FI106459B - Process for preparing 3-substituted 2-oxoindole derivatives - Google Patents

Description

1 106459

A process for the preparation of 3-substituted 2-oxoindole derivatives

Divided by application 901915.

This invention relates to a novel process for the preparation of certain 3-substituted 2-oxoindole derivatives. More particularly, the invention relates to a process

Preparation of 3-substituted 2-oxoindole derivatives of formula I

(2 ™> n-Q

R 20 wherein X is H, F, Cl, Br, (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, NO 2, CF 3, CN, SH, S (O) m R 3, OR 4, COR 4 or CONR 4 R 5; Y is H, F, Cl, Br, (C 1 -C 8) alkyl, (C 3 -C 6) cycloalkyl, NO 2, CF 3, CN, SH, S (O) q R 17, OR 18 or CONR 18 R 19; R 1 is H; R20 is COR6, CONR7R8, phenyl or mono- or disubstituted phenyl wherein the substituent (s) are each Cl, F, Br, (C1-C8) alkyl, (C1-C8) alkoxy or CF3; Q is 30 O 1 or Q 2 -A *; • · A is H, F, Cl, Br, I, CF3, OR9, S (O) pR10, COOR11, CONR9R11, CN, NO2, COR10, CH2ORX1, OCOR10, NR ^ 11, N (R9) COR11, 35 SOaNR9R11, • · i 10ί459

i_v R12 H

O '··· -0 · <r, i

w-'N

o- * ·· - <> ”- <r - o- B is H, F, Cl, Br, I, CF3, OR13, S (O) tR14, COOR15, CONR13R15, CN, NO2, COR14, CH2OR15, OCOR14, NR13R15, N (R13) COR15 or SO2NR13R15; with the proviso that A and B cannot both be H, or A and B together are bonded to the same carbon of the Q3 ring and form an oxo group, or when A is not H, B is as defined above or (C1-C3) alkyl ; A1 is F, Cl, Br, I, CF3, OR9, S (O) pR10, COOR11, CONR9Ru, CN, NO2, COR10, CH3OR11, OCOR10, NR9Ri: 1, N (R9) COR11 or SO2NR9R1]; Q1 is “O.0.0.

30 -, / N \ O. o. o.

B

N W, .N — W, / NS

O O Q

3 106459 öO 'o o - o Q2 on

B

° K '<s I

N N / ~ \ r M

// \\ f \ tai ft \\ 15 \ y 'N / N Nv 3; ra, n, p, q and t are each zero, one or two; W and Z are each O, S or NR11; W 1 and W 2 are each O, S or NR 10 with the proviso that when one of W 1 and W 2 is O, S or NR 10, the other is O or S; R 3, R 6, R 10, R 14 and R 17 are each (C 1 -C 8) alkyl or phenyl; R 5, R 8, R 11, R 15 and R 19 are each H, (C 1 -C 8) alkyl or phenyl; R 4, R 7, R 9, R 13 and R 18 are each H or (C 1 -C 8) alkyl; and R12 is H, F, Cl, Br, CF3 or (C-L-C8) alkyl.

Said 3-substituted 2-oxoindole derivatives are inhibitors of prostaglandin H2 synthase, 5-lipooxygenase and interleukin-1 biosynthesis, and are thus useful as inhibitors of prostaglandin H2 synthase and inter-leukine-1 biosynthesis, and as analgesic, anti-inflammatory and anti-inflammatory agents in the treatment of chronic inflammatory diseases.

U.S. Patent 4,569,942 discloses certain formulas of 35? 106459

O

x II 1 ®or 5 Y I 2

0 ** C-NH-R

2-oxoindole-1-carboxamides according to the formula, inter alia. X is H, fluoro, chloro, bromo, (C 1 -C 7) alkyl, (C 3 -C 7) cycloalkyl, (C 1 -C 6) alkoxy, (C 1 -C 4) alkylthio, tri-10 fluoromethyl, (C 1 -C 4) -C 8) alkylsulfinyl, (C 1 -C 4 alkylsulfonyl, nitro, phenyl, (C 2 -C 4) alkanoyl, benzoyl, tenoyl, (C 1 -C 4 alkanamido, benzamido or N, N-dialkylsulfamoyl) having 1 to 3 carbon at each of said alkyl; Y is H, fluoro, chloro, bromo, (C 1 -C 7) cycloalkyl, (C 1 -C 7) alkoxy, (C 1 -C 4) alkylthio, and trifluoromethyl; R 1 is ( C 1 -C 8 alkyl, (C 3 -C 7) cycloalkyl, (C 4 -C 7) cycloalkenyl, phenyl, substituted phenyl, phenylalkyl having 1-3 carbons in said alkyl, (substituted phenyl) alkyl having 1-3 carbons m-20 in said alkyl, (substituted phenoxy) alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy) alkyl having 1 to 3 carbons in said alkyl, naphthyl, bicyclo (2.2.1) heptan-2-yl, bicyclo (2.2.1) hept-5-en-2-yl or - (CH 2) n Q R 0; n is zero, 1 or 2; Q is divalent i 25 radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, iso-thiazole, oxazole, iso-oxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1 , 2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo (b) furan and benzo (b) "thiophene; R 0 is H or (C 1 -C 1) alkyl; and R 2 is (C 1 -C 8) alkyl, (C 3 -C 7) cycloalkyl, benzyl, furyl, thienyl, pyridyl, or wherein R 3 and R 4 are each H, fluoro, chloro, (C 1 -C 7) -alkyl, (C 1 -C 10) alkoxy or trifluoromethyl.

This patent also discloses that said 2-oxoindole-1-carboxamides are inhibitors of cyclooxygenase and lipooxygenase, exhibit analgesic activity in mammals, and are useful in treating pain and ameliorating symptoms associated with arthritis and rheumatoid arthritis pain.

U.S. Patent 4,556,672 discloses certain 3-acyl-sub-15-substituted 2-oxoindole-1-carboxamides of formula

y I

O = C-NH 2 wherein X, Y and R 1 are as described above for compounds of U.S. Patent 4,569,942. Compounds 25 of U.S. Patent 4,556,672 are shown to have the same activity as compounds of U.S. Patent 4,569,942 discussed above.

U.S. Patent 4,861,794 discloses a formula

O

30 R-R

/ C

3 5 θ '"ΝΗ 2 6 106459 and pharmaceutically acceptable base salts thereof, wherein X is H, Cl, or F, Y is H or Cl and R is benzyl or thienyl, interleukin-1 (IL -1) for inhibiting biosynthesis and for the treatment of diseases and disorders associated with IL-1.

PCT Patent Application Serial No. PCT / US88 / 03658, filed October 18, 1988, discloses the formula

10J

x A

Non-steroidal anti-inflammatory agents according to O 2 C-NH 15 2 wherein each of X and Y is hydrogen, fluorine or chlorine; R 1 is 2-thienyl or benzyl; and R is alkanoyl, cycloalkylcarbonyl, phenylalkanoyl, benzoyl and a certain substituted benzoyl group, tenoyl, omega-alkoxycarbonylalkanoyl, alkoxycarbonyl, phenoxycarbonyl, 1-alkoxycarbonyloxy, alkylsulfonyl and methylphenyl.

In the novel process of the invention, which will also be described later in the reaction scheme, a compound of formula II is reacted with 1,11-carbonyldiimidate Sol, the resulting product of formula V is then reacted with a compound of formula IV to give a compound of formula I.

This new process is not, as such, proposed or even suggested in the prior art since it does not disclose or suggest C-acylation of oxindoles with 1,1'-carbonyldiimidazole-activated carboxylic acids.

* 7 106459

Young, D.W., Heterocyclic Chemistry, Longman, New York 1975, pp. 62-63 discloses the use of N-acylimidazoles in peptide synthesis to form a peptide bond [- (C = O) -NH-]. However, Young's reference 5 does not disclose the formation of a C-C bond using N-acylimidazoles.

In Ullmanns Encyclopedia of Industrial Chemistry, 5th Ed., Vol. Al., VCH Weinheim 1985, p. 185, 215, 220 discloses CH-alkylation and CH-acylation of non-aromatic compounds by reaction using an alkyl or aryl halide as the alkylating or acylating agent. Thus, that reference does not disclose or even suggest alkylation or acylation with N-acylimidazoles.

In reference 100 Modem Reagents, Ed. Simpkins, N.S., 15 Moss Publishing, Nottingham 1989, pp. 43-44, on the other hand, discloses that 1,1 * -carbonyldiimidazole is a peptide coupling reagent as well as a reagent for carbonate and ester formation, as well as a further oxidizing agent and dehydrating agent. However, that reference does not disclose C-acylation of oxindoles with 1,1'-carbonyldiimidazole-activated carboxylic acids.

Also, it is not apparent to those skilled in the art from the use of 1,1'-carbonyldiimidazole-activated carboxylic acids for the C-acylation of oxindoles according to columns 4-5 of US 4,556,672.

In view of the foregoing, the novel process according to the invention, wherein the oxindoles are C-acylated with 1,1'-carbonyldiimidazole-activated carboxylic acids, must also be considered to be inventive in relation to the state of the art.

:] Interleukin-1 (IL-1) has been reported to stimulate bone resorption both in vitro and in vivo. Hayward, M. and Fiedler-Nagy, Ch., Agents and Actions, 22, 251-254 (1987). It is also disclosed that IL-1, inter alia. 35 induced prostaglandin E2 (PGE2) production. PGE2 is a bone resorption stimulator and is associated with bone loss. See 8,106,459

Hayward, M.A. and Caggiano, T.J., Annual Reports in Medicinal Chemistry, 22, Volume IV, Chapter 17, 169-178 (1987). Osteoporosis has been defined as a loss due to bone mineral degradation leading to higher fracture densities. See Hayward, M.A. and Caggiano, T.J., Direct. and the quotes quoted there.

Interleukin-1 has been reported to be involved in the pathogenesis of many diseases. See Dinarello, C.A., J. Clin. Immunol., 5, 287-297 (1985), the teachings of which are incorporated herein by reference. In addition, elevated levels of IL-1-like material have been found to be associated with psoriasis. Camp, R.D. et al., J. Immunol. 137: 3469-3474 (1986).

While the compounds of formula I above are presented as enoles, enol ethers and esters, it is to be understood that when R 1 is H, the compounds of formula I having R 20 = R 2 can adopt their tautomeric ketone form. Namely

(CH,) -Q

20th 2 n - C6 "'R2 25

A

(OCH) n-Q

All such tautomeric forms are within the scope of this invention and the appended claims.

9 106459 and is intended to be represented by Formula I. In addition, the substituents on the exocyclic double bond in position 3 of the compounds of Formula I may be in the syn form, in the anti form, or in a combination of both forms. Thus, the compounds of formula I and mixtures thereof having the structures

(CH2) n-Q

Γι 0'Rl L2 15 OR1

-J ^ NC H 2) n-Q

20 I 2

R

are within the scope of this invention and the appended claims, and all such isomers are intended to be represented by Formula I.

A group of preferred compounds obtainable according to the present invention is the group of formula I above wherein X and Y are each H, F, Cl, NO 2, (C 1 -C 4) alkyl or CF 3. Another group of preferred compounds is that wherein R20 is COR6, CONR'R8 or (C1-C6) alkyl wherein R6, R7 and R8 are as defined above. Another group of preferred compounds of this invention is that group of formula I wherein Q is A-Q1-B where Q1 is ··.

35 10 106459

___ N — W

Q or ^ or ^ 5 w and W is O or S. One group of preferred compounds is that wherein Q is Q2-A1, wherein Q2 is fr "'> / τλ ^ v / or" V "and W is S.

A more preferred group of compounds is where Q1 is

O

and I is O or S. Particularly preferred compounds are those wherein X and Y are each H, F, Cl, NO 2, (C 1 -C 1) alkyl or CF 3; R20 is COR6, CONR7R8 or (C1-C4 alkyl wherein R6, R7 and R8 are as defined above and Q is A-Q1-B where Q1 is 1! O '·· O Ώ where W is O or S , or Q is Q2-A1 where Q2 is 30 or

V w tal N N

vw ν '• «11 106459 wherein W is S. Further preferred compounds are those as above wherein W is S, R 20 is CONR 7 R 8 and R 7 and R 8 are H. More preferred are said compounds wherein X is H, Cl or CF 3 ; Y is H, Cl or F; A is Cl, Br, F, CF 3, SCH 3, OCH 3, COCH 3 or CH 2 OCH 3; and B is H, Cl, Br or CH 3. Other particularly preferred compounds are said compounds wherein n is zero or 1, while a compound wherein n is zero is even more particularly preferred.

Further preferred groups of compounds are compounds of formula I and groups of preferred, more preferred or particularly preferred compounds as defined above, wherein A is H, F, Cl, Br, CF 3, OR 9, CN, NO 2, COR 10, CH 2 OR 1 x or N (R 9). COR 1x and B are H, F, Cl, 15 Br, CF 3, OR 13, CN, NO 2, COR 14, CH 2 OR 15 or N (R 13) COR 15 where R 9, R 10, R 11, R 13, R 14 and R 15 are as defined above, or A and B are bonded together on the same carbon of the Qx ring and form an oxo group, or when A is not H, B is as defined above or (C 1 -C 3) alkyl; and A1 is F, 20 more preferred compounds being those wherein R6 is CH3; R7 is H and R8 is H or (Cx-C4) alkyl.

A novel process for the preparation of the compounds of formula I as defined above is characterized in that it comprises a compound of formula II

Q- (CH 2) n COOH (II)

with a molar excess of 1,1'-carbonyldiimidazole in a reaction inert solvent in an inert atmosphere and reacting the product of formula IV with a molar excess of

• ·.

With a substituted 2-oxoindole according to 11e, wherein X, Y and R 20 are as defined above in the presence of a basic agent at about 0-50 ° C in a reaction inert solvent under an inert atmosphere.

The intermediates of formula II include a number of novel compounds. These novel compounds are carboxylic acids of formula II '11' 15 H00C- (CH 2) 5 and salts thereof, wherein A 2 is H; B1 is at position 4 and is S (O) p'R16 or COOCH3, or B1 is at position 5 and is SO2NHCH3 or B1 is gun-20 where 4 or 5 is CON (CH3) 2, -O- "".

25 • 1. V.

... tv 30 n 'is zero; p'one one; W3 is S; Z 1 is O or S; R 12 is H, F, Cl, Br, CF 3 or alkyl; and R 16 is (C 1 -C 1 alkyl).

Substituted 2-oxoindole compounds of formula IV are prepared according to the methods disclosed in U.S. Pat. No. 3,634,453, U.S. 4,556,672, U.S. Pat. No. 4,569,942, U.S. Pat. No. 4,695,571, and U.S. Pat. references. The carboxylic acid compounds of formula II are prepared as described below.

5 REACTION SCHEME

O

Q- (CH 2) n C 0 ° H + ^ N-ON - * 10 (II)

O

Il / "V

Q- (CHJ C-N N 15 2 ”W

(V) 20

(V) + Y

R20 25 (IV) 30! 2 n Y X> '\ N ^ o (R = H) b ° 35 (I) 14 106459

Compounds of formula I wherein R 1 is H can be prepared by the novel process of this invention as shown in the reaction scheme above and described below. The carboxylic acid compound of formula II, prepared as described below, is reacted with a slight molar excess of 1,1'-carbonyldiimidazole in a reaction inert solvent. The reaction is carried out at about 25 ° C and stirred under an inert atmosphere. The reaction is allowed to proceed for about two hours, after which time the entire reaction mixture is added to a mixture of substantially the same molar amount of the 2-oxoindole compound of formula IV prepared as described above in the presence of a molar excess of basic material in a reaction inert solvent. in the ring. Suitable reaction inert solvents are those which at least partially solubilize one or all of the reactants and do not react adversely with the reactants or the product. In practice, the reaction inert solvent is usually a polar aprotic solvent, such as N, N-Dinie-20-styleformamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide. The preferred solvent is N, N-dimethylformamide. An inert atmosphere is obtained by carrying out the reaction under an inert gas such as nitrogen or argon. Preferred basic substances are tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine, pyridine and 4- (N, N-dimethylamino) pyridine, and particularly preferred basic substances are 4- (N, N-dimethylamino) pyridine and triethylamine.

Certain carboxylic acid compounds of formula II are known and carboxylic acid compounds of formula II, including novel carboxylic acid compounds of formula II ', are prepared according to known methods or by methods consistent with known methods. Such methods may involve the preparation of the corresponding esters or nitriles of the corresponding carboxylic acids, in which case the hydrolysis by known methods will yield the desired carboxylic acid. For such methods, consider the following: 5 Taylor, E.C. et al., J.O.C. 50: 1002 (1985); Noto, R. et al., J. Chem. Soc. PT II, 689 (1987); Schick, J.W. et al., J. Am. Chem. Soc. 7C): 286 (1948); Carpenter, A.J. et al., Tetrahedron 41: 3808 (1985); Gronowitz, S. et al.

