DK152733B - (D) -5-BENZOYL-1,2-DIHYDRO-3H-PYRROLOOE1,2-AAA-PYRROL-1-CARBOXYLIC ACID OR ESTERS OR SALTS THEREOF USED AS INTERMEDIATES (PRODUCTS OF DELIVERED PRODUCTS) - Google Patents

Description

DK 152733B

The invention relates to novel (d) ~] 5-phenzoyl-1,2-dihydro-3H-pyrrolo [1,2a] pyrrole1-carboxylic acids which can be illustrated by the formula "OJXXy ™ ( a) or II esters or salts thereof, which are intermediates in the preparation of the corresponding (1) acid isomers and (dl) acid isomers and the 2

DK 152733 B

pharmaceutically acceptable, non-toxic esters and salts thereof, wherein R represents hydrogen or a lower alkyl group of 1-4 carbon = atoms, and represents hydrogen, a lower alkyl group of 1-4 carbon = atoms, a lower alkoxy group of 1-4 carbon atoms, chlorine, fluorine or bromine.

The (dl) and (1) forms of the compounds of formula A and their esters and salts exert anti-inflammatory, analgesic and antipyretic action and are thus useful in the treatment of mammalian inflammation, pain and / or pyrexia, as described in more detail herein. following.

They are also smooth muscle relaxants.

Typical alkyl ester groups are, for example, methyl, ethyl, propyl, iso = propyl, butyl, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, , 6-Methyldecyl and dodecyl esters.

lypiste salts barrel wb salts derived from uacganistic fca include ratriun, tliiun, ILfhiun, ammonium, calcium, magnesium, ferro, zinc, copper, manganese, aluminum, ferric, manganese salts and the like. . The ammonium, potassium, sodium, calcium and magnesium salts are especially preferred. Salts derived from pharmaceutically acceptable organic, non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, tri = methylamine, diethylamine, triethylamine, tripropamine. , 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethyl and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

3

DK 152 73 SB

The novel compounds of formulas (A) and (XI) described below exist as pairs of optical isomers (or enantiomorphs), i.e. a (dl) blend. However, each optical isomer as well as the (dl) mixtures thereof are included in the present op-5. -invention.

in

The (dl) or (1) compounds prepared on the basis of the intermediates of the invention can be used to produce a physiological reaction (e.g., anti-inflammatory, analgesic or anti-pyretic effect), ie. they may be used as medicine, and a preferred subgroup is the group consisting of the compounds of formula (A) and (1) acid isomers thereof and the esters and the pharmaceutically acceptable salts thereof.

Yet another subset of compounds which can be used as medicine are the compounds of formula (A) and (1) the acid isomer of formula (A) and the esters and pharmaceutically acceptable salts thereof, wherein R and R are both hydrogen.

The 20 (d) acid isomer of formula (A) and the esters and pharmaceutically acceptable salts thereof are useful as intermediates for the preparation of the (dl) acid of formula (A), as described further below.

A solution of the d-acid isomer of formula A in a polar organic or organic / aqueous solvent such as ethanol / water or methanol is heated to about 60-100 ° C and acidified with an acid such as hydrochloric or sulfuric acid. The mixture is heated for a period of about 15 minutes to 24 hours until the racemization is complete. The racemate iso-3Q is then leached in the usual manner and the resulting carboxylic acid residue is converted to the corresponding ester or pharmaceutically acceptable salt as described below.

The racemate can then be cleaved and the 1-isomer is isolated by the ne-33 methods shown. The isolated 1-isomer can then be converted to the corresponding ester or salt in the same manner as indicated for the dl ** form.

V

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• ·. 4 NH COOCII3 · COOCH3 I 2 + S R = H lf 9H2 · COOCIJ, - * p COOCH-.

I 1 (III)

CH-O ^. X UN

in 2 ... 7 'C -¾. IN

'L / H, C-CH, ° H; - -. (II), 2i 2 - .- 5 Vs ΌΗ. }: - · «> '- -Ϊ ·>%, · ·':, · cccc ·· :, XE 'cooch3' vn-Π ^ li—“ Ϊ 'J, Vs ^ / c00CH3 ^ · I! ^ JIn ^ cooch3 · CH_ \. !

I 2. - \ · · H2C-CH

CK-, (v) \ · I (IV) ·. | <\ OH __ '? OS02CH2 * · _ γ'ήογ'Τ} ^ COOCH- R \; _ ^ COOCE3 * ^ 3 L j \ / C00CH3 1 "A ^ -C00CH3 'V -"' · Γ2 (VI).:: (VII )

IH2C

: ·. '. ··. 7

'R _ COOH · - R jCOOH

• "LiL ^ °" 2 v ..... '' U ^ yccs !; (i- /; · ... (IX); |. - ·· twin)] l J COOR2 __Λ- JL ^ 00r2 (X) (XI) p1 Nj-n ^ Λϋ for: wherein R and R are as defined above and R is a lower alkyl group of 1-4 carbon atoms, e.g. When the above process is carried out to prepare the compound of formula (IV) wherein R is hydrogen, equimolar amounts of ethanolamine (i) and dimethyl-1,3-acetonedicarboxylate ( II) at a temperature of from about 0 ° C to about room temperature to readily form a solution of the vinylamine of formula (III) which is then treated, preferably in situ, in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at from about 40 ° C to about 100 ° C for a period of from about 30 minutes to about 16 hours. Suitable solvents for this reaction are the tical solvents such as acetonitrile, tetrahydrofuran, dimeth = 5 he, chloroform, dichloromethane and the like. In the preferred embodiments, the reaction is carried out in acetonitrile solution at the reflux temperature for about 1 hour. The 2-bromo (chloro) acetaldehyde = reagents are known compounds or can be obtained by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

20: ·.

To prepare the compounds of formula (IV) wherein R is a lower alkyl group, preferably straight chain, of 1-4 carbon atoms, treat an aqueous mixture of ethanolamine (i) and dimethyl-1,3-acetone = dicarboxylate (II) with a compound of formula 25.

0 3 ti R ^ -c-ciyc, 1

Esterification of the compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine, i.e. triethylamine, pyridine and the like, wherein X is bromine or chlorine and R 1 is a lower alkyl group, preferably straight chain, of 1-4 carbon atoms and best 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2 -pentanone and l-bromo-2-hexanone, at from ca. 40 ° C to approx. 100 ° C for a period of approx. 30 minutes to approx. 16 hours. In the preferred embodiment, the reaction is carried out at a temperature of approx. -10 ° C to about room temperature for from approx. 1 hour to approx. 6 hours.

35 0 3 π R -C-C 2 X reagents are known compounds *

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6 or in the presence of a co-solvent such as dichloromethane at a temperature of ca. -10 ° C to about room temperature for approx. 10 minutes to approx. For 2 hours, the corresponding mesylate of formula (V) forms, which is converted to the corresponding i - (2-iodoethyl) pyrrole of formula. (VI) 5 by reaction with sodium iodide in acetonitrile solution at reflux temperature for from ca. 1 to approx. 10 hours.

By reaction of the iodoethyl compound of formula (VI) with sodium hydride in a suitable inert organic solvent such as dimethylformamide, dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7 dicarboxyla and the 6-alkyl-substituted derivatives thereof (Vil). This ring closure is carried out under an inactive atmosphere, i.e. under argon or nitrogen atmosphere, at temperatures of the order of ca. 15 ° C

to approx. 40 ° C for a period of approx. 15 minutes to approx. 4 hours. The best 15 results are obtained by conducting the reaction at room temperature for approx. 30 minutes when R is hydrogen.

Alternatively, the compounds of formula (VII) can be prepared by direct cyclization of the mesylate (V) with sodium hydride dimethylform = 20 amide solution at off. ca. -10 ° C to about room temperature for from approx. 30 minutes to approx. 2 hours.

