DK161311B - METHOD OF ANALOGY FOR THE PREPARATION OF 2-SUBSTITUTED 3-CARBOXYLKYL-4,5-CONDENSED PYRROLINE-1 SUBSTANCES OR SALTS THEREOF - Google Patents

Description

in

DK 161311B

The present invention relates to an analogous process for the preparation of novel 2-substituted 3-carboxyalkyl-4,5-fused pyrroline-1-one derivatives of the general formula I shown in claim 1, wherein X, Y, Z 5 and A have the same meanings stated, or salts thereof. The connections include valuable as anxiolytic drugs.

The process according to the invention is characterized by the characterizing part of claim 1.

To date, benzodiazepine compounds have been extensively used as anti-anxiety drugs, but due to drug dependence and side effects such as hypnotic and muscle relaxant effects, they do not appear to be completely satisfactory. Therefore, a number of studies have been conducted to develop anti-anxiety drugs which are not benzodiazepines, and these studies have now resulted in providing a process for the preparation of the compounds of this invention which have very satisfactory properties.

From Danish Patent Specification No. 129,715, 20 isoindoline derivatives of the general formula are known.

ISLAND

O - CO - N * SN - CHO W 3 where X represents hydrogen, halogen, alkyl, alkoxy, alkylthio, dialkylamino or phenoxy. It is stated in the script that the compounds are particularly effective as tranquilizers and anticonvulsants.

From Danish Patent Specification No. 138,117, isoindole derivatives of the general formula 35 are known.

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2

ISLAND

i || N - \ - | -J- Ϊ 2 5 0 - CO - if ^ S - CH-, v ^ j 3 (0) n where Y represents halogen or nitro and n is the number 0 or 1 q 1. The compounds are attributed to the same effects as those of the above formula first

Swedish Patent Specification No. 398,503 discloses 5,6-dihydropyrrolo [3,4-b] pyrazine derivatives of the general formula 15 O λΛ IN - Ά 3 O - CO - N VN - CEL · 20 \ / Å where A represents optionally halogen substituted pyridyl or 2-quinolyl. In the script, these compounds are attributed to the same effects as compounds 1 and 2.

Finally, U.S. Patent No. 4,124,711 derivatives of ditiepino [1,4] [2,3-c] pyrrole of the general formula are known.

Okay

O — CO — N N — R

wherein Ά represents phenyl, pyrid-2-yl, quinol-2-yl or 1,8-35 naphthyridin-2-yl, each optionally substituted by halogen, alkyl, alkoxy, cyano or nitro; and R represents hydrogen, alkyl, alkenyl or alkanoyl. It is enlightened

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3 of the script that the compounds are particularly effective as tranquilizers and anticonvulsants as well as relaxants and hypnotics.

It is common for the compounds of formulas 1 to 4 that they all have the carbonyl group associated with the pyrrole ring over an oxygen atom. In contrast, in the compounds of formula I prepared by the process of the invention, there is a C1- group between the pyrrole ring and the carbonyl group Y.

Thus, there is a substantial structural difference which implies that the compounds of formula I prepared by the process according to the invention have higher physicochemical stability than the known compounds of formulas 1-4. The linking group ~ CH2- between the pyrrole group and the carbonyl group is not bioequivalent to the linking group -O-, so one cannot conclude from the biological properties of the compounds of the formula I according to the invention of the formula I Thus, it is known from Thompkins and Lee (Journal of Pharmaceutical Sciences 64, no. 5, pp. 760-763 (1975)) that while acetylsalicylic acid has analgesic effect, the thus isosteric compound 2-acetonylbenzoic acid has no such effect. . The difference is precisely that the link between the benzene ring and the carbonyl group in acetylsalicylic acid is -O-, while in 2-acetonylbenzoic acid it is -C1-.

1) A compound of formula I wherein Y is a carboxyl group, i. a compound of the formula

ISLAND

3 ° oA- z A tj-X I-a

' "' T

CH2COOH

can be prepared by the following reactions 35 4

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-V ° τ OH '0R °

III IV

, o oA- οΛ-> οΛ '

Z A] | N-X -> 2i A I N-X> \ A J1 JI "X

hydrolysis - I / COOR 4

CH CH ^ COOR4 CH9C00H

COOR 2 1 5 3 V II-a I-a wherein X, Z and ring A have the meanings specified in claim 1 and R4 and R ° are lower alkyl.

The starting compound of the general formula III can be prepared according to the procedure described in J. Org. Chem. 26, 2273, 1961, or by the method described in J. Org. Chem. 26, 2273, 1961, from a compound of general formula III 'which can be prepared by or in accordance with the processes described in Japanese Patent Publication No. 11940/1973, Japanese Published and Unexamined Patent No. 100495/1977 (Kokai Sho-52-100495), Helv. Chim. Acta 52, 2228 (1965), J. Heterocycl.

Chem. 7, 1121, 1970, and Chem. Ber. 40, 4850, 1907.

ISLAND

GlJ> o

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5 wherein Z and ring A are as defined in claim 1.

Thus, a compound of general formula III is dissolved in a lower alkanol R ° OH and the solution is heated together with a catalytic amount of concentrated hydrochloric acid, thereby easily recovering the alkyl ether IV. The ether compound IV can be readily converted to a compound V by reaction with a malonic acid diester, e.g., dimethylmalonate or diethylmalonate, under the usual conditions of a Friedel-Crafts reaction, e.g., in dichloromethane or dichloroethane in the presence of aluminum chloride. When the compound V

10 is heated to 170 to 180 ° C in dimethyl sulfoxide in the presence of a small excess of sodium chloride and water, compound II-a is obtained. This compound is then hydrolyzed in the presence of a base such as potassium carbonate, sodium hydroxide or potassium hydroxide to form compound I-a. This reaction is generally carried out in a solvent such as methanol, ethanol, tetrahydrofuran or dimethylformamide. The reaction is carried out at a temperature of from -10 ° C to + 100 ° C and generally at a temperature between room temperature and the boiling point of the solvent (e.g. methanol).

2) A compound I wherein Y is an esterified carboxyl group, i. a compound of the formula

ISLAND

II

I-b '' -V,

CH 2 COOR

30, wherein Z, X, A and R have the meanings given in claim 1, can be prepared by esterification of the carboxylic acid I-a obtained in the ways described in 1) or a reactive derivative thereof.

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with an alcohol of the formula

R1OH X

where R "* · has the meaning given above.

