CS991A2 - Azaoxindole derivatives and method of their production - Google Patents

Description

The present invention relates to azaoxindole derivatives, in particular 4-, 5-, 6- and 7-azaoxindole derivatives and pharmaceutical compositions containing them. These means can be used for therapeutic purposes.

U.S. Pat. No. 4,569,942 discloses certain 2-oxindole-1-carboxamides of formula (0).

XO = C-NH-R2 where X is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy or alkylthio of 1 to 4 carbon atoms, trifluoromethyl, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, nitroso, phenyl, alkanoyl of 2 to 4 carbon atoms, benzoyl, tenoyl, alkylamido of 1 to 4 carbon atoms, benzamido or Ν, Ν-dialkylsulfamoyl of 1 to 3 carbon atoms in each X is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy or alkylthio of 1 to 4 carbon atoms, or trifluoro, 2 is alkyl of 1 to 4 carbon atoms, up to 6 carbon atoms, cycloalkyl of 3-7 carbon atoms, cycloalkenyl of 4-7 carbon atoms, phenyl optionally substituted, phenylalkyl of 1-3 carbon atoms, optionally substituted by naphenyl, phenoxyalkyl of 1 up to 3 carbon atoms in the alkyl radical, substituted on phenoxy, thiophenoxyalkyl of 1 to 3 carbon atoms, naphthyl, bicyclo [2.2.1] heptan-2-yl, bicyclo [2.2.1] -hept-5-en-2-yl or a group of the formula - (CH 2) n QR 0, wherein n is an integer of 0, 1 or 2, Q is a divalent radical derived from furan, thiophenopyrrole, parasol, imidazole, thia -zol, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, pyridine, tetrahydrothiopyran, pyrimidine, pyrazine, benzo [b] furan or benzeneEblthiophene and R0 represents a hydrogen atom or an alkyl moiety of 1 to 3 carbon atoms, R2 represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 carbon atoms, benzyl, furyl, thienyl, pyridine or a group of formula

wherein R5 and R6 are hydrogen, fluorine, chlorine, alkyl or alkoxy each having 1 to 4 carbon atoms or trifluoromethyl. - 3 -

Said patent discloses that 2-oxindole-1-carboxamide is a cyclooxygenase inhibitor and lipexygenase, has analgesic activity in mammals and can therefore be used against pain and to alleviate the symptoms of chronic diseases such as inflammation and pain associated with srheumatoid arthritis and osteoarthritis. U.S. Pat. No. 5,556,672 discloses certain 3-acylsulfated 2-oxindole-1-carboxamides of the general formula

wherein X, Y and are as defined for the compounds of U.S. Pat. No. 4,569,942.

According to the authors, these compounds have the same efficacy as those described in U.S. Patent No. 4,569,942. U.S. Patent Application No. 181,131, filed April 13, 1988 (Fitzer), discloses compounds of Formula 0.

Y

wherein X is hydrogen, chlorine or fluorine, Y is hydrogen or chlorine, and R is benzyl or theinyl, and their pharmaceutically acceptable base salts thereof. These compounds are said to act by inhibiting interleukin-1- (IL-1) biosynthesis and are therefore useful for the treatment of IL-1-mediated disorders and dysfunctions. In PCT Patent Application No. PCT / US88 / 03658, filed 18. October 1988 (Pfitzer) describe non-steroidal anti-inflammatory agents of the general formula

wherein X and Y are hydrogen, fluorine or chlorine, R 1 is 2-thienyl or benzyl, R is C 2 -C 10 alkanoyl, C 5 -C 7 cycloalkylcarbonyl, C 7 -C 10 phenylalkanoyl, chlorobenzoyl, methoxybenzoyl, thenoyl, omega-alkoxycarbonylalkanoyl, containing in the alkoxy group 1 to 3 and in the alkanoyl group 3 to 5 carbon atoms, further alkoxycarbonyl of 2 to 10 carbon atoms, phenoxycarbonyl, 1- (acyloxy) alkyl with 1 to 4 and C 2 -C 4 alkyl, C 2 -C 5 alkoxycarbonyloxy (C 1 -C 4) alkoxy, C 1 -C 3 alkyl (C 1 -C 3) alkyl, methylphenylsulfonyl or a dialkylphosphonate radical having an alkyl radical of 1 to 3 carbon atoms.

SUMMARY OF THE INVENTION

The compounds of the invention are anti-inflammatory and analgesic agents and inhibitors of one or more of the prostaglandin-Hg-synthetase and 5-lipoxygenase enzymes, and are also inhibitors of interleukin-1 biosynthesis. Said enzymes catalyze the in vivo synthesis of compounds known as prostaglandins and leukotrienes and mediators in various inflammatory c-patients. For example, aglandin-H2-synthetase is involved in the formation of various disease states, such as joint inflammation in mammals. Leukotrienes are known mediators of various diseases, such as asthma, inflammation of the joints, psoriasis, ulcers, stroke, heart attack and irritable bowel syndrome.

The ability of the compounds of the present invention to inhibit said enzymes, thereby inhibiting the synthesis of prostaglanins and leukotrienes, makes them useful in the prevention and treatment of prostaglandin and leukotriene mediated diseases.

Thus, the ability of compounds of formula I to inhibit IL-1 biosynthesis allows these compounds to treat the agents-mediated disorders and function of the immune system in mammals. Among IL-1 mediated diseases, for example, disorders of metabolism and connective tissue such as osteoporosis, disease of periodontium and other tissues can be mentioned. Immunological system dysfunctions are, for example, allergies, psoriasis, and systemic lupus eruption-hematosus.

The analgesic activity of the compounds of formula (I) allows their use in mammals for pain relief, for example, after surgery and injury. They can also be administered for a long time in chronic diseases such as inflammation and rheumatoid arthritis and in the case of pain associated with sosteoarthridis and other skeletal and muscle disorders.

The essence of the invention lies in the compounds of general formula I

wherein one of A, B, D and E is nitrogen and the others are -CH, X and Y are each independently hydrogen, OR 3 hydroxy, alkyl of 1 to 6 carbon atoms, CP 2, COR 3, halogen, e.g. fluorine, chlorine, bromine or iodine, COOR 3, CONR 3 R 3, CN, NO 2, SR 3, SOR 3, SO 2 R 3, and SO 2 NR 3 R 3, R 3 represents alkyl of 1 to 6 carbon atoms, phenyl, benzyl, allyl or hydrogen, wherein the phenyl radical and the phenyl portion of the benzyl radical are optionally substituted one or more independent substituents from the group of fluorine, chlorine, bromine, iodine, hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms and trifluoromethyl, R being alkyl of 1 to 8 carbon atoms, preferably 3 to 5 carbon atoms, preferably cycloalkyl; 8 carbon atoms, (CH 2) n R kn where n is 0 or 1, or NHR 1 where R 1 is cycloalkyl of 3 to 8 carbon atoms, hydrogen, phenyl, optionally substituted, heteroaryl optionally substituted in which heteroaryl is a group optionally substituted by thiophene and furan, and the phenyl and heteroaryl moiety is substituted by one or more independent substituents from the group of fluorine, chlorine, bromine, iodine and hydroxyl, and alkyl of 1 to 3 carbon atoms, or trifluoromethyl, and R6 is phenyl, thiophenyl or furan, in each case optionally substituted by one or more non-dependent substituents from the group of fluorine, chlorine, bromine, iodine, hydroxy, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 3 carbon atoms and trifluoromethyl; C 1 -C 6 or CONH a 4 wherein R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COr phenyl, optionally substituted, heteroaryl, optionally substituted, wherein the heteroaryl group is derived from thiophene and furan and the substituent on phenyl or the heteroaryl group is selected from one or two independent substituents from fluorine, chlorine, bromine, iodine, hydroxy, alkyl or alkoxy having 1 to 3 carbon atoms and trifluoromethyl, W is hydrogen, alkanoyl of 2 to 10 atoms carbon, C 5 -C 7 cycloalkylcarbonyl, C 7 -C 10 phenyl-alkanoyl C 2 -C 4 chlorobenzoyl, the-oyl, omega-alkoxycarbonylalkanoyl in C 3 -C 5 alkoxy, alkoxycarbonyl of 2 to 10 carbon atoms, phenoxycarbonyl, 1-acyloxyalkyl of 1 to 4 carbon atoms in the acyloxy group of 2 to 4 carbon atoms in the alkyl group, 1-alkoxycarbonyloxyalkyl of 2 to 5 carbon atoms in the alkoxy group and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl or alkyl of 1 to 3 carbon atoms, methylphenyloxysulfonyl and dialkylphosphonate of 1 to 3 carbon atoms in each alkyl moiety, provided that a) in the case of E is a nitrogen atom, then at least one of X and Y has a meaning different from hydrogen; b) when either R is NHR or R is alkyl of 1 to 6 carbon atoms, W is hydrogen.

The invention also relates to pharmaceutically acceptable acid addition salts or pharmaceutically acceptable salts. Examples of suitable acid salts may be acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic, e.g. benzenesulfonic acid and related acids. A preferred addition salt is a phosphoric acid salt. Typical salts of cave with primary, secondary and tertiary amine and salts with alkali metals and alkaline earth metals. Particularly valuable are ethanolamine, diethanolamine and triethanolamine. Particularly preferred are those compounds of formula I wherein 5 or E is nitrogen, at least one of X and Ϊ is chloro, R is (CHO) R15, n is 0, R is unsubstituted heteroaryl, R z is 4-CONHR, where R is hydrogen or alkyl of 1 to 6 carbon atoms.

Particularly preferred compounds of formula (I) are the following: 5-chloro-3- (2-thenoyl) -4-azaoxindole-N-tert-butylcarbamide, 5-chloro-3- (2-furoyl) -4-azaoxindole- N-tert-butylcarboxamide, 9-6-chloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide, 5-chloro-3- (2-thenoyl) -6-azaoxindole-1N-tert-butylcarboxamide, 5,6-dichloro-3- (2-theonyl) -4-azaoxindole-1N-tert-butylcarboxamide, 5-chloro-3- (4-methyl-2-thenoyl) -4-azaoxindole-1N-target. butylcarboxamide, 5-chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide, 5-chloro-3- (3-furoyl) -4-azaoxindole-1N- tert-butylcarboxamide and 5-chloro-3- (2-thenoyl) -4-azaoxindole-1 H -phenylcarboxamide.

Other specific compounds of formula I are as follows; 5-chloro-3- (3-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide, 3- (2-furoyl) -5-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide, 3- (2 -thenoyl) -6-trifluoromethyl-4-azaoxindole-1-carboxamide, 6-chloro-3- (3-furoyl) -5-azaoxindole-1N-tert-butylcarboxamide, 5-acetyl-3- (2-thenoyl) - 4-azaoxindole-1N-tert-butylcarboxamide, 5-cyano-3- (2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide, 3- (2-furoyl) -5-trifluoromethyl-6-azaoxindole-1N- cyclohexylcarboxamide and 5-chloro-3-phenylacetyl-6-azaoxindole-1N-tert-butylcarboxamide.

The invention also relates to compounds of the general formula V (V)

H-10 - wherein A, B, D, B, X and Y are as defined in formula (I). These compounds are intermediates for the preparation of compounds of formula (I).

The invention also relates to pharmaceutical compositions for the prevention or treatment of conditions in the group of chronic-inflammatory diseases such as asthma, psoriasis, rheumatoid arthritis and osteoarthritis, and immunological system dysfunction such as systemic lupus erythematosus in mammals including humans. An effective amount of a compound of formula (I) or an effective amount of a pharmaceutically acceptable salt thereof is administered to provide effective prevention or amelioration of said conditions. The compounds are usually administered together with a conventional pharmaceutical carrier.

Pharmaceutical compositions for preventing and treating pain in mammals, including humans, comprise an amount of a compound of formula (I) or a salt thereof acceptable from a pharmaceutical aspect that effectively prevents or alleviates pain, in addition to containing a pharmaceutical carrier.

Accordingly, the compounds can be used to prevent and treat the aforementioned group. In addition, pain relief may be used.

The invention also relates to pharmaceutical compositions for the inhibition of 5-lipoxygenase or interleukin-1 synthesis, including humans, the composition comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof effective to inhibit the synthesis of the above compounds. 3 together with a pharmaceutical carrier.

The invention also relates to pharmaceutical compositions for the inhibition of prostaglandin-Hg-synthetase synthesis in mammals including humans, the compositions comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof effective to inhibit the synthesis of the above, together with a pharmaceutical carrier.

The term "alkyl" refers to a monovalent saturated hydrocarbon radical having a straight, branched or cyclic 11-chain or combinations thereof. chain.

The compounds of formula (I) wherein W is as defined above are hydrogen precursors of compounds wherein W is hydrogen. When administered to mammals, a compound of formula (I) wherein W is hydrogen is released from the precursors by metabolic process.

The compounds of formula (I) exist in several tauary forms due to the presence of carbon in the carbonyl group at the 2-position of the azaoxindole ring and the carbonate of the acyl group, which is attached to the carbon atom at the 3-position of the ring. These compounds also exist as geometric isomers of the tautomeric structure in which a double bond exists between the nitrogen atom in the 1-position and the carbon atom in the half-ring. The invention relates to all tautomeric forms and geometric isomers of the compounds of formula (I).

Compounds of formula I wherein W is hydrogen atom may be prepared as shown in the following Reaction Schemes 1 to 5.

Unless otherwise indicated, the symbols A, B, D, E, X, Y, R 1, R 2, R 3, R 4, R 5 and R 6 in the above reaction schemes and the following explanations of these reaction schemes are as defined above. -12-

Schemft 1

-13-

Schema 2

IN

in

XII -14-

Scheme 4: <in

II o.

xvi

XV

XVII

-15-

Schemt 5

VIII

XX

Cl R '

AND

In Scheme 1, XIX can be obtained by reacting a compound of formula (I) by reacting a compound of formula (II) wherein Q is halogen with a dialkyl malonate of formula R 7 O 2 CCH 2 CO 2 R 8 wherein R 8 and R 8 are the same or different are alkyl of 1 to 6 carbon atoms or benzyl, or with cyanoacetate of formula ncch2c2r7, wherein R7 is as defined above, in an aprotic solvent such as dimethylformamide or 1,2-dimethoxyethane at -30 to 50 ° C. The preferred solvent is 1,2-dimethoxyethane and the preferred temperature is 25 ° C. The nitro compound of formula (III) is obtained in which G z-8 7 8 is COgR or cyano and R 1 and R are as defined above.

The compound of formula (III) is then reduced by introducing the corresponding amino compound of formula (IV) wherein S and G are as defined above, or to form a azaoxindole of formula (IV *) wherein G is as defined above. One or both of these products may be formed. The reaction is typically conducted under a hydrogen atmosphere in a suitable solvent in the presence of a metal catalyst at a temperature of 0 to 70, preferably 20 ° C, ie substantially at room temperature. A suitable solvent is methanol, ethanol, propanol, ethyl acetate and dimethylformamide, especially ethanol. A preferred catalyst is Reney nickel. The hydrogen pressure of the reaction is to be maintained in the range of 0.1 to 0.5, preferably 0.3 MPa. The catalyst is filtered off and the solvent is evaporated, whereby one of the compounds of the formulas IV or IV * or the compounds is obtained. - 17 -

It is also possible to reduce the nitro compound of general formula (III) using a metal, for example zinc, iron or tin and an acid, for example an aqueous solution of hydrochloric acid or acetic acid. This reaction also yields one of the compounds of Formulas IV or IV * 7 or both, wherein R and G are as defined above. A temperature range of 0 to 120 ° C, preferably room temperature is preferred.

Azaoxindoles of the formula V can be obtained from the corresponding compounds of the formulas TV or IV * wherein R 1 and G are as described above, after their isolation and reaction with dilute hydrochloric acid, hydrobromic acid. or sulfuric acid at a temperature of about 50 ° C to reflux, preferably at the reflux temperature of the reaction mixture.

Once the azaoxindole compound of Formula V is obtained, it is possible to obtain the azaoxindole-1-carboxamides of Formula I as follows. In the first step, a 3-acyl substituent is attached. This acylation reaction can be carried out by reacting a compound of formula V with a derivative of the appropriate acid of formula R 2 COOH in a lower alkanol, for example ethanol as a solvent in the presence of an alkali metal salt of a lower alkanol such as sodium ethoxide in a conventional manner . A typical derivative of said acid includes the chloride, anhydride of the formula R 2 COOCOR 2, alkyl esters of the formula R 2 COO- (alkyl of 1 to 6 carbon atoms).

An excess of the acid derivative may be used, the alkoxide may be present in an amount of 1 to 7 molar equivalents based on the acid derivative. Preferably, five equivalents of alkoxide and two equivalents of single alkyl ester or 7 equivalents of alkoxide and two equivalents of acid chloride or anhydride are used. 18 -

The reaction between the acid derivative of formula ROOH and the compound of formula V is usually initiated at 0-25 ° C. Then, the reaction mixture is usually heated to a temperature of 50 to 130, preferably 80 ° C, to complete the reaction. Under these conditions, the reaction time is usually several hours, for example 2 hours to several days, for example two days. The reaction mixture was then cooled, diluted with excess water and then acidified.

The alkylated product of formula (VI) can then be isolated by filtration or by conventional solvent extraction.

The compound of formula (VI) thus obtained may be reacted with chlorosulfonyl isocyanate to give a compound of formula (I) except that R 1 is CONH 6 O 2 Cl (hereinafter referred to as compound of formula (VII). inert under the reaction conditions, such as in a solvent which does not react with chlorosulfonyl isocyanate or the N-chlorosulfonyl-2-oxindole-1-carboxamide product of general formula (VII) Examples of suitable solvents include di-alkyl ethers, such as diethyl ether, cyclic ethers, as dioxane tetrahydrofuran, aromatic hydrocarbons such as benzene, xylene toluene, chlorinated hydrocarbons such as methylene chloride and chloroform, acetonitrile and mixtures of these solvents.

The reaction is usually carried out at room temperature to the reflux temperature of the solvent used. Temperatures in the range of 25 ° C to 110 ° C are usually suitable. However, temperatures lower than 20, for example up to -70 ° C, may be used if desired. However, if possible, temperatures below 0 ° C are used for economic reasons since lower yields are obtained at these temperatures.

The compounds of formula (VI) and chlorosulfonyl isocyanate are usually reacted in equimolar amounts, or up to 30% molar excess of chlorosulfonyl-isocyanate may be used, resulting in a molar ratio of 1: 1 to 1: 1.3. no other benefits and is not used for economic reasons. - 19 -

The chlorosulfonyl derivatives of the formula (VII) obtained in this way can be isolated or can be directly converted by hydrolysis in the same reaction vessel without isolation of the compound of the formula (I) wherein CONH2 is present. solvent.

Hydrolysis of the chlorosulfonyl derivative of formula VII is accomplished by contacting the compound with or without isolation with water, preferably a mixture of water and ice, with an aqueous acid solution or with an aqueous base solution. Water or aqueous acid solutions are usually suitable, even in cases where hydrolysis is carried out in a two-phase system. The rate of hydrolysis should be sufficient to overcome the solubility problems, the use of water alone is more cost-effective in terms of large-scale performance than other hydrolysis methods.

The amount of acid in this step is not critical. Less than or greater than equimolar amounts may be used. Also, the acid concentration is not critical. Usually 0.1 to 3.0 moles of acid per mole of the compound of the general formula (VII) are used when aqueous acid is used for hydrolysis. Usually, an acid concentration of 1 to 6 M is used to facilitate the reaction. The use of an aqueous acid is often useful when the intermediate of Formula VII is isolated and the hydrolysis is carried out in a single step. Suitable acids are hydrochloric, sulfuric, nitric, phosphoric, acetic, formic, citric and benzoic acids. Often, it is convenient to carry out the hydrolysis in a simple manner by mixing the N-chlorosulfonylcarboxamides in a dimethylsulfoxide solution with air at room temperature. Higher temperatures, especially greater than 50 ° C, can lead to subsequent product hydrolysis. Lower temperatures to dimethyl sulfoxide (DMSO) may also be used, but in this case the reaction rate is reduced. The reaction is readily observed using 1 H-NMR and DMSO-d 6 as solvent. After completion of the reaction, the mixture is poured into excess water and the asuric product is isolated by filtration. Solvents other than DMSO may also be used. An example of a suitable solvent may be chloroform and dimethylformamide.

Compounds of formula I wherein W is hydrogen atom, r! represents a group CONHR4 in which R6 is different from hydrogen, can be prepared according to Reaction Scheme 1 by reacting a compound of formula VI or a compound of formula VII with an isocyanate of formula R --N = C = O. Usually, the reaction is carried out by contacting a substantially equimolar amount of the reactants in an inert solvent at a temperature in the range of 25 to 150, preferably 80 to 130 ° C. In this sense, the inert solvent is a solvent that dissolves at least one of the reactants and does not adversely affect either the quaternary ingredients or the resulting product. Typical useful solvents are aliphatic hydrocarbons such as octane, nonane, decane and decalin, aromatic hydrocarbons such as benzene, chlorobenzene, toluene, xylenes, and tetralin, chlorinated hydrocarbons as 1,2-dichloroethane, ethers such as tetrahydrofuran, dioxane, 1 2-dimethoxyethane and di- (2-methoxyethyl) ether, polar aprotic solvents such as N, N-dimethylformamide,,, Ν-dimethylacetamide, N-methylpyrrolidone and sulfoxide can also be used. The reaction time depends on the reaction temperature, at a temperature in the range of 100 to 130 ° C, the reaction time is usually several hours, for example 5 to 10 hours. When a relatively non-polar solvent is used in the reaction of compounds of formula VI with an isocyanate of formula R 1 -N = C-O, the product usually precipitates from the solution 21 - upon completion of the reaction after cooling the reaction mixture to room temperature. In these cases, the product is usually isolated by filtration. However, when relatively polar solvents are used and the product does not precipitate from the solution after the reaction, it can be isolated by evaporation of the solvent. When using water-miscible solvents, it is also possible to precipitate the product by diluting the reaction mixture with water. the product precipitates, which can be recovered by filtration. The product can then be purified by conventional means, for example by recrystallization.

