CS252828B2 - Method of n,3-disubstituted 2-oxindole-1-carboxamides production - Google Patents

Description

The present invention provides novel chemical compounds. In particular, the novel compounds are 2-oxindole-1-carboxamide derivatives which are further substituted at the 3-position with an acyl group and ⁷ on the nitrogen of the carboxamide moiety with an alkyl, cycloalkyl, phenyl or substituted phenyl group. These novel compounds are inhibitors of cyclooxygenase and lipoxygenase enzymes.

The compounds of the invention exhibit analgesic activity in mammals, especially humans, and are therefore useful for acute administration for the relief or removal of pain, such as pain occurring in patients after surgery or trauma.

In addition to its utility for acute administration to alleviate or eliminate pain, the compounds of the invention may be used for chronic administration to mammals, particularly humans, to alleviate the symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

The present invention relates to novel 2-oxindole-1-carboxamide derivatives of formula (I)

in which

X represents a hydrogen, fluorine or chlorine atom, a trifluoromethyl group, a nitro group, a C2 -C4 alkanoyl group or a benzoyl group and

Y represents a hydrogen, fluorine or chlorine atom;

X and Y, when attached to adjacent carbon atoms, together form the bivalent radical Z ⁵ w - »w -

C 'in (Z) (Z °) in which W represents an oxygen or sulfur atom,

Selected from groups comprising radicals of formulas C. C. C· (Z ¹ ) (Z ² ) (Z ³ )

R ¹ represents an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group optionally substituted by a fluorine or chlorine atom, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety optionally substituted on the phenyl chloro or fluoro, C 1 -C 3 phenoxyalkyl, bicyclo [2.2.1] heptan-2-yl, furyl radical optionally substituted with C 1 -C 3 alkyl, carbon, thienyl radical , a thienylmethyl radical, a tetrahydrofuranyl radical or a pyridyl radical and

R represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a benzyl group or a radical of formula

where

4

R and R are independently selected from the group consisting of hydrogen, fluorine and chlorine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and trifluoromethyl, and pharmaceutically acceptable base salts thereof.

The compounds of formula I are effective as analgesic agents and as agents for the treatment of inflammatory diseases such as arthritis. Accordingly, the invention also provides a method of inducing analgesia in a mammal, particularly a human, a method of treating inflammatory diseases in a mammal, particularly a human, and a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

A preferred group of compounds of the invention are those compounds of formula I wherein X and Y are independently selected from the group consisting of hydrogen, 5-fluoro,

2

S-fluoro, 5-chloro, 6-chloro, 5-trifluoromethyl and 6-trifluoromethyl, and R and R are as defined above. Of this preferred group, those compounds in which R @ 1 is 2-phthyl, Z-thienyl or (2-thienyl) methyl are particularly preferred.

Particularly preferred individual compounds of the invention are:

N-tert-butyl-5-chloro-3- (2-juloyl) -2-oxazol-1-carboxylic acid (I: X-5-chloro, Y = hydrogen,

2

R @ ¹ = Z-furyl (R @ ² -). '

N-5-terc.OujtlL · flttr-3- (2-furtyl) 22l0Xěddol L-kaotoaaiid (I: X - 5-fluoro, Y = H, ^{R 1} = R ^ fury ^ ² = t ^ u ^ l);

N-tert-ethyl-6-chloro-3- (2-henylyl) -2-oxidol-1-cartoaid (I: X = 6-chloro, Y = hydrogen,

2

^R1. = Phenylthio ^^ ^r ^ ^- t ^ tert. ^o utyl);

N- (4-iiUhhιtyffe-L-3- ^{(2 h} uno ^t -t) -2-tl txiě ^d · ^{t and} IC -l- oaaiid (I: X = H, Y = H, R ¹ = ^ TME ^- phenyl , R = 1 ^) and,

·· N ^{(2 -} -d ^Sf LtoR ^phenyl) L3- ⁽² - ^f trt ^yl) · -2ooxindtl-l- ^{and t} and ^s xxaii (I: ^X = hydrogen У »H ^R1 = ^R2 ^^ roar ~ ² ^ - ^ Ллг ^ пп! ¹ .

The compounds of formula (I) were named as 2-oxididol derivatives, which is the corresponding compound. formula II

Annagetická and ^r t ^t ináiёtlivá agents of formula I bear a carboxamide subosituent

1 of the formula -C (= O) -NH-R at the 1-position and the acyl subosituent of the formula -C (= O) -R at the 3-position 2-class (IIt), whereas the non-fused benzene ring may be further substituted by X and Y The radicals X and Y may be a certain monovalent substituent as defined above, or the symbols X and Y, attached to adjacent carbon atoms of the 2-thienyl-ring benzene ring, may form a bivalent Z moiety such that the Z moiety, together with the carbon atoms, which it is attached forms a fused karOoccýlický or hetur <lcyýlicrý ring. Konkrééní divalent radicals represented by Z (i.e. residues z1 to z3 Oyly already mentioned above. P ^ R ^ C ^ sst ^ avujelLL thus from the remainder ^mod orce Z ³ tv ° ^{of manufacture X} and ^Y ^ SJ ^ yet with the carbon atoms to Jrteé IAV are ^{plated .náiy, characterized} naJkondezovan ^CY LO) ^{to p} eiteiOvý ru ^H and ^Z is ^plated zlsyte of ^the formula ^Z-Y tvoV MboI ^X and ^Y Y s ^ρ t] ^ ^t with carbon atoms to which they are bonded, bo thi ^ window circle.

5

It should also be zdůraanit that of ^the RTD · Z represents a radical of the formula Z or Z 'may oyl the group with the meaning of Z is attached from two possible npůstOr. Thus napííUaS when X and Y nachhzzčí at carbon atoms 5 and 6 positions and poses a radical of formula ^Z1 include the ^b ecný Formula I and the ^O názledsjící formula

О

O = C-NH-R 2

Further, it will be appreciated that the analgesic and anti-inflammatory active compounds of formula (I)

2 according to the invention, wherein X, Y, R and R 'are as defined above, are capable of enolization and therefore can exist in one or more tautomeric (enol) forms. All such tautomeric (enol) forms of the compounds of formula I are within the scope of the invention.

Compounds of general formula

I are prepared from the corresponding 2-oxindole of formula III

(III) wherein X and Y are as defined above.

'2

This preparation is accomplished by introducing the substituent -C (= O) -NH-R at the 1-position and the substituent ^-c (= O) -r; ^{p y} ocations to 3. Said substituents may be introduced at any ^p ORAD That ^KŽ e method for preparing compounds of formula I may be performed in two variants, as is apparent from následuícího reaction scheme:

The present invention provides a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (V)

X

O = C-NH - R ² (V) kt.éiém> ϊ. as defined above, it is allowed to react in the solvent to react with an activated carboxylic acid derivative of the formula ## STR2 ##

^R] -C (= 0) -0H in which ^{R 1} has the meaning indicated ora ^h and the resulting product is optionally converted into a pharmaceutically acceptable salt thereof.

The second variant resulting from the above reaction scheme, resulting in the displacement of the -C (= O) -NH-R substituent at the i-position of the compound of formula IV, is the subject of our co-pending Czech patent specification.

In accordance with the ^invention were ostranní etězec ^of formula ^{-C (-} °) - ^R * having up] _oučenin ^y of general formula V by reaction with one introduces mooekvivalentem or slight excess of an activated carboxylic acid derivative of the formula R'-C (= O) OH , in the presence of up to 4 equivalents of the basic agent. Suitable inert solvents are those which dissolve at least one of the reactants and do not react adversely with either the reactants or the product. In practice, usually pouuívčjJí polar iprotická lip ^ (^ L ^ US (^ C ^ la _/ as N, N-ddmeehylformamid, N, N-dieeehllacetaeid, N meethlpplrolidon or dimeehhlsulftxid. The activation of the acid ^generally it formula R1-C ( = 0) 0H ou ^p is ^at ívají ^usually via MMTO ^. ^ for example, an ad may be generally ^u sing acid halides, for example acid chlorides, acid anhydrides symeerické formula

R ¹ -C (= O) -O-C (= O) -R ⁱ Low anhydride hindered carboxylic acid hindered anhydrides corresponding to the general formula

R ¹ -C (= O) -O- (= O) -R ⁵ wherein R 'represents a lower alkyl volume by volume, such as tert. and mixed carboxylic and carbonic anhydrides corresponding to the general formula

R ¹ -C (= 0) -0-C (= 0) -0R ⁶ wherein R ⁶ represents a ^{plurality of projections} it ^{harder for} a nominal in ^P inu. In addition, N-hydroxyidyl esters (such as N-hydroxyyuccinimide and N-hydroxydimethylsilyl), 4-nitrophenyl ester ester (such as 11-phenylphenyl esters) and 2,4,5-tricyclohexyl ester, and the like can be used.

The reaction between a compound of formula V with an activated acid derivative of formula ^R LG (= O) ^0H may be ^p OUZ ^of t Šúroltou variety ^b azickýc ^h ^ n ^ e ^ preferred Mzickými agents are typically tertiary am-reverse to such trimethylainin, treelhylaein , tributylamine, N-methylpiperidine, N-methylpiperidine and 4- ((, die-diethylamine) pyridine.

Reaction mmzi compound of formula V with an activated acid derivative of formula R ¹ -C (= O) OH, ^b is interpreted emb ^ i ^p r ⁱ te ^ o ^ ^ in dimensions; ^ L from -10 to ^-25 ° C . After standing for ^{R d} Oby usually ranges from 30 minutes to several hours. After completion of the reaction, the reaction medium is usually diluted with water and acidified, whereupon the reaction product can be isolated by filtration. The product can be distinguished by standard methods such as recrystallization.

The starting materials of formula V are prepared by reacting a compound of formula III with an isocyanate of formula r ² -N = C = O

Nejobvvykeji this reaction is conducted so as to brought into contact in substantially equimolar mnnžs ^with knows reaWních with ^l RES ^to the I-ncrt ^ him rozpouštětile incubator at about ^{d 5} 0 ^d ol ⁵ 0 ° C, The advantage ^d ou of ^{d 100 d} at ¹³⁰ ° C. Anema in ^{d p} ^ ertním řípaclě is meant a solvent dissolves ^kt ns rozpouUtí at least one reactant, which do not deleteriously react with either the reactants or the products. Typical usable solvents include aliphatic hydrocarbons such as octane, nonane, decane and decline, aromatic hydrocarbons such as benzene, chlorobenzene, toluene, xylene and tetraline, chlorinated hydrocarbons such as 1,2-di-benzoate, ethers such as tetrahydrofuran, di-oxane, 1,2-dimethoxyethane and di (2-methoxyltylether), and polar aprotic solvents such as N, N-dimethylloreateide, Ν, Ν-dimethylacidamide, N-dimethylproprolidone and dimethylsulfoxide. At temperatures of from ¹⁰⁰ to ¹³⁰ ° C, reaction times of about a few hours, for example 5 to 10 hours, are usually employed.

When a relatively non-reactive reaction solvent is used to react a compound of formula III with an isocyanate of formula R --N.dbd.C.dbd.O, the resulting product of formula V is usually from solution after completion of the reaction and after cooling the reaction to room temperature. excluded. Under these conditions, the product is generally isolated by filtration. However, if relatively polar solvents are used and the product is still in solution after completion of the reaction, it can be isolated by evaporation of the solvent. Alternatively, when water-miscible solvents are used, diluting the reaction medium with water precipitates the product and can be recovered by filtration. The reaction product of formula (V) may be aylistil by standard procedures, by crystallization.

A valuable subgroup of compounds of formula (V) are those wherein X and Y are independently selected from the group consisting of hydrogen, S-fluoro, 6-fluoro, S-chloro, 6-chloro,

5-trifluoromethyl and 6-trifluoromethyl, with the proviso that X and Y did not simultaneously represent hydrogen atoms. The compounds of formula (V) from this latter group are novel.

The isocyanates of the formula R = -N = C = O can be prepared by standard procedures - see below, Organic Funntimal Group, Saanier and Kara, Part I, Second Edition, Academic Press, Inc, New York, NY, 1983, Kapp la-12, pp. 364 to 369. Zvlátř suitable method consists in reacting přislaného amine of the formula R _-NH2 with phosgene, PR ^ b ^ HAIC následuuícího according to the reaction scheme:

R ² -NH ² + COCl ² -----> R ² -N = C = O + 2 HCl

Numerous of the isocyanates of the formula R -N = C = O are known in the art.

Bxinloll-2) → compound of formula III rřirrtvují known methods or analogous to known methods [see, Rodd's Chheistry Comeoounl of Carbon ^", second edition, ed. S.C. IV, Part A, Elsevier Scieznifii PpUVising Company, 1973, pp. 448-450; Gassman et al., Journal Organic Journal, p. 2, 1340 (1977); W. J. et al., Journal of the American Chemistry 1 Sobiety, 78, 221 (1956); Bezckz et al., Tetraulzln, 24, 6,093 (1968); U.S. Patent Nos. 3,882,236, 4,006,161 and 4,160,032; Waaker, Journal of the American Chemical Sodeti, 77, 3,844 (1955); Protiva et al., CoUzHim of Czychoslovak Chhmica 1 Coemelnations, £ 4, 2,108 (1979); M etvoy et al., Journal of Organic Chemistry, 38, 3,350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland and SPO ^, ^^^ Chemise Βεζ .96 ²⁵³ Ц9 ⁶³⁾ and there will ^{b e} o ^d ovan kazyj.

The compounds of formula I are acidic and form a salt with bases. All of these bases which can be adapted to conventional methods are within the scope of the invention. Thus, these salts can be prepared simply by contacting either the acidic and the basic component, usually the stricter, with either a non-aqueous or aqueous or partially aqueous medium, as appropriate in each case. .

The resulting salts are isolated either by filtration, by precipitation with a solvent followed by filtration, or by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. Typical salts of the compounds of formula (I) which can be prepared are salts with primary, secondary or tertiary amines, salts with alkaline or alkaline earth metal salts. Especially valuable are the salts with ethanol than diaminophen. t r Lothar i amine.

Inorganic bases such as organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, carbonates can also be used in the manufacture of salts. alkaline earth metal hydrides, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative 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, Nd imethylamine, N-ethylpiperidine and N-methylmorpholine, hydroxides 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 compounds of formula I exhibit analgesic activity. This activity can be demonstrated in mice by blocking abdomen convulsions induced by the application of 2-phenyl-1,4-benzoquinone. This assay is performed using a method based on the procedure described by Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731 (1957), adapted for a large number of experiments [see Milne and Twomey, Agents and Actions, 10, 31-37 (1980)]. These experiments were performed on male Carworth white mice (CF-1 strain) weighing 18-20 g. All mice were fasted overnight before administration of the drug and starting the test.

Compounds of formula (T) are dissolved or suspended in a vehicle comprising 5% ethanol, 5% surfactant emulsphor 620 (mixture of oxethylated fatty acid esters) and 90% saline. This vehicle also serves as a counter, a. Logarithmically scaled doses (i.e. ... 0.32, J, 0, 3.2, 10, 32 ... mg / kg) are used. Test substances are administered, orally at various concentrations, to maintain a constant volume at 10 ml / kg body weight. The method described above by Milné and Twomey is used to determine potency and potency.

Mice were dosed orally with test compound and, after 1 hour, 2 mg / kg 2-phenyl-1,4-benzoquinone intraperitoneally. Immediately thereafter, mice were individually housed in heated plastic chambers and the number of abdominal constrictions was recorded 5 minutes after application of 2-phenyl-1,4-benzoquinone. This recording is performed for 5 minutes. The degree of analgesia (% MPE) is then calculated by suppressing the number of abdominal constrictions compared to the control animals tested the same day. For the calculation of the MPE value, which is the best estimate of the dose reducing abdominal constriction to 50% of the control value, the data found in the dose response determination are used in at least four such assays (N. £ 5).

The compounds of formula I also exhibit anti-inflammatory activity. This efficacy was demonstrated in rat tests using a method based on a standard test for edema induced on the rat limb by carrageenin (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1962).

Non-anesthetized adult male white rats weighing 150-190 g are numbered, weighed and inked on their hind limb in the ankle region. The labeled limb of the animal is then immersed in the mercury so that the mercury level is accurate to the mark. Mercury is found in a glass cylinder connected to a pressure transducer (Statham). The output of the converter is led through the control unit to the microvolt meter. The volume of mercury displaced by the immersed limb is recorded. Test substances are administered by gavage.

One hour after administration of the test substance, injection of 0.05 ml of a 1% carrageenin solution into the plantar tissue of the labeled limb induced edema. Immediately thereafter, the volume of this limb is measured. the volume of the limb 3 hours after carrageenin injection, compared to the condition in control animals receiving only the vehicle without drug, represents an individual inflammatory response.

The results obtained with the test just described are summarized in the following table, where they are given in percent inhibition of edema formation when the test substances are administered, compared to: with control animals.

Table

O = C-NH -R ²

2

X R R dose inhibition (mg / kg) (%)

H methyl phenyl 33 40 H methyl phenyl 10 20 May H methyl 4-chlorophenyl 33 4 fl methyl 3- (trifluoromethyl) phenyl 33 24 H methyl 2,4-difluorophenyl 33 19 Dec H methyl 4-fluorophenyl 33 20 May H phenyl phenyl 33 8 H phenyl 4-chlorophenyl 33 6 H 3-pyridyl phenyl 33 39 H 3-pyridyl 4-chlorophenyl 33 10 II phenyl 2,4-difluoromethyl 33 22nd Ií benzyl phenyl 33 17 H benzyl 2, N, N-difluorophenyl 33 23 H benzyl 4-chlorophenyl 33 14 H 2-thienyl 4-fluorophenyl 33 17 H 2-furyl 4-fluorophenyl 33 34 H 2-furyl N -fluorophenyl 10 7

T a b at 1 k a continued

X ^r1 r dose (mm / kg) inhibition (WITH) H cyclohexyl 4-fluorophenyl 33 13 H 2-thenyl 2,4-difluorophenyl 33 23 H 2-thenyl phenyl 33 40 H isopropyl N 4 -fluorophenyl 33 26 H cyclopropyl N -fluorophenyl 33 26 H 2-furyl phenyl 33 48 H 2-furyl phenyl 10 16 H 2-furyl 2,4-difluorophenyl 33 53 H 2-furyl 2,4-difluorophenyl 10 23 H 2-thienyl phenyl 33 36 H 2-thienyl 2,4-difluorophenyl 33 37 H 2-thienyl 2,4-difluorophenyl 18 13 H 2-thienyl 2,4-difluorophenyl 1,8 10 H trifluoromethyl 4-fluorophenyl 33 12 H 2-furyl ‘1-chlorophenyl 32 12 H 2-furyl 2- (trifluoromethyl) phenyl 32 30 H Tenoxymeehyl phenyl 32 20 May H trffloormethyl phenyl 32 24 H trifluoromethyl 2,1-difluorophenyl 33 2 H phenoxymethyl 4-chlorophenyl 32 35 H ienuxymethyf 4-chlorophenyl 10 6 H ienuxymeehyf 2,4-difluorophenyl 32 25 H 2-thenyl 4-chlurfenyf 32 26 H 2-thenyl 4-fluorophenyl 32 8 H 2-thenyl 3-tolyl 32 7

Continuation table

XR ¹ R ² dose inhibition (mg / kg) (%)

H 2-thenyl 3-fluorophenyl 32 9 H 2-thenyl 3-trifluoromethylphenyl 32 3 H 1-phenylethyl 2,4-difluorophenyl 32 17 H 2-thienyl 2-trifluoromethylphenyl 32 25 H 1-phenylethyl 4-fluorophenyl 32 25 H 2-furyl 2,4-dichlorophenyl 32 10 H 2-furyl 3-anisyl 32 12 H 2-thienyl 2,4-dichlorophenyl 32 7 H 2-thienyl 3-anisyl 32 8 H 2-furyl cyclohexyl 32 18 H 2-thienyl cyclohexyl 32 14 H phenoxymethyl cyclohexyl 32 23 H benzyl cyclohexyl 32 11 H 2-furyl 4-anisyl 32 36 H 2-thienyl 4-anisyl 32 40 H 2-furyl 2,4-dimethylphenyl 32 34 H 2-thienyl 2,4-dimethylphenyl 32 28 H 2-furyl 4-ethylphenyl 32 19 Dec H 2-thienyl 4-ethylphenyl 32 26 H 4-chlorobenzyl phenyl 32 15 Dec H 4-chlorobenzyl 2,4-difluorophenyl 32 10 H 4-chlorobenzyl 4-chlorophenyl 32 16 H 4-chlorobenzyl 4-fluorophenyl 32 10 H 4-fluorobenzyl phenyl 32 23 H 4-fluorobenzyl phenyl 32 21

252825

Table continued ·;

X R R d á v к a (mg / kg) inh (and) H 4-fluorobenzyl ¹ 4-chlorophenyl 1 32 27 Mar: H 4-fluorobenzyl 4-fluorophenyl 32 No. H 3-thenyl phenyl 32 30 H 3-thenyl 2,4-difluorophenyl 3 2 14 H 3-thenyl. 4-chlorophenyl 32 11 H 3-thenyl 4-fluorophenyl 32 25 H 3-furyl · phenyl 32 26 H 3-furyl 2,4-difluorophenyl 32 39 H 3-furyl 4-chlorophenyl 32 - H 3-furyl 4-fluorophenyl 32 2 9 H 3-th.i.eny 1 phenyl 32 19 Dec H 3-thienyl 2,4-difluorophenyl 32 if H 3-thienyl 4-chlorophenyl 32 23 H 3-thienyl 4-fluorophenyl 32 16 H 4-chlorine f с. ri} ' 4-fluor Гапу.! 32 12 H methy1 benz: 1 3 2 1 9 H 2-furyl berryl 32 2 0 H 2-thienyl benzvl 32 26 H phenyl phenyl 32 23 H 4-pyridy1 4-chlorophenyl 32 3 H 5-methyl-2-furyl phenyl 32 3 H 5-methyl-2-furyl 2,4-difluorophenyl 32 23 H 2-pyridyl 4-chlorophenyl 32 4 H 2-furyl ethyl 32 30 H 2-thienyl ethyl 32 2 2

Г a b u X 1 к and continuation R ¹ R ² dose (mg / kg) inhibition (%) H 2-thenyl ethyl 32 15 Dec H methyl ethyl 32 5 5-C1 2-furyl etnyl 32 27 Mar: 5-C1 2-thienyl ethyl 32 38 5-Cl methyl ethyl 32 3 5-C1 2-thenyl ethyl 32 16 5-C1 2-thienyl isopropyl 32 32 5-C1 2-thenyl isopropyl 32 25 5-C1 methyl isopropyl J Δ 16 5-CL 2-turyl n-butyl 32 42 5-C1 2-furyl n-butyl 10 23 5-C1 2-furyl n-butyl 3.2 16 5-Cl 2-thenyl n-butyl 32 3 5-Cl 2-furyl tert.butyl 32 54 5-C1 2-furyl tert.butyl 10 3 5 5-C1 2-furyl tert.butyl 3.2 31 H 2-furyl isopropyl 32 42 11 2-furyl isopropyl 10 29 H 2-furyl isopropyl 3.2 17 H 2-thienyl isopropyl 32 46 H 2-thienyl isopropyl 10 38 H 2-thienyl isopropyl 3.2 24 5-Cl methyl tert.butyl 32 43 5-C1 methyl tert.butyl 10 39 5-C1 methyl tert.butyl 3.2 24

Table .1 k: f

X r 'C dose inhibition (mg / kg) (%)

H 2-fury1 tert.butyl 32 31 5-Cl 2-thienyl terc.buty ¹ 32 41 5-Cl 2-thienyl tert.butyl 10 34 5-Cl 2-thienyl tert.butyl 3.2 13 5-Cl 2-furyl cyclohexyl 32 18 5-Cl methyl cyclohexyl 32 4 5-Cl 2-thenyl cyclohexyl 32  17 H 2-thenyl tert.butyl 32 14 H 2-thienyl tert.butyl 32 51 H 2-thienyl tert.butyl 10, 31 H 2-thienyl tert.butyl 3.2 18 H methyl tert.butyl 32 27 Mar: 5-Cl 2-thenyl tert.butyl '32 3 5 H methyl isopropyl 32 17 H 2-furyl n-butyl 32 20 May 5-CL 2-thienyl n-butyl 32 10 5-Cl methyl n-butyl 32 10 5-CL 2-thienyl cyclohexyl 32 40 5-Cl 2-thienyl cyclohexyl 10 25 5-Cl 2-thienyl cyclohexyl 3.2 17 H 2-thienyl n-butyl 32 33 5-Cl cyclohexyl tert-butyl 32 8 5-Cl cyclopentyl tert.butyl 32 26 5-Cl cyclobutyl tert.butyl 32 43 5-Cl cyclobutyl tert.butyl 10 20 May

Continuation table

X R ¹ R dose (mg / kg) inhibcee (%) 5-CF ₃ 2-thienyl. tert-butyl 32 14 ⁵ -CF ₃ 2-furyl tert.butyl 32 30 5-CF3 2-thenyl tert.butyl 32 5 5-CF ₃ bicycle [2,2, lj - heptan-2-yl tert.butyl 32 1 5 6-Cl 2-thienyl tert.butyl 32 63 6-Cl 2-thienyl tert.butyl 10 29 6-Cl 2-thienyl tert.butyl 3.2 27 Mar: 6-Cl 2-furyl tert.butyl 32 68 6-Cl 2-furyl tert.butyl 1 0 27 Mar: 6-Cl 2-furyl tert.butyl 3.2 15 Dec 5-C1 ^ cy ^ o _^[f 2 ^{2, 1]} heptane-2-y1 tert.butyl 32 3 6-Cl 2-thenyl tere.butyl 32 17 6-Cl bic ^ who ^[2,2, 1] - heptane-2-yl tert.butyl 32 7 5-F 2-furyl tert.butyl 32 67 5-F 2-furyl tert.butyl 10 51 5-F 2-furyl tert.butyl 3.2 40 5-F 2-thienyl tert-butyl 32 51 5-F 2-thenyl tert.butyl 32 32 6-Cl 2-furyl isopropyl 32 66 6-Cl 2-furyl cyclohexyl 32 38 5-C1 2-furyl phenyl 32 55 5-C1 2-furyl 2,4-difluorophenyl 32 36 5-Cl 2-thienyl phenyl 32 26 5-C1 2-thenyl phenyl 32 56

5

Continuation table

X К R dose (mg / kg) inhibition (%) 5-C1 2-thenyl 2,4-difluorophenyl 32 28 6-C1 2-thienyl isopropyl 32 14 6-C1 2-thienyl cyclohexyl 32 22nd 6-C1 3-thenyl tert.butyl 32 22nd 6-C1 3-furyl tert.butyl 32 54 6-C1 3-thienyl tert.butyl 32 32 6-C1 2-furyl ethyl 32 36 6-C1 2-thienyl ethyl 32 29 5-C1 2-chlorobenzyl phenyl 32 4 5-C1 2-thienyl 2,4-difluorophenyl 32 11 5-C1 4-chlorobenzyl tert.butyl 32 22nd 5-F 2-furyl isopropyl 32 50 5-F 2-thienyl isopropyl 32 37 5-F 2-thenyl isopropyl 32 38 5-F 3-furyl isopropyl 32 45 5-F 3-thienyl isopropyl 32 22nd 5-F 3-thenyl isopropyl 32 40 ^6_CF 3 benzyl phenyl 32 8 6-F 2-thienyl phenyl 32 19 Dec

Because of their analgesic activity, the compounds of formula I are useful for acute administration to mammals for the purpose of reducing pain, such as post-operative pain or post-traumatic pain. Further, the compounds of formula I are useful for chronic administration to mammals for the relief of symptoms of chronic diseases such as inflammation in rheumatoid arthritis and pain in osteoarthritis and other musculoskeletal disorders.

When a compound of formula I or a pharmaceutically acceptable salt thereof is used as either an analgesic agent or an anti-inflammatory agent, the compound may be administered to the mammal either alone or preferably in combination with pharmaceutically acceptable diluents or carriers in the form of pharmaceutical compositions according to standard pharmaceutical practice. .

The active ingredient may be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.

In a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active agent normally ranges from 1: 4 to 4: 1, preferably from 1: 2 to 2: 1. In any particular case, however, the exact ratio depends on such factors as the solubility of the active agent, the intended dosage and the intended route of administration.

Orally, the compound of formula (I) of the invention may be administered, for example, in the form of tablets or capsules, or in the form of an aqueous solution or suspension. Tablets for oral administration usually contain carriers commonly used for such purposes, including lactose and corn starch, and generally use glidants such as magnesium stearate in their manufacture. Suitable diluents for the preparation of capsules for oral administration are lactose and dried corn starch. To prepare aqueous suspensions for oral administration, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active compounds are usually prepared, the pH of which should be suitably adjusted and buffered. In the preparation of preparations for intravenous administration, the total concentration of soluble components should be controlled so that the resulting preparation is still isotonic.

The daily dose of a compound of formula I or a salt thereof in human medicine is usually determined by the attending physician. In addition, this dose will vary depending on the age, weight and response of the patient, as well as the severity of the symptom in the patient and the efficacy of the compound administered. When administered acutely for pain relief, the dose eliciting an effective analgesic response will in most cases range from 0.02 to 0.5 g as needed (for example, every 4 hours to 24 hours). In the case of chronic applications for the alleviation (treatment) of inflammation and pain, in most cases the daily dose will be from 0.02 to 1.0 g, preferably from 0.05 to 0.5 g, which may be administered as a single daily dose. or in several sub-doses. However, in individual cases, doses outside these limits may need to be administered.

The invention is illustrated by the following non-limiting examples.

Example 1

N-tert-butyl-6-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide

A solution of 667 mg (2.5 mmol) of N-tert-butyl-6-chloro-2-oxindole-1-carboxamide and 684 mg (5.6 mmol) of 4- (N, N-dimethylamino) pyridine in 8 ml of N, The N-dimethylformamide was cooled in ice and a solution of 410 mg (2.8 mmol) of 2-thenoyl chloride in 2 ml of N, N-dimethylformamide was added dropwise with stirring. Stirring is continued for about 30 minutes and then the reaction mixture is poured into a mixture of 60 ml of 3N hydrochloric acid. The resulting mixture was cooled in ice, the precipitated solid material was filtered off and recrystallized from about 30 ml of acetic acid. 425 mg of the title compound is obtained as yellow crystals melting with slight decomposition at 160.5 to 161.5 ° C.

Analysis: for ^C g ^H 2 ° L7 ^C1N 3 ^S calculated 57.36% C, 4.55% H, 7.43% N; Found: C, 57.29; H, 4.48; N, 7.38.

Example 2

N- (4-fluorophenyl) -3-acetyl-2-oxindole-1-carboxamide

To a suspension of 811 mg (3.0 mol) of N- (4-fluorophenyl) -2-oxindole-crboxboxamide in 4 ml of formamide was added, with stirring, 806 mg (6.6 mmol) of 4- (N, N-dimethylalamino). pyrrdinu. Stirring was continued for a few minutes, after which the suspension was cooled in ice and a solution of 337 mg (3.3 mmmop of acetic anhydride in 2 ml of N, N-dimethylformamide) was added. SMMS mixture was poured into 60 ml of ice water and 2.2 ml of 3N hydrochloric acid and the precipitated solid collected by filtration. This was recrystallized maateiál acetoniirilu of 600 mg of the title compound, as a dark-colored crystals of melting point 18 ¹ and ^{mp 182} ° C.

Analysis: calculated C, 65.38; C, 4.19; N, 8.97. found: C, 65.44; I, 4.31;

Example 3

The following compounds were prepared in an analogous manner to Examples 1 and 2:

O = C-NH-R ²

X ^{r1 r2} Melting point No. 2-furyl ethyl 201 to 201.5 No. β-thienyl ethyl 128 to 129.5 No. (2-thienyl) methyl ethyl 130 to 131 No. methyl ethyl 157 to 158 5-Cl 2-furyl ethyl 134 to 135 5-Cl 2-tУienrl ethyl 154 to 155 5-Cl methyl ethyl 173 to 174 5-Cl (d-thienyl) methyl ethyl 154 to 155 5-Cl 2-thienrl isopropyl 129 to 130 5-Cl (2-thienyl) methyl isopropyl 155 to 156 5-Cl mehyi isopropyl 186 to 187 5-Cl 2-furyl n-rutyl '100 to 101

Table X continued ^r1 R ² Melting point (° C) 5-C1. 2-thienyl n-butyl 152 to 153 5-C1 2-furyl tert.butyl 171-171.5 H 2-furyl isopropyl 114 to 115 H 2-thienyl isopropyl 177-178.5 5-C1 methyl target. butyl 219 to 220 H 2-furyl tert.butyl 160 to 161 5-C1 2-thienyl terč.buuyl 178-179.5 H (2-thitnyl) methyl tert.butyl 141 to 142 (decomposition) H ' 2-thienyl tert.butyl 163 to 164 H mme.hyl tere.butyl 163 to 164 5-C1 (2-thienyl) methyl tert.butyl 218 to 219 (decomposition) H methyl isopropyl 162.5 to 163.5 H 2-furyl n-butyl 87 to 88 5-C1 2-thienyl n-butyl 123 to 124 5-C1 meehyl n-buuyl 167 to 169 H 2-thienyl n-butyl 137 to 138 5-C1 cyclohexyl terč.buuyl 239 to 240 (decomposition) 5-C1 cyclohexyl tert.butyl 229 to 230 (decomposition) 5-C1 cyclobutyl terč.buuyl 226 to 227 (decomposition) 5-CF ₃ 2-thienyl terč.buuyl 162 to 163 5-CF ₃ terč.buuyl 171.5 to 172.5 5-CF3 (2-thienyl) methyl target. buuyl 133 to 134 6-C1 2-furyl terč.buUyl 168.5 to 169.5 6-C1 (2-thienyl) methyl target. buuyl 151 to 152 5-C1 2-furyl cyclohexyl 138 to 139 5-C1. meehyl cyclohexyl 226 to 227

Continuation table

X ^r1 7 R " Temperature even melting (° C) 5-C1 (2-thienylmethyl) cyclohexyl 153 to 154 5-C1 2-thienyl cyclohexyl 158 to 159 H methyl 3- (trifluoromethyl-Hop mctliy 2) ^phenoxy-yl 186 to 188 H methyl 2,4-Difluoro phenyl 161 to, 162 H methyl 4-fluorophenyf 181 to 183 H benzyl phenyl 14 5 to 147 H (2-thienyl) methyl 2.4 .mu.g phenyl 165 to 1 6 7 H (2-thienyl) methyl phenyl 16 5 to 167 H isopropyl 4-fluorophenyl 176 to 177 H cyclopropyl 4-fluoro-phenyl 202 and ž 203 H 2-thienyl phenyl 152 to 153 H 2-thienyl 2,1-difluorophenyl 164 to 165 H 2-fůry1 Chlorophenyl 200.5 to 2 01.5 (decomposition) H 2-furyl 2- (trifluoromethyl) phenyl 202 to 203 (decomposition) H triflurrmethyl 4-chlorophenyl 202 to 230 H trflUurrmethyl 2,4-difluorophenyl 133,5 ' to 134.5 H 2-thienyl 2- (trifluoromethyl) phenyl 166.5 to 167.5 (decomposition) H 2-furyl 2,4-dllurphenyf 235.5 (decomposition) H 2-furyl 3-methoxyphenyl 137 to 138 H 2-thienyl 2,4-dichlorophenyl 221.5 to 222.5 (decomposition) H 2-furyl 4-methoxyphenyl 16 8 to 16 9,5 H 2-thienyl 4-methoxyphenyl 17 8,5 to 179.5 H 2-furyl 2,1'-dimethylphenyl 176 to 177 H 2-thienyl 2,4-diethyphenyl 171 to 172 H 2-furyl 1-ethylphenyl 154.5 to 155.5 H 2-thienyl 4-ethylphenyl 131 to 132

Continuation table

XR ¹ R ² Melting point (° C)

H methyl 4-chlorophthyl 225 to 227 H ftnyl · ftnyl 176 to 177 H ftnyl · 4-chlorophthyl 215 to 217 H 3-pyridyl ftnyl 193 to 195 H 4-fluorophenyl 4-chlorophenyl 212 to 213 H 3-pyridy1 4-chlorophthyl 220 to 221 H 4-fluorophenyl ftnyl 189 to 191 H ftn ^^ L 2,4-Diphenylphenyls 204 to 206 H btnzyl 2,4-difluorienr1 151 to 152 H btnzyl 4-chlorophthyl 178 to 179 H 2-thienyl 4-fluorophenyl 175-176.5 H 2-furyl 4-f 166.5 to 167.5 (decomposition) H cycloltxyl 4-fluorophenyl 180 to 181 H 2-furyl females 1 162 to 163 H 3-pyridyl 2,4-diylsuccinol 254 (decomposition) H trfflurrmethyl Fluorine 1 203 to 204 H trifloormtthyl ftnyl 139.5 to 140.5 H phthnoxymethyl ftnyl 158 to 159 H phthnoxymrthyl ^ chlo ^ cny! 137.5 to 138.5 H phthnoxymethyl 2,4-diiluurfenrl 137.5 to 138.5 H (2-thitnyl) methyl 4-0111 (3 ^ 0 ^ 1 165 to 166 H (2-thitnyl) methyl ^ МюМспг 1 161 to 163 H (2-thitnyl) methyl 3- ^ 1г1 147 to 149 H (2-thitnyl) methyl 3-iluurfenrl 152 to 154 H (2-thitnyl) methyl 3-trilloorretrine 139 to 140 H 1-phthylthyl 2,4-di-fluorophenol 152.5 to 154

Table continued

X r ^r2 Melting point if 2-thienyl 4-chlorophenyl 196.5 to 197.5 H 1-phenylethyl 4-fluorophenyl 166 to 167 H 2-thienyl 3-methoxyphenyl 148.5 to 149.5 H 2-t’ury1 cyclohexyl 104 to 105 H 2-thienyl cyclohexyl 116 to 117 H • phenoxymethyl cyclohexyl 159 to 160 H benzyl cyclohexyl 122 to 123 H 4-chlorobenzyl phenyl 180 to 181 11 4-chlorobenzyl 2,4-difluorophenyl 182 to 183 H 4-chlorobenzyl 4-chlorophenyl 184 to 186 H 4-chlorobenzyl 4-fluorophenyl 165 to 166 H 4-fluorobenzyl phenyl 179 to 181 H 4-fluorobenzyl 2,4-difluorophenyl 189 to 191 H 4-fluorobenzyl 4-chlorophenyl 205 to 207 H 4-fluorobenzyl 4-fluorophenyl 198 to 199 H (3-thienyl) methyl phenyl 133 to 134 H (3-thienyl) methyl 2,4-difluorophenyl 162 to 163 H (3-thienyl) methyl 4-chlorophenyl 182? To 184 and (3-thienyl) methyl 4-fluorophenyl 145 to 147 H 3-furyl phenyl 145 to 146 H 3-furyl 2,4-difluorophenyl 178 to 179 H 3-furyl 4-chlorophenyl 190 to 191 H 3-furyl 4-1 'fluorophenyl 18 to 190 H 3-thienvl enyl 166 to 168 H 3-thienyl 2,4-difluorophenyl 188 to 190 H 3-thienyl 4-chlorophenyl 216 to 218

Continuation table

XR ^{1 r2} Melting point (° C)

H 3-thienyl 4-fluorophenyl 209.5 to 210.5 H 4-chlorophenyl 4-fluorophenyl 219 to 220 H methyl benzyl 162 164 H 2-thienyl benzyl - * ’ to 118 H 2-furyl benzyl ¹²⁴ to 126 H 4-pyridyl phenyl 212.5 to 213.5 (decomposition) H 4-pyridyl 2,4-difluorophenyl 229 to 230 H 4-pyridyl 4-chlorophenyl 211 to 213 (decomposition) H 2-pyridyl phenyl 208 to 209 H 5-methyl-2-furyl phenyl 156 to 157 H 5-methyl-2-furyl 2,4-difluorophenyl. 189 to 191 H 2-pyridyl 2,4-difluorophenyl 230 to 232 (decomposition) H 2-pyridyl 4-chlorophenyl 2G7 to 208 (decomposition) ⁵ -CF ₃ bicyk.lo ^{[2> 2,} 1] heptane-2-yl tert-butyl 212.5 (decomposition) 5-C1 ^bic^yklo p^2.2 _rlJ heptan-2-yl tert-butyl 235 to 236 (decomposition) 6-C1 ^bicyklo f²,², l] heptan-2-yl tert.butyl 225 (decomposition) 5-F 2-furyl tert-butyl 184.5 to 185.5 5-F 2-thienyl target. butyl 183.5 (decomposition) 5-F (2-thienyl) methyl tert.butyl 182.5 to 183.5 6-C1 2-furyl p 165.5 to. 166.5 6-C1 2-furyl cyclohexyl 164 to 165 5-C1 2-furyl phenyl 191.5 to 192.5 5-C1 2-furyl 2,4-difluorophenyl 214 to 215 5-C1 2-thienyl phenyl 194 to 195 5-C1 (2-thienyl) methyl phenyl 167.5 to 169

Continuation table

XR ¹ R ² Melting point (° C)

5-C1 (2-thienyl) methyl • 2,4-difluorophenyl 211.5 to 212.5 6-C1 2-thienyl isopropyl 118 to 119 6-C1 2-thienyl cyclohexyl 145 to 146 5-C1 (3-thienyl) methyl tert.butyl 222 to 224 5-C1 3-furyl tert-butyl 181 to 182 (decomposition) 5-C1 3-thienyl tert.butyl 209 to 211 (decomposition) 6-C1 2-furyl ethyl 157.5 to 158.5 6-C1 2-thienyl ethyl 138 to 139 5-C1 2-chlorobenzyl phenyl 218 to 219 (decomposition) 5-C1 2-chlorobenzyl 2,4-difluorophenyl • 216 (decomposition) 5-C1 2-thienyl 2,4-difluorophenyl 200.5 to 201.5 5-C1 4-chlorobenzyl tert.butyl 214 to 216 (decomposition) 5-F 2-furyl isopropyl 141 to 142 5-F 2-thienyl isopropyl 185 to 187 5-F (2-thienyl) methyl isopropyl 143 to 144 5-F 3-furyl isopropyl 163 to 164 5-F 3-thienyl isopropyl 179 to 180.5 5-F (3-thienyl) methyl isopropyl 156 to 157 6-CF ₃ 2-thienyl phenyl 187 to 189 ^6-CF 3 benzyl phenyl 169 to 170 6-F 2-thienyl phenyl 174 to 175 6-F 2-thienyl 4-methoxyphenyl 175 to 176 5-C ₈ H ₅ CO benzyl phenyl 167 to 170 5-CH 3 CO (2-thienes Dmethyl) phenyl 194 to 196 5-C1 benzyl 4-methoxyphenyl 198 to 200 5-C1 (2-thienyl) methyl 4-methoxyphenyl 195 to 197

Continuation table

XR ¹ R ² Melting point (° C)

5-F 2-thienyl phenyl 164 to 166 5-F 2-thienyl * 4-methoxyphenyl 177 to 179 5-NO ₂ phenoxymethyl phenyl 224 to 225 5-0, .11, 00 0 Э 2-thienyl phenyl 160 to 163 5-0 ^ Η (_00 (2-thienyl) methyl phenyl 171 to 173 5-CfRCO 2-thienyl phenyl 193 to 195 5-CH ₃ CO benzyl phenyl 195 to 198 5-01 2-thienyl 4-methoxyphenyl 185 to 187 5-01 benzyl phenyl 156 to 158 5-F benzyl phenyl 175 to 177 5-01 4-chlorophenyl phenyl 239 to 240 6-F 2-tetrahydrofuranyl 4-methoxyphenyl 170 to 172

The following compounds were prepared analogously to Example 1:

X X R ¹ R ² Melting point 4-C1 5-F (2-thienyl) methyl phenyl 154 5-F 6-01 benzyl phenyl 203 to 204 5-F 6-01 2-thienyl phenyl 212 to 214 5-F 6-C1 benzyl n-butyl 129 to 130 5-F 6-C1 2-furyl n-butyl 122 to 123 5-F 6-C1 benzyl 4-methoxyphenyl 194 to 196 5-F 6-C1 2-thienyl 4-methoxyphenyl 210 to 212

Example 1 or ii 4

For posting only; ·. .. SoJ ...

The reaction is carried out by the reaction of the appropriate acid chloride with the corresponding N-sub-compound (II), to prepare the following compounds:

= C -ΜΗ. r2

1-CHCl 2 Cl 1 -b 2-furyl phenyl 5-CH11CHnCH2-6 2-thienyl cyclohexyl _6-CH-N-CH ,, - _CH2 -CIl ₂ -7 2-furyl 4-fluorophenyl 5-CH-CH-CH = CH-6; (21-eny1) me thy1 tert.butyl 5-O-CH 2 -CH 2-6 2-thienyl i. sopropyl 5-CH.-CH 2 -O-6 2 — furyi phenyl 5-S-CH ₃ -CH ₂ -6 2-thienyl cyclohexyl 5-O-CH = CH-6 2-ruryl tert.butyl 5-S-CH = Cl-6 (2-thienyl) methyl cyclohexyl 5-CH-CH-S-6 2-furyl phenyl

Legend:

^And in this column, the number on the left side of the formula indicates the attachment of this end of the formula to the 2-oxindole core and the number on the right side of the formula indicates the point of attachment of this end of the formula to the 2-oxindole core

Example 1 a d 5

Salt N-tert. butyl-3- (2-thienoyl) -1-oxoimidazol- ¹ -carboxamide with ethanolamine

To a suspension of 3.77 g of N-leoc-butyl-b-chloro-3- (2-thonoyl) -2-oxindoo-1-carboxamide in 60 ml of ethanol was added 610 g of ethanol-amino. The resulting mixture was heated to reflux for 5 minutes and allowed to cool. They are! the title compound is obtained by filtration of the precipitate formed.

Example 6

N-isopropyl-4-oxindole-T-carboxaniide

To a suspension of 5.0 g (37.6 mml) of 2-oindole in 50 ml of toluene was added 8.0 g (94.0 ool) of isopropyl isocyanate with stirring, and the mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool and then stirred at room temperature overnight. The rooin was evaporated in vacuo, the residue spread in hot cyclohexane, the solution was allowed to cool and the solid product was filtered off. 7.0 g of the title compound, as pink ^to stal.ů r ^{y t} e ^pl of the ^{I th} n: s ⁸⁴ to ^85.5 ° C.

Example 7

In analogy to Example 6, the following compounds are obtained by reacting the corresponding 2-oindole with the corresponding isocyanate of the formula R-N-00:

X Y ^r2 Reaction solvent Melting point (° C) 6-C1 H tert.butyl xylene 124 to ^{125 11} H H N-fluorenyl toluene 145 to I ^{46 21} H H ethyl benzene 98 to 99 5-C1 H ethyl Xylene 121 to 122 5-C1 H isopropyl oylene 164 to 165 5-C1 H n-butyl oylene 67 to 68 5-C1 H tert-butyl xylene 153 to 154 H H tert-butyl toluene 60 to 62 H H n-butyl toluene 49 to 51 5-CF ₃ H tert.butyl xylene 116 to 117 5-C1 H cycloheoyl oylene 139 to 140 Legend: 1) product was cleaned by columnar chrormatorr fií

the product precipitated upon completion of the reaction and was isolated by filtration

2)

Example 8

Using the procedure of Example 6, the following N-substituted 2-oxindole-L-carboxamides can be prepared by reacting the corresponding 2-oxindole with the corresponding isocyanate:

^X and ^{γ X} > ^r2

4-CH ₂ -CH ₂ -CH ₂ -5 phenyl 5-CH ₂ -CH ₂ -CH ₂ -6 cyclohexyl 6-CH ₂ -CH ₉ -CH ₂ -CH ₂ -7 ‘J-fluorophenyl 5-CH = CH-CH = CH-6 terč.buty1 5-OCH ₂ -CH ₂ -6 · isopropyl 5-CH ₂ CH ₂ -O-6 phenyl 5-S-CH ₂ -CH ₂ -6 cyclohexyl 5-O-CH = CH-6; tert.butyl 5-S-CH-CH-6 cyclohexyl 5-CH = CH-S-6 phenyl

Legend:

in this column indicates the number on the left side of the formula instead of attaching this end of the formula to the 2-oxindole nucleus and the number on the right side of the formula indicates that this end of the formula connects to the 2-oxindole core

Preparation 1

5-chloro-2-oxindole

To a suspension of 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added, with stirring, ml (0.826 mol) of hydrazine hydrate to give a red solution. The solution was heated at reflux for 3.5 hours, whereupon a precipitate formed. The reaction mixture was stirred overnight and then the precipitate was filtered off. 5-Chloro-3-hydrazono-2-oxidnol is obtained as a yellow solid.

This material, which after drying in a vacuum oven has a mass of 105.4 g, is added portionwise over a period of 10 minutes to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol. The resulting solution was heated to reflux for 10 minutes and then concentrated in vacuo. The resinous solid residue was dissolved in 400 ml of water, the aqueous solution was decolorized with activated charcoal and poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing chunks of ice. The precipitated red-yellow solid is filtered off, washed thoroughly with water, dried, washed with diethyl ether and finally recrystallized from ethanol. 38.9 g of the title compound, melting at 193-195 ° C, decomposes.

In an analogous manner, 5-methylisatin is first converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate and then sodium ethoxide in ethanol. The product melts at 173-174 ° C.

Preparation 2

4-chloro-2-oxindole and 6-chloro-2-oxindole

A. 3-Chloro-isonitrosoacetanilide

To a solution of 113.23 g (0.686 mol) of chloral hydrate in 2 liters of water, 419 g (2.95 mol) of sodium sulphate was added first with stirring, followed by a solution prepared from 89.25 g (0.70 mol)

3-chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water, a thick precipitate formed. A solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water is added to the mixture while stirring, the reaction mixture is slowly warmed with continuous stirring and maintained at a temperature between 60-75 ° C for about 6 hours, during which time add 1 liter of water to facilitate mixing. The resulting mixture was cooled, the precipitate formed was filtered off and dried. 136.1 g of 3-chloro-isonitrosoacetanilide are obtained.

B. 4-Chloroisatin and 6-Chloroisatin

To 775 ml of concentrated sulfuric acid, preheated to 70 ° C, is added with stirring

136 g of 3-chloro-isonitrosoacetanilide at a rate such that the temperature of the reaction medium is maintained between 75 and 85 ° C. After all the solid material had been added, the reaction mixture was heated to 90 ° C for 30 minutes, then cooled and poured slowly into about 2 liters of ice with stirring. Additional ice is added as necessary to keep the temperature below room temperature. The red-orange precipitate formed is filtered off and dried after washing with water. The solid material was suspended in 2 liters of water and dissolved in about 700 ml of 3N sodium hydroxide. The solution was filtered and adjusted to pH 8 with concentrated hydrochloric acid.

120 ml of a mixture of 80 parts of water and 20 parts of concentrated hydrochloric acid are added, the precipitated solid product is filtered off and, after washing with water, dried. 50 g of crude 4-chloroisatin are obtained. The filtrate was acidified to pH 0 with 4-chloroisatin with concentrated hydrochloric acid, whereupon a further precipitate formed which, after filtration, washed with water and dried, yielded 43 g of crude 6-chloroisatin.

The crude 4-chloroisatin was recrystallized from acetic acid to give 43.3 g of a melting point at 258-259 ° C.

The crude 6-chloroisatin was recrystallized from acetic acid to give 36.2 g of a melting point at 261-262 ° C.

C. 4-Chloro-2-oxindole

To a suspension of 43.3 g of 4-chloroisatin in 350 ml of ethanol, 17.3 ml of hydrazine hydrate is added, the reaction mixture is refluxed for 2 hours, then cooled and the precipitate formed is filtered off. 43.5 g of 4-chloro-3-hydrazono-2-oxindole, m.p. 235 DEG-236 DEG C., are obtained.

To a solution of 22 g of sodium in 450 ml of anhydrous ethanol, 43.5 g of 4-chloro-3-hydrazono-2-oxindole are added in portions while stirring, and the resulting solution is refluxed for 30 minutes, cooled and concentrated. to a gummy residue which is dissolved in 400 ml of water. The solution was decolorized with charcoal and poured into a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate formed is filtered off and, after drying, recrystallized from ethanol. 22.4 g of 4-chloro-2-oxides having a melting point of 216 DEG-218 DEG C. are obtained.

D. 6-Chloro-2-oxindole

By the procedure of Preparation 2C by reaction with tydrazin-tydráteo ^ZIS-6 -chllr ^{14.2 g} 2-LXII ^and the te ^ llu rotation point ¹⁹ 6 and ¹⁹⁸ ° C.

Prepare 3

5,6-difluoro-2-oxindole

In an analogous manner to paragraphs A and B of the above-mentioned preparation, the reaction is carried out by reacting 3,4-fluoroaniline with chloro-hydrate and hydroxylamine, followed by cyclization with sulfuric acid. This was treated with hydrazine hydrate and then sodium methoxide in ethanol in an analogous manner to Preparation 1. The title compound was obtained, m.p. 187-190 ° C.

Pípirava 4

5-fluoro-2-oxindole from

To a solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 mL of dichloromethane at -60 ° C to "65 ° C"

ml of methylene chloride. in ^stirring te s ^pl ol ^{of -60} to - ⁶⁵ for Smee solution of 13.4 g (0.1 ^C stirring solution of ^{10 (8 g, 0.1} oou TTRCA. ^b on ^{the hyp} l oc ^{c t} loli with the ^C to u is still continued ^{c e} l ⁰ min to ^c ^ e ^Z mol) of ethyl 2- (meth ^ylthio) acetate in 25 ml of dichloro-. at ^p te lot ^of -6 ° C and then at te ^pl ~ rt ^{of 60} to mol) in ²⁵ ml of ^{dichloro th} anus. 100 ml of water was added to the room temperature cooling solution.

with methane. ^A solution of ^{11.1 g} was added dropwise to the solution for ¹ hour at ^-65 ° ^C ( ^0.11 bath was removed and the reaction was

The phases are separated, the organic phase is washed with saturated sodium chloride solution and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether to which 40 ml of 2N hydrochloric acid was added. The mixture is stirred overnight at room temperature, then the phases are separated and the ether phase is washed first with water and then with a saturated sodium chloride solution. After drying over sodium sulfate, the ether phase is evaporated; in vacuum. 17 g of an orange-brown solid are obtained which is triturated. with itlpropyletheteo. Fixed it! then gave, after přtkryttllovSií from ethanol 5.58 ^{g of 5} - ^{f t} lulr- ³ -oettylt IL- ^l uo ² -lxirlil Melting ¹ 5 ^1, 5 and ^152, 5 ° C.

Analysis: Calculated for C 8 H 8 ONFS: C, 54.80; H, 4.49; N, 7.10. found: C, 54.14; H, 4.41; N, 7.11.

986 mg (5.0 mol) of the above 5-fluoro-3-methyl-til-2-lxiii (2 teaspoons of Raneye) in 50% absolute ethanol were added and the mixture was heated to reflux for 2 hours. The catalytic salt was separated by emanation and ethanol.

The dichloromethane solution was dried over sodium sulfate and evaporated

5- ^fl ulr- ² -lxiiiolt a melting point ^{of 134 121} ° C.

To the absolute ethanolic solutions, evaporate in vacuo and dissolve the residue in dichloromethane. in vacuo to give 475 mg of tert-butylhycholine, 3-thiomethyl-5-trifluoromethyl. Ranielniklem. There was obtained 5-trifluoromethyl-2-oxyl (II), m.p. 189.5-190.5 ° C.

Preparation 5

6- c h o o-5-fl-2-oxine nSol

To 130 ml of toluene was added, with stirring, 24.0 g (0.165 mol) of 1-chloro-4-fluorophenyl and 13.5 ml (0.166 mol) of pyridine. The resulting solution was cooled to about 0 ° C and 13.2 mL (0.166 mol) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then extracted twice with 100 ml of 1N NaCl each time and then with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried (MgSO4) and concentrated in vacuo. 32.6 g (88% of 1 N- (2-chloro-4-yl) -3-chloro-4-fluoriniline) are obtained.

26.63 g of N- (2-cciooajiey1L "3-cC1olг4 flttrjnilint is thoroughly mixed! With 64 g tezvoděto ^ 1 ^ 1 ^ Vinjélio and the mixture was 8.5 ^{h y} Odin heated to 10 ^{and 2 230} ° C. ^R ^ e ^ l ^ <^ i ^: ^{s t} t mixture was poured with stirring into ice and 1N smměi rýseUiný hydrochloric acid, the resulting mixture was stirred for 30 minutes, then solid maaeriál odSfltruje. there were obtained 22.0 g of solid product, The mixture was concentrated in a mixture of equal parts of ethyl acetate and hexane, and Cu was added to 800 g of silica gel, and after evaporation of the eluted fractions, 11.7 g of N were obtained first. - (2-chloroacetyl) -3- (4-fluoro-4-flilinilir) followed by 3.0 g of 6-chloro-5-fluoro-2-thinoSoit, which product after recrystallization from toluene gave 1.70 g (7% yield of the title compound). title t.ání about 19 ⁶ and ^{20 6} ° C. ^p ccording NM ^{R of} eкtгts ^к t IU ^of this ^p and ^d uct contaminated ur ^ y ^ mnoožtvím 4-ch1ooa5 fl.лг-2-txind 0.8 g of this product is obtained as the second sub-dl here.

pPípícvc 6

5-acetyl-2-thiamine (II). To 95 ml of silica, 27 g (0.202 mol) of aluminum chloride was added first, and then a solution of 3 µl was added dropwise with stirring. (0.042 mol) of acetic ^y lchltгidt in 5 ml νη ΐί ^ ^. Stirring was continued for a further 5 minutes, then 4.4 g (0.033 mol) of 2-thinololt was added, the resulting mixture was heated under reflux for 4 hours and then cooled. The silica was separated by decantation and the residue was formed with water. After filtration and drying, 3.2 g of the title compound of melting point 225-227 ° C are obtained.

Analogous to the above procedure, the reaction of 2-oxiodyl with Oenzoolchloride in the trichloroalkylamine chloride yields 5-O-nitro-2-oxindole, m.p. from mmeharaol at 203 to 205 ° C.

Claims (7)

1. A process for the preparation of N, 3-Sistonated 2-txinSoljraaoxaaiidr of formula I O = C-NH-R ² in which X is hydrogen, fluorine, chlorine ouOo, triuoormehhylovot group iitlosrtoiiu Al aooylovtt Lupine ^{R 2} and ^{Z 4} atoms in ^Z not leech ^{h O} o and ^b enzoylovou Sapiną Y represents hydrogen atom, fluorine ouOo chlorine ouOo X and Y are bonded to adjacent carbon atoms together to form a bivalent radical Z selected from the group consisting of the radicals of formulas ¹ to Z ⁵ C. C. C. C C (Z ¹ ) ^(z2) (Z ³ ) (Z ⁴ ) (Z ⁵ ) in which W represents an oxygen or sulfur atom, R ¹ represents an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group optionally substituted by a fluorine or chlorine atom, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety optionally substituted on the phenyl nucleus by chlorine or fluorine, ^alkyl fenoxyal alkoxycarbonyl having ^{1 and 3, the} atom ^Y uhKku VA nominal CAAS ^{plurality of projections,} the ^YKL bic ^[2 _r 2 _r lj ^h eptan-2- ^yl nominal group, a furyl radical optionally substituted by alkyl of 1 up to 3 carbon atoms, thienyl, thienymethyl, tetrahydrofuranyl or pyridyl; and R is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl Is selected from the group consisting of carbon atoms, a benzyl group or a radical of formula wherein R ³ and R ⁴ are nezááisle to SO ^{It runs} you ^b r ^and ny of with ^the UPIN zahhnující hydrogen atoms, fluorine and chlorine, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and trifluoromethoxy ^ ormethylovou group, and their pharmaceutically acceptable salts with bases, characterized in that the compound of formula V O = C-NH-R ² (V) wherein X, Y and R ^ m JRI above meanings, is reacted in an inert solvent with a carboxylic aktíoovaným kyseeiny formula R ^X -C (= O) -OH in which R ¹ has the above meaning, and the resulting ^P ro ^d uct was eventually ^p ad ^e ^ ^f EVET to Svoi armaceetic ^to y acceptable salt thereof. 2. The process of claim 1, wherein the uncoupling starting material is formed to form a compound of formula I wherein: X is attached at the 5 or 6 position and represents a hydrogen, fluorine, chlorine or bromine atom or a tritomethyl group; and Y represents a hydrogen atom, R ³ of ⁿ ^ Amen ^and alkyl group with ^1-6 carbon atoms iykllj ^l k ^y Loil sJcupinu to ^{3, and 7} carbon atoms, ^y, fu ^^ Vou group thienyoovou group phen ^{y y} lalki loiou group having from 1 to 3 the carbon atoms in the alkyl moiety, the thienyl lithium or the trifluoromethyl group; and R is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl Or a radical of formula wherein: R @ ³ and R ^{@ 4} are each independently hydrogen, fluorine or chlorine, C1 -C4 alkyl or trifluoromethyl and the pharmaceutically acceptable salts thereof. 3. A process according to claim 1 or 2, wherein the compound of formula V (V) wherein X, Y is reacted _2x and R have the above-mentioned known, with an activated carboxylic acid derivative of the general formula R ¹ -C (= O) -OH in which R ¹ is as defined above, in an inert solvent, in the presence of one to four mol equivalents of the basic agent, at a temperature of from -10 to 25 ° C. 4. A process according to claim 3, wherein the activated derivative is an acid chloride and the reaction is carried out in a polar aprotic solvent. 5. A process according to any one of claims 1, 3 and 4, wherein the corresponding starting materials are used to form a compound of formula I wherein Y is hydrogen and X is hydrogen, 5-chloro, 6-chloro , 5-fluoro or 6-fluoro and the remaining general symbols are as defined above. 6. Method according to claim 5, characterized in that the application of the corresponding starting material, to give a compound of formula I wherein R ¹ is benzyl, 2-furyl, 2-thienyl or (2-thienyl) methyl and the remaining generic symbols have the meaning as in point 5. 7. A method according to claim 6, characterized in that using the corresponding starting material, to give a compound of formula I wherein X is 5-chloro, R ¹ is 2-furyl 2 *, R is t-butyl and Y is as in point 6.