Arkiv. for Kemi. 21: 265 (1963); Benseker, R.A. et al., 10 J.O.C. 38: 3660 (1973); Corral, C. et al., Heterocycles 23: 1431 (1985); Iriarte, J. et al., J. Het. Chem. 13: 393 (1976); Reinecke, M.G. et al., Synthesis, 327 (1980); Lawesson, S.O., Arkiv. for Kemi. 11: 317 (1957);

Gronowitz, S., Arkiv. for Kemi. 8: 87 (1955); Knight, D.W. 15 et al., J. Chem. Soc. P.T.I., 791 (1983); Gronowitz, S.,

Arkiv. for Kemi. 12: 239 (1958); Sice, J., J. Am. Chem.

Soc. 75: 3697 (1953); Bohlmann, F. et al., Chem. Ber. 106: 497 (1973); Thames, S.F. et al., J. Het. Chem. 3: 104 (1966); Arndt, F. et al., Chem. Ber. 94: 1757 (1961); 20 Cyme rman-Craig, J. et al., J. Chem. Soc., 237 (1954);

Lora-Tamayo, M. et al., Anales Real Soc. Spain. F sharp. Quim. Ser. B 62: 187 (1966); Nemec, N. et al., Coll. Czech.

Chem. Comm. 39: 3527 (1974); Janda, M. et al., Coll. Czech. Chem. Comm. 27: 1191 (1962); Carpenter, A.J. et al., Tetrahedron Letters 26: 1777 (1985); Satonaka, H., • ·.

Bull. Chem. Soc. Japan 56: 2463 (1983); Kinoshita, T., et al., Bull. Chem. Soc. Japan 48: 1865 (1975); Schwertner, E., et al., CA 88: 105790c (1978); Takaya, T. et al., Bull. Chem. Soc. Japan 41: 2086 (1968); Kim, H. et al., J. Med. 30 Chem. 29: 1374 (1986); Dostert, P. et al., Eur. J. Med.

Chem-Chim. Ther. 17: 437 (1982); Sato, N. et al., J.

«

Heterocyclic Chem. 19: 407 (1982); Ladruee, D. et al., Heterocycles 22: 299 (1984); Leanza, W.J. et al., JACS 75: 4086 (1953); Barlin, G.B. et al., Aust. J. Chem. 3.0: 2319 35 (1977); Gregory, G.I. et al., JCS P. T.I., 47 (1973); • 16 106459

Moriarty, R.M. et al., JACS 89: 5958 (1967); Ross, J.M. et al., JACS 86: 2861 (1964); Goerdeler, J. et al., Chem. Ber. 99: 1618 (1966); Demaree, P. et al., Can. J. Chem. 55: 243 (1977); U.S. Patent 4,001,238; Kawazu, M. et al., 5 J. Med. Chem. i5: 914 (1972); Buckle, D.R. et al., JCS

P. T.I., 627 (1982); Naik, S.R. et al., JOC 38 = 4353 (1973); Okada, M. et al., Macromolecules 19: 503 (1986);

Ondetti, M.A. et al., CA £ 2: 76268p (1980); Dutch Patent Application 6503440, September 20, 1965; Kenley, R.A. et al., CA101: 90841f (1984); Schmidt, U. et al., CA 96: 104572m (1982); Lukes, R. et al., Chem. listy 51: 1510 (1957); Krowicki, K. et al., JOC 52: 3493-3501 (1987);

Goya, P. et al., Heterocycles 24: 3451 (1986); Montero, J.L. et al., J. Heterocyclic Chem. 15: 929 (1978); Yasuda, 15 N. et al., J. Heterocyclic Chem. 24: 303 (1987); Hosmana, R.S. et al., Heterocycles 24: 2743 (1986); Rapoport, H. et al., Environ. Health Persp. 67: 41 (1986); Kravchenko, T.B. et al., CA107: 189533t (1987); Stanovnik, B. et al., Heterocycles 12: 761 (1979); Smith, R.C. et al., Biochem. 20 Pharmacol. 36: 1457 (1987); Bosso, C., et al., Org. Mass

Spectrom. 20: 263 (1985); Takagi, T. et al., CA83: 164172x (1975); Bende, Z. et al., CA98: 89254e (1983); Sarodnick, G. et al., CAI 01: 38426k (1984); Fletton, R.A. et al., CA107: 39474k (1987); Solomon, D.M. et al., Heterocycles 25 26: 651 (1987); Erlenmeyer, H. et al., Helv. Chim. Acta • 27: 1432 (1944); CA98: 95673g (1983); U.S. Patent 4,437,876; Hundle, B.S. et al., Biochemistry 26: 4505 (1987); Marutani, Y. et al., CAI04: 193202q (1986); Golubev, A.A. et al., CA107: 236584X (1987); Higushi, M. 30 et al., CAI04: 216392t (1986); Nakagawa, M. et al., Tetrahedron Letters 27: 6087-6090 (1986); Pereira, M.A. et al., CAI01: 165001 (1984); Fujii, S. et al., CA102: 45788d (1985); Bredereck, H. et al., Chem. Ber. 97: 1414 (1964); Howe, R.K. et al., CA95: 80933f (1981); Ibarra, C.A. et al., Tetrahedron Letters 26: 243 (1985); Hoppe, D., Justus • 17 106459

Liebigs Ann, Chetn. : 1843 (1976); Evans, D.L. et al., JOC 44: 497 (1979); Ozaki, Y., et al., Synthesis 216 (1979); Ehler, K.W. et al., CA87: 136361X (1977); Scolastico, C. et al., 5 Synthesis, 850 (1985); Corsico-Coda, A. et al.

Heterocycles 26: 745 (1987); Fields, R. et al. , CA90: 152072w (1979); Farina, F. et al., Heterocycles 24: 2587 (1986); Manaev, Y.A. et al., CA98: 71993k (1983); Beck, J.R., CA107: 23332b (1987); Aoki, I. et al., CA107: 10176057r (1987); Beck, J.R. et al., J. Heterocyclic Chem.

24: 267 (1987); Sato, T. et al. , CA107: 39807w (1987);

Ege, G. et al., Chem. Ber. 120: 1375 (1987); Klein, H.J. et al., CA102: 203932c (1985); Perevalov, V.P. et al., CA101: 171198d (1984); Hamilton, H.W., CA107: 59053a 15 (1987); Sabate-Alduy, C. et al. , CA87: 23137k (1977);

Bastide, J. et al., Tetrahedron 30: 3355 (1974);

Chrzaszcewska, A. Lodz. Tow. Navk. Wydz. Ill, 12: 119 (1967) (CA71: 124091r (1969)); English Patent 705950 (CA41: 2233 (1955)); and DeNardo, M., CA87: 118063X / 1977); 20 and references cited therein. Their teachings are incorporated herein by reference.

Compounds of formula I wherein R 1 is H are acidic and form base salts. All such base salts are within the scope of this invention and can be prepared by conventional methods. They may be prepared, for example, by simply placing the acidic and basic substances in contact with one another, usually in a stoichiometric ratio, either in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with an inert solvent followed by filtration, by evaporation of the solvent as appropriate, or by lyophilization in the case of aqueous solutions. Typical salts of the compounds of Formula I that may be prepared are primary, secondary and tertiary salts, i.e. alkali metal salts and alkaline earth metal salts. Especially valuable are the ethanolamine, diethanolamine and triethanolamine salts.

Suitable bases for salt formation include both organic and inorganic types and include organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal hydroxides, . Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, N, N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; hyd-20 oxides such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.

The ability of the compounds of the formula I to inhibit the biosynthesis of in-25 terleukin-1 is demonstrated by the test procedure, ♦ «as described below.

C3H / HeN mice (Charles River, Wilmington, Massachusetts) are sacrificed by cervical dislocation and their stomachs are injected with 70% ethanol to prevent bacterial contamination in subsequent cell preparation.

Each mouse is injected intraperitoneally with 8 ml RPMI1, RPMI-1640 medium (Hazelton Research Products, Inc., Lenexa, Kansas).

19,656,959 containing 5% FCS2, penicillin-streptomycin (100 units / ral to 100 µg / ml) and glutamine (2 mM). The abdominal cavity is agitated to promote cell release. An incision is then made through the abdominal skin to expose the underlying layer of muscle 5. Abdominal fluid is removed using a 20-gauge needle by inserting the needle through the exposed muscle layer just below the sternum. Abdominal fluid from six mice is combined with a plastic conical tube and examined microscopically for bacterial contamination. The contaminants are liquid centrifuged at about 600 x g for six minutes and the supernatant is discarded. Cells pelleted from 5 to 6 tubes are pooled and resuspended in a total volume of 20 ml RPMI-FCS3. Cell counts are then determined using a hemacytometer and cell viability is also determined by Trypan Blue staining using a hemacytometer. The cells are then diluted to a concentration of 3 x 10 6 cells / ml using RPMI-FCS. Add 1 ml of the above cell suspension to the wells of the 35 mm well plate. Cells are incubated for 2 hours at 37 ° C in a 5% CO 2 atmosphere to adhere macrophages to the well walls. Remove the supernatant by vigorously rotating the wells and pouring out. The adherent cells (namely macrophages) are washed twice with RPMI-SF4. To wells containing 25 adherent cells, add 1 ml of test compound at concentrations ranging from 0.1 to 100 µg / ml in RPMI-SF or 1 ml RPMI-SF for control. Fetal bovine serum, which has been screened to be highly responsive to IL-1 in a thymocyte assay (Hyclone Labora-30 tories, Logan, Utah) and has low spontaneous growth in the absence of IL-1, is then added.

3RPMI-1640 medium containing 5% fetal bovine serum.

4 4RPMI containing penicillin-terepeptomycin (100 Units / ml - 100 μ $ / χη1) and glutamine (2 mM).

20 1 0 6 4 5 9 100 µL of LPS in RPMI-SF (1 mg / 5 ml) for each well. The plates are incubated at 37 ° C in 5% CO 2 for 24 hours. Supernatants are removed and assayed for IL-1 either immediately or otherwise stored in a refrigerator or frozen for subsequent testing.

Supernatants are quantitatively tested for IL-1 according to the receptor binding assay described below. The standard curve is formed as follows. Rodent EL4-6.1 thymoma cells (10-15 x 102 cells in 0.4 in 10 ml of binding buffer (RPMI-1640, 5% FCS, 25 mM HEPES, 0.01% NaN3, pH 7.3)) are added in varying amounts to rodent rIL-1 alpha (recombinant IL-1 alpha produced by Escherichia coli from the published sequence of amino acids 115-270 of IL-1 alpha, Lomedico, PM 15 et al., Nature, 312, 458-462 (1984)) (40 pg to 40 ng in 0.5 ml buffer) and incubated for 1 hour at 4 ° C with continuous shaking followed by addition of 0.6 ng (0.1 ml) of human 125I-rIL-1- beta (New England Nuclear, Boston, Massachusetts) and shaking is continued for 3 hours. The samples are filtered through a Yeda instrument (Linea Co., Tel-Aviv, Israel) through Whatman GF / C2.4 cm glass fiber filters (coated with 0.5% milk powder for 2 hours at 37 ° C) and washed once. 3 ml ice-cold buffer. Filters are counted in a Searle gamma counter and non-specific binding is considered as cpm values that bind in the presence of

• I

contains 200 ng of unlabeled rIL-1 alpha. The Hill calibration curve is prepared by plotting log (Y / 100-Y) as a function of log C, where Y represents the percent binding of control 125 I-rIL-1-beta and C is the concentration of unlabeled rIL-1 alpha. A linear 'least-square' curve is fitted to travel through the Y-values between 20 and 80%. Then, to determine IL-1 levels as described above,

Clarified purified lipopolysaccharide from Salmonella minus 2 war bacteria that has been verified to not respond to C3H / Hej mouse 35.

At 106459 in two supernatants, diluted supernatants replace rIL-1 alpha in the above method and measured binding percentages are used to determine IL-1 concentrations from a Hill standard curve. Each dilution 5 is tested in duplicate and generally only dilutions with Y values between 20 and 80% are used to calculate average IL-1 levels.

The ability of the compounds of the formula I to inhibit prostaglandin H2 synthase and 5-lipooxygenase is demonstrated by the following test methods. Using the method described below, the levels of known products of prostaglandin H2 synthase and 5-lipooxygenase in cells treated with the test compound are measured, with inhibition of prostaglandin H2 synthase and / or 5-lipooxygenase in the presence or absence of known products of these enzymes.

RBL-1 cells maintained as a monolayer are cultured for 1-2 days in Spinner culture on Minimum Essential Medium (Eagle) with Earl's Marsh-20 Lats plus 15% Antibiotic / Anti-Fungal Serum. solution (Gibco), according to the method described by Jakschik, BA et al., Nature, 287: 51-52 (1980). Cells are washed twice and resuspended in cold RPMI-25 1640 at a cell density of 4 x 10 6 cells / ml. Then, 0.25 mL of a test compound at the desired concentration in RPMI-1640 is equilibrated at 37 ° C for 5 minutes. A 0.25 ml portion of the preheated cell suspension is added to the balanced dose and the mixture is incubated at 37 ° C for 5 minutes. Add 10 ul of a solution containing 14C-arachidonic acid and A-23187 (calcium ionophore, Sigma

Chemical) and incubate at 37 ° C for another 5 minutes. 267 µl of acetonitrile / 0.3% acetic acid are then added and the mixture allowed to stand on ice for 30 minutes. The tube containing mixture 35 is mixed, clarified by centrifugation at 22 106459 (3000 rpm, 10 minutes) and the supernatant is discarded and centrifuged again for 2 minutes at high speed in a microfuge. A 100 µl portion of the supernatant is then tested by HPLC on a Perkin Elmer-HS column-5 (3 microns) using a gradient solvent system containing acetonitrile / H 2 O with 0.1% trifluoroacetic acid and a flow rate of 2 mL / min. Radioactivity measurement is performed on a Berthold LB504 Radioactivity Monitor equipped with an 800 µl flow chamber mixing Omni-10 fluorine (New England Nuclear, Boston, Massachusetts, Commercial Item) with 2.4 ml / min of fluid exiting the column. The amount of radioactivity released is determined using the Spectra Physics SP4200 computer integrator. The data thus obtained is used in a results reduction program, in which the integration units for each product are calculated as a percentage of the total integration units and compared to the average control levels.

The compounds of formula I have analgesic activity. This activity is demonstrated in 20 mice by demonstrating inhibition of abdominal tension induced by the administration of 2-phenyl-1,4-benzoquinone (PBQ). The method used is based on Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731 (1957) applied to high throughput (see also Milne and Twomey, Agents and Actions, 10, 31-37 (1980)). All mice were fasted overnight prior to drug administration and testing.

Compounds of formula I are dissolved or suspended in a solvent containing ethanol (5%), emulsion 302 O (mixture of polyoxyethylene fatty acid esters, 5%) and brine (90%). This solution also serves as a control. Doses were on a logarithmic scale (namely ... 0.32, 1.0, 3.2, 10, 32 ... mg / kg). The route of administration is orally at varying concentrations so that the dose volume is constant at 10 ml / kg body weight. You mentioned- «...

23 106459 The Milne and Twomey method is used to determine effectiveness and strength. The mice are treated with the compounds orally and one hour later they receive 2 mg / kg of intraperitoneal PBQ. Individual mice are then placed immediately in a heated, illuminated chamber and, starting 5 minutes after administration of PBQ, the number of abdominal contractions is recorded over the next 5 minutes. The degree of protection (% MPE) for analgesia relief is calculated based on a reduction in abdominal contractions of 10 relative to that of control animals tested at the same time. At least 4 such assays (N = 5) give dose-dependent results for MPE50 formation, which is the best estimate of the dose that reduces abdominal contractions to 50% of control levels.

The compounds of formula I also possess anti-inflammatory activity. This activity is demonstrated in rats by a method based on the standard carrageenan-induced rat foot swelling assay (Winter et al., 20, Proc. Soc. Exp. Biol. Med., 111, 544 (1963)).

Non-anesthetized adult male albino rats weighing 150 g to 190 g are numbered, weighed, and marked with an ink mark on the outer calf of the right calf. Each paw is immersed in mercury just up to the mus-v 25 mark. Mercury is contained in a glass cylinder connected to a Statham Pressure Transducer. The output from the transducer is fed through a control unit to a microvolt tymmeter. The volume of mercury displaced by the immersed paw is determined. The drugs are administered by gavage. One 30 hours after drug administration, swelling is induced by injecting 0.05 ml of a 1% solution of carrageenan in the tissue of the soles of the affected paws. Immediately thereafter, the volume of the injected foot is measured. An increase in foot volume 3 hours after carrageenan injection forms an inflammatory response of the individual.

