally substituted with halogen, (ness.)the alkyl, (ness.)haloalkyl or (ness.)alkyloxy(ness.)the alkyl, pyridyl, optionally substituted (ness.)the alkyl, carboxypropyl or (ness.)allyloxycarbonyl, pyrrolyl, optional oxadiazolyl, optionally substituted by optionally substituted aryl (ness.)the alkyl, isooxazolyl, optionally substituted (ness.)the alkyl, thiazolyl, optionally substituted (ness.)the alkyl, thienyl, furyl, thiadiazolyl, oxazolyl, optionally substituted (ness.)the alkyl, or imidazolyl, optionally substituted (ness.)the alkyl, his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

9. Connection on p. 8, in which Y denotes tetrazolyl, triazolyl, optionally substituted with halogen, (ness.)the alkyl, (ness.)haloalkyl or (ness.)alkyloxy(ness.)by alkyl; pyridyl, optionally substituted (ness.)the alkyl, carboxypropyl or (ness.)allyloxycarbonyl, or pyrimidinyl; his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

10. The compound according to any one of paragraphs.3-9, in which Z2denotes a bond, -CO-, -O-, -S-, -SO2-, -CH2- or -(CH2)2- his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

11. The compound according to any one of paragraphs.3-10, in which R1denotes optionally substituted phenyl, his tautomer, prodrug, pharmaceutically acceptable salt or hydrate.

12. Connection on p. 11, in which R1denotes paraterphenyl, his taut the traveler antiviral activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

14. Pharmaceutical composition having antiviral activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

15. Pharmaceutical composition having anti-HIV activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

16. Pharmaceutical composition having anti-HTLV-1 activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

17. Pharmaceutical composition having anti-VICK-activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

18. Pharmaceutical composition having anti-SIV activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

19. Pharmaceutical composition having the integrase inhibiting activity and containing as active ingredient a compound according to any one of paragraphs.2-12.

20. Medicinal mixture, which has anti-HIV activity and containing in addition to the integrase inhibitor under item 1 or 19 one or two inhibitor selected from the group comprising an inhibitor absorption inhibitor TAT, REV inhibitor, nucleoside reverse transcriptase inhibitor and a protease inhibitor.

21. Farmaceutici, including absorption inhibitor, an inhibitor of the TAT, REV inhibitor, nucleoside reverse transcriptase inhibitor and a protease inhibitor.

22. A method of treating AIDS, introducing a compound according to any one of paragraphs.1-12.

23. The method of obtaining the compounds of formula (V)

where a1denotes optionally substituted heteroaryl;

And indicates C-W, where W represents hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N, with the exception of compounds in which And1denotes optionally substituted indol-3-yl,

including interaction of the compounds of formula (III)

where a1has the above values,

with the compound of the formula (IV)

where a has the above meanings;

Q denotes a protective group;

L denotes a leaving group,

in the presence of a base and removing the protective group q

24. The method according to p. 23, where a group of the formula

denotes a group of the formula

where a1denotes optionally substituted heteroaryl;

Z1and Z3each communication means;

Z2indicates keylen, or-CO-;

R1denotes optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycle;

R2denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (ness.)allyloxycarbonyl, optionally substituted aryl, optionally substituted by alloctype, carboxypropyl or halogen;

p denotes 0 or 1, provided that the group in which And1denotes optionally substituted indol-3-yl is excluded.

25. The method according to p. 24, where a1denotes optionally substituted furyl, Z1and Z3each denotes a bond, Z2denotes a bond, -CO-, -O-, -S-, -SO2-, -CH2- or -(CH2)2and R1denotes optionally substituted phenyl.

26. The connection formulas

where Z2denotes a bond, -CO-, -O-, -CH2- or -(CH2)2-;

R1denotes phenyl, substituted by fluorine.

27. The compound of formula (VI)

in which Z2denotes-CH2- or -(CH2)2-;

R1denotes phenyl'll neobsahuje C-W, where W denotes hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N;

Q denotes trityl;

L denotes ethoxypropan.

Priorities on items and attributes:

25.12.1998 on PP.1-27;

01.09.1999 - clarification of signs on PP.1-27.

 

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