CS252498B2 - Method of 1,3-disubstituted 2-oxindoles production - Google Patents

Description

The invention relates to novel 2-oxindole derivatives of the general formula I

O = C — NH—

C —R ^z

II o

in which

(I) is hydrogen, fluorine or chlorine, (C1-C4) alkyl or trifluoromethyl, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C3) phenylalkyl in the alkyl part, a phenoxyalkyl group having 1 to 3 carbon atoms in the alkyl part, a juxyl group, a thienyl group, an alkylfuryl group having 1 to 3 carbon atoms in an alkyl part or a thienylmethyl group and is an alkyl group having 1 to 6 carbon atoms; C 3 to C 7, phenoxymethyl or a radical of formula wherein R 3 is C 3 -C 7;

represents a hydrogen atom, a fluorine or chlorine atom, a (C1-C4) alkyl group or a (C1-C4) alkoxy group, and pharmaceutically acceptable bases thereof.

The above 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 pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

A first preferred group of compounds of the invention are those compounds of formula (I) wherein X is hydrogen and is 2-furyl, 2-thienyl or (2-thienyl) methyl. Of this first preferred group, those compounds in which R represents a phenyl group are particularly preferred.

A second preferred group of compounds are compounds of formula I wherein X is chlorine in the 5-position and R ¹ is 2-furyl, 2-thienyl or (2-thienyl) methyl. Of this second preferred group, those 2 compounds in which R represents a cyclohexyl group are particularly preferred.

Particularly preferred individual compounds of the invention are N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide (Formula 1 wherein X is hydrogen, R ¹ is 2

2-furyl and R is phenyl) and N-cyclohexylcarbonyl-5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide (Formula I wherein X is 5-chloro, R ¹ is 2

2-thienyl and R is cyclohexyl).

The analgesic and anti-inflammatory compounds of the present invention are compounds of formula (I) wherein X, R and R are as defined above. The compounds of the invention are 2-oxindole derivatives, which is a bicyclic amide of formula

The analgesic and anti-inflammatory agents of the invention carry an N-acylcarboxamide substituent

1 of the formula -C (= O) -NH-C (= O) -R at the 1-position and an acyl substituent -C (= O) -R at the 3-position of 2-oxindole, wherein the fused benzo ring may be further substituted by X .

It will be appreciated that the analgesic and anti-inflammatory active compounds of formula (I) according to the invention wherein X, R and R are as defined above are capable of enolization and therefore may 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 formula I are prepared from the corresponding 2-oxindole of formula III

in which

X and Y are as defined above.

This preparation is carried out by introducing the substituent -C (= O) -NH-C (= O) -R 'into position 1 and the substituent -C (= O) -R 6 into position 3. Said substituents can be carried out in any order so that The process for the preparation of the compounds of the formula I can be carried out in two variants, as shown in the following reaction scheme.

Reaction scheme

(lil)

C-R .1

H (IV)

O = C — NH — C — R ^from II (I.) ^O

Thus, the first variant comprises a process from a compound of formula III through a compound of formula IV to a compound of formula I, a second variant then a process from a compound of formula III through a compound of formula II to a compound of formula I.

The object of the invention is a process for the preparation of the compounds of the formula I and their pharmaceutically acceptable salts with bases, characterized in that the compounds of the formula II

(II) in which

R and X are as defined above, reacted with an activated carboxylic acid derivative of the general formula

R ^1_ C (= 0) -OH wherein

R ¹ has the abovementioned meanings, in an inert solvent, and the resulting product is optionally converted into a pharmaceutically acceptable salt with a base.

The second variant resulting from the above reaction scheme is the subject of the related Czechoslovak Patent Specification No. 252,480.

The side chain -C (= O) -R 6 can be introduced into a compound of formula II by reaction with an activated carboxylic acid derivative of formula

R @ ¹ -C (= O) - OH

This reaction is carried out by treating a compound of formula II in an inert solvent with one mole equivalent or a slight excess of an activated derivative of a compound of formula R 1 -C (= O) -OH in the presence of 1 to 4 equivalents of a basic agent. The inert solvent used is one which dissolves at least one reactant and does not react adversely with either the reactants or the product. In practice, a polar aprotic solvent such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide is usually used. Activation of the acid of formula R @ 1 --C (.dbd.O) --OH is carried out by conventional methods. For the above reaction, it is possible to use, for example, the halides of the above-mentioned acid, such as the acid chloride, symmetrical anhydrides of the formula

R ¹ -C (= O) -OC (= O) -R ¹ low molecular weight hindered carboxylic acid mixed anhydrides of formula

R ¹ -C (= O) -O-C (= O) -R ⁵ wherein R represents a bulky lower alkyl group, such as a tert-butyl group, as well as mixed carboxylic and carbonic anhydrides of the general formula

R ¹ -C (= O) -O-C (= O) -R ⁶ wherein r ⁶ is lower alkyl. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (such as thiol-phenyl esters) and 2,4,5-trichlorophenyl esters, and the like can be used.

A wide variety of basic reagents can be used in the reaction between a compound of formula II and an activated acid derivative of formula RC (= O) -OH, but preferred basic agents are tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (Ν, Ν-dimethylamino) pyridine

The reaction of a compound of formula II with an activated acid derivative of formula r1-C (= O) -OH is usually carried out at a temperature ranging from -10 to 25 ° C. The reaction time generally ranges from 30 minutes to several hours. After completion of the reaction, the reaction medium is usually diluted with water and acidified, whereupon the product can be filtered off. The product obtained can be purified by standard methods such as recrystallization.

The 2-oxindole compounds of formula III are prepared by known methods or by methods analogous to those known [see Chemistry of Carbon Compound, 2nd edition, ed.

S. Coffey, Vol. IV Part A, Elsevier Scientific Publishing Company, 1973, pp. 448-450?

Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977); Wright et al., Journal of the American Chemical Society, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 6,093 (1968); U.S. Patent Nos. 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society, 7, 7, 3,844 (1955); Protiva et al., Collection of Czechoslovakian Chemical Communications, 44, 2,108 (1979); McEvoy et al., Journal of Organic Chemistry,

38, 3,350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland et al., Chemische Berichte, 96, 253 (1963) and references cited therein.

The compounds of formula I are acidic and form salts with bases. All such base salts, which can be prepared by conventional methods, are within the scope of the invention. For example, these salts can be prepared simply by contacting the acid and base components, usually in a stoichiometric ratio, either in a non-aqueous, aqueous or partially aqueous medium, as appropriate in each case. The resulting salts are isolated either by filtration, by precipitation with a non-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 that can be prepared are salts with primary, secondary or tertiary amines, alkali metal salts and alkaline earth metal salts. Especially valuable are the salts with ethanolamine, diethanolamine and triethanolamine.

Both organic and inorganic alkaline agents can be used to produce salts, including organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, hydrides alkaline earth metal and alkaline earth metal alkoxides. Representative bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toludine, ethanolamine and glucamine, secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine , pyrrolidine and piperidine, tertiary amines such as triethylamine, triethanolamine, Ν, Ν-dimethylaniline, 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 or suppressing 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 Milné and Twomey, Agents and Actions, 10, 31-37 (1980f)]. 1) weighing 18 to 20 g. All mice are fasted overnight before administration of the active ingredient and start of the test.

The compounds of formula I are dissolved or suspended in a vehicle comprising 5% ethanol, 5% surfactant emulsion 620 (a mixture of oxethylated fatty acid esters) and 90% saline. This environment also slogs as a control. Logarithmically scaled doses are used (ie ... 0.32, 1.0, 3.2, 10, 32 ... mg / kg), which are calculated on the basis of the weight of the salts (where applicable and not from Test substances are administered orally at various concentrations to maintain a constant volume at 10 ml / kg body weight, using the method described above by Milne and Twomey to determine potency and potency.

Mice are dosed orally with test compound and after 1 hour intraperitoneally with 2 mg / kg 2-phenyl-1,4-benzoquinone. 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. Záznamοπίο recording is performed for 5 minutes. Based on the suppression of abdominal constrictions in the lazing with control animals that were tested on the same day, the degree of analgesia (% MPE) was then calculated using the following formula:

t (average number of constrictions _ (average number of constrictions in com- mon animals) in test animals)% MPE = -------------— x 100 average number of constrictions in control animals

Approaching a% MPE of 100% means that the test substance has the highest possible effect; if approaching 0% it means that the test substance is not active.

The results obtained in this test with the compounds of the invention are summarized in the following table:

X R ¹ R ² Dose (mg / kg) % MPE H methyl phenyl 32 92.5 H 4-fluorophenyl phenyl 32 24.0 H benzyl phenyl 32 9.9 H 2-furyl phenyl 10 35.5 H (2-thienyl) methyl phenyl 32 73.5 H 2-thienyl phenyl 32 55.6 H cyclopropyl phenyl 32 3.0 H isopropyl phenyl 32 33.6 H cyclohexyl phenyl 32 28.2 H 2-thienyl 4-fluorophenyl 10 57.9 H 2-furyl 4-fluorophenyl 32 97.6 H methyl 4-fluorophenyl 32 65.8 5-C1 methyl phenyl 32 31.9 5-Cl isopropyl phenyl 32 22.3 5-Cl cyclohexyl phenyl 32 34.0 H benzyl 4-fluorophenyl 32 20.6

2524

Continuation table

X R ¹ R ² Dose (mg / kg) % MPE H phenoxymethyl phenyl 32 9.9 H phenoxymethyl 4-fluorophenyl 32 23.9 H cyclopropyl 4-fluorophenyl 32 5.7 H cyclohexyl 4-fluorophenyl 32 16.3 H 2-furyl isopropyl 32 96.3 5-Cl (2-thienyl) methyl phenyl 32 77.0 H (2-thienyl) methyl 4-fluorophenyl 32 75.3 5-Cl 2-furyl phenyl 32 66.9 H 3-furyl phenyl 32 45.4 5-Cl 2-thienyl phenyl 32 92.2 5-Cl 2-furyl 4-fluorophenyl 32 66.7 5-Cl cyclopropyl phenyl 32 6.5 5-C ^H 3 2-furyl 4-fluorophenyl 32 30.5 H 1-phenylethyl phenyl 32 45.4 H 2-thienyl isopropyl 32 98.9 H (2-thienyl) methyl isopropyl 32 81.1 5-Cl benzyl phenyl 32 38.2 5-Cl benzyl 4-fluorophenyl 32 35.5 5-Cl 2-thienyl 4-fluorophenyl 32 96.7 5-Cl phenoxymethyl 4-fluorophenyl 32 45.3 _5-CH3 2-furyl phenyl 32 32.2 _5-CH3 2-thienyl isopropyl 32 46.7 _5-CH3 2-furyl isopropyl 32 67.5 _5-CH3 phenoxymethyl isopropyl 32 33.3 5-Cl 2-thienyl isopropyl · 32 100 ALIGN!

continuation

Table

X R ¹ R ² Dose (mg / kg) MPI 5-Cl 2-furyl isopropyl 32 94.4 5-Cl phenoxymethyl isopropyl 32 62.4 5-Cl benzyl isopropyl 32 100 ALIGN! H 2-furyl 4-chlorophenyl 100 ALIGN! 30.3 H 2-thienyl 4-chlorophenyl 100 ALIGN! 65.4 H 4-fluorobenzyl phenyl 32 2.6 H (3-thienyl) methyl phenyl 32 45.0 H methyl cyclohexyl 32 19.8 H propyl 4-chlorophenyl 32 18.3 H 2-thienyl cyclohexyl 32 78.2 H 2-furyl cyclohexyl 32 57.9 H 2-thienyl 2-tolyl 10 2,0 H 2-furyl 2-tolyl 32 94.7 H (2-thienyl) methyl cyclohexyl 32 89.1 5-Cl isopropyl 4-fluorophenyl 32 4.8 5-Cl (2-thienyl) methyl 4-fluorophenyl 32 98.5 5-Cl (2-thienyl) methyl isopropyl 10 76.1 5-Cl cyclohexyl isopropyl 10 33.7 5-Cl 2-furyl cyclohexyl 10 81.6 5-Cl 2-thienyl cyclohexyl 10 98.8 5-Cl (2-thienyl) methyl cyclohexyl 32 98.9 H 2-furyl tert.butyl 32 95.7 H 2-thienyl tert.butyl 32 55.5 H benzyl tert.butyl 32 46.7 H (2-thienyl) methyl tert.butyl 32 100 ALIGN!

Continuation table

X R ¹ R ² Dose (mg / kg) % MPE 5-Cl 5-methyl-2-furyl cyclohexyl 32 82.3 5-Cl 5-methyl-2-furyl isopropyl 32 91.9 5-Cl 2-furyl tert.butyl 32 73.9 5-Cl methyl isopropyl 32 37.0 5 —Cl propyl cyclohexyl 32 99.3 5-Cl isopropy1 cyclohexyl 32 12.1 5-Cl 5-ethyl-2-furyl isopropyl 32 59.7 5-Cl 2-thienyl tert.butyl 32 43.6 H 5-ethyl-2-furyl cyclohexyl 32 18.3 5-Cl (2-thienyl (methyl tert.butyl 10 85.5 5-Cl methyl tert.butyl 32 45.2 5-Cl 5-ethyl-2-furyl cyclohexyl 32 100 ALIGN! 6-C1 2-thienyl females 1 32 51.1 5-Cl 5-ethyl-2-furyl phenyl 32 16.9 6-C1 2-furyl cyclohexyl 32 94.7 5-Cl 5-ethyl-2-furyl terč.butvl 32 19.6 H 2-thienyl fonoxymethyl 10 67.3 5-F 2-furyl phenyl 32 92.2 5-F (2-thienyl) methyl females 1 32 100 ALIGN! 5-F 2-furyl cyclohexyl 32 100 ALIGN! 5-F 2-thienyl cyclohexyl 32 ] 00 5-F 2-furyl ture.butyl 32 80.9 5-F 2-thienyl tert.butyl 32 85.9 5-F (2-thienyl) methyl tert.butyl 32 92.2 5-F (2-thienyl) methyl cyclohexyl 32 100 ALIGN! 5-Cl 2-thienyl phenoxymethyl 32 94.3

continue <> ιηί

T a b u 1 k d

X R ¹ R ² Dose (mg / kg) % MPE 6-Cl 2-thienyl tert.butyl 32 71.6 6-Cl 2-thienyl cyclohexyl 32 100 ALIGN! 6-Cl (2-thienyl) methyl cyclohexyl 32 95.0 6-Cl 2-furyl isopropyl 10 97.4 6-Cl 2-thienyl isopropyl 10 90.4 H 2-furyl phenoxymethyl 32 28.7 6-Cl 2-furyl phenyl 10 91.7 5-F 2-thienyl phenyl 32 95.0 6-F 2-furyl phenyl 10 90.1 6-Cl (2-thienyl) methyl phenyl 10 20.9 H (2-thienyl) methyl phenoxymethyl 10 47.3 6-Cl 2-furyl phenoxymethyl 10 98.9 5-F 2-furyl phenyl 10 91.9 6-Cl methyl phenyl 32 84.7 6-F 2-thienyl phenyl 10 18.9

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 limb of a rat by carrageenin (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1963).

Non-anesthetized adult male white rats weighing 150 g and 190 g are numbered, weighed and inked on their hind legs in the outer ankle area. The labeled limb of the animal is then immersed in mercury so that the level of mercury reaches exactly the mark. Mercury. is located 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. An increase in limb volume at 3 hours after carrageenin injection represents an individual inflammatory response.

Because of their analgesic activity, the compounds of formula I are useful for acute administration to mammals for the purpose of controlling pain, for example post-operative pain or post-traumatic pain. Further, the compounds of formula I are useful for chronic administration to mammals for the alleviation 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 alone or preferably in combination with pharmaceutically acceptable carriers or diluents in the form of pharmaceutical compositions. . 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 these purposes, including lactose and corn starch, and generally use glidants such as magnesium stearate to make them. Suitable diluents for preparing 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 customarily prepared and the pH of these solutions should be suitably adjusted and buffered. In the preparation of preparations for intravenous administration, the total concentration of soluble components should be controlled in order to keep the resulting preparation isotonic.

The daily dose of a compound of formula I or a salt thereof in human medicine is usually determined by the attending physician. This dose will vary depending on the age, weight and response of the patient, as well as the severity of the patient's symptoms and the efficacy of the compound administered.

For acute pain relief, the dose eliciting an effective analgesic response will in most cases range from 0.1 to 1.0 g as needed (for example, every 4 or 6 hours). In the case of chronic applications for the alleviation (treatment) of inflammation and pain, in most cases the daily dose will be from 0.5 to 0.3 g, preferably from 0.5 to 1.5 g, which can be administered as a single 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.

Ρ k k 1 and d 1

N-benzoyl-3- (p-furoyl) -2-oxindole-1-carboxaniide

To 30 ml of Ν, Ν-dimethylformamide was added with stirring first 2.8 g (10 mmol) of N-benzoyl-2-oxindole-1-carboxamide and then 2.9 g (24 mmol) of 4- ((, Ν-dimethylamino) ) pyridine. The mixture was cooled in ice and a solution of 1.6 g (12 mmol) of 2-furoyl chloride in 10 ml of Ν, Ν-dimethylformamide was added dropwise with stirring over 10 minutes. Stirring is continued for 30 minutes and then the reaction mixture is poured into a mixture of 250 ml of water and 8.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in ice, the precipitated solid material was filtered off and recrystallized from about 75 ml of acetic acid. 2.94 g of the title compound are obtained in the form of tan crystals, m.p. 190 ° C.

The UC spectrum of the title compound contains the following absorption:

Solvent

·.

Wavelength (nm)

methanol 245 375 6 920 2 530 methanol + 1 drop 249 7 200 0.1N sodium hydroxide 38 7 2 710

methanol + 1 drop

P, 1N hydrochloric acid 241 9 070

Example 2

N-benzoyl-3-acetyl-2-oxindole-1-carboxamide

To a suspension of 841 mg (3.0 mmol) of N-benzoyl-2-oxindole-1-carboxamide in 5 mL of N, N-dimethylformamide was added 806 mg (6.6 mmol) of 4- (Ν, Ν-dimethylamino) pyridine, stirring was continued for several minutes, then the resulting suspension was cooled in ice and a solution of 337 mg (3.3 mmol) of acetic anhydride in 2 ml of Ν, dimethyl-dimethylformamide was added dropwise. The reaction mixture is stirred for an additional hour and then poured into a mixture of 65-70 ml of ice-water and 2.2 ml of 3N hydrochloric acid. The precipitated solid material was filtered off and recrystallized from ethanol. 385 mg of the title compound are obtained as red-yellow crystals, m.p. 198 ° C.

For C 4,3 gHH^^O ^N NO requires C, 67.07; H, 4.38; N, 8.69. Found: C, 66.78; H, 4.65; N, 8.62.

Example 3

In analogy to Example 1, the corresponding N-substituted 2-oxindole-1-carboxamide is reacted in each case with the corresponding acid chloride of the formula

R ^{@ 1} --CO - C1 gives the following compounds.

X

O c

Φ

N

Φ rH ffi <0 2 rH σ> in r- cn

CN0 CN rH TP

X For p cn o o s in in o o p <O000P-P-00 ro x r- σ cn ro ro

-thienyl phenyl 165-166 64.60 3.61 7.18 64.53

CN r- rr · rc-j ro σ tp cn

ΓΟ 10 rH

CN <0 ro ’τ e ~ - σ

CN CN tP oo o ro oo 0 © σ

σ> cn σ

TP rH

10 lo σ i0 ro o τΡΜ * 00τΡ0τΡτΡ ro 0 σ σ co 0 σ o σ cn oo ro

CO Tp

O Tp ro ro ro o Γ o co σ o τ-H CN r ~ σ

τρ

CN cn σ 0

P-0 0 ro τρ> 0 10 o

what

WHAT

TP rH CN <0 10 co r- ro- ro o oo pO ro rH σ

σ rH

CN CN

P- 0

10

Γ ~ Γ- Γrο σ ro o CN tp 0 τρ 0 τρ t · cn o tp ι-t σ CN τρ τρ * 3 *

TP 0 TP

Ι'- rH o CN ro cn ro 0 σ o 0 ro

0 0 0

CN Tp σ x rH CN> N> N> N

CO Φ flj

CO 0 o

rH CN> 1b

Φ x

χ:

X

Φ £

> ι β

Φ • r | χ:

χ ι

CN

Ro- o ro co ρ ro ro co - σ

TP 0> N <0 o r r rH rH CN τρ

WHAT

TP rH CN CO

0 0 0> 1 β

Φ> ι μ

X

I <Ν rH β

Φ • rl χ:

χ

I (Ν

0 «0 · 0 0

Tp p-COrHrHrH> N> N fO fO> N co

WHAT

Γ—> ·

Φ

Xi

Ο

X

-rt> í υ

ro co> N i0

0 CN

0 ro 0

TP P0 Pco 0 x — I rH rH rH γοο o pX CN rH

CN σ

rH> 1 χ:

χ »φ

£ tx β

Φ • r |

Χ5

X

AND

CN> 1

X β

X

AND

CN

X X i - I

U Ο Ο

I I I

0 0 2 rt φ

χ;

ο .rt> 1 υ

rt φ Χ3 Ο, —ι -rt> ι ϋ rt φ

-β ο

> 1 rt φ

χ:

ο ι — I -rt> 1 □> 1 rt φ

-β

Ο r — I, rt> 1 υ

> 1 • μ β

-Q

χ »

Φ ε

> Η

X β

X

I <Ν> ι β

Φ it

X β

X

AND

CN

X

CJ

X ο

ι

-Cl 2-thienyl tert-butyl 200,5 56,36 4,23 6,92 56,55 cn m co in oj cr>

i £>

m>

ΓΩ rσ>

li- 'CO Γ'

-R- r> l £?

and

TJ (Tj

C • H t

O + J> 0 o

a. > 1>

Ή

C 'i0 • P o

d) o

H * C 'τΰ>

O> 0

About <U a:

Λ

E- <X

υ

I to B ffi

AT

AND

ID u

i in i — l

AT

Lfl (O

TJ β

ω cn o

O

T (TJ

H

N

O

P

N

O

Λ o

• n ftJ

Λί

O

I.E

O

TO,

Cl

Example 4

The following compounds can also be prepared using the methods described in the preceding examples:

XR ¹ R ² Melting point (° C)

H methyl phenyl 198 to 200 (decomposition) H isopropyl phenyl 165 (decomposition) H cyclohexyl phenyl 181 (decomposition) 5-C1 methyl phenyl 215 to 217 (decomposition) 5-C1 isopropyl phenyl 185.5 to 187, .5 (decomposition) 5-C1 cyclohexyl phenyl 192 to 194 (decomposition) H phenoxymethyl phenyl 202 (decomposition) H 3-furyl phenyl 187 (decomposition) 5-C1 cyclopropyl phenyl 213 to 215 (decomposition) H cyclopropyl phenyl 173 (decomposition) H isopropyl phenyl 165 (decomposition) H 1-phenylethyl phenyl 173 (decomposition) 5-C1 benzyl phenyl 239 to 240 (decomposition) ^5-CH3 2-furyl phenyl 204 to 205 (decomposition) H (3-thienyl) methyl phenyl 195 to 197 (decomposition) 6-C1 2-thienyl phenyl 192 to 193 (decomposition) 6-F 2-furyl phenyl 189 to 190 6-F 2-thienyl phenyl 190 to 194 5-C1 5-ethyl-2-furyl phenyl 202 to 203, 5 (decomposition) H 5-ethyl-2-furyl phenyl 174 to 175 5-F 2-furyl phenyl 172 (decomposition)

Continuation table

X R ¹ ) ** Trp 1 ¹ 01 <melting (° C) 5-F (2-thienyl) methyl. bitches l 189 (decomposition) 6-C1 2-fury L phenyl 199 to 20U 5-F (2-thienyl) methyl females 1 167 (roz k1 ad) 6-C1 (2-thienyl) methyl phenyl 199 to 200 (decomposition) H 2-thienyl 4-fluorophenyl 16 3,5 to 164, 5 (decomposition) H 2-furyl 4-fluorophenyl 164, 5 (decomposition) H methyl 4-fluorophenyl 205 to 20 Z (decomposition) H benzyl 4-fluoro phenyl 2 97 to 2 09 (decomposition) H cyclopropyl 4-fluorophenyls] 167, 6 (decomposition) H (2-thienyl) methyl 4-fluoro phenyl 216 to 2 1 7 (decomposition) 5-CH3 2-thienyl 4-fluorophenyl 178 to 1 79 (decomposition) 5-Cl 2-furyl 4-fluorophenyl 197 to 199 (decomposition) 5 ~ ^ch 3 2-furyl 4-fluorophenyl 179 to 181 (decomposition) 5-Cl 2-thienyl 4-fluorophenyl 191.5 to 192, 5 (decomposition) H (2-thienyl) methyl 4-Methoxyphenyls 197 to 198 (decomposition) H 2-thienyl 4-methoxyphenyl 173 (decomposition) H 2-furyl 4-methoxyphenyl 146 (decomposition) H cyclopropyl 4-methoxyphenyl 193 (decomposition) H isopropyl 4-methoxyphenyl 125 (decomposition) H 2-furyl 4-chlorophenyl ISO to 181 (decomposition) H 2-thienyl 4-chlorophenyl 170 to 171 (decomposition) H isopropyl 4-chlorophenyl 164 to 165 (decomposition) H propyl 4-chlorophenyl 184 to 185 (decomposition) H 2-thienyl 2-methylphenyl 173, 5 (decomposition) H 2-furyl 2-methylphenyl 167 to 168 (decomposition)

Continuation table

X R ¹ R ² Temp. and melting (° C) H (2-thienyl) methyl 2-methylphenyl 179.5 (decomposition) H cyclopropyl cyclohexyl 153 to 154 (decomposition) H methyl cyclohexyl 167 až 168 (decomposition) H 1-phenylethyl cyclohexyl 191 (decomposition) H 5-methyl-2-furyl cyclohexyl 163 až 165 (decomposition) 5-Cl 5-methyl-2-furyl cyclohexyl 197.5 (decomposition) 5-Cl methyl cyclohexyl 214.5 (decomposition) 5-Cl propyl cyclohexyl 162 až 163 (decomposition) 5-Cl isopropyl cyclohexyl 205 až 206 (decomposition) _5-CH3 2-furyl cyclohexyl 170 to 171 _5-CH3 2-thienyl cyclohexyl 153 to 154.5 (decomposition) H 5-ethyl-2-furyl cyclohexyl 146 to 147 _5-CH3 5-ethyl-2-furyl cyclohexyl 190 to 191 5 “ ^ch 3 (2-thienyl) methyl cyclohexyl 158 až 159 5-Cl 5-ethyl-2-furyl cyclohexyl 210 to 211 (decomposition) 6-Cl 2-furyl cyclohexyl 183 až 184 5-F 2-furyl cyclohexyl 186.5 to 187.5 (decomposition) 5-F 2-thienyl cyclohexyl 145.5 to 146.5 (decomposition) 5-F (2-thienyl) methyl cyclohexyl 164 až 165 6-Cl 2-thienyl cyclohexyl 172 až 173 6-Cl (2-thienyl) methyl cyclohexyl 173 až 175 (decomposition) 4-Cl 2-thienyl cyclohexyl 189 až 190 4-Cl (2-thienyl) methyl cyclohexyl 172 až 173 4-Cl methyl cyclohexyl 131 to 132 5-CF ₃ 2-furyl cyclohexyl 194 až 195 (decomposition)

Continuation table

X R ^] R ² Melting point (° C) 5- _C F ₃ 2-thienyl cyclohexyl 171 to 172 (decomposition) 6-F 2-furyl cyclohexyl 164 to 166 6-F 2-thienyl cyclohexyl _5-CH3 2-thienyl tert.butyl 189.5 (decomposition) 5-CH3 methyl tert.butyl 194 (decomposition) 5-C1 methyl tert.butyl 211.5 (decomposition) _5-CH3 5-ethyl-2-furyl tert.butyl • 214 to 215 5-C1 5-ethyl-2-furyl terč.butyl ' 224 to 225 5-F 2-furyl tert.butyl 212.5 (decomposition) 5-F 2-thienyl tert.butyl 183.5 (decomposition) 5-F (2-thienyl) methyl tert.butyl 161 (decomposition) 6-Cl 2-thienyl tert.butyl 191 to 192 ^5-CH3 2-thienyl isopropyl 146 to 147 (decomposition) 5-CH3 2-furyl isopropyl 166 to 167 (decomposition) 5-CH3 phenoxymethyl isopropyl 184 to 186 5-C1 phenoxymethyl isopropyl 186 to 188 (decomposition) 5-C1 benzyl isopropyl 184 to 185 5-C1 cyclohexyl isopropyl 206 to 208 (decomposition) ⁵ ~ ^CH3 5-methyl-2-furyl isopropyl 194 (decomposition) 5- ^ch 3 methyl isopropyl 158 to 159 5-C1 5-methyl-2-furyl isopropyl 198.5 to 199.5 5-C1 methyl isopropyl 215 to 216 H methyl isopropyl 170 to 172 H cyclohexyl isopropyl 188 to 189 H benzyl isopropyl 145 to 146

Continuation table

XR ¹ R ² Melting point (° C)

H phenoxymethyl isopropyl 157 to 158 5-Cl 5-ethyl-2-furyl isopropyl 209 to 211 (decomposition) 5-C1 isopropyl isopropyl 142 to 143 6-C1 2-furyl isopropyl 184 to 185 (decomposition) 6-C1 2-thienyl isopropyl 174.5 to 175 6-C1 (2-thienyl) methyl isopropyl 157 to 158 (decomposition) H 2-thienyl phenoxymethyl 161 to 162 5-C1 2-thienyl phenoxymethyl 182 to 183 H 2-furyl phenoxymethyl 173 to 175 (decomposition) H (2-thienyl) methyl phenoxymethyl 193 to 194 5-C1 2-furyl phenoxymethyl 194 to 195, .5

Example 5

Ethanolamine salt of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide

To a suspension of 562 mg (1.5 mmol) of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide in 10 mL of methanol was added 101 mg (1.65 mmol) of ethanolamine. The resulting mixture was heated to boiling for a few minutes and then allowed to cool. Filtration of the precipitated solid material gave 524 mg of the title salt, melting at 165-166 ° C. Yield: 80%.

Analysis: for ^C 23 ^H 21 ^N ° 6 3 calculated 63.44% C, 4.86% H, 9.65% N; Found: C, 63.27; H, 4.95; N, 9.58.

Example 6

Using the procedure of the previous example, using diethanolamine instead of ethanolamine, the diethanolamine salt of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide was prepared. The product resulting in a yield of 74% melts at 157-158 ° C.

Analysis calculated for: ^C 25 ^HH °% ° ^N NO 62: C, 62.62; H, 5.26; N, 8.76. Found: C, 62.53; H, 5.31; N, 8.74.

AND

Example 7

Using the procedure of Example 5, using triethanolamine instead of ethanolamine, the N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide salt with triethanolamine was prepared. The product resulting in a yield of 60% melts at 154-155 ° C.

Analysis: for ^C 27 ^H 29 ^N 3 ° 8 calculated 61.94% C, 5.58% H, 8.03% N; Found: C 61.84, H 5.61, N 7.99.

Example 8

N-benzoyl-2-oxindole-1-carboxamide

To a suspension of 399 mg (3.0 mmol) of 2-oxindole in 7 ml of toluene was added 485 mg (3.3 mmol) of benzoyl isocyanate. The reaction mixture was heated under reflux for 2.2 hours and then cooled to room temperature. The solid material is filtered off and dissolved in about 10 ml of hot acetonitrile. The acetonitrile solution is decolorized with activated carbon, allowed to cool and the precipitate formed is filtered off. Recrystallization of this precipitate from acetonitrile gave the title compound (131 mg), m.p. 183.5-184.5 ° C.

Analysis: for ^C i6 ^H i2 ° 3 ^N 2 calculated 68.56% C, 4.32% H, 9.99% N; Found: C, 68.37; H, 4.58; N, 10.16.

Example 9

In analogy to Example 8, the following compounds are reacted in each case with an appropriately substituted 2-oxindole with the corresponding acyl isocyanate:

II o

X R ^ Melting point (° C) Yield (t)

5-Cl phenyl 193 to 195 43 _5-CH3 phenyl 202 to 203 68 6-C1 phenyl 206 to 207 59 6-F phenyl 174 to 175, , 5 5-F phenyl 187 (decomposition) 37 H 4-fluorophenyl 177 to 178 (decomposition) 21 _5-CH3 4-fluorophenyl 209 to 211 (decomposition) 78

Table X continuation R ² Melting point <° C) Yield 5-Cl 4-fluorophenyl 198 to 199 (decomposition) 59 H 4-methoxyphenyl 180 (decomposition) 72 H 4-chlorophenyl 186.5 to 187.5 (decomposition) 53 H 2-methylphenyl 166.5 to 167.5 59 H cyclohexyl 144.5 to 145.5 62 5-Cl cyclohexyl 172 to 174 63 _5-CH3 cyclohexyl 140-141.5 68 6-Cl cyclohexyl 181 to 182 56 5-F cyclohexyl 163.5 to 164.5 63 4-Cl cyclohexyl 173 to 174 69 5-CF ₃ cyclohexyl 177.5 to 178.5 (decomposition) 40 6-F cyclohexyl 203 to 206 43 H tert.butyl 151 to 152 35 S-CHa tert.butyl 202.5 (decomposition) 34 5-Cl tert.butyl 176.5 to 177.5 (decomposition) 43 5-F tert.butyl 161.5 to 162.5 (decomposition) 31 6-Cl tert.butyl 146 to 147 42 H isopropyl 114 to 115 23 5-CH3 isopropyl 169 to 171 38 5-Cl isopropyl 164 to 165 77 6-Cl isopropyl 128 to 129 69 H fenoxymethyl · 187 to 188 78 5-Cl phenoxymethyl 218 to 219 51

«

25249H

SUBJECT OF THE INVENTION

Claims (6)

SUBJECT OF THE INVENTION 3. A process for the preparation of 1,3-disubstituted 2-oxindoles of general formula I In which X represents a hydrogen, fluorine or chlorine atom, a C1-C4 alkyl group or a trifluoromethyl group represents a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a 1-phenylalkyl group up to 3 carbon atoms in the alkyl moiety, phenoxyalkyl of 1 to 3 carbon atoms in the alkyl moiety, furyl group, thienyl, alkylfuryl group of 1 to 3 carbon atoms in the alkyl moiety or thienylmethyl group and is an alkyl group of 1 to 6 carbon atoms C 3 -C 7 cycloalkyl, phenoxymethyl or the radical of the formula hydrogen, fluorine or chlorine, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and their pharmaceutically acceptable base salts, characterized by: in that the compound of formula II (II) 0 = ^C-NH-C-R2 II o wherein R ² and X are as defined above, reacted with an activated carboxylic acid derivative of the general formula R ^X -C (= O) -OH in which R is as defined above, in an inert solvent, and the resulting product is optionally converted to its pharmaceutically acceptable base salt. 2. A process according to claim 1, wherein the reaction is carried out using one molar equivalent of an activated carboxylic acid derivative of the formula: R ^1_ C (= 0) -OH wherein ^R1 has the meaning as in claim 1 in an inert solvent in the presence of one to four molar equivalents of a basic agent at temperatures ranging from -10 to 25 ° C. 3. A process according to claim 2 wherein the activated derivative of the above acid is a chloride of the acid and the reaction is carried out in a polar aprotic solvent. 4. A process according to any one of claims 1 to 3, wherein the corresponding starting materials are used to form compounds of formula I wherein X is hydrogen or chlorine at the 5-position and the remaining general symbols are as defined above. 5. A process according to claim 4, wherein the corresponding starting materials are used to form compounds of formula I wherein 2 is furyl, 2-thienyl, or (2-thienyl) methyl, X has and R is as defined above. 6. A process according to claim 5, wherein the corresponding starting materials are used to form a compound of formula I wherein X is hydrogen, 2-furyl and R is phenyl.