24 106459

The analgesic activity of the compounds of the formula I makes them useful for the acute administration to mammals for the control of pain, e.g., post-operative pain and pain. In addition, the compounds of Formula I are useful for continuous administration to mammals for the relief of symptoms of chronic diseases such as rheumatoid arthritis and pain associated with osteoarthritis and other skeletal muscle disorders.

The ability of the compounds of formula I to inhibit IL-1 biosynthesis makes them useful as IL-1 biosynthesis inhibitors, per se. It also makes them useful in treating IL-1 related diseases and immune disorders in mammals. Said IL-1-related diseases include, but are not limited to, bone and connective tissue metabolic diseases such as osteoporosis, dental surrounding tissue, and tissue degeneration. Immune disorders associated with IL-lreen include, but are not limited to, allergies and psoriasis.

The ability of the compounds of the formula I to inhibit prostaglandin H2 synthase renders them useful as prostaglandin H2 synthase inhibitors, per se, being known to be involved in the pathogenesis of arthritic joints in mammals.

. When used as an inhibitor of IL-1, an inhibitor of prostaglandin H2 synthase, a pain reliever or an anti-inflammatory agent, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered to a mammalian recipient either alone or preferably in association with pharmaceutically acceptable carriers. in pharmaceutical composition according to standard pharmaceutical practice. The compound may be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.

In a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active agent will normally be in the range of 1: 4 to 4: 1, and preferably 1: 2 to 2: 1. However, in all cases, the ratio chosen will depend on such factors as the solubility of the active moiety, the dose contemplated, and the precise route of administration.

For oral use, Formula I of this invention

for example, in the form of tablets or capsules or as an aqueous solution or suspension. In the case of tablets for oral use, carriers commonly used include lactose and corn starch, and lubricants such as magnesium stearate are usually added. Useful diluents for oral administration in capsule form are lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous use, the active ingredient is usually formulated in sterile solutions and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, total solvent concentrations should be adjusted so that the preparation is isotonic.

When a compound of formula I or a salt thereof is administered to a human subject, the daily dosage will usually be determined by the attending physician. In addition, the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the strength of the particular compound administered. However, when a sudden dose of 35 is used to relieve pain, the dose that produces an effective analgesic response will in most cases be about 5 mg to 500 mg taken as needed (e.g., every 4 to 24 hours). For continuous administration to alleviate (treat) pain and inflammation, inhibit IL-1 biosynthesis, and / or inhibit prostaglandin H 2 synthase, the effective dose in most cases is from 5 mg to 1.0 g per day, and preferably from 50 mg to 500 g / day. mg per day, in single or divided doses. On the other hand, in some cases it may be necessary to use doses outside these limits.

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

15 EXAMPLE 1 4-Methylsulfinyl-2-thiophenecarboxylic acid

A stirred solution of 2.46 g (14.1 mmol) of 4-methylthio-2-thiophenecarboxylic acid (prepared as described in Example 28 below) in 150 mL of 20 dichloromethane and 10 mL of methanol was cooled to ice bath temperature. To the cooled reaction solution was slowly added 120 mL of a dichloromethane solution of 2.82 g (13.9 mmol) of m-chloroperoxybenzoic acid (technical grade, 80-85%). After 1 hour, the reaction was substantially complete, forming a colorless precipitate.

The precipitate was filtered and dried to give 1.18 g (6.20 mmol) of the desired compound as a colorless solid, m.p. 188-190 ° C. The concentrated mother liquor was chromatographed (silica gel) to give 0.83 g (4.36 mmol) of the desired 4-30 methylsulfinyl-2-thiophenecarboxylic acid, overall yield 75% (10.56 mmol).

Analysis: Calculated for C 6 H 60 3 S 2: C, 37.88; H, 3.18%. Found: C, 37.89; H, 3.18%. EIMS (m / z): 190 (M +, 45%) and 175 (M + -CH 3). 1 HNMR (DMSO-d 6) delta, 13.4 (1H, alternating), δ 8.27 (1H, d, J = 1.5 Hz), 7.96 (1H, d, J = 1.5 Hz) and 2.86 27 106459 (3H, s). 13CNMR (DMSO-d6) delta 162.1, 146.4, 137.2, 131.7, 128.9 and 42.2; ir (potassium bromide): 3420, 2550, 1705, 1245, 1015 cm -1.

EXAMPLE 2 5 5- (N-Methylaminosulfonyl) -2-thiophenecarboxylic acid

Lithium diisopropylamide was prepared by slowly adding 17.5 mL (43.8 mmol) of 2.5 M n-butyllithium in hexanes to cooled (2-propanol / dry ice) diisopropyl-10-pyramine (7.0 mL, 50.0 mmol). ) in tetrahydrofuran solution (200 mL) keeping the reaction temperature below -60 ° C. After 5 minutes, the reaction mixture was warmed to room temperature for 30 minutes and then re-cooled to below -70 ° C. 100 ml of a tetrahydrofuran-15 solution of 3.54 g (20.0 mmol) of 2- (N-methylaminosulfonyl) thiophene (prepared by Slocum, D.W. et al., JOC) was added slowly.

38, 4189 (1973)), adjusting the reaction temperature to below -70 ° C. After all was added, the reaction was stirred for 30 minutes and then 20 excess carbon dioxide was bubbled through the solution. The solution was then warmed to 5 ° C and quenched by the addition of 50 mL of 1N sodium hydroxide. To the aqueous tetrahydrofuran solution was added a 300 mL portion of diethyl ether and the phases were separated in a separatory funnel. The organic layer was extracted with 50 mL of 1N sodium hydroxide. The two basic aqueous solutions were combined, washed with 50 mL of diethyl ether and acidified with concentrated hydrochloric acid. The acidic aqueous mixture was extracted with diethyl ether (2 x 100 mL). The ether solution was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 3.38 g (15.3 mmol) of the desired thiophenecarboxylic acid as a colorless solid, m.p. 145-148 ° C. The overall yield was 76%.

Analysis: Calculated for C 6 H 7 NO 4 S 2: C, 32.57; H, 3.19;

35 N, 6.33%. Found: C, 32.43; H, 3.08; N, 6.30%. EIMS

28 106459 (m / z): 221 (M + base), 191 (M + -NHMe, 98%), 157 (unknown, 95%), 127 (unknown, 45%) and 115 (unknown, 73%). 1 HNMR (DMSO-d 6) delta, 7.92 (1H, alternating), 7.74 (1H, d, J = 4.0 Hz), 7.58 (1H, d, J = 4.0 Hz) and 2 , 51 (3H, 5 d, J = 5.2 Hz); ir (potassium bromide): 3440 br, 3000 br, 1680, 1170 cm -1.

EXAMPLE 3 5-Iodo-2-thiophenecarboxylic acid The title compound is described by Schick, J.W. et al., J. Am. Chem. Soc. 70: 286 (1948) and was prepared according to the following procedure. A volume of 25 mL (62.5 mmol) of n-butyllithium in 2.5 M hexane solution was added slowly to a syringe-cooled (dry ice / 2-propanol) 100 mL tetrahydrofuran solution containing 9.0 mL (64.2 mmol) of di- ethyldiisopropylamine. The mixture was kept below -60 ° C during the addition of n-butyllithium. After the addition, the cooling bath was removed and the mixture allowed to reach room temperature (22 ° C) and then re-cooled to below -60 ° C. 3.2 g (25.0 mmol) of 2-thiophenecarboxylic acid dissolved in 100 ml of tetrahydrofuran were slowly added to the cooled reaction vessel. After 30 minutes after all 2-thiophenecarboxylic acid had been added, about 17.2 g (87.8 mmol) of ioditrifluoromethane was condensed into the reaction. 5 minute picture ·. After 25 hours, the cooling bath was removed and the reaction was warmed to 0 ° C and quenched with 50 mL of water. The basic aqueous solution was washed with 500 mL of diethyl ether. meters. The ether solution was extracted with 50 mL of 1N sodium hydroxide and the two aqueous solutions were combined and washed with ether. The basic solution was acidified and extracted. three times with 100 ml of diethyl ether. Drying of the organic solution with anhydrous magnesium sulfate followed by filtration and concentration gave a crude solid product. Partial purification was accomplished by reprecipitation of the solid product from hot aqueous ethyl acetate 106459 to give 3.79 g of a slightly impure desired product as a mixture of a dark red solid and yellow crystals. Recrystallization of the solid mixture gave 2.18 g (8.58 mmol, 34% yield) of the pure title compound 5 as pale yellow needle crystals, m.p. 132-134 ° C (hexanes).

Analysis: Calculated for C 5 H 31 IO 2 S: C, 23.64; H, 1.19%. Found: C, 23.86; H, 1.10%. EIMS (m / z): 254 (M + base), 237 (M + -OH, 79%), 209 (M + -CO 2 H, 5%), 127 (M + -I, 10-18%), and 82 (C 4 H 2 S, 36%). %); 1 H NMR (CDCl 3) delta, 7.50 (1H, d, J = 3.9 Hz) and 7.29 (1H, d, J = 3.9 Hz); and (CHCl3): 2977 br, 2565, 1679 and 1410 cm @ -1.

EXAMPLE 4 5 - ((N, N-Dimethylamino) carbonyl) -2-thiophene-15-carboxaldehyde

To a solution of 5-formyl-2-thiophenecarboxylic acid (prepared according to the method described by Carpenter, AJ et al., Tetrahedron 41: 3808 (1985)) (2.75 g, 17.61 mmol) in 75 mL of tetrahydrofuran , 1,11-carbonyldiimidazole (3.71 g, 22.88 mmol) was added, the mixture was stirred under argon for 2.5 hours and treated with excess gaseous dimethylamine. The solution was concentrated in vacuo to an oil which was dissolved in ethyl acetate (100 mL) and extracted with 1 N hydrochloric acid (2 x 50 · 25 mL) followed by 5% sodium bicarbonate (2 x 50 mL).

Each of the aqueous layers was then washed with ethyl acetate (2 x 50 mL) and the combined organic layers were dried (magnesium sulfate). Concentration in vacuo gave a pale yellow solid (2.42 g, 30 75%). EIMS (m / z): 183 (M +, 82%), 154 (M + - CHO, 7%), 139 (M + - (CH 3) 2 N, base) and 111 (M + - (CH 3) 2 NCO, 59%); ¹HNMR (CDCl13) δ, 9.91 (1H, s), 7.67 (1H, d, J = 4.0 Hz), 7.35 (1H, d, J = 4.0 Hz), 3.13 (6H, br s). This material was used directly without further purification.

35 30 1 0 6 4 5 9 EXAMPLE 5 5 - ((N, N-Dimethylamino) carbonyl) -2-thiophenecarboxylic acid 2.39 g (13.04 mmol) of crude 5 - ((N, N-dimethylamino) 5 Liamino) carbonyl) -2-thiophenecarboxaldehyde was added to a stirred silver oxide suspension prepared by adding 2.29 g (57.13 mmol) of sodium hydroxide to 5.85 g (34.44 mmol) of silver nitrate in 100 mL of water. After stirring at ambient temperature for 15 minutes 10 and filtration through a pad of diatomaceous earth, the filtrate was acidified from pH 12 to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The extracts were dried (magnesium sulfate) and concentrated in vacuo to give a white solid (2.01 g, 77%). An analytical sample was obtained by trituration with warm ethyl acetate, m.p. 158-159 ° C.

Analysis: Calculated for CBH 9 NO 3 S: C, 48.23; H, 4.55; N, 7.03%. Found: C, 48.30; H, 4.42; N, 6.79%. EIMS (m / z): 199 (M + 68%), 155 (M + - (CH 3) 2 N, base), 111 (M * -20 (CH 3) 2 NCO, 44%); 1 H NMR (DMSO-d 6) delta, 7.66 (1H, d, J = 4.0 Hz), 7.46 (1H, d, J = 4.0 Hz), 3.09 (6H, s); ir (Potassium umbromide): 3430, 1710, 1594, 1246 cm -1.

EXAMPLE 6 4 - ((N, N-Dimethylamino) carbonyl) -2-thiophene, 25 carboxaldehyde

To a solution of 2-formyl-4-thiophenecarboxylic acid (prepared according to the procedure described by Gronowitz, S. et al., Archiv. For Chem. 21: 265 (1963)) (1.24 g, 7.94 mmol). ml of tetrahydrofuran, add 1,1'-carbonyldiimidazole (1.80 g, 11.10 mmol), 30 ml. the solution was stirred under dry argon for 1.5 hours and treated with excess gaseous dimethylamine. The solution was concentrated in vacuo to an oil which was dissolved in ethyl acetate (60 mL) and extracted with 1N hydrochloric acid (13 x 30 mL) followed by 5% sodium bicarbonate (1 x 30 mL). Each of the aqueous extracts was then washed with 31,106,459 ethyl acetate (2 x 50 mL) and the combined organic layers dried (magnesium sulfate). Concentration in vacuo gave a tan solid (1.15 g, 79%). E IMS (m / z): 183 (M +, 31%), 155 (M + -CO, 38%), 139 (M + - (CH 3) 2 N, base) and 111 (M + - (CH 3) 2 NCO, 25%). ); 1 HNMR (DMSO-d 6) delta, 9.89 (1H, d, J = 1.4 Hz), 7.89 (1H, dd, J = 1.5, 1.4 Hz), 7.86 (1H, d, J = 1.5 Hz), 3.08 (6H, s). This material was used directly without further purification.

EXAMPLE 710 4 - ((N, N-Dimethylamino) carbonyl) -2-thiophenecarboxylic acid 1.12 g (6.11 mmol) of crude 4 - ((N, N-dimethylamino) carbonyl) - 2-Thiophenecarboxaldehyde was added to a stirred silver oxide suspension prepared by adding 1.08 g (26.90 mmol) of sodium hydroxide to 2.74 g (16.14 mmol) of silver nitrate in 40 mL of water. After stirring at ambient temperature for 15 minutes, the mixture was filtered through a pad of diatomaceous earth, acidified from pH 12 to pH 2 with concentrated hydrochloric acid and saturated with solid sodium chloride. After extraction with ethyl acetate (3 x 75 mL), the dried (magnesium sulfate) extracts were concentrated in vacuo to a light yellow crystalline solid (1.10 g, 90%). An analytical sample was obtained by trituration with warm ethyl acetate, 25 m.p. 112-114 ° C.

Analysis: Calculated for C 8 H 9 NO 3 S: C, 48.23; H, 4.55; N, 7.03%. Found: C, 48.07; H, 4.58; N, 6.86%. EIMS (m / z): 199 (M + 26%), 181 (M + -H 2 O, 7%), 155 M + - (CH 3) 2 N, base); 1 H NMR (DMSO-d 6) delta, 8.09 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 1.8 Hz), 2.98 (6H, d, J = 13.0 Hz); ir (potassium bromide): 3388, 1706, 1594, 1250, 1186 cm -1.

* 'EXAMPLE 8

Methyl-2-formyl-4-thiophenecarboxylate The title compound is described by Gronowitz, S. et al., Arkiv. for Kemi. 21: 265 (1963) and prepared 32 106459 according to the following procedure · Methyl iodide (1.32 g, 9.30 mmol) was added to a stirred suspension of 2-formyl-4-thiophenecarboxylic acid (prepared by Grono-Witz, S. et al. ., Arkiv. For Chem. 21: 265 (1963) (1.21 g, 7.75 mmol) and sodium carbonate (2.87 g, 27.12 mmol) in 40 mL of N, N dimethyl-formamide. After stirring overnight at room temperature, the mixture was poured into water (200 mL), saturated with solid sodium chloride and extracted with ethyl acetate.

The combined extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo to a pale yellow solid (1.20 g, 91%), m.p. 110-112 ° C. EIMS (m / z): 170 (M + 84%), 139 (M + -CH 3 O, base), 111 (M + -CH 3 O 2, 29%); 1 HNMR (CDCl 3) delta, 9.90 (1H, d, 1.5 Hz), 8.41 (1H, s), 8.13 (1H, d, J = 1.5 Hz), 3.88 ( 3H, s).

EXAMPLE 9 4-Methoxycarbonyl-2-thiophenecarboxylic acid A stirred solution of methyl 2-formyl-4-thiophenecarboxyl-20 (823 mg, 4.85 mmol) in 50 mL of acetone was treated dropwise with Jones reagent (5 mL). After the addition was complete, the mixture was stirred at room temperature for 30 minutes, the excess oxidant was decomposed with isopropanol and the mixture filtered through diatomaceous earth. The acetone was removed in vacuo, the residue was dissolved in ethyl acetate (30 mL) and the solution was dried over magnesium sulfate. Concentration in vacuo gave a light solid (880 mg, 98%). The analytical sample was obtained by trituration with a small amount of ethyl acetate, m.p. 141-143 ° C.

