Derivatives oxindoles or their pharmaceutically acceptable salts

 

(57) Abstract:

The present invention relates to new derivatives of 3-substituted 2-oxindole (I) which are inhibitors of prostaglandin H2synthase, 5-lipoxygenase and biosynthesis of interleukin-1.

(I)

where X, Y = H, Cl, F, Br, C1- C6alkyl, CF3; R = CONR1R2;

< / BR>
R1, R2= H, C1- C6alkyl;

,

F, Cl, Br, I, OR3,S(O)nR4, COOR5, CONR3R5, COR4, CN, NO2CH2OR5, OCOR4, SO2NR3R5, NR3R5N(R3)COR5; R3=H, C1- C6alkyl; R4=C1- C6alkyl; R5=H,C1- C6alkyl; n =0, 1, 2; B = H, F, Cl, Br, CF3C1- C6alkyl. 2 s and 5 C.p. f-crystals, 4 PL.

This application is a partial continuation of pending application serial N 07/340 113, filed April 18, 1989.

The present invention relates to new derivatives of 3-substituted 2-oxindole, which are inhibitors of prostaglandin H2synthase, 5-lipoxygenase and biosynthesis of interleukin-1.

Compounds of the invention are useful as inhibitors protag vospaliteleny and antiarrhythmic agents in the treatment of chronic inflammatory diseases. The present invention also relates to pharmaceutical compositions containing these derivatives of 3-substituted 2-oxindole; to methods of inhibiting prostaglandin H2synthase and biosynthesis of interleukin-1 and to the treatment of chronic inflammatory diseases in mammals using these compounds. In addition, the present invention relates to certain new carboxylic acids, useful as intermediates in obtaining the 3-substituted 2-oxindole of the present invention and to a method for producing derivatives of 3-substituted 2-oxindole.

In U.S. patent No. 5 469 942 describes some 2-oxindole-1-carboxamide formula:

< / BR>
where X is H, fluorine, chlorine, bromine, (C1-C4)-alkyl, (C3-C7-cycloalkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, trifluoromethyl,

(C1-C4-alkylsulfonyl, (C1-C4-alkylsulfonyl, nitro, phenyl, (C2-C4-alkanoyl, benzoyl, tonola, (C1-C4)-alcanada, benzamido or N, N dialkylamino having 1 to 3 carbon atoms in each of these Akilov; Y is H, fluorine, chlorine, bromine, (C1C4)-alkyl, (C3- C7)-qi is SUB>C8)-alkyl, (C3C7-cycloalkyl, (C4- C7-cycloalkenyl, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbon atoms in the specified alkyl, substituted /phenoxy/alkyl containing 1 to 3 carbon atoms in the specified alkyl, /thiophenoxy/ alkyl containing 1 to 3 carbon atoms in the specified alkyl, naphthyl, bicyclo (2.2.1) heptane-2-yl, bicyclo (2.2.1)hept-5-EN-2-yl or -(CH2)n-Q-Ro' n is zero, 1 or 2; Q is a divalent radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazol, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrabromomethane, pyridine, pyrimidine, pyrazine, benzo(b) furan and benzo(g) thiophene; Rois H or (C1- C3)-alkyl; and a is a (C1C6)-alkyl, (C3- C7-cycloalkyl, benzyl, fullam, teinila, pyridium or

< / BR>
where R3and R4each is H, fluorine, chlorine, (C1-C4)-alkyl, (C1C4)-alkoxy or trifluoromethyl.

This patent also describes that these 2-oxindole-1-carboxamide are inhibitors of cyclooxygenase and oblegcheniya symptoms of chronic diseases, such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

In U.S. patent N 4556672 describes some 3-alizamani 2-oxindole-1-carboxamide formula:

< / BR>
where X, Y and R1have the meanings given above for compounds of U.S. patent N 4569942. Join US patent N 4556672 described as having the same activity as the compounds of U.S. patent N 4569942 above.

In U.S. patent N 4861794 describes the use of compounds of the formula:

< / BR>
and pharmaceutically acceptable basic salts, where X is H, CL or F, Y is H or CL, and R is a benzyl or tiomila, for the inhibition of biosynthesis of interleukin-1 (IL-1) and for the treatment induced IL-1 disorders and dysfunctions.

In the patent application PCT serial N PCT US 88/03658, filed October 18, 1988, describes non-steroidal anti-inflammatory agents of the formula:

< / BR>
where each of X and Y is hydrogen, fluorine or chlorine; R1is a 2-tanila or benzyl; R1is alkanoyl, cycloalkylcarbonyl, phenylalkanoic, benzoyl and some substituted benzoline groups, tenolol, omega-alkoxy-carbonylation, alkoxycarbonyl, phenoxycarbonyl, 1-alkoxycarbonyl-1 (IL-1) stimulates bone resorption both in vitro and in vivo, Hayward M. U. Fiedler-Hagy Cn. Agents and actions, 22, 251 254 (1987). It was also reported here that IL-1, among other things, induces the production of prostaglandin E2(PGE2), PGE2is a stimulator of bone resorption and is involved in bone loss. See Hayward M. and T. J. Caggiano annual Reports in Medicinae Chemistry, 22, Sect. IV, Chapter 17, 169 178 (1987). Osteoporosis is defined as the attenuation loss of the mineral components of the bone, which results in a higher rate of fracture. See Hayward M. and T. J. Caggiano above, and following links.

It was reported that interleukin-1 is included in the pathogenesis of many diseases. See Sinarello C. A. J. Clin Jmmunjc 5, 287 237 (1985), the content of which is given here as prior art. In addition, it was found that increased levels of IL-1 similar material associated with psoriasis. Camp, R. S. al. J. Jmmunal 137, 3469 3474 t (1986).

The present invention provides a new 3-substituted 2-oxindole the compounds of formula:

< / BR>
and their pharmaceutically acceptable salts,

where X is H, F, Cl, Br, (1C1-C6)-alkyl, (C3-C8-cycloalkyl, NO2, CF3, CN, CH, S(O)mR3, OR4, COR4or CONR4R5.

Y is H, F, CL, Br, (C1-C2(ALNILAM (C>< / BR>
R1is H, alkanoyl with 2 to 10 carbon atoms, cycloalkylcarbonyl with 5 to 7 carbon atoms, phenylalkanoic from 7 to 10 carbon atoms, chlorbenzol, methoxybenzoyl, tenolol, omega-alkoxycarbonylmethyl, this alkoxygroup contains 1 to 3 carbon atoms, and the said alcoolica group contains 3 to 5 carbon atoms, alkoxycarbonyl with 2 to 10 carbon atoms, phenoxycarbonyl, 1-(acyloxy)-alkyl, where the acyl has 1 to 4 carbon atoms, 1-(alkoxycarbonyl) - alkyl, where the specified alkoxygroup has 2 to 5 carbon atoms, and the alkyl has 1 to 4 carbon atoms, alkyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, methylphenylsulfonyl or dialkylphosphate, where each of these Akilov contains 1 to 3 carbon atoms;

R2is fulfills I TS cor6, CONR7R8(C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl or mono-or disubstituted by phenyl, where the Deputy or deputies each is CL, Br, F (C1-C6)-alkyl, (C1-C6)-alkoxy or CF3;

Q is

or Q2-A1< / BR>
And is H, F, Cl, Br. I, CF3, OR9, S(O)pR10, COOR11, CONR9R11, CN, NO2, COR10or

B is H, F, Cl, Br, I, CF3, OR19, S(O)tR14, COOR15, CONR13R15, CN, NO2, COR14CH2OR15, OCOR14, NR13R15N(R13)COOR15or SO2NR13R15< / BR>
provided that a and b cannot be both H or a and b taken together, United with one and the same carbon ring Q, and equal oxo, or when a is not H and has these values or is a (C1-C4)-alkyl;

A1is F, Cl, Br, J, CF3, OR9, S(O)pR10, COOR11, CONR9R11, CN, NO2, COR10CH2OR11, OCOR10, NR9R11N(R9)COOR11or SO2NR9R11< / BR>
Q1is

, , ,

, , , , , , , , , or

Q2is

, , , or

m, n, p, q and t are each zero, 1 or 2;

W1and each Z is O, S or NR11;

W1and W2each is O, S or NR10provided that when one of W1or W2is O, S or NR10, the other is O or S, R3, R10, R6, R14and R17each is (C C)-alkyl or phenyl; R5, R8, R11, R15and R19each is H, (C1-C6)-alkyl; and is H, F, Cl, Br, CF3or (C1-C6)-alkyl.

Although the above compounds of formula I as shown analy, ethers and esters of enelow, it should be clear that when R1is H, the compounds of formula I can be in their tautomeric ketone form. That is,

< / BR>
All such tautomeric forms are included in the scope of the present invention and appended claims, and are represented by formula I. Further, the substituents at ekzoticheskoy double bond in position 3 of the compounds of formula I can be SYN, anti, or a mixture of both. Consequently the compounds of formula I having the structure

and

and their mixtures are included in the scope of the present invention, and all such isomers are described by formula I and the scope of the applied claims.

The compounds of formula I, in which R1is other than H, are prodrugs of compounds of the formula I, in which R1is N, and their salts.

The term "prodrug" refers to compounds, which are precursors of drugs, which after the introduction and absorption of mammals, produce the drug in vivo via some metabolic processes.

After gastrointestinal abasolo prodrugs of the invention are not enol acids, minimizes exposure of the gastrointestinal tract related acid compound.

A preferred group of compounds of the present invention is composed of the compounds of formula I above where R1is N. Another preferred group of compounds is that group of compounds of the formula I, in which X and Y each is H, F, Cl, NO2(C1-C3)-alkyl or CF3. Another preferred group of compounds is that group of compounds of the formula I, in which R2is COR6, CONR7R8or (C1-C6)-alkyl, where R6, R7and R8have the previously indicated meanings. Another preferred group of compounds of the present invention is the group of compounds of formula I, where Q is Q1a Q1is

or

Another preferred group of compounds are compounds of formula I in which Q is Q1where Q1is

,

W is O or S; a W1is O or S. in Another preferred group of compounds consists of compounds in which Q is Q2where Q2is

or, and W is S

A more preferred group of compounds are compounds in which unity are those in which R1is N; X and Y each is H, F, Cl, NO2(C1-C3)-alkyl or CF3; R2is COR6, CONR7T8or (C1-C6)-alkyl, where R6, R7and R8have the previously indicated meanings; and Q is Q1where Q1is

or

where W has the previously indicated meanings, or Q is Q1where Q1is

< / BR>
where W is Q or S, or Q is Q, where Q1is

or

where W is Q or S and W1is Q or S or Q is Q2where Q2is

or

where W is S. more preferred compounds are those from directly above, which is S, R2is CONR7R8and R7and R8are N. Even more preferred are the above compounds in which X is H, Cl or CF3; Y is H, Cl or F; A is Cl, Br, F, CF, SCH3, OCH3or CH2OCH3; and is H, Cl, Br or CH3. Other especially preferred compounds are the above compounds in which n is zero or 1, when n is zero, these compounds are more preferred.

Another FAV is the ones, preferred and particularly preferred in which a is H, F, Cl, Br, CF3, OR9, CN, NO2, COR10CH2OR11N(R9)COR11and is H, F, Cl, Br, CF3, OR13, CN, NO2, COR14CH2OR15or N(R13)COR15where R9, R10, R11, R13, R14and R15have the previously indicated meanings, or a and b taken together are associated with the same carbon ring Q1and equal oxo, or when a is not H, has previously indicated value or is (C1-C3)-alkyl; and1is F in an even more preferred compounds are compounds in which R6is CH3; R7is H and R8is H or (C1-C4)-alkyl.

The compounds of formula I above in which R1is N, are active as inhibitors of prostaglandin H2synthase (cyclooxigenase), as inhibitors of 5-lipoxygenase and as inhibitors of the biosynthesis of interleukin-1 (IL-1) in mammals. The compounds of formula I in addition to their usefulness as such inhibitors are useful as analgesics, anti-inflammatory and antiarthritis agents in the treatment of chronic vocalistcomposer, containing the compounds of formula I. Further, the present invention provides methods of inhibiting prostaglandin H2synthase and biosynthesis of interleukin-1 in mammals by introduction of an effective amount of compounds of formula I specified mammal. The present invention also provides methods of treatment-induced interleukin-1 disorders and immune dysfunction and/or chronic inflammatory diseases in mammals by introduction of a specified mammal an effective amount of the compounds of formula I. Within the framework of the present invention such chronic diseases include, but are not limited to, psoriasis, rheumatoid arthritis and osteoarthritis.

In addition, the present invention provides a new carboxylic acid of the formula

< / BR>
and their salts, in which AND2is N;1is in position 4 and is S(O)p, R16or SOON3or1is in position 5 and is SO2NHCH3or1is in position 4 or 5 and is the SOP(CH3)2< / BR>
, , , or

n' is zero; p' is 1;

W3is S; Z1is O or S, R12is H, Cl, Br, CF3or (C1-C6-alkylate intermediates in obtaining some of the compounds of formula I.

In addition, the present invention provides a new method to produce some compounds of formula I above in which R1is N, and R2is R20as defined below, which lies in the interaction of the compounds of formula

Q-(CH2)nCOOH (II),

where Q and n have the previously indicated values for the compounds of formula I with a molar excess of 1,1'-carbonyldiimidazole in an inert reaction solvent in an inert atmosphere and the interaction of the product in the presence of a basic agent with a derivative of 2-oxindole formula

(IV)

where X and Y are defined above for compounds of formula I, and R20is COR6CONR7R8the phenyl or mono - or disubstituted by phenyl, in which a Deputy or deputies are Cl, F, Br, (C1-C6)-alkyl, (C1-C6)-alkoxy or CF3where R6, R7and R8defined above for compounds of formula I, at a temperature of about 0 50oWith in an inert reaction solvent in an inert atmosphere.

Method of producing compounds of the formula I, in which R1is H, shown in reaction scheme a above and described below. Substituted 2-oxindole the compounds of formula IV get methods, describe what the quality of the prior art. Carboxylic acids of formula receive, as described below, and activate in the interaction of the compounds of formula II with a molar excess of thionyl chloride, optionally in the presence of an inert reaction solvent. Suitable inert reaction solvents are those which will at least partially dissolve one or all of the reactants or the product. The resulting carbonylchloride compound of formula III is dissolved in an inert reaction solvent and slowly added to a solution, cooled to about 0oWith, consisting of approximately equimolecular number of substituted 2-oxindole formula IV and a molar excess of a basic agent in an inert reaction solvent. Reaction inert solvent described above, but in practice we usually use a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N is an organic or dimethylsulfoxide. The preferred solvent is dimethylformamide. Can be used with a wide variety of the main agents in the reaction between carbonylchloride formula III and substituted 2-oxindole formula IV. However, the preferred basic agents are tertiary amines, that is/pyridine, particularly preferred basic agent is 4-/N, N-dimethylamino/pyridine. After adding carbonylchloride the compounds of formula III to substituted 2-oxindole formula IV, the reaction mixture is allowed to warm to about 25oWith and continue the reaction at this temperature. The reaction time is from about 30 minutes to 2 hours after the reaction, the reaction mixture is acidified, and then extracted product, for example, by filtration. Then the product can be washed, dried and re-cleaned by standard methods such as recrystallization.

< / BR>
< / BR>
Alternative compounds of formula I in which R is H, can be obtained by the new method of the invention, shown in the reaction scheme described below. Carboxylic acids of the formula H, obtained as described below, is introduced into reaction with a slight molar excess of 1,1-carbonyldiimidazole in an inert reaction solvent. The reaction is carried out at a temperature of approximately 25oAnd stirred in an inert atmosphere. The reaction is carried out for approximately 2 h, after which the entire reaction mixture was added to a mixture consisting of about equimolecular number of substituted 2-oxindole the compounds of formula IV obtained as described the ore. Suitable inert reaction solvents are those described above for reaction scheme a, And preferred for use here, the solvent is N,N-dimethylformamide. The inert atmosphere is obtained when carrying out the reaction in an inert gas, such as nitrogen or argon. Suitable basic agents are those described above for reaction scheme a, a preferred basic agents are 4-/N,N-dimethylamino/pyridine and triethylamine.

Another method useful for preparing compounds of the formula I, in which R1is N, is joining Deputy

< / BR>
in position 3 of the desired 2-oxindole the compounds of formula:

< / BR>
in the interaction of the compounds of formula VI with a derivative of the corresponding acid of formula H above according to the method described in U.S. patent 4556672. The resulting compounds of the formula

< / BR>
then converted into the corresponding compounds of formula I' above according to the methods described in U.S. patent 3634453, 4556672, 4569942, 4695571 in the EP 175551 and here the link.

< / BR>
There are two methods that can be applied for the synthesis of compounds of formula I in which R1is other than hydrogen (formula is Ndola formula I' above and equimolecular number of triethylamine in an inert reaction solvent, such as chloroform, at 0oWith equimolecular number, plus a slight excess of the required carboxylic acid, chloroformate, oxanabol salt or an alkylating agent. After 2 h the reaction mixture is allowed to warm to room temperature and leave for 2 to 3 hours If the source oxindol not reacted completely, the mixture is cooled to 0oC, add additional allerease or alkylating agent and repeat the process until, until you used up all the original oxindol.

The product is separated from the reaction solvent by filtration and washed with 1N. hydrochloric acid, then distribute in an organic solvent and a saturated solution of sodium bicarbonate. The organic layer is dried, filtered and concentrated in vacuo. The resulting product was then purified by recrystallization or chromatography.

The second procedure, useful for obtaining the compounds of the present invention, in which R1is not hydrogen, is participation in an anhydrous inert reaction solvent such as acetone, correspondingly substituted 2-oxindole formula I' with a threefold molar excess of the required alpha-chlorocinnamate, five bocom vacuum at 165oC for 1 h) and heating the reaction mixture at the specified boiling under reflux for 16 hours

The reaction mixture is cooled, diluted with water and extracted the product is not miscible with water solvent, such as diethyl ether or chloroform. The combined extracts dried, filtered and the filtrate concentrated in vacuo. The resulting crude product is purified by recrystallization and/or chromatography.