The reaction between the compound of formula VI and the isocyanate of formula R4-N = C = O can be accelerated by the addition of benzoate, for example tertiary amine such as trimethylamine, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine or Ν, Ν. -dimethylanlline. Typically, 1 to 4 equivalents of base are required. In this way, reaction temperatures of 20 to 100 ° C are allowed. After the reaction is complete, the reaction mixture is neutralized or acidified and the product can then be isolated as described above. Thus, the preferred conditions for producing compounds of formula IA wherein R 1 is CONHR 4 are: using DMSO as a solvent, temperature 80 to 100 ° C, using two equivalents of triethylamine as the base, using 1.5 equivalent isocyanate and a reaction time of 3 to 6 hours.

Isocyanates of the formula R4-N = C = O can be obtained by standard procedures described by Sandler Daro, Organic Functional Group Preparations, Vol. I, 2nd Ed. Academy Press, Inc., New Yor, N.Y., Chapter 12, pp. 364-369 (1983). A particularly suitable procedure is the reaction of the corresponding amine of the formula R 4 -NH 2 with phosgene according to the formula: R 4 -NH 2 + COC 12 -> R 4 -N = C = O + 2HCl 22 -

Process variants according to Scheme 1 for the preparation of compounds of formula V wherein X and Y are hydrogen, i. for the production of unsubstituted 4-and 6-azaoxindoles have been described, for example, in Finch et al., Journal of Organic Chemistry, 37, 51 (1972), Diasley and Hanbali, Syntheic Communications, 11, 743 (1981), Parrick et al. , Journalof the Chemical Society, 1531 (1974).

Schemes 2 and 3 illustrate other possible methods for the preparation of azaoxindoles of formula V.

According to Scheme 2, the azaindole of formula VIII is reacted with 3 equivalents of bromine to form the di-brominated compound of formula IX. Examples of suitable reagents are bromine, pyridinium bromide, perbromide and N-bromosuccinimide. The reaction is carried out in an inert polar solvent such as a mixture of tert-butyl alcohol and water or tert-butyl alcohol, preferably in a mixture of tert-butyl alcohol and water at a pH of 1 to 7. The reaction temperature is in the range of 0 to 50, preferably 25 °. C. The compound of formula (IX) obtained is then reduced with hydrogen as a gas to form the azaoxindole (V). The reduction is typically carried out at 25 to 50 ° C at a pressure of 0.1 to 0.5 MPa. The preferred temperature is 25 ° C, the preferred pressure is 0.3 MPa.

The azaoxindole derivatives of formula V wherein D is N- (5-azaoxindoles) can be obtained according to Scheme 2 in a different embodiment of the above process. Compounds of formula (VIII) wherein D is nitrogen are reacted with four equivalents of bromine (instead of three) to slowly adjust the pH of the mixture to 6.5 to 7 to give compounds of formula (IX) wherein X is atomomium , which is bonded to the carbon atom at the 7-position of the azaoxinol ring. Subsequent hydrogenolysis of the bond between the carbon atom and the bromine atom affords compounds of formula V wherein D is nitrogen. The reaction is usually carried out using 10% palladium on charcoal at a pressure of 0.1 to 0.5 MPa, preferably at 0.3 MPa. The preparation of compounds of formula V wherein A is nitrogen is described in Scheme 2, for example, in Marfat and Carta, Tetrahedron Letters, 28, 4027 (1987).

Scheme 3 illustrates another possible process for producing compounds of formula V and hence the compound of formula I. In this case, the compound of formula X is reacted with 2- (4-chlorophenoxy) acetonitrile to give compounds of formula XI wherein K is CN. The reaction is usually carried out in the presence of a strong base in a suitable solvent as described in Makosza et al., Liebigs, Inc. Chem., 1988, 203. A suitable tertiary alkoxide is hydrogen or potassium. A preferred solvent is potassium tert-butoxide. A suitable solvent is tetrahydrofuran, diethyl ether, and dimethylformamide. The preferred solvent is tetrahydrofuran. The reaction is carried out at -78 to 25 ° C, preferably -10 ° C. The compound of formula XI obtained is purified by neutralization of the reaction mixture using inorganic acid, preferably dilute hydrochloric acid and conventional extraction using ethyl acetate, diethyl ether or methylene chloride, preferably diethyl ether. The organic residue after extraction is reduced to yield the compound of formula XII in which K is CN. The reaction is usually carried out in a hydrogen atmosphere in a suitable solvent using a metal catalyst at a temperature of 0 to 70 ° C, preferably at a temperature of about 20 ° C. Suitable solvents are methanol, ethanol, propanol, ethyl acetate and dimethylformamide. Most preferred is ethanol. The preferred catalyst is Raney nickel. The hydrogen pressure should be maintained between 0.1 and 0.5 MPa, preferably 0.3 MPa. Filtration of the catalyst and evaporation of the solvent gave the resulting product of formula XII. 24 -

The compound of formula XII thus obtained is then cyclized to the azaoxindole of formula V by hydrolysis in aqueous inorganic acid. A suitable acid is sulfuric acid, hydrochloric acid and hydrobromic acid. A reaction temperature of 25 to 150, preferably 150, is suitable. In the following, the process of another embodiment of Scheme 3 will be described. In this case, the compound of Formula X is reacted with tert-butyl (phenylthio) acetate to give a strong base in a suitable solvent as described by JSakosza and Winaria, J. Org. Chem., 49 (1984). For example, sodium hydride or sodium hydroxide is suitable. Sodium hydroxide is preferred. A suitable solvent is dimethylsulfoxide, liquid ammonia and pyridine. The preferred solvent is methylsulfoxide. The reaction is carried out at -78 to 50, preferably at 25 ° C. The compound of formula XI is obtained in which K is CO2-tert-butyl, which compound is then purified as described above for compounds of formula XI wherein K is CN. The compound of formula (XI) wherein K is CO 2 - tert -butyl is then reduced to form a compound of formula (XII) wherein K is the same. The reduction can be carried out by the aforementioned catalytic hydrogenation of the compounds of formula XI wherein K is CN by non-reaction with a metal such as zinc, iron or tin in an acid such as aqueous hydrochloric acid or acetic acid. After isolation of the compound of formula (XII) in which K is CO 2 -t-butyl, the compound is cyclized with the corresponding azaoxindole of formula (V) by treatment with an acid in an inert solvent. Examples of suitable acids are hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid. A suitable solvent is methylene chloride, benzene and toluene. The preferred solvent is benzene. The reaction temperature is preferably in the range of 25 to 150, preferably 80 ° C. In some instances, for example, in the reduction of a compound of formula (I) wherein K is CO 2 - tert-butyl using a metal in the acid, cyclization of a compound of formula (XII) wherein K is CO 2 t-butyl in situ can be achieved. In the case of the cyclization tomtotype, a suitable temperature is 100 ° C and the preferred acid is acetic acid. The preparation of some of the compounds of formula V in which one of X and Y is methyl and the other is a hydrogen atom has been described by Daisley et al., Synthetic Communictions, (1), 53-57 (1975).

Compounds of formula I wherein R 1 is CONHR 3 and W is hydrogen may also be prepared according to Scheme 4. This procedure is a variation of Scheme 1 and involves acylation of the azaoxindole core at position 3 before by attaching the substituent R 1 to position 1. The process is carried out by reacting a compound of formula II with an ester of formula CH 2 (CO 2 B 2) 2 Bz = benzyl in an aprotic solvent such as 1,2-dimethoxyethane or Ν, β-dimethylformamide in the presence of a base, for example sodium hydride at -30 to 50 ° C. The reaction yields a compound of formula (XIV) which is then converted to the corresponding amine of formula (XV) and the azaoxindole of formula (XVI) as shown in Scheme 1 as described for the preparation of azaoxindoles of formula (V) from esters of formula (III). The azaoxindoles of formula XVI are then substituted at the 1-position to form the azaoxindoles of the formula

XVII, wherein R5 is a CONHR2 group, is reacted with an isocyanate re-A of the formula R -N = C = O according to Scheme 1 as described in the preparation of compounds of Formula I from a compound of Formula VI .

Reduction of the ester of formula XVII with hydrogen affords the corresponding carboxylic acid of formula VIII. This reaction is typically carried out at a pressure of 0.1 to 0.5 L at a temperature of 25 to 50 ° C in the presence of 10% palladium-on-charcoal catalyst. The acid of formula (VIIIV) is then heated to 50-200 ° C to give 26 - a compound of formula (XIX) which is not substituted at position 3 of the azaoxindole core.

The resulting compound of formula (XIX) is then reacted in the 3-position by reaction with an acid chloride (2) of formula (R) COOCOR to form a compound of formula (I). The reaction is usually carried out in a polar, aprotic solvent such as Ν, Ν- dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide or methylene chloride in the presence of a base such as triethylamine or 4-dimethylaminopyridine. The preferred solvent is N, N-dimethylformamide. During the slow addition of the acid chloride or anhydride to the solution of the compound of formula (XIX), the solvent and the base are typically cooled to 0 ° C. The reaction mixture was then allowed to warm to 25 ° C and further reacted at this temperature. The reaction time is about 30 minutes to 2 hours. At the end of the reaction, the reaction mixture is acidified and the product isolated, for example, by filtration. The isolated product can be washed, dried and further purified by conventional techniques such as recrystallization. p

The following procedure is preferred for the preparation of a compound of formula (I) wherein R is NHR 1 from compounds of formula (XIX). The compound of formula XIX is reacted with a compound of formula R 1 NCO. This reaction is usually carried out in a solvent inert under reaction conditions, preferably in a polar, aprotic solvent such as dimethylformamide, diethylformamide, N-methyl-2-pyrrolidine or dimethylsulfoxide. Furthermore, it is preferred to carry out the reaction in the presence of a base. These may be alkali metal and alkaline earth metal hydrides. In practice, the isocyanate is added to the oxindole derivative and the base in the appropriate solvent. It is preferred to use about 1 molar equivalent of isocyanate and base, with the best results 27 being possible at 5056 in excess of each.

It is preferable to mix the reactants cold, usually at -10 to 0 ° C, and then leave the reaction mixture to cool to room temperature. At room temperature to 45 ° C, the reaction is completed over a period of several minutes to 18 hours depending on the reactivity of the isocyanate used. Upon completion of the reaction, the product is isolated by adding a mixture of water and crushed ice to the reaction mixture, and then adding sufficient acid to adjust the pH to 2-5. The product can be filtered off or extracted with a water-immiscible solvent.

Scheme 5 illustrates the preparation of compounds of formula I wherein R 1 is alkyl of 1 to 6 carbon atoms using azaindole compounds of formula VIII. The azaindole of formula VIII is reacted with a compound of formula R 1 Br or R 5 R 1 wherein R 1 is alkyl of 1 to 6 carbon atoms to form an N-substituted azaindole of formula XX. The reaction is usually carried out in a solvent inert to the reaction conditions in the presence of a base. A suitable base is sodium or potassium hydroxide or sodium hydroxide. When using hydroxide, a suitable solvent is acetone and dimethylsulfoxide, preferably acetone. When hydride is used, a suitable solvent is dimethylsulfoxide and Ν, β-dimethylformamide. The reaction is usually carried out at 0 to 150 ° C. The preferred temperature is 25 ° C.

The following two procedures can be used to prepare N-substituted azaoxindoles of formula XIX wherein R 1 is an alkyl of 1 to 6 carbon atoms from the azaindole of formula XX.

The first is analogous to that shown in Scheme 2 for the preparation of N-substituted azaoxindoles of formula V from azaindoles of formula VIII. This process involves the formation of a dibromazaoxindole intermediate, similar to the intermediate of formula IX, except that the 1-position nitrogen is substituted with an alkali radical of 1 to 6 carbon atoms. 28 -

The second procedure involves the reaction of a compound of formula XX with N-chlorosuccinimide to form the 3-chloro-andindole of formula XXI. The reaction is usually carried out in a solvent inert under the reaction conditions, for example methylene chloride, chloroform or tert-butanol. The preferred solvent is methylene chloride. Suitable temperatures range from 0 to 80 ° C. The conversion of the 3-chlorazaindole of formula XXI to the azaoxindolefin XIX is carried out by reaction with a strong acid, for example phosphoric, sulfuric or perchlorate, using glacial acetic acid as solvent. A suitable temperature is 25 to 120, preferably about 60 ° C. The preferred acid is phosphoric acid. The reaction time ranges from 1 hour to 7 days depending on the substrate and the temperature used.

The azaoxindole derivatives of formula (XIX) wherein R1 is C1-6 alkyl are converted into compounds of formula (I) wherein R1 is as described in Scheme 4 for the preparation of compounds of formula (I) from compounds of formula (XIX).

Compounds of formula (I) wherein W is different from hydrogen, i.e., precursors of compounds wherein W is hydrogen, may be prepared by two methods starting from the appropriate 3-acyl-3-azaoxindole-1-carbox amide or N-substituted carboxamide. In carrying out the first of these processes, a solution of the appropriate 3-acylazaoxindole-1-carboxamide or N-substituted carboxamide and an equimolar amount of triethylamine is treated in a solvent inert under the reaction conditions, for example in chloroform or tetrahydrofuran with a small excess of the respective acid chloride. , chloroformate, oxonium salt or alkylating agent at a temperature of -10 to + 10 ° C, preferably 0 ° C. The reaction mixture was allowed to warm to room temperature and maintained at that temperature for 2 to 3 hours. If the starting oxindole is not completely consumed, it is necessary to re-cool the mixture, add an additional amount of acylating or alkylating agent and a corresponding amount of triethylamine and repeat the process until all of the starting oxindole has been recovered. The product was isolated from the reaction medium after being washed with 1N hydrochloric acid and extracted with saturated sodium bicarbonate solution. The evaporation residue of the solvent in the vessel is purified by recrystallization or chromatography. In some cases, the product can be directly isolated by filtration of the reaction mixture to isolate the insoluble product.

The second method involves contacting the appropriate 3-acylazaoxindole-1-carboxamide or N-substituted carboxamide with a 3-fold molar excess of the corresponding alpha-chloroalkyl carbonate, five times the excess of iodide, in an anhydrous, inert reaction solvent such as acetone. The reaction mixture was then refluxed for 16 hours at the boiling point of the solvent. The reaction mixture is diluted with water and extracted with a water-immiscible solvent such as diethyl ether or chloroform. Evaporation of the solvent gave a product which could then be purified by recrystallization and / or chromatography. In each of the above reactions, the pressure is not critical. It is possible to use a pressure of 0.05 to 5 MPa, usually a pressure of 0.1 MPa is used for economic reasons.

Addition salts of the compounds of formula (I) may be prepared in conventional manner by treating the solution or suspension base (I) with about one chemical equivalent of a pharmaceutically acceptable acid. Common salt concentration and re-crystallization techniques are used. The base addition salts of these compounds can be obtained by reacting the compounds of formula I with about one chemical equivalent of an organic or inorganic base.

The ability of compounds of formula (I) to inhibit interleukin 1 biosynthesis can be demonstrated by the following biological tests.

C3H / HeN mice (Charles River, Wilmington, Massachusetts) are sacrificed by ligament fracture and 70% ethanol sprayed on their abdominal duodenum to prevent bacterial contamination of the following cell preparations. 8 ml of RPMI medium containing 5% FCS, 100 units / ml penicillin and 100 µg / ml strepromycin and 2 mM glutamine are injected into the peritoneal cavity of each mouse. RPMI-1640 can be obtained from Hazelton Research Products, Inc., Lenexa, Kansas. FCS is a fetal body that has been altered to provide IL-1 responses in a thymocyte assay (Hyclone Laboratories, Logan, Utah) and low spontaneous proliferation in the absence of IL-1. Bend the peritoneum to release the cells. Then the abdominal skin is incised so that the muscle layer is accessible. The peritoneal fluid is removed by the injection needle (# 20), which is introduced through the muscle layer into the abdominal cavity just below the breast bone. The liquid obtained from 6 mice is mixed in a plastic tube with a conical tube and microscopically tested for bacterial contamination. The non-contaminate liquid is centrifuged at 600 g for 6 minutes and the supernatant is decanted. The settled cells from 5-6 tubes are mixed and resuspended in 20 ml RPMI-1640 medium containing 5% FCS. The cell number is then determined using a hemocytocyte, the viability of the cells is determined by trypan blue using the same instrument. The cells were then diluted to 3 x 10 5 cells / ml using the same medium. 1 ml of the thus obtained cell suspension is placed in the wells of 35 mm wide wells. Cells are incubated for 2 hours at 37 ° C in a 5% carbon dioxide atmosphere to capture macrophages on the walls of the well. The supernatant is removed by pouring. The adherent cells, i.e. macrophages, are washed twice with RPMI containing 100 units / ml penicillin, 100 µg / ml strepromycin and 2 mM glutamine. Then, 1 ml of test substance is added at a concentration of 0.1 to 100 µg / ml in the same medium or only the maintenance medium (RPMI-SF) is added as a control. LPS is then added to each 100 / µl well in RPMI-SF (1 mg / f ft / 5 ml) and the plates are incubated at 37 ° C for 24 hours with 5% carbon dioxide. LPS is a refined purified lipopolysaccharide from Salmonella minnesota that has been shown to be non-responsive to C3H / HeN strain. The supernatants are then removed and examined for IL-1 immediately or frozen and tested later.

The IL-1 assay is performed quantitatively by nareceptor binding as described below. The standard curve is drawn as follows: '6

Mouse thymoma EL4-6.1 cells (10-15 x 10 cells 0.4 ml binding buffer consisting of RPMI 1640 with 5% FCS, 25 mM Hepes, 0.01% NaN 4 at pH 7.3) are added to the rat the amount of unlabeled mouse rIL-1. It is a recombinant IL-1 derived from Escherichia coli, an amino acid chain of 115 to 270 for IL-1 has been published in LomedicoP. M. et al., Nature, 312, 458-462 (1984) · Add 40 pg to 40 ng of this substance in 0.5 ml buffer and incubate for 1 hour at 4 ° C with continuous shaking, followed by 0.8 ng, 0.1 ml human 125 I-rIL-1 (New England Nuclear, Boston, Masachusetts) and the material was shaken for 3 hours. Samples were filtered (Yeda apparatus, Linea Co., Tel-Aviv, Israel) using a 2.4 cm glass fiber filter layer (Whatman GF / C), filters blocked with 0.5% powdered milk for 2 hours at 37 ° C and then washed with 3 ml of buffer at a temperature of 12 ° C. A gamma-32-irradiation (Searle) computer is used to read the filters, non-specific binding is determined in the presence of the test compound and 200 ng of unlabeled rIL-1. The calibration curve is obtained by plotting the log (Y / 100-Y) against 125 log C, where Y is the control binding of I-rIL-1 in percent and C is the concentration of unlabeled rIL-1. The linear least-squares line is passed through the Y-values in the range of 20-80%. The IL-1 in the supernatant is determined by replacing the diluted supernatants in the above rIL-1 assay and then measuring the percent binding to determine IL-1 concentration according to known standard fence (Hill plot). Each dilution is examined twice, and only those dilutions in which 20-80% of the Y-values are obtained are usually used to calculate the mean IL-1 values.

The ability of the compounds of formula (I) to cause adhesion of prostaglandin H2 synthetase and 5-lipoxygenase can be determined as follows. In this process, it measures the amount of known prostaglandin-H2-synthase and 5-lipoxygenase products in cells that have been pretreated with the test compounds, inhibiting both enzymes by decreasing the amount of known products of these enzymes or by their complete absence. .