Analysis: Calculated for C7H604S: C, 45.15; H, 3.25%.

Found: C, 45.09; H, 3.14%. EIMS (m / z): 186 (M + 42%), 155 (M + -CH 3 O, base); 1 H NMR (DMSO-d 6) δ, 8.59 (1H, d, J = 1.2 Hz), 7.91 (1H, d, J = 1.2 Hz), 3.81 (3H, s); ir (potassium bromide): 3419, 1706, 1681 cm @ -1.

35 33 106459 EXAMPLE 10

Methyl-5-formyl-2-thiophenecarboxylate The title compound is described by Gronowitz, S. et al., Arkiv. for Kemi. 21: 265 (1963) and was prepared according to the following procedure. Methyl iodide (4.36 g, 30.74 mmol) was added to a stirred suspension of 5-formyl-2-thiophenecarboxylic acid (prepared

Carpenter, A.J. et al., Tetrahedron 41: 3808 (1985)) (4.00 g, 25.61 mmol) and sodium 10 carbonate (9.50 g, 89.65 mmol) in 75 mL of N, N- dimethyl-formamide. After stirring overnight at room temperature, the mixture was poured into water (350 mL), saturated with solid sodium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried (mag-15sulfate) and concentrated in vacuo to a gray solid (3.83 g, 88%), m.p. 85-87 ° C. EIMS (m / z): 170 (M +, 95%), 139 (M + -CH 3 O, base), 111 (M + -CH 3 O 2, 64%); 1 H NMR (DMSO-d 6) delta, 9.94 (1H, s), 7.81 (1H, d, J = 3.9 Hz), 7.71 (1H, d, J = 3.9 Hz), 3 , 91 (3H, s).

20 EXAMPLE 11 5-Methoxycarbonyl-2-thiophenecarboxylic acid The title compound is described by Benseker, R.A. et al., J.O.C. 38: 3660 (1973) and British Patent 705950 and was prepared according to the following procedure. A mixed solution of methyl 5-formyl-2-thiophenecarboxylate (2.00 g, 11.75 mmol) in 100 mL of acetone was treated dropwise with Jones reagent (9 mL). After the addition was complete, the mixture was stirred at room temperature for one hour, the excess oxidant was decomposed with isopropanol and the mixture filtered through diatomaceous earth. The acetone was removed in vacuo, the residue was dissolved in ethyl acetate (75 mL) and the solution was dried over magnesium sulfate. Filtration and concentration gave a yellow solid (1.60 g, 73%). An analytical sample was obtained by trituration with 35 warm ethyl acetate, m.p. 186-189 ° C.

t 34 106459

Analysis: Calculated for C7H604S: C, 45.15; H, 3.25%. Found: C, 45.12%; H, 3.09%. EIMS (m / z): 186 (M +, 70%), 169 (NT-OH, 7%), 155 (M + -CH 3 O, base); 1 HNMR (DMSO-d 6) delta, 7.78 (1H, d, J = 4.0 Hz), 7.72 (1H, d, J = 4.0 Hz), 3.85 (3H, s) IR (potassium bromide): 3416, 1712, 1666, 1258 cm @ -1.

EXAMPLE 12 5-Methoxycarbonyl-2-1-iophenecarboxylic acid hydrazide A stirred suspension of 5-methoxycarbonyl-10-yl-2-thiophenecarboxylic acid (1.86 g, 10.0 mmol) in 20 mL of thionyl chloride was refluxed for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to an almost colorless oil which crystallized in vacuo. This solid was then dissolved in 25 mL of chloroform and added dropwise to a cooled (5 ° C) solution of anhydrous hydrazine (800 mg, 25.0 mmol) in 25 mL of chloroform, under argon. After the addition was complete, the mixture was stirred at room temperature for one hour and then evaporated to dryness in vacuo. The remaining solid was suspended in 25 mL of water, stirred for 15 minutes and filtered to give a light solid (1.79 g, 90%). An analytical sample was prepared by recrystallization from ethanol, m.p. 198-200 ° C.

Analysis: Calculated for C7H8N2O3S: C, 41.99; H, 4.03;

N, 13.99%. Found: C, 41.88; H, 3.91; N, 13.86%. EIMS (m / z): 200 (M +, 26%), 169 (M + -CH 3 O or N 2 H 3, base); 1 H NMR

(DMSO-d6) delta, 10.05 (1H, br s), 7.77 (1H, d, J = 3.9 Hz), 7.71 (1H, d, J = 3.9 Hz), 4 , 56 (2H, br s), 3.82 30 (3H, s); ir (potassium bromide): 3319, 3285, 1723, 1618, 1264, 746 cm @ -1.

35 106459 EXAMPLE 13

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

A stirred suspension of 5-methoxycarbonyl-5-yl-2-thiophenecarboxylic acid hydrazide (548 mg, 2.74 mmol) and ethyl acetimidate hydrochloride (372 mg, 3.01 mmol) in 10 mL of pyridine was refluxed for 4 hours, cooled to room temperature and evaporated. . The residual oily solid was dissolved in ethyl acetate and washed with water, 1N hydrochloric acid and 5% sodium bicarbonate. The ethyl acetate was dried (magnesium sulfate) and evaporated in vacuo to a light tan solid (242 mg, 39%), m.p. 142-145 ° C. This material was used directly without further purification. Exact Mass: 224.0253, Calculated: 224.0256; EIMS (m / z): 224 (M + base), 193 (M + -CH 3 O, 33%), 169 (C 12 H 50 3 S, 83%); 1 HNMR (DMSO-d 6) delta, 7.88 (1H, d, J = 3.9 Hz), 7.80 (1H, d, J = 3.9 Hz), 3.87 (3H, s), 2 , 58 (3H, s); ir (potassium bromide): 1705, 1571, 1291, 1101, 20,751 cm -1.

EXAMPLE 14 5- (5-Methyl-1,3,4-oxadiazol-2-yl) -2-thiophenecarboxylic acid

A mixture of methyl 5- (5-methyl-1,3,4-oxa-25 diazol-2-yl) -2-thiophenecarboxylate (100 mg, 0.45 mmol) in 3 mL of 2 N sodium hydroxide was diluted 1 ml of methanol and stirred at room temperature for 2 hours. The solution was filtered to remove some insoluble residues and acidified to pH 3 with concentrated hydrochloric acid. The precipitate was collected and air dried to give a pale yellow solid (67 mg, 1 '71%), m.p. 281-284 ° C.

Analysis: Calculated for C 8 H 6 N 2 O 3 S: C, 45.70; H, 2.88; N, 13.33%. Found: C, 45.81; H, 2.81; N, 13.26%. EIMS 35 (m / z): 210 (M +, base), 193 (M + -OH, 3%), 168 (unknown, 36 106459 8%), 155 (C 6 H 30 3 S, 56%); 1 HNMR (DMSO-d 6) delta, 7.79 (1H, d, J = 3.9 Hz), 7.77 (1H, d, J = 3.9 Hz), 2.57 (3H, s) / ir (potassium bromide): 3443, 1693, 1599, 1574, 1264, 744 cm -1.

EXAMPLE 15 Methyl 4-acetyl-2-thiophenecarboxylate ti

Methyl iodide (783 mg, 5.51 mmol) was added to a stirred suspension of 4-acetyl-2-thiophenecarboxylic acid (prepared by Satonaka, H., Bull. Chem. Soc. Japan,> 6: 2463 (1983)). ) (782 10 mg, 4.59 mmol) and sodium carbonate (1.70 g, 16.08 mmol) in 25 mL of Ν, Ν-dimethylformamide. After stirring overnight at room temperature, the mixture was poured into water (125 mL), saturated with solid sodium chloride and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo to a viscous solid (761 mg, 90%), m.p. 94-96 ° C. EIMS (m / z): 184 (M +, 74%), 169 (M + -CH 3, base), 153 (M + -CH 3 O, 51%); 1 HNMR (DMSO-d 6) delta, 8.17 (1H, d, J = 1.5 Hz), 8.13 (1H, d, J = 1.5 Hz), 3.88 (3H, S), 2.51 (3H, s).

EXAMPLE 16

Methyl-4-bromiasetwli-2-thiophenecarboxylate

Following the procedure described by Japan Kokai Tokkyo Koho JP 60 11,487 CA 103: 22580m (1985), a solution of bromine (4.29 g, 26.87 mmol) in 40 mL of chloroform was added dropwise to a stirred solution of methyl 4-acetyl-2-thiophenecarboxylate (4.95 g, 26.87 mmol) prepared according to example 15 in 150 ml of chloroform containing four drops of 50% (v / v) 30% of 48% hydrobromic acid / glacial acetic acid. After 10 minutes at 40 ° C, the solution was cooled to room temperature, concentrated in vacuo and the residue triturated with methanol (25 mL). Filtration gave a light solid (4.96 g, 63%), m.p. 112-114 ° C. EIMS (m / z): 35 264/262 (M +, 11%), 233/231 (M + -CH 3 O, 11%), 171/169 (M + - 106459 37 CH 2 Br, base); 1 HNMR (CDCl 3) delta, 8.31 (1H, d, J = 1.5 Hz), 8.17 (1H, d, J = 1.5 Hz), 4.29 (2H, s), 3.90 (3H, s).

EXAMPLE 17

Methyl 4- (2-methylthiazol-4-yl) -2-thiophene-5 carboxylate mono-hydrobromide

A solution of methyl 4-bromoacetyl-2-thiophenecarboxylate (398 mg, 1.51 mmol) prepared in Example 16 and thioacetamide (125 mg, 1.66 mmol) in 15 mL of acetone was refluxed for 2 hours. . The mixture 10 was cooled to room temperature, filtered and the residue was dried in vacuo to give a white solid (375 mg, 77%), m.p. 224-225 ° C.

Analysis: Calculated for C10H9NO2S2.HBr: C, 37.50; H, 3.15; N, 4.36%. Found: C, 37.53; H, 3.09; N, 4.28%.

EIMS (m / z): 239 (M + base), 208 (M + -CH 3 O, 65%), 198 (M + - C 2 H 3 N, 76%); 1 HNMR (DMSO-d 6) delta, 8.25 (1H, d, J = 1.5 Hz), 8.22 (1H, d, J = 1.5 Hz), 7.98 (1H, s), δ , 98 (alternating), 3.82 (3H, s), 2.68 (3H, s); and (potassium bromide): 3091, 1703, 1285 cm @ -1.

EXAMPLE 18 4- (2-Methyl-thiazol-4-yl) -2-thiophenecarboxylic acid A mixture of methyl 4- (2-methyl-thiazol-4-yl) -2-thiophenecarboxylate mono-hydrobromide (3.20 g, 10.0 mmol). , prepared according to Example 17, in 50 ml of 25 N 2N sodium hydroxide, diluted with 15 ml of methanol and refluxed for 1 hour. The methanol was removed in vacuo and the remaining aqueous solution was acidified to pH 3 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 50 mL) and the dried (mag-30-sulfate) extracts were concentrated to a white solid (2.12 g, 94%). An analytical sample was obtained by trituration with warm ethyl acetate, m.p. 195-197 ° C.

Analysis: Calculated for C 9 H 7 NO 2 S 2: C, 47.98; H, 3.13; 35 N, 6.22%. Found: C, 47.84; H, 3.01; N, 6.14%. EIMS

M / z: 225 (M + base), 208 (M + -OH, 1%), 184 (M + -C 2 H 3 N, 90%); ir (potassium bromide): 3103, 1676, 1284 cm @ -1.

EXAMPLE 19

Methyl-5-formyl-2-thiophenecarboxylate oxime A solution of methyl 5-formyl-2-thiophenecarboxylate (6.26 g, 36.78 mmol) prepared according to Example 10, hydroxylamine hydrochloride (3.07 g, 44 g). , 14 mmol) and pyridine (3.49 g, 44.14 mmol) in 200 mL of ethanol were refluxed for 2 hours. The ethanol was removed in vacuo, the residue dissolved in ether and washed with water. The organic layer was dried (magnesium sulfate) and evaporated to a yellow solid. Trituration with a small amount of ether gave the title compound as a white solid (4.93 g, 72%), m.p. 164 -15167 ° C. Oxime Z: E ratio: (82:18).

Analysis: Calculated for C 7 H 7 NO 3 S: C, 45.39; H, 3.81; N, 7.56%. Found: C, 45.41; H, 3.69; N, 7.48%. EIMS (m / z): 185 (M +, 97%), 154 (M + -CH 3 O, base); 1 H NMR (DMSO-d 6) delta, Z-isomer: 12.52 (1H, br s), 7.99 (1H, s), 7.77 (1H, d, J = 4.0 Hz), 7, 50 (1H, d, J = 4.0 Hz), 3.83 (3H, s); E-Isomer: 11.66 (1H, br s), 8.38 (1H, s), 7.74 (1H, d, J = 4.0 Hz), 7.34 (1H, d, J = 4 , 0 Hz), 3.82 (3H, s); ir (potassium bromide): 3400, 1649, 918 cm @ -1.

EXAMPLE 20. 25 Me of methyl 5-svano-2-thiophenecarboxylic acid

The title compound is described by Decroix, B. et al., J. Chem. Res. (M), 1848 (1978) and was prepared according to the following procedure. A stirred mixture of methyl 5-formyl-2-thiophenecarboxylate oxime (4.87 g, 30 26.29 mmol), prepared according to Example 19, was refluxed in 60 ml of acetic anhydride overnight. The solution was cooled to room temperature, poured into 400 ml of water and shaken vigorously. The mixture was extracted with ether (3 x 100 mL) and the extracts were then washed with 35% potassium hydroxide (3 x 50 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to a viscous solid (3.50 g, 80%), m.p. 76-78 ° C. EIMS (m / z): 167 (M + 34%) and 136 (M + -CH 3 O, base); 1 H NMR (DMSO-d 6) delta, 8.03 (1H, d, J = 4.2 Hz), 7.88 (1H, d, J = 4.2 Hz), 3.87 (3H, s); ir (potassium bromide): 2228, 1726 cm @ -1.

EXAMPLE 21

Methyl 5- (N-hydroxy) carboximidamido-2-thiophenecarboxylate A mixture of methyl 5-cyano-2-thiophenecarboxylate (901 mg, 5.39 mmol) prepared according to Example 20, hydroxylamine hydrochloride (412 mg, 5.93 mmol) and sodium acetate (553 mg, 6.74 mmol) in 25 mL of 5: 1 ethanol-water solution were refluxed for 45 minutes. The ethanol was removed in vacuo and the crystalline residue was collected by filtration. Additional material was collected from the cooled filtrate to finally give 932 mg (86%) of a pale yellow crystalline solid, m.p. 144-146 ° C.

Analysis: Calculated for C7H8N2O3S: C, 41.99; H, 4.03; N, 13.99%. Found: C, 42.24; H, 3.91; N, 13.59%. EIMS (m / z): 200 (M + base), 185 (M + -CH 3, 83%), 169 (M + -CH 3 O, 60%); 1 H NMR (DMSO-d 6) delta, 9.97 (1H, s), 7.72 (1H, d, J = 4.0 Hz), 7.51 (1H, d, J = 4.0 Hz), δ , 11 (2H, br s), 25 3.80 (3H, s); ir (potassium bromide): 3491, 1725 and 1636 cm @ -1.

EXAMPLE 22

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

A mixture of methyl 5- (N-hydroxy) carboxy-30-imidiamido-2-thiophenecarboxylate (734 mg, 3.67 mmol) prepared according to Example 21 and acetic anhydride (1.12 g, 11.0 g). mmol) in 25 mL of toluene, refluxed for 24 hours. The solvent was removed in vacuo and the residue was triturated with a small amount of toluene to give 35 light solids (547 mg, 67%), m.p. 134 - •.

40 1 0 6 4 5 9 136 ° C. EIMS (m / z): 224 (M + 99%), 193 (M + -CH 3 O, base), 183 (M + -C 2 H 3 N, 58%), 152 (C 6 H 2 NO 2 S, 89%); 1 HNMR (DMSO-d 6) delta, 7.77 (1H, d, J = 4.0 Hz), 7.69 (1H, d, J = 4.0 Hz), 3.89 (3H), 2.64 (3H, s); ir (potassium bromide): 1720, 1597 and 887 cm @ -1. This material was used directly without further purification.