Some carboxylic acids of the formula II are known and carboxylic acid compounds of formula II include new carboxylic acid of the formula II', obtained by known methods or by methods analogous to known methods. Such methods may include receiving the corresponding esters or nitrides of the corresponding carboxylic acids, which in the case of hydrolysis by known methods give interested carboxylic acid. Such methods are described: Taylor, E. C. at al. J O. C. 50:1002 (1985); Noto, R. et al. J. Chem. Soc. P. T. 11, 689 (1987); Schick, J. W. et al. J. Am. Chem. Soc. 70: 286 (1948); Carpenter, A. J. et al. Tetrahedron 41:3808 (1985); Gronowitz, S. et al. Arkiv. for Kemi. 21:265 (1963); Benkeser, R. A. et al. J. O. C. 38: 3660 (1973); Corral, C. et al. Heterocycles 23:1431 (1985); Iriarte, J. et al. J. Het. Chem. 13: 393 (1976); Reinecke, M. G. et al. Synthesis, 327 (1980); Lawesson, S. O. Arkiv. for Kemi. 11:317 (1957); Gronowitz, S. Ark6:497 (1973); Thames, S. F. et al. J. Het. Chem. 3:104 (1966); Arndt, F. et al. Chem. Ber. 94:1757 (1961); Cymerman-Craig, J. et al. J. Chem.Soc. 237 (1954); Lora-Tamayo, M. et al. Anales Real Soc. Espan. Fis. Quim. Ser. B 62:187 (1966); Nemec, N. et al. Coll. Czech. Chem. Comm. 39:3527 (1974); Janda, M. et al. Coll. Czech. Chem. Comm. 27: 1191 (1962); Carpenter, A. J. et al. Tetrahedron Letters 26:1777 (1985); Satonaka, H. Bull. Chem. Soc. Japan 56:2463 (1983); Kinoshita, T. et al. Bull. Chem. SOc. Japan 48:1865 (1975); Schwertner, E. et al. CA 88: 105790c (1978); Takaya, T. et al. bull. Chem. Soc. Japan 41:2086 Takaya, T. et al. Bill. Chem. Soc. Japan 41:2086 (1968); Kim, H. et al. J. Med. Chem. 29: 1374 (1986); Dostert, P. et al. Eur. J. Med. Chem. Chim. Ther. 17:437 (198); Sato, N. et al. J. Heterocyclis Chem. 19:407 (1982); Ladruee, D. et al. Heterocycles 22: 299 (1984); Leanxa, W. J. et al. JACS 75:4086 (1953); Barlin, G. B. et al. Aust. J. Chem. 30:2319 (1977); Gregory, G. I. et al. JCS P. T. 1: 47 (1973); Moriarty, R. M. et al. JACS 89:5958 (1967); Ross, J. M. et al. JACS 86: 2861 (1964); Goerdeler, J. et al. Chem. Ber. 99:1618 (1966); Demaree, P. et al. Can. J. Chem. 55:243 (1977); U. S. Patent 4,001,238; Kawazu, M. et al. J. Med. Chem. 15:914 (1972); Buckle, D. R. et al. JCS P. T. 1: 627 (1982); Naikm S. R. et al. GAME 38:4353 (1973); Okada, M. et al. Marcomolecules 19: 503 (1986); Jndetti, M. A. et al. CA 92:76268p (1980); Neth. Appl. 6,503,440, Sept. 20, 1965; Kenley, R. A. et al. CA 101:90841f (1984);

Schmidt, U. et al. CA 96:104572m (1982); Lukes, R. et al.Cjem. listy 51: 1510 (1957); Krowicki, K. et al. GAME 52:3493-3501 (1987); Goya, P. et al. Heterocycles 24:3451 (1986); Montero, J. L. et al. J. Heterocyclic Chem. 15: 929 (1978); Yasuda, N. et al. J. Heterocyclic Chem. 24:303 (1987); Hosmane, R. S. et al. Heterocycles 24:2743 (1986); Rapoport, H. et al. Environ. Health Persp. 67: 41 (1986); Kravchenko, T. B. et al. CA 107:18953t (1987); Stanovnik, B. et al. Heterocycles 12:761 (1979); Smithm R. C. et al. Biochem. Oharmacol. 36:1457 (1987); Bosso, C. et al. Org. Mass Spectrom. 20:263 (1985); Takagi, T. et al. CA 83:164172x (1975); Bende, Z. et al. CA98:89254e (19833 (1983); U. S. Patent 4, 437, 876; Hundle, B. S. et al. Biochemistry 26:4505 (1987); Marutani, Y. et al. CA104: 19320q (1986); Golubev, A. A. et al. CA107:236584x (1987); Higuchi, M. et al. CA104: 215392t (1986); Nakagawa, M. et al. Tetrahedron Letters 27: 6087-6090 (1986); Pereira, M. A. et al. CA101:165001t (1984); Fujii, S. et al. CA102: 45788d (1985); Bredereck, H. et al. Chem. Ber. 97:1414 (1964); Howe, R. K. et al. CA95:80933f (1981); Ibarra, C. A. et al. Tetrahedron Letters 26:243 (1985);

Hoppe, D. Justus Liebigs Ann. Chem:1843 (1976); Evans, D. L. et al. GAME 44: 497 (1979); Ozaki, Y. et al. Synthesis (1979) 216; Ehler, K. W. et al. CA87: 136361x (1977); Scolastico, C. et al. Synthesis:850 (1985); Corsico, Coda, A. et al. Heterocycles 26:745 (1987); Fields, R. et al. CA90:152072w (1979); Farina, F. et al. Heterocyclec 24:2587 (1986); Manaev, Y. A. et al. CA98: 71993k (1983); Beck, J. R. CA107:23332b (1987); Ajki, I. et al. CA107: 176057r (1987); Beck, J. R. et al. J. Heteroceclic Chem. 24:267 (1987); Sato, T. et al. CA107:39807w (1987), Ege, G. et al. Chem. Ber. 120:1375 (1987); Klein, H. J. et al. CA102:203932c (1985); Perevalov, V. R. et al. CA101: 171198d (1984); Hamilton, H. W. C. A. 107; 59059a (1987); Sabate-Alduy, C. et al. CA 87, 23137k (1977); Bastide, J. et al. Tetrahedron 30:3355 (1974); Chrzaszawska, A. Lodz. Tow. Navk, Wydz. 111, 112:119 (1967) (CA 71:124091r (1969)); British Patent 705,950 (CA4S:2233 (1955)); and Se Nardo, M. CA 87: 118063x (1977);

The compounds of formula I, in which R1is N, are acidic and they form basic salts. All such basic salts are included in the scope of the invention and they can be obtained by traditional methods. For example, they can be obtained by simply contacting the acidic and basic substances, usually in a stoichiometric ratio, or in aqueous or non-aqueous or partially vampirtrace, or by evaporation of the solvent, as appropriate, or in the case of aqueous solutions, by lyophilization. Typical salts of the compounds of formula I which may be obtained, are salts of primary, secondary and tertiary amines, salts of alkali metals and salts of alkaline-earth metals. Especially valuable are the salt of ethanolamine, diethanolamine, triethanolamine.

The main agents, especially suitable for the formation of salts, belong to both organic and inorganic type and they include organic amines, hydroxides, alkali metal carbonates, alkali metal bicarbonates of alkali metals, hydrides of alkali metals, alkoxides of alkali metals, hydroxides of alkaline-earth metals, carbonates of alkaline-earth metals, hydrides of alkali-earth metals and alkoxides of alkali-earth metals. Typical examples of such bases are primary amines, such as n-Propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glutamin; secondary amines, such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, pyrrolidine, and piperidine; tertiary amines, such as xed sodium, alkoxides, such as ethoxide sodium and potassium methoxide; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate.

The ability of the compounds of formula I to inhibit the biosynthesis of interleukin-1 are shown in the procedure below.

AWN/HeN mice (Charles One, Wilmington, Massachusetts) kill cervical dislocation and the abdominal cavity is sprayed with 70% ethanol to prevent bacterial contamination of subsequently received cell preparations. In the peritoneum of each mouse injected with 8 ml/RPMI (RPMI-1640 medium (Hazelton research products. Inc. Lenexa, Kansas), Kansas) containing 5% FCS (Fetal calf serum, which was skanirovana good responsiveness to IL-1 in timeritem analysis (Hollon the laboratories, Logan, ut) and low spontaneous proliferation in the absence of the IL-1) penicillin-streptomycin (100 units/ml 100 ág/ml) and glutamine (2 mm). The peritoneum is mixed into the General mass, to help release the cells. Then make an incision through the skin and peritoneum, in order to reveal the underlying muscle layer. Remove peritoneal fluid needle 20 gauge by inserting the needle tip down through naked muscle layer just below the sternum. Peritoneal Jew is bacterial contamination. Uncontaminated fluid is centrifuged at about HD for 6 min and decanted the supernatant layer. Combine cellular balls 5 6 test tubes and re-suspended all in 20 ml RP MI-FCS3. Then find out the number of cells using hemocytometer, and determine cell viability by staining Trypan blue, also using hemacytometer. The cells are then diluted to a concentration of 3106cells/ml using RPMI-FC. In the cell plate with 35 mm cells make 1 ml of the above cell suspension. Cells incubated 2 h at 37oC in an atmosphere of 5% CO2to cause the attachment of macrophages to the walls of the cells. Remove the supernatant layer, creating an intense whirling suspension in cells and decanter. Adherent cells (because macrophages) twice washed with RPMI-SF4. In cells containing adherent cells, add 1 ml of the studied compounds at concentrations from 0.1 to 100 μg/ml in RI-SF or 1 ml of RPMI-SF as a control. Then in each cell add 100 ál of P RPMI-SF (1 mg/5 ml).

1RPMI-1640 medium containing 5% fetal calf serum

4RPMI containing penicillin-streptomycin (100 units/ml 100 ág/ml) and glutamine (2 mm).

5Finely purified lipopolysaccharide is g/5 ml). Plates are incubated at 37oC in an atmosphere of 5% CO2within 24 hours the Supernatant liquid is removed and examined for IL-1 immediately or after cooling or freezing for later analysis.

The supernatant liquid was analyzed quantitatively by IL-1 in accordance with the analytical receptor binding, described below. A standard curve is built as follows, EZ 4 6,1 cells in the mouse thymus (10 - 15106cells) in 0.4 ml of binding buffer (RPMI 1640, 5% FCS, 25 mm S 0.01% of NaNO3, pH 7.3)was added, varying the number of its rat rIZ-I recombinant IZ-I produced in Eseherichia coli from the published amino acid sequence 115 270 for IZ-I, Lomeclico, P. M. et al. Nature 312, 458 462, 1984) (40 PG to 49 ng in 0.5 ml buffer) and incubated for 1 h at 4oWith continuous shaking, after which add 0.8 ng (0.1 ml) of human125I-rIZ-I (new England Nuclear, Boston, Massachusetts) and continue to shake for another 3 hours, the Samples are filtered on the device information (Lins To. Tel Aviv, Israel) through glass fiber filters Whatman (C2. 4 cm), blocked with 0.5% milk powder for 2 h at 37oAnd once washed with 3 ml ice buffer. The filters are counted in a gamma counter Searle, Respecify the La is constructed as a graph of log(Y) (100-Y) against logC, where Y represents the percentage of control125I-rIZ-I binding.

The line straightened least-squares corresponds to the values of Y between 20 and 80% and Then to quantify the levels of IL-1 in the supernatant liquids obtained as described above, diluted supernatant replace rIZ-I in the above Protocol, and use the measured percentage value binding for determination of the concentration of IL-1 from the standard graph of the hill. Each dilution was analyzed twice, and usually use only dilution, in which the Y values are between 20 and 80% to calculate the mean levels of IL-1.

The ability of the compounds of formula I to inhibit prostaglandin H2synthase and 5-lipoxygenase shown in the following assay procedure. Using the procedure described below to measure the levels known to produce prostaglandin H2synthase and 5-lipoxygenase for cells treated with the studied compound for inhibition of prostaglandin H2synthase and/or 5-lipoxygenase, which is proved by the reduction or absence of known products of these enzymes.

Cells RBZ-I supported monolayer grown for 1 to 2 days in Kul is Noi a solution of the antibiotic/antimycotic (Flexible) according to the method Jackschik B. A. et al. Nature 287:51 52 (1980). Cells are washed twice and re-suspended in cold RM 1640 to the density of cells 4106cells/ml and Then 0.25 ml of the aliquot of the studied compounds at the desired concentration in RPMI 1640 balance at 37oWith over 5 minutes To a balanced add an aliquot of 0.25 ml aliquot of pre-warmed cell suspension and the mixture incubated at 37oC for 5 minutes Add 10 ml of a solution containing 14-C-arachidonic acid and a-23187 (ionophore calcium, Sigma chemical) and the mixture is incubated at 37oC for another 5 minutes Then add 267 μl of acetonitrile and 0.3% acetic acid and the mixture is left to stand on ice for 30 minutes Mix the contents of test tubes, clarify by centrifugation (3000 rpm, 10 min), decanted the supernatant and re-centrifuged for 2 min in microprobing with high speed. Then analyze 100 μl of an aliquot of the supernatant layer using high-performance liquid chromatography on a column of Perkin-Elmer-H5 (3 micron), using a gradient system of acetonitrile, N2O c 0,1% triperoxonane acid and a flow rate of 2 ml/min Determination of radioactivity performed on the device by determination of radioactivity Berthold LB, Boston, Massachusetts) output from the column. Quantification of radioactivity carried out using computer integrator Spectrum Physics SP4200. The resulting data are used in the program data-reduction, where the integration of units of each product are calculated as a percentage of the amount of integrated units and compared with the average control levels.

The compounds of formula I possess analgesic activity. This activity is shown on mice by showing blocking abdominal stretching caused by the introduction of 2-phenyl-1,4-benzoquinone (FBH). The used method is based on the method of Siegmund et al. Proc.Soc. Exp.Biol.Hed. 95, 729 731 (1957), as adapted to the large consumption of material per unit of time (see also Milne and T. womey, Agents and actions, 10, 31, 37 (1980)). All mice not fed the night before the introduction of drugs and tests.

The compounds of formula I is dissolved or suspended in a medium consisting of ethanol (5% ), emulphor 620 (mixture polyethoxylated esters of fatty acids, 5%) and brine (90%). This carrier also serves as a control. Doses taken on a logarithmic scale (namely, 032, 1,0, 3,3, 10, 32 mg/kg). The route of administration is oral, contisport to determine the effectiveness and power. Mice treated orally the test compound in an hour get administered intraperitoneally 2 mg/kg TBH. Individually mouse then immediately placed in a warm transparent cage and start in 5 min after injection FBH to register the number of abdominal contractions in the next 5 minutes is Calculated degree of analgesic protection (% MPE) based on the suppression of peritoneal reduction relative to data for competitive control animals experience the same day. At least four such definitions (N=5) provide data dose dose-response for MPE50the best estimate of the dose that reduces abdominal reduction by 50% of control level.

The compounds of formula I also possess anti-inflammatory activity. This activity is shown in rats using a method based on standard test Karenina, calling adeolu paws of rats Winter et al. Proc. Soc. Exp. Biol. Med. 111, 544 (1963)).

Count and weigh nanostation adult male albino rats weighing from 150 to 190 g and mark ink on the right side of the ankle. Each paw is dipped in mercury just before the ink marks. Mercury is in a glass cylinder that is connected to a pressure transducer statistics of the main character is mercury, moved shipped paw. Medications given to drink. One hour after drug administration induce adeolu injection of 0.05 ml of 1% solution ceragenin in plantar tissue marked legs. Immediately after that, measure the volume of the limb, in which an injection was used. The increase in volume of the limb after 3 h after injection karagina individual is anti-inflammatory response.

Analgesic activity of the compounds of formula I makes them useful for the urgent introduction of mammals to control the pain during injury. In addition, the compounds of formula I are useful for chronic introduction of mammals to relieve symptoms of chronic diseases, such as inflammation, rheumatoid arthritis, and pain associated with osteoarthritis and other musculoskeletal disorders.

Below are the tables 1 to 4, in which data for compounds of the present invention (table. 1 3) and compounds known level (table.4).

In these tables, "NR" denotes "no data".

The ability of the compounds of formula I to inhibit the biosynthesis of IL-1 makes them useful as an inhibitor of the biosynthesis of IL-1 in General. It also makes a useful IL-1 disorders include, but not limited to, disorders of the metabolism in the bones and connective tissues, such as osteoporosis, periodontia disease and scarring of the tissues. Mediasound IL-1 immune dysfunction include, but are not limited to, allergies and psoriasis.

The ability of the compounds of formula I to inhibit prostaglandin H synthase makes them useful as inhibitors of prostaglandin H2synthase in General, as the functioning of this enzyme, as is known, includes the pathogenesis of arthritic joints in mammals.

When the compounds of formula I or their pharmaceutically acceptable salts are used as an inhibitor of IL-1, an inhibitor of prostaglandin H2synthase, an analgesic agent or an anti-inflammatory agent, they can be administered to the mammal, or one or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition in accordance with standard pharmaceutical practice. The compounds may be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous or local administration.

In the pharmaceutical compositions, the active ingredient is usually in the range from 1:4 to 4:1, and preferably from 1: 2 to 2:1. However, in any given case, the selected ratio will depend on such factors as the solubility of the active ingredient, the expected dosage and accurate way of introduction.

For oral use of the compounds of formula I of the present invention compounds may be introduced, for example, in the form of tablets or capsules or in the form of aqueous solutions or suspensions. In the case of tablets for oral administration of the media that are commonly used include lactose and corn starch, and a lubricant such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When oral administration is required aqueous suspensions of the active ingredient is combined with emulsifying and suspendresume agents. If desired, can be added podslushivala and/or odorants. For intramuscular, intraperitoneal subcutaneous and intravenous use is usually prepared sterile solutions of the active ingredient and pH of the solutions must be properly installed or sabotinova. For intravenous use must be controlled by the concentration of total solute that the drug was doing what the rule will be determined by the attending physician. In addition, the dosage will vary depending on the age, weight and individual response of the patient, and the severity of the symptoms of the patient and the specific power input connection. However, for acute injection for pain dose that gives effective analgesic response in most cases will be from about 5 mg to 500 mg, depending on the need (for example, every 4

24 h). Chronic introduction to facilitate the medical treatment of inflammation and pain, inhibition of the biosynthesis of IL/1 and/or inhibition of prostaglandin H2synthase in most cases, the effective dose will be from about 5 mg to 1.0 g per day, and preferably from 50 to 500 mg per day, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

The following examples illustrate the present invention and should not be construed as limiting its scope in any way.

Example 1. 4-Methylsulfinyl-2-thiencarbazone acid.

Cooled to a temperature of an ice bath with stirring, a solution of 2.46 g (14.1 mmol) of 4-methylthio-2-theoperational acid (obtained as described in palermitano solution 2,82 g (a 13.9 mmol) m-chloroperbenzoic acid (technical, 80-85%). After 1 h the reaction essentially ends with the formation of a colorless precipitate. The precipitate is filtered off and dried, obtaining 1.18 g (of 6.20 mmol) of target compound as a colourless solid product, so pl. 188 190oC. the Concentrated mother liquor chromatographic (on silica gel) to obtain additional 0,83 g (4,36 mmol) target 4-methylsulfinyl-2-thiophencarboxylic acid, the total yield of 75% (10,56 mmol).

Analysis: Calculated for C6H6O3S2< / BR>
C 37,88; H 3,18

Found, 37,89; N 3,18.

IMS (m/Z): 190 (M+, 45%) and 175 (- CH3).

IH NMR (DMSO-d6) Delta, 13,4 (1H, exchangeable), of 8.27 (1H, d, J=1.5 Hz), of 7.96 (1H, d, J=1.5 Hz) and 2.86 (3H, s). 13 SAMR (DSMO-d6) Delta, 162,1, 146,4, 137,2, 131,7, 128,9 and 42.2.

IR-spectrum (potassium bromide): 3420, 2550, 1705, 1245, 1015 cm-1.

Example 2. 5-(N-methylaminomethyl)-2-thiencarbazone acid.

Prepare diisopropylamide lithium by slow addition of 17.5 ml (range 43.8 mmol) of 2.5 M n-utility in hexane to 200 ml chilled 2-propanol/dry ice/tertrahydrofuran ring solution of 7.0 ml (50.0 mmol) Diisopropylamine, maintaining the reaction temperature below -60oC. After 5 min the reaction solution is heated to room temperature in the anew solution of 3.54 g (20.0 mmol) 2-/N-methylaminomethyl/-thiophene (obtained according to S. W. Slocum et al. J. O. C. 38, 4189, 1973) at the reaction temperature controlled below -70oC. Upon completion of addition, the reaction mixture is stirred for 30 min, and then bubbled through a solution of an excess of carbon dioxide. Then the solution is heated to 5oC and quenched with 50 ml of 1N. of sodium hydroxide. Water tertrahydrofuran ring solution is added portion 300 ml of diethyl ether and separated phase in a separating funnel. The organic layer is extracted with 50 ml of 1N. of sodium hydroxide. Combine both basic aqueous solution, washed with 50 ml of diethyl ether and acidified with concentrated hydrochloric acid. The acidified aqueous mixture is extracted with 2 x 100 ml diethyl ether. The ether solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, get to 3.38 g (15,3 mmol) target thiencarbazone acid as colorless solid product, so pl. 145-148oC. the Total yield is 76%

Analysis: Calculated for C6H7NO2C 32,57; H 3,19; N 6,33.

Found, C 32,43; H Is 3.08; N 6,30.

EIMS (m/Z): 221 (M+, base), 191 (M+HMe, 98), 157 (unknown 95%), 127 (unknown, 45%) and 115 (unknown, 73%)

IH NMR (DMSO-d6) Delta, a 7.92 (1H, exchangeable), 7,74 (1H, d, J=4.0 Hz), 7,58 (1H, d, J=4.0 G Is 5-Iodo-2-thiencarbazone acid.