Base hydrolysis of a compound of formula (VII) with an alkali metal = 2 hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like in an aqueous lower-aliphatic alcohol, e.g. methanol or ethanol, at a temperature between room temperature and the reflux temperature for from ca. 4 to approx. 24 hours, the corresponding free diacid of formula (VIII), i.e. 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and the 6- w V, alkyl derivatives thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for approx. 10 hours.

The carboxylic acid group at the C-1 position of compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g. methanol, ethanol, isopropanol, n-butanol and the like, in the presence of hydrogen chloride to prepare the corresponding alkyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid of formula 4Q (IX). The reaction is carried out at a temperature of approx. 0 ° C to approx.

Ί 4-- -1__ /. -U -___

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7

Decarboxylation of the mono-esterified compounds (IX) to the corresponding compounds of formula (X), the key intermediates of the process for the preparation of the compounds of the present invention, is achieved by heating (IX) at an elevated temperature 5 230 ° C to about-280 ° C for a time sufficient to complete the reaction. The course of the reaction can be followed by the carbon dioxide development rate and thin layer chromatographic analysis, with decarboxylation usually completed in about 10 minutes. 45 to approx. 90 minutes. The reaction product, namely 1 ° alkyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and its 6-alkyl derivatives (X), can be purified by chromatographic methods. Alternatively and especially for decarboxylating small portions of compound (IX), the reaction product (X) can be distilled directly from the reaction vessel. _! .

15 '. ·

Condensation of a compound (X) with an amide of the formula con (ch3) 3 20 '- R1' 'wherein R4 is as defined above gives the corresponding alkyl-5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI).

This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for from ca. 1 to approx. 175 hours under an inert atmosphere followed by further reflux in the presence of sodium acetate for from ca. 2 to approx. 10 hours. Alternatively, instead of phosphorus oxychloride, other acid chlorides such as phosgene or oxalyl chloride may be used.

In the preferred embodiments, this condensation is carried out by adding a solution of compound (X) in a suitable solvent to a previously refluxed mixture of 1.1-5 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, refluxing it thus obtained reaction mixture for from ca. 6 to approx. 72 hours under an argon atmosphere and thereafter set from approx. 3 to approx. 10 molar equivalents of sodium acetate followed by a further reflux period of from approx. 4 to approx. 6 hours.

40 8

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Suitable solvents for this reaction are the halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Examples of N, N-dimethylarylamides that can be used are: N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl-p-toluamide, 3 N, N-dimethyl -p-methoxy-benzamide, N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-o-chloro-benzamide, N, N-dimethyl-m-chloro-benzamide, N, N-dimethyl-p -chloro-benzamide, 5N, N-dimethyl-p-fluoro-benzamide, and N, N-dimethyl-m-ethoxy-benzamide.

These amides are known, commercially available compounds or can be prepared in the usual manner from the corresponding acids, i.e. by conversion to the acid chlorides followed by treatment with dimethylamine

Alkaline hydrolysis of the alkyl ester group in a compound of formula (XI) gives the corresponding free acid of formula (A). This hydrolysis is carried out in the usual manner with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like in an aqueous lower aliphatic alcohol, e.g. methanol, ethanol and the like, at a temperature of approx. room temperature to reflux temperature from approx. 15 minutes 0 to approx. 2 hours under an inactive atmosphere. In the preferred embodiments, this hydrolysis is carried out with aqueous methanolic potassium carbonate at the reflux temperature for approx. 30 minutes.

The compounds of formula (A) may be cleaved in accordance with known methods in the art to obtain the corresponding single isomers thereof.

9

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The (1) acid acid ores and (d) acid isomers of the compounds of formula (A) 'can be obtained by applying the prior art high pressure liquid chromatography (HPLC) to α-phenethyl diastereoisomeric esters of the compounds of formula (A) followed by acid decomposition . Thus, the compounds of formula (A) wherein R and both are hydrogen may e.g. is subjected to further processing in accordance with the following diagram: yS 'n ~ Y - x—— ~ .....

* -j *. '' 3. * c ·. · * '' 'V ··'> '' · / ·. ^ several steps ·. . ·· · ‘·.

; 'v * X: "· · - .4". '; ··. * /. · "C (A ^) - (1) ->: acid isomer (1) -cc-phenethyl ester-Mixture-of p, - / (? I) - (d) - acid isomer · (!) -Α-pheiiGthyl ester m · ^ '. -' · ['. Separation under. · *' -; · · · ·. " Use of e:]; ; .. · · ^ ·. High Pressure Liquid. (AT) - (1) -.- acid isomer - (1) -phenethyl ester

γ 'V

(Λ) “(d) - Acid isomer - (-) -phenethyl es ter * *! V '. Y / (A) - (1) acid isomer. (Aj- (d) acidomer) 10.

DK 152733B

A more detailed description of this method can be found in the following Example 1 '.

The free acids of formula (A) can be converted to other alkyl esters having from 1 to 12 carbon atoms by conventional methods, e.g. by treatment with (a) the alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) an ethereal diazoalkane or (c) the desired alkyl iodide in the presence of lithium carbonate. The (1) acid = isomers can be converted to their alkyl esters by the aforementioned methods of (b) and (c).

10

The salt derivatives of the compounds of formula (A) and the (1) acido-, more thereof, are prepared by treating these free acids with an appropriate amount of one. pharmaceutically acceptable. hse. Representative pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, aluminum hydroxide, ferric hydroxide, aluminum hydroxide, , ethanolamine, 2-dimethylamino = noethanol.,. 2-diethyl amino ethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glueosamine, methylglucamine, theobromine, purines, piperazine, piperidine N.ethylpiperidine, polyamine resins and the like. The reaction is carried out in water, alone or in combination with an inert, water-miscible organic solvent at a temperature of ca. 0 ° C to 25 ° C. 100 C, preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of compounds of formula (A) or (1) acid isomers thereof to the base used is selected to provide the desired ratio 30 for any particular salt. For manufacturing e.g. of the calcium salts or magnesium salts of the compounds of formula (A) or the (1) acid isomers thereof, the free acid starting material can be treated with at least% molar equivalent of pharmaceutically acceptable base to produce a neutral salt. When the aluminum salts of the compounds of formula (A) or their (1) acid isomer are prepared, at least 1/3 molar equivalent of the pharmaceutically acceptable base is used if a neutral salt product is desired.

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11

In the preferred method, the calcium salts and magnesium salts of the compounds of formula (A) and (1) acid isomers thereof can be prepared by treating the corresponding sodium or potassium salts thereof with at least -¼ molar equivalent of calcium chloride or magnesium = 5 chloride in an aqueous solution, respectively. alone or in combination with an inert, water-miscible organic solvent at a temperature of ca. 20 ° C to approx. 100 ° C. The aluminum salts of the compounds of this invention may preferably be prepared by treating the corresponding free acids with at least 1/3 molar equivalent of aluminum alkoxide, such as aluminum triethoxide, aluminum tripropoxide and the like, in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like. from approx. 20 ° C to approx. 115 ° C. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble to readily react.

15 ·

It is to be understood that the isolation of the compounds disclosed herein. the desired can be accomplished by any suitable separation or purification method, such as e.g. extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or a combination of these methods. Examples illustrate suitable separation and isolation methods. Of course, other equivalent separation or isolation methods can also be used.

O C *

Although the (d) acid isomers are not used as a medicament, if desired, they can be converted to their pharmaceutically acceptable, non-toxic esters and salts thereof in accordance with the methods described for the conversion of (l) acid isomers to their pharmaceutically acceptable, non-toxic esters and their salts.

30

The compounds of formula (A) and (1) acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof are useful as anti-inflammatory, analgesic, platelet aggregation inhibitors, fibrinolytic agents and as smooth muscle relaxants. These compounds can be used both prophylactically and therapeutically.

