Derivatives of new tetrazole-containing amide, a mixture of their isomers, individual isomers or a pharmaceutically acceptable salt

 

(57) Abstract:

Derivatives of new tetrazole-containing amide of General formula I

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where R1- phenyl, possibly substituted C1-4the alkyl, C1-3alkoxyl, phenyl or fluorine; a group of the formula

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where R5- C1-3alkyl; a group of the formula:

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where R6- C1-4alkyl; R7- 2-, 3 - or 4-pyridyl; groups of the formula

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a hydrocarbon with 1 to 18 C-atoms, which is saturated or unsaturated, C3-8cycloalkyl, 2-, 3 - or 4-pyridyl, possibly substituted C1-4the alkyl, 2-, 4 - or 5-pyrimidinyl, and their N-oxides; R2and R3is independently H, Hal, C1-12alkyl, C3-8cycloalkyl, phenyl, phenylalkyl, possibly substituted at the phenyl, C2-6alkenyl, 1 - or 2-naphthyl; or form together with the C atom of the C1-4alkylidene or C3-7spiralcell; R4- C1-20hydrocarbon chain or C1-20allylthiourea, n = 0, 1, or 2, are highly active inhibitors transferase acylation of cholesterol; low toxicity. 30 C.p. f-crystals, 8 PL.

1. Derivatives of new tetrazole-containing amide of General formula I

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where R1is phenyl, unsubstituted or substituted by 1 to 3 residues from the group comprising an unbranched or branched alkyl with 1 to 4 ATA formula

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where R5is unbranched or branched alkyl with 1 to 3 carbon atoms,

a group of General formula

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where R6is unbranched or branched alkyl with 1 to 4 carbon atoms, and R7- 2-, 3 - or 4-pyridyl,

group of the formula

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unbranched or branched hydrocarbon with 1 to 18 carbon atoms, which is saturated or unsaturated and has one double bond or two nonadjacent double bonds, cycloalkyl with 3 to 8 carbon atoms, 2-, 3 - or 4-pyridyl, unsubstituted or substituted by alkyl with 1 to 4 carbon atoms, 2-, 4 - or 5-pyrimidinyl and their N-oxides;

R2and R3the same or different, is hydrogen, halogen, an unbranched or branched alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, phenyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, unsubstituted or substituted at the phenyl 1 - 3 residues from the group comprising an unbranched or branched alkyl with 1 to 4 carbon atoms, unbranched or branched alkoxy with 1 to 4 carbon atoms, fluorine and dialkylamino with 1 to 4 carbon atoms, unbranched or branched alkenyl with 2 to 6 carbon atoms, 1 - or 2-naphthyl, or R2and R3together with the carbon atom to which they is hydrogen, fluorine or alkyl with 1 to 12 carbon atoms, R3may additionally mean heteroaryl from among 5 - or 6-membered monocyclic or the condensation of a bicyclic heterocyclic group containing 1 to 4 nitrogen atom;

R4is unbranched or branched Neisseria hydrocarbon chain with 1 to 20 carbon atoms or saturation of allylthiourea from 1 to 20 carbon atoms;

n = 0, 1, or 2,

the mixture of their isomers, individual isomers or a pharmaceutically acceptable salt.

2. Connection on p. 1, where R4is in position 2 tetrazole ring and the side chain is linked to a carbon atom tetrazole rings.

3. Connection on p. 2, where n = 0.

4. Connection on p. 3, where R2or R3- hydrogen.

5. Connection on p. 4, where R4- saturated hydrocarbon chain of from 8 to 18 carbon atoms.

6. Connection on p. 5, where R1is unsubstituted or substituted specified in paragraph 1 remains phenyl.

7. Connection on p. 6, representing N-[2,6-bis(1-methylethyl)phenyl] -2-dodecyl-2H-tetrazol-5-ndimethylacetamide, 2-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, N-(2,4-differenl)-2-dodecyl-2H-tetrazol-5-ndimethylacetamide, 2-tetradecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetraz sweetlenny or branched alkyl with 1 to 3 carbon atoms.