Target n connection described Schik J. W. et al. J. Am. Chem. Soc. 70: 286 (1948) and obtained according to the following procedure. Slowly added via syringe 25 ml (62.5 mmol) of 2.5 M hexane solution of n-utillity to a cooled (dry ice propanol-2) tertrahydrofuran ring solution (100 ml) and 9.0 ml (64,2 mmol) Diisopropylamine. The solution is maintained at a temperature below -60oAt the time of adding n-utillity. Upon completion of addition, remove the cooling bath and allow the solution to warm to room temperature (22oWith), and then again cooled below -60oC. To the cooled reaction flask slowly added 3.2 g (25,0 mmol) 2-thiophencarboxylic acid dissolved in 100 ml of tetrahydrofuran. After 30 min after the addition of 2-thiophencarboxylic acid in the reaction mixture condense about 17,2 g (of 87.8 mmol) iodotrifluoromethane. After 5 min, remove the cooling bath and the reaction mixture is heated to 0oC and quenched with 50 ml water. The alkaline aqueous solution is washed with 500 ml of diethyl ether. The ether solution is extracted with 50 ml of 1N. sodium hydroxide and two combined aqueous solution was washed with ether. The alkaline solution is acidified and extracted three times with 100 ml diethyl ether. The organic solution is dried on the TKA is achieved when presideni solid product from hot aqueous ethanol, get 3,79 g weakly polluted the target product as a mixture of dark red solution and a yellow crystals. Recrystallization of the solid mixture gives 2,18 g (8,58 mmol, yield 34% ) of the pure target compound as pale yellow needles, so pl. 132 134o(Hexane).

Analysis: Calculated for C5H3IO2S 23,64; N 1,19.

Found, With 23,86; N 1,10.

EIMS (m/Z): 254 (M+, base), 237 (M+-OH, 79%), 209 (M+-CO2H, 5%), 127 (M+-1,18%) and 82 (C4H2S 36%);

IH NMR (l3) Delta, to 7.50 (1H, d, J=3,9 Hz), (1H, d, J=3,9 Hz); IR-spectrum (l3); 2977 shoulder, 2565, 1679 and 1410 cm-1.

Example 4. 5-[(N,N-dimethylamino)carbonyl]-2-thiophenecarboxaldehyde.

To a solution of 2.75 (17,61 mmol) 5-formail-2-thiophencarboxylic acid (obtained according to the method carpenter with TCS. Tetrahedron 41:3808, 1985) in 75 ml of tetrahydrofuran was added 3,71 g (22,88 mmol) of 1,1'-carbonyldiimidazole, the solution is stirred for 2.5 h in an atmosphere of dry argon and treated with excess gaseous dimethylamine. The solution is concentrated in vacuo to an oil which is dissolved in 100 ml ethyl acetate and extracted with 2 x 50 ml N. hydrochloric acid, then 2 x 50 ml 5% sodium bicarbonate. Each aqueous layer was again washed with 2x50 ml of e is velo-yellow solid product. IMS(m/Z): 183 (M+, 82%) 154 (M+-SSC, 7%), 139 (M+(CH3)2N base) and III/M+-(CH3)NCO 59%);

IH NMR (l3) Delta, to 9.91 (1H, s), to 7.67 (1H, d, J=4.0 Hz, to 7.35 (1H, d, J= 4.0 Hz), 3,13 (6N, Shir.C). This material is used directly without further purification.

Example 5. 5-[(N,N-dimethylamino)carbonyl)]-2-thiencarbazone acid.

Add 2,39 g (13,04 mmol) as part of the crude 5-[(N,N-dimethylamino)carbonyl)]-2-thiophenecarboxaldehyde to a stirred suspension of silver oxide prepared by adding to 2.29 g (57,13 mmol) of sodium hydroxide to 5,85 g (34,44 mmol) of silver nitrate in 100 ml of water. After 15 min stirring at room temperature and filtering through a layer of hard-shelled land filtrate is acidified from pH 12 to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are dried (magnesium sulfate) and concentrated in vacuo, get a 2.01 g (77%). An analytical sample is obtained when a thorough rubbing with warm ethyl acetate, so pl. 158 - 159oC.

Analysis: Calculated for C8H9NO3S C 48,23; H 4,55; N 7,03.

Found, C 48,30; H 4,42; N 6,79. EIMS (m/Z): 199 (M+, 68%), 155 (M+-(CH3)2the base III(M+-(CH3)2NCO, 44%);

I<, 594, 1246 cm-1< / BR>
Example 6. 4-[(N,N-dimethylamino)carbonyl]-2-thiophenecarboxaldehyde.

To a solution of 1.24 g (7,94 mmol) of 2-formyl-4-thiophencarboxylic acid (prepared by the method of S. Gronowitz et al. Arkiv for Kemi 21:265 (1963)) in 50 ml of tetrahydrofuran was added 1.80 g (11,10 mmol) of 1,1'-carbonyldiimidazole, the solution is stirred for 1.5 h in a dry argon and treated with excess gaseous dimethylamine. The solution is concentrated in vacuo to an oil which is dissolved in 60 ml of ethyl acetate and extracted with CH ml of 1 N. hydrochloric acid, then h ml of 5% aqueous sodium bicarbonate. Each of the aqueous extracts washed again I ml of ethyl acetate and the combined organic layers are dried (magnesium sulfate). Concentration in vacuo gives 1,15 g (79%) of a brown solid product. EIMS (m/Z): 183 (M+, 31%), 155 (M+-CO, 38%), 139 (M+-(CH3)2N base) and III (M+-(CH3)2-NCO, 25%);IH NMR (DMSO-d6) Delta of 9.89 (1H, d, J=1.4 Hz), 7,89 (1H, d, J=1,5, 1,4 Hz), 7,86 (1H, d, J=1.5 Hz), is 3.08 (6N, C).

This material is used directly without further purification.

Example 7. 4-[(N,N-dimethylamino)carbonyl]-2-thiencarbazone acid.

Added 1.12 g (6,11 mmol) of crude 4-[(N,N-dimethylamino)carbonyl]-2-thiophenecarboxaldehyde to PE is(16,14 mmol) of silver nitrate in 40 ml of water. After 15 min stirring, the mixture is filtered over a hard-shelled land, acidified from pH 12 to pH 2 with concentrated hydrochloric acid and saturated sodium chloride (solid). After extraction with 3 x 75 ml of dried ethyl acetate extracts with magnesium sulfate and concentrate them in a vacuum, obtain 1.10 g (90) light yellow crystals. An analytical sample is obtained when a thorough rubbing with warm ethyl acetate, so pl. 112 114oC.

Analysis: Calculated for C8H9NO3S 48,23; N 4,55; N 7,03.

Found, With 48,07; H 4,58; N 6,86.

EIMS (m/Z): 199 (M+, 26%), 181 (M+-H2O, 7%), 155 (M+-(CH3)2basis);

IH NMR (DMSO-d6Delta, of 8.09 (1H, d, J=1,8 Hz), 7,74 (1H, d, J=1,8 Hz), 2,98 (6H, d, J=13,0 Hz);

IR-spectrum (potassium bromide): 3388, 1706, 1594, 1250, 1186 cm-1.

Example 8. Methyl-2-formyl-4-thiophenecarboxylate.

The target compound was described by S. Gronowitz et al. Arkiv for Kemi 21: 265 (1963) and received in accordance with the following procedure. Add 1,32 g (of 9.30 mmol) under the conditions to a stirred suspension of 1.21 g (27,12 mmol) of 2-formyl-4-thiophencarboxylic acid (prepared by the method of S. Gronowitz et al. Arkiv Kemi 21:265 (1963)) are 2.87 g (27,12 mmol) of sodium bicarbonate in 40 ml of dimethylformamide. After stirring for tearout with ethyl acetate. The combined extracts washed with brine, dried (magnesium sulfate) and concentrated in vacuo, to obtain 1.20 g (91%), so pl. 110 112o.

EIMS (m/Z): 170 (M+, 84), 139 (M+CH3O, base), W(M+-CH5O2C, 29%);

IH NMR (l3) Delta, for 9.90 (1H, d, 1.5 Hz), to 8.41 (1H, s), 8,13 (1H, d, J=1.5 Hz), 3,88 (3H, s).

Example 9. 4-Methoxycarbonyl-2-thiencarbazone acid.

Treated with stirring, a solution of 823 mm (4,84 mmol) of methyl 2-formyl-4-thiophenecarboxylate in 50 ml of acetone and 5 ml of Jones reagent. Upon completion of addition, the mixture is stirred at room temperature for 30 min, the excess oxidizing agent is decomposed by isopropanol and the mixture is filtered over a hard-shelled land. The acetone is removed in vacuo, the residue is dissolved in 30 ml of ethyl acetate and the solution is dried over magnesium sulfate. Concentrated in vacuo, to obtain 880 mg (98%) whitish solid product. An analytical sample is obtained when a thorough rubbing with a small amount of ethyl acetate, so pl. 141 143oC.

Analysis: Calculated for C7H6O4S C 45,15; H 3,25.

Found, C 45,09; H 3,14.

EIMS (m/Z): 186 (M+, 42%), 155 (M+-CH3O, base);

IH NMR (DMSO-d6) Delta, 8,59 (1H, d, J the Il-5-formyl-2-thiophenecarboxylate.

The whole connection is described by S. Gronowitz et al. Arkiv for Kemi 21:265 (1963) and was obtained by the following method. Add 4,36 g (30,74 mmol) under the conditions for suspension of 4.00 g (25,61 mmol) of 5-formyl-2-thiophencarboxylic acid (obtained by the method of A. J. Carpenter et al. Tetrahedron 41: 3808 (1985)) and 9.50 g (89,65 mmol) in 75 ml of N,N-dimethylformamide with stirring. After stirring over night at room temperature the mixture was poured into 350 ml of water, saturated with solid sodium chloride and extracted with ethyl acetate. The combined extract washed with brine, dried (magnesium sulfate) and concentrated in vacuo, get a 3.83 g (88%) of a gray solid product so pl. 85 87oC.

EIMS (m/S): 170 (M+, 95%), 139 (M+CH3O, base), 111 (M+-CH3O2C, 64% );

IH NMR (DMSO-d6) Delta, 9,94 (1H, s), 7,81 (1H, d, J=3,9 Hz), 7,71 (1H, d, J=3,9 Hz), 3,91 (3H, c).

Example 11. 5-Methoxycarbonyl-2-tiofenkarbonovoi acid.

The target compound was described Ben Keser R. A. et al. J. O. C. 38, 3660 (1973) and in British patent 705950 and was obtained by the following method. Treated with stirring, a solution of 2.00 g (of 11.75 mmol) of methyl 5-formyl-2-thiophenecarboxylate in 100 ml of acetone, adding dropwise, 9 ml of Jones reagent. Upon completion of addition, the mixture paramesh through hard-shelled land. The acetone is removed in vacuo. The residue is dissolved in 75 ml of ethyl acetate solution and dried over magnesium sulfate. After filtration and concentration get to 1.60 g (73%) of yellow solid product.

An analytical sample is obtained when a thorough rubbing with warm ethyl acetate, so pl. 186 189oC.

Analysis: Calculated for C7H6O4S 45,15; N 3,25.

Found, C 45,12; H 3,09.

EIMS (m/Z): 186 (M+, 70%), 169 (M-OH), 7%), 155 (M-CH3O, base):

IH NMR (DMSO-d6) Delta, 7,78 (1H, d, J=4.0 Hz), 7,72 (1H, d, J=4.0 Hz), 3,85 (3H, S);

IR-spectrum (potassium bromide): 3416, 1712, 1666, 1258 cm-1< / BR>
Example 12. 5-Methoxycarbonyl-2-thiencarbazone acid, hydrazide.

Boiled for 2 hours under reflux with stirring suspension of 1.86 g (10.0 mmol) of 5-methoxycarbonyl-2-thiophencarboxylic acid in 20 ml of thionyl chloride. Cool the solution to room temperature and concentrated in vacuo. Then dissolve this solid product in 25 ml of chloroform and added dropwise to a chilled (5oC) a solution of 800 mg (25 mmol) of anhydrous hydrazine in 25 ml of chloroform in tiefere argon. Upon completion of addition, the mixture is stirred for 1 h at room temperature, then evaporated to dryness in vacuolate solid product. An analytical sample prepared by recrystallization from ethanol, so pl. 198 200oC.

Analysis: Calculated for C7H8NO3S C 41,99; H IS 4.03; N 13,99.

Found, C 41,88; H 3,91; N 13,86. EIMS (m/Z): 200 (M, 26%), 169 (M+-CH3O or H3, base);

IH NMR (DMSO-d6) Delta of 10.05 (1H, Shir.C) to 7.77 (1H, d, J=3,9 Hz), 7,71 (1H, d, J= 3,9 Hz), 4,56 (2H, Shir.C), 3,82 (3H, s); IR-spectrum (potassium bromide): 3319, 3285, 1723, 1618, 1264, 746 cm-1.

Example 13. Methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-thiophenecarboxylate.

Refluxed for 4 h 548 mg (2,74 mmol) hydrazide 5-methoxycarbonyl-2-thiophencarboxylic acid and 372 mg (3,01 mmol) of hydrochloric acid of ethyl climinate in 10 ml of pyridine, cooled to room temperature and evaporated in vacuum. Dissolve the residual oily product in ethyl acetate and washed with water, 1 N. hydrochloric acid and 5% sodium bicarbonate. An ethyl acetate solution is dried (magnesium sulfate) and evaporated in vacuo, get 242 mg (39% ) of light brown solid product, so pl. 142 - 150oC. This material is used directly without additional purification. Exact mass: 224, 0253. Calculated 224, 0256. IMS (m/Z): 224 (M+, base), 193 (M+-CH3O, 33%), 169 (C7H5O3-1
.

Example 14. 5-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-thiencarbazone acid.

A mixture of 100 mg (0.45 mmol) of methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-thiophenecarboxylate in 3 ml of 2 n sodium hydroxide diluted with 1 ml of methanol and stirred for 2 h at room temperature. The solution is filtered to remove traces of insoluble products and acidified to pH 3 with concentrated hydrochloric acid. The precipitate is collected and air-dried, receive 67 mg (71%) of light yellow solid product, so pl. 281 -284oC.

Analysis: Calculated for C8H6N2O3S C 45,70; H 2,88; N 13,33.

Found, 45,81; N 2,81; N 13,26.

EIMS(m/Z): 210 (M+, base), 193 (M+-OH, 3%), 168 (unknown, 8%), 155 (C6H3O356%); NAMR (DMSO-d6) Delta, 7,79 (1H, d, J=3,9 Hz), to 7.77 (1H, d, J=3,9 Hz), to 2.57 (3H, s);

IR-spectrum (potassium bromide): 3443, 1693, 1599, 1574, 1264, 744 cm-1.

Example 15. Methyl-4-acetyl-2-thiophenecarboxylate.

Add 783 mg (5.51 mmol) under the conditions under stirring to a suspension 782 mg (4,59 mmol) of 4-acetyl-2-thiophenecarboxylic acid (obtained according Satonata H. Bull. CHem. Soc. Japan 56:2463 (1983)) and 1.70 g (16,08 mmol) of sodium carbonate in 25 ml of dimethylformamide. After stirring over night the l of ethyl acetate, the combined extracts washed with brine, dried over magnesium sulfate and concentrated in vacuo, get 761 mg (90%) whitish solid product, so pl. 94 96oWith EIMS (m/Z): 184 M+, 74), 169 (M+-CH3, base), 153 (M+-CH30,51);

IH NMR (DMSO-d6) Delta, 8,17 (1H, d, J=1.5 Hz, b (1H, d, J=1.5 Hz), 3,88 (3H, s), of 2.51 (3H, s).

Example 16. Methyl-4-bromoacetyl-2-thiophenecarboxylate.

Work according to the method described in Japan Kokai Tokkyo koho yp 60 11, 487 CA 103:22580 (1985), was added dropwise a solution of the 4.29 g (26,87 mmol) in 40 ml of chloroform with stirring to a solution of 4.95 g (26,87 mmol) of methyl 4-acetyl-2-thiophenecarboxylate obtained in example 15, in 150 ml of chloroform containing 4 drops of 50% (volume/volume) of 48% Hydrobromic acid/glacial acetic acid. After 10 min at 40oThe solution is cooled to room t, concentrated in vacuo and the residue triturated with 25 ml of methanol. After filtering receive 4,96 g (63%) whitish solid product, so pl. 112 114oC.

EIMS(m/Z): 264/262 (M+,11%), 233/231 (M+-CH3O, 11%), 171/169 M+-CH2Br, base);

IH NMR (l3) Delta, 8,31 (1H, d, J=1.5 Hz), 8,17 (1H, d, J=1.5 Hz), the 4.29 (2H, s), 3,90 (3H, s).

Example 17. Monobromide methyl-4-(2-methylthiazole-4-yl)-2-thiophenecarboxylate.

Boil is the iMER 16 and 125 mg (from 1.66 mmol) of thioacetamide 15 ml of acetone. The mixture is cooled to room temperature, filtered and the residue is dried in vacuo get 375 mg (77%) of white product, so pl. 224 225oC.

Analysis: Calculated for C10H9NO2S2HBr C 37,50; H 3,15; N 4,36.

Found, 37,53; 3,00; N 4,28.

EIMS (m/S): 239 (M+, base), 208 (M+0CH3O, 65%), 198 (M+0C2H3, 76%);

IH NMR (DMSO-d6) Delta of 8.25 (1H, d, J=1.5 Hz), by 8.22 (1H, d, J=1.5 Hz), 7,98 (1H, s), 5,98 (exchange), 3,82 (3H, s), 2,68 (3H, s);

IR-spectrum (potassium bromide): 3091, 1703, 1285 cm-1.

Example 18. 4-(2-Methylthiazole-4-yl)-2-thiencarbazone acid.

The mixture 3,20 g (10.0 mmol) of methyl-4-(2-methylthiazole-4-yl)-2-thiophenecarboxylate of monohydrobromide obtained by the method of example 17, 50 ml of 2 n sodium hydroxide diluted with 15 ml of methanol and refluxed 1 hour, the Methanol is removed in vacuo and the remaining aqueous solution is acidified to pH 3 with concentrated hydrochloric acid. The mixture is extracted with CH ml of ethyl acetate and dried over magnesium sulfate, concentrated extracts, get 2,12 g (94% ) of white solid product. An analytical sample is obtained when a thorough rubbing with warm ethyl acetate, so pl. 195 7oC.

Analysis: Calculated for C9 base), 208 (M+-OH, 1%), 184 (M+-C2H3, 90%);

IR-spectrum (potassium bromide): 3103, 1676, 1284 cm-1.

Example 19. The oxime methyl-5-formyl-2-thiophenecarboxylate.

A solution of 6.26 g (36,78 mmol) of methyl 5-formyl-2-thiophenecarboxylate obtained by the method of example 10, of 3.07 g (to 44.1 mmol) of hydrochloric acid hydroxylamine and 3,49 g (44,41 mmol) of pyridine in 200 ml of ethanol is refluxed for 2 hours to Remove the ethanol in vacuo, the residue is dissolved in ether and washed with water. The organic layer is dried over magnesium sulfate and evaporated, receives a yellow solid product. A thorough rubbing with a small amount of ether to give the target compound as a white solid product (4,93 g, 72), so pl. 164 7oC. The Oxime. E ratio: (82:18).

Analysis: Calculated for C7H7NO3S C 45,39; H 3,81; N 7,56.

Found, 45,41; H 3,69; N Of 7.48.

EIMS (m/Z): 185 (M+, 97%), 154 (M+-CH3O, base),

IH NMR (DMSO-d6) Delta isomer: to 12.52 (1H, Shir.C) to 7.99 (1H, s), to 7.77 (1H, d, J= 4.0 Hz), to 7.50 (2H, d, J=4.0 Hz), 3,83 (3H, s): E isomer: 11,66 (1H, Shir. C), scored 8.38 (1H, s), 7,74 (1H, d, J=4.0 Hz), 7,34 (1H, d, J=4,0 G2), 3,82 (3H, s); IR-spectrum (potassium bromide): 3400, 1649, 918 cm-1.