Thus, the products containing these compounds are useful for the treatment and elimination of inflammation, such as inflammation.

DK 152733 B

in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, fractures, post-traumatic conditions and arthritis. In cases where the above conditions include pain and pyrexia in connection with inflammation, the present compounds are useful in alleviating these conditions as well as the inflammation.

Administration of the active compounds of the formula (A) or (1) acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof in a suitable pharmaceutical product may be effected by any of the accepted methods of administration. agents for the treatment of inflammation, pain or pyrexia or its prevention. Thus, the administration can e.g. taken orally, parenterally or topically in the form of solid, semi-solid or liquid dosage forms such as e.g. tablets, suppositories, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments or the like, preferably in the form of unit doses suitable for simple administration of accurate doses. The products will comprise a conventional pharmaceutical carrier or adjuvant and an active compound of the formula (A) or (1) acidomer thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof and may additionally contain other medicinal substances, pharmaceuticals, agents, carriers, excipients, etc. ...

The preferred mode of administration for the conditions described above is the oral one, using an appropriate daily dose amount that can be adjusted according to the nature and extent of the disorder. A daily dose of 25 mg to 500 mg of the active compound of the formula (A) or (1) acid isomer thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof is used. Most disorders respond to a treatment comprising a dose amount of the order of 0.5 mg to 6 mg per day. kg body weight per day. For such oral administration, a pharmaceutically acceptable, non-toxic product is formed by the incorporation of any of the normally used excipients, such as e.g. pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. Such products may be in the form of solutions, suspensions, tablets, pills, capsules, powders, delayed release preparations and the like.

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13

The active compounds of the formula (A) or (1) acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof may be prepared as a suppository by e.g. using polyalkylene glycols, e.g. polypropylene glycol, which carries. Liquid pharmaceutically acceptable products can e.g. are prepared by dissolving, dispersing, etc. an active compound as described above and any pharmaceutical excipients in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, so that. form a solution or suspension. If desired, the pharmaceutical .0 product to be administered may also contain minor amounts of non-toxic excipients such as wetting or emulsifying agents, pH buffering agents and the like, such as e.g. sodium acetate, sorbitan monolaurate, triethanolaminoleate, etc.

.5 Actual methods of preparing such dosage forms are known and will be well known to those skilled in the art, see e.g. Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition 1970. The products to be administered will in each case contain an amount of the active compound or the active compounds in a pharmaceutically effective amount to relieve the particular disorder being treated according to the teachings of the invention.

The compounds of the formula (A) and (1) acid isomers thereof and the non-5. toxic, pharmaceutically acceptable esters and salts described above are also uterine muscle relaxants and thus useful as agents for maintaining pregnancy in pregnant women and pregnant mammals for the benefit of the mother and / or fetus, until termination of pregnancy from a medical viewpoint is found favorable or more favorable to the mother and / or the fetus. However, it should be understood that in certain cases, e.g. where the birth has already begun (i.e., the mother has uterine contractions, especially near the end of the gestation period), administration of the compounds described herein cannot maintain the state of pregnancy for an unlimited 55 times. In such cases, on the other hand, pregnancy is most likely to be "prolonged" slightly, a factor that may be beneficial to either the mother, and / or the fetus.

The compounds of formula (A) and (1) acid isomers thereof and

A / vt.J ··} rtV Λ * T 1 ris · Λ 4 * λ1γπ i «Ir« Λ Λ 4 * A ha a. Av aa λ a. Ά 4ά J a vh a 4? A.A..A J A A

14 DK 152733 B

especially as means for delaying the initiation of or postponing birth. In the present text, the term "delaying the onset of birth" means the delaying of the birth caused by the administration of the compounds of formula (A) or (l) acidic esters thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof on any time before uterine muscle contractions have begun. Thus, the above sentence is intended to cover the prevention of abortion early in pregnancy (ie, before the fetus is "viable") as well as the postponement of a premature birth, a term sometimes used in conjunction with the premature birth, which takes place earlier in pregnancy, when the fetus is estimated to be "viable". In each case, the compounds are administered as prophylactic agents, such administration being intended to prevent the initiation of birth. This administration is particularly useful in the treatment of women who have previously had a spontaneous abortion or premature birth (i.e., birth has occurred before the normal time of birth). Such administration is also useful where there are clinical indications that the pregnancy may possibly be terminated before the time that is considered most favorable to the mother and / or the fetus. '

In the case of animals, this treatment may also be used to synchronize the births of a group of pregnant animals, so that they proceed simultaneously or almost simultaneously or proceed at or near a desired time and / or place where the births can be carried out in a more convenient manner. .

In the present text, the term "postponement of birth" is intended to cover the birth delay caused by the administration of the compounds of formula (A) or (1) acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, after the onset of uterine muscle contractions. The condition of the patient, including the period within the gestation or gestation period when the contractions have begun, the strength of the contractions, and the duration of the contractions, will affect the results obtained with the administration of the compounds herein. The effect can be e.g. be to reduce the intensity and / or duration of the contractions (i.e., the actual period of birth is "extended" or to stop the contractions completely. In each case, the effect will be an extension of the pregnancy or gestation period,

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15, although the effect, depending on the patient's condition, as described above, may be either minor or, under appropriate circumstances, somewhat greater. Such administration can be done to prevent spontaneous abortion, to make the birth easier and / or less painful for the mother and / or to take place at a more convenient time and / or place.

In all cases, the administration of the compounds of formula (A) or (l) acid isomers thereof and the pharmaceutically acceptable, non-L0 toxic esters and salts thereof for the purposes herein stated should be consistent with the best and / or accepted medical or veterinary practices. to achieve the best effect for the mother and the fetus. Thus, administration should not be continued for so long 'after the full gestation period has passed that the fetus dies in the uterus.

L5

In practicing the methods of the present invention, a therapeutically effective amount of a compound of formula (A) or (1) acid isomer thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof or a pharmaceutical product having a content thereof is administered to pregnant mammals or pregnant women by any of the methods useful and acceptable in the art '. The compound may be administered either individually or in combination with another compound or compounds as defined above or other pharmaceutical agents, adjuvants, carriers, etc. Such compound or compounds or products may be administered orally, parenterally, either in the form of solid, semi-solid or liquid dosage forms. Typically, the administration is by eb pharmaceutical product containing the pharmaceutically active compound and one or more pharmaceutical carriers or * adjuvants.

* 1

The administrable pharmaceutical product may be in the form of oral tablets, vaginal or uterine tablets or suppositories, pills, capsules, liquid solutions, suspensions or the like.

) C

preferably in the form of dosage units suitable for simple administration of accurate doses. Non-toxic solid carriers usually comprise e.g. pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. The active ^: Ρητ * Ηι nrJ αΊ aa snrn rJft'f infiPfit. nvAnfnr can * hi "ΙΉρτργΙ a α« ηιτι _q "M Ιττνϊ Ί Ί ino-k 16

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♦ »*» * · ♦ which e.g. polyalkylene glycols are used e.g. polypropylene glycol which corrodes. Liquid pharmaceutically administrable products may e.g. is prepared by dissolving, dispersing, etc. an active compound as defined above and any pharmaceutical excipients in a carrier such as e.g. water, saline, aqueous dextrose, glycerol, ethanel and the like, thereby forming a solution or suspension. If desired, the pharmaceutical product to be administered may also contain smaller amounts of non-toxic excipients such as wetting or emulsifying agents, pH buffering agents and the like, e.g. sodium = 10 acetate, sorbitan monolaurate, triethanolaminoleate, etc. Actual methods for preparing such dosage forms are known or will be readily apparent to those skilled in the art, see e.g. Remington * s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition 1970. The product or preparation to be administered will in each case contain an amount of the active compound (s) of a magnitude effective for to delay delivery or postpone birth if uterine contractions have already begun. A daily dose of from 0.5 mg to approx. 25 mg of the active compound 20 and the administration will be as a single daily dose or in the form of three or four smaller doses given regularly throughout the day. The amount of active compound administered will, of course, depend on its relative efficacy.