9. Connection on p. 8, representing N-(4,6-dimethoxy-5-pyrimidinyl)-2-dodecyl-2H-tetrazol-5-ndimethylacetamide or N-(4,6-dimethoxy-5-pyrimidyl)-2-dodecyl-1H-tetrazol-5-ndimethylacetamide.

10. Connection on p. 5, where R1- 2-, 3 - and 4-pyridyl, unsubstituted or substituted by alkyl with 1 to 4 carbon atoms, 2-, 4 - and 5-pyrimidinyl and their N-oxides.

11. Connection on p. 10, which represents a 2-dodecyl-N-(3-methyl-2-pyridinyl)-2H-tetrazol-5-ndimethylacetamide.

12. Connection on p. 5, where R1group of General formula

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where R6and R7are specified in paragraph 1.

13. Connection on p. 12, which represents a 2-dodecyl-N- (1,3,5-trimethyl-1H-pyrazole-4-yl)-2H-tetrazol-5-ndimethylacetamide or 1-dodecyl-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-tetrazol-5-ndimethylacetamide.

14. Connection on p. 3, where one of R2and R3is hydrogen and the other is unsubstituted or substituted specified in paragraph 1 remains phenyl.

15. Connection on p. 14, where R4- saturated hydrocarbon chain of from 8 to 18 carbon atoms.

16. Connection on p. 15, where R1is unsubstituted or substituted specified in paragraph 1 remains phenyl.

17. Connection on p. 16, which represents a ()-2-dodecyl-phenyl-N-(2,4,6-trim(1-methylethyl)phenyl] -2-dodecyl-phenyl-2H-tetrazol-5-ndimethylacetamide, ()-N-(2,4-differenl)-2-dodecyl-phenyl-2H-tetrazol-5-ndimethylacetamide, ()-2-octyl -- phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide or ()-2-hexadecyl -- phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide.

18. Connection on p. 15, representing ()-N-(4,6-dimethoxy-5-pyrimidinyl)-2-dodecyl-phenyl-2H-tetrazol-5-ndimethylacetamide, ()-N-(5,7-dimethyl-1,8-naphthiridine-2-yl)-2-dodecyl-phenyl-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl-phenyl-N-(1,3,5-trimethyl-1H-pyrazole-4-yl)-2H-tetrazol-5-ndimethylacetamide, ()-N-cyclopropyl-2-dodecyl-phenyl-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl-phenyl-N-2-pyridinyl-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl-N-(3-methyl-2-pyridinyl) - phenyl-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl-N-(3-methyl-2 - pyridinyl)-2-phenyl-2H-tetrazol-5-acetamol in the form of N-oxide or ()-N-(1,1-dimethylethyl)-2-dodecyl-phenyl-2H-tetrazol-5-ndimethylacetamide.

19. Connection on p. 3, where R3- 5 - or 6-membered monocyclic or condensed bicyclic heterocyclic residue containing 1 to 4 nitrogen atom.

20. Connection on p. 19, where R3- 2-, 3 - or 4-pyridyl.

21. Connection on p. 20, which represents ()-2-dodecyl -- (2-pyridyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-acetamido(- 2-pyridyl-2H-tetrazol-5-ndimethylacetamide.

22. Connection on p. 3, where R2and R3 is oxyphenyl)-2H-tetrazol-5-ndimethylacetamide, 2-dodecyl -- (2-propenyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, 1-(2-dodecyl-2H-tetrazol-5-yl)-N-(2,4,6-trimethoxyphenyl)-cyclopentanecarboxylic or 2-tridecyl -,- dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide.

24. Connection on p. 2, where n = 1 or 2.

25. Connection on p. 24, where R1is unsubstituted or substituted specified in paragraph 1 remains phenyl.

26. Connection on p. 25, which represents a 2-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-propanamide, N-[2,6-bis (1-methylethyl)phenyl]-2-dodecyl-2H-tetrazol-5-propanamide, N-(2,4-differenl)-2-dodecyl-2H-tetrazol-5-propanamide or 1-dodecyl-N-(2,4,6-trimethoxyphenyl)-1H-tetrazol-5-propanamide.