RBL-1 cells were grown in a continuous layer for 1 to 2 days (Spinner culture) in Eagle's minimal Earle base mixture and 15% fetal serum bovine, supplemented with a solution of antibiotics and antifungal agents (Gibco) according to Jakschik BA et al. , Nature 287, 51-52 (1980). The cells were washed twice and then resuspended in cold RPMI 1640 to a cell density of 4 x 10 5 cells / ml. 0.5 ml of the solution of the substance to be examined is then added at the desired concentration in RPMI 1640 and the mixture is allowed to stand for 5 minutes at 37 ° C. Then, 0.25 ml of pre-warmed cell suspension is added and the mixture is incubated for 5 minutes at 37 ° C. Then 10 µl of C-arachinonic acid-containing solution and A-23187 (calcium-containing ionophor), Sigma Chemical) was added and incubated for a further 5 minutes at 37 ° C. - 33 -

Then, 267 µl of a mixture of acetonitrile with 0.3% acetic acid were added and the mixture was allowed to stand on ice for 30 minutes. The tube is then mixed with the mixture, centrifuged at 3000 rpm for 10 minutes, decanted and the supernatant centrifuged for two minutes in a microcentrifuge at high speed. The 100 µl of supernatant was then analyzed by HPLC using a Perkin Elmer-HS column (3 µm) using an acetonitrile in water gradient of 0.1% trifluoroacetic acid at a flow rate of 2 ml / min. Detection of radioactivity was performed using a Berthold LB-504 Radioactivity Monitor equipped with a 800 µL flow cell, the material flowing out of the blend mixed with Omnifluor (New England Nuclear, Boston, Nassachusetts) in an amount of 2. 4 ml / min. The quantitative determination of radioactivity in this material was determined using a Spectra Phy sics SP4200 computer integrator. The data thus obtained is used to calculate the integration units for each product as a percentage of the total integration units compared to the average for the control.

The analgesic activity of the compounds of formula (I) can be determined in mice by suppressing the abdominal cramps of 2-phenyl-1,4-benzoquinone (PBQ) as described by Siegmund et al., Proc. Soc. Εχρ. Biol. Med., 95, 729-731, (1957) as modified by Milne and Twomey, Agents and Actions, 10, 31-37 (1980).

The anti-inflammatory effect of the compounds of formula (I) can be detected in rats at standard pressure-induced edema induced by carrageenin according to Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544 (1963). Where a compound of formula (I) or a pharmaceutically acceptable salt thereof is to be used as an IL-1 inhibitor, an analgesic agent or an anti-inflammatory agent, the compound may be administered as such, or Preferably in admixture with conventional pharmaceutical carriers or diluents in the form of a pharmaceutical composition. The compounds may be administered orally or parenterally, intravenously, intramuscularly, subcutaneously or intraperitoneally and topically.

In a pharmaceutical composition containing said substances or salts thereof, the weight ratio of the carrier to the active ingredient is usually 1: 4 to 4: 1, preferably 1: 2 to 2: 1. and the route of administration. For oral administration, the compound of general formula (I) may be used, for example, in the form of tablets or capsules or in aqueous solution or suspension. In the case of tablets, conventional carriers such as lactose and corn starch are used. Glidants such as magnesium stearate are usually also added. For oral administration in the form of capsules, suitable diluents are, for example, milk sugar and dried cornstarch. When an aqueous suspension is to be used for oral administration, the active ingredient is mixed with the emulsifying agents or suspending agents. If desired, sweetening and / or flavoring agents may be added. In the case of intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared, the pH of these solutions being suitably adjusted and provided by the addition of a buffer. In the case of intravenous administration, the concentration must be adjusted by dissolving the substances so that the composition is isotonic. When a compound of formula (I) or a salt thereof is used in human medicine, the daily dose will usually be varied as proposed by the attending physician. The daily dose will vary depending on the age, weight and condition of the patient, as well as the severity of the symptoms and the efficacy of the selected agent. In the case where the compound of general formula (I) is administered as an analgesic, the effective analgesic dose is in the majority of cases between 5 and 500 mg, for example between four and 24 hours. This range is particularly true for acute administration where rapid relief of major pain is required. In the case of chronic administration to alleviate inflammation with concomitant pain or IL-1 biosynthesis, the effective dose in most cases is in the range of 5 mg to 1.0 g per day, preferably 50 to 500 mg per day, either in a single dose or in divided doses.

The following examples illustrate the invention. In these examples, all heats are shown without repair. Unless otherwise indicated, all reactions were conducted under a nitrogen atmosphere. EXAMPLE 1 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1-N-tert-butylcartoxamide A. 5-Chloro-4-azaoxindole

A dry flask equipped with a nitrogen inlet and a mechanical stirrer was charged with 12.8 g, 0.32 mole of a suspension of sodium hydrogen in oil (60%). Most of the oil was removed by washing twice with hexane. The remaining solid sodium hydride is suspended in 350 ml of anhydrous 1,2-dimethoxyethane (DME). A solution of 49.3 µL, 0.325 mol of diethyl malonate in 178 mL of DME was added dropwise to the resulting suspension with stirring. The mixture was stirred at room temperature for 1 hour and then a solution of 25 g, 0.13 mol of the commercially available 2.6- dichloro-3-nitro-pyridine in 175 ml of DME to give a dark red solution.

The mixture was stirred overnight at room temperature and then poured into water. The resulting mixture was acidified to pH 3 by addition of 6N hydrochloric acid solution and then extracted with ether. The ether phase was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to give a yellow oil. Most of the excess diethyl malonate was removed by heating to 60 ° C in a high vacuum. The mixture was examined by a 1 H-NMR spectrum and it was shown that the mixture was a 2: 1 mixture of 2-bis- (ethoxycarbonyl) methyl-6 -chloro-3-nitropyridine and the undesired isomer of 6-bis- (ethoxycarbonyl) methyl-2-chloro-3-nitropyridine, resulting from the displacement of the chlorine atom from position 6 of the starting material; diethyl malonate. The mixture was then flash chromatographed on silica gel using 4: 1 hexane / ethyl acetate as eluent. Fractions containing the desired product were collected and evaporated to give an oil containing 2-bis- (ethoxycarbonyl) -3- methyl-6-chloro-3-nitropyridine, 6-bis- (ethoxycarbonyl) methyl- 2-chloro-3-nitropyridine and diethyl malonate in a molar ratio of about 10: 4: 3 gave a total of 40.5 g of material. ga 63% ·

Dissolve a mixture of 2-bis- (ethoxycarbonyl) methyl-6-chloro-3-nitropyridine, 6-bis- (ethoxycarbonyl) methyl-2-chloro-3-nitropiridine and diethylmalonate in 300 mL of ethanol and add a suspension of 26 g of 50%. % Saney nickel in water and then diluted with 700 ml of ethanol and hydrogenated in a Parr apparatus at a pressure of 0.3 MPa for 4 hours, and then the diatomaceous earth is filtered to remove the catalyst. The solvent was evaporated in vacuo to give a mixture of 3-amino-2-bis- (ethoxycarbonyl) methyl-6-chloropyridine, 3-amino-6-bis-fethoxycarbonyl) methyl-2-chloropyridine, i.e. undesired isomer and diethyl malonate as a 35.7 g waxy solid.

The mixture was dissolved in 700 ml of 6N hydrochloric acid and heated to reflux for 5 hours. After evaporation of the aqueous acid in the flask, the residue was dissolved in water and then the solution was evaporated again to give 5-chloro-4-azaoxindole as a brown solid which was air dried. Yield: 7.04 g, 32% of theory, based on starting 2,6-dichloro-3-nitro-pyridine. An analytical sample prepared by recrystallization from isopropanol had a melting point of 250 DEG-254 DEG C. with decomposition. B. 5-Chloro-3- (2-thenoyl) -4-azaoxindole Sodium metal pellets (2.0 g, 87.0 mmol) were added to 50 mL of anhydrous ethanol in a dry round bottom flask. 5-chloro-4-azaoxindole (3.0 g, 17.8 mmol) was added followed by ethyl 2-thiophenecarboxylate (4.8 mL, 40 mmol). The resulting mixture was refluxed under nitrogen at reflux overnight. A precipitate forms during this time. The mixture was cooled, poured into ice-water and acidified to pH 3 with 6N hydrochloric acid. 3.7 g of product are obtained, yield 75%, m.p. 235-238 ° C, filtered and washed with water and ether. Yield: 375 mg (8%) from the filtrate with a melting point of 240-241 ° C. This product is also isolated by filtration. C. 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide To a solution of 500 mg 1.79 mmol of 5-chloro-3- (2-thenoyl) -4-azaoxindole in 10 triethylamine (0.54 mL, 3.87 mmol) and tert-butyl isocyanate (0.3 mL, 2.63 mmol) were added sequentially to anhydrous DMSO (mL). The resulting mixture was heated under nitrogen for 3 hours in an 85 ° C oil bath. After cooling to room temperature, the solution was poured into a mixture of water and ice-water and acidified to pH 2 by addition of 6N hydrochloric acid solution. Insoluble matter is filtered off. This was flash chromatographed on two successive silica gel columns using ethyl acetate as the eluent for the first column and 20% hexane in the chloroform form for the second column. Recrystallization of the chromatographed material from acetonitrile afforded the title compound (300mg, 44%) as a yellow solid, m.p. 150-152 ° C. 1 H-NMR (DMSO-d 6): δ 9.00 (s, 1H), 8.83 (d, J · 3.6 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H) ), 8.00 (d, J = 4.9 Hz, 1H), 7.28-7.25 (m, 1H), 7.24 (d, J = 8.1 Hz, 1H), 1, 40 (s, 9H), IB spectrum (KBr disc) 1713, 1647, 1582, 1461 cm @ -1.

Mass spectrum m / e (relative percentage) 379 (4), 377 (18), 280 (23), 278 (70), 196 (38), 194 (100), 111 (12).

H, 4.27; N, 11.12. Found: C, 53.59; H, 4.01; N, 10.92%. C17H16ClN3O3S requires C, 54.04; Example 2 6-Chloro-3- (2-thonyl) -4-azaoxindole-1-carboxamide A. 6-Chloro-4-azaoxindole 2,5-dichloro-3-nitropyridine was prepared from 2-hydroxy- 3-nitro-5-chloropyridine by the method of Chem.

Abs., 22, 68286y (1969). 2-Hydroxy-3-nitro-5-chloropyridine is prepared by nitration of commercially available 2-hydroxy-5-nitropyridine with sulfuric acid and nitric acid at 60 ° C. In this way, a purer product can be obtained in a higher yield than by the conventional method of nitrating 2-amino-5-chloropyridine and described in Chem. Abs. 70, 68286y (1969).

To a dry flask equipped with a nitrogen gas inlet with a mechanical stirrer was charged 4.0 g, 0.10 mole of hydrogen hydride as a 60% suspension in oil. Most of the oil was removed by washing twice with hexane. The remaining hydride hydrogen was then suspended in 125 mL of anhydrous 1,2-dimethoxyethane (DME). A solution of 15.7 mL, 0.10 mol of diethyl malonate in 50 mL of DME was added dropwise to the resulting suspension with stirring. The mixture was stirred at room temperature for 1 hour and a solution of 10 g, 51.8 mmol of 2,5-dichloro-3-nitropyridine in 75 mL of DME was added after 1 hour. The mixture was stirred overnight at room temperature and then diluted with water. After acidification to pH2 with 1N hydrochloric acid, the mixture was extracted with ether. The ether phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to a red oil liquid in a vacuum. The liquid was flash chromatographed on silica gel using hexane / ethyl acetate 9: 1 as the eluent. All fractions containing the desired product were combined and evaporated to give 13.5 g (82%). -bis- (ethoxycarbinyl) methyl-5-chloro-3-nitropyridine as an oil. - 40 -

The diester solution in 200 mL of ethanol was added to 8.8 g of a 5056 suspension of Raney nickel in water and the mixture was diluted with 300 mL of ethanol. The mixture was then hydrogenated in a Farr apparatus at 0.3 MPa for 4 hours and filtered through diatomaceous earth to remove the catalyst. The solvent was evaporated in vacuo to give 3-amino-2-bis (ethoxycarbonyl) -methyl-5-chloropyridine (12.6 g) as a pale yellow solid.

A mixture of the resulting material in 325 ml of 6N hydrochloric acid was heated to reflux for 4 hours. After removing the aqueous acid solution in vacuo, the residue is dissolved in water and the solution is filtered to remove a small amount of black insoluble material. Then the filtrate was adjusted to pH 6.5 by the addition of solid sodium bicarbonate to precipitate 2.6 g of 6-chloro-4-azaoxindole as an off-white solid which was filtered off. The filtrate was extracted with ethyl acetate, the extracts were combined, dried over magnesium sulfate and evaporated to give 3.6 g of 6-chloro-4-azaoxindole. Thus, the total yield is 71.56, i.e. 6.2 g, based on 2,5-dichloro-3-nitropyridine. B. 6-Chloro-3- (2-thenoyl) -4-azaoxindole 3.4 δ, 0.15 mol of sodium metal pellet is added to 90 ml of anhydrous ethanol in a dry round-bottomed flask. After the sodium has completely dissolved, 6-chloro-4-azaoxindole (5.0 g, 29.7 mmol) is added, followed by ethyl 2-thiophenecarboxylate (8 ml, 55 mmol). The mixture was heated under nitrogen to reflux overnight to form a precipitate. The mixture was cooled, poured into a mixture of water and ice and acidified to pH 3 by addition of 6N hydrochloric acid solution. 7.8 g of solidazaoxindole with a melting point of 250 DEG C. are obtained in a yield of 94.5%. The product was filtered off, washed with water and ether and dried in vacuo without further heating. 41-C. 6-Chloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide

6-Chloro-3- (2-thenoyl) -4-aza-oxindole (3.3 g, 11.8 mmol) and acetonitrile (100 mL) were cooled to 0 ° C and N (1.5 mL, 17.2 mmol) was added. -chlorosulfonyl isocyanate. «

The mixture is stirred for 6 hours at room temperature and then a mixture of water and ice is poured. The solid was filtered off, washed with water and then stirred for 20 minutes in water at 100 ° C. Then the solid is filtered off and dried. Recrystallization from acetic acid gave analytically pure 6-chloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide with a melting point above 250 ° C. (DMSO-d6): δ 8.78 (d, J = 3 Hz, 1H), 8.57 (broad s, 1H), 8.39 (s, 1H), 7.92 - 7.89 cm -1, 3H), 7.23-7.21 (m, 1H), IR spectrum (KBr disc) 17.1, 1602, 1420 cm MS m / e (relative percentages): 321 (13) , 280 (11), 278 (36), 196 (40), 194 (100), 111 (333).

H, 2.51; N, 13.06. Found: C, 48.56; H, 2.42; N, 12.95%. Example 3 5-chloro-3- (2-thenoyl) -6-azaoxindole-1N-tert-butylcarboxamide A. (5-amino-2-chloro-4-pyridyl) acetonitrile To a solution of 24.69 g, 220 mmol, 2 Of 2 equivalents of potassium tert-butoxide in 150 ml of anhydrous tetrahydrofuran was added dropwise to a solution of 15.85 g, 100 mmol of 2-chloro-5-nitropyridine and 18.44 g, 110 mmol in a dropwise manner at -50 ° C under nitrogen. 1.1 equivalents of (4-chlorophenoxy) acetonitrile obtained from E. Grochowski et al., Bull. Acad. Pol.Sci. Ser. Sfci. Chim., 11, 443 (1963) in 150 ml of anhydrous tetrahydrofuran at such a rate as to cool the mixture of dry ice and acetone to a temperature in the range of -40 to -50 ° C. The resulting purple-colored mixture was then stirred under nitrogen at -78 ° C for 1 hour - 42 °, then 20 ml, 0.35 mol, 3.5 equivalents of glacial acetic acid was added to the reaction mixture and the mixture was allowed to warm to room temperature. room. To the reaction mixture was added 100 ml of 5% hydrochloric acid solution and the aqueous mixture was extracted first with 100 ml of ethyl ether and then with 2 x 100 ml of methylene chloride. The extracts are combined, dried (MgSO4) and passed through a 150 g silica gel pad, then the silica gel is washed with 1200 ml of methylene chloride. The filtrate was evaporated under reduced pressure and the residual oil was chromatographed on 300 g of silica gel, eluting the silica gel with 25% hexane in methylene chloride, to give an oil of Rf = 0.52 in methylene chloride, this oil was seroset with cold anhydrous diethyl ether to give the title compound. 7% yield 1.37 g of 6-chloro-3-nitro-2-pyridylacetonitrile as a white crystalline solid with a melting point of 121.5-123.5 ° C. Further elution gave an additional oily Rf = 0.48 in methylene chloride which was triturated with cold anhydrous ethyl ether to give 1.80 g of (2-chloro-5-nitro-4-pyridyl) acetonitrile as a 9% yield. white crystalline solid, mp 87-89 ° C. IR (KBr) 3080, 2240, 1600, 1545, 1520, 1450, 1390, 1340, 1135 cm -1.

A solution of (2-chloro-5-nitro-4-pyridyl) acetonitrile in 100 mL of ethanol was added to a suspension of 50% Raney nickel in water (3.2 g) diluted with 150 mL of ethanol. The resulting mixture was hydrogenated in a Parr apparatus at 0.3 MPa for 2.5 hours and then filtered through a pad of Celite (diatomaceous earth) to remove the catalyst. The solvent was evaporated in vacuo to give a dark oil which was subjected to flash chromatography on silica gel using ethyl acetate / hexane as eluent. The fractions containing the resulting product were combined and evaporated to dryness to give 850 mg of an oil (32%). The less pure fraction is also combined and evaporated to 600 mg of oil in which the resulting material is about 75% of the content.

B. 5-Chloro-6-azaoxindole 1.40 g (8.4 mmol) of (5-amino-2-chloro-4-pyridyl) acetonitrile was dissolved in 100 mL of 6N hydrochloric acid and heated for 2 hours. at a temperature of 50 to 100 ° C. After cooling, the solution was adjusted to pH 7 by the addition of solid sodium bicarbonate and extracted with ethyl acetate. The extracts are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is flash chromatographed on silica gel using ethyl acetate as eluent, a small amount of methanol may be added to dissolve the solid more rapidly. The product fractions are combined and evaporated to give 650 mg of a solid product with a melting point of 230 ° C. under decomposition. The NMR spectrum showed that this material still contained a small amount of by-product, 2-amino-5-chloro-6-azaindole, in addition to the final product. However, the material could be used in the next step without further purification. C. 5-Chloro-3- (2-thenoyl) -6-azaoxindole Sodium metal (232 mg, 10 mmol) was pelleted in a round bottom flask to 10 mL of anhydrous ethanol.

After dissolution of sodium, 340 mg, 2.0 mmol of 5-chloro-6-azaoxindole and then 0.54 ml, 4.0 mmol of ethyl 2-thiophenylcarboxylate were added. The mixture was refluxed under nitrogen to form a precipitate. The mixture was cooled, poured into a mixture of water and ice-water, and the resulting mixture was acidified to pH 4 with 6N hydrochloric acid. 475 ml of the resulting product was collected by filtration and washed with water and air dried. Recrystallization from methanol afforded 190 mg (34%) of the title compound. H NMR (DMSO-d6): δ 10.62 (broad s, 1H), 8.79 (d, J = 3.2Hz, 1H), 7.92 (s, 1H), 7.77 (d, 1H), J = 5 Hz, 1H), 7.65 (s, 1H), 7.17-7.14 (m, 1H). - 44 - D. 5-Chloro-3- (2-thenoyl) -6-azaoxindole-1N-tert-butylcarboxamide To a solution of 190 mg, 0.68 mmol of 5-chloro-3- (2-thenoyl) -6 - azaoxindole in 3 ml of anhydrous DMSO is added sequentially with 0.20 ml, 1.44 mmol of triethylamine and 0.11 ml, 0.96 mmol of tert-butyl isocyanate. The resulting mixture was heated to 85 ° C under nitrogen on an oilseed for 4 hours. The solution is cooled to room temperature and then poured into a mixture of water and ice and acidified to pH 2 by addition of 1N hydrochloric acid. The insoluble matter is filtered off, dried in air and not recrystallized from methanol to give a 68% yield. % gives 175 mg of ptodutane with a melting point of 224 ° C with decomposition. 1 H-NMR (DMSO-d 6): δ 9.45 (s, 1H), 8.70 (s, 1H), 8.43 (dd, J = 1.2, 3.4 Hz, 1H), δ, 06 (s, 1H), 7.82 (dd, J = 1.2, 4.9Hz, 1H), 7.18 (dd, J = 3.4, 4.9 Hz, 1H), 1.40 ( IR (KBr) 1723, 1660, 1624, 1586, 1552, 1474 cm, m / e (relative percentages) 377 (2), 280 (21), 278 (59), 196. (41), 194 (100), 111 (41).

H, 4.27; N, 11.04%. Found: C, 53.88; H, 4.21; N, 11.04%. (2-thenoyl) -5-azaoxindole-1N-tert-butylcarboxamide A. 3,3,7-tribromo-5-azaoxindole The starting material for the 3,3,7-tribromo is azaoxindole, 5-azaindole, prepared according to The same substance can also be prepared by the method of Yamanaka et al., Chem. Pharm. Bull., 35, 1823 (1987) or Okuda and Robinson (J. Org. &Amp; Hem., 14, 1008 (1959)) To a stirred solution of 1.5 g, 12.7 mmol of 5-azain-dole in 100 ml of tert-butanol and 100 ml of water at a temperature of <RTIgt; t, </RTI> i (1 &lt; -1 &gt; 1 ', &quot; A &quot; ? ih, '; 1' 'i 1 i *' i ^> “ίι <'Ή-' li ^

Bromine (2.6 mL, 50.5 mmol) was added dropwise over 20 min. After the addition of bromine, the pH of the mixture is about 1. A saturated aqueous sodium bicarbonate solution is slowly added slowly over 1/2 hour to adjust the pH of the mixture to between 6.5 and 7. A precipitate is formed over the same period. The precipitate was collected by filtration, washed with water, and air dried to give 6.7 g of a yellow solid (79%), m.p. 250 ° C. The filtrate was extracted with ethyl acetate to give 700 mg (15%) of the title compound but was less clear as shown by thin layer chromatography. The less pure fractions of several reactions were combined and purified by flash chromatography on silica gel using 10% methanol in chloroform as eluent. B. 5-Azaoxindole To a solution of 3,3,7-tribromo-5-azaoxindole (6.4 g, 17.3 mmol) in 1200 mL of ethanol was added 3.2 g of 10% palladium on charcoal. The mixture was hydrogenated for 3 hours under a hydrogen pressure of 0.3 MPa using a Parr apparatus. The catalyst is filtered off through a pad of Celite, the pad is washed thoroughly with ethanol. The solvent was evaporated to give 3.5 g of a brown solid, mainly the hydrobromide of the resulting product. This material was dissolved in water, activated carbon was added and the mixture was passed through a pad of Celite. The sepH of the filtrate was then adjusted to 7.5 by the addition of saturated aqueous sodium bicarbonate solution. The mixture is extracted three times with n-butanol. The extracts are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo to a solid which is triturated with butanone and filtered to give 1.6 g of 5-azaoxindole as an off-white solid in 69% yield. white solid.