25

The following preparation methods and examples illustrate the preparation of starting materials and products according to the invention, respectively.

All mixing ratios used with regard to liquids refer to volume ratios. Where necessary, examples are repeated to prepare additional material for subsequent examples, and unless otherwise stated, the reactions are carried out at room temperature (20-30 ° C).

35

Preparation method 1

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17

A 250 ml 3-necked, round-mouthed flask containing a magnetic stir bar and fitted with calcium chloride-filled drying tube is connected directly (via one of the external necks) by means of a publishing beaker and a short 5 (3 ") water cooler to the acetal pyrolysis apparatus. the latter apparatus consists of a 100 ml round bottom flask (pre-filled with 15.6 g of oxal = acid dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal, prepared from vinyl acetate as described by PZ Bedoukian, J. Am. Chem. Soc. 66, 651 (1944 )) with a 6 "Vigreux column at the top provided with a thermo-2_0 meter connected to the above swallow.

The 3-neck flask is charged with 3.36 g of ethanolamine cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1,3-acetone dicarboxylate. Methyl 3-carbomethoxymethyl-3 (2'-hy = droxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 100 ml of dry acetonitrile. The pyrolysis part of the apparatus is placed in an oil bath and the temperature of the bath is raised to 150-160 ° C. The bromoacetaldehyde solution formed is distilled (boiling point 80-83 ° C / 580 mm Hg) directly to the magnetically stirred solution 20 of the vinylamine (ill). When the distillation temperature falls below 80 ° C, the pyrolysis apparatus is switched off and a reflux condenser containing calcium chloride is replaced instead. The solution is heated to reflux for 1 hour, the solvent is removed under reduced pressure, and then 200 ml of methanol 25 and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and placed on top of a column of 200 g of silica gel packed in hexane. The column is then eluted with hexane / ethyl acetate (80:20; 500 mL) and hexane / ethyl acetate (1: 1; 9 x 500 mL). Fractions 2 and 3 contain minor polar impurities and dimethyl-1,3-acetone dicarboxylate. Fractions 4-8 give 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyr = rol 2-acetate (IV, R = H) which, after recrystallization from ether / hexane, has a melting point at 52-54 ° C.

Preparation Method · 2 35

To a stirred solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carboxy methoxypyrrole-2-acetate in 35 ml of dry dichloromethane cooled to -10 ° C is added 2.65 ml of triethylamine, and then added dropwise 1 46 ml of methane = sulfonyl chloride, keeping the temperature of the reaction mixture at -10 ° C

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18 to -5 ° C. The reaction is followed by a thin layer chromatographic analysis using chloroform / acetone (90:10). When the reaction is found to be complete (about 30 minutes after completion of the methanesulfonyl chloride addition), 10 ml of water is added slowly. The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane / hexane gives 4.75 g (77.7 / 0 methyl N- (2-mesyl = oxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 99-101 ° C.

10

Method of preparation 3

A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is refluxed for 1 hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is decomposed with water. The insoluble material is separated by filtration and air dried. There is thus obtained 840 mg (97/0 methyl-N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp 137-138 ° C.

20

Preparation Method 4 A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred under an argon atmosphere with 137 mg of 50 o sodium hydride in mineral oil. The reaction mixture is kept for 30 minutes at room temperature and then cooled rapidly with ICO ml of water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue on 20 g of silica gel using hexane / ethyl acetate (4: 1) as eluent gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 7-dicarboxylate (VII, R = H), m.p. 70-71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of 5 g of potassium hydroxide in 20 ml. and the reaction mixture is refluxed for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N-hydrochloric acid and extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated

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19 steam to dryness under reduced pressure. There is thus obtained 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), melting point 220 ° C during decomposition.

Preparation Method 5

A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is saturated with hydrogen = chloride gas, keeping the temperature of the reaction mixture below 50 ° C.

The ice bath is then removed and the reaction mixture is stirred for 1 1/2 hours at room temperature and evaporated to dryness under reduced pressure. 10 ml of benzene is added to the residue and the solution is evaporated again under vacuum, repeating this process a total of three times to completely remove excess hydrogen chloride. Thus, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate ~ 7-carboxylic acid (IX, R = H, 2 R = iso-C ^ Hy), which after recrystallization from methanol / ethyl acetate has a melting point of 144-145 ° C.

Similarly, but using methanol, ethanol, pro-2-panol and n-butanol instead of isopropanol are obtained by the above-mentioned process, respectively, the compounds of formula IX: methyl-1,2-dihydro-3H-pyrrolo [1,2 -a] pyrrole-1-carboxylate-7-carboxylic acid ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, propyl-1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid and butyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid.

Preparation Method 6 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250 ° C in a dry 10 ml round bottom flask, the reaction product is distilled directly from the reaction vessel.

In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] n pyrrole-1-carboxylate (X, R = H, R = iso-C a pale yellow oil with the following physical constants: UV : 215 nm (e 6020), * I.R. 1 H NMR: 1.22 (d, J = 7Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H) , 4.65-5.2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3Hz, 1H), 6.43-6.53 ppm. (m, 1H).

Method of preparation 7

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20

A 100 ml 3-necked, round-mouthed cold is provided with a cooler, nitrogen supply pipe and a gas bubbler is provided with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate -7-carboxylic acid. The apparatus is purged with nitrogen and the nitrogen flow is then stopped.

The apparatus is immersed in an oil bath heated to 270 ° C and the reaction is monitored by the rate of carbon dioxide evolution (gas bubbles) and by thin layer chromatography on silica gel using benzene / di = oxane / acetic acid (90: 10: 1) as the developing agent. After 45 minutes, the reaction is almost complete. After 1 hour for · 10 runs, the vessel is removed from the oil bath and the contents of the reaction flask are transferred to a round bottom flask with 500 ml acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography on 100 g of silica gel. The fractions eluted with hexane / benzene (70: 30) and hexane / benzene (50:50) give 2.77 g (68%) of isopropyl-1,2-dihydro-β-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H, R = iso-Cyano), an oil whose physical constants are identical to those obtained in Preparation 6.

Method of preparation 8 20

A solution of 179 mg of N, N-dimethyl-p-toluamide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 405 mg of sodium acetate and refluxed for an additional 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluting with hexane / ethyl acetate (3: 1). Thus, 208 mg (66%) of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = H, = p-CH , R 2 = iso-C 6 Hy), an oil having the following physical constants: UV 256, 312 run, (e 8700, 19500); IR mik mix 1735 1 1β20 160 1605 cm "1; Ν · · κ ·: 1> 23 (d> J = 7Hz, 6H), 2.38 (s, 3H), 2.5-3.0 ( m, 2H), 3.75-4.10 (m, 1H), 4.2-4.60 (m, 2H), 4.85-5.20 (m, 1H), 5.95 (d, J = 4hTz, 1H), 6.70 (d, J = 4Hz, 35H), 7.10 (d, J = 8Hz, 2H), 7.60 ppm (d, J = 8Hz, 2H).

Preparation Method 9

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21

A solution of 336 mg of isoprene-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 690 mg of potassium carbonate in 5 ml of water. . The reaction mixture is refluxed under a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. The residue is taken up in 10 ml of 10 $ aqueous hydrochloric acid and 50 ml of water and the resulting mixture is extracted with ethyl acetate (2 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate / hexane gives 238 mg (89/0 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-aj-10-pyrrole-1-carboxylic acid [(A), R = H, R 2 = p-CH 2], mp 182-183 ° C.