EXAMPLE 23 5- (5-Methyl-1,2,4-oxadiazol-3-yl) -2-thiophenecarboxylic acid A mixture of methyl 5- (5-methyl-1,2,4-oxadiazole) -3-yl) -2-thiophenecarboxylate (86 mg, 0.38 mmol) prepared according to Example 22 in 3 mL of 2N sodium hydroxide, diluted with 1 mL of methanol and heated at 60 ° C for 10 minutes. The solution was cooled to room temperature, diluted with 2 ml of water and acidified to pH 2 with concentrated hydrochloric acid. After standing for 30 minutes, a fluffy crystalline solid which slowly separated was collected by filtration and dried in vacuo to give the title compound (45 mg, 56%), 20 m.p. 218-220 ° C.

Analysis: Calculated for C 6 H 6 N 2 O 3 S: C, 45.70; H, 2.88; N, 13.33%. Found: C, 45.69; H, 2.81; N, 13.06%. EIMS (m / z): 210 (M + 89%), 169 (M + -C 2 H 3 N, base), 152 (C 6 H 2 NO 2 S, 27%); 1 HNMR (DMSO-d 6) delta, 7.77 (2H, s), 2.65 (3H, s); 25 ir (potassium bromide): 3429, 1668 and 889 cm @ -1.

EXAMPLE 24

Methyl 5- (5-trifluoromethyl-1,2,4-oxadiazol-3-yl) -2-thiophenecarboxylate

A stirred mixture of methyl 5- (N-hydroxy-30) carboximidamide-2-thiophenecarboxylate (833 mg, 4.16 mmol) prepared according to Example 21 and trifluoroacetic anhydride (2.62 g, 12 , 48 mmol) in 25 mL of toluene was refluxed for one hour. The solvent was evaporated in vacuo, the residue was triturated with a little toluene and filtered to give a white crystalline solid (400 mg, 35%), m.p. 126-127 ° C. The product was used directly without further purification. Exact Mass: 277,9998; Calculated: 277.9974; EIMS (m / z): 278 (M + 67 h), 247 (M + -CH 3 O, base), 152 (C 6 H 2 NO 2 S, 41%); 1 HNMR (CDCl 3) del-δ, 7.81 (2H, s), 3.91 (3H, s); ir (potassium bromide): 1712, 1255, 912 cm @ -1.

EXAMPLE 25 5- (5-Trifluoromethyl-1,2,4-oxadiazol-3-yl) -2-thiophenecarboxylic acid A mixture of methyl 5- (5-trifluoromethyl-1,2,4-oxadiazol-3-yl) - 2-Thiophenecarboxylate (100 mg, 0.36 mmol) prepared according to Example 24 in 3 mL of 2N sodium hydroxide was diluted with 1 mL of methanol and warmed to 50 ° C for 10 minutes. The solution 15 was cooled to room temperature, diluted with 3 ml of water and acidified to pH 2 with concentrated hydrochloric acid. After standing for one hour, the off-white crystalline solid (41 mg, 43%) was collected by filtration and dried in vacuo, m.p. 175-177 ° C.

Analysis: Calculated for C8H3F3N2O3S: C, 36.37; H, 1.14; N, 10.61%. Found: C, 36.65; H, 1.18; N, 10.24%. EIMS (m / z): 264 (M +, base), 247 (M + -OH, 43%), 169 (M + -C 2 F 3 N, 24%); 1HNMR (DMSO-d6) delta, 7.94 (1H, d, J = 4.0 Hz), 7.83 (1H, d, J = 4.0 Hz); ir (potassium bromide): 25 3430 br, 1661, 1208, 847 cm -1.

EXAMPLE 26

Methyl 4- (thiazol-4-yl) -2-thiophenecarboxylate hydrobromide

A solution of methyl 4- (bromoacetyl) -2-thio-30-carboxylate (1.25 g, 4.75 mmol) prepared according to Example 16 and thioformamide (436 mg, 7.13 mmol) in 35 mL acetone, refluxed for one hour. The mixture was slightly cooled and filtered to give a yellow solid (941 mg, 65%). Analytical sample 35 was recrystallized from ethanol, m.p. Mp 201-202 ° C.

«· 42 106459

Analysis: Calculated for C9H7NO2S2.HBr: C, 35.30; H, 2.63; N, 4.58%. Found: C, 35.31; H, 2.60; N, 4.48%.

E IMS (m / z): 225 (M + base), 194 (M + -CH 3 O, 92%), 167 (C 8 H 70 2 S, 25%); 1 HNMR (DMSO-d 6) delta, 9.18 (1H, d, J = 1.7 Hz), 8.31 (1H, d, J = 1.2 Hz), 8.30 (1H, d, J = 1.2 Hz), 8.21 (1H, d, J = 1.7 Hz), 4.50 (1H, alternating), 3.85 (3H, s); ir (potassium bromide): 3054, 1711, 1272, 778 cm -1.

EXAMPLE 27 10 4- (Thiazol-4-yl) -2-thiophenecarboxylic acid

A mixture of methyl 4- (thiazol-4-yl) -2-thiophenecarboxylate hydrobromide (500 mg, 1.63 mmol) prepared according to Example 26 in 8 mL of 2 N sodium hydroxide was diluted with 1 mL: 11a methanol and reflux-15 were diseased for 30 minutes. The methanol was removed in vacuo and the remaining aqueous solution was acidified to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate and the dried (magnesium sulfate) extracts were concentrated to a pale yellow solid 20 (318 mg, 92%), m.p. 183-185 ° C.

Analysis: Calculated for C8 H5 NO2 S2: C, 45.48; H, 2.39; N, 6.63%. Found: C, 45.42; H, 2.29; N, 6.46%. EIMS (m / z): 211 (M +, base), 194 (M + -OH, 23%) and 184 (C 7 H 40 2 S 2, 80%); 1 HNMR (DMSO-d 6) delta, 9.16 (1H, d, J = 1.2 Hz), δ 8.23 (2H, br s), 8.16 (1H, d, J = 1.2 Hz) ); and (potassium midi): 3440 br, 3110, 1691, 1285 cm -1.

EXAMPLE 28 4-Methyl-lithio-2-thiophenecarboxylic acid Lithium diisopropylamide was prepared by slowly adding 31.0 ml (77.5 mmol) of 2.5 M in n-butyl lithium in hexanes to a cooled (2-propanol / dry ice) solution in tetrahydrofuran 200 ml) in diisopropylamine (11.0 ml, 78.5 mmol) while maintaining the reaction temperature below -60 ° C. After 15 minutes, the reaction solution was warmed to room temperature for 30 minutes and then re-frozen to below -70 ° C. 100 ml of a tetrahydrofuran solution of 9.9 g (76.0 mmol) of 3-methylthiothiophene (prepared according to the procedure described by Henrio, G. et al., Tetrahedron 3J5., 191 (1977)) were added slowly while maintaining reaction temperature below -70 ° C. After the addition was complete, the reaction was stirred for 15 minutes and then excess carbon dioxide was bubbled through the solution. The solution was then warmed to 10 ° C and quenched with 100 mL water. After stirring for a few minutes, the reaction mixture was poured into a separatory funnel and extracted with 500 ml portion of diethyl ether. The organic layer was extracted with 100 mL of 1N sodium hydroxide, then the two basic aqueous solutions were combined, washed with 100 mL of diethyl ether and acidified with concentrated hydrochloric acid. The acidic aqueous mixture was then extracted with diethyl ether (2 x 250 mL). The ether solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to 11.75 g (67.4 mmol) of a yellow solid, which NMR showed to be a 3: 2 mixture of the desired thiophenecarboxylic acid (4-to-3). . This crude product was stirred in 50 mL of diethyl ether for 30 min then filtered and the filtrate concentrated in vacuo to 8.68 g (49.8 mmol) of a solid containing more than 80% (estimated by 25 NMR) of the desired 4-methylthio -2-thiophenecarboxylic acid. Recrystallization from chloroform gave 4.11 g (23.6 mmol) of a light yellow solid, m.p. 118-120 ° C (lit. m.p. 123-124 ° C), which was 95% 4-methylthio-2-thiophenecarboxylic acid (purity assessed by NMR). The overall yield of Ko-30 was 31%.

. EXAMPLE 29 5- (N, N-Dimethylaminosulfonyl) -2-thiophenecarboxylic acid

Lithium diisopropylamide was prepared by slowly adding 10.5 mL (26.3 mmol) of 2.5 M in hexanes

·, 44 106459 n-butyllithium in a cooled solution of (2-propanol / dry ice) diisopropylamine (5.0 mL, 35.7 mmol) in tetrahydrofuran (200 mL) while maintaining the reaction temperature below -60 ° C. After 5 minutes, the reaction solution was warmed to room temperature for 30 minutes and then re-cooled to below -70 ° C. 100 ml of a tetrahydrofuran solution of 3.4 g (17.8 mmol) of 2- (N, N-dimethylaminosulfonyl) thiophene (prepared by Slocum, DW et al., JOC 3.8, 4189 (1973)) were added slowly. 10) while maintaining the reaction temperature below -70 ° C. After the addition was complete, the reaction was stirred for 30 minutes and then excess carbon dioxide was bubbled through the solution. The solution was then warmed to 0 ° C and quenched with 50 mL of 1N sodium hydroxide. 300 ml of diethyl ether were added to an aqueous solution of tetrahydrofuran and the phases were separated in a separatory funnel. The organic layer was extracted with 50 mL of 1N sodium hydroxide. The two basic aqueous solutions were combined, washed with 50 mL of diethyl ether, and made acidic with concentrated hydrochloric acid. The acidic aqueous mixture was extracted with diethyl ether (2 x 100 mL). The ether solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to 3.66 g (15.6 mmol) of the desired thiophenecarboxylic acid as a colorless solid, m.p. 184-186 ° C (lit. m.p. 170-172 ° C). The overall yield was 87%.

EXAMPLE 30 5-Aminosulfone-2-thiophenecarboxylic acid Lithium diisopropylamide was prepared by slowly adding 26.5 mL (66.3 mmol) of 2.5 M n-butyl lithium in hexanes to cooled (2-propanol / dry ice) diisopropylamine (11, 0 mL, 78.5 mmol) in tetrahydrofuran solution (200 mL) while maintaining the reaction temperature below -60 ° C. After 5 minutes, the reaction solution was warmed to 35 room temperature for 30 minutes and then re-cooled to below -70 ° C. 100 ml of a tetrahydrofuran solution of 3.26 g (20.0 mmol) of 2-aminosulfonylthiophene (prepared according to the method described by Slocum, DW et al., JOC 3J, 4189 (1973)) were slowly added, pi-5 reaction temperature below -70 ° C. After the addition was complete, the reaction was stirred for 30 minutes and then excess carbon dioxide was bubbled through the solution. The solution was then warmed to 2 ° C and quenched with 50 mL of 1N sodium hydroxide. 300 ml of diethyl ether were added to the aqueous tetrahydro-10 furan and the phases were separated in a separatory funnel. The organic layer was extracted with 50 mL of 1N sodium hydroxide. The two basic aqueous solutions were combined, washed with 50 mL of diethyl ether and acidified with concentrated hydrochloric acid. The acidic aqueous mixture was extracted with diethyl ether (2 x 100 mL). The ether solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to 2.56 g (12.4 mmol) of the desired thiophenecarboxylic acid as a colorless solid. Recrystallization from water gave 1.79 g (8.6 mmol) of a tan solid, m.p. 228-231 ° C (lit. m.p. 231-232 ° C). The overall yield was 43%.

EXAMPLE 31 5-Chloro-3- (4-acetyl-2-tenowl) -2-oxo-25-indole-1-carboxamide A sample of 0.78 g (4.59 mmol) of 4-acetyl-2-thiophenecarboxylic acid (prepared by the method of Satonaka, H., Bull. Chem. Soc. Japan 56: 2463 (1983)) was combined with 0.95 g (5.85 mmol) of 1,1'-car-30-butyldiimidazole. of Ν, Ν-dimethylformamide and. * were stirred at room temperature under an argon atmosphere.

After 2 hours, the contents of the reaction were transferred to an addition funnel and slowly added to a solution of 0.88 g (4.18 mmol) of 5-chloro-2-oxoindole-1-carboxamide 35 and 1.38 g (11.28 mmol) of 4 - (N, N-Dimethylamino) pyridine in 30 4 4 46 106459 ml of Ν, Ν-dimethylformamide with stirring at 5 ° C (ice bath) under an inert atmosphere. Reaction contents were stirred for 15 minutes at 5 ° C until complete addition, followed by stirring at room temperature for 24 hours. Pouring the reaction mixture into 110 ml of 0.3 N hydrochloric acid caused a greenish-yellow solid to precipitate. Filtration followed by successive washing with 3N hydrochloric acid and water gave the crude product which was recrystallized twice from acetic acid to give 0.34 g (0.94 mmol, 22% yield) of pure 5-chloro-3- (4-acetyl). 2-tenoyl) -2-oxoindole-1-carboxamide in the form of a green-yellow dissolved complex with 0.2 equivalents of acetic acid, m.p. 230-233 ° C.

Analysis: Calculated for C 16 H 11 ClCl 2 O 4 S x 0.2 for C 2 H 4 O 2: C, 152.55; H, 3.17; N, 7.47%. Found: C, 52.24; H, 2.88; N, 7.61%. E IMS (m / z): 362/364 (M + 9%), 319/321 (M + -CONH, 43%), 193/195 (M + -CONH-C 6 H 6 OS, base) and 153 (C 7 H 50 2 S, 79%). ; 1 HNMR (DMSO-d 6) delta, 8.64 (1H, br s), 8.47 (1H, d, J = 1.3 Hz), 8.07 (1H, d, J = 8.5 Hz), 8.00 (1H, br s), 7.07 (1H, br d, J = 8.5 Hz), 5.94 (1H, br s, alternating) and 2.52 (3H, s); ir (potassium bromide): 3387, 3230 br, 1743, 1692, 1623, 1592, 1577, 1384, 1272 and 1192 cm -1.

EXAMPLE 32 5-Chloro-3- (4-methylsulfinyl-2-tenoyl) -2-oxo-25-indole-1-carboxamide

The title compound was prepared according to the procedure of Example 31. Acylation of 1.64 g (8.6 mmol) of 4-methylsulfinyl-2-thiophenecarboxylic acid (prepared as described in Example 1) with 1.65 g (10.0 30 mmol) of 1,1'-carbonyldiimidazole gave the corresponding reaction. A dense acylimidazole derivative used directly and fixed with 1.65 g (7.8 mmol) of 5-chloro-2-oxoindole-1-carboxamide in the presence of 2.87 g (23.5 mmol) ) 4- (N, N-dimethylamino) pyridine to give 35 crude yellow product. Trituration of this yellow solid with «47 106459 with 2-butanone gave 1.67 g (4.36 mmol, 56% yield) of pure 5-chloro-3- (4-methylsulfinyl-2-tenoyl) -2- oxoindole-1-carboxamide as a yellow solid, m.p. Mp 204-206 ° C.

Analysis: Calculated for C ^ HH ^ dNNO;: C, 47.06; H, 2.90; N, 7.32%. Found: C, 47.11; H, 2.91; N, 7.27%. EIMS (m / z): 382/384 (M +, 7%), 339/341 (NT-CHNO, 16%), 193/195 (M + -CHNO-C 5 H 6 OS 2, base) and 173 (C 6 H 50 2 S 2, 31%); 1 H NMR (DMSO-d 6) delta, 8.36 (1H, br s), 8.27 (1H, br s), 8.11 (1H, d, J = 8.5 Hz), 7.99 ( 1H, br s), 7.13 (1H, br d, J = 8.5 Hz) and 2.88 (3H, s); ir (potassium bromide): 3385, 3220 br, 1721, 1612, 1573, 1376 and 1193 cm @ -1.

EXAMPLE 33 5-Chloro-3- (5-sulfonamido-2-tenowl) -2-oxo-15-indole-1-carboxamide A sample of 1.48 g (7.2 mmol) of 5-sulfonamido-2-thiophenecarboxylic acid (prepared as described in Example 30) was converted to acylimidazole by reacting with 1.39 g (8.6 mmol) of 1,1'-carbonyldiimidazole. The acylimidazole intermediate was directly attached with 1.26 g (6.0 mmol) of 5-chloro-2-oxoindole-1-carboxamide in the presence of 2.2 g (18.0 mmol) of 4- (Ν, Ν). -dimethylamino) pyridine to give 2.34 g of a crude orange solid. Recrystallization gave 1.22 g (3.05 mmol, 51% -25% yield) of pure 5-chloro-3- (5-sulfonamido-2-tenoyl) -2-oxoindole-1-carboxamide as a yellow-green solid. , m.p. 227-229 ° C (acetic acid).