After removal of the butanone, a solid is obtained from the mother liquor, which is recrystallized from methanol to yield a further 50 mg of product having a melting point above 250 ° C (46 ° C). '** - 4ri, 7if <ri /! f z? C. C. 3- (2-Thenoyl) -5-azaoxindole Sodium metal (1.15 g, 50 mmol) was pelleted to 30 mL of ethanol in a round bottom flask. After complete dissolution of sodium, 1.40 mg, 10.4 mmol of 5-azaoxindole were added followed by 2.7 mL of 20.1 mmol of ethyl 2-thiophenecarboxylate. The mixture was then heated under reflux for 1 hour. Then the volume of the mixture is reduced to 50% by distilling off the ethanol at atmospheric pressure. The mixture is cooled and poured into a mixture of water and ice. The resulting solution was filtered to remove a small amount of insoluble material, which was washed well with water. After acidifying the filtrate to pH 7 with 6N hydrochloric acid, the product precipitated, filtered, washed with water and air dried to give 2.0 g of the title compound as a tan solid (83%). D. (2-Thenoyl) -5-azaoxindole-1N-tert-butylcarboxamide To a solution of 3- (2-thenoyl) -5-aza-oxindole (500 mg, 2.05 mmol) in 10 mL of anhydrous DMSO was added 0.60 mL sequentially. Triethylamine (4.3 mmol) and tert-butyl isocyanate (0.35 mL, 3.06 mmol). The resulting mixture was heated to 85 ° C under nitrogen in an oil bath for 5 hours. After cooling to room temperature, the solution was poured into a mixture of water and ice and acidified to pH 2 by addition of 6N hydrochloric acid solution. The insoluble solid was filtered off, washed with water and air dried. The crude product was flash chromatographed on silica gel, eluting with a 9: 1 mixture of chloroform and methanol. The fractions containing the desired product were combined and evaporated to a solid which was recrystallized from a mixture of methanol, chloroform and acetonitrile and then from chloroform / methanol to give 210 mg (31%) of the title compound, m.p. 250 ° G. ί ^ 'ΐΛί' ^ Μ

4 - 47 - 1 H-NMR (DMSO d 6): δ 9.85 (s, 1H), 9.18 (s, 1H), 8.70 (dd, J = 1.6, 3.5 Hz, 1H) ), 8.41 (d, J = 6.2 Hz, 1H), 8.26 (d, J = 6.2 Hz, 1H), 7.73 (dd, J = 1.5, 4.9 Hz) , 1H), 7.16 (dd, J = 3.5, 4.9 Hz, 1H), 1.41 (s, 9H), IR spectrum (KBr disc) 1723, 1653, 1615, 1549, 1474, 1427 cm “1. MS m / e (rel.%) 343 (2), 244 (30), 160 (90), 111 (38), 84 (100).

H, 4.99; N, 12.24. Found: C, 58.68; H, 4.87; N, 11.54%. Example 5 5-fluoro-3- (2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide A. 5-fluoro-2-hydroxy-3-nitropyridine 5-fluoro-2-hydroxypyridine (5-fluoro- 2-pyridone) was prepared from a commercially available 5-amino-2-fluoropyridine as described in Nesnow and Heidelberger, J. Heterocyclic. Chem., 10, 779 (1973), except that it was used for the final hydrolysis of 48µl hydrobromic acid at reflux to hydrolyze 2-fluoro-5-methoxypyridine instead of the conditions described in that publication, using 25% hydrochloric acid in a sealed glass tube at 145 ° C. 5-Fluoro-2-hydroxypyridine (11.16 g, 98.7 mmol) was then added in portions to 90 mL of concentrated sulfuric acid at 0 ° C. The fuming acid is then added dropwise. The reaction mixture was allowed to warm to room temperature and then heated to 55-60 ° C for 3 hours. The mixture was cooled to room temperature and poured into a mixture of water and ice. The yellow product is filtered off, washed with water and air dried to yield 53% yield. The title compound (8.24 g) is obtained. The filtrate was adjusted to pH 2 with solid sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and evaporated to give 1.71 (11%). g of the final product. B. 2-Chloro-5-fluoro-3-nitropyridine

To a mixture of phosphorus pentachloride (9.41 g, 45.2 mmol) and phosphorus oxychloride (4.2 mL, 45.1 mmol) was added 5-fluoro-2- (6-g, 41.1 mmol) at 60 ° C. -hydroxy-3-nitropyridine. The mixture was stirred in an oil bath overnight at 100 ° C, cooled to room temperature and poured into a mixture of water and ice. Water and ethyl acetate were then added and the mixture was filtered through a pad of Celite to remove dark colored insoluble material. The organic phase was washed with saturated aqueous sodium chloride solution, filtered again to remove further dark colored material, dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel using chloroform as the eluent. The fractions containing the resulting product were combined and evaporated to give 3.51 g (48%) of a yellow oil which solidified overnight at 5 ° C. 6-Fluoro-4-azaoxindole

To a dry flask was charged 3.1 g (77.5 mmol) of hydrogen halide in the form of a 60 µl suspension in oil. Most of the oil was removed by washing twice with hexane. The remaining hydride hydrogen was then suspended in 100 ml of anhydrous dimethylformamide (DMF) and cooled to 0 ° C. Diethyl malonate (11.8 mL, 77.7 mmol) was added dropwise with stirring, and the mixture was stirred at 0 ° C for 1 hour. A solution of 2-chloro-5-fluoro (5.21 g, 29.5 mmol) was then added. - 3-nitropyridine in 40 ml DMFt The mixture was stirred overnight at room temperature and then poured into a mixture of ice water and water. After acidifying to pH 3 with 6N hydrochloric acid solution, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to give a red oil which was subjected to flash chromatography on silica gel. with ethyl acetate / hexane 3: 7 as eluent. The traction containing the desired product is combined and evaporated to an oil containing 2-bis- (ethoxycarbonyl) methyl-5-fluoro-3-nitropyridine and diethyl malonate in a molar ratio of about 11: 9 to give 11.5 g of the mixture. The yield of the first is 8 g, about 90% of the theoretical.

The mixture obtained in the preceding step is dissolved in 100 ml of ethanol and added to a suspension of 7.8 g of 50% Raney nickel in water diluted with 150 ml of ethanol. The mixture is hydrogenated in a Parr apparatus at a pressure of 0.3 MPa and then filtered through a pad of diatomaceous earth (Celite) to remove the catalyst. The solvent was removed in vacuo to give a mixture of 3-amino-2-bis- (ethoxycarbonyl) methyl-5-fluoropyridine and diethyl malonate as an oily liquid. This mixture was treated with 280 ml of 6N hydrochloric acid and refluxed for 3 hours. After evaporation of the aqueous acid in vacuo, the residue is mixed with water and the solution is evaporated to a solid which is dissolved in anhydrous ethanol and evaporated twice to give 4.07 g of product as a pale green solid which is triturated with hot ethyl acetate and dried to dryness. air. When performing the spectra, the material is shown not to be completely pure, but can be used without further purification to react to the next step. (- 50 - D. 5-Fluoro-3- (2-thenoyl) -4-azaoxindole Sodium metal, 0.75 g, 32.6 mmol, pellet, was added to 30 mL of anhydrous ethanol in a round bottom flask. of sodium 6-fluoro-4-azaoxindole (1.0 g, 6.57 mmol) followed by ethyl 2-thiophenecarboxylate (4.8 mL, 13.4 mmol) was added and the mixture heated under reflux for 2 days. The mixture is cooled, poured into a mixture of water and ice and acidified to pH 2 by addition of 6N hydrochloric acid to give a total of 854 mg of product in 50% yield, which is filtered off. 32 mg of product is obtained from the filtrate in a 2% yield as a second crop, which also isolates E. 5-fluoro-3- (2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide To a solution of 5-fluoro-3- (2-thenoyl) -4-azaoxindole (450 mg, 1.72 mmol) in anhydrous DMSO (15 mL) was added triethylamine (0.50 mL, 3.59 mmol) and 0. Tert-butyl isocyanate (30 ml, 2.62 mmol) and the resulting mixture was heated to 85 ° C under an oil bath overnight. The solution is not allowed to cool to room temperature and then poured into a mixture of water and ice and acidified to pH 2 with 1N hydrochloric acid. The insoluble green solid was filtered off, dried in air and flash chromatographed on silica gel using ethyl acetate as eluent, using a small amount of acetonitrile to dissolve the solid. The product fractions were collected and evaporated, and the residue obtained was recrystallized from a mixture of ethyl acetate and acetonitrile to give the title compound (29%) as green needle crystals, mp 258 ° C.

51-1NMR- (DMSO-α): δ 14.00 (broad, s, 1H), 9.28 (s, 1H), 8.77 (d, J = 4 Hz, 1H), 8.44 (dd) , J = 1.9, 9.5 Hz, 1H), 7.98-7.96 (m, 1H), 7.89 (d, J = 4.9 Hz, 1H), 7.24 (dd, 1H), J = 4.49 Hz, 1H), 1.40 (s, 9H), IR (KBr) 1721, 1609, 1552, 1423 cm @ -1.

MS m / e (rel%%) 361 (4), 262 (40), 178 (100), 111 (13). Analysis for C ^ HH ^ gFN ^O ^ SS requires C, 56.50; 46, N 11.63%, found C 55.86, H 4.48, N 11.41%. Example 6

5,6-dichloro-3- (2-theonyl) -4-azaoxindole-1N-tert-butylcarboxamide J 5,6-dichloro-4-azaoxindole 3-nitro-2,5,6-trichloropyridine was prepare the method according to Helv. Chim. Acta, 59, 190 (1976), the commercially available pentachloropyridine is used as the starting material. In the first step, a mixture of the desired 2,5,6-trichloropyridine and a small amount of three tetrachloropyridine isomers is obtained. The mixture is nitrated as described above to give a mixture of 3-nitro-2,5,6-trichloropyridines. but a small amount of 2,5,6-trichloropyridine and a small amount of tetra-chloropyridine isomers, which are difficult to remove. Hydride hydride (7.92 g, 198 mmol) was added to the dry flask as a 60% suspension in oil, and 90 mL of anhydrous dimethylformamide (DMF) was added to the suspension. Diethylmalonate (24.7 ml, 180 mmol) was then added dropwise with stirring and the mixture was stirred at room temperature for 1/4 hour and then cooled to 0 ° C. A solution of 12.5 g, 55 mol of 3-nitro-2,5,6-trichloropyridine, 1.6 g of 2,5,6-trichloropyridine and a total of 6.4 g of tetrachloropyridine isomers in 40 ml of DMF is cooled to The resulting mixture was stirred for a further 1/4 hour at -52-0 ° C, then the mixture was treated with water and acidified by the addition of 6N hydrochloric acid solution.

After extraction with ether, the ether layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to an oil which is passed through a thicker layer of silica gel which is then washed first with hexane to remove the oil, trichloropyridine and tetrachloropyridine derivatives and then with ethyl acetate. to elute the product mixture.

After removal of the solvent, the mixture was flash chromatographed using silica gel and hexane / ethyl acetate (19: 1) as eluent. All fractions containing the desired product were combined and evaporated to give an oil which contained a total of 5.2 g of the desired 2-bis- (ethoxycarbonyl) methyl-5,6-dichloro-3-nitropyridine in 10.5% yield, 10.5 g. -bis (ethoxycarbonyl) methyl-3,6-dichloro-5-nitropyridine (54% yield) and diethyl malonate.

Dissolve a mixture of 2-bis (ethoxycarbonyl) methyl-5,6-dichloro-3-nitropyridine, 2-bis (ethoxycarbonyl) methyl-3,6-dichloro-5-nitropyridine and diethylmalonate in 100 ml of ethanol and solution. to a suspension of 30 g of 50% Raney nickel in water, diluted with 10 ml of ethanol. The mixture was hydrogenated in a pressure apparatus at 0.3 MPa for 5 hours and then filtered through diatomaceous earth to remove the catalyst. The solvent was removed in vacuo to give an oil which was subjected to flash chromatography on silica gel, eluting with a 4: 1 mixture of heptane and ethyl acetate. Each of the fractions was separated and evaporated in 1 H-NMR spectrum in deutero-chloroform. The diethyl malonate eluted the desired product, i.e., 3 "amino-2-bis- (ethoxycarbonyl) methyl-5,6-dichloropyridine, followed by the removal of the undesired isomer, 5-amino-2-bis (ethoxycarbonyl) methyl-3,6-dichloropyridine. Although good separation from diethyl malonate has occurred, the majority of the desired product and isomer is obtained in the mixed fractions. Fractions containing only the desired isomer and mixed fractions containing at least 10% of this material were pooled, thereby

53 - a solid is obtained, consisting of 3.17 g of the desired isomer and 4.03 g of the undesired isomer. The mixture is dissolved in 120 ml of 6N hydrochloric acid and refluxed for 3 hours. After cooling to room temperature, the volatiles were evaporated in vacuo. Ethanol was added to facilitate evaporation. The process was repeated and the resulting brown solid was flash chromatographed on silica gel using a 9: 1 mixture of chloroform and methanol as the eluent. All fractions containing the desired product were combined and evaporated to give a solid which was triturated with methanol to yield 71% of 3-amino-2-bis- (ethoxycarbonyl) methyl-5,6-dichloropyridine. % total of 1.42 g of 5,6-dichloro-4-aza-oxindole, overall yield of 3-nitro-2,5,6-trichloropyridine was 13%. Melting point: 230-233 ° C with decomposition. B. 5,6-Dichloro-3- (2-thenoyl) -4-azaoxindole # 29 g, 12.6 mmol of sodium metal pellets are added to 10 mL of anhydrous ethanol in a dry round bottom flask.

After complete dissolution of the sodium, 5,6-dichloro-4-azaoxindole (500 mg, 2.46 mmol) was added followed by ethyl 2-thiophenecarboxylate (0.67 mL, 5.0 mmol). The mixture was heated to reflux overnight with nitrogen for one day. The mixture was cooled, poured into ice water and acidified to pH 3 by addition of 6N hydrochloric acid. The resulting material was filtered off and dried in vacuo to give 607 mg of product in 79% yield. 0. 5,6-Dichloro-3- (2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide To a solution of 300 mg, 0.96 mmol of 5,6-dichloro-3- (2-thenoyl) - Triethylamine (0.20 mL, 1.43 mmol) and tert-butyl isocyanate (0.16 mL, 1.40 mmol) are added sequentially to 8-azaoxindole in 8 mL of anhydrous DM90. The resulting mixture was heated to 85 ° C under an oil bath for 5 hours. The solution was poured into a mixture of water and ice and acidified to pH 2 with 1N hydrochloric acid. The insoluble matter is filtered off, dried and flash chromatographed on silica gel using a 99: 1 mixture of chloroform and methanol as eluent. The fractions containing the desired product were combined and evaporated. The resulting solid was recrystallized from chloroform / methanol to give 207 mg of the title compound (m.p. 189-190 ° C). 1 H-NMR (LMSO-d 6): δ 9.66 (d, J = 4 Hz, 0.4 H), 9.02 (d, J = 4 Hz, 0.6H), 8.84 (broad s, 0.6H), 8.70 (s, 0.4H), 8.58 (s, 0.6H), 8.44 (broad s, 0.9H), 7.83 (d, J = 5 Hz, 0.4H), 7.76 (d, J = 5 Hz, 0.6H), 7.30 (dd, J = 4.5 Hz, 0.4H), 7.23 (dd, J = 4.5). H, 0.6 H), 1.47 (s, 9H). IR spectrum (KBr disc): 1712, 1640, 1579, 1534 cm @ -1.

Mass spectrum m / e (relative percentages) 413 (1), 411 (2), 314 (30), 312 (38), 230 (75), 228 (100), 111 (38).

Analysis for calculated found

C, 49.52; H, 3.67; N, 10.19%. C, 49.45; H, 3.58; N, 9.91%. Example 7 3- (2-Thenoyl-6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide A. 2-Chloro-3-nitro-5-trifluoromethylpyridine Starting material, 2-hydroxy-3-nitro-5- trifluoromethylpyridine was prepared according to British Patent No. 1,421,619 from commercially available 2-chloro-5-trifluoromethylpyridine, 55-5.8 g, 42.3 mmol 2-hydroxy-3-nitro-5-trifluoromethyl pyridine is added to a mixture of 4.2 ml, 45.9 mmol oxychloride phosphorous and 9.6 g, 46.1 mmol phosphorus pentachloride at a temperature of 60 DEG C. The reaction mixture is then heated under nitrogen at 80 DEG C. overnight. The product was cooled to room temperature and poured into a mixture of ice water, extracted with ether and the ether extract washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated to give a dark oil which was subjected to flash chromatography on silica gel. the column is eluted with chloroform, fractions containing it only the desired product was combined and evaporated to give 5.0 g (52%) of a brown oil product. 1 H-NMR (DMSO-d 6): δ 9.20 (s, 1H), 9.07 (s, 1H), B. 2-bis- (benzyloxycarbonyl) methyl-3-nitro-5-trifluoromethylpyridine

To the dry flask was charged 800 mg (2.0 mmol) of hydrogen hydride as a 60% suspension in oil. Most of the oil was removed by washing twice with hexane. The remaining solid hydride was suspended in 20 mL of 1,2-dimethoxyethane (DME). A solution of dibenzyl malonate (5.0 mL, 2.0 mmol) in DME (15 mL) was then added dropwise with stirring. The mixture was stirred at room temperature for 2 hours and then a solution of 2-chloro-3-nitro-5-trifluoromethylpyridine (2.3 g, 10.2 mmol) in 15 ml of DME was added. The mixture was stirred at room temperature overnight and then poured into water / ice. After acidification with pH 3 by addition of 1ΙΊ hydrochloric acid solution, the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo to an oil which is subjected to flash chromatography on silica gel using toluene as eluent. The fractions containing the desired product were combined and evaporated to give 3.8 g (79%) of off-white solid, mp 82-84 ° C. - 56 - C. 3-Benzyloxycarbonyl-6-trifluoromethyl-4-azaoxindole

A mechanically stirred mixture of 2-bis (benzyloxycarbonyl) methyl-3-nitro-5-trifluoromethylpyridine 2-bis (benzyloxycarbonyl) methyl-3-nitro-5-trifluoromethylpyridine, 495 mg, 8.9 mmol of iron powder and 50 ml of glacial acetic acid was heated to 2 ° C. to reflux. After cooling, the mixture was poured into ice-water. The resulting white precipitate was filtered, dried in air, and then dried in vacuo overnight to give 780 mg (93%) of the product, m.p. &gt; 250 ° C. D. 3-Benzyloxycarbonyl-6-trifluoromethyl-4-azaoxindole-H-tert-butylcarboxamide To a solution of 750 mg, 2.23 mmol of 3-benzyloxycarbonyl-6-trifluoromethyl-4-azaoxindole in 15 mL of anhydrous DMSO, add 0, Triethylamine (60 ml, 4.3 mmol) and tert-butyl isocyanate (0.38 ml, 3.33 mmol). The resulting mixture was heated under nitrogen in an oil bath for 5 hours at 90-100 ° C. After cooling to room temperature, the solution was poured into water / ice and acidified to pH 3 by addition of 1N hydrochloric acid. The insoluble matter is filtered off and dissolved in chloroform. The resulting solution was dried with magnesium sulfate and evaporated in vacuo. The residue is flash chromatographed on silica gel using chloroform as the eluent. The fractions containing the desired product were combined and evaporated to give 830 mg (86%) of the product as a white solid, m.p. &gt; 250 ° C. E. 6-Trifluoromethyl-4-azaoxindole-1-N-tert-butylcarboxamide

A mixture of 3-benzyloxycarbonyl-6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide (1.10 g, 2.53 mmol), palladium on charcoal (300 mg, 10% charcoal) and ethanol (100 mL) was hydrogenated in a Panro apparatus for 2 h. - 57 - pressure 0.3 MPa. The catalyst was filtered off through Celite and the solvent was evaporated, yielding 850 mg of 6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide-3-carboxylic acid as a gray solid, which was dissolved in 100 mL of ethanol and heated to 1. For 5 hours under reflux. After cooling to room temperature, the solvent was evaporated in vacuo. The residue is subjected to flash chromatography on silica gel, eluting first with chloroform and then with 10% of methanol in chloroform. The desired product fractions were collected and evaporated to give 610 mg (80%) of the product as an off-white solid. F. 3- (2-Thonyl) -6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide To a solution of 530 mg, 1.16 mmol of 6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide and 317 mg, Thiophene-2-carbonyl chloride (0.14 mL, 1.3 mmol) was added in 4 mL of 4-dimethylaminopyridine in 5 mL of anhydrous dimethylformamide. The mixture was stirred at room temperature for 1.5 hours and then poured into water / ice. After adjusting the pH to 2 with 1N HCl, the resulting precipitate was filtered off, washed with water and air dried. Then the material was recrystallized twice from acetonitrile to give 160 mg of a yellow solid in 32% yield, m.p. &gt; 250 ° C. 1 H-NMR (CDCl 3): δ 14.12 (broad, s, 1H), 9.18 (s, 1H), 8.74 (d, J = 3 Hz, 1H), 8.52 (s, 1H) ), 8.14 (s, 1H), 7.94 (d, J = 5 Hz, 1H), 7.25 (dd, J = 3.5 Hz, 1H), 1.41 (s, 9)

Mass spectrum: m / e (relative percentages); 411 (2), 312 (23), 228 (100), 111 (27), IR spectrum (KBr disc): 1725, 1675, 1645, 1605, 1535, 1520, 1500, 1415 cm -1.