Proceed to Method 10

A solution of 250 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [alpha] [1,2-a] pyrrole-1-carboxylate in 8 ml of methanol is treated under a nitro gene atmosphere with a solution of 200 mg. sodium hydroxide in 1 ml of water, keeping the reaction mixture at room temperature for 11/2 hours. Methanol is removed under reduced pressure and the residual basic solution is diluted with 5 ml of water and extracted with ether to remove 2q of any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure and the residue is crystallized from ethyl acetate / hexane. There is thus obtained 5-p-toluyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, identical to the product obtained in Preparation Method 9.

Preparation Method 11

Following the method of Preparation Method 8 using 3Q of 1,1 molar equivalents N, N-dimethylbenzamide, N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl1-p -methoxybenzamide, N, N-dimethyl-p-ethoxybenzamide, N, N-dimethyl-o-chlorobenzamide,

22 DK 152733 B

N, N-dimethyl-m-chlorobenzamide, N, N-dimethyl-p-chlorobenzamide, N, N-dimethyl-p-fluorobenzamide, and N, N-dimethyl-m-ethoxybenzamide 3 instead of N, N-dimethylbenzamide p-toluamide and monitoring of the reaction process by thin layer chromatography are obtained, respectively: isopropyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate. a pale yellow oil with the following physical constants: U.V. : 245, 311 nm (e 7230, 17800); KR -: ^ max 3 1735 '1620 cm -1;' NJ> LR ·: ^ TFiS3 3 124 (d, 6H (CH3) 2CH), 250-3.13 (m, 2H; H-2); 3.97 (dd, 1H, H1), 4.18-4.70 (m, 2H, H-3), 5.00 (sept, 1H, (CH 2 CH), 6.00 (d, 1H) , H-7), 6, S6 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons); MS: m / e 297 (M +), isopropyl-5 -o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate an oil having the following physical constants: UV: 252, 303 nm (e 4460, 19100): IR: 3 1735 ′ 1620 cm ~ 1; N R R: 6 ^ 1.18 (d, 6H, (CH 3) 2 CH), 2.28 (s ″, 3H-, o-CH-j), 2.50 -3.13 (m, 2H, * H-2), 3.92 (dd, 1H, H1), 4.17-4.70 (m, 2H, H-3), 4.98 (Sept. 1H) , (CH 2 CH), 5.92 (d, 1H, H-7), 6.43 (d, 1H, H-6), 6.97-7.45 ppm. (M, 4K, phenyl = protons), isopropyl-5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate an oil having the following physical constants: UV 250-251, 310-312 nm (e 6460, 17400); IR: 9 ™ s3 1735, 1620 cm -1 · NMR: 1.25 (d, 6H, (CH3) 2CH), 2.27 (s, 3H, CH 3.13 (m, 2H, H-2), ° 3.92 (dd, 1H, H1), 4.13-4.70 (m, 2H, H-3), 4.95 (Sept. 1, (CH3) 2CH), 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm (m, 4H; phenyl = protons ), 30 isop ropyl-5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: UV: 218, 270-284 (shoulder), 314 nm (e 9780 , 9320, 22400); . . I.R.

—1 rj-npi IH SK s • 1730, 1605 cm; N.M.R. : δ ^ Χ3 1.24 (d, 6H, J = 6Hz; (CH₂Cl₂CH-), 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH30O)) , 3.93 (dd, 1H, = 6Hz JBX = 7Hz; Π "1)" 4.13-4.60 (Μ, 2H; H-3), 4.95 (sept, 1H, J = 6Hz ; (CH3) 2CH), 5.95 (s, 1H, J = 4Hz; H-7), 6.68 (d, 1H, J = 4Hz; H-6), 6.70-790 ppm. (M , 4H; phenyl protons); MS: in / e 327 (M +), 23

DK 152733 B

isopropyl-5-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 50-51 ° C, isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 94-95 ° C, 5 isopropyl-5-o- chlorobenzoyl-l, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-L-

NeOH

carboxylate, an oil with the following physical constants: U.V. : 251, 306 nm (e 5750, 16600); IR: 9.3 g3 1735, 1625 cm -1; N.m.R .: 61.3 1.22 (d, 6H, (CH 3) 2 CH), 2.55-3.05 (m, 2H; H -2), 3.97 (dd, 1H, H1), 4.17-4.70 (m, 2H, H-3), 4.97 '(Sept., 1H, (CH3) 2CH), [5.93 (d, 2 / 3H), 6.00 (d, 1 / 3H) H-7], [6.42 (d, 2 / 3H), 6.67 (d, 1 / 3H) , H-6], 7.07-7.80 ppm (m, 4H; phenyl protons), isopropyl-5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 -carb = oxylate, an oil having the following physical constants: UV: λ 241, 313 nm (ε 6600, 15100); IR: δ 1735, 1620, 1570 cm cm -1; δ NMR: 1.27 (d, 6H, (CH3) 2CH), 2.50-3.18 (m, 2H, H-2), 3.93 (dd, 1H, H1), 4.10-4.63 (m, 2H, H- 3), 4.98 (sept., 1H, (CH 3) 2CH), 5.98 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.07-7, 78 ppm.

(m, 4H, phenyl protons); MS: m / e 331-333 (M +), 2Q isopropyl-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 80.5-81 ° C, and isopropyl 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 72-72.5 ° C.

By hydrolysis of the isopropyl ester group according to the procedures of Preparation Methods 9 or 10, the corresponding free acids are obtained, namely: 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 160-166 ° C, 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, an oil having the following physical constants: UV : Δ ks ^ 53, 307 nm (e 3310, 16980); I.R. 1320; 1620 cm "1; nMR: 2.32 (s, 3H, CH3), 2.53-3.03 (m, 2H, H-2), 3.97 (dd, 1H, H1) * 4.17-35 4.67 (m, 2H, H-3), 6.92 (d, 1H, H-7), 6.40 (d, 1H, H-6), 6, 83-7.37 (m, 4H, phenyl protons), 8.60 ppm (bs, 1H, C00H),

DK 152733 B

24 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 144-145 ° C, 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, melting point 187-187.5 ° C, ____________________________________________________. .....

5-m-Ethoxybenzoyl 1-1,2-dihydro "3H-pyrrolo [1,2-a] pyrrole-1" carboxylic acid, m.p. 155-156 ° C, 5-p-Ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 699-170 ° C, 5-p-isopropoxybenzoyl-1 , 2-Dibydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 157-158 ° C, 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid with the following physical constants: UV: 250, 307.5 ran (s 4360, 17400); I-R -: max 3 1715> 1620 cm cm 1; N.M.R. : 2.60-3.15 (m, 2H; H-2), 4.02 (dd, 1H, = 6Hz, = 7Hz; H1), 4.20-4.70 · (m, 2H; H -3), 5.98 (d, 1H, J = 4Hz; H-7), 6.42 (d, 1H, J = 4Hz; H-6), 7.00-7 / 77 (m, 4H; phenyl protons), 8.67 ppm. (s, (br), 1H; C00H), 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [ly2-a] pyrrole-1-carboxylic acid, mp 180-181 ° C, 5-p chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 201.5-202.5 ° C, and 5-p-fluorobenzoyl-1,2-dihydro-3H-carboxylic acid pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 179.5-180.5 ° C.

