Imidazolyl-cyclic acetals, intermediate compounds, pharmaceutical composition and method of treatment

 

The invention relates to new imidazole-cyclic acetals of the formula I, where R1- optionally substituted 4-pyridyl or optionally substituted 4-pyrimidinyl; R2is phenyl, substituted with halogen; R3is hydrogen; R4refers to a group - L3-R14; R5is hydrogen, alkyl or hydroxyalkyl; or R4and R5when attached to the same carbon atom, may form with the specified carbon atom kernel cycloalkyl or the group C=CH2; R6is hydrogen or alkyl and m=1; L3and R14have the meanings specified in the description, and pharmaceutically acceptable salts and solvate (for example, hydrates), which have inhibitory activity against TNF-alpha, as well as to intermediate compounds, pharmaceutical compositions and method of treatment. The technical result is to provide new compounds used in the production of pharmaceuticals for the treatment of a condition that can be improved by the introduction of an inhibitor of TNF-alpha, namely for the treatment of asthma or inflammation of the joints. 9 C. and 15 C.p. f-crystals, 14 PL.

(I)

Description text in facsimile form (see graphic part)and

where R1denotes optionally substituted 4-pyridyl or optionally substituted 4-pyrimidinyl;

R2denotes phenyl, substituted with halogen;

R3denotes hydrogen;

R4refers to a group-L3-R14[where L3refers to the direct chemical bond or a linear or branched Allenby bridge containing from 1 to 6 carbon atoms (optionally substituted by oxo and R14denotes hydrogen, alkyl, azido, hydroxy, alkoxy, aryl, arylalkyl, aryloxy, carboxy, heteroaryl, heteroseksualci, NY4Y5(where Y4and Y5independently represent hydrogen, aryl, cycloalkyl, heteroseksualci, heteroaryl or alkyl, optionally substituted aryl, cycloalkyl, heteroaryl, heterocyclization, hydroxy or the group-NY4Y5may form a 5-7 membered cyclic amine which (i) may optionally be substituted by one or more substituents, which are selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5, 6 or 7-membered cyclic acetal-derived), R9or alkyl substituted carboxy, carboxamido or hydroxy, (ii) may also contain an additional heteroatom, which is a system of dual cycles), where R9denotes alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroaromatic or heteroseksualci,

-N(R10)-C(=Z)-R15(where R15denotes alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl); -N(R10)-C(=Z)-L4-R16(where R16denotes alkoxy, aryl, arylalkyl, a L4denotes a linear or branched Allenby bridge containing from 1 to 6 carbon atoms), -NH-C(=Z)-NH-R15, -NH-C(=Z)-NH-L4-R16N(R10)-SO2-R15N(R10)-SO2-L4-R16or-C(=Z)-NY4Y5];

R5denotes hydrogen, alkyl or hydroxyalkyl or

R4and R5when attached to the same carbon atom, may form with the specified carbon atom kernel cycloalkyl or the group C=CH2;

R6denotes hydrogen or alkyl and m=1,

and pharmaceutically acceptable salt and solvate (for example, hydrates) of compounds of formula (I).

2. Connection on p. 1, where R1denotes the 2-substituted 4-pyrimidinyl.

3. Connection on p. 2, where 2 is the Deputy refers to a group which is selected from R17Z3- [where R17denotes alkyl, aryl, or heteroaryl, substituted alkoxy, aryl, cycloalkyl, heteropar is.

4. Connection on p. 2, where 2 is the Deputy refers NY4Y5(where one of the Y4and Y5denotes hydrogen and the other denotes hydrogen, aryl, cycloalkyl, heteroseksualci, heteroaryl or alkyl, optionally substituted aryl, cycloalkyl, heteroaryl, heterocyclization, hydroxy).

5. Connection on p. 4, where R2denotes 4-forfinal.

6. The compound according to any one of the preceding paragraphs, where R6denotes hydrogen.

7. The compound of formula (Ib)

where R4and R5accept specified in paragraph 1 values, and R18means R17Z3or Y4Y5N- (where R17, Y4, Y5and Z3take the values specified in paras.1 and 4),

and pharmaceutically acceptable salt and solvate of the compounds of formula (Ib).