H, 3.92; N, 10.12. Found: C, 52.52; H, 3.84; N, 10.12%. Example 8 3- (2-Furoyl) -6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide The resulting product is obtained from 6-trifluoromethyl-4-aza-oxindole-1N-tert-butylcarboxamide from Example 7E of Example 7F using 6-trifluoromethyl-4-azaoxindole-1N-tert-butylcarboxamide (300 mg, 1.0 mmol), 2-furoyl chloride (0.11 mL, 1.1 mmol, 244 mg, 2.0 mmol) N, N-dimethylaminopyridine and 10 mL of DMF. The crude product was triturated with methanol, recrystallized from acetic acid and triturated with methanol to yield a total of 230 mg (58%) of the title compound, m.p. &gt; 250 ° C. 1 H-NMR (DMSO-d 6): δ 9.22 (s, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8.18-8.17 (m, 2H), 8.00 (d, J = 1.7 Hz, 1H), 6.74-6.72 (m, 1H), 1.41 (s, 9H).

Mass spectrum m / e (relative percentages): 395 (3), 296 (53), 228 (100). IR spectrum (KBr disc): 1720, 1670, 1640, 1615, 1540, 1515, 1460, 1425 cm -1.

H, 4.16; N, 10.51. Found: C, 53.89; H, 3.97; N, 10.41%. Example 9 5-isopropoxy-3- (2-thenoyl) -4-azaoxindole-1N-tert, butyl carboxamide A. (3-amino-6-isopropoxy-2-pyridyl) acetonitrile To a stirred solution of 12.34 g, 110%. mmol tert-butoxide

of potassium in anhydrous DMF (30 ml) cooled to -10 ° C - 59 °, a solution of 9.22 g (55 mmol) of (4-chlorophenoxy) acetonitrile and 9.11 g, 50 mmol of 2-isopropanol is added dropwise under nitrogen. poxy-5-nitropyridine, prepared according to Friedman et al., J. Am. Chem. Soc., 69, 1204 (1947), in 30 mL of dimethylformamide. The resulting purple-colored solution was kept at 0-10 ° C for 1 hour, then 80 mL of 5% aqueous hydrochloric acid was added and the resulting mixture was allowed to warm to room temperature. The mixture was then extracted twice with methylene chloride. The extracts were combined, dried (MgSO4) and evaporated in vacuo to an oil which was passed through a pad of silica gel, eluting with a 1: 1 mixture of methylene chloride and hexane. The filtrate is evaporated under reduced pressure and the residue is dissolved in 10 ml of a 6: 1 mixture of ethanol and acetic acid with the addition of 0.8 g of 5% palladium on charcoal. This oil contained the desired (6-isopropoxy-3-nitro-2-pyridyl) -acetonitrile. The mixture was hydrogenated for 5 hours in a Parr apparatus at 0.3 MPa. The catalyst was filtered off through a pad of diatomaceous earth (Celite) and the filtrate evaporated in vacuo. The residual oil is mixed with water and the pH is adjusted to 10 by the addition of sodium carbonate. The mixture was extracted twice with methylene chloride, the extracts combined, dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel, eluting with a 1: 2 mixture of ether and hexane, 1: 1 ethyl acetate / hexane, and ethyl acetate. The product fractions, eluted with ethyl acetate, were combined and evaporated to give 5.60 g (59%) of the resulting (3-amino-6-isopropoxy-2-pyridyl) acetonitrile as a off-white solid, m.p. 83-85 ° C. B. 5-Isopropoxy-4-azaoxindole

A solution of 4.5 g (23.5 mmol) of (3-amino-6-isopropoxy-2-pyridyl) acetonitrile in 3N hydrochloric acid was heated to 50-55 ° C overnight. After cooling 4 <. To 0 ° C, the mixture was basified by slow addition of concentrated sodium hydroxide solution. The mixture was extracted twice with ethyl acetate, the fractions were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to a solid which was flash chromatographed on silica gel, eluting with 9: 1 chloroform / methanol. The desired product, 5-ixopropoxy-4-azaoxindole, was evaporated to give 1.0 g (22%) of product as an off-white solid. C. 5-Isopropoxy-3- (2-thenoyl) -4-azaoxindole Sodium metal 250 mg, 11 mmol pellet was added to 10 mL of anhydrous ethanol in a dry round bottom flask. After the sodium was completely dissolved, solid 5-isopropoxy-4-azaoxindole (419 mg, 2.22 mmol) was added followed by 688 mg of ethyl 2-thiophenecarboxylate (0.59 ml). The mixture was heated to reflux overnight and cooled to room temperature. The mixture was quenched with water / ice and acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extracts were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in vacuo. silica gel, eluting with chloroform: chloroform: methanol = 49: 1 to give fractions containing the desired product which are combined and evaporated. The residue was subjected to flash chromatography on silica gel, eluting with chloroform. The fractions containing the desired product were combined and evaporated to give 300 mg of 4-isopropoxy-3- (2-thenoyl) -4-azaoxindole as a yellow gum in 45% yield. D. 5-Isopropoxy-3- (2-thenoyl) -4-aaoxindole-1N-tert-butylcarboxamide To a solution of 300 mg, 1.3 mwol of 5-isopropoxy-3- (2-theoyl) -4-azaoxindole- 1 N-tert-butylcarboxamide in 7 mL of J. Triethylamine (0.3 L, 2.2 mmol) and 0.17 L (1.5 mol) tert-butyl isocyanate are added sequentially. The resulting mixture was heated in an oil bath at 80 ° C for 4 hours. After cooling to room temperature, the mixture is poured into a water / ice mixture and acidified. adding 1N hydrochloric acid solution. The resulting precipitate was filtered off and dried in air. The material was dissolved in ether and activated carbon was added to the solution. The mixture was filtered through Celite and the filtrate evaporated in vacuo to give a yellow solid. This crude 5-isopropoxy-3- (2-thenoyl) -4-azaoxindole-1-N-tert-butylcarboxamide is recrystallized from cyclohexane to yield 26 mg of pure title compound in a yield of 26%. of bright yellow crystals having a melting point of 160-163 ° C. 1 H-NMR (MSO-d 6): / 9.20 (broad s, 1H, 8.87 4d, J = 3Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 5Hz, 1H), 7.23d, J = 3.5Hz, 1H), 6.71 (d, J = 8.5Hz, 1H), 4.90 (heptet, J = 6 1H, 1H), 1.40 (s, 9H), 1.38 (d, J = 6Hz, 6H), mass spectrum m / e (relative%) 401 (12), 302 (61), 176 (100) ), 148 (18), 111 (59) IR spectrum (KBr disc): 1703, 1654, 1624, 1604, 1547, 1518, 1472, 1421 cm -1.

H, 5.77; N, 10.47. Found: C, 59.59; H, 5.62; N, 10.46%. Example 10 5-Phenylthio-3- (2-thenoyl) -6-azaoxindole-1-N-tert-butyl-carboxamide A. tert-butyl (3-nitro-6-phenylthio-2-pyridyl) acetate - 72 - A mechanically stirred suspension of 16.0 g, 400 mmol of powdered sodium hydroxide in 75 mL of HISO was added dropwise to a solution of 5.7 g, 40 mmol of 2-fluoro-5-nitropyridine prepared according to Finger and Starr, J. Am. Chem. Soc., 8ft, 2674 (1959) and 9.0 g, 40 mmol of tert-butyl (phenylene) acetate in 75 mL of EMSO while maintaining the reaction mixture temperature below 30 ° C. The mixture was then stirred overnight at room temperature and poured into a mixture of water and ice.

After adjusting the pH to 2 with 1N hydrochloric acid, the mixture is extracted with ethanol, the combined organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. silica gel, eluting with chloroform / hexane (2: 1). The product fractions were combined and evaporated to give a yellow solid which was triturated with ether to give 1.5 g of tert-butyl (3-nitro-6-phenylthio-2-pyridyl) in 11% yield. ) acetate with a melting point of 104-107 ° C. B. 5-Phenylthio-6-azaoxindole

A solution of 1.04 g, 3.0 mmol of tert.butyl (3-nitro-6-phenylthio-2-pyridyl) acetate in 600 mg, 10.7 mmol of iron powder containing glacial acetic acid is heated to reflux for 5 hours. with a reflux condenser. After cooling to room temperature, the mixture was poured into ice / water and extracted with chloroform. The chloroform extracts were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give 560 mg of 5-phenylthio-6-azaoxindole as a pale yellow solid (77% yield), m.p. 186-189 ° C. C. 5-Phenylthio-3- (2-thenoyl) -6-azaoxindole 264 mg, 11.5 mmol of pelleted sodium metal is added to 10 ml of anhydrous ethanol in a round bottom flask. After complete dissolution of the sodium, a suspension of 560 mg, 2.3 bb, 5-phenylthio-6-azaoxindole in 5 L ethanol was added. The mixture was heated to 50 ° C and ethyl 2-thiophenecarboxylate (0.55 mL, 4.6 mmol) was added at this temperature. The mixture was then heated to reflux for 30 hours. After cooling to room temperature, the mixture was poured into ice water and the pH was adjusted to 1 by addition of 6N hydrochloric acid. The precipitated solid was filtered off, dried and chromatographed on silica gel using chloroform / methanol 9: 1 as eluent. The fractions containing the desired sample were combined and evaporated under reduced pressure to give 620 mg (76%) of the product as a golden solid, m.p. 248-252 ° C with decomposition. D. 5-Phenylthio-3- (2-thenoyl) -6-azaoxindole-1N-tert-butylcarboxamide To a solution of 255 mg, 0.72 mmol of 5-phenylthio-3- (2-thenoyl) -6-azaoxindole from triethylamine (0.2 mL, 1.4 mmol) was added sequentially to tert-butyl isocyanate (0.12 mL, 1.1 mmol). The solution was heated to 85 ° C overnight. After cooling, the mixture was poured into ice-water and the pH was adjusted to 2.5 by addition of 1N hydrochloric acid. The solid was filtered off, dried in air and recrystallized from chloroform and then from methanol / chloroform to give 70 mg of 5-phenylthio-3- (2, thenoyl) -6-azaoxindole in 22% yield. 1-N-tert-butylcarboxamidus, m.p. > 250 ° C. 1H-NB4R (DMSO-d6): c> 9.885, (s, 1H), 8.95 (s, 1H), 8.52-8.50 (m, 1H), 7.92 (s, 1H) , 7.64-7.62 (m, 1H), 7.42-7.30 (m, 5H), 7.12-7.07 (m, 1H), 1.39 (s, 9H). IR spectrum (KBr): 1706, 1619, 1587, 1554, 1465, 1427 cm @ -1.

H, 4.38; N, 8.55. Found: C, 56.74; H, 4.60; N, 8.23%. Example 11 6-Chloro-3- (2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide The title compound was prepared from 6-chloro-3- (2-thenoyl) -4-azaoxindole obtained in the Example 2B by the method of Example 1C using 5-chloro-3- (2-thenoyl) -4-azaoxindole, 450 mg, 1.6 mmol, 0.78 mL, 2.4 mmol tert-butyl isocyanate, 0.49 mL, 3 , 5 mmol triethylamine and 10 mL DMSO. After recrystallization of the resulting product from a mixture of methanol and chloroform, 33 mg of product was obtained in 55% yield.

Mass spectrum m / e (relative%) 379 (3), 377 (10), 280 (24), 278 (71), 196 (40), 194 (100), 111 (20). ): 1717, 1659, 1597, 1424 cm -1.

H, 4.27; N, 11.12. Found: C, 53.64; H, 4.14; N, 10.99%. Example 12 6-Chloro-3- (2-furoyl) -4-azaoxindil-1-N-tert-butylcarboxamide

First, 6-chloro-3- (2-furoyl) -4-aza-oxindole according to Example 2B was prepared using 1.0 g, 5.9 mmol of 6-chloro-4-azaoxindole, 678 g, 29.5 mmol of sodium, Ethyl 2-furoate (1.65 g, 11.8 mmol) and ethanol (30 mL). The crude product was triturated with hot methanol. Yield 825 mg (53%), m.p. 250 ° C. or - 75 -

Then, from 6-chloro-3- (2-furoyl) -4-azaoxindole, the resulting compound was prepared according to Example 1C using 400 mg, 1.5 mmol of 6-chloro-3- (2-furoyl) -4- of azaoxindole, 0.26 mg, 2.2 mmol of tert-butyl isocyanate and 0.41 mg, 3.0 mmol of triethylamine. After a reaction time of 4 hours, the crude product was recrystallized from chloroform. 190 mg of the product with a melting point above 250 ° C were obtained.

H, 4.46; N, 11.61. Found: C, 56.17; H, 4.26; N, 11.20%. Example 13 6-Chloro-3- (3-furoyl) -4-azaoxindole-1-carboxamide

First, 6-chloro-3- (3-furoyl) -4-aza-oxindole was prepared according to Example 2B using 1.5 g, 8.9 mmol of 6-chloro-4-azaoxindole, 1g, 44.5 mmol of sodium. Ethyl 3-furoate (2.4 mL, 17.8 mmol) and ethanol (40 mL). 1 g of product having a melting point above 250 ° C was recovered in a 43% yield of the crude product with hot oethanol. 6-Chloro-3- (3-foroyl) -4-azaoxindole was then prepared as described in Example 20 using 500 mg, 1.9 mmol of 6-chloro-3- (3-furoyl) -4-azaox N-chlorosulfonyl isocyanate and 20 mL of acetonitrile. After recrystallization of the crude product from acetic acid, 175 mg of the product with a melting point above 250 ° C was obtained in 30% yield.

H, 2.64; N, 13.75. Found: C, 51.04; H, 2.41; N, 13.46%. Example 14 3-Benzoyl-6-chloro-4-azaoxindole-1-N-tert-butylcarboxamide

First, 3-benzoyl-6-chloro-4-azaoxindole was prepared according to the procedure of Example 2B using 1.5 g, 8.9 mmol of 6-chloro-4-azaoxindole, 1 g, 44.5 mmol of sodium, 2.5 ml, 17, 5 mmol of ethylbenzoate and 40 ml of ethanol. After trituration of the crude product with hot methanol, 1.2 g of product was obtained in 49% yield. From this 3-benzoyl-6-chloro-4-azaoxindole the resulting product was as described in Example 1C using 3-benzoyl-6-chloro-4-azaoxindole (500 mg, 1.83 mmol, 0.3 mL, 2.62 mmol tert.). butyl iocyanate, 0.5 mL, 3.59 mmol triethylamine and 15 mL DMSO. The crude product was recrystallized from methanol / chloroform to a temperature above 260 ° C. @ 1 H-NMR (DMSO-d6): 9.10 (s, 1H), 8.43 (d, J = 1.4 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H) , 7.73 (d, J = 7 Hz, 2H), 7.52-7.42 (m, 3H), 1.35 (s, 9H).

H, 4.88; N, 11.30. Found: C, 61.19; H, 4.51; N, 10.99%. EXAMPLE 15 6-Chloro-3- (2-furoyl) - 4-azaoxindole-1-carboxamide The resulting product was prepared from 6-chloro-3- (2-furoyl) -4-azaoxindole from Example 12 by the procedure of Example 20 using 400 mg, 1.5 mmol of 6-chloro-3-one. (2-furoyl) -4-azaoxindole, 0.19 ml, 2.25 mmol of N-chlorosulfonyl isocyanate and 15 ml of acetonitrile. The crude N-chlorosulfonylcarboxamide was hydrolyzed by stirring for 2 hours - η - in an air flask in an open flask. The product was isolated after dilution with water by filtration, after recrystallization from acetic acid, 160 mg of the product with a melting point above 250 ° C was obtained in 35% yield.

H, 2.64; N, 13.75%. Found: C, 51.24; H, 2.55; N, 13.44%. Example 16 6-Chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole-1-N-tert-butylcarboxamide

First, the method of Example 2B6-chloro-3 '(4-chloro-2-thenoyl) -4-azaoxindole was prepared using 1.5 g, 8.9 mmol of 6-chloro-4-azaoxindole, 1.0 g, 44%. Of ethyl 4-chloro-2-thiophenecarboxylate and 40 ml of ethanol. 1.8 g of product with a melting point above 250 ° C are obtained in 64% yield. The resulting product was prepared from 6-chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole by the method of Example 1C using 900 mg, 2.8 mmol of 6-chloro-3- (4-chloro-2- thenoyl) -4-azaoxindole, 0.49 ml, 4.3 mmol tert-butyl isocyanate, 0.77 ml, 5.6 mmol triethylamine and 25 ml DMSO. After recrystallization of the crude product from methanol, 140 mg of the product with a melting point above 250 ° C is obtained in a yield of 12%.

H, 3.67; N, 10.19. Found: C, 49.18; H, 3.31; N, 10.00%. C17H15Cl2N3O3S requires C, 49.52; EXAMPLE 17 6-Chloro-3- (3-furoyl) -4-azaoxindole-1N-tert-butylcarboxamide A product was prepared from 6-chloro-3- (3-furoyl) -4-azaoxindole from of Example 13 as described in Example 1C using 500 mg, 1.9 mol of 6-chloro-3- (3-furoyl) -4-azaoxindole, 0.32 ml, 2.8 mol of tert-butyl isocyanate, 0.52 ml , 3.8 mmol of triethylamine and 15 ml of MISO.

The crude product is purified by chromatography on silica gel using chloroform as the eluent, then recrystallization / cyclohexane, then flash chromatography on silica gel using ethyl acetate / hexane (1: 1) and recrystallization from cyclohexane to give a 23% yield. 160 mg of the title compound are obtained with a tpp-melting point above 250 ° C.

H, 4.46; N, 11.61. Found: C, 56.38; H, 4.45; N, 10.67%. Example 18 3-Benzoyl-6-chloro-4-azaoxindole-1-carboxamide The resulting product was obtained from 3-benzoyl-6-chloro-4-azaoxindole from Example 14 by the procedure of Example 2C using 500 mg, 1.83 mmol 3 -benzoyl-6-chloro-4-aza-oxindole, 0.24 mL, 2.76 mmol of N-chlorosulfonyl isocyanate and 20 mL of acetonitrile. Recrystallization of the crude product from acetonitrile / chloroform gave 121 mg (21%) of the product, m.p. &gt; 260 ° C.

Anal. H, 2.98; N, 12.16. Found: C, 53.14; H, 2.78; N, 11.92%. Example 19 6-Chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole-1-carboxamide Prepared from 6-chloro-3- (4-chloro-2-thenoyl) - 4-azaoxindole by the method of Example 2C using 850 mg, 2.7 mmol of 6-chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole, 0.35 mL, 4.0 mmol of N-chlorosulfonyl isocyanate and 30 ml acetonitrile. After the crude product was reinstalled from acetic acid, 280 mg of product with a melting point of greater than 250 DEG C. were obtained in a yield of 29%. 1 H-NMR (DMSO-d 6): δ 8.75 (d, J = 1.2 Hz, 1H), 8.49 (broad s, 1H), 8.38 (d, J x 1.6) Hz, 1H), 7.92 (m, 3H),

Mass spectrum m / e (relative%): 355 (5), 314 (8), 312 (14), 196 (21), 194 (72), 145 (30).

IR spectrum (KBr disc) 1730, 1680, 1600, 1510, 1415 cm -1.