Analysis: Calculated for C 14 H 10 ClN 3 O 5 S 2: C, 42.06; H, 2.52; N, 10.51%. Found: C, 41.78; H, 2.48; N, 10.15%. 30 EIMS (m / z): 399/401 (M + 2%), 356/358 (M + -CHNO, 23%), · 193/195 (M + -CHNO-C 4 H 5 NO 2 S 2, base) and 190 (C 5 H 4 NO 3 S 2, 53 %); 1 HNMR (DMSO-d 6) delta, 8.23 (1H, d, J = 4Hz), 8.05 (1H, br d, J = 1.5Hz), 8.02 (1H, d, J = 8 , 5 Hz), 7.71 (br s, alternating), 7.49 (1H, d, J = 4 Hz), 6.95 (1H, dd, J = 8.5, 35 1.5 Hz), and 5.56 (br s, alternating); ir (potassium bromide): 3393, 3250, 3109 br, 1722, 1600, 1569, 1345, 1203 and 1150 cm -1.

106459 EXAMPLE 34 5-Chloro-3- (5- (N-methylsulfonamido) -2-tenowl) -2-oxoindole-1-carboxamide The title compound was prepared according to the procedure for Example 31. Acylation of 2.21 g (10.0 mmol) of 5- (N-methylsulfonamido) -2-thiophenecarboxylic acid (prepared as described in Example 2) with 1.95 g (12.0 mmol) of 1,1'-carbonyl -imidazole formed the corresponding acylimidazole intermediate in 20 mL of N, N-dimethylform-10 amide. This solution was transferred and slowly added to 1.75 g (8.33 mmol) of 5-chloro-2-oxoindole-1-carboxamide in 40 mL of N, N-dimethylformamide containing 3.05 g (25.0 mmol) ) 4- (N, N-dimethylamino) pyridine. Acid acceleration of the reaction afforded 2.96 g of a yellow-orange solid. Recrystallization from acetic acid gave 1.90 g (4.59 mmol, 55% yield) of the pure title compound as a yellow solid, m.p. 225-227 ° C.

Analysis: Calculated for C 18 H 12 ClN 3 O 5 S 2: C, 43.53; H, 2.92; N, 10.15%. Found: C, 43.49; H, 2.86; N, 10.15%.

20 E IMS (m / z): 413/415 (M +, 2%), 370/372 (M + -CHNO, 20%), 205 (C 6 H 7 NO 3 S 2, 68%) and 193/195 (M + -CHNO-C 5 H 7 NO 2 S 2, base ); 1 HNMR (DMSO-d 6) delta, 8.32 (1H, d, J = 4 Hz), 8.08 (1H, d, J = 1.5 Hz), 8.05 (1H, d, J = 8, 5 Hz), 7.71 (br s, alternating), 7.53 (1H, d, J = 4 Hz), 6.97 (1H, dd, J = 8.5, 1.5 Hz), 25 , 77 (1H, br s, alternating) and 2.54 (3H, s); and (potassium bromide): 3433 br, 3323 br, 1731, 1607, 1566 and 1151 cm -1.

EXAMPLE 35 5-Chloro-3- (5-carboxy-2-tenowl) -2-oxoindole-1-carboxamide The title compound was prepared according to the procedure of Example 31. A 1.00 g (5.81 mmol) sample of commercially available 2,5-thiophenedicarboxylic acid was reacted with 1.88 g (11.62 mmol) of 1,1'-carbonyldiimidazole in 15 mL of N , N-dimethylformamide to give ac-35 activated acylimidazole. Slow addition of acylimidazole to 1.11 g (5.28 mmol) of 5-chloro-2-oxoindole-1-carboxamide in Ν, Ν-dimethylformamide and 1.92 g of 106 106459 (15.68 mmol) 4 - (.beta., .Beta.-dimethylamino) -pyridine gave an yellow-green solid after acidic acceleration. Final purification was carried out from hot broth of the title compound in acetic acid. This afforded 1.51 g (4.14 5 mmol, 78% yield) of 5-chloro-3- (5-carboxy-2-tenoyl) -2-oxoindole-1-carboxamide as a yellow solid, m.p. 274-278 ° C.

Analysis: Calculated for C 15 H 9 ClN 2 O 5 S: C, 49.39, -H, 2.49; N, 7.68%. Found: C, 49.19; H, 2.45; N, 7.38%.

10 E IMS (m / z): 364/366 (M +, 17%), 321/323) M + -CHNO, 73%), 193/195 (M + -CHNO-C 5 H 4 O 2 A, 98%) and 186 (unknown, base ); 1 HNMR (DMSO-d 6) delta, 8.10 (1H, d, J = 4Hz), 8.09 (1H, d, J = 8.5Hz), 8.03 (1H, br d, J = 1) , 5 Hz), 7.74 (1H, d, J = 4 Hz) and 7.08 (1H, dd, J = 8.5, 1.5 Hz); ir (potassium bromo-15 di): 3388, 3276 br, 1718, 1695, 1551 and 1273 cm @ -1.

EXAMPLE 36 5-Chloro-3- (4-methoxycarbonyl-2-tenowl) -2-oxo-indole-1-carboxamide

The title compound was prepared according to the procedure of Example 31. To a solution of 1.50 g (8.06 mmol) of 4-methoxycarbonyl-2-thiophenecarboxylic acid (prepared as described in Example 9) in 15 ml of N, N-dimethylformamide was added 1.57 g (9 67 mmol) of 1,11-carbonyldiimidazole. After 2 hours, the reaction contents were added slowly to 1.54 g (7.32 mmol) of 5-chloro-2-oxoindole-1-carboxamide in Ν, Ν-dimethylformamide and 2.66 g (21.75 mmol) of 4 - (Ν, Ν-dimethylamino) pyridine. The acidic acceleration of this reaction, followed by filtration, drying and trituration with hot acetic acid, afforded 1.88 g (4.97 mmol, 68% yield) of the title compound as a yellow solid, m.p. 244-246 ° C.

Analysis: Calculated for C 16 H 16 Cl 1 N 2 O 5 S: H, C, 50.73; H, 2.93; N, 7.40%. Found: C, 50.52; H, 2.86; N, 7.12%.

E IMS (m / z): 378/380 (M + 1%), 335/337 (M + -CONH, 7%),

35 193/195 (M + -CONH-C6H502S, base), 169 (C7H503S, 35%); 1 H NMR

(DMSO-d6) delta, 8.59 (1H, d, J = 1.4 Hz), 8.48 (1H, br s), 8.06 (1H, d, J = 8.5 Hz), δ , 05 (1H, br s), 7.02 (br d, J = 50 10 6 4.55 8.5 Hz), 4.64 (1H, br s, alternating) and 3.82 (3H, s) ); ir (potassium bromide): 3383, 3217 br, 1746, 1590, 1375, 1279 and 745 cm @ -1.

EXAMPLE 37 5-Chloro-3- (5-methoxycarbonyl-2-tenowl) -2-oxoindole-1-carboxamide

Following the procedure of Example 31, a solution of N, N-dimethylformamide containing 1.25 g (6.71 mmol) of 5-methoxycarbonyl-2-thiophenecarboxylic acid (prepared as described in Example 11) was added to 1.19 g. (7.35 mmol) of 1,11-carbonyldiimidazole to give the activated acyl intermediate. The reaction solution of this intermediate was also slowly added to 1.29 g (6.10 mmol) of 5-chloro-2-oxoindole-1-carboxamide in Ν, Ν-dimethylformamide and 2.02 g of 15 (16.54 mmol) of 4 - (n, n-dimethylamino) pyridine. Acid acceleration followed by filtration, drying and recrystallization gave 1.29 g (3.41 mmol, 56% yield) of the title compound as a yellow solid, m.p. 219-221 ° C (acetic acid).

Analysis: Calculated for C 18 H 17 CH 2 O 2 S 5: C, 50.73; H, 2.93; N, 7.40%. Found: C, 50.76; H, 2.84; N, 7.38%.

E IMS (m / z): 378/380 (M +, 2%), 335/337 (M + -CONH, 11%), 193/195 (M + -CONH-C6H502S, base) and 169 (C7H503S, 46%). ; 1 HNMR (DMSO-d 6) delta, 8.16 (1H, d, J = 3.9 Hz), 8.05 (1H, d, J = 8.5 Hz), 8.03 (1H, br s) , 7.78 (1H, d, J = 3.9 Hz), 7.02 (1H, dd, J = 8.5, 2.3 Hz), 5.55 (1H, br s, alternating) and 3 , 84 (3H, s); ir (potassium bromide): 3388, 3216 br, 1730, 1589, 1290 and 745 cm @ -1.

EXAMPLE 38 30-5-Chloro-3- (4-N, N-dimethylcarbamido-2-tenowl) -2-oxoindole-1-carboxamide • "

The title compound was prepared according to the procedure of Example 31. A sample of 1.70 g (8.56 mmol) of 4 - ((N, N-dimethylamino) carbonyl) -2-thiophenecarboxylic acid (prepared as described in Example 5) was reacted with 1.77 g. (10.90 mmol) of 1,1'-carbonyldiimidazole sol to give the acyl imidazole intermediate which was added

Sl 106459 was slowly added to a Ν, Ν-dimethylformamide solution of 1.64 g (7.80 rams) of 5-chloro-2-oxoindole-1-carboxamide and 2.57 g (21.02 rams) of 4- (N, N- dimethylamino) pyridine. Acid acceleration followed by filtration gave an orange-colored solid which was recrystallized twice from acetic acid to give 0.86 g (2.19 mmol, 28% yield) of the pure title compound as a yellow dissolved complex of 0.2 equivalents. acetic acid, m.p.

240-243 ° C.

Analysis: Calculated for C 17 H 14 ClN 3 O 4 S x 0.2 C 2 H 4 O 2: C, 51.75; H, 3.69; N, 10.41%. Found: C, 51.58; H, 3.46; N, 10.42%. E IMS (m / z): 391/393 (M + 26%), 348/350 (M + - CONH, 20%), 193/195 (M + -CONH-C 7 HBNOS, base) and 182 (C 8 H 8 NO 2 S, 46%). ; 1 HNMR (DMSO-d 6) delta, 8.16 (1H, br s), δ 8.08 (1H, d, J = 8.5 Hz), 8.04 (1H, br s), 7.95 (1H , br s), 7.10 (1H, br d, J = 8.5 Hz), 6.38 (1H, br s, alternating), 3.07 (3H, br s), and 2.98 (3H, br s); and (potassium bromide): 3390, 3233, 1744, 1622, 1375 and 1195 cm @ -1.

EXAMPLE 39 5-Chloro-3- (4- (2-methyl-4-thiazolyl) -2-tenowl) -2-oxoindole-1-carboxamide The title compound was prepared according to the procedure of Example 31. A sample of 1.25 g (5.55 mmol) of 4- (2-methyl-4-thiazolyl) -2-thiophenecarboxylic acid (prepared as described in Example 18) was converted to acyl imidazole by reacting 0.98 g (6.05 mmol) of 1,1'-carbonyldiimidazole in 15 mL of N, N-dimethylformamide. When the reaction was complete, this solution was transferred to a funnel and 50 mL of N, N-30 dimethylformamide containing 1.06 g (5.04 mmol) of 5-chloro-2-oxoindole-1-carboxamide and 1 66 g (13.59 mmol) of 4- (N, N-dimethylamino) pyridine. Acid acceleration followed by filtration and trituration with 2-butanone gave 0.50 g (1.20 mmol) of the title compound as a yellow solid, m.p. 238-241 ° C.

Analysis: Calculated for C 11 H 12 ClN 3 O 3 S 2: C, 51.73; H, 2.90; N, 10.06%. Found: C, 51.63; H, 2.95; N, 9.75%.

52 1 0 6 4 5 9 E IMS (m / z): 417/419 (M + 1%), 374/376 (M + -CONH, 8%), 208 (C 9 H 6 NOS 2, 34%), 193/195 (M +) -CONH-C8H7NS2, 20%) and 181 (CbH7NS2; base); 1 HNMR (DMSO-d 6) delta, 8.44 (1H, br s), 8.13 (1H, br s), 8.09 (1H, d, J = 8.4 Hz), 7.94 (1H, br 5s), 7.79 (1H, s), 7.10 (1H, d, J = 8.4Hz), 4.88 (1H, br s, alternating) and 2.71 (3H, s) ; ir (potassium bromide): 3385, 2919, 1747, 1587, 1374, 1196 and 729 cm @ -1.

EXAMPLE 40 5-Chloro-3- (6-chloro-cinotinyl) -2-oxoindole-10'-carboxamide

The title compound was prepared according to the procedure of Example 31. Acylation of 823 mg (5.22 mmol) of a commercially available 6-chloro-nicotinic acid sample with 924 mg (5.70 mmol) of 1,1'-carbonyldiimidazole yielded the corresponding reactive acylimidazole intermediate, which was used directly and With 00 g (4.75 mmol) of 5-chloro-2-oxoindole-1-carboxamide in the presence of 1.57 g (12.85 mmol) of 4- (Ν, Ν-dimethylamino) pyridine to give the crude greenish-brown solid. Recrystallization of this solid gave 400 mg (1.14 mmol, 24% yield) of a green-yellow solid, m.p. 236-238 ° C (acetic acid).

Analysis: Calculated for C 15 H 9 Cl 2 N 3 O 3: 0, 51.45; H, 2.59; N, 12.00%. Found: C, 51.54; H, 2.54; N, 11.69%.

25 E IMS (m / z): 349/351/353 (M +, 8%), 306/308/310 (M + -CONH, 64%), 193/195 (M + -CONH-CSH 4 Cl, N) and 140 / 142 (C 6 H 3 ClNO, 61%); 1 HNMR (DMSO-d 6) delta, 8.56 (1H, d, J = 2.3 Hz), 8.37 (br s, alternating), 8.07 (1H, d, J = 8.5 Hz), 8.01 (1H, dd, J = 8.2, 2.3 Hz), 7.94 (1H, d, J = 2.3 Hz), 7.60 (1H, 30 d, J = 8.2 Hz), 7.41 (br s, alternating), 7.11 (1H, dd, J = 8.5, 2.3 Hz), and 4.93 (br s, alternating); ir (potassium bromide): 3390, 3210 (br), 1730, 1580, 1380, 1290, 1110 and 820 cm -1.

«53 106459 EXAMPLE 41 5-Fluoro-3- (4-chloro-2-tenoyl) -2-oxoindole-1-carboxamide

The title compound was prepared according to the procedure of Example 31. A portion of 329 mg (2.02 mmol) of 4-chloro-2-thiophenecarboxylic acid (prepared according to the method described by Iriarte, J. et al., J. Het. Chem., 13, 393 (1976)) was combined with 358 mg. of 1,1'-carbonyldiimidazole in 5 ml of Ν, Ν-dimethylformamide, and the imidazole formed as intermediate 10 were directly attached with 357 mg (1.84 mmol) of 5 chloro-2-oxoindole-1-carboxamide in the presence of 607 mg (4.96 mmol) of 4- (N, N-dimethylamino) pyridine. The resulting yellow crude product was recrystallized to give 189 mg (0.558 mmol, 30% yield-15 to) of a yellow solid, m.p. 224-226 ° C (acetic acid).

Analysis: Calculated for C 14 H 8 ClFN 2 O 3 S: C, 49.64; H, 2.38; N, 8.27%. Found: C, 49.41; H, 2.28; N, 8.12%. EIMS (m / z): 338/340 (M% 4%), 295/297 (M + -CONH, 19%), 177 20 (M + -CONH-C 4 H 3 ClS, base), and 145/147 (C 5 H 2 Cl 10 S, 39%) ); 1 HNMR (DMSO-d 6) delta, 8.80 (br s, alternating), 8.42 (1H, d, J = 1.8 Hz), 8.04 (1H, dd, J = 9.0, 5, 8 Hz), 7.80 (1H, dd, J = 10.5, 2.1 Hz), 7.74 (1H, br s), 7.30 (br s, alternating), 6.74 (1H, ddd, J = 10.1, 9.0, 2.1 Hz) and 5.00 (br s, alternating); ir (potassium bromide): 3392, 3242 (br), 3112, 1743, 1588, 1381, 1182 and 838 cm -1.

EXAMPLE 42 5-Trifluoromethyl-3- (4-chloro-2-tenowl) -2-oxoindole-1-carboxamide The experimental method used to prepare the title compound was based on the procedure of Example 31. A sample of 388 mg (2.39 mmol) of 4-chloro-2-thiophenecarboxylic acid (prepared by Iriarte, J. et al., J. Het. Chem., 13, 393 (19769)) was converted to acyl imidate-35. by reacting with 420 mg (2.59 mmol) of 54 106459 1,1'-carbonyldiimidazole The 4-chloro-2-thiophene (1-imidazo) carboxamide intermediate was directly attached to 486 mg (1.99 mmol) ) with 5-trifluoromethyl-2-oxoindole-1-carboxamide in the presence of 657 mg (5.37 mmol) of 4- (N, N-5-dimethylamino) pyridine to give 634 mg (1.63 mmol, 82%) of the title as a yellow solid, mp 164-166 ° C.