8. The compound according to any one of the preceding paragraphs, where R4refers to a group-L3R14[in which L3represents a direct chemical bond, and R14selected from alkyl, -NY4Y5, - N(R10)-C(=Z)-R15, -NH-C(=Z)-NH-L4R16, -C(=Z)-NY4Y5and C(=Z)-OR9].

9. Connection at one PM.1-8, where R4refers to a group-L3R14[in which L3-N(R10)-C(=Z)-L4-R16, -NH-C(=Z)-NH-L4-R16, -NY4Y5N(R10)-SO2-R15and-NH-C(=Z)-NH-R15].

10. The compound according to any one of the preceding paragraphs, where R5denotes hydrogen, C1-4alkyl or hydroxyalkyl.

11. Connection on p. 10, where R5denotes methyl.

12. Connection at one PM.7-11, where R18means-NY4Y5in which Y4denotes hydrogen, a Y5selected from the group: aryl, arylalkyl, cycloalkyl, heteroaromatic and C2-6alkyl, substituted hydroxy,alkoxy.

13. Connection on p. 1, which is selected from a group including:

{2-[5-(2-cyclopropylamine-4-yl)-4-(4-forfinal)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-yl}-morpholine-4-ylmethanol (Connection GH);

{2-[5-[2-(cyclopropylamino)pyrimidine-4-yl]-4-(4-forfinal)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-yl}-(4-methylpiperazin-1-yl)-methanon (Connection A);

cyclopropylamine 2-[4-(4-forfinal)-5-(2-Propylenediamine-4-yl)-1H-imidazol-2-yl]-5-methyl-[1,3]dioxane-5-carboxylic acid (Compound A);

propylamide-(4-(4-forfinal)-5-[2-(2-methoxyethylamine)pyrimidine-4-yl]-1H-imidazol-2-yl}-5-methyl-[1,3]dioxane-5-carboxylic acid (Compound A),

and pharmaceutically acceptable is against TNF-alpha and including connection on p. 1 together with a pharmaceutically acceptable carrier or excipient.

15. Connection on p. 1, having inhibitory activity against TNF-alpha.

16. Connection on p. 1, used in the manufacture of medicinal products for the treatment of a condition that can be improved by the introduction of an inhibitor of TNF-alpha.

17. Connection on p. 16, used in the manufacture of a medicinal product for the treatment of asthma.

18. Connection on p. 16, used in the manufacture of drugs for the treatment of joint inflammation.

19. Pharmaceutical composition for treatment of a condition that can be improved by the introduction of an inhibitor of TNF-alpha comprising an effective amount of the compounds under item 1.

20. The method of treatment of a patient (human or animal) suffering from or susceptible to conditions that may be improved by the introduction of an inhibitor of TNF-alpha, including the introduction of a specified patient an effective amount of the compounds under item 1.

21. The compound of formula (II)

where R1denotes optionally substituted heteroaryl;

R2denotes optionally substituted aryl or optionally substituted heteroaryl;

R19denotes hydrogen or a protective group;

R20represents-Cho or-CH(OMe)2.

22. >and m take the values specified in paragraph 1.

23. Resin With:

where R2, R3, R4, R5, R6and m take the values specified in paragraph 1.

24. Resin D:

where R2, R3, R4, R5, R6and m take the values specified in paragraph 1.

Priority points and attributes:

12.06.1997 and 10.07.1997 on PP.1 and 14-20 for compounds of formula 1, TRANS-isomer, where R1is 4-pyridinyl; R2is 4-forfinal; R3-N; m=1; R4is-L3-R14where L3-methyl, substituted by oxo, R14-morpholine-4-yl; R5represents methyl and R6is hydrogen, and pharmaceutically acceptable salt and solvate of such compound;

21.11.1997 and 14.05.1998 on PP.1 and 14-20 for mesilate salts of the compounds of formula 1, TRANS-isomer, where R1is 4-pyridinyl; R2is 4-forfinal; R3-H; m=1; R4is-L3-R14where L3-methyl, substituted by oxo, R14-morpholine-4-yl; R5represents methyl and R6is hydrogen, and pharmaceutically acceptable salt and solvate of such compound;

12.06.1998 on PP.1-14 for the other specified in paragraph 1 of the definitions of the radicals R1-R<

 

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