H, 1.98; N, 11.80. Found: C, 43.90; H, 2.01; N, 11.23. (4-methyl-2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide

First, 6-chloro-3- (4-methyl-2-thenoyl) -4-azaoxindole was prepared as in Example 2B using 1.3 g, 7.71 mmol of 6-chloro-4-azaoxindole, 1.75 g Sodium 49.7 mmol, 1.93 g (12.0 mmol) of 4-methylthiophene-2-carbonyl chloride and 40 ml of ethanol. Ethyl 4-methylthiophene-2-carboxylate was prepared in situ by addition of acid chloride to the sodium ethoxide solution. Azaoxindole is added and the reaction is carried out as in Example 1B to give 1.64 g of the product with a melting point of greater than 2 ° C in a yield of 46%. The resulting material was prepared from 6-chloro-3- (4- (4-methyl-2-thenoyl) -4-azaoxindole according to Example 1C using 470 mg, 1.6 mmol of 6-chloro-3- (4-methyl) -thio. Of 2-thenoyl) -4-aza-oxindole, 0.27 ml, 2.4 mmol of tert-butyl isocyanate, 1.1 ml, 3.2 mmol of triethylamine and 30 ml of EMSO. The crude product was purified by flash chromatography on silica gel using chloroform followed by recrystallization from chloroform / ethanol to give 300 mg (48%) of the product, m.p. &gt; 250 ° C. 1 H-NMR (DMSO-d 6): δ 9.19 (5, 1H), 8.57 (s, 1H), 8.42, 1H, 7.91 (s, 1H), 7.50 (s, 1H). 1H), 2.27 (s, 3H), 1.41 (s, 9H).

Mass spectrum m / e (relative percentages): 393 (1), 391 (3), 294 (10), 292 (27), 196 (33), 194 (100), 125 (23). IR spectrum (KBr disc): 1725, 1710, 1660, 1630, 1600, 1560, 1525, 1500 cm @ -1.

H, 4.63; N, 10.72. Found: C, 55.17; H, 4.34; N, 10.51. EXAMPLE 21 6-Chloro-3- (2-thenoyl) - 4-azaoxindole-1N-phenylcarboxamide The resulting product was prepared from 6-chloro-1- (2-theoyl) -4-azaoxindole from Example 2B by the procedure of Example 1B using 1.0 g, 3.6 mmol 6-chloro-3- (2-thenoyl) -4-azaoxindole, 0.58 ml, 5.4 mmol of phenyl isocyanate, 1.0 ml, 7.2 mmol of triethylamine and 35 ml of D1SO4. After recrystallization of the crude product from acetic acid and then from DMSO, the DMSO traces were removed by trituration with methanol, yielding 515 mg (36%) of the title compound, m.p. &gt; 250 ° C.

Mass spectrum m / e (relative: 399 (8), 397 (23), - 81-280 (37), 278 (100), 196 (28), 194 (86), 119 (93). KBr disc): 1720, 1680, 1630, 10505, 1580, 1500, 1425, 1405 cm -1.

H, 3.04; N, 10.56. Found: C, 56.58; H, 2.95; N, 10.27%. Example 22 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide The title compound was prepared from 5-chloro-3- (2-thenoyl) -4-azaoxindole from Example 1B by the procedure of Example 2C using 500. 5-chloro-3- (2-thenoyl) -4-azaoxindole mg, 1.79 mmol, 0.18 ml, 2.15 mmol N-chlorosulfonyl isocyanate and 15 ml acetonitrile »Crude N-chlorosulfonylcarboxamide is hydrolyzed by stirring in 1.5 ml of DMSO for 1 hour in air in an open flask. The product was then precipitated by the addition of water, the precipitate was filtered off and recrystallized from acetic acid to give 36 mg (6%), m.p. 222-224 ° C.

Mass spectrum m / e (relative%): 323 (7), 321 (17), 280 (9), 278 (24), 196 (22), 194 (62), 170 (25), 168 (100). calculated: 320.9975 found: 320.9977. IR spectrum (KBr disc): 1724, 1623, 1570, 1512, 1415, cm &lt; -1 &gt;. EXAMPLE 23 5-Chloro-3- (2-furoyl) -4-azaoxindole-1N-tert, butyl carboxamide Exact molecular weight for pro ^ .Ηθ - ^^ ΟΙΝβΟ> c '? - 82 -

First, 5-chloro-3- (2-furoyl) -4-azaoxindole was prepared according to Example 1B using 1.0 g, 5.9 mmol of 5-chloro-4-azaoxindole, 0.68 g, 29.6 nnol sodium, 30 ml ethanol and 1.65 g, 11.8 nol ethyl-2-furoate. A yield of 33% yields 500 mg of product with a melting point of greater than 250 ° C. The resulting product was then prepared according to Example 1C using 500 mg of 1.90 mmol of 5-chloro-3- (2-furoyl) -4-azaoxindole, 0.33 mL, 2.9 mmol of tert-butyl isocyanate, 0.53 mL, 3.8 mmol triethylamine and 10 ml DMSO. After recrystallization of the crude product from methanol, 240 mg of the product with a melting point of 194-195 ° C is obtained in a yield of 35%. 1 H-NMR (DMSO-d 6): δ 8.96 (s, 1H), 8.38 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.06 (s, s) 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.80-5.78 (m, 1H), 1.40 (s, 9H). IR spectrum (KBr disc): 1725, 1590, 1569, 1541 cm @ -1.

Mass spectrum m / e (%): 361 (10), 262 (13), 196 (37), 194 (100), 95 (4).

H, 4.46; N, 11.66. Found: C, 56.18; H, 4.43; N, 11.56%. - (2-furoyl) -4-azaoxindole-1-carboxamide The resulting product is obtained from 5-chloro-3- (2-furoyl) -4-azaoxindole from Example 23 by the method of Example 2C using 200 mg, 0.76. 5-chloro-3- (2-furoyl) -4-azaoxindole, 0.10 ml, 1.1 mmol N-chlorosulfonyl isocyanate and 8 ml acetonitrile. Hydrolysis of the N-chlorosulfonylcarboxamide is accomplished by adding water followed by stirring the reaction mixture overnight at room temperature. The product is filtered and recrystallized from MeSO 4. In this way

75 mg of the title compound are obtained in a yield of 32%, m.p. 248-260 ° C. FAB mass spectrum m / e 306. Example 25 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1 H -phenylcarboxamide The resulting product is obtained from 5-chloro-3- (2-thenoyl) -4-azaoxindole from Example 1B by the method of Example 1, using 500 mg, 1.8 mmol of 5-chloro-3- (2-thenoyl) -4-azaoxindole, 0.29 mL, 2.7 mmol of phenyl isocyanate, 0.54 mL, 3.9 mmol of triethylamine and 10 ml of MeSO4. The crude product was recrystallized from ethyl acetate.

Molecular weight for C ^ HH ^^NINNINN QO ^ ^S

Calculated: 397.0287 found: 397.0295. IR spectrum (KBr disc): 1728, 1622, 1603, 1582, 1563, 1412 cm -1.

H, 3.04; N, 10.56%. Found: C, 56.84; H, 2.87; N, 10.52%.

Melting point: 226-228 ° C. Example 26 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1-N-cyclohexylcarboxamide

The resulting compound can be obtained from 5-chloro-3- (2-thenoyl) -4-azaoxindole from Example 1B by the procedure of Example 1Cf using 560 mg, 2.0 mmol of 5-chloro-3- (2-thenoyl) - 4-azaoxindole, 0.38 mL, 3.0 mmol cyclohexyl isocyanate, 0.56 mL, 4.0 mmol triethylamine and 10 mL DMSO

- 84 -

The crude product was triturated with methanol and recrystallized from methanol / chloroform to give 91 mg (11%), m.p. 169-170 ° C.

H, 4.64; N, 10.17. Found: C, 55.17; H, 4.34; N, 9.87.

Mass spectrum m / e (relative%): 405 (1), 403 (3), 280 (22), 278 (56), 196 (33), 194 (100), 111 (14). disc): 1712, 1625, 1585, 1518, 1417 cm -1. Example 27 5-Chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole-1-N-tert-butylcarooxamide

First, 5-chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole was prepared according to Example 20 using 1.0 g, 5.93 mmol of 5-chloro-4-azaoxindole, 0.95 g, 41.3 mmol of hydrogen, 25 ml of ethanol and 2.2 g, 11.3 mmol of 4-chlorothtophene-2-carbonyl chloride. 1.68 g of product are obtained in 90% yield. The resulting product was then prepared from 5-chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole according to Example 1C using 0.75 g, 2.39 mmol of this material, 0.4 mL, 3, 5 mmol tert-butyl isocyanate, 0.65 ml, 4.7 mmol triethylamine and 20 ml DMSO. The crude product was purified by successive flash chromatography on silica gel using ethyl acetate as eluent and then recrystallization from methanol / chloroform. Yield: 438 mg (44%), mp 208-209 ° C.

H, 3.67; N, 10.19%. Found: C, 49.58; H, 3.39; N, 9.94%. Example 28 5-Chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole-1-carboxamide The product is obtained from 5-chloro-3- (4-chloro-2-thenoyl) - Of 4-azaoxindole from Example 27 according to Example 2C using 0.75 g, 2.39 mmol of 5-chloro-3- (4-chloro-2-thenoyl) -4-azaoxindole, 0.31 ml, 3 56 mmol of N-chlorosulfonyl isocyanate and 12 ml of acetonitrile. Hydrolysis of N-chlorosulfonylcarboxamide is carried out by stirring for 4 hours in 8 mlEMSO at room temperature in air in an open flask.

The mixture was diluted with water, filtered and recrystallized from acetic acid to give 352 mg (41%) of the product, m.p. &gt; 250 ° C.

H, 1.98; N, 11.80. Found: C, 43.52; H, 1.93; N, 11.52%. Example 29 $ -chloro-3- (2-thenpyl) -4-azaoxindole-1-N- (2,4-dichlorophenyl) carboxamide

Obtained from 5-chloro-3- (2-thenoyl) -4-azaoxindole from Example 1B as in Example 1C using 580 mg, 2.08 mmol of 5-chloro-3- (2-thenoyl) Triethylamine, 0.58 ml, 4.15 mmol of triethylamine, 0.57 g, 3.1 mmol of 2,4-dichlorophenyl isocyanate and 10 ml of EMSO. The crude product was recrystallized from methanol / chloroform to give 231 mg (24%) of the title compound, mp 244.5-245 ° C.

H, 2.16; N, 9.00. Found: C, 48.73; H, 1.95; N, 8.97%. Example 30 5-Chloro-3- (4-methyl-2-thenoyl) -4-azaoxindole-1-N-tert-butylcarboxamide

First, 275-chloro-3- (4-methyl-2-thenoyl) -4-aaoxindole was prepared by the method of Example 1.45 g, 8.60 mmol of 5-chloro-4-azaoxindole, 1.3 g, 56%. 5 mmol of hydrogen, 40 ml of ethanol and 2.38 g, 14.8 mmol of 4-methylthio-2-carbonyl chloride. The mixture was reacted overnight to give 1.71 g (76%) of product. From 5-chloro-3- (4-methyl-2-thenoyl) -4-azaoxindole, the resulting product of Example 1C was prepared using 0.8 g, 2.73 mmol of this material, 0.5 mL, 4.36 mmol tert. triethyl amine, 0.8 ml, 5.74 mmol triethylamine and 25 ml DMSO. The crude product was first flash chromatographed on silica using ethyl acetate as eluent. The product was recrystallized from methanol / methylene chloride to give the title compound (600 mg), m.p. 167-169 ° C. 1 H-NMR (EMSO-d 6) δ 9.06 (s, 1H), 8.63 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 7.61 (s, 1H) ), 7.23 (d, J = 8.2 Hz, 1H), 2.31 (s, 3H), 1.42 (s, 9B),

Mass spectrum m / e (relative%): 393 (1), 391 (4)

294 (16), 292 (43), 196 (33), 194 (100), 125 (11). IR-spectrum (KBr disc): 1720, 1670, 1585, 1540, 1415 and 111. H, 4.63; N, 10.72. Found: C, 55.14; H, 4.38; N, 10.57%. in? EXAMPLE 31 5-Chloro-3- (4-methyl-2-thenoyl) -4-azaoxindole-1-carboxamide The title compound can be obtained as described in Example 2C using 0.90 g. 3.07 mmol of 5-chloro-3- (4-methyl-2-thenoyl) -4-azaoxindole from Example 30, 0.40 mL, 4.60 mmol of N-chlorosulfonyl isocyanate and 15 mL of acetonitrile. hydrolysed by stirring in DMSO in an open flask. The product is isolated by dilution with water followed by filtration and recrystallized from acetic acid. Yield: 190 mg (18%), m.p. 227-228 ° C.

H, 3.00; N, 12.5%. Found: C, 49.88; H, 2.96; N, 12.39%. 1 H-NMR (IHSO-d 6): $ 8.71 (s, 1H), 8.46 (broad s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.84 (broad s (1H), 7.61 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 2.31 (s, 3H),

Mass spectrum m / e (relative%): 337 (33), 336 (42), 335 (100) IR spectrum (KBr disc): 1730, 1630, 1500, 1430 cn "Example 32 3-Benzoyl-5 -chloro-4-azaoxindole-1N-tert-butylcarooxamide

First, 3-benzoyl-5-chloro-4-azaoxindole was prepared according to the method of Example 1B using 1.5 g, 8.9 mmol of 5-chloro-4-azaoxindole, 1.0 g, 44.4 mmol of sodium, 40 mL ethanol and 2.5 ml, 17.5 mmol ethyl benzoate. 1.6 g of product are obtained in 66% yield. The resulting product was then prepared as described in Example 1C using 800 mg, 2.93 mmol, 3-benzoyl-5-chloro-4-azaoxindole, 0.8 mL, 5.74 mmol of triethylamine. , 0.5 ml, 4.36 mmol tert, butyl isocyanate and 25 ml ESSO4.

The crude product was purified by silica gel flash chromatography using ethyl acetate as eluent and then recrystallized from hexane. 320 mg (29%) of the title compound are obtained.

H, 4.88; N, 11.30. Found: G, 62.00; H, 5.11; N, 10.75%. 1 H-NMR (DMSO-d 6): δ 9.03 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 6.9 Hz, 2H) , 7.59-7.46 (m, 3H), 7.20 (d, J = 8.2 Hz, 1H), 1.35 (s, 9H).

Mass spectrum m / e (relative%): 373 (1), 371 (3 (, 274 (34), 272 (100), 194 (44), 105 (55). IR spectrum (KBr disc): 1730, EXAMPLE 33 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1N-methylcarboxamide: The title compound can be obtained from 5-chloro-3- (2-thenoyl). The reaction is carried out at 55 ° C using a dry ice cooler to prevent methylisocyanate loss, and the reaction time is 5 hours, 560 mg, 2.0 mmol of 5-chloro-4-azaoxindole as described in Example 1C. 3- (2-thenoyl) -4-aza-oxindole, 0.18 mL, 3.0 mmol of methyl isocyanate, 0.56 mL, 4.0 mmol of triethylamine and 10 mL of DMSO.

After recrystallization of the crude product from a mixture of methanol and chloroform, 151 mg of product with a melting point of 179-180 DEG C. is obtained in a yield of 23%. 1 H-NMR (CDCl 3): δ 8.98 - 8.94 (a, 2H), 8.45 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 5 Hz) , 1HJ, 7.22 (dd, J = 3.5 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 3.01 (s, 0.5H), 2.99 ( s, 0.5 H).

Analysis for C ^ HH ^ qClINN OO SS. H, 3.21; N, 12.18. Found: C, 49.00; H, 2.84;

Molecular weight for θ ^ Η ^ θ CIN ^ O ^ S: calculated: 335 · 1121 found: 335.0012. Example 34 5-Chloro-3- (3-furoyl) -4-azaoxidol-1-N-tert-butylcarboxamide

First, by the method of Example 1B, 5-chloro-3- (3-furoyl) -4-azaoxindole was prepared using 1.0 g, 5.9 mmol of 5-chloro-4-azaoxindole, 6.82 mg, 29.6 mmol of hydrogen, 1.5 ml, 11.8 mmol of ethyl 3-furoate and 25 ml of methanol. 1.2 g of product are obtained in 80% yield. The resulting product was prepared according to the procedure of Example 1C using 1.2 g, 4.5 mmol of 5-chloro-3- (3-phenyl) -4-azaoxindole, 0.78 mL, 6.8 mmol tert. of butyl isocyanate, 1.2 mL, 9.0 mmol of triethylamine and 45 mL of DMSO.

The crude product was subjected to flash chromatography on silica gel using ethyl acetate / hexane (4: 1) as eluent. From the fractions containing the desired product, a solid was obtained which was serosetred with methanol and recrystallized from acetonitrile. 740 mg of product with a melting point of 182 DEG-184 DEG C. are obtained in this way. 90H-NMR (DMSO-d6): c 9.13 (br s, 1H), 8.77 (br s, 1H), 8.32 (d, J = 8.6 Ha, 1H), 7 , 86 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 1.40 (s, 9H).

Mass spectrum m / e (relative%): 363 (5), 361 (16), 264 (34), 262 (100), 247 (6), 245 (19), 236 (17), 234 (41), 194 (24). IR spectrum (KBr disc): 1725, 149Q 1545 cm @ -1

H, 4.46; N, 11.61. Found: C, 56.33; H, 4.17; N, 11.68%. EXAMPLE 35 6-Fluoro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide The title compound can be obtained as in Example 2C using 419 mg, 1.60 mmol of 6-fluoro-3- (2- -thenoyl) -4-azaoxindole from Example 5, 0.2 ml, 2.3 mmol of N-chlorosulfonyl isocyanate and 8 ml of acetonitrile. The reaction period is 3 days. The crude N-chlorosulfonylcarboxamide is hydrolyzed by stirring in DMSO in an open flask in air, the reaction mixture is diluted with water and the product is filtered off. The crude product was recrystallized from acetic acid to give 210 mg (43%) of the title product, m.p.

H, 2.64; N, 13.45. Found: C, 50.90; H, 2.46; N, 13.45%. - (4-methyl-2-thenoyl) -4-azaoxindole-1N-tert-butylcarboxamide 91 -

First, 6-fluoro-3- (4-methyl-2-thenoyl) -4-azaoxindole was prepared according to Example 20 using 1.0 g, 657 mmol of 6-fluoro-4-azaoxindole, 1.05 g, 45.6 mmol of hydrogen. , 30 µl of ethanol and 1.86 g, 11.6 mmol of 4-methylthinophen-2-carbonyl chloride, yielding 1.17 g of product in 64% yield. The resulting product is then obtained from 6-fluoro-3- (4-methyl-2-thenoyl) -azaoxindole by the method of Example 5E. Chromatography allowed the product to recrystallize from methanol to give 234 mg (31%) of the product with a melting point of 275 ° C. 1 H-NMR (DMSO-d 6): δ 14.0 (broad s, 1H), 9.24 (s, 1H), 8.60 (s, 1H), 8.45 (dd, J = 2.3) , 9.4 Hz, 1H), 7.99-7.96 (m, 1H), 7.50 (s, 1H), 2.28 (s, 3H), 1.42 (s, 9H).

Mass spectrum m / e (relative%): 375 (15), 276 (67), 178 (100), 125 (12). XR-spectrum (KBr disc): 1720, 1670, 1610, 1560, 1530, 1425 cm25-.

Analysis calculated for C18H18FN3O3S: C, 57.59; H, 4.83; N, 11.19. Found: C, 57.37; H, 4.73; N, 11.33. -thenoyl) -4-azaoxindole-1-carboxamide The title compound was obtained as in Example 2C using 614 mg, 2.22 mmol of 6-fluoro-3- (4-methyl-2-thenoyl) -4-azaoxindole from the example N-chlorosulfonyl isocyanate (36 ml, 0.30 ml, 3.45 mmol) and acetonitrile (10 ml). The N-chlorosulfonylcarboxamide was hydrolyzed by stirring in air in 4 ml DMSO overnight. The product is isolated by diluting the mixture with water, filtering off the product, and recrystallizing it from acetic acid. 249 mg of the product is obtained in a yield of 35% in a stepwise melting point above 250 ° C.

H, 3.16; N, 13.16. Found: C, 52.16; H, 3.00; N, 13.00%. 1 H-NMR (DMSO-d 6): 13.96 (br s, 1H), 8.64 (s, 1H), 8.60 (br s, 1H), 8.39 (dd, J = 2.3) , 9.5 Hz, 1H), 7.96 (dd, J x 2.3, 3.5 Hz, 1H), 7.89 (broad s, 1H), 7.49 (s, 1H), 2, 26 (s, 3H).

Mass spectrum m / e (relative%): 319 (7), 276 (13 $, 178 (100), 125 (19). IR spectrum (KBr disc): 1725, 1610, 1590, 1510, 1430 cm -1. Example 38 3- (2-Thenoyl) -6-azaoxindole-1-N-tert-butylcarboxamide

First, 3- (2-thenoyl) -6-azaoxindole was prepared by the method of Example 1B using 2.8 g of 20-azaoxindole, 20.9 mmol of sodium, 2.4 g, 104 mmol of sodium, 45 mL of ethanol and 55 mL, 40.9 mmol. ethylthiophene-2-carboxylate. Yield: 4.05 g (79%), m.p. &gt; 280 ° C. The resulting product was then prepared as in Example 1C using 3- (2-thenoyl) -4-azaoxindole (500 mg, 2.0 mmol), tert-butyl isocyanate (0.35 mL, 3.0 mmol), 0.6 mL, 4.4. mmol triethylamine and 10 ml DMSO.

The crude product was flash chromatographed using a 9: 1 mixture of chloroform and methanol.

Fractions containing only the desired product are combined and evaporated to give a solid which is allowed to cool.