Analysis: Calculated for C 15 H 8 ClF 3 N 2 O 3 S: C, 46.34; H, 2.07; N, 7.21%. Found: C, 46.29; H, 2.07; N, 7.79%.

EIMS 10 (m / z): 388/390 (M +, 7%), 345/347 (NT-CONH, 25%), 227 (M + -CONH-CH 4 H 3 Cl 1, base) and 145/147 (C 5 H 2 Cl 2 S, 26%). ; 1 HNMR (DMSO-d 6) delta, 9.10 (br s, alternating), 8.63 (1H, d, J = 1.1 Hz), 8.46 (1H, S), 8.20 (1H, d) , J = 8.4 Hz), 7.69 (1H, d, J = 1.1 Hz), 7.30 (br s, alternating), 7.20 (1H, dd, J = 8.4, 1.5 Hz) and 5.28 (br s, alternating); ir (potassium bromide): 3397, 3233 (br), 1747, 1583, 1324, 1270, 1188 and 1122 cm @ -1.

EXAMPLE 43 6-Chloro-3- (4-chloro-2-tenowl) -2-oxoindole-1- (N-ethyl) carboxamide The title compound was prepared according to the experimental procedure described in Example 31. Acyl activation of 412 mg (384 mg) of 4-chloro-2-thiophenecarboxylic acid (prepared according to the method described by Iriarte, J. et al., J. het. Chem., 13, 393 (1976)) with 412 mg (2.54 x 25 mmol) 1,1'-carbonyldiimidazole gave the corresponding reactive acyl imidazole, which was used directly and fixed with 466 mg (1.95 mmol) of 6-chloro-2-oxoindole-1- ( N-ethyl) carboxide in the presence. 644 mg (5.27 mmol) of 4- (N, N-dimethylamino) pyridine to give 30,445 mg (59%) of a crude yellow solid. Recrystallization I gave the pure title compound (200 mg, 0.552 mmol, 27% yield) as a yellow crystalline solid, m.p. 164-166 ° C (acetic acid).

Analysis: Calculated for C 16 H 12 Cl 2 N 2 O 3 S: C, 50.14; H, 35 3.16; N, 7.31%. Found: C, 49.95; H, 3.01; N, 7.21%.

55 106459 E IMS (m / z): 382/384/386 (M + 5%), 311/313/315 (M + -C 3 H 5 NO, 21%), 193/195 (M + -C 3 H 5 NO / C 4 H 3 ClS, base) and 145 / 147 (C 5 H 2 Cl 10 S, 40%); 1 HNMR (DMSO-d 6) delta, 9.43 (br s, alternating), 8.34 (1H, d, J = 1.8 Hz), 8.12 (1H, d, J = 1.9 Hz), Δ 8.04 (1H, d, J = 8.2 Hz), 7.74 (1H, br s), 7.04 (1H, dd, J = 8.2, 1.9 Hz), 4.92 (br s, alternating), 3.29 (2H, br g, J = 7.3 Hz) and 1.13 (3H, t, J = 7.3 Hz); ir (potassium bromide): 3336, 3084, 1720, 1530, 1375, 1196 and 809 cm -1.

EXAMPLE 44 10 5-Fluoro-3- (4-chloro-2-tenowl) -2-oxoindole-1- (N-t-butyl) carboxamide The title compound was prepared by the method of Example 31. A sample of 390 mg (2.40 mmol) of 4-chloro-2-thiophenecarboxylic acid (prepared according to the procedure described by Iriarte, J. et al., J. Het Chem., 13, 393 (1976)) was reacted with 481 mg. (2.60 mmol) of 1,11-carbonyldiimidazole to give the intermediate acylimidazole, which was added slowly to a solution of N, N-dimethylformamide in 500 mg (2.00 mmol) of 5-fluoro-2-oxo 20 dol-1- (Nt-butyl) carboxamide and 659 mg (5.39 mmol) of 4- (N, N-dimethylamino) pyridine. Acid acceleration followed by recrystallization gave the title compound (260 mg, 0.66 mmol, 33% yield) as a yellow solid, m.p. 202-205 ° C (acetic acid).

Analysis: Calculated for C 18 H 16 ClFN 2 O 3 S: C, 54.75; H, 4.08; N, 7.10%. Found: C, 54.21; H, 3.76; N, 6.94%. E IMS (m / z): 394/396 (M + 1%), 295/297 (M + -C 5 H 9 NO, 28%), 177 (M + -C 5 H 9 NO-C 4 H 3 Cl 1, base) and 145/147 (C 5 H 2 Cl 2 S, 24%). ; 1 HNMR (DMSO-d 6) delta, 9.55 (br s, alternating), 8.37 (1H, d, 30 J = 1.1 Hz), 8.05 (1H, dd, J = 9.0, δ , 2 Hz), 7.81 (1H, dd, J = 10.5, 2.0 Hz), 7.73 (1H, br s), 6.73 (1H, ddd, J = 10.5, 9 , 0, 2.0 Hz), 4.13 (br s, alternating) and 1.38 (9H, s); ir (potassium bromide): 3305, 3075, 2988, 1721, 1615, 1548, 1193 and 835 cm @ -1.

35 56 106459 EXAMPLE 45 6-Chloro-3- (4-chloro-2-tenowl) -2-oxoindole-1-carboxamide

The test method for the preparation of the title compound was based on the method of Example 31. A portion of 463 mg (2.85 mmol) of 4-chloro-2-thiophenecarboxylic acid (prepared according to the procedure described by Iriarte, J. et al., J. Het. Chem., 13, 393 (1976)) was converted to acylimidazole by administration. with 500 mg (3.09 mmol) of 1,1'-car-10-butyldiimidazole. The 4-chloro-2-thiophene (1-imidazo) carboxamide intermediate was directly attached with 500 mg (2.37 mmol) of 6-chloro-2-oxoindole-1-carboxamide in the presence of 783 mg (6.41 mmol). ) 4- (Ν, Ν-dimethylamino) -pyridine to give 665 mg of a crude green-yellow solid. Recrystallization gave 450 mg (1.27 mmol, 53% yield) of the pure title compound as a yellow solid, m.p. 231-233 ° C (acetic acid).

Analysis: Calculated for C 14 H 8 Cl 2 N 2 O 3 S: C, 47.34; H, 2.27; N, 7.89%. Found: C, 47.11; H, 2.11; N, 7.73%. 20 E IMS (m / z): 354/356/358 (M + 5%), 311/313/315 (M + -CONH, 15%), 193/195 (M + -CONH-C 4 H 3 Cl, S), and 145 / 147 (C 5 H 2 Cl 10 S, 49%); 1 HNMR (DMSO-d 6) delta, 8.80 (br s, alternating), 8.31 (1H, d, J = 1.1 Hz), 8.10 (1H, d, J = 2.2 Hz), 8.03 (1H, d, J = 8.2 Hz), 7.74 (1H, br s), 7.36 (br s, alternating), 7.04 (1H, dd, J = 8.2) , 2.2 Hz) and 5.32 (br s, alternating); ir (potassium bromide): 3398, 3191 (br), 1749, 1726, 1587, 1368, 1196 and 807 cm @ -1.

EXAMPLE 46 3- (4-Chloro-2-tenowl) -2-oxoindole-1-carboxamide The title compound was prepared according to the procedure for Example 31. . A portion of 831 mg (5.11 mmol) of 4-chloro-2-thiophenecarboxylic acid (prepared according to the procedure described by Iriarte, J. et al., J. Het. Chem., 13, 393 (1976)) was combined with 897 mg. (5.53 mmol) of 1,1'-carbonyl-35-diimidazole in 5 mL of Ν, Ν-dimethylformamide and imidazole was directly attached with 750 mg (4.26 mmol) of 2- oxoindole-1-carboxamide in the presence of 1.40 g (11.49 mmol) of 4- (N, N-dimethylamino) pyridine. The resulting crude yellow solid (803 mg, 59% yield) was recrystallized from acetic acid to give 376 mg (1.17 mmol, 27% yield) of flaky yellow crystals, m.p. 221-222 ° C.

Analysis: Calculated for C 14 H 9 ClN 2 O 3 S: C, 52.42; H, 2.83; N, 8.74%. Found: C, 52.04; H, 2.62; N, 8.51%.

10 EIMS (m / z): 320/322 (M +, 3%), 277/279 (M + -CONH, 6%), 159 (M + -CONH-C 4 H 3 Cl 1, base), and 145/147 (CsH 2 ClOS, 50%). ; 1 HNMR (DMSO-d 6) delta, 8.10 (1H, br s), 8.09 (1H, d, J = 8.5 Hz), 7.95 (br s), 7.83 (br s), 7.75 (br s), 7.30 (br), 7.08 (br), and 4.92 (br s, alternating); ir (potassium bromide): 3392, 153243 (br), 3117, 1744, 1591, 1379, 1268 and 1183 cm @ -1.

EXAMPLE 47 5-Fluoro-6-chloro-3- (4-chloro-2-tenowl) -2-oxo-indole-1-carboxamide

The title compound was prepared using the procedure of Example 31. A sample of 427 mg (2.62 mmol) of 4-chloro-2-thiophenecarboxylic acid (prepared according to the procedure described by Iriarte, J. et al., J. Het. Chem., 13, 393 (1976)) was reacted with 461 mg. mg (2.84 mmol) of 1,1'-carbonyldiimidazole in 5 mL of N, N-dimethylformamide to give the activated acylimidazole. Slow addition of acylimidazole to 500 mg (2.19 mmol) of 5-fluoro-6-chloro-2-oxoindole-1-carboxamide in Ν, Ν-dimethylformamide and 721 mg (5.90 mmol) of 4- (N , N-dimethylamino) -pyridine gave a crude yellow solid (635 mg, 30 78% yield) after acidic acceleration. Recrystallization from acetic acid gave a tan solid crystalline solid (390 mg, 1.05 mmol, 48% yield), m.p. 235-237 ° C.

Analysis: Calculated for C 14 H 7 Cl 2 FN 2 O 3 S: C, 45.05; H, 35 1.89; N, 7.51%. Found: C, 44.81; H, 1.87; N, 7.44%.

58 106459 EIMS (m / z): 372/374/376 (M + 7%), 329/331/333 (M + -CONH, 23%), 211/213 (M + -CONH-C 4 H 3 ClS, base) and 145 / 147 (C 5 H 2 Cl 2 S, 33%); 1 HNMR (DMSO-d 6) delta, 9.00 (br s, alternating), 8.62 (1H, d, J = 1.2 Hz), 8.14 (1H, d, J = 7.2 Hz) , 8.02 (1H, d, J = 11.2 Hz), 7.69 (1H, d, J = 1.2 Hz), 7.25 (br s, alternating) and 4.32 (br s, alternating) ; ir (potassium bromide): 3386, 3231, 1715, 1610, 1580, 1464, 1366 and 1183 cm @ -1.

EXAMPLE 48 6-Chloro-3- (5-bromo-3-furowl) -2-oxoindole-1-carboxamide

The test procedure used to prepare the title compound was based on the procedure of Example 31. A portion of 750 mg (3.93 mmol) of 5-bromo-3-furoic acid (prepared according to the method described by Amaral, 15 L. et al., JOC, 41, 2350 (1976)) was converted to acylimidazole by reacting 690 mg: with n (4.25 mmol) 1,11-carbonyldiimidazole. The intermediate 5-bromo-3-furan (1-imidazo) carboxamide was directly attached with 689 mg (3.27 mmol) of 6-20 chloro-2-oxoindole-1-carboxamide in the presence of 1.08 g (8, 83 mmol) of 4- (N, N-dimethylamino) pyridine to give 500 mg (40% yield) of a crude green-yellow solid. Recrystallization gave 143 mg (0.37 mmol, 11% yield) of the pure title compound as a greenish solid, m.p. 232-234 ° C (acetic acid).

Analysis: Calculated for C 14 H 8 BrClN 2 O 4: C, 43.83; H, 2.10; N, 7.30%. Found: C, 43.54; H, 2.00; N, 7.19%. EIMS (m / z): 382/384/386 (M +, 11%), 339/341/343 (M + -CONH, 30%), 260/262 (M + -CONH-Br, 90%), 232/234 (unknown, 90% 90), 193/195 (M + -CONH-C 4 H 3 BrO, 92%) and 173/175 (C 5 H 2 Br 2 O, V 'base); 1 HNMR (DMSO-d 6) delta, 8.43 (br s, alternating), 8.40 (1H, br s), 8.14 (1H, d, J = 1.8 Hz), 7.92 (1H, d, J = 8.2 Hz), 7.54 (br s, alternating), 7.15 (1H, dd, J = 8.2, 1.9 Hz), 6.96 (1H, d, J = 1, 8 Hz) and 4.04 (br s, alternating 591064559); ir (potassium bromide): 3470, 3389, 3305 (br), 1757, 1718, 1579, 1387, 1198, 1122 and 915 cm -1.

EXAMPLE 49 5-Fluoro-3- (5-bromo-2-furoyl) -2-oxoindole-5 1- (N-t-butyl) carboxamide

The experimental procedure of Example 31 was used to prepare the title compound. A sample of 641 mg (3.36 mmol) of 5-bromo-3-furoic acid (prepared according to the method described by Amaral, L. et al., JOC, 41, 2350 (1976)) was reacted with 590 mg (3, 64 mmol) of 1,1'-carbonyldiimidazole to give the intermediate acylimidazole, which was added slowly to a solution of N, N-dimethylformamide in 700 mg (2.80 mmol) of 5-fluoro-2-oxoindole-1- (Nt). butyl) carboxamide and 923 mg (7.56 mmol) of 4- (N, N-di-15-methylamino) pyridine. Acid acceleration afforded the crude title compound (777 mg, 66% yield) as a tan solid. Recrystallization gave 256 mg (0.60 mmol, 22% yield) of an off-white crystalline solid, m.p. 190-192 ° C (acetonitrile).

Analysis: Calculated for C 18 H 16 BrFN 2 O 4: C, 51.08; H, 3.81; N, 6.62%. Found: C, 50.98; H, 3.57; N, 6.61%. EIMS (m / z): 423/425 (M +, 1%), 323/325 (M + -C 5 H 10 NO, 35%), 244 (M + -CSH 10 NO-Br, base), 216 (unknown, 95%) and 57 (C 4 H 9/99%}; 1 HNMR (DMSO-d 6) delta, 9.07 (br s, alternating), δ 8.44 (1H, d, J = 1.4 Hz), 8.10 (1H, dd, J = 9.0, 4.1 Hz), 7.67 (1H, dd, J = 9.5, 2.8 Hz), 6.96 (1H, d, J = 1.4 Hz), 6, 91 (1H, ddd, J = 9.5, 9.0, 2.8 Hz), 3.93 (br s, alternating) and 1.36 (9H, s); ir (potassium bromide): 3300, 3205, 2960, 1720, 1550, 1179 and 820 cm @ -1.

EXAMPLE 50; 5-Chloro-3- (5-bromo-3-tenowl) -2-oxoindole-1-carboxamide

The title compound was prepared according to the procedure of Example 31. A portion of 100 g (4.83 mmol) of 5-bromo-3-thio-35-phenocarboxylic acid (prepared by the method described by J. Am. Chem. Soc., 76, 601060454545 (1954)) was combined. With 848 mg (5.23 mmol) of 1,1'-carbonyldiimidazole in 5 mL of Ν, Ν-dimethylformamide and the imidazole intermediate was directly attached with 848 mg (4.02 mmol) of 5-chloro-2-oxo-5 soindole-1-carboxamide in the presence of 1.33 g (10.89 mmol) of 4- (N, N-dimethylamino) pyridine. The resulting crude green solid (1.22 g, 76% yield) was recrystallized to give 540 mg (1.35 mmol, 34% yield) of a yellow solid, m.p. 238-240 ° C (acetic acid-10 po).

Analysis: Calculated for C 14 H 8 BrClN 2 O 3 S: C, 42.07; H, 2.02; N, 7.01%. Found: C, 42.26; H, 1.98; N, 6.99%.

E IMS (m / z): 398/400/402 (M \ 39%), 355/357/359 (M + -CONH, base), 276/278 (M + -CONH-Br, 30%) and 193/195. (M + -COONH-C 1 HNMR (DMSO-d 6) delta, 8.36 (br s, alternating), 8.09 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 1.6 Hz), 7.85 (1H, d, J = 2.0 Hz), 7.52 (br s, alternating), 7.49 (1H, d, J = 1.6 Hz), 7.16 (1H, dd, J = 8.5, 2.0 Hz) and 3.73 (br s, alternating); ir (potassium bromide): 3389, 3218 (br), 1744, 20 1585, 1391, 1272 and 1194 cm -1.