27. Connection on p. 1, representing ()-n-(2,4-differenl)-1-dodecyl-phenyl-1H-tetrazol-5-ndimethylacetamide or ()-N-[2,6-bis(1-methylethyl)phenyl]-1-dodecyl-phenyl-1H-tetrazol-5-ndimethylacetamide.

28. Connection on p. 6, where R1- 2,6-(1-methylethyl)phenyl or 2,4,6-trimethoxyphenyl, n= 0, R2and R3independent from each other hydrogen, fluorine, cyclohexyl, unsubstituted or substituted specified in paragraph 1 remains phenyl or phenylalkyl, R4is in position 2 and has 12 carbon atoms and the side chain is linked to a carbon atom tetrazole rings.

Mead, ()-2-dodecyl -- (4-forfinal)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl -- 2-naphthalenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, (a) -- (1,1'-biphenyl)-4-yl)-2-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl -- methyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, () -2-dodecyl-phenylmethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, ()-2-dodecyl-cyclohexyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, (-)-2-dodecyl-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, ()-dodecyl-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide, ()-N-(2,6-bis(1-methylethylidene)-2-dodecyl -- fluoro -- phenyl-2H-tetrazol-5-ndimethylacetamide, or ()-2-dodecyl -- fluoro -- phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-ndimethylacetamide.

30. Connection on p. 1, where R4connected with the carbon atom tetrazole ring and the side chain is in position 2 tetrazole rings.

31. Connection on p. 30, representing N-[2,6-bis(1-methylethyl)phenyl] -5-decyl-2H-tetrazol-2-ndimethylacetamide, N-[2,6-bis(1-methylethyl)phenyl]-5-dodecyl-2H-tetrazol-2-ndimethylacetamide, ()-N-[2,6-bis(1-methylethyl)phenyl] -5-dodecyl-phenyl-2H-tetrazol-2-ndimethylacetamide, ()-N-[2,6-bis(1-methylethyl)phenyl]-5-dodecyl-pentyl-2H-tetrazol-2-ndimethylacetamide, ()-N-[2,6-bis(1-methylethyl)phenyl] -5-(dodecylthio) -- phenyl-2H-tetraz tetrazol-2-ndimethylacetamide, ()-5-dodecyl-phenyl-N-(2,4,6-trimethoxyphenyl-2H-tetrazol-2-ndimethylacetamide, ()-5-dodecyl-pentyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-2-ndimethylacetamide, ()-N-(2,4-differenl)-5-dodecyl-phenyl-2H-tetrazol-2-ndimethylacetamide, 5-dodecyl -,- dimethyl-N-(2,4,6-trimetoksi-phenyl)-2H-tetrazol-2-ndimethylacetamide, or ()-5-(dodecylthio) -- phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-2-ndimethylacetamide.

Priority signs:

22.08.91 when R1all values specified in the claims, R2and R3the same or different, is hydrogen, unbranched or branched alkyl with 1 to 6 carbon atoms, phenyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, unsubstituted or substituted at the phenyl 1 - 3 residues from the group comprising an unbranched or branched alkyl with 1 to 4 carbon atoms, fluorine and dialkylamino with 1 to 4 carbon atoms, unbranched or branched alkenyl with 2 to 6 carbon atoms; R2and R3together with the carbon atom to which they are bound, form alkyliden with 1 to 4 carbon atoms or spiralcell with 3 to 7 carbon atoms, and when R2is hydrogen, R3may additionally mean heteroaryl from among 5 - or 6-membered monocyclic or condensed bicyclic heterocyclic group, R3the same or different, is halogen, unbranched or branched alkyl with 7 to 12 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, phenyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, unsubstituted or substituted at the phenyl 1 - 3 residues from the number of unbranched or branched alkoxyl with 1 to 4 carbon atoms, naphthyl, if R2- fluorine, or alkyl with 1 to 12 carbon atoms, R3may additionally mean heteroaryl from among 5 - or 6-membered monocyclic or condensed bicyclic heterocyclic group containing 1 to 4 nitrogen atom.

 

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