Example 1 25

To a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 25 ml of dry benzene is added 0.58 g of trifluoroacetic acid anhydride. The mixture is stirred at room temperature for 10 minutes and the resulting solution is cooled to 0-5 ° C and 1.4 g of dry triethyl 30 amine is added, followed immediately by the addition of 0.5 g of (1) -α-phenyl = ethyl alcohol. The reaction solution thus obtained is stirred at room temperature for 15 minutes and poured into 20 ml of water containing 1 ml of triethylamine followed by extraction with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate followed by removal of the solvent and excess (1) -α-phenylethyl alcohol under vacuum. There is obtained 0.42 g of a mixture of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-

DK 152733 B

A) pyrrole-1-carboxylic acid (1) -α-phenethyl ester and (d) -5-benzoyl-1,2-di ·· hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -α-Phene thyl ester separated by high pressure liquid chromatography (using 4% EtOAc / hexane on an 11 mm x 50 cm 10 µm Lichrosord S1-60 column) to prepare 180 mg of a more polar ester ( a ^ e ^^ 145.7 °) and 178 mg of a minor polar ester (cc ^ e <^ + 128.6 °).

Cleavage of the less polar ester in accordance with the method described above for the cleavage of the more polar ester gives similarly 85 mg (d) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a_ pyrrole-1-carboxylic acid with an oc 3 = + 15551 C and a melting point of 154-156 ° C. The (d) acidomer thus obtained can, if desired, be racemized (recycled) according to methods known in the art.

Similarly, other (dl) compounds can be converted to their respective (1) isomers and (d) isomers.

Example 2 20

A solution of 200 mg of d-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid is dissolved in 50 ml of ethanol / water and heated to boiling. 20 ml of concentrated hydrochloric acid is then added and the mixture refluxed for 30 minutes. The resulting (dl) -5-benzoyl-1,2-di = 25-hydro-3H-pyrrolo [1,2a] pyrrole-1-carboxylic acid, mp 160-161 ° C, is isolated in the usual manner,

Other of the present d-carboxylic acids can similarly be racemized to give the following dl compounds of formula A: 5-p-tolouyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 -carboxylic acid, m.p. 182-183 ° C, 5-o-tolouyl, -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, oil, 5- (4-methoxybenzoyl) - 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl = 2g acid, m.p. 187-187.5 ° C, 5- (4-ethoxybenzoyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxyl =

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26 acid, m.p. 169.5-170 ° C, 5- (3-chlorobenzoyl-1,2 "dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 180-181 ° C, 5- (4-chlorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 201.5-202.5 ° C, 5- (4-fluorobenzoyl) ) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 179.5-180.5 ° C, 5-p-tolouyl-6-methyl-1,2 -dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 187 ° C, 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylic acid, m.p. 169 ° C, 5- (4-methoxybenzoyl) -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 182 ° C, 5- (4-Chlorobenzoyl) -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 204 ° C, 6-propyl-6-methyl -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 1.72 ° C and 5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo , 2-a] pyrrole-1-carboxylic acid, m.p. 196 ° C, 20

Example 3

To a solution of 300 mg of 5-benzoyl-1,2-dihydro-3n-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 25 ralbenzene is added 0.58 g of trifluoroacetic acid anhydride. The mixture is stirred at room temperature for 10 minutes, and the resulting solution is cooled to 0-5 ° C and 1.4 g of tri triethyl araine are added immediately followed by the addition of 0.5 g of (1) - - - phenyl = ethyl alcoholchol, Ben thus obtained reaction solution was stirred at room temperature for 15 minutes and poured into 20 ml of water containing 1: 1R triethylamine followed by extraction with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate followed by removal of the solvent and excess (1) -α-phenylethyl alcohol under vacuum. There is thus obtained 0.42 g of a mixture of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2a] pyrrole-1-carboxylic acid (1) -α-phenethyl ester and (d) 5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -α-phenethyl ester which is separated by high pressure liquid chromatography (using 4; EtOAc / hexane on an 11 mm x 50 cm 10 µm Lichrosord Sl-60 column) to produce 180 mg of a more polar ester (ccLjeC ^ -144.7 °) and 178 mg of a less polar ester (a ^ 8® * 1 + 128.6 °),

27 DK 152733B

Dissolve 148 mg of the more polar ester in 8 ml of dry benzene. The solution is cooled to 15-20 ° C and 5 ml of trifluoroacetic acid is added and the solution is stirred at room temperature for 1 hour and 10 minutes. The reaction solution is poured into 60 ml of dry benzene and the solvents 5 are removed under vacuum and at ambient temperature. Purification is carried out by high-pressure liquid chromatography (using a column like the one described above except that 35% EtOAc / hexane in acetic acid is used instead of k% EtOAc / hexane) to prepare 63 mg (1) -5-benzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 10 having a άρ1ΐ ("" 3 = -153.7 ° C and a melting point of 153-155 ° C).

Example 4 a) A solution of 200 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethyl diazomethane and the reaction mixture kept at room temperature for 30 minutes. The solvents and reagent excess are removed under reduced pressure and the residue is crystallized from ethyl acetate / methanol. There is thus obtained methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate.

Similarly, but using diazoethane and diazopropa: instead of diazomethane, ethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and propyl-5 are obtained, respectively. -benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carboxylate.

Similarly, the residual free acids obtained in f-rice preparation method 12 (and Example 1) and the acids from preparation method 17 are converted to the corresponding methyl, ethyl and propyl esters.

B) A solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue is purified by chromatography on alumina to give 35 isoamyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Other esters, e.g. pentyl, hexyl, octyl, nonyl, dodecyl and the like of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid using other alcohols, e.g. . pentyl, hexyl,

28 DK 152733 B

By the same method, the free acid compounds obtained are esterified! preparation methods "12 and 17, with the appropriate alcohol, thus obtaining the corresponding esters, for example: isoamyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate , 5-pentyl-5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, hexyl-5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxyla isoamyl-5-o-propylbenzoyl-1,2-dihydr o-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, 10-octyl-5 -p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, nonyl-5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2 -a] pyrrole-1-carboxylate, dodecyl-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-alpyrrole-1-carb = oxylate, isoamyl-5-m-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, dodecyl-5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 -carb = oxylate, hexyl-5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat, nonyl-5-p-bromobenzoyl-1,2, dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat, isoamyl-5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2 -a] pyrrolo-1-carboxylate, hexyl 5-p-ethylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, nonyl-5-o-methoxybenzoyl -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, dodecyl-5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1 , 2-a] pyrrole-1-carboxylate, nonyl-5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat, isoamyl-5-p ethoxybenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate,

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& y bM

pentyl 5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, hexyl-5-m-chlorobenzoyl-1,2-dihydro-6- butyl 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and dodecyl-5-p-bromobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate, and octyl (dl). -5 ^ b.enzoyl-1,2-dibydydroT-3H ^ pyrrolo [1,2- a] pyrrole-1-carb = oxyla.t, -. Oil.

10 _

c) To a solution of 300 rag 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-aJ

pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide in the form of a 0.1 N solution. The solvent is then evaporated under reduced pressure and the residue taken up in 2 ml of methanol followed by precipitation with ether to prepare crude sodium 5-ρ-toluoyl-1,2-dihydro-3H-pyrrolo [-1,2-a] pyrrole-1-carboxylate which can be crystallized from ethyl acetate / hexane.

Other salts, e.g. ammonium and potassium salts of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are also prepared

M U

by using ammonium hydroxide and potassium hydroxide instead of sodium hydroxide.

Similarly, the Preparation Method 2 (and Example 1) obtained 5-22 substituted-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid compounds can be converted to the corresponding sodium, potassium and ammonium = salts.