Example 20. Methyl-5-cyano-2-thiophenecarboxylate.

th fridge over night under stirring the mixture to 4.87 g (26,29 mmol) of oxime, methyl-5-formyl-2-thiophenecarboxylate obtained by the method of example 19, in 60 ml of acetic anhydride. The solution is cooled to room temperature, poured into 400 ml of water and vigorously shaken. The mixture is extracted with CH ml of ether and the extracts washed h ml of 10% aqueous potassium hydroxide. The combined organic layers are dried over magnesium sulfate and concentrated, to obtain 3.50 g (80%) whitish solid product, so pl. 76 78oC.

EIMS (m/Z): 167 (M+, 34%) and 136 (M+-CH3O, base);

IH NMR (DMSO-d6) Delta, 8,03 (1H, d, J=4, 2 Hz), 7,88 (N, d, J=4, 2 Hz), a 3.87 (3H, s); IR-spectrum (potassium bromide): 2228, 1726 cm-1;

Example 21. Methyl-5-N-oxycarboxylic-2-thiophenecarboxylate.

Refluxed for 45 min the mixture 901 mg (5,39 mmol) of methyl 5-cyano-2-thiophenecarboxylate obtained by the method of example 20, 412 mg (5,93 mmol) hydrochloric acid hydroxylamine and 553 mg (6,74 mmol) of sodium acetate in 25 ml of a mixture of 5:1 ethanol-water. The ethanol is removed in vacuo and filtered crystalline precipitate. Additional product is recovered from the cooled filtrate, the total yield 932 mg (86) of light yellow crystals, so pl. 144 146oC.

Analysis: Calculated for C7H8N2O3S C 41UB>, 83%), 169 (M+-CH3O, 60%);

IH NMR (DMSO-d6) Delta becomes 9.97 (1H, s), 7,72 (1H, d, J= 4.0 Hz), 7,51 (1H, d, J=4.0 Hz), 6,11 (2H, Shir.C) of 3.80 (3H, s); IR-spectrum (potassium bromide): 3491, 1725 and 1636 cm-1.

Example 22. Methyl-5-/5-methyl-1,2,4-oxadiazol-3-yl/-2-thiophenecarboxylate.

Refluxed for 24 h under stirring 734 mg (to 3.67 mmol) methyl-5-/N-oxy/carboxymethylamino-2-thiophenecarboxylate obtained by the method of example 21, and 1.12 g (11.0 mmol) of acetic anhydride in 25 ml of toluene. The solvent is removed in vacuo and the residue triturated with a small amount of toluene, receive 547 mg (67%) whitish solid product so pl. 134 136oC.

EIMS (m/Z): 224 (M+, 99%), 193 (M+-CH3O, base), (183 (M+-C2H358%), 152 (C6H2NO2S 89%);

IH NMR (DMSO-d6) Delta, to 7.77 (1H, d, J=4.0 Hz) to 3.89 (3H), OF 2.64 (3H); IR-spectrum (potassium bromide): 1720, 1597 and 887 cm-1. This material is used directly without further purification.

Example 23. 5-/5-Methyl-1,2,4-oxadiazol-3-yl/-2-thiencarbazone acid.

A mixture of 86 mg (0.38 mmol) of methyl 5-/5-methyl-1,2,4-oxadiazol-3-yl/-2-thiophenecarboxylate obtained by the method of example 22, 3 ml of 2 n sodium hydroxide razbavlyayut 2 ml of water and acidified to pH 2 with concentrated hydrochloric acid. After 30 min of standing stand out flaky crystalline product slowly separated, it is filtered and dried in vacuum, to obtain 45 mg (56) of the target product, so pl. 218 220oC.

Analysis: Calculated for C8H6N2O3S C 45,70; H 2,88; N 13,33.

Found, 45,69; N 2,81; N 13,06.

EIMS (m/Z): 210 (M+, 89%), 169 (M+-C2H3base), 152 (C6H2NO2S 27%).

IH NMR (DMSO-d6) Delta, to 7.77 (2H, s) to 2.65 (3H, s);

IR-spectrum (potassium bromide): 3429, 1668 and 889 cm-1.

Example 24. Methyl-5-/trifluoromethyl-1,2,4-oxadiazol-3-yl/-2-thiophenecarboxylate.

Refluxed for 1 h under stirring 833 mg (4,16 mmol) methyl-5-/N-oxy/carboxanilido-2-thiophenecarboxylate obtained by the method of example 21, and 2,62 g (12,48 mmol) of anhydride triperoxonane acid in 25 ml of toluene. The solvent is evaporated in vacuo, the residue triturated with a small amount of toluene and filtered receive 400 mg (35% ) of white crystals, etc. 126 127oC. the Product is used directly without additional purification. Exact mass: 277,9998;

Calculated: 277,9974;

EIMS (m/Z): 278 (M, 67%), 247 (M-CH3O, base), 152 (C6H2O2

< / BR>
Example 25. 5-/5-Trifluoromethyl-1,2,4-oxadiazol-3-yl/2-thiencarbazone acid.

A mixture of 100 mg (0.36 mmol) of methyl 5-/5-trifluoromethyl-1,2,4-oxadiazol-3-yl/-2-thiophenecarboxylate obtained by the method of example 24, 3 ml of 2 n sodium hydroxide diluted with 1 ml of methanol and heated to 50oC for 10 minutes the Solution is cooled to room temperature, diluted with 3 ml of water and acidified to pH 2 with concentrated hydrochloric acid. After standing for 1 h, filtered whitish crystals and dried in vacuum, to obtain 41 mg (43%) of white crystals, so pl. 175 177oC.

Analysis: Calculated for C8H3F3NO2S C 36,37; H 1,14; N 10,61.

Found, C 36,65; H 1,18; N 10,24.

EIMS (m/Z): 264 (M, base), 247 (M+-OH, 43%), 169 (M+-C2F3N 24%);

IH NMR (DMSO-d6) Delta, 7,94 (1H, d, J=4.0 Hz), 7,83 (1H, d, J=4.0 Hz);

IR-spectrum (potassium bromide): 3430 shoulder, 1661, 1208, 847 cm-1.

Example 26. The hydrobromide methyl-4-/thiazol-4-yl/-2-thiophenecarboxylate.

Refluxed solution of 1.25 g (of 4.75 mmol) of methyl-4-/bromacetyl/-2-thiophenecarboxylate obtained by the method of example 16, and 436 mg (7,13 mmol) thioformate in 35 ml of acetone for 1 h the Mixture cool slightly and Phil is so pl. 201 202oC.

Analysis: Calculated for C9H7NO2S2HBr C 35,80; H 2,63; N 4,58.

Found, 35,31; H 2,60; N 4,48.

EIMS (m/Z): 225 (M+, base), 194 (M+-CHNO, 92%), 267 (C8H7O225%);

IH NMR (DMSO-d6) Delta, 9,18 (1H, d, J=1.7 Hz), 8,31 (1H, d, J=1,2 Z), 8,30 (1H, d, J= 1.2 Hz), 8,21 (1H, d, J=1.7 Hz), 4,50 (1H, exchangeable), 3,85 (3H, s); IR-spectrum (potassium bromide): 3054, 1711, 1272, 778 cm-1.

Example 27. A mixture of 500 mg (1,63 mmol) to the hydrobromide methyl-/thiazol-4-yl)-2-thiophenecarboxylate obtained by the method of example 26, in 8 ml of 2 n sodium hydroxide diluted with 1 ml of methanol and refluxed 30 minutes, the Methanol is removed in vacuo and the residual aqueous solution is acidified to pH 2 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried with magnesium sulfate extracts concentrate, get 318 mg (92%) light yellow solid product, so pl. 183 185oC.

Analysis: Calculated for C8H5NO2S2WITH 45,48; H 2,39; N 6,63.

Found, C Of 45.42; H 2,39; N 6,46.

EIMS (m/Z): 211 (M+, base), 194 (M+-OH, 23%) and 184 (C7H4O280%);

IH NMR (DMSO-d6) Delta, 9,16 (1H, d, J=1.2 Hz), 8,23 (2H, Shir.C), 8,16 (1H, d, J=1.2 Hz); IR-SP is ptx2">

Prepare diisopropylamide lithium, slowly adding 31,0 ml (77.5 mmol) of 2.5 M n-utility in hexano to 200 ml of tertrahydrofuran ring solution of 11.0 ml (about 78.5 mmol) Diisopropylamine, cooled in a bath with 2-propanol /dry ice, the temperature of the reaction support below -60oC. After 15 min the reaction solution warmed to room temperature for 30 min, then cooled to a temperature below -70oC. Slowly add 100 ml of tertrahydrofuran ring solution of 9.9 g (76,0 mmol) 3-methylthiophene (obtained by the method Henrio G. et al. Tetrahedron 33, 191 (1977), controlling the reaction temperature below -70oC. After the addition, the reaction mixture is stirred for 15 min, and then bubbled through a solution of an excess of carbon dioxide. Then the solution is heated to 10oC and quenched with 100 ml water. After a few minutes of stirring the reaction mixture was poured into a separating funnel and extracted with a portion of 500 ml of diethyl ether. The organic layer is extracted with 100 ml of 1 n sodium hydroxide, then combine both basic solution, washed with 100 ml of diethyl ether and acidified with concentrated hydrochloric acid. The acidified aqueous mixture was then extracted with 2x250 ml of diethyl ether. Essential dissolve the yellow solid product, which according to NMR is a mixture of 3: 2 isomers (4 and 3) target thiencarbazone acid. This crude product is stirred for 30 min with a portion of 50 ml of diethyl ether, then filter and concentrate the filtrate in vacuo, get 8,68 g (49,8 mmol) of solid product, which contains more than 80% (estimated by NMR) target 4-methylthio-2-thiophencarboxylic acid. Recrystallization from chloroform gives 4.11 g (23.6 mmol) of light-yellow solid product, so pl. 118 120oC (lit.T. sq. 123 124o(C) that contains 95% of 4-methylthio-2-thiophencarboxylic acid (purity estimated by NMR). Total output is 31%

Example 29. 5-/N,N-dimethylaminomethyl/-2-thiencarbazone acid.

Prepare diisopropylamide lithium, slowly adding 10.5 ml (about 26.5 mmol) of 2.5 M n-utility in hexano to 200 ml of tertrahydrofuran ring solution of 5.0 ml (35,7 mmol) Diisopropylamine, cooled in a bath of 2-propanol/dry ice, the temperature of the reaction support below -60o. After 5 min the reaction mixture was warmed to room temperature for 30 min, and then cooled again to a temperature below -70oC. Slowly add 100 ml of tertrahydrofuran ring solution of 3.4 g (17.8 mmol) 2-/N,N-dimethylaminomethyl/thiophene, prepared with the Alenia the reaction mixture was stirred for 30 min, and then bubbled through a solution of an excess of carbon dioxide. Then the solution is heated to 0oC and quenched with 50 ml of 1 n sodium hydroxide. Add portion 300 ml of diethyl ether to the water-tertrahydrofuran ring solution and separate phase in a separating funnel. The organic layer is extracted with 50 ml of 1 n sodium hydroxide. Combine both basic solution, washed with 50 ml of diethyl ether and acidified with concentrated hydrochloric acid. The acidic aqueous mixture is extracted with CH ml of diethyl ether. The ether solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, get 3,66 g (15.6 mmol) of the target product thiencarbazone acid as colorless solid product, so pl. 184 186oC (lit.T. sq. 170 172oC). The total yield is 87%

Example 30. 5-Aminosulfonyl-2-thiencarbazone acid.

Prepare diisopropylamide lithium, slowly adding of 26.5 ml (to 66.3 mmol) of 2.5 M n-utility in hexano to chilled in a bath of 2-propanol/dry ice tertrahydrofuran ring (200 ml) solution of 11.0 ml (about 78.5 mmol) Diisopropylamine, maintaining the reaction temperature below -60oC. After 5 min the reaction solution warmed to room temperature for 30 min, then again Oh) 2-aminosulphonylphenyl (prepared by the method of S. W. Slocum et al. OC 38, 4189, 1973), controlling the temperature of the reaction mixture below -70oC. After the addition, the reaction mixture is stirred for 30 min, and then bubbled through a solution of an excess of carbon dioxide. Then the solution is heated to 2oC and quenched with 50 ml of 1 n sodium hydroxide. Add portion 300 ml of diethyl ether to the water tertrahydrofuran ring solution and separate phase in a separating funnel. The organic layer is extracted with 50 ml of 1 n sodium hydroxide. Combine both basic solution, washed with 50 ml of diethyl ether and acidified with concentrated hydrochloric acid. The acidified aqueous mixture is extracted with CH ml of diethyl ether. The ether solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, gain of 2.56 g (12.4 mmol) of the target thiencarbazone acid as colorless solid product. Recrystallization from water gives 1,79 g (8.6 mmol) brown solid product, so pl. 228 231oC (lit. so pl. 231 232oC). The total yield is 43%

Example 31. 5-Chloro-3-/3-chloro-2-thenoyl/-2-oxindole-1-carboxamide.

Add an excess of thionyl chloride (3.5 ml, 48,0 mmol) of 0.85 g (5.2 mmol) of 3-chloro-2-thiophencarboxylic acid (prepared according to the method Cavial is I the solution is refluxed for 3 h to obtain 3-chloro-2-thiophenecarbonitrile. Countryowned reaction solution gives the acid chloride of the acid in the form of a white solid product. Then the acid chloride of the acid dissolved in 4 ml of dimethylformamide and slowly added to cooled in a bath of ice/water mixed solution of 1.0 g (4,71 mmol) 5-chloro-2-oxindole-1-carboxamide and 1.3 g (10.5 mmol) 4-/N,N-dimethylamino/pyridine in 10 ml of N,N-dimethylformamide. After 45 min the solution is allowed to warm to room temperature and after 2 h handle it, pouring into a mixture of ice /6 N. hydrochloric acid. Formed yellow precipitate. The precipitate is filtered off, washed with water and dried, to obtain 1.3 g of the contaminated product in the form of a yellow solid product. Recrystallization from a mixture of 2:1 acetic acid/heptane gives 0,77 g (2.2 mmol) of the desired product as yellow needles, so pl. 222 224oC. the Total yield is 42%

Analysis: Calculated for C14H8Cl2N2O3S C 47,34; H 2,27; N 7,89.

Found, 47,59; H 2,20; N 7,92.

EIMS (m/S): 354 (356) 358 (M+, 12% ), 311 (313/315 (M+-CHNO, 31%), 276/278/M+-CHClNO 14% ), 193/195 (M+-CHNO-C4H3ClS basis), 145/247/ C5H2ClOS 34%).

IH NMR (DMSO-d6) Delta, 8,18 (1H, Shir.with exchanged), 8,11 (1H, d, J= 8.5 Hz), to $ 7.91 (1H, d, J=5.3 Hz), 7,80 (1H, d, J=2 Hz), 7,60 (1H, 161,2, 152,5, 134,7, 129,4, 129,3, 127,8, 127,7, 125,7, 125,1, 124,0, 121,2, 116,1 and 104,1.

IR-spectrum (potassium bromide): 3386, 1732, 1618, 1575, 1375, 1274 and 1196 cm-1.

Example 32. 5-Chloro-3-/4-chloro-2-thenoyl/-2-oxindole-1-carboxamide 1.63 g (10.0 mmol) 4-chloro-2-thiophencarboxylic acid (obtained by the method Iriarte, J. et al. J. Het.Chem. 13:393, 1976) dissolved in 10 ml of thionyl chloride and heated to boiling under reflux. After such boiling for 1.5 hours, the excess thionyl chloride is evaporated, leaving 1.88 g of the crude 4-chloro-2-thiophenecarbonitrile in the form of a dark brown oil. This acid chloride was dissolved in 10 ml of N,N-dimethylformamide and added slowly to 40 ml of chilled (in a mixture of ice-water) N,N-dimethylformamide solution of 1.75 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25,0 mmol) of 4-(N,N-dimethylamino) pyridine. The reaction is complete within one hour. The mixture is then poured into 100 ml of 1 N. hydrochloric acid, which causes the formation of sludge. The crude solid product is filtered, dried and recrystallized to obtain 1.89 g (5.3 mmol, yield 64%) specified in the title compound in the form of yellow needles with tons of melting point 212 214oC (2-butanone).

Elemental analysis for C14H8Cl2N2O3S

Calculated C 47,34; H 2,27; /SUP>-CONH, C4H3Cl main) and 145/147 (C5H2OIOS),

IH NMR (DMSO-d6d to 3.38 (1H, d, J= 1 Hz), of 8.06 (1H, Shir.C), with 8.05 (1H, d, J=8.5 Hz), of 7.75 (1H, Shir.C) b (1H), Shir.D. J=8.5 Hz) and 5,94 (1H, Shir.in exchange).

IR (KBR): 3380, 3220 Shir. 1741, 1620, 1540, 1575, 1375, 1270, 1195 and 1180 cm-1.

Example 33. 5-Chloro-3-(5-chloro-2-thenoyl)-2-oxindole-1-carboxamide.

2,44 g (15.0 mmol) of a commercial sample of 5-chloro-2-thiophencarboxylic acid and 10 ml of thionyl chloride is subjected to interaction by the method of example 32. Yield of crude 5-chloro-2-thiophenecarbonitrile amounted to 2.64 g in the form of an oily solid product. Then this material is combined with 2,42 g (11.5 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence 3,52 g (28.8 mmol) 4-/N, N-dimethylamino/pyridine as in example 32. As a result of processing receive 4,33 g wet crude product. After drying and recrystallization get to 2.99 g (8,42 mmol, yield 73%) specified in the title compound as yellow crystals, so melting 220 222oWith /2-butanone/.

Elemental analysis:

Calculated for C14H8Cl2N2O3S C 47,34; H 2,27; N 7,89.

Found, 47,32; N 2,21; N 7,80.

ACE/EIMS /m/Z/: 354/356/358/M+, 22% ), 311/313/315 (M+-CONH, 60%), 193/195 (M+CONH-C4H3Hz), to 7.09 (1H, Shir.D. J=3.5 Hz), 6.89 in (1H, Shir.D. J=8 Hz) and a 4.86 (1H, Shir.in exchange).

IR (KBR): 3640, 1745, 1640, 1565, 1380, 1355, 1280 and 805 cm-1.

Example 34. 5-Chloro-3-/3-bromo-2-thenoyl/-2-oxindole-1-carboxamide.

By way of example 31, 2,07 g (10.0 mmol) 3-bromo-2-thiophencarboxylic acid (obtained by the method Reincke, M. G. et al. Synthesi - 327, 1980) is subjected to interaction with 1.1 ml (15.0 mmol) of thionyl chloride until receipt of 2.27 g of the crude acid chloride as a solid product. 10 ml dimethylformamide solution of 2.27 g (10.0 mmol) 3-bromo-2-thiophenecarbonitrile subjected to interaction by the method of example 32 from 1.75 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 3.05 g (25,0 mmol) 4-/N,N-dimethylamino)-pyridine in 40 ml of N,N-dimethylformamide. After processing gain of 3.28 g of a dark orange solid. After recrystallization of this solid product is obtained 1.63 g (4,08 mmol, yield 41%) specified in the title compound as an orange crystalline substance, so pl. 216 217o(2 butanone).

Elemental analysis:

Calculated for C14H8BrClN2O3S 42,08; H 2,02; N 7,01.

Found, C 42,15; H 2,05; N 7,0.

ACE-EIMS (m/Z): 398/400/402 (M+, 8% ), 355/357/359 (M+-CHNO, 21% 276/278/M+-CHNO-Br, 13% ), 193/195 (M-CHNO)-Cjenő), 8,10 (1H, d, J=8.5 Hz), 7,87 (1H, d, J=5 Hz), 7,81 (1H, Shir.D. J=1.5 Hz), 7,54 1H, Shir.with. in exchange) 7,21 (2H, m), and 5.7 (1H, Shir.in exchange); enol form: d 10,27 (1H, Shir.in exchange), 8,19 (1H, Shir.in exchange) 8,13 (1H, d, J=8,5 Hz to $ 7.91 (1H, d, J= 5 Hz), 7,81 (1H, Shir.D. J= 1.5 Hz), 7,60 (1H, Shir.with the exchange), 7,25 (1H, DV.d J=8.5 Hz) and of 7.23 (1H, d, J=5 Hz)

13C NMR (DMSO-d6d 167,0, 162,2, 152,4, 134,6, 131,4, 130,2, 129,8, 127,6, 125,5, 124,9, 121,1, 116,0, 111,5 and to 103.8

IR (KBr): 3375, 3217 Shir. 1726, 16170 1583, 1752, 1374, 1267 and 1196 cm-1.

Example 35. 5-Chloro-2-/4-bromo-2-thenoyl/-2-oxindole-1-carboxamide.

By way of example 32 2,48 g (12,0 mmol) 4-bromo-2-thiophencarboxylic acid (obtained by the method Zawesson S: J Arkiv for Kemi 11: 317, 1957) and 10 ml of thionyl chloride are combined and heated. In reaction get to 2.99 g of 4-bromo-2-thiophenecarbonitrile in the form of a dark oil. By way of example 32 the acid chloride, 2,11 g (10.0 mmol) of 5-chloro-2-oxindole-1-carboxamide and 3.67 g (30.0 mmol) of 4-(N,N-dimethylamino)pyridine is subjected to interaction in N,N-dimethylformamide to obtain a 4.03 g of the crude orange solid product. After recrystallization obtain 2.67 g (of 6.68 mmol, yield 66,8%) specified in the title compound as a yellow solid crystals, so pl. 217 219o(C) decomposition (2-butanone).

Elemental analysis:

Calculated for C14, 1%) 355/357/359 (M+-CHNO, 8%), 193/195 (M+-CHNO-C4H3Br, main) and 189/191 (C6H2BrOS 35%);

IH NMR (DMSO-d6d to 8.41 (1H, d, J=1.6 Hz), of 8.06 (1H, Shir.D. J=1.2 Hz), with 8.05 (1H, d, J=8.5 Hz), 7,86 (1H, Shir.C) 6,98 (1H, DD, J=8,5 Hz, 1.2 Hz) and 6,05 (Shir.in exchange).

IR (KBr) 3384, 3228 Shir, 1741, 1620, 1588, 1573, 1375, 1269, 1193 and 1180 cm-1.

Example 36. 5-Chloro-3-/5-bromo-2-thenoyl/-2-oxindole-1-carboxamide.

By way of example 32 2,07 g (10.0 mmol) of commercial 5-bromo-2-thiophencarboxylic acid is subjected to interaction with 10 ml of thionyl chloride to obtain 2.35 g of crude 5-bromo-2-thiophenecarbonitrile in the form of a red oil. All the crude acid chloride was combined from 1.76 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide by the method of example 32 using 3,05 g (25,0 mmol) 4-N, N-dimethylaminopyridine and 50 ml of N,N-dimethylformamide. After treatment with acid to obtain a solid product, which after recrystallization gives 1,77 g (4,43 mmol, yield 53%) specified in the title compound in the form of red-brown crystals. So pl. 228 229oWith (tetrahydrofuran).

Elemental analysis:

Calculated for C14H8BrClN2O3S C 42,08; H 2,02; N 7,01.

Found, 42,25; H 1,97; N 6,77.

ACE-EIMS (m/Z): 397/399/401 (M+, 5% ), 354/356/358 (M+

IR (KBr): 3386, 3208 Shir. 1750, 1569, 1375, 1344, 1203 and 794 cm-1.

Example 37. 5-Chloro-3-/5-iodo-2-thenoyl/-2-oxindole-1-carboxamide.

By way of example 32 1,96 g (7,72 mmol) 5-iodo-2-thiophencarboxylic acid (obtained by the method of example 3) is mixed with 10 ml of thionyl chloride and heated under reflux. In response gain of 2.10 g of crude 5-ion-2-thiophenecarbonitrile in the form of a yellow solid. This yellow solid is dissolved in 10 ml of N,N-dimethylformamide and added slowly to 40 ml of N,N-dimethylformamide solution of 1.75 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25 mmol) of 4-(N,N-dimethylamino)pyridine according to the method of example 32. After processing receive 3,18 g of the crude product as an orange solid product. After recrystallization from tetrahydrofuran obtain 1.47 g (3,29 mmol, yield 40%) of the net specified in the title compound in the form of pure orange crystals, so pl. 230 232oC.

Elemental analysis:

Calculated for C14H8ClIN2O3S C 37,65; H 1,81; N 6,27.

Found, With 37,93; H 1,73; N 6,13.

EIMS (m/Z): 446/448 (M+-CHNO, 13%) 237 (C5H2IO 39%), 193/195 is, J= 4.0 Hz), 7,38 (1H, Shir.d, J=4.0 Hz), 7,01 (1H, Shir.d, J=8.5 Hz) and lower than the 5.37 (1H, Shir.with the exchange)

NC (KBr): 3389 Shire. 3216 Shire. 1749, 1565 and 1373 cm-1< / BR>
Example 38. 5-Chloro-3-/4,5-dibromo-2-thenoyl/-2-oxindole-1-carboxamide.

By way of example 32 2.86 g (10.0 mmol) of commercial 4,5-dibromo-2-thiophencarboxylic acid is added to 10 ml of thionyl chloride to obtain a heterogeneous mixture. Heating of the reaction mixture helps homogenize the solution. After concentrating the reaction solution is get a 3.15 g of the crude 4,5-dibromo-2-thiophenecarbonitrile in the form of a brown oil. The crude acid chloride dissolved in 10 ml of N,N-dimethylformamide is added slowly to 1,76 g (8,33 mmol) 5-chloro-2-oxin Dol-1-carboxamide and 3.05 g (25,0 mmol) 4-/N,N-dimethylamino/pyridine in 40 ml of N,N-dimethylformamide in the conditions of example 32. After processing receive 2,82 g orange solid product, which is recrystallized from 2-butanol to obtain 1,61 g (3,37 mmol, yield 40% ) of the net specified in the title compound as a yellow solid product. So pl. 229 31oC.

Elemental analysis for C14H7Br2ClN22O3S

Designed, 35,14; N 1,47; N 5,85.

Found, 35,34; H 1,34; N 5,66.

ACE/EIMS/m/Z): 476/478/480/482 (M+, 4%) 433/435/437/439 (MI
H NMR (DMSO-d6d to 8.62 (1H, c) to 8.14 (1H, Shir.C) b (1H, d, J=8,5 Hz) 6,93 (1H, Shir.D. J=8,5 Hz) & 6.86 (1H, Shir.in exchange)

IR (KBr): 3397, 3238 Shir. 1748, 1614, 1574, 1375, 1193 and 816-1< / BR>
Example 39. 5-chloro-3-/4-methylthio-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. In the interaction of 1.74 g (10.0 mmol) of 4-methylthio-2-thiophencarboxylic acid (obtained by the method of example 28) with 10 ml of thionyl chloride receive 2,02 g of 4-methylthio-2-thiophene-carbonylchloride in the form of a yellow solid product. The acid chloride is combined with a 1.75 g (8,33 mmol) 5-chloro-2-oxynol-1-carb-oksamida in the presence of 3.05 g (25 mmol) of 4-(N,N-dimethylamino)pyridine in example 32. After processing receive 4,56 g of an orange solid product. After recrystallization get 1.40 g (3,82 mmol, 46%) of the net specified in the title compound as a yellow-orange solid product, so melting 216 19oWith (tetrahydrofuran).

Elemental analysis:

Calculated for C15H11ClN2O3S2< / BR>
C 49,11; H 3,02; N OF 7.64.

Found, With 49,06; H 3,09; N 7,53.

EIMS (m/Z): 366 (368 (M+, 6% ), 323/325 (M+-CONH, 20%), 193 /195 (M+-CONH-C5H6S 43%), 157 (C6H5O 66%) and 130 (C5H6main)

IN) and 2.52 (3H, C)

IR (KBr) 3387, 3220 Shir, 1741, 1616, 1588, 1376, 1195 and 1185 cm-1< / BR>
Example 40. 5-Chloro-3-/5-methylthio-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. 1,74 g (10.0 mmol) sample of 5-methylthio-2-thiophencarboxylic acid (obtained according to the method of Knight, S. W. et al. J. Chem. Soc. P. T. J. 791 (1983)) in turn of 1.93 g of the corresponding acid chloride in the interaction with 10 ml of thionyl chloride. The acid chloride is subjected to the direct interaction of 1.75 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 3.05 (25 mmol) of 4-(N, N-dimethylamino)pyridine according to the method of example 32. After processing the water-acid get to 3.02 g of an orange solid product. After recrystallization of the crude solid orange product from tetrahydrofuran get 1,32 g (3,57 mmol, 43% yield) of pure 5-chloro-3-/methyl-thio-2-thenoyl)-2-oxindole-1-carboxamide as an orange solid product. Determination of the melting point showed that the material melts first at 180oWith, then re-solidifies and then melts again at 247 250oC (with decomposition).

Elemental analysis:

Calculated for C15H11ClN2O3S2C 49,11; H 3,02; N OF 7.64.

Found, C 48,92; H 2,98; N 7,52.

5OS283%) and 130 (C5H6S2main)

IH NMR (DMSO-d6d 8,11 (1H, d, J=3,9 Hz), of 8.09 (1H, d, J=8,5 Hz) of 7.96 (1H, Shir.C), 7,12 (1H, Shir.D. J=3,9 Hz) was 7.08 (1H, Shir.m), 5,43 (1H, Shir.C) 2,63 (3H, s)

IR (KBr): 3362, 3191 Shir 1729, 1600, 1565, 1374, 1348 and 1190 cm-1.

Example 41. 5-Chloro-3-/3-methoxy-2-thenoyl/-2-oxindole-1-carboxamide.

2,00 (12,69 mmol) sample of 3-methoxy-2-thiophencarboxylic acid (obtained by the method Gronowitz.S. Arkiv for Kemi 12:239, 1958) is subjected to interaction with 10 ml of thionyl chloride by the method of example 32. After evaporation of the excess thionyl chloride remains 2.17 g of 3-methoxy-2-thiophenecarbonitrile in the form of solid crystals, so pl. 86 88oC. the acid chloride connect with 2.1 6 g (10,24 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 3,30 g (27 mmol) 4-/N, N-dimethylamino/pyridine according to the method of example 32. Damping of the aqueous acid, followed by filtration yields a yellow solid product, which was purified by recrystallization to obtain 1.04 g (2,96 mmol, yield 29% ) of 5-chloro-3-(3-methoxy-2-thenoyl)-2-oxindole-1-carboxamide in the form of a solid yellow color, so pl. 272 274o(Acetic acid).

Elemental analysis

Calculated for C15H11ClN2O4S

C 51,36; H 3,16; N 7,99.

Nai is. 2%), 141 (C6H5O2S 79%) and 114 (C5H6O2S main)

IH NMR (DMSO-d6d of 8.28 (1H, Shir.C), 8,13 (1H, d, J=8 Hz) 7,92 (1H, d, J= 5 Hz), 7,69 (1H, Shir.C), 7,56 (1H, Shir.with the exchange) of 7.23 (1H, DV.d J=8,1,5 Hz), 7,19 (1H, d, J=5 Hz) and 3,88 (3H, s).

IR (EVG): 3375, 3230 Shire. 17450 1574, 1383 and 1074 cm-1< / BR>
Example 42. 5-Chloro-3-/4-methoxy-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32, of 1.30 g (by 8.22 mmol) 4-methoxy-2-thiophencarboxylic acid (obtained by the method Gronowitz, S. Arkiv. for Kemi 12: 239, 1958) turn in 1.19 g of pure acid chloride (i.e. boiling 58 60oC, 0.03 mm) with 10 ml of thionyl chloride. The acid chloride is combined with 1.18 g (5,61 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 1.73 g (14,15 mmol) 4-/N,N-dimethylamino/pyridine to obtain 1.88 g of the crude product after acid treatment.

After recrystallization obtain 1.39 g (of 3.96 mmol, 71% yield) of pure 5-chloro-3-(4-methoxy-2-thenoyl)-2-oxindole-1-carboxamide in the form of a yellow solid product, so pl. 221 223o(Acetic acid)

Analysis: Calculated for C15H11N2O4S C 51,36; H 3,16; N 7,99.

Found, 51,16; N 3,11; N 7,84.

EIMS /m/Z/: 350/352 (M+, 27%), 307/309/M+-CONH, 71%/ 193/195 (M+-CONH-C5H6
d 8,08 (1H, d, J=8 Hz), 7,92 (1H, Shir.C.), 7,76 (1H, Shir. C. ), 7,10 (1H, Shir.D. J=8 Hz), 6,93 (1H, Shir.C.), are 5.36 (1H, Shir.with. in exchange) and of 3.80 (3H, s),

IR (KBr): 3388, 3216 Shire. 1746, 1613, 1588, 1378 and 1189 cm-1.

Example 43. 5-Chloro-3-/5-methoxy-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. When interacting with 10 ml of thionyl chloride from 1.75 g (11,06 mmol) 5-methoxy-2-thiophencarboxylic acid (obtained according to the method of product sice, J. J. Am.Chem.Soc. 75:3697 (1953)) receive 1.83 g of the corresponding acid chloride as a brown oil. When the compound 5-methoxy-2-thiophenecarbonitrile with 1,82 g (8,63 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 2.66 g (21,76 mmol) of 4-(N, N-dimethylamino)pyridine obtain 3.11 g of the crude product as a yellow solid product. After recrystallization from acetic acid to obtain 0.87 g of pure 5-chloro-3-/5-methoxy-2-thenoyl/-2-oxindole-1-carboxamide in the form of a solid yellow color so pl. 180 182oC.

Analysis:

Calculated for C15H11ClIN2O4S 51,36; H 3,16; N 7,99.

Found, 51,15; H Of 3.07; N To 7.77.

EIMS (m/Z): 350/352/M+22%), 307/309/M+-CONH, 81%), 193/195 (M+-CONH-C5H6OS, 75%), 141 (C6H5O2S 98%) and 114 (C5H6O2S OS (1H, Shir.C), 4.0 (3H, s).

IR (KBr): 3393, 3200 Shir. 1755, 1605, 1585, 1544, 1489, 1423, 1301 and 1052 cm-1.

Example 44. 5-Chloro-3-/5-ethoxy-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. In the interaction of 1.39 g (8,07 mmol) 5-ethoxy-2-thiophencarboxylic acid (obtained by the method member of SIEC, J. J. Am.Chem.Soc. 75:3697,1953) with 10 ml of thionyl chloride receive 1,05 g (5.51 mmol, yield (68%) of pure acid chloride after distillation (so Kip. 72 75o(0.1 mm) as a low melting solid product. The acylation of 0.94 g (4,46 mmol) 5-chloro-2-oxindole-1-carboxamide with 1,02 g (5,35 mmol) 5-ethoxy-2-thiophenecarbonitrile in the presence of 1.37 g (11,23 mmol) of 4-(N,N-dimethylamino) pyridine leads to obtain 1.50 g of crude solid product. After recrystallization of the crude solid product in acetic acid is obtained 0.20 g (0.55 mmol, 12% yield) of pure specified in the title compound as a yellow solid product.

So pl. 183 185oC.

Analysis:

Calculated for C16H13ClN2O4C 52,67; H 3,59; N 7,68.

Found, 52,70; N 3,49; N 7,60.

EIMS (m/Z): 366 (M+main) 321 (323 (M+-CONH, 80% ), 193 195 (M+-CONH-C6H8O 74%), 155 (C7H7O2S 72%) and 128 (C
IR (KBr): 3394, 3209 Shir, 1752, 1609, 1585, 1481, 1375, 1352 and 1296 cm-1.

Example 45. 5-Chloro-3-/4-acetoxy-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. In the interaction of 15 ml of thionyl chloride with 3,59 g (19,23 mmol) of 4-acetoxy-2-thiophencarboxylic acid (obtained by the method Bohlmann FV. et al. Chem.Ber. 106:497, 1973) receives a yellow oil. of 3.32 g (16,32 mmol) sample of 4-acetoxy-2-thiophenecarbonitrile connect with 2.85 g (13,52 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 4.16 g (34,07 mmol) of 4-(N,N-dimethylamino) pyridine to obtain of 5.40 g of the crude yellow product. After purification by recrystallization get 4,18 g (11,02 mmol, 82%) crude specified in the title compound as a yellow solid product. So pl. 222 224o(Acetic acid).

Analysis:

Calculated for C16H11ClN2O5S C 50,73; H 2,93; N 7,40.

Found, C 50,53; H 2,89; N 7,22.

EIMS (m/Z): 378 (M+, 3%), 355 (337 (M+-CONH, 12%), 293/295 (M+-CONH-COCH2, 9%) 193/195 (M+-CONH-C6H6O2main) 169 (C7H5O3S, 24%)

IH NMR (DMSO-d6d of 8.15 (1H, d, J=1.5 Hz), 8,07 (1H, d, J=8,5 Hz) 8,01 (1H, Shir. the UP>-1.

Example 46. 5-Chloro-3-(5-acetyl-2-thenoyl)-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. First, 2.0 g (of 11.75 mmol) 5-acetyl-2-thiophencarboxylic acid (obtained by the method Thames, S. T. et al. J. Het.Aum 3:104, 1966) is treated with 15 ml of thionyl chloride. After evaporation of the excess thionyl chloride receive resinous residue which is triturated with carbon tetrachloride to obtain 0,92 g (4,88 mmol, yield 42%) of 5-acetyl-2-thiophenecarbonitrile in the form of a light orange solid product. So melting 78 80oC. Then 0,90 g (4.77 mmol) of the acid chloride is subjected to interaction with 0,83 g (3.95 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.22 g (9.97 mmol) of 4-(N,N-dimethylamino)pyridine to obtain 1.42 g (3,91 mmol, 99%) of the net specified in the title compound after treatment aqueous acid and drying in the form of an orange-yellow solid product. So melting 218 21oC.

Analysis:

Calculated for C16H11ClN2O4S C 52,97; H A 3.06; N 7,71.

Found, C 52,76; H 3,01; N 7,58.

EIMS (m/Z): 362 (364 (M+, 1%), 319/321 (M1-CONH, 7%) 193/195 (M+-CONH-C6H6OS, 58%) and 153 (C7H5O2S main)

IH NMR (DMSO-d6d 8,08 (1H, is (KBr): 3379, 3170 Shir. 1734, 1672, 1607, 1599, 1573, 1354, 1264 and 1194 cm-1.

Example 47. 5-Chloro-3-/4-methylsulphonyl-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. When interacting with 10 ml of thionyl chloride with 1.39 g (6.7 mmol) of 4-methylsulphonyl-2-thiophencarboxylic acid obtained according to the method of F. Arndt et al. Chem.Ber 94: 1757 (1961), obtain 1.54 g of the crude acid chloride as a solid product. The whole amount of 4-methylsulphonyl-2-thiophenecarbonitrile connect with 1.28 g (6.1 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence of 2.24 g (to 18.3 mmol) of 4-(N,N-dimethylamino)pyridine. After treatment with acid to obtain 2.28 g of the crude product as an orange solid product. After recrystallization from 2-butanone get two servings not pure yellow crystalline product with a total weight of 2.18, After further purification by recrystallization obtain 1.19 g (2,98 mmol, yield 49%) of pure 5-chloro-3-/4-methylsulphonyl-2-thenoyl/-2-oxindole-1-carboxamide as a yellow crystalline substance, so pl. 228 230o(Acetic acid).

Analysis:

Calculated for C15H11ClN2O5S2C 45,17; H 2,17; N 7,02.

Found, C 45,05; H 2,68; N 6,83.

EIMS (M/Z): 398/400 (MSUB>O3S239%).

IH NMR (DMSO-d6d 8,83 (1H, d, J=1 Hz), 8,43 (1H, Shir.(C) to 8.12 (1H, Shir. D. J=1.5 Hz), 8,03 (1H, d, J=8.5 Hz), 6,91 DV.D. J=8,5 1,5 Hz), of 5.05 (1H, exchange) or 3.24 (3H, s).

IR (KBr): 3380, 3206 Shir, 3084, 1732, 1574, 1311 and 1138 cm-1.

Example 48. 5-Chloro-3-/5-methylsulphonyl-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32 of 2.06 g (10.0 mmol) sample of 5-methylsulphonyl-2-thiophencarboxylic acid (obtained by the method Cymerman. Craing J. et al. J. Chem.Soc. 237, 1954) is subjected to interaction with 10 ml of thionyl chloride to obtain 2.14 g of the crude acid chloride as a solid product. In the interaction of 1.75 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide from 5-methyl-sulfonyl-2-thiophenecarbonitrile in the presence of 3.05 g (25,0 mmol) of 4-(N,N-dimethylamino) pyridine to obtain 3,17 g of the crude product after acid treatment. After one recrystallization from acetic acid get 2,31 g (5,80 mmol, 70% yield) of pure 5-chloro-3-/5-methylsulphonyl-2-thenoyl/-2-oxindole-1-carboxamide in the form of a dark orange solid product. So pl. 212 214oC.

Analysis:

Calculated for C15H11ClN3O5S2C 45,17; H 2,78; N 7,02.

Found, C EUR 54.15; H 2,78; N 6,75.

C6H5O3S 23%)

IH NMR (DMSO-d6d a 8.34 (1H, d, J=4 Hz), of 8.06 (1H, d, J=1.5 Hz), to 7.99 (1H, d, J= 8.5 Hz), 7,69 (1H, Shir.D. J=4.0 Hz), 6.89 in (1H, DV.d, J=8,5 1,5 Hz), USD 5.76 (1H, Shir.in exchange) and of 3.32 (3H, s)

IR (KBr), 3366, 3162 Shire. 1732, 1580, 1318 and 1148 cm-1.

Example 49. 5-Chloro-3-(5-(N,N-dimethylsulfone)-2-thenoyl)-2-oxindole-1

carboxamid.

Specified in the title compound, receive by way of example 32. When interacting with 10 ml of thionyl chloride from 2.35 g (10.0 mmol) of 5-(N,N-dimethylsulfone)-2-thiophencarboxylic acid (obtained by the method of example 29) to obtain 2.58 g of the crude acid chloride as a solid product. of 2.54 g of the sample 5-/N,N-dimethylsulfone/-2-thiophenecarbonitrile connect from 1.75 g (8,33 mmol) 5-chloro-2-oxindole-1-carboxamide using an excess of 3.05 g (25,0 mmol) of 4-(N,N-dimethylamino)pyridine to obtain 3.55 g of the crude product in the form of a solid orange product. After recrystallization of the crude product get 2,40 g (5,61 mmol, yield 67%) of the net specified in the title product as a yellow-orange solid product, so melting 227 30oC (2-butanone).

Analysis: Calculated for C16H14ClN3O5S2C 44,91; H 3,30; N 9,82.

Found, C 45,02; H 3,26; N 9,62.

EIMS (M/B>2
S main)

IH NMR (DMSO-d6d and 8.50 (1H, d, J=3,9) 8,13 (1H, d, J=1.5 Hz) of 8.06 (1H, d, J= 8.5 Hz), 7,60 (1H, d, J=3,9 Hz), of 6.96 (1H, DV.d J=8,5 1,5 Hz), the 5.65 (1H, Shir.with. in exchange) and a 2.71 (6N, C).

IR (KBr): 3454 Shir, 3336, 1729, 1595, 1566, 1335, 1209 and 1155 cm-1.

Example 50. 5-Chloro-3-/4-methoxymethyl-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. 1.40 g (8,13 mmol) sample of 4-methoxymethyl-2-thiophencarboxylic acid (obtained according to the method of N. Nemec et al. Coll Crech.Chem.Comm 39:3527, 1974) is treated with 10 ml of thionyl chloride to obtain the crude acid chloride. Fractional distillation allocate 0,89 g of pure 4-methoxymethyl-2-thiophenecarbonitrile, so boiling 65 67o(0.05 mm). When interacting 0.88 g (4.61 mmol) of the acid chloride from 0.81 g (of 3.84 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 1.18 g (9,67 mmol) 4-/N,N-dimethylamino/pyridine obtain 1.27 g of orange solid product, isolated after treatment of aqueous acid. After recrystallization of the orange solid product with subsequent chromatographic processing on silica gel obtain 0.32 g (0.88 mmol, 23% yield) of pure 5-chloro-3-(4-methoxymethyl-2-thenoyl)-2-oxindole-1-carboxamide in the form of a greenish-yellow solid product, so pl. 193-195oC.

H 3,38; N 7,51.

EIMS (m/Z): 364/366 (M+, 21%) 332/334 (M+-CH3OH, 12%), 321/323 (M+-CHNO, 20%), 289/291 (M+-CHNO, -CH3OH, 56%) 193/195 (M+-CHNO-C6H8O), the main and 155 (C7H7O2S 44%).

IH NMR (DMSO-d6) d (1H, d, J=8.5 Hz), 7,98 (of 7.90 (1H, Shir.C) 7,71 (1H, Shir.C), 7,10 (1H, Shir.D. J=8,5 Hz) a 4.86 (1H, Shir.in exchange), was 4.42 (2H, s), and 3.30 (3H, s)

IR (KBr) 3391, 3222 Shir. 1744, 1615, 1587, 1574, 1380 and 1195 cm-1.

Example 51. 5-Chloro-3-/5-methoxymethyl-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 32. of 2.06 g (11,96 mmol) sample of 5-methoxymethyl-2-thiophencarboxylic acid (obtained by the method Jauda M. et al. Coll. Crech.Chem.Comm 27:1191, 1962) is heated with 20 ml of thionyl chloride. After completion of the reaction, the excess thionyl chloride is evaporated and the residue distilled to obtain 1,83 g (a 9.60 mmol, 80%) of pure 5-methoxymethyl-2-thiophenecarbonitrile in the form of a colorless oil, so boiling 62 67o(0.05 mm). After interaction of the acid chloride (total) with 1.68 g (8,00 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 2.46 g (20,16 mmol) 4-/N, N-dimethylamino/pyridine get 2,61 g orange solid product after treatment with acid. After recrystallization of the product get 0,98 g (2,69 mmol, yield 34%) of pure ptx2">

Analysis:

Calculated for C16H13ClN3O4S C 52,67; H 3,59; N 7,68.

Found, C 52,88; H To 3.64; N 7,55.

EIMS (m/Z): 364 (366 (M+, 19% ) 321 /323 (M+-CHNO, 27% ) 289/291 (M+-CHNO-CH3OH, 20%), 193/195 (M+-CHNO-C6H8OS core) and 155 (C7H7O2S 76%).

IH NMR (DMSO-d6d 8,08 (1H, d, J=8,5 Hz) 7,87 (1 or 2 N, Shir.C) 7,10 (1 or 2H, Shir.C) 4,89 (1H, Shir.in exchange) 4,63 (1H, s), and of 3.32 (3H, s)

IR (KBr): 3382, 3205 Shire. 1752, 1605, 1584 and 1287 cm-1.

Example 52. 5-Chloro-3-/5-N, N-dimethylcarbamyl-2-thenoyl/-2-oxindole-1 - carboxamide.

By way of example 32, of 1.25 g (6,27 mmol) 5-(N,N-dimethylamino/carbonyl/-2-thiophencarboxylic acid) obtained by the method of example 5, turn 1.32 g (between 6.08 mmol, yield 97%) of the corresponding acid chloride, so pl. 109 111oWith, when interacting with excess thionyl chloride. The compound 5-[(N,N-dimethylamino)carbonyl]-2-thiophenecarbonitrile with 1.06 g (of 5.05 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 1.56 g (of 12.73 mmol) 4-/N, N-dimethylamino/pyridine gives the orange solid product after acid treatment.

After recrystallization of the solid product is obtained 0,80 g (2.05 mmol, yield 40%) of the net specified in the title compound as an orange solid SUB>ClN3O4S C BR52.11; H OF 3.60; N OF 10.72.

Found, 51,85; H 3,49; N 10,42.

EIMS (m/Z): 391/393 (M+, 6%) 348/350 (M+-CONH, 10%), 193/195 (M+-CONH-C7H8OS core) and 182 (C3H8NO2S 56%)

IH NMR (DMSO-d6d 8,08 (1H, d, J=8.5 Hz), 8,00 (1H, d, J=4.0 Hz) of 7.96 (N Shire. C) of 7.48 (1H, d, J=4.0 Hz, 7,07 Hz), was 7.08 (1H, d, J=8,5 Hz) of 6.20 (1H, Shir.with the exchange) and 3,13 (6N, Shir.C).

IR (KBr): 3372, 3224, 1726, 1604, 1392 and 1193 cm-1.

Example 53. 5-Chloro-3-/3-fluoro-2-thenoyl/-2-oxindole-1-carboxamide.

The excess of thionyl chloride (3.0 ml 41,1 mmol) and 0,89 g (6,10 mmol) 3-fluoro-2-thiophencarboxylic acid (obtained by the method orral, C. et al, Heterocycles 23: 1431, 1985) are mixed in 10 ml of toluene and subjected to interaction by way of example 31. This gives the corresponding acid chloride as a yellow oil after processing. Yellow acid chloride are dissolved in 3 ml of N,N-dimethylformamide and subjected to interaction with 1,28 (6,10 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 1.64 g (13,42 mmol) 4-/N,N-dimethylamino/pyridine in 5 ml of N,N-dimethylformamide. After processing gain of 1.7 g of yellow solid product. After recrystallization of this material was obtained 0.65 g (yield 31%) specified in the title compound as yellow needles, so pl. 235 240o(Acetic acid).

ACE/EIMS /m/Z/ 338/340 (M+10% ) OF 295/297 (M+-CHNO, 45%), 193/195 (M+-CHNO-C4H3FS main) and 129 (C5H2FOS 70%)

IH NMR (DMSO-d6d to 9.15 (1H, Shir. S. currency) 8,28 (1H, Shir.with. in volume) 8,10 (1H, d, 8.5 Hz) 7,88 (1H, DV.in J=5,1 4,3 Hz) 7,81 (1H, d, J=1.5 Hz), 7,60 (1H, Shir.with. in exchange) 7,21 (1H, DV.d J=8,5 1,5 Hz) and 7,11 (1H, d, J=5,2 Hz).

13With NMR (DMSO-d6d 176,1 160,2 158, and 154,6 152,6 134,2 129,2 127,6 125,4 125,2 120,8 117,4 115,9 114,9 and to 114.7 and 103,0

IR (KBr): 3400, 3240 Shir, 1750, 1625; 1585, 1390, 1290, 1205 and 930 cm-1.

Example 54. 5-Chloro-3-/3-methylthio-2-thenoyl/-2-oxindole-1-carboxamide.

3-methylthio-2-thiencarbazone acid (obtained by the method Carpenter, A. J. et al. Tetraludron Jetter 26:1777, 1985) (2,61 g, 15.0 mmol) is subjected to interaction with 10 ml of thionyl chloride to obtain 2083 g of the crude 3-methylthio-2-thiophenecarbonitrile in the form of a light yellow solid product. Then the acid chloride is combined with to 2.57 g (12.2 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence 4,47 g (36.6 mmol) of 4-(N,N-dimethylamino)pyridine according to the method of example 32 to obtain of 3.73 g of the crude product as an orange solid product. This product is partially clean off by recrystallization from 2-butanone to obtain 1.44 g of a greenish yellow solid product. Net specified in the title of the product. Net connection is first melted at 178oWith, then re-solidifies and melts again at temperatures above 275oC (with decomposition).

Analysis:

Calculated for C15H11ClN2O3S2C 49,11; H 3,02; N OF 7.64.

Found, C 49,22; H 2,98; N EUR 7.57.

EIMS (m/Z): 366/369 (M+, 8%), 193/195 (M+-CONH-C5H6S248%) 157 (C6H5OS292%) and 130 (C5H6S2main)

IH NMR (DMSO-d6) d compared to 8.26 (1H, Shir.in exchange), 8,11 (1H, d, J=8.5 Hz), 7,87 (1H, d, J= 4.5 Hz), 7,71 (1H, Shir.C) 7,58 (1H, Shir.in exchange) 7,26 (1H, d, J=4.5 Hz), 7,21 (1H, Shir.D. J=8,5 Hz) and 2.43 (3H, s)

IR (EBr): 3388, 3198 Shir. 1727, 1670, 1611, 1571, 1367, 1265, 1191 and 805 cm-1.

Example 55. 5-Chloro-3-/4-acetyl-2-thenoyl/-2-oxindole-1-carboxamide.

0,78 g (4: 59 mmol) sample of 4-acetyl-2-thiophencarboxylic acid (obtained by the method Satonaka, H. Bull.Chem.Soc.Japan 56:2463, 1983) combined with 0.95 g (of 5.85 mmol) of 1,1'-carbonyldiimidazole in 10 ml of dimethylformamide and stirred at room temperature under nitrogen atmosphere. After 2 h, the contents of the reactor are transferred into an additional funnel and slowly added to lime 0.88 g (4,18 mmol) 5-chloro-2-oxindole-1-carboxamide and 1.38 g (111,28 mmol) of 4-N,N-dimethylamino-pyridine in 30 ml of N,N-dimethylformamide paramesh the 5oAfter completion of the addition, and then 24 h at room temperature. The reaction mixture is poured into 110 ml of 0.3 N. hydrochloric acid, which causes the precipitation of a greenish-yellow solid product. After filtration, followed by washing 3 N. hydrochloric acid and water to get the crude product which is recrystallized twice from acetic acid to obtain 0.34 g (0,94 mmol, yield 22%) of pure 5-chloro-3-/4-acetyl-2-thenoyl/-2-oxindole-1-carboxamide in the form of a greenish-yellow solvated complex with 0.2 equivalents of acetic acid, so melting 230 233oC.

Analysis:

Calculated for C16H11ClN2O4S C 52,55; H 3,17; N 7,47.

Found, 52,24; H 2,88; N To 7.61.

EIMS (m/Z): 362/364 (M+, 9%) 319/321 (M+-CONH, 43%), 193/195 (M+-CONH-C6H6OS, main) and 153 (C7H5O2S 79%)

IH NMR (DMSO-d6d 8,64 (1H, Shir.C) of 8.47 (1H, d, J=1.3 Hz) 8,07 (1H, d, J= 8.5 Hz), 8,00 (1H, Shir.C) 7,07 (1H, Shir.d J=9.5 Hz) 5,94 (1H, Shir.in exchange) and 2.52 (3H, s)

IR (KBr): 3387, 3230 Shir. 1743, 1692, 1623, 1592, 1577, 1384, 1272 and 1192 cm-1.

Example 56. 5-Chloro-3-/4-methylsulfinyl-2-thenoyl/-2-oxindole-1 - carboxamide.

The specified connection receive by way of example 55. Acyl activated is carbonyldiimidazole leads to the production of reactive intermediate compounds, which are used directly and connect with 1.65 g (7.8 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence 2,87 g (23.5 mmol) of 4-(N,N-dimethylamino)pyridine to obtain the crude yellow product. After thoroughly rubbing the yellow solid product with 2-butanone get 1,67 g (4,36 mmol, yield 56%) of pure 5-chloro-3-(4-methylsulfinyl-2-tenolol)-2-oxindole-1-carboxamide as a yellow solid. So melting 204 206oC.

Analysis:

Calculated for C15H11ClN2O4S2C 47,06; H 2,90; N 7,32.

Found, C 47,11; H-2.91 In; N 7,27.

EIMS (m/Z): 382/384 (M+, 7%), 339/341 (M+-CHNO, 16%), 193/195 (M+-CHNO-C5H6OS2the main one) and 173 (C6H5O2S231%)

IH NMR (DMSO-d6d at 8.36 (1H, Shir.C) of 8.27 (1H, Shir.C) 8,11 (1H, d, J=8.5 Hz), to 7.99 (1H, Shir.C) 7,13 (1H, Shir.d, J=8,5 Hz) and 2.88 (3H, s).

IR (KBr): 3385, 3220 Shir, 1721, 1612, 1573, 1376 and 1193 cm-1.

Example 57. 5-Chloro-3-/5-sulphonamido-2-thenoyl/-2-oxindole-1-carboxamide.

1.48 g (7.2 mmol) sample of 5-sulphonamido-2-thiophencarboxylic acid obtained by the method of example 30, is turned into allmydata in the reaction with 1.39 g (8.6 mmol) of 1,1'-carbonyldiimidazole. Intermediate allmydata connect directly with 1,26 G2,34 g of the crude orange solid product. After recrystallization obtain 1.22 g (3,05 mmol, 51% yield) of pure 5-chloro-3-/5-sulphonamido-2-thenoyl/-2-oxindole-1-carboxamide as a yellow-green solid product, so melting 227 229o(Acetic acid).

Analysis:

Calculated for C14H10ClN3O5S2C 42,06; H 2,52; N 10,51.

Found, C 41,78; H 2,48; N 10,51.

EIMS (m/Z) 399/401 (M+, 2%) 356/358 (M+-CHNO, 23%) 193/195 (M+-CHNO-C4H5NO2S2the main one) and 190 (C5H4NO3S253%)

IH NMR (DMSO-d6d 8,23 (1H, d, J=4 Hz) with 8.05 (1H, Shir.D. J=1.5 Hz), 8,02 (1H, d, J=8,5 Hz) 7,71 (Shir.in exchange) 7,49 (1H, d, J=4 Hz), to 6.95 (1H, DV. D. J=8,5 1,5 Hz) and 5.56 (Shir. in exchange)

IR (KBr): 3393, 3250, 3109 Shir. 1722, 1600, 1569, 1345, 1203 and 1150 cm-1.

Example 58. 5-Chloro-3-/5-/N-methylsulfonylamino/-2-thenoyl/-2-oxindole-1 - carboxamide.

Specified in the title compound was obtained according to the method of example 55. Acyl activation of 2.21 g (10.0 mmol) 5-/N-methylsulfonylamino/-2-thiophencarboxylic acid, obtained as described in example 2 1,95 g (12,0 mmol) of 1,1'-carbonyldiimidazole leads to the corresponding eliminating intermediate in 20 ml of N,N-dimethylformamide. This solution is transferred and added slowly to 1075 (8,33 mmol) 5-is now processing the reaction is obtaining 2.6 g of a yellowish-orange solid product. After recrystallization from acetic acid gain of 1.80 g (4,59 mmol, yield 55%) of the net specified in the title compound as a yellow solid product, so pl. 225 227oC.

Analysis:

Calculated for C15H12N3O5S2C 43,53; H 2,92; N 10,15.

Found, 43,49; N 2,86; N 10,15.

EIMS (m/Z): 413/415 (M+, 2%), 370 (372 (M+-CHNO, 20%), 205 (C6H768%) and 193/195 (M+-CHNO-C5H7main)

IH NMR (DMSO-d6d 8,32 (1H, d, J= 4 Hz), 8,08 (1H, d, J=1.5 Hz), with 8.05 (1H, d, J=8,5 Hz) 7,71 (Shir.with. in exchange) 7,53 (1H, d, J=4 Hz), 6,97 (1H, DV. D. J=8,5 1,5 Hz), 5,77 (1H, Shir.with. in exchange) and 2.54 (3H, s)

IR (KBr) 3433 Shire. 3323 W, 1731, 1607, 1566 and 1151 cm-1.

Example 59. 5-Chloro-3-/5-carboxy-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. 1.0 g (of 5.81 mmol) sample of commercial 2,5-typediabetes acid is subjected to interaction with 1.88 g (are 11.62 mmol) of 1,1'-carbonyldiimidazole in 15 ml of N, N-dimethylformamide to obtain activated elimidate. Slow addition of elliminate to 1,11 g (5,28 mmol) 5-chloro-2-oxindole-1-carboxamide and 1.92 g (15,68 mmol) 4-/N,N-dimethylamino/pyridine in N,N-dimethylformamide yields a yellow-green solid product of the compound in acetic acid. This leads to obtain 1.51 g (4.14 mmol, 78% yield) of 5-chloro-3-/5-carboxy-2-thenoyl/-2-oxindole-1-carboxamide as a yellow solid product, so melting 274 287oC.

Analysis:

Calculated for C15H9ClN2O5S C OF 49.39; H 2,49; N 7,68.

Found, 49,19; H 2,45; N 7,38.

EIMS (m/Z): 364/366 (M+, 171) 321/232 (M+-CHNO, 73%), 193/195 (M+-CHNO-C5H4O2S 98%) and 186 (unknown. main)

IH NMR (DMSO-d6d 8,10 (1H, d, J=4 Hz), of 8.09 (1H, d, J=8,5 Hz) 8,03 (1H, Shir.d, J=1.5 Hz), 7,74 (1H, d, J=4 Hz) and was 7.08 (1H, DV.d J=8,5 1,5 Hz).

IR (KBr): 3388, 3276, 1718, 1695, 1551 and 1273 cm-1< / BR>
Example 60. 5-Chloro-3-/4-methoxycarbonyl-2-thenoyl/-2-oxindole-1 - carboxamide.

Specified in the title compound, receive by way of example 55. A solution of 1.50 g (of 8.06 mmol) 4-methoxycarbonyl-2-thiophencarboxylic acid (obtained by the method of example 9) in 15 ml of N,N-dimethylformamide type of 1.57 g (9,67 mmol) of 1,1'-carbonyldiimidazole. Two hours later, the reactor is slowly added to 1.54 g (to 7.32 mmol) 5-chloro-2-oxindole-1-carboxamide and 2.66 g (a 21.75 mmol) of 4-(N,N-dimethylamino)pyridine in N,N-dimethylformamide. After acid treatment of the reaction solution, followed by filtration, dried and triturated with hot acetic acid to Agogo product, so melting 244 246oC.

Analysis:

Calculated for C16H11ClN2O5S 50,73; N. OF 2.93; N 7,40.

Found, 50,52; N 2,86; N 7,12.

EIMS /m/Z/: 378/380 (M+, 1%), 355/337 (M+-CONH, 7%) 193/195 (M+-CONH-C6H5O2main) 169 (C7H5O3S 35%)

IH NMR (DMSO-d6d 8,59 (1H, d, J=1.4 Hz), 8,48 (1H, Shir.C) of 8.06 (1H, d, J=8,5 Hz) with 8.05 (1H, Shir.C) 7,02 (Shir.D. J=8.5 Hz), with 4.64 (1H, Shir.with the exchange) and 3,82, C.

IR (KBr): 3383, 3217 Shire. 1746, 1590, 1375, 1279 and 745 cm-1.

Example 61. 5-Chloro-3-/5-methoxycarbonyl-2-thenoyl/-2-oxindole-1 - carboxamide.

By way of example 55 and N,N-dimethylformamide solution of 1.25 g (of 6.71 mmol) 5-methoxycarbonyl-2-thiophencarboxylic acid (obtained by the method of example 11) are added to 1.19 g (7,35 mmol) of 1,1'-carbonyldiimidazole to produce an activated acyl intermediate. The reaction solution of this intermediate compound is added slowly to 1.29 g (6,10 mmol) 5-chloro-2-oxindole-1-carboxamide and 2.02 g (16,54 mmol) 4-/N,N-dimethylamino/pyridine in N,N-dimethylformamide. After acid treatment followed by filtration, drying and recrystallization obtain 1.29 g (3,41 mmol, yield 56% ) specified in the title compound as a yellow t/SUB>H11ClN2O5S C 50,73; H 2,93; N 7,40.

Found, 50,76; N 2,84; N 7,38.

EIMS (C/Z): 378/380 (M+, 2%), 335/337 (M+-CONH, 11%), 193/195 (M+-CONH-C6H5O2S main) and 169 (C7H5O3S 46%)

IH NMR (DMSO-d6d is 8.16 (1H, d, J=3,9 Hz), with 8.05 (1H, d, J=8.5 Hz), 8,03 (1H, Shir.C), 7,78 (1H, d, J=3,9 Hz), 7,02 (1H, DV.d J=8,5 2,3 Hz), of 5.55 (1H, Shir.in exchange) and of 3.84 (3H, s).

IR (KBr): 3388, 3216 W, 1730, 1589, 1290 and 745 cm-1.

Example 62. 5-Chloro-3-/4-N, N-dimethylcarbamyl-2-thenoyl/-2-oxindole-1 - carboxamide.

Specified in the title compound, receive by way of example 55. 1.70 g (8,56 mmol) sample of 4-[(N, N-dimethylamino)carbonyl] -2-thiophencarboxylic acid (obtained by the method of example 5) is subjected to interaction with 1.77 g (10,90 mmol) of 1,1'-carbonyldiimidazole to get eliminating intermediate compound, which is added slowly to dimethylformamide solution of 1.64 g (7,80 mmol) 5-chloro-2-oxindole-1-carboxamide and 2.57 g (21,02 mmol) 4-/N, N-dimethylamino/pyridine. After acid treatment, followed by filtration receive an orange solid, which was recrystallized twice from acetic acid to obtain 0,86 g (2,19 mmol, yield 28%) of the net specified in the title compound in the form of Liz:

Calculated for C17H14ClN3O4S x 0.2 C2H4O2C WON WITH 51.75; H 3,69; N 10,41.

Found, C 51,58; H Of 3.46; N 10,42.

EIMS (m/Z) 391/393/M+, 26% 348/350 (M+-CONH, 20%), 193/195 (M+-CONH-C7H8NOS primary) and 182 (C8H8NO2S 46%)

1H NMR (DMSO-d6d is 8.16 (1H, Shir.C) 8,08 (1H, d, 8.5 Hz) of 8.04 (1H: Shir. C) to 7.95 (1H; Shir.C), 7,10 (1H, Shir.d, J=8,5 Hz) 6,38 (1H, Shir.with. in volume), of 3.07 (3H, Shir.C) 2,98 (3H, Shir.C)

IR (KBr): 3390, 3233, 1744, 1622, 1375 and 1195 cm-1.

Example 63. 5-Chloro-3-/4-/2-methyl-4-thiazolyl/-2-thenoyl/-2-oxindole-1 - carboxamide.

Specified in the title compound, receive by way of example 55. 1,25 g (5,55 mmol) sample of 4-/2-methyl-4-thiazolyl/-2-thiophencarboxylic acid (obtained by the method of example 18) turn in allmydata when interacting with 0,98 g (6.05 mmol) of 1,1'-carbonyldiimidazole in 15 ml of N,N-dimethylformamide. After completion of the reaction, this solution was transferred into an additional funnel and slowly added 1.06 g (5,04 mmol) 5-chloro-2-oxindole-1-carboxamide and 1.66 g (13,59 mmol) of 4-(N,N-dimethylamino)pyridine in 50 ml of N, N-dimethylformamide. Acid treatment followed by filtration and thorough rubbing with 2-butanone give 0.50 g (1.20 mmol) specified in the title compound in the form of Zheltov the UB>3
S2C 51,73; H 2,90; N 10,06.

Found, C 51,63; H 2,95; N 9,75.

EIMS (m/Z): 417"419 (M+, 1%), 374/376 (M+-CONH, 8%), 208 (C9H9NOS 34%), 193/195 (M+-CONH-C8H7208%) and 181 (C8H7NS2main)

1H NMR (DMSO-d[) d 8,44 (1H, Shir.C) 8,13 (1H, Shir.C) of 8.09 (1H, d, J=8,4 Hz), 7,94 (1H, Shir.C) 7,79 (1H, s), 7,10 (1H, d, J=8,4 Hz) 4,88 (1H, Shir.with. in exchange) and a 2.71 (3H, s).

IR (KBr): 3385, 2919, 1747, 1587, 1374, 1196 and 729 cm[.

Example 64. 5-Chloro-3-/5-bromo-2-furanol/-2-oxindole-1-carboxamide.

By way of example 32 1,91 g (10.0 mmol) of commercial 5-bromo-2-frankenboob acid dissolved in 10 ml thionyl chloride and heated to boiling under reflux in nitrogen atmosphere for 1 h, and the resulting acid chloride emit. 40 ml of N,N-dimethylformamide solution of 1.75 g (8.3 mmol) of 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25 mmol) 4-/N,N-dimethylamino/pyridine subjected to interaction from 2.09 g (10 mmol) 5-bromo-2-furancarboxylic in 10 ml of N,N-dimethylformamide. After reaction for 45 min the mixture is acidified, pouring with 250 ml of 1N. HCl. The resulting product is recrystallized from acetic acid, washed with acetic acid and hexane and dried overnight under vacuum at room temperature. Obtained the value of 1.37 g specified in the title compound.

Analysis:

Calculated for C[H[BrClN[O[ C 43,84; H 2,10; N 7,30.

Found, C 43,94; H 2,02; N 7,16.

EIMS /m/Z/: 382/384 (M[, 10% ) 339/341 (M[-CONH, 35%) and 193/195/M[-CONH-C[H[BrO, main)

[H NMR (DMSO-d[) d 8,50 (exchange) 8,08 (1H, d, J=8,5 Hz) 8,00 (1H, Shir. C) 7,81 (1H, d, J=3.5 Hz), 7,63 (1H, exchange), 7,16 (1H, Shir.D.) J=8.5 Hz), 6.90 to (1H, d, J=3.5 Hz) and 5,04 (in currency).

IR (KBr): 3382, 3220, 17350 17230 1620, 1587, 1533, 1464, 1379 and 1022 cm[.

Example 65. 5-Chloro-3-/6-chloronicotinoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. Allactivitya 823 mg (5,22 mmol) commercial sample of 6-chloronicotinic acid 924 mg (5,70 mmol) of 1,1'-carbonyldiimidazole leads to the corresponding reactive eliminating intermediate compounds, which are used directly and connect from 1.00 g (of 4.75 mmol) 5-chloro-2-oxindole-1-carboxamide in the presence of 1.57 g (is 12.85 mmol) of 4-(N, N-dimethylamino)pyridine to obtain the crude greenish-brown solid product. After recrystallization of this solid product is obtained 400 mg (1,14 mmol, yield 24%) of a greenish-yellow solid product, so melting 236 238[C (acetic acid).

Analysis:

Calculated for C[H[ClNO[ C 51,45; H 2,59; N 12,00.

Found, C 51,54; H 2,54;) d of 9.56 (1H, d, J=2.3 Hz) of 8.37 (Shir.with the exchange) 8,07 (1H, d, J=8,5 Hz) 8,01 (1H, DV.d J=8,2 2,3 Hz), 7,94 (1H, d, J=2.3 Hz), 7,60 (1H, d, J=8.1 Hz) 7,41 (Shir.with the exchange) 7,11 (1H, DV.d J=8,5 2,3 Hz) and 4.93 (Shir.with the exchange)

IR (KBr): 3390, 3210 and Shir. 1730, 1580, 1380, 1290, 1110 and 820 cm[.

Example 66. 5-fluoro-3-/4-chloro-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. 329 mg (2.02 mmol) of 4-chloro-2-thiophencarboxylic acid (obtained by the method Jriarte J. et al. K. Het. Chem. 393, 1976) connect with 358 mg (2.21 mmol) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethyformamide and intermediate imidazole connect directly from 357 mg (of 1.84 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence of 60 ml (4,96 mmol) of 4-(N,N-dimethylamino)pyridine. The crude yellow product is recrystallized and get 189 ml (0,558 mmol, 30% yield) solid yellow color. So melting 224 226[C (acetic acid).

Analysis:

Calculated for C[H[ClFN[O[S C 49,64; H 2,38; N 8,27.

Found, C 49,41; H 2,28; N 8,12.

EIMS/m/Z/: 338/340 (M[, 4%) 295/297 (M[-CONH, 19%), 177 (M[-CONH-C[H[ClS main) and 145/147 (C[H[ClOS 39%).

[H NMR (DMSO-d[) d 8,80 (Shir.with. in exchange, 8,42 (1H, d, J=1,8 Hz) of 8.04 (1H, DV. d J= 9,0 5,8 Hz), 7,80 (,1H, DV.d J=10,5 2,1 Hz) 7,74 (1H, Shir.C) 7,30 (Shir.C) exchange (6,74 1H, DDD, J=10,1 9,0 2,1 Hz) and 5.0 (Shir.with the exchange)

IR (KBr): 3392, 3242 (width>/P>To obtain the title compound using the method of example 55. 388 mg (2,38 mmol) sample of 4-chloro-2-thiophencarboxylic acid (obtained by the method Jriarte, J. et al. J. Het.Chem. 13, 393, 1976) turn in allmydata when interacting with 420 mg (2,59 mmol) of 1,1'-carbonyldiimidazole. The intermediate 4-chloro-2-thiophene-/1 imidazo/carboxamid connect directly with 486 mg (1,99 mmol) of 5-trifluoromethyl-2-oxindole-1-carboxamide in the presence of 657 mg (5.37 mmol) 4-/N,N-dimethylamino/pyridine to obtain 634 mg (1,63 mmol, 82%) specified in the title compound as a yellow solid product so melting 164 166[S.

Analysis:

Calculated for C[H[ClF[N[O[S C 46,34; H 2,07; N 7,21.

Found, C 46,29; H 2,07; N 7,79.

EIMS /m/Z/: 388/390 (M[, 7% ) 345/345 (M[-CONH, 25%), 227 (M[-CONH-CH[H[Cl main) and 145/147/C[H[ClOS, 26%).

[H NMR (DMSO-d[) d 9,10 (Shir.in exchange 8,63 (1H, d, J=1.1 Hz), 8,46 (1H, s), to 8.20 (1H, d), J=to 8.20 (1H, d, J=8,4 Hz), 7,69 (1H, d, J=1.1 Hz) 7,30 (Shir.with. in exchange) 7,20 (1H, DV.d J=8.4 and 1.4 Hz and 5,28 (Shir.with the exchange)

IR (KBr): 3397, 3233 (Shir.), 1747, 1583, 1324, 1270, 1188 and 1122 cm=[.

Example 68. 6-Chloro-3-/4-chloro-2-thenoyl/-2-oxindole-1-/N-ethyl/carboxamid.

Specified in the title compound, receive by way of example 55. Allactivitya 381 (mg (2.34 mmol) of 4-chloro-2-thiophencarboxylic acid (obtained from the SPO is iaccino-capable elimidate, used directly, and connect with 466 mg (1,95 mmol) 6-chloro-2-oxindole-1-/N,N-ethyl/carboxamide in the presence of 644 mg (5,27 mmol) of 4-(N,N-dimethylamino)pyridine to obtain 445 mg (59% ) of the crude yellow solid product. After recrystallization receive net specified in the title compound (200 mg, 0,522 mmol, yield 27% ) as a yellow crystalline solid. So pl. 164 166[C (acetic acid).

Analysis:

Calculated for C[H[Cl[N[O[S C 50,14; H 3,16; N 7,31.

Found, C 49,95; H 3,01; N 7,21.

EIMS (m/Z): 382/384/386 (M[, 5%), 311/313/315 (M [C[H[NO 21%) 193/195 (M [C[H[NO, C[H[ClS main) and 145/147 (C[H[ClOS 40%)

[H NMR (DMSO-d[) d 9,43 (Shir. with the exchange), to 8.34 (1H, d, J=1,8 Hz) to 8.12 (1H, d, J=1.9 Hz) of 8.04 (1H, d, J=8,2 Hz), 7,74 (1H, Shir.C)? 7.04 baby mortality (1H, DV.d J= 8,2,1, 9 Hz) 4.92 in (lat.in exchange) 3,29 (2H, Shir.kV, J=7,3 Hz) and of 1.13 (3H, t, J=7,3 Hz)

IR (KBr): 3336, 3084, 1720, 1530, 1375, 1196 and 809 cm[.

Example 69. 5-fluoro-3-/4-chloro-2-thenoyl/-2-oxindole-1-/N-tert-butyl/-carboxamide.

To obtain the title compound using the method of example 55. 390 mg (2,40 mmol) sample of 4-chloro-2-thiophencarboxylic acid (obtained according to the method of J. Iriarte et al. J. Het.Chem. 13, 393, 1976) is subjected to interaction with 481 mg (2,60 mmol) of 1,1'-carbonyldiimidazole to get eliminating intermediate compounds, oksamida and 659 mg (5,39 mmol) of 4-(N,N-dimethylamino) pyridine. Acid treatment followed by recrystallization gives specified in the title compound (260 mg, 0.66 mmol, yield 33%) as a yellow solid product, so pl. 202 5 [/acetic acid/.

Analysis:

Calculated for C[H[CFN[O[S C 54,75; H 4,08; N 7,10.

Found, C 54,21; H 3,76; N 6,94.

EIMS (m/Z): 394/396 (M[, 1%) 295/297 (M [C[H[NO, 28%) 177 (M[-C[-H[NO-C[H[ClS main) and 145/147 (C[H[ClOS 24%)

[H NMR (DMSO-d[) d of 9.55 (Shir.in exchange) of 8.37 (1H, d, 1,11 Hz) with 8.05 (1H, DV.d J=9,0 5,2 Hz) 7,81 (1H, DV.d J=10,5 2,0 Hz) 7,73 (1H, Shir.C) of 6.73 (1H, DDD J=10,5 9,0 2,0 Hz) 7,73 (1H, Shir.C) of 6.73 (1H, DDD, J=10,5 9,0 2,0 Hz) 4,13 (Shir. with the exchange) and 1.38 (N, C)

IR (KBr): 3305, 3075, 29880 1721, 1615, 1548, 1193 and 835 cm[.

Example 70. 6-Chloro-3-/4-chloro-2-thenoyl/-2-oxindole-1-carboxamide.

To obtain the title compounds used method of example 55. 463 mg (2,85 mmol) 4-chloro-2-thiophencarboxylic acid (obtained by the method Iriarte, J. et al. J. Het.Chem. 130, 393, 1976) turn in allmydata when interacting with 500 mg (3,09 mmol) of 1,1'-carbonyldiimidazole. The intermediate 4-chloro-2-thiophene-1-imidazolecarboxamide connect directly with 500 mg (2,37 mmol) 6-chloro-2-oxindole-1-carboxamide in the presence of 783 mg (6,41 mmol) of 4-(N,N-dimethylamino)pyridine to obtain 665 mg of the crude greenish-yellow solid. After precrystallizer. So pl. 231 3[C (acetic acid).

Analysis:

Calculated for C[H[Cl[N[O[S 47,34; H 2,27; N 7,89.

Found, C 47,11; H 2,11; N 7,73.

EIMS (m/Z): 354/356/358 (M[, 5% ) 311/313/315 (M[-CONH, 15%) 193/195 (M[-CONH-C[H[ClS, main) and 145/147 (C[H[ClOS 49%).

[H NMR (DMSO-d[) d 8,80 (Shir.in exchange) 8,31 (1H, d, J=1.1 Hz), 8,10 (1H, d, J= 2.2 Hz) 8,03 (1H, d, J=8,2 Hz) 7,74 (1H, Shir.C) of 7.36 (Shir.in exchange)? 7.04 baby mortality (1H, DV.d J=8,2 2,2 Hz) and 5.32 (Shir.with. in exchange).

IR (KBr): 3398, 3191 (Shir), 1749, 1726, 1587, 1368, 1196 and 807 cm[.

Example 71. 3-/4-Chloro-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. 831 mg (5,11 mmol) 4-chloro-2-thiophencarboxylic acid (obtained by the method Iriarte, J. et al. J. Het.Chem. 13, 393, 1976) connect with 897 mg (of 5.53 mmol) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide, and the intermediate imidazolyl connect directly with 750 mg (4.26 deaths mmol) 2-oxindole-1-carboxamide in the presence of 1.40 g (11,49 mmol) 4-/N,N-dimethylamino/pyridine. The crude yellow solid product (803 mg, 59% yield) is recrystallized from acetic acid to obtain 376 mg (1,17 mmol, yield 27%) of fluffy yellow crystals, so melting 221 - 223[S.

Analysis:

Calculated for C[H[ClN[O[S C 52,42; H of 2.83; N, a total of 8.74.

Found, With 52,04; N 2,62; N 8,51.

EIMS (m/Z): 320/322 ( (Shir. C) 7,83 (Shir.C) 7,75 (Shir.C) 7,30 (Shir) 7,08 (Shir) and 4.92 in (lat.with the exchange).

IR (KBr): 3392, 3243 (Shir) 3117, 1744, 1591, 1379, 1268 and 1183 cm[.

Example 72. 5-fluoro-6-chloro-3-/4-chloro-2-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive, using the method of example 55. 427 mg (2,62 mmol) sample of 4-chloro-2-thiophencarboxylic acid (obtained according to the method of J. Iriarte et al. J. Het.Chem. 13, 393, 1976) is subjected to interaction with 461 mg (2,84 mmol) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide to obtain activated elimidate. Slow addition of elliminate to 500 mg (2,19 mmol) 5-fluoro-6-chloro-2-oxindole-1-carboxamide and 721 mg (5,90 mmol) 4-/N, N-dimethylamino/pyridine in N,N-dimethylformamide yields a crude yellow product (635 mg, 78) after acid treatment. After recrystallization from acetic acid receives a yellow-brown crystalline solid product (390 mg, 1.05 mmol, yield 48% ), so pl. 235 237[S.

Analysis:

Calculated for C[H[ClFN[O[S C 45,05; H 1,89; N 7,51.

Found, C 44,81; H 1,87; N 7,44.

EIMS (m/Z): 372/374/376 (M[, 7%), 329/331/333 (M[-CONH, 23%) 211/213 (M[-CONH-C[H[Cl, main) and 145/147 (C[H[ClOS, 33%).

[H NMR (DMSO-d[) d: 9,00 (Shir.with the exchange) to 8.62 (1H, d, J=1.2 Hz), 8,14 (1H, d, J= 7,2 Hz), 8,02 (1H, d, J=11.2 Hz), 7,69 (1H, d, J=1.2 Hz), 7,25 Shire.(C) in omeprol/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. 750 mg (3.93 mmol) of 5-bromo-3-frankenboob acid (obtained according to the method of L. Amaral et al. J. O. C. 41, 2350, 1976) turn in allmydata when interacting with 690 mg (4,25 mmol) of 1,1'-carbonyldiimidazole. The intermediate 5-bromo-3-furan-/1 imidazo/carboxamid directly connect with 689 mg (3,27 mmol) 6-chloro-2-oxindole-1-carboxamide in the presence of 1.08 g (8,83 mmol) of 4-(N, N-dimethylamino)pyridine to obtain 500 mg (yield 40%) of the crude greenish-yellow solid product. After recrystallization obtain 143 mg (from 0.37 mmol, 11% yield) of pure specified in the title compound as a greenish solid product, so melting 232 234[C (acetic acid).

Analysis:

Calculated for C[H[BrClN[O[ C 43,83; H 2,10; N 7,30.

Found, C 43,54; H 2,00; N 7,19.

EIMS (m/Z): 382/384/386 (M[, 11%) 339/341/343 (M[-CONH, 30%), 260/262 (M[-CONH-Br, 90% ), 232/234 (unknown. 90%) 193/194 ([-CONH-C[H[BrO, 92%) and 173/175 (C[H[BrO[ main)

[H NMR (DMSO-d[) d 8,43 (Shir.in exchange) to 8.40 (1H, Shir.C) to 8.14 (1H, d, J= 1,8 Hz) 7,92 (1H, d, J=8,2 Hz) 7:54 (lat.with. in exchange), to 7.15 (1H, DV.d J= 8,2 1,9 Hz) of 6.96 (1H, d, J=1,8 Hz) and 4.04 Shire.with. in exchange).

IR (KBr): 3470, 3389, 3305 (Shir, 1757, 1718, 1579, 1387, 1198, 1122 and 015 cm[.

Example 74. 5-fluoro-3-/5-bromo-3-furoyl/-2-oxindole-1-/N-tert-butyl/-carboxamide.

Acid treatment gives the crude specified in the title compound (777 mg, 66% yield) as a yellow-brown solid product. After recrystallization obtain 256 mg (0,60 mmol, 22% yield) of off-white crystalline solid product, so melting 190 2[C (acetonitrile).

Analysis:

Calculated for C[H[BrN[O[ C 51,08; H 3,81; N 6,62.

Found, 50,98; H 3,57; N 6,62.

EIMS (m/Z): 423/235 (M[, 1%) 323/325 (M [C[H[O, 35%), 244 (M [C[H[O-Br, main) 216 (unknown. 95%) and 57 (C[H[, 99%)

[H NMR (DMSO-d[) d: 9,07 (Shir.in exchange), 8,44 (1H, d, J=1.4 Hz), 8,10 (1H, DV.D. J=9,0 4,1 Hz), to 7.67 (1H, DV.D. J=9,5 2,8 Hz), of 6.96 (1H, d, J=1,4) 6,91 (1H, DDD J=9,5, 9,0 2,8 Hz), 3,93 (Shir.since, in the currency and 1.36 (N, C)

IR (KBr): 3300, 3205, 2960, 1720, 1550, 1179 and 820 cm[.

Example 75. 5-Chloro-3-/5-bromo-3-thenoyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. 100 g (a 4.83 mmol) 5-bromo-3-thiophencarboxylic acid (obtained by the method described in J. Am. Chem. Soc. 76, l connect directly with 848 mg (4.02 mmol) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.33 g (10,89 mmol) of 4-(N,N-dimethylamino)pyridine. The crude green product (1.22 g, 76% yield) recrystallized to obtain 540 mg (1.35 mmol, 34%) of yellow solid product, so melting 239 240[C (acetic acid).

Analysis:

Calculated for C[H[BrN[O[S 42,07; H 2,02; N 7,01.

Found, 42,26; H 1,98; N 6,99.

EIMS (m/Z): 398/400/402 (M[, 39% ), 355/357/359 (M[-CONH, main) 276/278 (M[-CONH-Br, 30%), 193/195 (M[-CONH-C[H[HS 75%)

[H NMR (DMSO-d[) d: at 8.36 (Shir.in exchange) of 8.09 (1H, d, J=8.7 Hz, 8,08 (1H, d, J=1.6 Hz), the 7.85 (1H, d, J=2.0 Hz), 7,52 (Shir.in exchange) 7,49 (1H, d, J=1.6 Hz), 7,16 (1H, DD, J=8,5 2,0 Hz) and to 3.73 (Shir.with. in exchange)

IR (KBr): 3389, 3218 (W), 1744, 1585, 1391, 1272 and 1194 cm[.

Example 76. 5-Chloro-3-/5-chloro-2-thiopheneacetyl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive, using the method of example 55. to 1.00 g (5,66 mmol) 5-chloro-2-tifemoxone acid obtained by the method of Ford et al. J. Am.Chem.Soc. 72, 2109, 1950) is subjected to interaction with 995 mg (6,13 mmol) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide to obtain activated elimidate. Slow addition of elliminate to 994 mg (4,72 mmol) 5-chloro-2-oxindole-1-carboxamide and 1.44 g (to 11.79 mmol) of 4-(N,N-dimethylamino)pyridine in N,N-dimethylformamide yields a crude brownish-gray solid product (1.52 g, 87% yield). After Perekrest the th product (387 mg, 1.05 mmol, yield 22%), melting point 238 41[S.

Analysis:

Calculated for C[H[Cl[N[O[S C 48,74; H 2,68; N 7,51.

Found, C 48,79; H 2,73; N To 7.59.

EIMS (m/Z): 368/370/372 (M[, 4% ) 324/326/328 (M[-CONH, 4%) 237/239 (M [C[H[ClS, 49% ) and 194/195 (M[-CONH-C[H[ClS main) 8,07 (1H, d, J=8,5 Hz) 7,80 (1H, d, J=2.6 Hz), 7,12 (1H, DV.d, J=8,5 2,6 Hz) 6,94 (1H, d, J=4,1 Hz), make 6.90 (1H, d, J=4,1 Hz), 4,43 (2N, C) and 3,71 (Shir.with. in exchange)

IR (KBr): 3392, 3249 (Shir), 1724, 1695, 1664, 1582, 1381, 1287, 1202, 995 and 847 cm[.

Example 77. 5-Chloro-3-/5-methylthio-1,3,4-oxadiazol-2-yl/-2-oxindole-1 - carboxamide.

By way of example 32,30 ml of N,N-dimethylformamide solution 958 mg (4,55 mmol) 5-chloro-2-oxindole-1-carboxamide and 1.50 g (to 12.28 mmol) of 4-(N,N-dimethylamino)pyridine is subjected to interaction with 975 mg (5.46 mmol) of 5-methylthio-1,3,4-oxadiazol-2-carbonylchloride (U.S. patent 4001238). After acid treatment get the crude orange solid compound (1.25 g, 78% yield). Suspended in hot glacial acetic acid, filtered and receive the net specified in the title compound (710 mg, a 2.01 mmol, 44%) as a bright yellow solid product. So melting 297 79[S.

Analysis:

Calculated for C[H[ClN[O[S C 44,26; H to 2.57; N 15,88.

Found, C 44,37; H 2,52; N 15,66.

EIMS (m/Z): 352/354 (M[, 4% ) 309/311 (M[-CONH, 12%), 193/195 (M[-CONH-C[H[N[main OS)

[H NMR (DMSO-d[) d 8,54 (Shi is.

IR (KBr): 3496, 3348, 3107, 1728, 1551, 1442, 1306, 1216 and 849 cm[.

Example 78. Methyl-3-ethoxy-5-isoxazolecarboxylic.

Stir a suspension of 3.53 g (24,67 mmol) commercial sample of methyl 3-hydroxy-5-isoxazolecarboxylic in 50 ml of methylene chloride is treated dropwise with a solution of triethylorthoformate (5,62 g, 29,60 mmol) dissolved in 30 ml of methylene chloride at room temperature. After stirring overnight the solution was washed with water (2 x 30 ml), 5% sodium bicarbonate (230 ml) and again water. The organic layer is dried over magnesium sulfate and evaporated in vacuo to obtain the title compound (3,61 g, yield 86%) as a pale yellow solid product, so pl. 77 79[C.

[H NMR (DMSO-d[) d c of 6.65 (1H, s), 3,93 (2H, q, J=7.4 Hz), a 3.87 (3H, s), and to 1.21 (3H, t, J=7,4 Hz)

EIMS (m/Z): 171 (M[ 48% ), 156 (M[-CH[, 4%), 143 (C[H[NO[ 31%), 112 (C[H[NO[ 12%) and 69 (C[H[NO main.

IR (KBr): 3105, 1744, 1611, 1441, 1241, 1106, 974 and 797 cm[.

Example 79. 3 Ethoxy-5-isoxazolidinone acid.

Mix a solution of methyl-3-ethoxy-5-isoxazolecarboxylic obtained by the method of example 78 (3.00 g, 17,53 mmol) in 75 ml of 2n. sodium hydroxide is stirred at room temperature for 10 min, cooled in a bath of ice and acidified to pH 3 koncentrirane saturating the aqueous filtrate is chloride of sodium and extragere with ethyl acetate (CH ml). So get 2,46 g (yield 89%) specified in the title compounds. A sample recrystallized from acetonitrile, so pl. 210 213 [S.

Analysis:

Calculated for C[H[NO[ C 45,80; H 4,32; N 8,87.

EIMS (m/Z): 157 (M[-CH[, 22%), 129 (C[H[NO[, 70%), 112 (C[H[NO[, 15%) and 69 (C[H[NO, main) 1H NMR (DMSO-d[) d 6,51 (1H, s), 3,91 (2H, sq J=7,4 Hz) and 1.20 (3H, t, J=7,4 Hz)

IR (KBr): 3136 (W), 1726, 1626, 1238 and 984 cm[.

Example 80. 5-Chloro-3-/3-ethoxyethoxy-5-yl/-2-oxindole-1-carboxamide.

Specified in the title compound, receive by way of example 55. 1.50 g (of 9.55 mmol) 3-ethoxy-5-isoxazolecarboxylic acid obtained by the method of example 79, is subjected to the interaction with 1.68 g (10,34 mmol) of 1,1'-carbonyldiimidazole to get eliminating intermediate compound, which is added slowly to N,N-dimethylformamide a solution of 1.68 g (of 7.96 mmol) 5-chloro-2-oxindole-1-carboxamide and 2,62 g (21,48 mmol) of 4-(N,N-dimethylamino)pyridine. After acid treatment receive untreated specified in the title compound as an orange-yellow solid product (2,43 g, yield 87%). It is suspended in hot glacial acetic acid, and then filtered, obtaining the net specified in the title compound as a bright yellow solid (1.75 g, 5.00 mmol, yield 63%). So the water is CLASS="ptx2">

EIMS (m/Z): 349/351 (M 10%), 306/308 (M-CONH, 45%), 235/237 (M-CH NO 20%) and 193/195 (M-CONH, CH O 44%)

H NMR (DMSO-d) d 8,76 (Shir.in exchange) 8,01 (1H, d, J=8.6 Hz), of 7.97 (1H, d, J= 2.2 Hz), 7,30 (Shir.in exchange) of 6.96 (1H, DV.d J=8,6 2,2 Hz), 6,30 (1H, s), 4,98 (Shir.(C) in exchange) 3,86 (2H, sq J=7,4 Hz) and to 1.21 (3H, t, J=7,4 Hz)

IR (KBr) 3315, 3228 (Shir.), 1748, 1673, 1549, 1370, 843 and 819 cm

Example 81. Methyl-5-/3-methyl-1,2,4-oxadiazol-5-yl/-2-thiophenecarboxylate.

Stir a suspension of 5-methoxycarbonyl-2-thiophencarboxylic acid (1.50 g, of 8.06 mmol) in 15 ml of thionyl chloride is refluxed for two hours. The solution is cooled to room temperature and concentrated in vacuo to obtain an almost colorless oil, which was recrystallized in a vacuum. This solid product was dissolved in 5 ml of chloroform and added dropwise at room temperature to stir the mixture acetamidoxime (getting in the way Eloy, et al. Heln.Chim.Acta 45, 441, 1961) (657 mg, 8,86 mmol) and triethylamine (897 mg, 1,24 ml, 8,86 mmol) in 30 ml of chloroform. After complete addition the solution was stirred at room temperature for one hour and washed with water (2x20 ml). The organic layer is dried (magnesium sulfate), evaporated and the residue triturated with toluene to obtain the intermediate O-/2-methoxycarbonyl-5-feet J=7.9 Hz), 7,83 (1H, d, J=3,9 Hz), 7,83 (1H, d, J= 3,9 Hz), 6,54 (Shir.with. in exchange), 3,85 (3H, s), or 1.80 (3H, s). This material is used without further purification.

Part of 1.43 g (5,90 mmol) O-/2-methoxycarbonyl-5-thenoyl/-acetamidoxime suspended in 75 ml of toluene and heated to boiling under reflux overnight. The solvent is removed in vacuo, and the residue triturated with a small amount of toluene to obtain 1.10 g (83%) specified in the title compound as off-white crystalline solid product, so pl. 154 156C. This material is used directly without further purification.

Exact mass: 224,0241.

Calculated: 224,0256

EIMS (m/Z): 224 (M 98%) and 193 (MCHO, main) H NMR (DMSO-d) d 8,01 (1H, d, J=4.3 Hz) 7,92 (1H, d, J=4.3 Hz) 3,88 (3H, s) and 2.41 (3H, s).

Example 82. 5-/3-Methyl-1,2,4-oxadiazol-5-yl/-2-thiencarbazone acid.

A mixture of methyl 5-/3-methyl-1,2,4-oxadiazol-5-yl)-2-thiophenecarboxylate obtained by the method of example 81 (1,09 g, a 4.86 mmol) in 35 ml of 2 n sodium hydroxide diluted with 5 ml of ethanol and heated to 65C for thirty minutes. This solution is cooled in an ice bath and acidified to pH 2 with concentrated hydrochloric acid. After filtration and drying obtain 870 mg (yield 85% ) ukazannoj is from methanol, so pl. 226 S.

Analysis:

Calculated for CH OS C 45,70; H 2,88; N 13,33.

Found, C 45,57; H 2,75; N 13,37.

EIMS (m/Z): 210 (M main) and 153 (M-CHO, 99%) H NMR (DMSO-d) d of 7.97 (1H, d, J=3,9 Hz), 7,82 (1H, d, J=3,9 Hz) and 2,49 (3H, s).

IR (KBr): 3112 (Shir) 1699, 1289, 1112 and 840 cm

1. Derivatives oxyindole General formula

< / BR>
where X and Y are H, F, Cl, Br, C1-C6-alkyl, CF3;

R-CONR1R2where R1, R2H, C1-C6-alkyl,

< / BR>
where

< / BR>
F, Cl, Br, I, OR3, S(O)nR4, COOR5, CONR3R5, COR4, CN, NO2CH2OR5, OCOR4, SO2NR3R5, NR3R5N(R3)COR5,

where R3H, C1-C6-alkyl;

R4=C1-C6-alkyl;

R5H, C1-C6-alkyl;

n 0, 1, 2;

In H, F, Cl, Br, CF3C1-C6-alkyl, or Q -

< / BR>
< / BR>
< / BR>
or their pharmaceutically acceptable salts.

2. Connection on p. 1, where Q is

< / BR>
3. Connection on p. 2, where a And C1.

4. Connection on p. 3, And 4-C1.

5. Connection on p. 4, where X is 5-F, and Y is 6-C1.

6. Connection on p. 4, where X is 5-or C1 N.

7. The connection formulas

< / BR>
or its salt, where B1is 4 pasn3or B1is 4 or 5 position and is CON(CH3)2< / BR>
< / BR>
where H, F, Cl, Br, CF3or1-C6-alkyl;

R16C1-C4-alkyl.

 

Same patents:

The invention relates to organic synthesis and concerns a method for obtaining 7-substituted hepten-6-OIC acid, its derivatives and intermediates to obtain

The invention relates to veterinary medicine, in particular to methods for treating visceral mycosis rabbits, caused by a pathogenic fungus of the genus Aspergillus fumigatus

The invention relates to the field of medicines, in particular to the creation of drugs used in medicine and veterinary medicine for the treatment and prevention of diseases and conditions involving intoxication, vomiting, diarrhea, such as gastrointestinal diseases, food poisoning, septic conditions

The invention relates to new amino acid derivatives and their pharmaceutically acceptable salts, specifically to new amino acid derivatives and their pharmaceutically acceptable salts, which have an inhibiting activity against renin, to methods for their preparation, to pharmaceutical compositions containing them and to a method for the treatment of hypertension and heart failure in humans or animals

The invention relates to medicine, namely to drugs acting on the cardiovascular system

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to new biologically active compounds, namely derivatives of 2-mercaptobenzimidazole General formula

< / BR>
where n 0,2,5; R is allyl, dialkylamino or balance monocyclic saturated amine, which may contain an additional heteroatom R1and R2same or different: H, lower alkali, alkoxy or their pharmaceutically acceptable salts, which have a selective anxiolytic activity

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

EFFECT: valuable medicinal properties of composition.

9 cl, 6 dwg, 6 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with mixing water for injections, conservation agent, metronidasol till complete dissolving at 50-60 C, adding a buffer (NaOH solution) pH 4.5-6.5 at pre-estimated quantity of water, then one should sterilize the obtained medicinal form due to membranous filtration followed by sterile packaging. As a conservation agent one should apply sodium chloride at the quantity of 1.5-2.0 against metronidasol weight, then metronidasol solution should be supplemented with a half-volume of sodium chloride solution, after complete dissolving the obtained solution should be supplemented with the rest quantity of sodium chloride solution. As for membranous filtration it should be carried out by applying a capsule out of polypropylene with hydrophilic membrane of 1.2 mcm. The method provides no crystallization of an active substance during prolonged period of time.

EFFECT: higher therapeutic efficiency.

1 ex, 1 tbl

Up!