EXAMPLE 51 5-Chloro-3- (5-chloro-2-thiopheneacetyl) -2-oxoindole-1-carboxamide

The title compound was prepared using the procedure of Example 31. A sample of 1.00 g (5.66 mmol) of 5-chloro-2-thio-phenacetic acid (prepared according to the procedure described by Ford, et al., J. Am. Chem. Soc., 72, 2109 (1950)) was administered. reaction with 995 mg (6.13 mmol) of 1,1'-carbonyldiimidazole in 5 mL of Ν, Ν-dimethylformamide 30 to give the activated acylimidazole. Slow addition of acylimidazole to 994 mg (4.72 mmol) of 5-chloro-2-oxoindole-1-carboxamide in Ν, Ν-dimethylformamide and 1.44 g (11.79 mmol) of 4- (N, N-dimethylamino) pyridine gave a crude tan solid (1.52 g, 87% yield). Recrystallization from acetic acid gave the title compound 1106459 as a gray crystalline solid (387 mg, 1.05 mmol, 22% yield), m.p. 238-241 ° C.

Analysis: Calculated for C 15 H 10 Cl 2 N 2 O 3 S: C, 48.74; H, 2.68; N, 7.51%. Found: C, 48.79; H, 2.73; N, 7.59%.

EIMS (m / z): 368/370/372 (M +, 4%), 324/326/328 (M + -CONH, 4%), 237/239 (M + -C 5 H 4 Cl 1 S, 49%) and 194/195 ( M + -CONH- C 5 H 4 Cl 1 (base); 1 HNMR (DMSO-d 6) delta, 8.52 (br s, alternating), 8.07 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 2.6 Hz), 7.12 (1H, dd, J = 8.5, 2.6 Hz), 6.94 (1H, d, J = 4.1 Hz), 6.90 (1H, d, J = 4.1) Hz), 4.43 (2H, s) and 3.71 (br s, alternating); ir (potassium bromide): 3392, 3249 (br), 1724, 1695, 1664, 1582, 1381, 1287, 1202, 995 and 847 cm -1.

EXAMPLE 52

Methyl 3-ethoxy-5-isooxazolecarboxylate A stirred suspension of 3.53 g (24.67 mmol) of commercial methyl 3-hydroxy-5-isooxazole carboxylate in 50 mL of methylene chloride was treated dropwise at room temperature with of triethyloxonium tetrafluoroborate (5.62 g, 29.60 mmol) dissolved in 30 ml of methylene chloride. After stirring overnight, the solution was washed with water (2 x 30 mL), 5% sodium bicarbonate (2 x 30 mL), and once more with water. The organic layer was dried (magnesium sulfate) and evaporated in vacuo to give the title compound (3.61 g, 86% yield) as a bright yellow solid, m.p. 77-79 ° C. 1 HNMR (DMSO-d 6) delta, 6.65 (1H, s), 3.93 (2H, q, J = 7.4 Hz), 3.87 (3H, s) and 1.21 (3H, t, J = 7.4 Hz); EIMS (m / z): 171 (M + 48%), 156 (M + -CH 3, 4%), 143 (C 5 H 5 NO 4, 31%), 112 (C 4 H 2 NO 3, 12%) and 69 (C 3 H 3 NO, base); ir (potassium 30 bromide): 3105, 1744, 1611, 1441, 1241, 1106, 974 and T 797 cm -1.

EXAMPLE 53 3-Ethoxy-5-iso-oxazole-carboxylic acid A stirred solution of methyl 3-ethoxy-5-iso-oxazole-carboxylate 106459 (3.00 g, 17.53 mmol) prepared as in Example 52 (75 mL) 2 N sodium hydroxide, stirred at room temperature for 10 minutes, cooled in an ice bath and acidified to pH 3 with concentrated hydrochloric acid. The precipitated solid was then collected by filtration. The remaining desired product was isolated by saturating the aqueous filtrate with solid sodium chloride and extracting with ethyl acetate (3 x 100 mL). Overall, 2.46 g (89% yield) of the title compound was obtained in this way. A sample was recrystallized from acetonitrile, m.p. 210-213 ° C.

Analysis: Calculated for C 6 H 7 NO 4: C, 45.86; H, 4.49; N, 8.92%. Found: C, 45.80; H, 4.32; N, 8.87%. EIMS (m / z): 157 (M + -CH 3, 22%), 129 (C 4 H 3 NO 4, 70%), 112 (C 4 H 2 NO 3, 15%) and 69 (C 3 H 3 NO, base); 1 H NMR (DMSO-d 6) delta, 6.51 (1H, 15 s), 3.91 (2H, q, J = 7.4 Hz) and 1.20 (3H, t, J = 7.4 Hz); ir (potassium bromide): 3136 (br), 1726, 1626, 1238 and 984 cm @ -1.

EXAMPLE 54 5-Chloro-3- (3-ethoxy-iso-oxazol-5-yl) -2-oxo-20-indole-1-carboxamide

The experimental procedure of Example 31 was used to prepare the title compound. A sample of 1.50 g (9.55 mmol) of 3-ethoxy-5-isooxazole carboxylic acid prepared according to Example 53 was reacted with 1.68 g (10.34 mmol) of 1,1'-carbonyldiimidazole. to give the acylimidazole intermediate, which was added slowly to N, N-dimethylformamide, 1.68 g (7.96 mmol) of 5-chloro-2-oxoindole-1-carboxamide and 2.62 g (21.48 g). mmol) 4- (N, N-dimethylamino) pyridine. Acid acceleration gave the title compound as an orange-yellow solid (2.43 g, 87% yield). Suspension in hot glacial acetic acid followed by filtration gave the pure title compound as a bright yellow solid (1.75 g, 5.00 mmol, 63% yield), m.p. 260-262 ° C.

63 106459

Analysis: Calculated for C 18 H 12 ClN 3 O 5: C, 51.51; H, 3.46; N, 12.01%. Found: C, 51.57; H, 3.22; N, 11.89%. E IMS (m / z): 349/351 (M +, 10%), 306/308 (M + -CONH, 45%), 235/237 (M + -C 5 H 8 NO 2, 20%), and 193/195 (M + -CONH). C5H7NO2,? 44%); 1 HNMR (DMSO-d 6) delta, 8.76 (br s, alternating), 8.01 (1H, d, J = 8.6 Hz), 7.97 (1H, d, J = 2.2 Hz), 7.30 (br s, alternating), 6.96 {1H, dd, J = 8.6, 2.2 Hz), 6.30 (1H, s), 4.98 (br s, alternating), 3 , 86 (2H, q, J = 7.4 Hz) and 1.21 (3H, t, J = 7.4 Hz); ir (potassium bromide): 3315, 3228 (br), 10 1748, 1673, 1549, 1370, 843 and 819 cm -1.

EXAMPLE 55

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

A stirred suspension of 5-methoxycarbo-15-yl-2-thiophenecarboxylic acid (1.50 g, 8.06 mmol) in 15 mL of thionyl chloride was refluxed for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to an almost colorless oil which crystallized in vacuo. This solid was dissolved in 5 mL of chloroform-20 and added dropwise at room temperature to a stirred mixture of acetamide dioxide (prepared by the method described by Eloy, et al., Helv. Chim. Acta., 45, 441 (1962)) (657). mg, 8.86 mmol) and triethylamine (897 mg, 1.24 mL, 8.86 mmol) in 30 mL of chloroform. After the addition was complete, the solution was stirred at room temperature for one hour and washed with water (2 x 20 mL). The organic layer was dried (magnesium sulfate), evaporated and the residue was triturated with toluene to give O- (2-methoxycarbonyl-5-tenoyl) acetamidoxime intermediate, 1.55 g (80% yield), as a white solid, m.p. 150-152 ° C. 1 HNMR (DMSO-d 6) delta, 8.03 (1H, d, J = 3.9 Hz), 7.83 (1H, d, J = 3.9 Hz), 6.54 (br s, alternating), 3.85 (3H, s) and 1.80 (3H, s). This material was used without further purification.

A portion of 1.43 g (5.90 mmol) of O- (2-methoxycarbonyl-5-tenoyl) acetamide oxime was suspended in 75 mL of toluene and heated to reflux overnight. The solvent was removed in vacuo and the residue was triturated with pie-5 square toluene to give 1.10 g (83%) of the title compound as an off-white crystalline solid, m.p. 154-156 ° C. This material was used directly without further purification. Exact Mass: 224.0241, Calculated: 224.0256. E IMS (m / z): 224 (M +, 98%) and 193 (M + -CH 3 O, base); 1 H NMR (DMSO-d 6) delta, 8.01 (1H, d, J = 4.3 Hz), 7.92 (1H, d, J = 4.3 Hz), 3.88 (3H, s) and 2.41 (3H, s).

EXAMPLE 56 5- (3-Methyl-1,2,4-oxadiazol-5-yl) -2-thiophenecarboxylic acid 15 A mixture of methyl 5- (3-methyl-1,2,4- oxadiazol-5-yl) -2-thiophenecarboxylate (1.09 g, 4.86 mmol) in 35 mL of 2N sodium hydroxide, diluted with 5 mL of ethanol and heated at 65 ° C for 35 minutes. The solution was cooled in 20 ice baths and acidified to pH 2 with concentrated hydrochloric acid. Filtration and drying gave 870 mg (85% yield) of the title compound as a light-colored solid. The analytical sample was recrystallized from methanol, m.p. 226-228 ° C.

Analysis: Calculated for C 8 H 6 N 2 O 3 S: C, 45.70; H, 2.88; N, 13.33%. Found: C, 45.57; H, 2.75; N, 13.37%. EIMS (m / z): 210 (M +, base) and 153 (M + -C 2 H 3 NO, 99%); 1 HNMR (DMSO-d 6) delta, 7.97 (1H, d, J = 3.9 Hz), 7.82 (1H, d, J = 3.9 Hz) and 2.40 (3H, s); ir (potassium bromide): 3112 (br), 301699, 1289, 1112 and 840 cm @ -1.

♦ · »

Claims (7)

65 106459 Claim A process for the preparation of 3-substituted 2-oxoindole derivatives of the formula I 5 (CH 2) n -Q x -τ'0-1-1 m y y Wherein X is H, F, Cl, Br, (Cx-C6) alkyl, (C3-C8) cycloalkyl-15, NO2, CF3, CN, SH, S (O) mR3, OR4, COR4 or CONR4R5 ; Y is H, F, Cl, Br, (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, NO 2, CF 3, CN, SH, S (O) q R 17, OR 18 or CONR 18 R 19; R 1 is H; R 20 is COR 6, CO 2 NR 7 R 8, phenyl or mono- or disubstituted phenyl wherein the substituent (s) is each Cl, F, Br, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy or CF 3; Q is KA 0 \ B 1 - Q 2 -A 2; 25 A is H, F, Cl, Br, I, CF 3, OR 9, S (O) p R 10, COOR 11, CONR 9 R 11, CN, NO 2, COR 10, CH 3 OR 11, OCOR 10, NR 9 RX 1, N (R 9) CO 10, SO .. 30 // - 1 r = x * X2 IL O * "<.i XN - N 35 NNN 12 / N ^ | 12 -O '<?' -O '66 106459 -0' Ό- '5 B is H, F, Cl, Br, I, CF 3, OR 13, S (O) t R 14, COOR 15, CONR 13 R 15, CN, NO 2, COR 14, CH 2 OR 15, OCOR 14, NR 13 R 15, N (R 13) CO 3 R 15 or SO 2 NR 13 R 15, provided that A and B cannot both be H, 10 or A and B together are bonded to the same carbon of the Q 4 ring and form an oxo group, or when A is not H, B is as above or (C 1 -C 4) alkyl, A 1 is F, Cl, Br, I, CF 3, OR 9, S (O) p R 10, COOR 11, CONR 9 R 11, CN, NO 2, COR 10, CH 3 OR 11, OCOR 10, NR 9 Ru, N (R 9) COR or 15 S02NR9R11; Q1 is O, 0.0. 20 ooo. 25 O 'OO' 30 o o · o 35 „1 λ rw" i - · M or M Q2 is 67 1 0 6 4 5 9 H o = \ '4 1 5 NN / - r / -N // \\ AA or // \\ \ / 3 '\ / NNJ »w Nf / 10 m, n, p, q and t are each zero, one or two; W and Z are each O, S or NR11; W 1 and W 2 are each O, S or NR 10 with the proviso that when either of W 1 and W 2 is O, S or NR 10, the other is O or S; R 3, R 8, R 10, R 14 and R 17 are each (C 1 -C 8) alkyl or phenyl; R 5, R 8, R 11, R 1 S and R 19 are each H, (C 1 -C 6) alkyl or phenyl; R 4, R 7, R 9, R 13 and R 18 are each H or (C 1 -C 6) alkyl; and R12 is H, F, Cl, Br, CF3 or (Cx-C6) alkyl; characterized in that the process comprises reacting a compound of formula II Q- (CH 2) n COOH (II), wherein Q and n are as defined above, with a molar excess of 1,1'-carbonyldiimidazole in a reaction inert solvent in an inert atmosphere and reacting the product thereof with a substituted 2-oxoindole of formula IV CDu »Y iso wherein X, Y and R20 are as defined above in the presence of a basic agent at about 0-50 ° C in a reaction inert solvent 35 in an inert atmosphere . • <68 1 0 6 4 5 9 Förfarande för framställning av 3-substituerade 2-oxoindolderivat med formeln I 5 x Τ ^ ιΊ — i ° "rI (i) 10 liters of B20 are X, H, F, Cl, Br, (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, 15 NO 2, CF 3, CN, SH, S (O) m R 3, OR 4, COR 4 ell CO 2 NR 4 R 5; Y is H, F, Cl, Br, (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, NO 2, CF 3, CN, SH, S (O) q R 17, OR 18 eller CONR 18 R 19; R1 is H; R20 and COR6, CONR7R8, phenyl eller mono-alkyl disubstituted phenyl, phenyl substituents substituted with C1, F, Br, (C1-C8) alkyl, (C1-C8) alkoxy-CF3; Q är l / A 0 * q2.a1. 25 eller U 'A is H, F, Cl, Br, I, CF3, OR9, S (O) pR10, COOR11, CONR9R11, CN, no2, cor10, ch2oru, ocor10, nr9r1x, n (r9) cor11, SOaNR ^. 11, <> * 12 '<Γ'Ι -N 35 N__ ,, N N 12 12 -Cr <? ' irv / r-Q 69 ioGnJ? O * · "· <> ' B is H, F, Cl, Br, I, CF3, OR13, S (O) t R14, C00R15, CONR13R15, CN, NO2, COR14, CH2OR15, OCOR14, NR13R15, N (R13) COR15 eller SO2NR13R15; under förutsättning att bäde A och B inte r H, eller A och B å tillammans bundna account samma ringkol i Q1 10 och bildar oxogruppen, eller N inte H, dä betecknar B samma som ovan definierats eller är (C1-C4) alkyl ; A1 is F, Cl, Br, I, CF3, OR9, S (O) pR10, COOR11, C0NR9R11, CN, NO2, COR10, CH3OR11, OCOR10, NR9R1X, N (R9) COR11 eller SO3NR111; 15 Q1 Business O. O '. o. 20 0.0. o. 25 O 'O' O '; - "Ö 0 'O 0 Q2 är 70 106459 <τ · <D · 5 N Ν / -r / -Ν // \\ Λη or // \\ V y - N Ν Η 3; 10 m, n, p , q och and var och en zero to eller; W och Z and O O, S eller NR11; W1 and W2 and O O, S eller NR10 under förutsättning att dä den ena av W1 and W2 O, S eller NR10 denotes O, R3, R6, R10, R14 and R17 are selected from (C1-C8) alkyl eller phenyl; R8, R8, R11, R15 and R19 are selected from H, (Ci) -Cg) alkyl eller phenyl; R4, R7, R9, R13 and R18 are selected from the group consisting of C1-C8 alkyl, and R12 is H, F, Cl, Br, CF3 eller 20 (C1-C8) alkyl; kännetecknat av att förfarandet inclu-derar att en for mediating forln II II- (CH2) nCOOH (II) 25 colors Qoochromes are defined, the reagent is used to make 1,1'-carbonyldiimidazole. tionsinert lösningsmedel i inert atmosphere och att prodrug reagerar med enubstituted 2-oxoindole med for-30 mein IV χ -; Y R20 35 color X, Y and R20 are som ovan defin The device is capable of reacting with an alkaline substance at a temperature of about 0-50 [deg.] C. in an inert atmosphere.