I. Crystallizing from a mixture of acetone, methanol and chloroform to give 390 mg (57%) of the title compound, m.p. 250-252 ° C. 1 H-NMR (D 6 SO-d 6): 9.57 (s, 1H), 8.91 (s, 1H), 8.43 (d, J = 3.5 Hz, 1H), 8.15 (d, 1H), J = 6.4 Hz, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 5 Hz, 1H), 7.17 (dd, J = 3.5, 5 Ηζ,,), 1.40 (s, 9H),

Mass spectrum m / e (relative%): 343 (0.4), 244 (6), 160 (27), 111 (9), 84 (100; IR spectrum (KBr disc): 1715, 1593, 1539 , 1408 cm '1.

H, 4.99; N, 12.24. Found: C, 58.9; H, 4.85; N, 12.10%. EXAMPLE 39 5-Fluoro-3- (2-thenoyl) -6-azaoxindole-1-carboxamide The title compound is obtained as in Example 2C using 5-chloro-3- (2-thenoyl), 140 mg, 0.5 mmol. Of 6-azaoxindole from Example 3C, 65 mL, 0.75 mmol of N-chlorosulfonyl isocyanate and 5 mL of acetonitrile. The crude N-cisulfonylcarboxamide is hydrolyzed by stirring in an SiSO 2 clock in an open flask in air. The product is precipitated by addition of water, filtered off and allowed to recrystallize with methanol. Yield 27 mg (17%), mp 252 ° C. 1 H-NMR (MSO-d 6): δ 8.73 (broad s, 1H), 8.61 (s, 1H), 8.42 (d, J = 4 Hz, 1H), 8.03 (s, 1H) ), 7.80 (d, J = 5 Hz, 1H), 7.76 (broad s, 1H), 7.14 (dd, J = 4.5 Hz, 1H). FAB mass spectrum m / e 322 · ’, '' '' - 94 - Example 40 <3- (2-Thenoyl) -7-azaoxindole-1-N-tert-butylcarboxamide

First, 3- (2-thenoyl) -7-azaoxindole was prepared by the method of Example 1B using 1.5-g, 11.2 mmol of 7-azaoxindole, 1.3 g, 56.5 mmol of sodium, 25 ml of ethanol and 3 ml, of 22 ml. , 3 mmol of ethylthiophene-2-carboxylate. Yield 2.54 g (93%). The resulting product was prepared according to Example 1C using 3- (2-thenoyl) -7-azaoxindole (500 mg, 2.0 mmol), tert-butyl isocyanate (0.35 mL, 3.0 mmol), 0.6 mL. Triethylamine (4.4 mmol) and EMSO (10 mL). The crude product was purified by flash chromatography on silica gel using a 9: 1 mixture of chloroform and methanol, recrystallized from methanol / chloroform to give 70 mg of the product, m.p. &gt; 250 ° C. 1 H-NMR (DMSO-d 6): 9.34 (s, 1H), 8.81 (d, J = 3.5 Hz, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.91-7.87 (m, 2H), 7.25-7.18 (m, 2H), 1.41 (s, 9H),

Mass spectrum m / e (relative%): 343 (35), 244 X81), 160 (100), 111 (9). IR (KBr) 1718, 1654, 1629, 1607, 1554, 1534, 1497, 1433 cm @ -1.

H, 4.99; N, 12.14. Found: C, 59.24; H, 4.77; N, 12.14%. Example 41 5,6-Dichloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide - 95 - The resulting product was prepared from 5,6-dichloro-3- (2-thenoyl) -4- of the azaoxindole of Example 6B by the method of Example 2C using 194 mg, 0.62 mmol of 5 &apos; -dichloro-3- (2-thenoyl) -4-azaoxindole, 81 mL, 0.93 mmol of N-chloreal- of the isocyanate, 10 ml of acetonitrile at 50 ° C. The crude N-chlorosulfonylcarboxamide is hydrolyzed by stirring in an air in an open flask. After dilution with water, the solid was filtered and recrystallized from acetic acid to give 129 mg (58%) of the product, m.p. 237-239.5 ° C. 1H-MMR (EMSO-dg): δ 8.66 (d, J = 3.5 Hz, 1H), 8.58 (broad s, 1H), 8.36 (s, 1H), 7.95 (d, J = 5 Hz, 1H), 7.78 (broad s, 1H), 7.26 (dd, J = 3.5, 5 Hz, 1H). IR spectrum (DMSO) 1710, 1550, 1515, 1455 cm @ -1.

H, 1.98; N, 11.68. Found: C, 43.65; H, 1.87; N, 11.68%. Example 42 3- (2-Thenoyl) -6-azaoxidole-1-carboxamide The title compound was prepared by the method of Example 2C using 3.09 g, 12.6 mmol of 3- (2-thenoyl) -6-azaoxindole from the Example. 38, 1.2 ml, 13.8 mmol N-cisulfonyl isocyanate and 60 ml acetonitrile. The reaction time is 3.5 hours

The crude N-chlorosulfonylcarboxamide is hydrolyzed by stirring in 30 ml DMSO overnight in an open flask in air. After dilution with water, the solid is filtered off and dried. The solid is recrystallized twice from acetic acid and once from methyl ethyl ketone. 163 mg of a product with a melting point of 213 DEG-215 DEG C. were obtained (5%). 1 H-NMR (DMSO-d 6): δ 8.86 (broad s, 2H), 8.45 (d, J = 3.6Hz, 1H), 8.16-8.09 (m, 2H), 8 , 80 (d, J = 4.3 Hz, 1H), -96-7.76 (broad s, 1H), 7.16 (dd, J = 3.6, 4.3 Hz, 1H). IR (KBr) 1733, 1708, 1630, 1559, 1517, 1479, 1418 cm @ -1.

H, 3.16; N, 14.63. Found: C, 54.04; H, 3.24; N, 14.16%. EXAMPLE 43 3-Phenylacetyl-6-azaoxindole-1- carboxamide

First, 3-phenylacetyl-6-azaoxindole was prepared by the method of Example 1B using 1 g, 7.4 mmol of 6-azaoxindole, 257 mg, 11.2 mmol of sodium, 2.3 and 14.9 mmol of ethylphenylacetate and 30 ml of ethanol. Reaction time 4.5 hours. The reaction mixture was poured into ice-water and the pH was adjusted to 6. The product was filtered off and washed with ethyl acetate to give 1.23 g (66%) of the product, m.p. 250 ° C. The resulting product was prepared by the method of Example 2C using 1.0 g (3.9 mmol) of 3-phenylacetyl-6-azaoxindole, 0.41 mL, 4.7 mmol of N-chlorosulfonyl isocyanate and 40 mL of acetonitrile. The reaction time is 4 hours. The crude N-cortlorsulfonylcarboxamide is hydrolyzed by stirring for 1 hour in 6 ml of DMSO in an open flask in air. Dilution with water filtered off the product, dried and recrystallized from acetic acid to give 172 mg (15%) of the title compound, m.p. 131-133 ° C with decomposition. 1 H-NMR (DMSO-d 6): &amp; 13.28 (s, 1H), 8.86 (broad s, 1H), 8.80-8.78 (m, 1H), 8.16 (broad s, 2H), 7.74 (broad s, 1H) , 7.26-7.12 (m, 5H), 4.21 (s, 2H). - 97 -

Mass spectrum m / e (relative%) 252 (30), 161 (100) .FAB mass spectrum, exact molecular mass for C16H14N3O3 (M + 1): 296.1035 found: 296.1021. EXAMPLE 44 5-Isopropoxy-3- (2-thenoyl) -4-azaoxindole-1-carboxamide The title compound was prepared according to the procedure of Example 2C using 5-isopropoxy-3- (2 -) - (70 mg, 0.23 mmol). thenoyl) -4-azaoxindole from Example 90, 25 mL, 0.29 mmol of N-chlorosulfonyl isocyanate and 1.5 mL of acetonitrile. After a reaction time of 4 hours, the crude N-chlorosulfonylcarboxamidhydrolyzovone was stirred in chloroform for 3 days. After removal of the solvent in vacuo, the product was purified by flash chromatography on silica gel eluting with 2: 1 ethyl acetate: hexane as eluent, followed by ether trituration to give 30 mg (37%), mp 194-196 ° C. 1 H-NWR (DMSO-d 6) δ 13.04 (s, 1H), 9.08 (br s, 1H), 8.99-8.98 (m, 1H), 8.48 (d, J). = 8.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.19-7.16 (m, 1H), 6.26 (d, J = 8.6 Hz, 1H) 5.29 (broad s, 1H), 4.74 (heptet, J = 6.4 Hz, 1H), 1.42 (d, J = 6.4 Hz, 1H). IR spectrum (KBr disc) 1720, 1607, 1565 cm @ -1. FAB mass spectrum, exact molecular mass for C16H16H3O4S (t6 + 1) calculated 346.0862 stained: 346.0844. Example 45 3- (4-Chloro-2-thenoyl) -5-azaoxindole-1-N-tert-butylcarboxamide - 98 -

First, 3- (4-chloro-2-thenoyl) -5-azaoxindole was prepared by the method of Example 20 using 5-azaoxindole (1.0 g, 7.45 mmol) from Example 4B, 1.21 g, 52.6 mmol of hydrogen, 2 4-chlorothiophene-2-carbonyl chloride (72 g, 15.0 mmol) and ethanol (40 mL). After a reaction time of 3 days, and after the crude product had been triturated with methanol, 427 mg of the title compound were obtained with a melting point of 250 ° C. The resulting product was prepared according to the procedure of Example 1C using 427 mg, 1.53 mmol of 3- (4-chloro-2-theyl) -5-azaoxindole, 0.26 mL, 2.3 mmol of tert-butyl isocyanate. triethylamine, 0.43 ml, 3.1 mmol triethylamine and 10 ml DMSO. The re-action took place overnight. The crude product was purified by flash chromatography using ethyl acetate as eluent, followed by recrystallization from acetonitrile. Yield: 172 mg (30%), m.p. 250 ° C. 1 HNMR (DMSOd 6) δ 9.72 (s, 1H), 9.19 (s, 1H), 8.73 (s, 1H), 8.44 (d, J = 7 Hz, 1H) , 8.31 (d, J = 7 Hz, 1H), 7.81 (s, 1H), 1.43 (s, 9H).

H, 4.27; N, 11.12. Found: C, 53.76; H, 3.93; N, 10.98. EXAMPLE 46 3- (2-Thenoyl) -5-azaoxindole- 1-Carboxamide The product was prepared according to Example 2C using 3- (2-thenoyl) -5-azaoxindole (500 mg, 2.0 mmol) from Example 4C, 0.26 g, 3.0 mmol of N-chloro. sulfonyl isocyanate and 15 ml acetonitrile. After a reaction time of 2.25 hours, the summed N-chlorosulfonylcarboxamide was hydrolysed for 1.5 hours in DMSO (1.5 ml) in an open-air 100-well flask. a homogeneous solution is formed.

After standing briefly, a green precipitate is formed which is filtered off. The filtrate is allowed to stand overnight, the product crystallized out over the course of time, which is separated by filtration to give 39 mg of product with a melting point of 250 ° C. . 1 H-NMR: 14.21 (broad s, 1H), 9.15 (s, 1H), 9.12 (broad s, 1H), 8.68 (d, J = 4 Hz, 1H), 8 , 37 (d, J = 7 Hz, 1H), 8.24 (d, J = 7 Hz, 1H), 7.85 (broad s, 1H), 7.72 (d, J = 4.5 Hz, 1H), 7.14 (dd, J = 4.5 Hz, 1H). IE-spectrum (KBr disc) - 1741, 1476, 1433 cm @ -1. FAB mass spectrum exact molecular mass for C13 H10 N3 O3 S (M + 1) calculated 288.0443 calculated: 288.0439.

Acetyl precursor 6-chloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide To a suspension of 500 mg, 1.55 mmol 6-chloro-3- (2-thenoyl) -4-azaoxindole-1-carboxamide triethylamine (0.4 mL, 2.87 mmol) and 0.2 mL (2.081 mmol) of acetyl chloride are added sequentially in 60 mL of THF. The mixture was stirred overnight at room temperature. Triethylamine (0.4 mL, 2.87 mmol) and acetyl chloride (0.2 mL, 2.81 mmol) were added. The mixture was stirred at room temperature for 3 days and the resulting product was filtered. The product was washed successively with chloroform, water and methanol to give 390 mg of a yellow solid in 69% yield. A second crop of product was obtained from the filtrate by filtration and washing with chloroform. Yield: 109 mg of product in 19% yield. The two samples were combined and recrystallized from chloroform to give 289 mg of a yellow solid (51%), m.p. &gt; 250 ° C. 101 - 1 H-NMR (DMSO-d 6): δ 8.51 (d, J = 4 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 8.36 (d, J = 2 Hz) (1H), 8.23 (d, J 5 Hz, 1H), 8.05 (broad s, 2H), 7.37 (dd, J = 4.5 Hz, 1H). The peak for the methyl residue of the acetyl group was covered by absorption of LMSO at 2.50.

H, 2.77; N, 11.55. Found: C, 49.23; H, 2.53; N, 11.52. EXAMPLE 48 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1N-ethylcarboxamide The title compound was prepared as described in Example 1C using 5-chloro-3- (1.25 g, 4.49 mmol). Of 2-theylyl) -4-azaoxindole from Example 1B, 3.2 mL, 23 mmol of triethylamine, 1.77 mL, 22.4 mmol of ethyl isocyanate and 30 mL of isSO4. After a reaction time of 6 hours, the product was first triturated with hexane and then recrystallized from the same solvent to give 1.09 g (70%) of the product, m.p. 153-154 ° C.

H, 3.46; N, 12.01. Found: C, 51.56; H, 3.21; N, 11.90%. C15H12ClN3O3S requires C, 51.51; 1 H-NMR (CDCl 3): δ 9.04 (broad s, 1H), 9.01 (dd, J = 1.4 Hz, 1H), 8.47 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 4.9, 1H), 7.22 (dd, J = 4.9 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H) ), 3.51-3.41 (m, 2H), 1.28 (t, J = 7.3Hz, 3H). IR spectrum (KBr disc): 1/20, 1605, 1575, 1540, 1415 cm @ -1

Mass Spectrum m / e (relative%) 351 (2), 394 (5), 280 (10), 278 (29), 196 (32), 194 (100), 111 (26). Example 49 5-Chloro-3- (2-thenoyl) -4-azaoxindole-1-N-isopropylcarboxamide

The resulting product can be obtained as in Example 1C using 5-chloro-3- (2-thenoyl) -4-azaoxindole (1.25 g, 4.49 mmol) from Example 1B, 3.2 mL, 23 mmol of triethylamine, 2.2. ml, 22.4 mmol isopropyl isocyanate and 30 mL DHSO. After a reaction time of 6 hours and after recrystallization of the crude product from hexane, 1.30 g of the product, m.p. H, 3.88; N, 11.31%. Found: C, 52.93; H, 3.65; N, 11.31%. 1 H-NMR (CDCl 3): δ 9.02 (dd, J = 1.4 Hz, 1H), 8.96 (broad d, 1H), 8.46 (d, J = 8.3 Hz, 1H) , 7.71 (dd, J = 1.5 Hz, 1H), 7.22 (J = 4.5 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.19 4.08 (m, 1H), 1.30 (d, J = 6.6 Hz, 6H). IR spectrum (KBr): 1710, 1605, 1585, 1540, 1520, 1420 cm @ -1.

Mass spectrum m / e (relative%) 365 (3), 363 (14), 280 (17), 278 (45), 196 (32), 194 (100), 111 (18). EXAMPLE 50 3-Benzoyl-5-chloro-4-azaoxindole-1-carboxamide The compound of Example 25 was obtained using 2.73 g (10.0 mmol) of 3-benzoyl-5-chloro-4-azaoxindole from Example 32, 1.3 mL, 15 mmol of N-chlorosulfonyl isocyanate and 80 mL of acetonitrile. After a reaction time of 20 hours, the crude N-chlorosulfonyicarboxamide is hydrolyzed for 20 hours by stirring in 15 ml of MISO. The crude product was then recrystallized from acetic acid and washed with methanol to give 0.36 g (11%) of the product, m.p. 220 ° C. 1 H-NMR (H 4 SO-d 6): 8.41 (broad s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 7.3 Hz, 2H) , 7.72 (broad s, 1H), 7.58-7.45 (o, 3H), 7.20 (d, J = 8.3 Hz, 1H). IR (KBr) 1750, 1660, 1620, 1600, 1590, 1575, 1390 cm @ -1. Example 51 5,6-Dichloro-3- (2-furoyl) -4-azaoxindole-1-N-tert-butylcarboxamide

First, 5,6-dichloro-3- (2-furoyl) -4-azaoxindole was prepared by the method of Example 1B using 763 mg, 3.76 mmol of 6,6-dichloro-4-azaoxindole, 0.43 g, 18.8. mmol of sodium, 1.05 g, 7.5 mmol of ethyl 2-furoate and 25 ml of ethanol. Yield: 0.98 g (88%). The resulting material was prepared according to Example 1C using 5,6-dichloro-3- (2-furoyl) -4-azaoxindole (721 mg, 2.43 mmol), triethylamine (1.8 mL, 15.4 mmol), 1 , 4 ml, 12.3 mmol tert-butyl isocyanate and 20 ml MISO.

After a reaction time of 22 hours, the crude product was triturated with methanol and recrystallized from hexane to give 218 mg (23%) of the title compound, mp 205-206 ° C.

H, 3.82; N, 10.60. Found: C, 51.70; H, 3.81; N, 10.57%. H-NMR (MH &lt; + &gt; -dg): [delta] 9.37 (broad s, 1H), 8.32 (s, 1H &apos;, 7.91 (s, 1H), 7.85 (d, J = 3.7) Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 1.38 (s, 9H).

- 104 - IR spectrum (KBr disc) 1730, 1620, 1605, 1590, 1555, 1535 cm -1.

Mass spectrum m / e (relative%) 397 (0.5), 395 (2), 298 (21), 296 (33), 230 (62), 228 (100), 95 (40). Example 52 5-Chloro-3- (2-furoyl) -4-azaoxindole-1N- (1-hydroxy-2-methyl) -prop-2-ylcarboxamide A. 2-Amino-1-benzyloxy-2- methylpropane

A solution of 7.1 mmol of 2-amino-2-methyl-1-piopanol in 25 mL of THF was added dropwise to a suspension of 3 g, 75 mmol of a 60% sodium hydroxide in oil suspension in 75 mL of THF. The mixture was stirred at room temperature for 1 hour and then cooled in a ice bath and a solution of 5.7 mL, 50 mmol of benzyl bromide was added dropwise. The mixture was stirred at 0 ° C for 2 hours, then poured into water / ice and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil which was flash chromatographed on silica gel using 5% methanol in chloroform as eluent. The desired product fractions were combined and evaporated to give 4.2 g of an oily product (47%). B) (1-Benzyloxy-2-ethyl) prop-2-yl isocyanate To a solution of 2-amino-1-benzyloxy-2-methylpropane (2.1 g, 10 mmol) and triethylamine (4.5 mL, 32 mmol) in 50 mL of methylene chloride was added. triphosphene (989 mg, 3.3 mmol) was added in three portions under ice-cooling. The reaction mixture was stirred at 0 ° C for 1/4 hour and then at room temperature for 4 hours. The volatiles were then evaporated in vacuo and the residue triturated with ether to give 1.9 g of the desired product as an oil (1.105-95%). C) 5-Chloro-3- (2-furoyl) -4-azaoxindole-1N- (1-benzyloxy-2-methyl) prop-2-ylcarboxamide The title compound was obtained according to Example 1 using 1.90 g, 7%. , 2 mmol of 5-chloro-3- (2-furoyl) -4-aza-oxindole from Example 23, 2.8 mL, 21 mmol of triethylamine, 2.2 g, 10.7 mmol of QL-benzyloxy-2-methyl- ) -prop-2-yl isocyanate and 75 ml DMSO. The reaction is overnight, and the crude product is purified by flash chromatography on silica gel, eluting with chloroform. The desired product fractions were combined and evaporated to give 2.2 g of product in a 65% yellow oil. D) 5-Chloro-3- (2-faroyl) -4-azaoxindole-1N- (1-hydroxy-2-methyl) prop-2-ylcarboxamide To a solution of 1.0 g, 2.1 mmol of 5-chloro- 3- (2-furoyl) -4-azaoxindole-1N- (1-benzyloxy-2-methyl) prop-2-ylcarboxamide in 25 mL of methylene chloride is added dropwise with 3 mL, 3 mmol of BBr solution under ice-cooling. in methylene chloride. The reaction mixture was stirred at 0 ° C for 2 hours and 0.5 M of a 1M solution of BBr in methylene chloride was added. After another hour at 0 ° C, the mixture was poured into water / ice and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to a yellow solid which is first triturated with methanol and then allowed to recrystallize from methanol. Yield: 552 mg (70%), m.p. 185-186 ° C.