Representative compounds obtained in this way are: sodium 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5-benzoyl-1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic potassium 5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = 35 potassium 5-o-butylbenzoyl-1,2-dihydro-3H-pyrrolo [1 , 2-a] pyrrole-1-carboxylate, sodium 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate,

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Ammonium 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, ammonium 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, 5-potassium 5-p-bromobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat, sodium 5-Benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, potassium 5-toluoyl-1,2-dihydro-6-methyl-3 pyrrolo [1,2-a] pyrrole-1-carb = oxylate, ammonium 5- o -methioxybenzyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole -1-carboxylate, sodium 5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and potassium 5-m-chlorobenzoyl-1, 2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-l-carboxylate. . .

d) To a solution of 175 mg: 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of potassium = hydroxide in the form of an O, IN solution. Thus, a solution containing potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is obtained. A solution of 40 mg of calcium carbonate is dissolved in the smallest amount of 1N hydrochloric acid necessary to effect the dissolution of the calcium carbonate formed in the buffer with 100 mg of solid ammonium chloride, and then an additional 5 ml of water is added. The buffered calcium solution thus obtained is then added to the solution of potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and the precipitate formed is filtered off, washed with water and air-dried. There is thus obtained calcium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate.

Magnesium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylai is also prepared using magnesium carbonate instead of calcium carbonate.

By using 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid instead:

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31 5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylic acid, 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-o-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5-benzoyl-1,2-dihydro -6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and 5-o-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1 -CARB =

oxylic acid 10 J J

the corresponding calcium and magnesium salts are obtained.

e) To a solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of potassium; 15 hydroxide in the form of a 0.1N solution. The solvent is stripped and the residue dissolved in 5 ml of water. The aqueous solution of potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate thus obtained is added to a solution of 150 mg of cupronitrate trihydrate in 5 ml of water. The formed precipitate is collected, washed with water and air dried. Separated 20 are given copper-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

In a similar manner, the free acid compounds obtained in Preparation Method 12 (and Example 1} and Preparation Method 17 can be converted to the tartaric copper salts.

f> A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is allowed to cool to room temperature and the product is filtered, washed with ether and dried, yielding the isopropylamine salt of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2- a] pyrrole-1-caro = oxylic acid.

Other amine salts, eg diethylamine, ethanolamine, piperidine, tro = methamine, choline and caffeine salts of 5-p-toluoyl-1,2-dihydro-3K-pyr =

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32 rolo [1,2-a] pyrrole-1-carboxylic acid is also prepared by using each of the respective amines instead of isopropylamine.

Similarly, the free acid compounds obtained in the stripping method 12 'of Example 1) and preparation method 17 can be converted into the corresponding isopropylamine, di = 5 ethylamine, ethanolamine, piperidine, tromethamine, choline and caffe salts.

g) A solution of 770 mg of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexyl = 10 amine. The reaction mixture is stirred for 10 minutes and the solid formed is filtered off and washed with anhydrous ether. Thus, 965 mg of the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid is obtained, m.p. 161-163 ° C. · Similarly, the residual free acid compounds obtained in the method of preparation may be obtained. 12 (and Example 1) and the compounds of Preparation Methods 9 and 16 are converted to the corresponding dicyclohexylamine salts, e.g. the dicyclohexylamine salt of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 175-175 ° C

Preparation Method 13

A 250 ml 3-necked, round bottom flask with magnetic stir bar and equipped with a calcium chloride-filled drying tube is provided with 3.36 g of ethanolamine, cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl. 1,3-acetonedicarboxylate. Methyl 3-carbomethoxymethyl-3- (21-hydroxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 80 ml of dry acetone triltrate. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then refluxed for 2 hours. The solvent is then removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and placed on top of a column of 200 g of silica gel packed in hexane, eluting with the mixture of hexane and ethyl acetate. The hexane / ethyl acetate (1: 1) fractions eluted with methyl N- (2-hydroxyethyl) -3-carbome thoxypyr = rol-2-acetate (IV, R = H) identical to that obtained in Example 1 product.

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33

Preparation Method 14

To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and treated dropwise over a period of 15 minutes while stirring with 1.67 ml of 1-bromoacetone while maintaining the temperature of the reaction mixture at a maximum of 40 ° C. After completion of the addition, the dark reaction mixture is stirred for an additional hour at room temperature and then poured into a mixture of hydrochloric acid and ice, saturated with solid sodium chloride and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts are washed with cold water for neutral reaction, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography the residue on 30 g of silica gel using hexane: ethyl acetate (70:30) as eluant to give 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate as recrystallized from methylene chloride / Hexane melts at 78 ° C and has the following analysis:

Calculated for C C HH ^NO NO: C 56.45, H 6.71

Found: C 56.41, H 6.73.

Similarly, but using a stoichiometric equivalent amount of 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-bromo-2-hexanone instead of 1-bromoacetone is obtained respectively: methyl-N- ( 2-hydroxyethyl) -3-carbanethoxy-4-ethylpyrrole-2-acetate, m.p. 61-62 ° C, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate and methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate .

Preparation Method 15

Following the methods of Examples 2, 3, 4, 5 and 7, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CHL) is successively converted to: 3 methyl N- (2-mesyloxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, m.p. 81 ° C methyl N- (2-iodoethyl) -3 ~ carbomethoxy-4-methylpyrrole * -2-acetate, m.p. 103 ° C,

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34

dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate, mp J5 ° C

1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid, m.p. 200-203 ° C, isopropyl-1,2 "dihydro-6-methyl-3H-pyrrolo [2-a] pyrrole-1" Carboxylate-7-carboxylic acid / m.p. 160 ° C and 5 isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = CH3, R2 = iso-C3 Hy)? oil.

Similarly, using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl-N- (2-hydroxyethyl) -3-10 carbomethoxy-4-propylpyrrole-2- acetate and methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate instead of methyl N- (2-hydroxy = ethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate respectively as final products: isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ol: isopropyl-1,2-dihydro-6-propyl-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylate and isopropyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

In accordance with the method of Preparation Method 8, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is condensed with N N-dimethyl-p-toluamide to prepare isopropyl-5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = CH = p-CH 2, R 2 = iso-C 2 Hy) T mp, 72 ° C - Similarly, but using the Ν, Ν-dimethylarylamides listed in Example 12A instead of N, N -dimethyl-p-toluamide is obtained respectively: isopropyl-5-o-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-n-carboxylate, mp 75 isopropyl 5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp, 89 ° C, isopropyl-5-p-chlorobenzoyl-1,2, dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 88 ° cr isopropyl-5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [l, 2-a] pyr = Ί ____ Ji -i> „1 ______ J -1- ^ i ______ λ ____ j_____

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35 U * V * mtl 250 »315 nm (e 6170, 14100); I, R 'max 3 1734> 16 ° 5, 1593 cm' 1; ΓΠΠ 5 N.M.R. δΤΜ3 3.25 (d, 6H, J = 6Hz; ester CH3), 1.83 (s, 3H; ring CH3), 2.49-3.00 (m, 2H; CH2), 3.90 (t , 1H, EJ = 7.4Hz; CHCO), 4.10-4.23 (m, 2H; N-CH 2), 4.93 (sept, 1H, J = 6Hz; ester CH), 5.84 ( s, 1H, H-3), 1.0 7.00 (t, 2H, Jortho = 8.4Hz, JHP = 8Hz; H-3 ', 5'), 7.55 (q, 2H, J.ortho = 8 , 4Hz, JHF = 5.5Hz; H-2.6 '); M.S. m / e 1% 329 25 M + 15 242 100 M + -Cp 2 CH (CH 3) 2 123 36 F-CgH 2 CO.

Method of preparation 17

A solution of 500 mg of isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 15 ml of methanol is treated with a solution of 1 05 g of potassium carbonate in 8 ml of water. The reaction mixture is refluxed under a nitrogen atmosphere for 30 minutes and cooled and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resulting mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure to prepare 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [{A ), R = CH3, R1 = p-CH3] r snip. 187 ° C, 30 / Similarly or alternatively, by the hydrolysis method of Example 10, the remaining isopropyl ester compounds obtained in Example 15 are converted to the corresponding free acids, namely:

5-Benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, snip. 169 ° C

5-o-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid,

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36 5-m-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-p-ethylbenzoyl-1,2-dihydro-6-methyl -3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5-o-propylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb carboxylic acid, 5-m-butylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5-o-methoxybenzoyl-1,2-dihydro-6- methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp, 182 ° C, 5-p-Ethoxybenzoyl-1 ', 2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-p-isopropoxybenzoyl-1,2 dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-o-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrblb [1,2-a] pyrrole 1-carb = oxylic acid, 5-m-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5-p-chlorobenzoyl-1 , 2-Dibydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 204 ° C, 5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, S-β-fluorobenzoyl-1,2-dihydro -6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 204 ° C, 5-m-bromobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [ 1,2-a] pyrrole-1-carb = oxylic acid, 5-p-bromobenzoyl-1,2-dibydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5 -benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-carboxylic acid, m.p. 177 ° C,

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37 5-Benzoyl-1. 2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid e, 5-benzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylic acid.

5-p-toluoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5-p-ethylbenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = 5-oxylic acid, 5-o-methoxybenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5-p-Ethoxybenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = 10-oxylic acid, 5-o-chlorobenzoyl-1,2-dihydro-6-propyl-3H -pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5-m-chlorobenzoyl-1,2-dihydr o-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, 5-o-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrol-1-carb = oxylic acid, 5-p-fluorobenzoyl-1,2-dihydro-6 -ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, mp 196 ° C, 2q 5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo [1, 2-a] pyrrole-1-carb = oxylic acid and

Preparation Method 18 710 mg of a 50% suspension of sodium hydride in mineral oil is washed with 25 anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate are added, stirring the reaction mixture at -5 ° C - 0 ° C for 1 hour. It is then poured into ice-cooled sodium chloride solution and extracted several times

30 W

benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether, thus obtaining dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate (VII, R = H) identical to that in product method 4 'obtained, m.p. 70-71 ° C.

35

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38

Preparation Method 19

To a 250 ml 3-necked, round bottom flask equipped with a nitrogen addition and relief valve, a magnetic stir bar and a pressure equalized addition funnel containing 10.08 g of ethanolamine, 26.1 g of dimethyl-1,3-acetone dicarboxylate is added dropwise with stirring. for a period of 30 minutes while keeping the temperature below 30 ° C. The methyl 3-carbomethoxymethyl-3 '(2'-hydroxyethyl) -aminoacrylate (III) formed is diluted with 20 ml of acetonitrile and chloroacetaldehyde, prepared by heating a mixture of 27.4 g of chloroacetaldehyde diethylacetal 10 with 46.8 g of oxalic acid dihydrate. 150-160 ° C, is added with stirring over a 2 minute period. The reaction mixture is refluxed for 5-10 minutes, after which the reaction by thin layer chromatographic analysis using acetone / chloroform (10:90) as the eluent is found to be complete. The solvent 15 is removed under reduced pressure, and to the residue are added 250 ml of benzene and 250 ml of heptane, and distillation is then carried out under reduced pressure. The oily residue remaining after distillation is suspended in 50 ml of methylene chloride and to this is added 20 g of silica gel. The methylene chloride mixture is poured onto a column containing 200 g of silica gel made in ethyl acetate: hexane (20:80). The column is first eluted with 6 liters of ethyl acetate: hexane (20:80) and then with 4 liters of ethyl acetate: hexane (50:50). The fractions eluted with ethyl acetate: hexane (50:50) are combined and concentrated to give 12.8 g of an oil which is decomposed with 20 ml of petroleum ether (30-60 ° C) followed by removal of the solvent under reduced pressure to prepare of 11.89 g (32.9% of theory) of methyl N- (2'-hydroxyethyl) -3-carbomethoxy = pyrrole-2-acetate (IV, R = H), m.p. C, the same product obtained in Example 1.

30

Biodata for intermediate products according to the invention produced end products.

A. Test for analgesic (anti-torsional) effect on mice.

35

Protocol: The compound to be tested is administered orally at ind 39

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giving in an aqueous carrier at time 0 to 18-20 g male Swiss-Webster mice. 20 minutes later 0.25 ml of a 0.02% solution of phenylquinone is injected intraperitoneally. This solution produces distortion. The animals are then observed for the next 10 minutes for twisting

End point: The total number of mice twisting and the average even number of turns per head. mouse.

Using the above protocol, it is determined that 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of about 430 times aspirin, and (l) -5- {benzoyl} -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of approx. 700 times aspirins.

In addition, the following strengths were determined: 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5-p-isopropoxybenzoyl-1,2-dihydroxy = 3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 1 5-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 1 2-5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 250 5-p-methylbenzoyl-6-methyl-1,2-dihydro-3H pyrrolo [1,2-a] pyrrole-1-carboxylic acid 250 5-p-methoxybenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 130 p-chlorobenzoyl ~ 6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 190 5-benzoyl-6-ethyl-1,2-dihydro-3H-1,5-pyrrolo [ 1,2-a] pyrrole-1-carboxylic acid 80 5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 130

DK 152733B

B. B. Acute oral toxicity (LD ^ q) in mice.

Protocol: The compound to be tested is suspended in an aqueous carboxymethyl cellulose suspending carrier. Concentrations are adjusted so that doses can be given in volumes of 10 ml / kg bodyweight. Five groups (consisting of six Swiss-Webster male mice in each group) mice are used. A single oral dose of either 200 mg, 400 mg, 800 mg or 1200 mg of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid per kg of body weight is administered by the stomach probe to the mice. (The fifth group is used as a control.) After administration, the mice are monitored for a 3-week period.

Using the above protocol, the acute oral LD 2 Q value of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-15 carboxylic acid is determined to be about 200 mg / kg.

The corresponding values for 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid and 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1 , 2-a] pyrrole-1-carboxylic acid is 606 mg / kg.

20 C. Test for anti-inflammatory effect using carageinin-induced protein inflammation in the rat.

Protocol: Simonsen female rats weighing 80-90 g were used.

25 0

The test materials are administered orally at time 0 by administration in 1 ml of aqueous vehicle. One hour later, 0.05 ml of a 1% solution (in 0.9% NaCl) of carrageenin was injected into the right hind paw.This injection caused an inflammation of the paw. The rats were sacrificed 4 hours after time 0, at which time both hind legs were cut and weighed separately. "

Endpoint; % increase in paw size calculated as follows: 'weight of right paw τ weight of left' paw 35 · weight of left paw ^ 100

Claims (1)

DK 152733B Using the above protocol, the following effects were determined (phenylbutazone = II: 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [l2-a] pyrrole-1-carb = Oxylic acid 5-p-isopropoxybenzoyl-1,2,2-dd hydro-3H-pyrrolo 11,2-a] pyrrol-rl-carboxylic acid 1,5-m-ethoxybenzoyl-1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 1 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid caf 25 5-p-methylbenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid approximately 5-p-methoxybenzoyl-6-methyl-1,2- dihydro-3H-pyrrolo [1,2-alpyrrole-1-carboxylic acid, about 45-p-chlorobenzoyl-6-methyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole -1-carboxylic acid - about 60 5-benzoyl-6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 25 / 5- (4-fluorobenzoyl) -6 -ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid OO patent (o) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2 -a] -pyrrole-1-carboxylic acids U or ester or salts thereof for use as intermediates in the preparation of the corresponding (dl) - or (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives, characterized by wherein they have the general formula R—-C CCO x (XII) wherein R represents hydrogen or an alkyl group of 1-4 carbon atoms, R · represents hydrogen, an alkyl group of 1-4 carbon atoms , an alk = 3 oxy group having 1-4 carbon atoms, chlorine, fluorine or bromine, and R is hydrogen, an alkyl group having 1-12 carbon atoms or a salt residue.