By reacting the carboxylic acid I-a with the alcohol X, a mixture thereof is heated in the presence of a catalyst to form an ester I-b. This reaction is generally carried out using excess alcohol X and can be accelerated by azeotropic removal of water formed during the reactions. The catalyst may be an inorganic acid such as sulfuric acid or hydrochloric acid, an organic acid or anhydride thereof such as p-toluenesulfonic acid, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride, or a salt of a heavy metal such as tin, cobalt, iron or aluminum, e.g. . An alternative process wherein the compound I-a is reacted with the alcohol X to form a compound I-b consists in reaction in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole.

This reaction is generally carried out in pyridine, but any other organic solvent which does not interfere with the reaction can be used. The reaction temperature can be from -20 ° C to approx. 150 ° C and generally the reaction proceeds satisfactorily at room temperature.

Examples of a reactive derivative of the compound 25 xa include acid halides such as acid chlorides and acid bromides, acid anhydrides obtained by the elimination of one molecule of water from two molecules of compound Ia and the mixed anhydrides obtained by replacement of the carboxyl hydrogen of compound Ia with, for example, ethoxycarbonyl, isobutyloxycarbonyl or benzyloxycarbonyl. Reaction of such a reactive derivative with the alcohol X can generally be carried out in a solvent which does not interfere with the reaction, e.g. ether, benzene, tetrahydrofuran, dichloromethane, chloroform or dimethylformamide. If necessary, this reaction is carried out in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine, diisopropylethylamine or triethylenediamine, and the reaction temperature is from ca. -10 ° C to + 100 ° C, preferably 0 to 30 ° C.

7

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Compound I-b can also be prepared by reacting an alkali metal salt, e.g., the sodium salt, or the silver salt of compound I-a with a halide of the formula

R ^ B XI

5 where R 1 has the meaning given above and B is a halogen atom.

The compound I-b, which is a t-butyl group, can also be prepared by adding the compound I-a to the isobutylene. This reaction is carried out in the presence of an acid catalyst such as sulfuric acid or boron trifluoride.

Furthermore, one can in the process of synthesis of compound

IIa-a from Compound IV using a di-lower alkyl ester of malonic acid or another suitable ester to prepare the corresponding ester I-b.

3) Compound I wherein Y is an amidated carboxyl group, i. a compound of formula 0

Ck "ll ^ N-X

Wherein X, Z, R, R and the ring A are as defined in claim 1, prepared by reacting an ester Ib or 2 ^ a carboxylic acid Ia obtained as described in 1) above, or a reactive derivative thereof, with an amino compound of formula R 2

HN XII

30 2 3 where R and R have the above meanings.

To prepare compound I-c by reacting the ester I-b with the amino compound XII, the reaction is carried out either in a solvent such as toluene, xylene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or dimethylformamide, or in no solvent. If necessary, the reaction may be carried out in the presence of a base such as pyridine, picoline, triethylamine, 4-dimethylaminopyridine, potassium carbonate or 8

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sodium carbonate, an acid such as p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid, or an alkali metal salt such as lithium chloride, sodium chloride, sodium iodide, lithium iodide, lithium bromide or sodium bromide. The reaction is usually carried out at a temperature of 0-260 ° C and preferably at 60-130 ° C.

As examples of reactive derivatives of the carboxyl group of compound 1a, in addition to the aforementioned process 2), such other derivatives as, for example, N . The reaction is generally carried out in a solvent such as dichloromethane, tetrahydrofuran, chloroform, dimethylformamide or acetonitrile. These solvents are mentioned by way of example only and any other solvent which does not interfere with the reaction can be used successfully. If necessary, this reaction can be carried out in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine, diisopropylethylamine, triethylenediamine, potassium carbonate or sodium hydroxide. The reaction temperature is generally from ca. -10 ° C to approx. + 100 ° C, preferably 0 to 30 ° C. When using compound I-a as such in place of a reactive derivative thereof, the reaction is carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, carbonyl diimidazole, diethylphosphorus cyanidate or diphenylphosphoryl azide. The reaction may also be carried out in the presence of a base such as pyridine, picoline, triethylamine, sodium hydroxide or potassium carbonate. The reaction is generally carried out at a temperature of approx.

-20 ° C to approx. + 150 ° C. In most cases, the reaction proceeds satisfactorily at room temperature.

In addition, a compound of the general formula 2m flour I can also be prepared in one step by reacting the compound III with a compound of the formula

Ph3P = CHY XIII

33 wherein Y is as defined in claim 1 and Ph is phenyl.

This reaction is carried out in an organic solvent such as toluene, ethyl acetate or methoxyethane.

In addition to these solvents, one can also use one

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9 any other organic solvent which does not interfere with the reaction. The reaction temperature is generally from ca. 10 to approx. 120 ° C. When Y is an esterified carboxyl group (I-b, n = 1), the amide i-c can be prepared by treating the ester 5 (I-b, n = 1) with the above-described amine XII under the reaction conditions stated. If necessary, it is first hydrolyzed to the free carboxyl group. It is then converted to a reactive derivative such as an acid chloride or mixed acid anhydride and reacted with the aforementioned amine. The carboxylic acid mentioned above may also be reacted with the amine in the presence of an acid activator such as carbonyl imidazole or diethylphosphorus cyanidate to form a compound I-c wherein Y is an amidated carboxyl group.

Among the aforementioned compounds XIII, the compound of formula 15 is Ph3P = CHCOOR1 XIII-b wherein R 2 and Bh have the meanings given and are known, for example, by the process described in Helv. Chim. Acta. 44, 1242, 1957.

The compound of formula 20

Ph0P = CHCON ^ XIII-C

Wherein Ph, R and R have the meanings indicated, 25 are novel and can be prepared, for example, by treating an α-haloacetamide compound of formula ^ 2

B 1CHLCON XIV

2 \ 3

R

Wherein B 'is a halogen atom and R and R have the meanings given in claim 1, with triphenylphosphine in known manner, for example by heating these two compounds together to 10-120 ° C in toluene, benzene, ethyl acetate, acetonitrile or dimethylformamide, and then treat the resulting phosphonium salt 35 s © © B 2

Ph3Pw -CH2CON 3 XV

R

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10 2 3 β © where Β ', R and R have the given meanings, in known manner, for example, by reacting the compound XV with alkali such as sodium hydroxide or potassium hydroxide in aqueous solution at 0-50 ° C.

The present compounds I, which can be prepared by the reactions described above, viz. The compounds I-a, I-b and I-c can all be isolated from the reaction mixture by known separation and purification processes known per se, eg extraction, recrystallization and / or column chromatography.

Compound I-a, where Y is a free carboxyl group, Ί0 can be isolated in the form of a salt, for example a metal salt such as the sodium, potassium or calcium salt. When the compound I is basic, it can be isolated in the form of a salt with an acid, and examples thereof are pharmaceutically acceptable salts such as salts with inorganic acids, e.g., the hydrochloride, nitrate, phosphate or hydrobromide, or salts with organic acids, e.g., acetate, fumarate. , the maleate, the oxalate, the tartrate or the methanesulfonate.

The present compounds may exist as optical isomers, and the invention is directed to the preparation of both such isomers and of racemates. In all of the aforementioned processes 20, a compound of formula I is generally prepared in racial form, but it can be resolved into two optically active compounds by the known methods for such purposes.

The compounds of the general formula I, according to the method of the invention, in particular the compounds of formula I-q ·, act on the central nervous system and here exhibit a strong anti-anxiety effect as demonstrated by anti-conflict tests in rats. The minimum lethal dose (MLD) of the subject compounds is at least 500 mg / kg in mice and the minimum effective dose (MED) is not more than 2.5 mg / kg in rats.

30 Since the safety margin of the compounds is very large and the side effects of the compounds in the form of hypnotic and muscle relaxation 35 11

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While the side effects are very weak compared to these side effects of the anti-anxiety drugs in the form of benzodiazepines currently on the market, the compounds can be safely and effectively administered as anti-anxiety drugs in mammals and humans. Indications for use of these compounds may include various psychosomatic disorders such as autonomic disability, nervous vomiting, neurodermatitis, alopecia areata, nervous angina, nervous dyspnea and similar conditions as well as anxiety disorders, and the compound of formula I

can be used to prevent or treat such a disease-1 Π me. Furthermore, these compounds have anticonvulsant effects and can therefore be used in cases of epilepsy and traumatic convulsions, among other things. The present compounds may be administered orally or otherwise to mammals and humans and in various dosage forms such as tablets, granules, capsules, 15. . .

injection preparations and suppositories. The dose depends, among other things, on the patient's illness and condition, but generally these compounds are administered in daily doses of 0.01 to 50 mg per day. kg of body weight in animals and in daily doses of 0.1 to 100 mg, preferably 0.5 to 20 mg in the case of adult humans.

20 o o

It will be understood from the foregoing that compounds I-a and I-b are useful as intermediates in the preparation of compounds of formula I-c.

The therapeutic effect of the compounds will be elucidated hereinafter in some experiments and the method of the invention subsequently cited in some examples.

Attempt

The pharmacological properties of compounds I were investigated by determining the compounds' substitutability of radioactive diazepam from a benzodiazepine receptor.

The method consisted of performing specific benzodiazepine receptor binding in accordance with that of C. Braestrup and R.F. Squiras in European J. Pharmacol., Vol. 48, 263-270, 1978. Thus, crude mitochondrial fractions from the cerebral cortex were suspended in male SD rats and at 9-10 weeks of age in 50 mmol tris-HCl buffer pH 7.4 and incubated with one of a series of concentrations of the test compound and (½) 12

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diazepam (final concentration 2 nM) at 4 ° C for 20 minutes. Then, the suspension was filtered through a Whatman GF / B glass fiber filter and the radioactivity of (H) diazepam on the filter was measured by the liquid scintillation method. The concentration of the test substance which caused 50% s inhibition of (H) diazepam-specific binding was taken as the IC The results are shown in Table 1 below.

Table 1 10 3

Effect of specific binding of (H) diazepam

Compound I: τη χ ^ 50 ring ΑΧ γ (ηΜ) 15 --- __ α ο «ο 8'86

Uk we “V-Q

Ik ~ 'ki ~ 0CH3 CON N-CH3 1.99 25 \ _J- ° CE3 C0 \ _y 0.794 30 | ^ j [^ -O0CH3 CoQ 4.46 ΓΤ CON ^ \ 2.40 02N /' S5V / XV — 7 \ / 35 rγ α ^ CON j 0.645

If zk A

N N ^ \ cl

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1 3 (Table 1 continued)

Compound I: ICcri

you

ring A X Y (nM) 5

XX -O-0 ™ 3 coO

H2N ^ 10 OC coQ 4'9 »

(X coQ

C X ~ <CX "ci -O 5.75 ^ r - / ~ Λ-OCH3 CcX \ 1.05 20 ^ 5Λ ^

Xs Y _jT \ / “Λ I - <y CON) 7.58 \ = / \ _ /

»OC" O.

OC i-C 776

/ s V. / / “X

30 I - \\ // 0CH3 con I 0.275 '-sA Α-Α' \ --- f ssν '/ = \ / ~ \

LSX \ j 'C0 \ J

χχχ ~ χ // ~ qch3 co \ J] '66

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14 (Table 1 continued)

Compound I: IC 50 ring A X Y (nM) (X ~ {_} - 0CS3 C00 9'55 Q (- <^ - and 3 C0®_) 21'4

Cx-O-cH3 coO

CX O ~ a coO

CX y «C ° VV CH3 457 20 α c ° N ^ 70.8

J-X / H

and jl I CON Y 0.794

^ N ^ N ^ Cl N '0H

Q (XXX covXCH] '' 29

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15

Further experiments with two compounds were performed.

The action against convulsions induced by pentylene tetrazole was performed with 4-5 week old mice, in groups of 5 eight. The mice were orally administered different doses of the test compound and 30 minutes later subcutaneous pentylenetetrazole was injected at a dose of 150 mg / kg. The mice were then placed in separate cages and observed for signs of seizures and deaths for the next 60 minutes.

ED 50 is a calculated dose that prevented tonic bends, tonic stretches, and death of 50% of animals for 60 minutes after the administration of pentylenetetrazole, see D.J. Finney, Probit Analysis, 3rd Edition (1971), Cambridge University Press.

15 The results are shown in the table below.

The measures of activity against anxiety were performed according to Vogel et al (Psychopharmacologica 2J, 1 (1979)) as follows:

An apparatus provided with a large clear box with a stainless steel grate as a floor and a smaller, opaque dark box provided with drinking pipes was arranged in such a way that a rat placed therein on the sole of the foot could have electric shocks through the grating floor every two seconds or after every twentieth candy. The test compound was given to 25 male rats (Wistar strain) who had not had access to water for 48 hours prior to the experiment, and each rat was then placed in the apparatus described 30 minutes after administration and the number of sweets was recorded through 3 minutes from the first shock. The increase in the number of sweets 30 compared to a group of rats that had received physiological saline was determined and taken as a measure of the strength of the anti-anxiety effect, and the least effective

dose (EDcn) determined accordingly. BU

The results of this are also shown in the table below.

The toxicity of the two in this compound was 0/4 with oral administration of 500 mg / kg to mice.

35 bell.

16

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Table

Compound Anti-pentylene-Vogel conflict-drinking tetrazole, ED 2% increase (mg / kg, (mouse) mg / kg pVo. Wistar rats) S 0 JT / ^ / ^ Λ,> 100 42 (40)

CH2COOH

10 o In iQn-Q. > 100 82 (40) ch2cooc2h5 15 _

Example 1 2Q 3-Oxo-2-phenylisoindolin-1-acetic acid a) 1 ml of concentrated sulfuric acid was added to a solution of 27 g of 3-hydroxy-2-enylisoindolin-1-one in 300 ml of methanol and the mixture was refluxed in 1.5 hours. Then 200 ml of the methanol was distilled off under reduced pressure and 500 ml of 21-saturated sodium hydrogen carbonate solution was added and extraction with ethyl acetate. The extract was washed with water and dried and the solvent was distilled off to give 28 g of crystals of 3-methoxy-2-phenylisoindolin-1-one which, after recrystallization from ethyl acetate, melted at 83-84 ° C.

2q Calculated for C15 H12 N2 O2: C 75.30 H 5.48 N 5.85

Found: C 75.57 H 5.33 N 5.93%.

35 17

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b) A solution of 8.3 g of the above product and 6.7 g of diethyl malonate in 50 ml of dichloroethane was added dropwise to a suspension of 7.5 g of aluminum chloride in 80 ml of dichloroethane with stirring at room temperature. After the addition is complete, the mixture is refluxed for 40 minutes and then cooled. Then 300 ml of 6N hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour, then 150 ml of dichloroethane was added. The resulting mixture was shaken well and the organic layer was separated, washed with water, aqueous sodium hydrogen carbonate and water in the above order and dried. The solvent was distilled off and 10.5 g of ethyl 3-oxo-2-phenylisoindoline-1-malonate was obtained as an oil.

c) 10.5 g of the above product was dissolved in 20 ml of dimethyl sulfoxide, to the solution was added 0.51 g of water and 1.7 g of sodium chloride and the mixture was stirred under heating at 170-180 ° C for 3 hours. After cooling, the reaction mixture was poured into 500 ml of ice water and extracted with 4 ml of a 1: 1 mixture of ethyl acetate and ether. After washing and removing water, the solvent was distilled off. The crystalline residue was washed with hexane and collected by filtration to give 5.6 g of ethyl 3-oxo-2-phenylisoindoline-1-acetate which was purified by recrystallization from ether and then melted at 109-110 ° C.

Calculated for C 73.20 H 5.80 N 4.74 Found: C 72.89 H 5.61 N 4.79%.

d) 5 g of the above crystals were dissolved in 50 ml of methanol, to the solution was added 15 ml of 15% aqueous solution of potassium carbonate and the mixture was refluxed for 1.5 hours. The methanol 30 was distilled off under reduced pressure followed by the addition of 100 ml of water and 100 ml of ether. The mixture was shaken and the aqueous layer was separated and acidified with concentrated hydrochloric acid. The crystalline precipitate was collected by filtration and dried. Recrystallization from methanol / ethyl acetate gave the title compound of m.p. 204-205 ° C in a yield of 3.8 g. Calculated for c16 H13 NO3: C 71.90 H 4.90 N 5.24

Found: C 72.07 H 5.00 N 5.30%

Example 2 18

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The following 3-oxo-2- (substituted phenyl) -isoindoline-1-acetic acid was prepared from the corresponding 3-hydroxy-2- (substituted phenyl) -isoindolin-1-ones in a similar manner as described in Example 1:

i) 3-Oxo-2- (2-chlorophenyl) -isoindoline-1-acetic acid, m.p. 163-165 ° C

Calcd for C C gH ^N NCC Cl Cl: C 63.82 H 4.00 N 4.64

Found: C, 63.79; H, 4.12; N, 4.77%.

1 ft

ii) 3-Oxo-2- (3-chlorophenyl) -isoindol-1-acetic acid, m.p. 157-160 ° C

Calcd. For C 16 H 12 NO 3 Cl: C 63.69 H 4.00 N 4.64

Found: C 63.82 H 4.04 N 4.46%.

iii) 3-Oxo-2- (4-chlorophenyl) -isoindoline-1-acetic acid, m.p.

204-205 ° C

Calculated for C C ^H- ^NO Cl Cl: C 63.69 H 4.00 N 4.64

Found: C 63.74 H 3.97 N 4.16%

iv) 3-Oxo-2- (4-methoxyphenyl) -isoindoline-1-acetic acid, m.p. 222-223 ° C

20

Calcd for C 17 H 15 NO 4: C 68.67 H 5.08 N 4.71

Found: C, 68.49; H, 4.90; N, 4.69%.

v) 3-Oxo-2- (5-chloro-2-pyridyl) -isoindoline-1-acetic acid, m.p. 159-160 ° C

Calculated for C C ^HH OO₂Cl: C 59.51 H 3.66 N 9.25 Found: C 59.76 H 3.66 N 9.11%.

Example 3 2-Phenyl-3-piperidinocarbonylmethylisoindolin-1-one A mixture of 1.8 g of 3-oxo-2-phenylisoindoline-1-acetic acid and 7 ml of thionyl chloride was heated to 70 ° C for 10 minutes and excess thionyl chloride was distilled off under reduced pressure. pressure to produce the corresponding acid chloride. 1 ml of triethylamine was added to a solution of 0.62 g of piperidine in 30 ml of methylene chloride and to this solution the above acid chloride was added portionwise with stirring at room temperature. The mixture was further stirred at room temperature for 30 minutes, adding

19 DK 161311 E

100 ml of methylene chloride were washed and the whole mixture was washed with water.

After drying, the solvent was distilled off to give 1.8 g of crystals which were recrystallized from ethyl acetate. Mp. 122-123 ° C and 134-136 ° C (double m.p.)

Calcd for C 21 H 22 N 2 O 2: C 75.42 H 6.63 N 8.38

Found: C, 75.42; H, 6.44; N, 8.25%.

Example 4 In the same way as in Example 3, the compounds listed in Table 2 were obtained.

15 20 25 30 35 2

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DK 161311 B

Example 5 22 3- (4-Benzylpiperazin-1-yl) carbonylmethyl-2-phenylisoindolin-1-one oxalate ________ 4.3 g of an oily product prepared from 2.67 g of 3-oxo-2- phenylisoindoline-1-acetic acid and 1.94 g of 1-benzylpiperazine in the same manner as described in Example 3 were dissolved in 4 ml of methanol and to this solution was added a solution of 1.5 g of oxalic acid dihydrate in 6 ml of methanol and the precipitated crystals were collected at filtration. Yield 4.90 g, 10 m.p. 207-210 ° C (recrystallization from methanol).

Calcd for ^ 7 ^ 27 ^ 3 ^ 2 '^ 2H2 ° 4' H2 O: c 66 * 40 H 5.76 N 8.01

Found: C 66.26 H 5.63 N 8.17%.

Example 6 3-Piperidinocarbonylmethyl-2- (5-chloro-2-pyridyl) -isoindolin-1-one 1 g 3-oxo-2- (5-chloro-2-pyridyl) -isoindoline-1-acetic acid and O, 8 g of triethylamine was dissolved in 20 ml of dry tetrahydrofuran and, under ice-cooling and stirring, 0.39 g of ethoxycarbonyl chloride was added portionwise. The mixture was stirred for 30 minutes, 0.56 g of piperidine was added and the whole mixture was stirred for a further 30 minutes. The reaction mixture was poured into 500 ml of ice water followed by extraction with ethyl acetate. The extract was washed with water and dried. Then the ethyl acetate was distilled off and the residue treated with ether. The resulting crystals thus obtained were collected by filtration and recrystallized from ethyl acetate to give 0.32 g of colorless crystals melting at 165-166 ° C.

Example 7 By proceeding in the manner described in Example 6 with the difference that 4-methylpiperazine was used instead of piperidine, 3- (4-methylpiperazin-1-yl) carbonylmethyl-2- (5-chloro-1-yl) carbonate was obtained. 2-pyridyl) -isoindolin-1-one with m.p. 190-193 ° C.

Example 8 23

DK 161311B

Methyl-3-oxo-2- (5-chloro-2-pyridyl) isoindolin-l-acetate

To 1 g of 3-OXO-2- (5-chloro-2-pyridyl) -isoindoline-1-acetic acid was added 20 ml of 10% methanolic hydrochloric acid and the mixture was refluxed. After 5 hours, the reaction mixture was concentrated under reduced pressure. 100 ml of aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give ca. 1 g of crystals which were recrystallized from 10 ethyl acetate / ether. Mp. 110-111 ° C.

Calculated for C 60.67 H 4.13 N 8.84

Found: C, 60.50; H, 4.13; N, 8.78%.

Example 9 In the manner described in Example 8, the compound was obtained methyl 3-oxo-2- (4-methoxyphenyl) -isoindoline-1-acetate, m.p. 80 ° C. Calc'd for C 18 H 17 NO 4: C 69.44 H 5.50 N 4.50

Found: C, 69.56; H, 5.07; N, 5.62%.

20

Example 10 In the same manner as sections a) - c) of Example 1, the following compounds were obtained: i) Ethyl 3-oxo-2- (3-chlorophenyl) isoindoline-1-acetate, m.p.

82-83 ° C.

Calculated for C C-HH gNOgCl: C 65.55 H 4.89 N 4.24

Found: C 65.51 H 4.73 N 4.11% ii) Ethyl 3-oxo-2- (4-chlorophenyl) isoindoline-1-acetate, m.p.

55-56 ° C.

Calculated for C C ^H ^ gNOgCl: C 65.55 H 4.89 N 4.24

Found: C, 65.27; H, 4.64; N, 4.00%.

Example 1.1 1.1 g of 3-hydroxy-2- (3,4,5-trimethoxyphenyl) -isoindolin-1-one and 1.8 g of piperidinocarbonylmethylenetriphenylphosphorane were dissolved.

DK 161311B

24 in 20 ml of toluene and the solution was refluxed for 2 hours. After cooling, the toluene was distilled off and ether was added to the residue to give crude crystals which were recrystallized from ether; 1.0 g of 2- (3,4,5-trimethoxyphenyl) -3-piperidinocarbonylmethylisoindolin-1-one were obtained with m.p. 84-86 ° C.

Calcd. For C24H2GN2O5: C, 67.90; H, 6.65; N, 6.60

Found: C, 67.88; H, 6.66; N, 6.56%.

Example 1.2 10 In the manner described in Example .9, the compounds listed in Table 3 were obtained.

25

DK 161311 B

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DK 161311 B

Example 13 26 i) A solution of 12.0 g of 3-hydroxy-2- (4-methoxyphenyl) isoindolin-1-one and 16.0 g of ethoxycarbonylmethylenetriphenylphosphorane in 200 ml of toluene was refluxed for 3 hours. After cooling, the toluene was distilled off and the residue dissolved in 100 ml of methanol.

A solution of 10 g of potassium carbonate in 70 ml of water was added to the above methanol solution and the mixture was gently refluxed for 1 hour. After cooling, 200 ml of water and 300 ml of ether were added and the mixture was shaken well. The aqueous layer 10 was separated and acidified with 5N hydrochloric acid to give 12 g of 3-oxo-2- (4-methoxyphenyl) -isoindoline-1-acetic acid, described in section iv) of Example 2.

ii) 6.53 g of the above acetic acid derivative was dissolved in 30 ml of thionyl chloride and the solution was gently refluxed for 10 ml-15 minutes. After cooling, excess thionyl chloride was distilled off under reduced pressure to give the corresponding acid chloride. Without purification, the product was dissolved in 100 ml of dichloromethane and a solution of 3.12 g of menthol in 100 ml of pyridine was added portionwise while cooling in ice water. After 3 hours, 400 ml of ice water was added followed by extraction with dichloromethane. The dichloromethane layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to give 7.9 g of crude crystals. This product is a diastereoisomer of the β-menthyl ester.

iii) 7.9 g of the above-menthyl ester were separated into two pure diastereoisomers by fractional recrystallization from ethyl acetate.

A) (-) - 3-Oxo-2- (4-methoxyphenyl) -isoindoline-1-acetic acid - - menthyl ester, m.p. 179.5-180.5 ° C.

Calc'd for £ 27 ^ 3 ^ 4: C 74.45 H 7.64 N 3.22 Found: C 74.50 H 7.66 N 3.18%.

2 λ

Optical rotation: [<*] D = -82.6 ° (c = 1.0 in chloroform).

B) (+) -3-Oxo-2- (4-methoxyphenyl) -isoindoline-1-acetic acid / β-menthyl ester, m.p. 199-200 ° C.

Calcd. For C 27 H 33 NO 4: C 74.45 H 7.64 N 3.22

Found: C 74.65 H 7.64 N 3.17%.

Optical rotation: [α] 33 = + 40.7 ° (c = 1.0 in chloroform).

DK 161311B

Iv) The above ester compounds A) and B) were separately hydrolyzed with 35% HCl in dioxane to form optically active carboxylic acids without racemization (recrystallization from methanol).

A) (-) - 3-Oxo-2- (4-methoxyphenyl) -isoindoline-1-acetic acid, m.p. 245-246 ° C.

Calculated for C CH ^ ^NOO: C, 68.67;

Found: C 68.59 H 5.04 N 4.70% 23 o

Optical rotation: [α] D = -60.3 ° (c = 0.5 in methanol).

B) (+) - 3-Oxo-2- (4-methoxyphenyl) -isoindoline-1-acetic acid, m.p. 245-246 ° C.

Calcd. For C 17 H 15 NO 4: C, 68.67; H, 5.08; N, 4.71

Found: C 68.55 H 5.02 N 4.72%

Optical rotation: [α] D = + 60.2 ° (c = 0.5 in methanol).

V) To a solution of the (-) acetic acid ester A), obtained as described above, in dimethylformamide was added 1 equivalent of piperidine and 1.2 equivalents of diethylphosphorus cyanidate at 0 ° C, followed by further addition of triethylamine. After the mixture was stirred for 15 minutes, water was added and the product treated with dichloromethane. The dichloromethane layer was extracted with water and dried over anhydrous sodium sulfate and the solvent was evaporated to give crude crystals. Recrystallization from ether gave the desired compound in optically active form in good yield.

A ') (-) - 2- (4-Methoxyphenyl) -3-piperidinocarbonylmethylisoindolin-1-one with m.p. 110-111 ° C.

Calculated for C 22 H 24 N 2 3: C 72.50 H 6.64 N 7.69

Found: C, 72.69; H, 6.65; N, 7.60%.

2 3

Optical rotation: [ot] D = -134 ° (c = 1.0 in chloroform).

vi) The above (+) acetic acid ester B) was worked up in the same manner as described under v) to give the following compound: (B) (+) -2- (4-Methoxyphenyl) -3-piperidinocarbonylmethylisoindoline

1-on with m.p. 110-111 ° C

Calcd for C 22 H 24 N 2 O 3: c 72.50 H 6.64 N 7.69

Found: C 72.55 H 6.64 N 7.66%

DK 161311 B

28 23 o

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DK 161311 B

Example 15 786 mg of 6- (5-chloro-2-pyridyl) -6,7-dihydro-7-hydroxy-5H-pyrrole [3,4-b] -pyrazin-5-one and 1.17 g of piperidinocarbonylmethylene triphenylphosphorane was dissolved in 15 ml of dry toluene and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and ether was added to the residue to give crude crystals. The crystals were collected by filtration and recrystallized from dichloromethane / ether 1: 5 to give 921 mg of 6- (5-chloro-3-pyridyl) -6,7-dihydro-7-piperidino-1-carbonylmethyl-5H-pyrrolo [3, 4-b] -pyrazin-5-one with m.p. 212-213 ° C. Calcd. For C 18 H 18 Cl 1 N 5 O 2: C, 58.14; H, 4.88; N, 18.84

Found: C, 58.15; H, 4.97; N, 18.81%.

Example 16 ----------- a) 1.05 g of 6- (5-chloro-2-pyridyl) -6,7-dihydro-7-hydroxy-5H-pyrrolo [3.4- b] -pyrazin-5-one and 1.39 g of ethoxycarbonylmethylene-triphenylphosphorane were dissolved in 30 ml of dry toluene and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and the residue purified by chromatography on a silica gel column. Fractions were eluted with 2: 1 dichloromethane / ethyl acetate and the solvent was distilled off to give crude crystals. Recrystallization from ether / dichloromethane 5: 1 gave 1.2 g of 6- (5-chloropyridyl) -6,7-dihydro-7-ethoxy-carbonylmethyl-5H-pyrrolo [3,4-b] -pyrazin-5-one with m.p. 170-171 ° C. Calcd for C 15 H 13 ClN 4 O 3: C, 54.14; H, 3.94; N, 16.84

Found: C 54.01 H 4.00 N 16.84%.

b) 1.2 g of the compound obtained under (a) was dissolved in 30 ml of methanol, to the solution 200 mg of sodium hydroxide was added and the mixture was heated to 60 ° C. After 1 hour, the reaction mixture was neutralized with 3N hydrochloric acid / methanol and the precipitated sodium chloride was filtered off. The filtrate was then concentrated to give a crystalline residue consisting of crude 6- (5-chloro-2-pyridyl) -6,7-dihydro-5H-pyrrolo- [3,4-b] -pyrazin-5-one. 7-acetic acid. This product was not purified but dissolved in 20 ml of dry dimethylformamide. The solution is ice-cooled

DK 161311B

31 and 0.5 g of N-methylpiperazine and 0.5 ml of triethylamine and then 0.82 g of diethylphosphorocyanidate were added. The mixture was stirred under ice-cooling for 3 hours. To the reaction mixture was added 100 ml of water followed by extraction with dichloromethane. The dichloromethane layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give crude crystals. This product was recrystallized from ether / dichloromethane 3: 1 to give 1.0 g of 6- (5-chloro-2-pyridyl) -6,7-dihydro-7- (4-methylpiperazin-1-yl) carbonylmethyl-5H -pyrrolo [3,4-b] -pyrazin-5-one hemihydrate, m.p. 244-246 ° C. Calcd for C C gH ^ClNgCC, 1/2 2O: C 54.61 H 5.09 N 21.23 Found: C 54.80 H 4.74 N 21.21%.

EXAMPLE 17 2.59 g of 2- (4-methoxyphenyl) -3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one and 4.6 g of piperidinocarbonylmethylenetriphenylphosphorus were dissolved in 50 ml of dry toluene and the solution is gently refluxed for 20 hours. After cooling, the solvent was distilled off and the residue purified by chromatography on a silica gel column. Fractions were collected eluting with dichloromethane / ethyl acetate 5: 1 and concentrated to crude crystals. This product was recrystallized from ether / hexane 1: 3 to give 1.87 g of 2- (4-methoxyphenyl) -3-piperidino-carbonylmethyl-4,5,6,7-tetrahydroisoindolin-1-one, m.p. 101-25 102 ° C.

Calcd for C 22 H 28 N 2 O 3: C 71.71 H 7.66 N 7.60

Found: C 71.83 H 7.59 N 7.75%.

Example 18 ----------- 2- (4-Chlorophenyl) -3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one was worked up in the same manner as described in Example 17 whereby 2- (4-chlorophenyl) -3-piperidinocarbonylmethyl-4,5,6,7-tetrahydroisoindolin-1-one, m.p. 120-122 ° C.

Calcd. For C 21 H 25 N 2 O 2: C, 67.64; H, 6.75; N, 7.51

Found: C 67.91 H 6.74 N 7.58%.

Example 19 32

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2- (4-Chlorophenyl) -3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one was worked up in the manner described in Example 17 to give 2- (4-chlorophenyl) -3-hexamethylene iminocarbonylmethyl-4, 5,6,5,7-tetrahydroisoindolin-1-one with m.p. 169-170 C.

Calculated for C₂2H₂ ^^N₂O₂: C 68.29 H 7.03 N 7.24

Found: C 68.46 H 6.87 N 7.28%

Example 20 -------- 0 ----------- In the manner described in Example 17, the following compounds were prepared: i) 2- (4-Methoxyphenyl) -3-pyrrolidinocarbonylmethyl-4,5,6,7-tetrahydroisoindoline- l-on with m.p. 114-115 ° C.

Calcd. For C 21 H 26 N 2 O 3: C 71.16 H 7/39 N 7.90

Found: C, 71.19; H, 7.21; N, 8.05%.

ii) 2- (4-Methoxyphenyl) -3-hexamethyleniminocarbonylmethyl-4,5,6,7-tetrahydroisoindolin-1-one with m.p. 113-114 ° C.

Calculated for C 23 H 30 N 2 O 3: C 72.22 H 7.91 N 7.32 Found: C 72.30 H 7.80 N 7.31%.

Example 21 i) 3.0 g of ethoxycarbonylmethylenetriphenylphosphorane was added to a solution of 2.59 g of 2- (4-methoxyphenyl) -3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one for 30 minutes. ml of toluene and the solution was gently refluxed for 48 hours. After cooling, the solvent was distilled off and the residue was dissolved in 30 ml of methanol. 3 g of potassium carbonate and 10 ml of water were added and the mixture refluxed for 1 hour. After cooling, the methanol was distilled off, 100 ml of water and 100 ml of dichloromethane were added and the mixture was stirred well. The aqueous layer was separated and acidified with 5% hydrochloric acid to give crystals which were washed with water, dried and recrystallized from methanol / ether 1: 3 to give 24.6 g of 2- (4-methoxyphenyl) -3-oxo-4, 5,6,7-tetrahydroiso-indoline-1-acetic acid, m.p. 203-204 ° C.

Calculated for C C-H ^ gNO ^: C, 67.76; H, 6.36; N, 4.65

Found: C 68.01 H 6.40 N 4.91%.

DK 161311B

Ii) In the same manner as described above, 2- (4-chloro-phenyl) -3-oxo-4,5,6,7-tetrahydroisoindoline-1-acetic acid was obtained with m.p. 177-178 ° C.

Calcd. For C18 H16 ClNO3: C 62.85 H 5.27 N 4.58 c Found: C 62.88 H 5.15 N 4.68%.

5

Example 22 2- (4-Methoxyphenyl) -5-nitro-3-piperidinocarbonylmethylisoindolin-1-one and 2- (4-methoxyphenyl) -6-nitro-3-piperidinocarbonylmethyliso-1 H -indolin-1-one 4-Methoxyphenyl) -4-nitrophthalamide was suspended in a mixture of 80 ml of methanol and 80 ml of tetahydrofuran and, under ice-cooling and stirring, 1.6 g of borohydride was added. 300 ml of water was added to the mixture and crude crystals were collected by filtration to give 11 g of 3-hydroxy-2- (4-methoxyphenyl) -5-nitroisoindolin-1-one and 3-hydroxy-2- (4) mixture. -metoxy-phenyl) -6-nitroisoindolin-l-one. 6.0 g of the thus obtained mixture and 9.3 g of piperidinocarbonylmethylenetriphenylphosphorane were dissolved in 200 ml of toluene under heating and the solution was refluxed for 3 hours. After cooling, separated crystals were collected by filtration and recrystallized from toluene to give 2.2 g of 2- (4-methoxyphenyl) -6-nitro-3-piperidinocarbonyl-isoindolin-1-one, m.p. 209-210 ° C.

Calcd for ^ 22 ^ 23 ^ 3 ^ 51 ^ H 5.66 N 10.26 ^ Found: C 64.37 H 5.51 N 10.24%.

NMR, δ (in CDCl 3): 7.88 (1H, d, 4-H), 8.38 (1Ή, dd, 5-H), 8.65 (1H, s, 7-H).

The mother liquor obtained was concentrated and the residue was purified by column chromatography on silica gel and eluted with toluene-ethyl acetate.

Crude crystals obtained from the initially eluted fractions were recrystallized from ethyl acetate to give 2.0 g of the corresponding 5-nitro compound, m.p. 187-189 ° C.

Calc'd for C 21 H 23 N 3 O 5: C, 64.53; H, 5.66; N, 10.26

Found: C, 64.26; H, 5.57; N, 10.22%.

NMR, δ (in CDCl3): 8.01 (1H, d, 7-H), 8.34 (1H, dd, 6-H), 8.52 (1H, d, 4-H).

34

DK 161311B

From the following fractions 2.4 g of mixture of the 5-nitro compound and the 6-nitro compound were obtained. Crude crystals obtained from still later fractions were recrystallized from toluene to give 1.0 g of 6-nitro compound.

5

Example 2 3 _ _ _ _ M tf ·· _ In the manner described in Example 25, the compounds listed in Table 5 were obtained.

10 15 20 25 30 35

DK 161311 B

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Example 24 36

DK 161311B

In the manner described in Example 11, 2- (7-chloro-1,8-naphthyridin-2-yl) -3-piperidinocarbonylmethylisoindolin-1-one was extracted from 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxyisoindolin-1-one and had m.p. 217-218 ° C.

Calculated for C CH ^CIN ^C C: C 65.63 H 5.03 N 13.31

Found: C 65.88 H 4.93 N 13.40%.

Example 25 In the manner described in Example 16, 2- (7-chloro-1,8-naphthyridin-2-yl) -3- (4-methylpiperazin-1-yl) carbonylmethyl-isoindolin-1-one was recovered from 3-oxo-2- (7-chloro-1,8-naphthyridin-2-yl) -isoindoline-1-acetic acid and N-methylpiperazine. Mp. 212-213 ° C. Calcd for c23 H22 ClN5 ° 2: C 63.37 H 5.09 N 16.07

Found: C, 63.36; H, 5.11; N, 16.09%.

Example 26 In the same manner as described in Example 17, 5-chloro-2- (7-chloro-1,8-naphthyridin-2-yl) -3-piperidinocarbonyl-methylisoin-dolin-1-one was recovered from 5-chloro -3-hydroxy-2- (7-chloro-1,8-naphthyridin-2-yl) -isoindolin-1-one and piperidinocarbonylmethylenetriphenylphosphorane and had a m.p. 272-274 ° C.

Calcd. For C 23 H 20 Cl 2 N 4 ° 2: C 60.67 H 4.43 N 12.30

Found: C, 60.54; H, 4.34; N, 12.25%.

Example 27 In the manner described in Example 17, 6-chloro-2- (7-chloro-1,8-naphthyridin-2-yl) -3-piperidinocarbonylmethyliso-indolin-1-one was obtained from 6-chloro-3-hydroxy -2- (7-chloro-1,8-naphthyridin-2-yl) -isoindolin-1-one and had m.p. 295-297 ° C.

Calcd for C 23 H 2 Cl 2 N 2 O 2: C 60.67 H 4.43 N 12.30

Found: C, 60.60; H, 4.25; N, 12.21%.

Example 28 37

DK 161311B

1.0 g of ethyl 6-chloro-3-oxo-2- (4-methoxyphenyl) -isoindoline-1-acetate and 1.3 g of N-methylpiperazine were heated to 110 ° C for 4 hours in a stream of nitrogen. After cooling, 40 ml of water was added to the reaction mixture and the separated crystals were collected by filtration, washed with water and then dried. Recrystallization from ether gave 1.0 g of 5-chloro-2- (4-methoxyphenyl) -3- (4-methylpiperazin-1-yl) carbonylmethylisoindolin-1-one. The product was identified with compound # 7 in Table 5 and had 10 m.p. 169-171UC.

Example 29 2- (7-Chloro-1,8-naphthyridin-2-yl) -3- (4-hydroxypiperidin-1-yl) carbonylmethylisoindolin-1-one was obtained from 2- (7-chloro-1.8) (Naphthyridin-2-yl) -3-hydroxyisoindolin-1-one and (4-hydroxypiperidin-1-yl) carbonylmethylene triphenylphosphorane, m.p. 270-271 ° C.

Calcd for C 25 H 22 ClN 2 O 3: C 63.23 H 4.84 N 12.82 Found: C 63.00 H 4.78 N 12.72%.

20

Example 30 2- (7-Chloro-1,8-naphthyridin-2-yl) -3- (4-dialkoxypiperidin-1-yl) carbonylmethylisoindolin-1-one was obtained from 2- (7-chloro-1.8) -naphthyridin-2-yl) -3-hydroxyisoindolin-1-one and (4-dialkoxy-piperidin-1-yl) carbonylmethylenetriphenylphosphorane, m.p.

207-208 ° C.

Calcd. For CasHasClN 2 O 2: C 62.43 H 5.24 N 11.65 Found: C 62.66 H 5.19 N 11.77%.

30 35

Reference Example 1 38

DK 161311B

A solution of 56.5 ml of chloroacetyl chloride in 400 ml of toluene was cooled to 5 ° C and a solution 5 of 85.2 g of piperidine in 200 ml of toluene was added portionwise. The mixture was stirred at 5 ° C for 3 hours and at 25 ° C for 1 hour. The resulting crystals which precipitated were filtered off and 117 g of triphenylphosphine was added to the filtrate and the mixture was heated to 80 ° C for 6 hours. After cooling, the precipitated crystals 10 were collected by filtration to give 125 g of piperidinocarbonylmethyl triphenylphosphonium chloride crystals. This product was dissolved in 1 liter of ice-water and, under ice-cooling, 500 ml of 0.5 N sodium hydroxide was added. The precipitated crystals were collected by filtration, washed with water and dried. Recrystallization from 15 methylene chloride / ether 1:10 gave 91 g crystals of piperidinocarbonylmethylene triphenylphosphorus with m.p. 180-188 ° C.

Calculates for C25H26NOP: C 77.50 H 9.37 N 3.62

Found: C 77.71 H 9.61 N 3.54%.

Reference Example 2 In the same way as in Reference Example 1, the following compounds were obtained: i) Pyrrolidinocarbonylmethylenetriphenylphosphorus with m.p. 202-

204 ° C

25

Calculated for C24H24NOP: C 77.19 H 6.48 N 3.75

Found: C 77.10 H 6.58 N 3.79%.

ii) Hexamethylene iminocarbonylmethylenetriphenylphosphorus with 30 m.p. 189-192 ° C.

Calculated for C26H28NOP: C 77.78 H 7.03 N 3.49

Found: C 77.49 H 6.96 N 3.49%.

35

Claims (2)

An analogous process for the preparation of 2-substituted 3-carboxyalkyl-4,5-condensed pyrroline-1-lower derivatives of the general formula 50 zCr> x - wherein X is phenyl, pyridyl or naphthyridinyl optionally substituted with halogen, C 1-4 alkyl or alkoxy; Y is a carboxyl group; a group of the formula -COOR ^ 15 in which R 'represents C1. alkyl; or a group of formula r * 2 3 -CONC 2 p3 wherein R and R are the same or different and each group 2 represents C 1-4 alkyl or phenyl-C 1-6 alkyl or where R and R 2 together with N the atom forms a 5- to 7-membered cyclic amino group wherein N or S may be included as another hetero atom and which may be substituted by hydroxy, C 1-4 alkoxy, or C 1-4 alkyl? Z is a group -CH = CH-CH = CH-, -S- (CH2) 2 ~ S-, -N = CH-CH = N- or - (CH2) 4-; and 2-ring Δ may be optionally substituted with halogen, nitro or amino; or salts thereof, characterized in that a) hydrolyzes a compound of the general formula 3 ° If z AI NX II ch 2 -q O c .J 40 DK 161311 B wherein X, Z and ring A behave as above and 4 4 Q represents a group -COOR wherein R is a lower alkyl group, or -CN, where desired, esterifying or amidating the resulting hydrolyzate compound, or b) reacting a compound of the general formula OZA NX III, ο Ογ X and A are as above, with a compound of the formula Ph3P = CHY, where Y has the meaning given above and Ph represents phenyl, and if desired, the compound formed is converted to a salt thereof. Process according to claim 1, characterized in that 2- (4-methoxyphenyl) -3-piperidinocarbonylmethylisoindolin-I-one, 5-chloro-2- (4-methoxyphenyl) -3-piperidinocarbonylmethyl-isoindoline-1 is prepared. -one, 5-nitro-2- (4-methoxyphenyl) -3-piperidinocarbonyl-methylisoindolin-1-one, 5-chloro-2- (7-chloro-1,8-naphthyridin-2-yl) -3-piperidinocarbonylmethylisoindoline -1-one or 6-chloro-2- (7-chloro-1,8-naphthyridin-2-yl) -3-piperidinocarbonylmethylisoindolin-1-one or 5-chloro-2- (4-methoxyphenyl) -3 - (4-methylpiperazin-1-yl) -carbonyl ylmethylisoindolin-1-one.