H, 4.27; N, 11.12. Found: C, 53.82; H, 4.05; N, 10.92%. - 106 -:, - 1Η-E (CDCl 3):: 9.3 (W broad s, 1H), 8.49 (dd, J = 1.3, 3.6 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.70 (dd, J = 1.3, 1.6 Hz, 1H), 6.98 (d, J and 8.2 Hz, 1H), 6.61 (dd, J). and 1.6, 3.6 Hz, 1H), 3.73 (broad s, 1H), 3.71 (s, 2H), 1.41 (s, 6H). IR (KBr) 1730, 1720, 1665, 1630, 1595, 1540, 1460, 1445, 1420 cm @ -1.

Mass spectrum m / e (relative%) 380 (1), 379 (3), 378 (5), 377 (9), 265 (18), 264 (50), 263 (53), 262 (100), 197 (12), 196 (60), 195 (33), 194 (97), 95 (25). Example 53 5-Chloro-1-ethyl-3- (2-thenoyl) -7-azaoxindole A) 1-Ethyl-7-azaindole 10 g, 0.0846 mol of 7-azaindole (Aldrich) was dissolved in 200 ml of analytically pure acetone at room temperature, and 10 g, 0.178 mol of potassium hydroxide powder are added. After 2-3 minutes, ethyl iodide (67 mL, 0.846 mol) was added over 5-10 minutes and the reaction mixture was stirred at room temperature for 30-40 minutes. Thin layer chromatography (95% methylene chloride / 5% ethyl acetate) indicated complete consumption of the starting material and the formation of a single less polar product. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and methylene chloride. 350 ml of the mixtures of these substances are used. The organic layer was separated, washed with water and saturated brine, dried over sodium, and evaporated in vacuo to a tan oil which was purified on a silica gel column using 95% methylene chloride / 5% ethyl acetate. 11.15 g (90%) of the title compound is obtained as a pale yellow oil. 1 H-NMR (CDCl 3) 60 MgHz: 1.35-1.65 (t, 3H), 4.20-4.60 (q, 2H), 6.35-8.45 (m, 5H ). B) 3,3-Dibromo-1-ethyl-7-azaoxindole To a solution of 5.4 g, 34 mmol of 1-ethyl-7-azaindole in 200 mL of tert-butanol was added 27.2 g, 85 g at 30 ° C. mmol pyridinium bromide perbromide. The reaction mixture is stirred overnight at room temperature and then water and ice are poured into the mixture. The mixture was stirred for 1/2 hour and then extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4) and evaporated to give a brown oil which was chromatographed on a silica gel column eluting with chloroform. Fractions containing only the desired product were combined and evaporated in vacuo to give 5.30 g of a yellow oil in 49% yield. C) 5-Chloro-3,3-dibromo-1-ethyl-7-azaoxindole

3,3-dibromo-1-ethyl-7-aza-oxindole (5.3 g, 16.5 mmol) in Ν, Ν-dimethylformamide in a three-necked flask, equipped with a dry ice condenser, was cooled to 0 ° C in an ice bath. Chlorine is then bubbled through the solution for 4 minutes to saturation. The reaction mixture was stirred at 0 ° C for 2 hours and then poured into water / ice. The mixture was stirred for 1/2 hour and then poured into ethyl acetate. The organic extract was washed with water, dried over magnesium sulphate and evaporated to a yellow oil which was chromatographed on a silica gel column eluting with ethyl acetate. The product fractions were evaporated in vacuo to give 4.69 g of a yellow solid in 80% yield. D) 5-Chloro-1-ethyl-7-azaoxindole To a solution of 5.60 g, 13.0 mmol of 5-chloro-3,3-dibromo-1-ethyl-7-azaoxindole in 75 mL of glacial acetic acid was added. 108 - zinc powder (2.5 g, 39 mmol) is added portionwise. An exothermic reaction occurred immediately and the mixture was stirred at room temperature for 1 hour, then poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated to an oil which was chromatographed on silica gel, eluting with chloroform. The desired product fractions were combined and evaporated in vacuo to give 1.70 g (68%) of an off-white solid, mp 78-82 ° C. E) 5-Chloro-1-ethyl-3- (2-thenoyl) -7-azaoxindole To a solution of 400 mg, 2.03 mmol of 5-chloro-1-ethyl-7-aza-oxindole and 537 mg, 4.4 mmol of 4-dimethylaminopyridine in 10 mL of DMF was added at 0 ° C with 0.24 mL, 2.24 mmol of thiophene-2-carbonyl chloride. The reaction mixture was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was then extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed on a silica gel column, eluting with chloroform. The fractions containing only the resulting product were combined and evaporated to give a solid which was recrystallized from hexane to give 29 mg of the product (50% yield), mp 111-112 ° C.

H, 3.61; N, 9.13. Found: C, 54.45; H, 3.34; N, 8.80%.

Mass spectrum m / e (relative%) 308 (6), 306 (19), 224 (32), 222 (100), 20y (8), 207 (24), 196 (24), 194 (77), 111 (77). EXAMPLE 54 5-Chloro-1-ethyl-3- (2-furoyl) -7-azaoxindole The title compound can be obtained by the method of Example 53E using 405 mg, 2.06 mmol of 5-chloro-1-ethyl- Of 7-azaoxindole from Example 53D, 500 mg, 4.09 mmol of 4-dimethylaminopyridine, 0.22 mL, 2.23 mmol of 2-furoyl chloride and 10 mL of EMF. The solid product is obtained by chromatography followed by recrystallization from hexane. Yield 110 mg (18%), m.p. 162-163 ° C. )

H, 3.81; N, 9.64. Found: C, 57.59; H, 3.54; N, 9.49%. 1 H-NMR (CDCl 3): δ 8.43 (d, J = 1.7 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.38 (d, J = 3.5 Hz, 1H), 6.72 (dd, J = 1.7, 3.5 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 1.35 (t J = 7.1 Hz, 3H). IR spectrum (KBr disc) 1645? 1620, 1535, 1470, 1440 and "1.

Mass spectrum m / e (relative%) 292 (8), 290 (27), 224 (32), 222 (100), 209 (8), 207 (27), 196 (28), 194 (86), 95 (70). EXAMPLE 55 5-Chloro-1-ethyl-7-azaoxindole-3-N- (4-fluorophenyl) carboxamide: The title compound of Example 53E was obtained using 400 mg, 2.03 mmol of 5-chloro. of 1-ethyl-7-azaoxindole from Example 53D, 4-diethylaminopyridine (537 mg, 4.4 mmol), 4-fluorophenylisocyanate (0.25 mL, 2.2 mmol) and DMF (10 mL). The only deviation from this process is that the reaction mixture is poured into a mixture of water and ice and then acidified to pH 3 by adding 6N hydrochloric acid solution. The solid obtained by chromatography was recrystallized from ether / hexane to give 95 mg (15%) of product, m.p. 155-157 ° C with decomposition.

N, 12.53. Found: C, 57.50; H, 3.64; N, 12.33 (CDCl3): δ 9.42 (broad s, 1H). , 8.22 (s, 1H), 8.05 (s, 1H), 7.53 (dd, J5.7 Hz, 1H), 7.02 (t, J = 7 Hz, 1H), 4, 43 (s, 1H), 3.90 (q, J = 7Hz, 2H), 1.29 (t, J = 7Hz, 3H). IR spectrum (EBr disc) 1725, 1665, 1605, 1580, 1550, 1510, 1470, 1435 cm @ -1.

Mass spectrum m / e (relative%) 335 (18), 333 (52), 198 (33), 196 (100), 170 (10), 168 (30), 111 (21). EXAMPLE 56 5-Chloro-1-ethyl-7-azaoxindole-3-N-phenylcarboxamide The title compound was prepared as in Example 55 using 5-chloro-1-ethyl-7-azaoxindole (451 mg, 2.29 mmol). 4H, 607 mg of 4-dimethylaminopyridine, 0.27 ml, 2.48 mmol of phenylisocyanate and 11 ml of DMF. The mixture was poured into water and acidified to give a solid which was filtered and triturated with ethyl acetate to give a white solid which was not the desired product. The mother liquor was evaporated to give a brown solid which was triturated with cold ethyl acetate. The resulting yellowish solid was recrystallized from cyclohexane to give 38 mg (5%) of the product as a white solid, mp 157-158 ° C. 111 -

H, 4.47; N, 13.13. Found: C, 60.83; H, 4.27; N, 13.13%. 1 H-NMK (CDCl 3): $ 9.43 (W broad s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.48-7.54 µg, 2H), 7 , 35 - 7.10 (a, 1H), 4.41 (s, 1H), 3.91 (q, J = 7.3 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H). IR spectrum (KBr disk) 1730, 1660, 1605, 1580, 1550, 1470, 1445 and " 1 &quot;.

Mass spectrum m / e (relative%) 317 (3), 315 (10), 198 (33), 196 (100), 183 (3), 181 (10), 170 (11), 168 (36), 93 (22), 77 (20).

Claims (11)

PATENT CLAIMS Azaoxindole derivatives of general formula I (I) wherein one of A, B, D and E is nitrogen and the others are -CH, X and Y are independently hydrogen, OR, hydroxy, alkyl of 1 to 6 carbon atoms, CF- ,, COR3. a halogen atom, such as fluorine, chlorine, bromine or iodine, 3OR ', COOR 3, CONR 3 R 3, CN, NO 2, SR 3, SOR 3, SO 2 R 3 and SO 2 NR 3 R 3, R 3 represents alkyl of 1 to 6 carbon atoms, phenyl, benzyl, allyl or hydrogen wherein the phenyl radical and the phenyl portion of the benzyl radical are optionally substituted by one or more independent substituents from fluoro, chloro, bromo, iodo, hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms and trifluoromethyl, meaning alkyl of 1 to 8 carbon atoms 1, preferably 5 cycloalkyl of 3 to 8 carbon atoms, (CH 2) n R where n is 0 or 1 or NHR 1, wherein R 5 is cycloalkyl of 3 to 8 carbon atoms, hydrogen, phenyl, optionally substituted, heteroaryl, optionally substituted wherein the heteroaryl group optionally substituted is selected from thiophene and furan and the phenyl and heteroaryl residue is substituted by one or two independent substituents of the ato group m is fluorine, chlorine, bromine, iodine, hydroxyl and alkyl of 1 to 3 carbon atoms or trifluoromethyl and is phenyl, thiophenyl or furan, in each case substituted by one or more independent substituents from the group of fluorine, chlorine, bromine , iodine, hydroxy, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 3 carbon atoms and trifluoromethyl, R 1 is alkyl of 1 to 6 carbon atoms or CONHR 4 where R 1 is hydrogen, alkyl of 1 to 6 carbon atoms C 2 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl, 3 COR, wherein R is as defined above, phenyl, optionally substituted, heteroaryl, optionally substituted, wherein the heteroaryl group is derived from thiophene and furan, and phenyl or the heteroaryl group is selected from one or two independent substituents of the group fluorine, chlorine, bromine, iodine, hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms and trifluoromethyl, W is hydrogen, alkanoyl of 2 to 10 carbon atoms, cycloalkylcarbonyl of 5 to 7 carbon atoms, phenylalkanoyl of 7 to 10 carbon atoms, chlorobenzoyl, thenoyl, omega-alkoxycarbonylalkanoyl of 2 to 4 carbon atoms in alkoxy and 3 up to 5 carbon atoms in the alkanoyl, alkoxycarbonyl of 2 to 10 carbon atoms, phenoxycarbonyl, 1-acyloxy-alkyl of 1 to 4 carbon atoms in the acyloxy group of 2 to 4 carbon atoms in the alkyl, 1-alkoxy-114-carbonyloxyalkyl o C 2 to C 5 alkoxy and C 1 to C 4 alkyl, alkylsulfonyl or C 1 -C 3 alkyl, methylphenyloxysulfonyl and C 1 -C 3 dialkyl sulfonate, provided that: ) when E is nitrogen, at least one of X and Y is different from hydrogen, b) when either R is NHR or R is 1 to 6 carbon atoms when W is hydrogen. 2. Method for producing azaoxindole derivatives of general formula Ia wherein one of A, B, D and E is nitrogen and the other is CH, X and Y are independently hydrogen, 3 OR, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, COR 3, halogen, R 33 is COOR, CONR R, cyano, nitro, SR 3, SOR 3, SO 2 R 3 or SO 2 NR 3 R 3, r 1 is CONH 2, R is alkyl of 1 to 8 carbon atoms, (CH 3) R 4, where n is 0 or 1 or NHR 1 -, - 115 - is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, allyl or hydrogen, wherein the phenyl radical and the phenyl portion of the benzyl radical are optionally substituted by one or more substituents independently selected from fluorine atom chloro, bromo, iodo, hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms or trifluoromethyl, cycloalkyl having 3 to 8 carbon atoms, hydrogen, phenyl, optionally substituted, heteroaryl, optionally substituted, wherein the heteroaryl moiety is thiophene or furan and the phenyl and heteroaryl moieties are optionally substituted with one or two substituents independently selected from fluoro, chloro, bromo, iodo, hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms or trifluoromethyl, R is phenyl, thiophene or furan, all of which are optionally substituted by one or more substituents independently selected from fluorine, chlorine, bromine, iodine, hydroxy, alkyl or alkoxy, with from 1 to 6 carbon atoms in the alkyl and 1 to 3 carbon atoms in the alkoxy radical, or trifluoromethyl, and W denotes a hydrogen atom, wherein when E is a nitrogen atom, at least one of X and Y is different from hydrogen, characterized by by reacting a compound of formula VI Wherein A, B, D, E, X, Y and R are as defined above, with chlorosulfonyl isocyanate and the reaction product is hydrolyzed. Process according to Claim 2, characterized in that the compound of general formula (VI) obtained by acylation of a compound of general formula (V) is reacted. Wherein A, B, D, E, X, Y and R are as defined in claim 2, by treatment with a corresponding acid derivative of formula (2) R COOH wherein R is as defined in claim 2. 4. Process for the preparation of a compound of the formula Ib - 117 - wherein one of A, B, D and E is nitrogen and the others are CH, X and Y are independently hydrogen, OR, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, COR3, halogen , COOR3, CONR3R3, cyano, nitro, SR3, SOR3, SO2R3 or SO2NR3R3; R is alkyl of 1 to 8 carbon atoms, (CH 2) R where n is 0 or 1 or NHR, n is R 1 is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, allyl or hydrogen, wherein the phenyl radical and the phenyl portion of the benzyl radical are optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine or iodine, hydroxy, alkyl or alkoxy of 1 to 3 carbon atoms or trifluoromethyl, 4 R is 1 to 1 alkyl 6 carbon atoms, hydroxy-alkyl of 2-6 carbon atoms, cycloalkyl of 3-33 carbon atoms, COR in which R is as defined above, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl, wherein the heteroaryl moiety is is a thiophene or furan moiety and any of the substituted phenyl or heteroaryl groups is substituted with one or two substituents independently selected from the group; m of fluorine, chlorine, bromine or iodine, hydroxy, alkyl or alkoxy. R is cycloalkyl of 3 to 8 carbon atoms, hydrogen, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, wherein the heteroaryl residue is a thiophene or furan moiety and each of the substituted phenyl or heteroaryl groups is substituted with one or two substitutents substituents independently selected from fluorine, chlorine, bromine or iodine, hydroxy, alkyl or alkoxy having from 1 to 3 carbon atoms and trifluoromethyl, R 1 is phenyl, thiophene or furan, each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, or trifluoromethyl, and W being hydrogen, provided that when E represents a nitrogen atom, at least one of X and Y is a meaning different from and wherein hydrogen is reacted with a compound of formula VI - 119 - R 4 - N = C = 0.4 wherein R m is as defined above; (VI) 2 wherein A, B, D, E, X, Y and R are as defined above. 5. A process for preparing a compound of formula Ic wherein one of A, B, D and E is nitrogen and the other is CH, X and Y are independently hydrogen, OR 3, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, COR 3, halogen, COOR 3, CONR 3 R 3, cyano, nitro, SR 3, SOR 3 and SC> 2R 3 aso 2 nr 3 r 3, r! R is alkyl of 1 to 8 carbon atoms, (CH 2) n R where n is 0 or 1, or NHR 1, R 3 is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, allyl or hydrogen, wherein the phenyl moiety 120 and the phenyl moiety of the benzyl moiety are optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, hydroxy alkyl, or alkoxy each having 1 to 3 carbon atoms or trifluoromethyl , represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a hydroxyalkyl group having from 2 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a CO 2 group in which R 1 is as defined above, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl, is a thiophene or furan moiety and each substituted phenyl or heteroaryl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, iodine, hydroxy C1-4 alkyl or alkoxy, or trifluoromethyl, R8 cycloalkyl having from 3 to 8 carbon atoms, hydrogen, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, wherein the heteroaryl residue is a thiophene or furan residue and each of the substituted phenyl and heteroaryl radicals are substituted with one or two substituents independently selected from fluoro, chloro, bromo, iodo, hydroxy, alkyl, or alkoxy each having 1 to 3 carbon atoms and trifluoromethyl, phenyl or the remainder of the thiophene or furan; the moieties are optionally substituted by one or more radicals, independently selected from fluorine, chlorine, bromine or iodine, hydroxy, C1-6 alkyl, C1-3 alkoxy or trifluoromethyl, and are known to be hydrogen, 121 wherein, when E is a nitrogen atom, at least one of X and Y has the meaning of characterized by the fact that the compound of formula (XIX) is acylated (XIX) wherein A, B, D, E, Ϊ, X and R 1 are as defined above, with an acid chloride or anhydride of the formula R ^COOCOR ^ wherein R mé is as defined above. 6. A process according to claim 5 wherein the compound of formula (XIX) is obtained by heating the corresponding carboxylic acid of formula (XVIII). (XVIII) wherein A, Bt D, E, X and Y are as defined in claim 5. 7. A process for the preparation of a compound of formula Id 122 - wherein one of A, B, D and E is nitrogen and the other is CH, X and Y are independently selected from hydrogen, OR 3, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, COR 3, halogen, COOR 3 , R 1 is alkyl of 1 to 6 carbon atoms, 2 R is alkyl of 1 to 8 carbon atoms, (CH 2) n R 4, where n is 0 or 1, or NHR 1, R 3 is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, allyl or hydrogen, wherein the phenyl radical and the phenyl portion of the benzyl radical are optionally substituted by one or more substituents independently selected from atomfluorine, chlorine, bromine or iodine , hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms or trifluoromethyl, 4 R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, a hydroxyalkyl of 2 to 6 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a group COR3 where R3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl, wherein the heteroaryl moiety is thiophene or -123-furan, and the phenyl or heteroaryl moiety is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, iodine; hydroxy, alkyl or alkoxy of 1 to 3 carbon atoms or trifluoromethyl, means cycloalkyl of 3 to 8 carbon atoms, hydrogen, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, wherein the heteroaryl residue is a thiophene or furan moiety and the phenyl and heteroaryl moieties are substituted by one or two the substituents independently selected from fluorine, chlorine, bromine, iodine, hydroxy, alkyl or alkoxy each having 1 to 3 carbon atoms or trifluoromethyl, r6 being phenyl or the remainder of the thiophene or furan, all of which are optionally substituted by one or more substi tents independently selected from the group consisting of fluoro, chloro, iodo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms or trifluoromethyl, and W is hydrogen, alkanoyl of 2 to 10 carbon atoms, cycloalkylcarbonyl of 5 to 7 carbon atoms in the cycloalkyl moiety, phenylalkanoyl of 7 to 10 carbon atoms, chlorobenzoyl, thenoyl, omega-alkoxycarbonylalkenoyl of 2 to 4 carbon atoms, alkoxycarbonyl of 2 to 10 carbon atoms, phenoxycarbonyl, 1- [acyloxy] alkyl of 1 to 4 carbon atoms in the acyloxy group and 2 to 4 carbon atoms in the alkyl moiety, 1-Calkoxycarbonyloxy] -alkyl of 2 to 5 carbon atoms in the alkoxy group of 1 to 4 carbon atoms in the alkyl moiety, alkyl-sulfonyl o With 1 to 3 carbon atoms, 1 to 3 carbon atoms, methylphenylsulfonyl or dialkyl-124-phosphonate having 1 to 3 carbon atoms in the alkyl moiety, provided that when z the nitrogen atom, at least one of X and Y is different from hydrogen, characterized in that it catalyses the compound of formula (XIX) (XIX) wherein A, B, D, E, X, Y and R are as defined above by treatment with an acid chloride or anhydride of formula (2) R (COOCOR) wherein R is as defined above. 8. The process of claim 7 wherein the compound of formula (XIX) is obtained by reacting a compound of formula (XX) (XX) wherein the symbols are as defined in claim 7, with bromine to form a dibrominated compound of formula 4-125 - wherein the individual symbols are as defined above before the dibrominated derivative is reduced. Process according to claim 7, characterized in that a compound of formula (XIX) is obtained by reaction of a compound of formula (XXI D) -Cl (XXI) wherein the individual symbols are as defined in claim 7, with a strong acid. 10. A process for the preparation of a pharmaceutically acceptable salt of a compound of formula (Ia) according to claim 2 or claim 1 according to claim 4 or claim 1, wherein said compound is reacted with an acid or pharmaceutically acceptable pharmaceutically acceptable salt. Process according to claims 2 to 6, characterized in that the product obtained is further reacted with triethylamine and an acid chloride, a chloroformate, an oxonium salt or an alkylating agent which is selected so as to obtain a compound which is identical to the product of the above claims, except that W is as defined in claim 7 with the exception of hydrogen. Represents: