IE45253B1

IE45253B1 - 1,2-dihydro-3h-pyrrolo (1,2-a)pyrrole-1-carboxylic acid derivaties and process for the production thereof

Info

Publication number: IE45253B1
Application number: IE1423/77A
Authority: IE
Original assignee: Syntex Inc
Priority date: 1976-07-14
Filing date: 1977-07-08
Publication date: 1982-07-14
Also published as: FR2375234A1; YU172177A; NO147564B; FI772153A; ES460706A1; DK151886B; DE2760330C2; IT1117313B; DE2731678C2; JPS6254109B2; FR2358406B1; CA1102809A; FI63406B; FI63406C; IL52493A0; AU513384B2; FR2358406A1; YU40816B; NL186318B; SU695558A3

Abstract

Novel carboxylic acid esters of the formula: in which R denotes hydrogen or C1-C4-alkyl, R<1> denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine or bromine, and R<2> denotes C1-C4-alkyl, are prepared by condensing an amide R<1>C6H4CON(CH3) 2 with a corresponding alkyl 1,2-dihydro-3H-pyrrolo[1,2a]pyrrole-1-carboxylate. The compounds may be used therapeutically as antiinflammatory agents, analgesic agents, fibrinolytic agents and muscle relaxants.

Description

^$3 The. present invention relates to certain, pyrrol o-pyrrole-l-carboxylic acid compounds and to a process for the production thereof.

More particularly, this invention relates to 5-aroyl-l, 2-dihydrO“3H-py rrolo {l, 2-a) py rrole-1carboxylic acids represented by the formula COOH (A) and the individual . (1)-acid isomers and the (d)-aoid isomers fehosiof and the pharmaceutically acceptable, non-toxic esters and salts thereof,.wherein R represents hydrogen or a lower alkyl group having from 1 ta 4 carbon atoms and represents hydrogen, a lowar alkyl group having from 1 to 4 carbon atoms, a lower alkoxy group having from 1 to 4 carbon atoms, chloro, fluoro or bromo, the R substituent being'at the ortho, msta or para position of the aroyl group, to tha method for the production thereof and to novel intermediates obtained thereby.

The compounds of the present invention as described above and more fully below, exclusive of the (d) — the acid isomer and/derivatives thereof, exhibit anti-inflammatory, analgesic and anti-pyretic activities and thus are useful in the treatment of inflammation, pain and/or pyrexia in mammals, as described hereinafter in detail. They are also smooth muscle relaxants.

The term pharmaceutically acceptable, nontoxic esters and salts as used herein refers to alkyl esters in which the alkyl group is--45253 derived from hydrocarbons of branched or straight chain having from one to twelve carbon atoms and salts derived from pharmaceutically acceptable non-toxic inorganic and organic bases, respectively.

Typical alkyl ester groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, S-methyldecyl and dodecyl esters.

Saits derived from inorganic bases include lc sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic •salts. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases j.5 include salts cf primary, secondary, and tertiary aminos, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-di20 ethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperiand dine, /pclyamir.a resins. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The compounds of Formulas (A) and (XI) depicted below exist as pairs of optical isomers (or enantio30 morphs), i.e., a (dl) mixture.

I'oftmevex, each optical isomer as well as the (dl) mixtures thereof ase included within the present invention.

' When the . - compounds of this invention are to fee used to elicit a physiological response (e.g., anti-inflammatory, analgesic or anti-pyretic activity), i.e., they are to be used as medicinals, a preferred sub. grouping is that of fhe compounds of Formula (A). and the (l)-acid isomers thereof and the esters and pharmaceutically acceptable salts thereof. ' a. still further sub-grouping, for compounds to ba used as medicinals, are the compounds of Formula (A) and the (l)-acid isomer of Formula (A) and the esters and pharmaceutically acceptable salts thereof wherein a and are both hydrogen, 3 The (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 more fully below.

The (dl) compounds of the present ® invention can be prepared: by a process illustrated by the follow ing reaction sequence: - 4 3S2S3 COOH wherein R and have the above-indicated meaning and 2 R is a lower alkyl group of 1 to 4 carbon atoms,e.g.«methyl, ethyl, isopropyl and n-butyl.

Xn practicing the process outlined above, for the preparation of the compound of Formula (IV) wherein S is hydrogen, eguimolecular amounts of ethanolamine (X) and dimethyl 1,3acefconediearboxylate (XX) are reacted at a temperature of from about Qa to about room temperature, to readily form a solution of the vipylamine.. of Formula (XXX), which is '•then treated, preferably in situ, in a suitable inert organic solvent, under anhydrous conditions, with 2-bromoacetaldehyde or 2-chloroaeetaldehyde, at from about 4Q° to about 1OO°C for a period of time of from about 30 minutes to about 16 hours. Suitable solvents for this reaction ara the aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxy• and ' · othans, chloroform,/dichloromethane. ' Xn the preferred embodiments, the reaction is conducted in aceto-. » , nitrile solution, at 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.

To prepare the compounds of Formula (IV) wherein R is a lowar alkyl group, preferably straight chain, having 1 to 4 carbon atoms, an aqueous mixture of ethanolamine (X) and dimethyl 1,3-acefconedicarboxylate (II) is treated with a compound of the formula R^-^-CK^X, wherein X is 3 bromo or chloro and R is a lower alkyl group, preferably - 6 45253 straight chain, of from 1 to 4 carbon atoms, and most preferably 1-broaoacetona, l-bromo-2-butanone, l-bromo-2-pentanono, and l-bromo-2-hexanone, at from about 40® to about 100®C for a period of time from about 30 minutes to about 5 16 hours. In the preferred embodiment the reaction is conducted at a temperature of from about -10®C to about room temperature for from about 1 hour to about 6 hours. The P R^-C-CHgX reagents are known compounds, • Esterification of compound (IV) with methane qg sulfonyl chloride in the presence of a tertiary amine, i.e., or triethylamine /pyridine s optionally in the presence of a cosolvent such as dichloromethane, at a temperature of from about -1O°C to about rcom temperature, for about io minutes to about 2 hours produces the corresponding mesylate of Formula (V), which is converted into the corresponding N-(2-iodoethyl)pyrrole of Formula (VI) by reaction vzith sodium iodide in acetonitrile solution, at reflux temperature for from about one tc about ten hours.

Upon reaction of the iodoethyl oompounds of Formula (VI) with sodium hydride in a suitable inert organic solvent such as dimethylformamide there are obtained dimethyl 1,2-dihydro-3H~pyrrolo[1,2-e3pyrrole-1,7-dicarboxylate and tha 6-alkyl substituted derivatives thereof (VII). This cyclization is conducted under an inert atmosphere, i„e., under argon cr nitrogen atmosphere, at temperatures of the order of from about 13° to about 40®C, for a period of time of from about 25 minutes to about 4 hours. Best results are obtained conducting the reaction at room temperature, for about 30 minutes when R is hydrogen. - 7 Alternatively) the compounds of Formula (VII) can be.prepared by direct cyclisation of the mesylate (V), with sodium hydride in dimethylformamide solution, at from about -10°C to about room temperature, for from about 30 .5 minutes fo about 2 hours.

Sasic hydrolysis of a compound of Formula (Vll) with an alkali metal hydroxide or alkali metal carbonate, e.g., sodium hydroxide, potassium hydroxide, sodium or carbonate/ potassium carbonate ., ia an aqueous • lower aliphatic alcohol, e.g., methanol or ethanol, at a temperature of between room temperature and reflux, for from about 4 to about 24 hours, affords the corresponding free diaeid of Formula (vxil), i.e., l,2-dihydso«-3H-pyrrolo[1,2-a] pysrole-l,7-dicarboxylic acid and the S-alkyl derivatives -.: 13 thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide, at' reflux temperature for about 10 hours..

The carboxylic acid group at the C-1 position in compound (VXXX) is then selectively esterified by 20 treatment with a lower aliphatic alcohol, e.g., methanol, or ethanol, isopropanol/ n-butanol - in the presence of hydrogen chloride, to produce the corresponding alkyl 1,2dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxy late-7-carboxylie acid of Formula (IX). Tho reaction- is conducted at a temper25 . ature of from about 0° to about 50eC., for about 1 to about. hours.

Decarboxylation of the monoesterified compounds (IX) to the corresponding compounds of Formula (X), the key intermediates in the process for obtaining tho com- 8 4B2S3 pounds of the'present invention, is achieved by heating. (IX) at an elevated temperature, of the order of from about 230° to about 2SO’C, for a period of time sufficient to complete the reaction. The course of the reaction can be followed by fche rate of carbon dioxide evolution and t.l.c. analysis, decarboxylation being generally completed within from about 45 to about 90 minutes. The reaction product, namely, alkyl l,2-^ihydro-3K-pyrrolo[l,2-alpyrrole-l“carboxylafce and the 5-alkyI' derivatives thereof (X) can be purified by chromatographic techniques. Alternatively, and particularly for the decarboxylation of small batches of compound (IX), the reaction product (X) can be distilled directly- from the reaction vessel.

Condensation cf a compound -(X) with an amide of the formula C0!1 ^'H3^ 2 i wherein R has the above-indicated meaning, affords the corresponding alkyl 5-aroyl-l,2-dihydro-3H-pyrrolo[l,2-aJpyrrole-lcan be carboxylate (XI). Thia reaction / conducted in an inert organic aprotic solvent and in the presence of phosphorous oxychloride, at reflux temperature for from about 1 to about 175 hours, under an inert atmosphere,followed hy further reflux in the presence of sodium acetate, for from about 2 to about 10 hours.Alternatively, instead of phosphorous 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 to 5 molar equivalents of both the desired amide and phosphorous oxychloride in the same solvent, refluxing the reaction mixture thus 43253 obtained for from about 6 to about 7 2 nours unaer an argon atmosphere and thereafter adding thereto from about 3 to about 10 molar equivalents of sodium acetate,followed by an addition al reflux period for from about 4 to ’about S hours.

Adequate solvents for this reaction are the halo genatsfi hydrocarbons such as dichloromethane, 1,2-dichloroand ethane, chloroform /carbon tetrachloride, . dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2dichloroetbane.

Representative of the N,N-dimethyl arylamides which can be used are: Ν,Ν-dimethyl-benzamide, N ,Ν-fiimethyl-o-toluaniide, H,N“dim3thyl-m-toluamide, N ,Ν-fiisaethyl-p-toluamide, , NiN-dimethyl-p-ethyl-benramide, N,Ν-fiimathyl-o-ptopyl-bensamide, ’ N ,Ν-difflsthyl-m-butyl-benzamide, N,H-dimsthyl-o-msthoxy-benzamide, Ν, N-dime thy l-m-methojty-bens ami de, S3,M-dimethyl-p-ethoxy-benssmida, Ν,Ν-dimethyl-p-isopropoxy-benzamida, N,Ν-dimethyl-o-chloro-bensamide, N,Ν-dimethyl-m-chloro-benzamide, SI,Ν-dimethy1-p-chloro-benzamide, N,H-dimethyl-o-fluoro-bensamide, Ν,N-fiimsthy1-p-fluoro-benzamide, N,N-dimethyl-m-bromo-banzamide and Ν,N-dimethyl-p-bromo-bensamide.

These amides are known, commercially available compounds or can be prepared in a conventional manner from the - 10 4S2S3 corresponding acids i.e.,fcy conversion intc the acid chlorides followed fay treatment with dimethylamine.

Upon alkaline hydrolysis of the alkyl ester group in a compound of Formula (IJ there is obtained the corresponding free acid of Formula (A). This hydrolysis is effect ed in a conventional manner, with an alkali metal hydroxide or alkali metal carbonate, e.g.,sodium hydroxide, potassium hydrcr oxide, sodium carbonate/ potassium carbonate, in . or an aqueous lower aliphatic alcohol, e.g., methanol/ ethanol, at a temperature of frcm about room temperature to reflux, for from about 15 minutes to about 2 hours, under an inert atmosphere. In the preferred embodiments, this hydrolysis is effected with agueous methanoiic potassium carbonate, at reflux temperature for about 30 minutes.

The-compounds of Formula (A) can be resolved, according to methods known in the art, to obtain the corresponding individual isomers thereof.

The (15-acid isomers and (d)-acid isomers of the compounds of Formula (A) can be obtained by applying the known technique of high pressure liquid chromotography (HPLC) to the α-phenethyl diastereoisomeric esters of the compounds of Formula (A), followed by acid cleavage. Thus, for example, the compounds of Formula (A) wherein R and R^ are both hydrogen can be subjected to further treatment in accordance with the following flow diagram: - 11 COOH a more detailed description ef this procedure is set Serfch in Example 12 B below. - 12 Λ Ρί ¢3 5ζ && *-* The tree acids of Formula (A) can he converted into other alkyl eaters 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 etheral diazoalkane or ;c) the desired alkyl iodide in the presence of lithium carbonate. The (l)-acid isomers can be converted into their alkyl esters by the methods os (bj and (o) above.

, , The salt fierivatives or th* compounds of Formula lb (A) and the (l)-acid isomers thereof are prepared by treating these free acids with aa appropriate amount of a pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are sodium hydroxide, potassium· hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, 2inc hydroxide, copper hydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide, manganic hydroxide, isopropyl- . amine, trinethyi/rsine, diethylamine, triethylamine, tripropyl20 amine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydr&bamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, Purines, piperaund zine, piperidine, N-ethylpiperidine /polyamine resins. me reaction is conducted in water, alone or in combination with an inert, water- Wi sci bi e organic solvent, at a temperature of from about 0°C. to about 100°C, preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanoi, 30 butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of compounds of Formula. (A) or the (l)-acid i'somars thereof to base used are chosen to provide the ratio desired for any particular salt. For preparing, for exam?)*, the calcium salts or magnesium salts of the compounds of Formula (A) or the (l)-acid isomers thereof# the freo acid starting material can be treated with at least one-half molar equivalent of pharmaceutically acceptable bass to yield a neutral salt. When tlie aluminum salts of the compounds of Formula (A) or the (l)-asid isomers thereof are prepared at least one-third molar equivalent of the pharmaceutically acceptable base are employed if a neutral salt product is desired, In the preferred procedure, the calcium salts and magnesium salts of the compounds of Formula (A) and (I)-aeid isomers thereof can he prepared by treating the corresponding sodium or potassium salts thereof with at least one-half molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or ia combination with an inert water-miscible organic solvent, at a temperature of f-om about 20°C to about 100°C. Preferably, the aluminum salts of the compounds hereof, can be prepared by treating the corresponding free acids with at least one-third molar equivalent of an aluminum alkoxide, or such as aluminum triethoxide /aluminum tripropoxide,. in a hydrocarbon solvent, such as benzene, xylene or cyclohexane, . at a temperature of frcm about °C to about 115°C. Similar procedures can be used to prepare salts of inorganic bases which are not sufficiently soluble for easy reaction. . ' - < St is to be understood that isolation of 453s3 the compounds described herein can be effected, if desired, by any suitable separation or purification procedure, such as, for example, extraction, filtration, evaporation, distillation, crystallization, thin-layer chromatography or column · chromatography, high pressure liquid chromotography (HPLC) or a combination of these procedures. Illustrations of euitable separation and isolation procedures can be had by reference to the Examples herein below. However, other equivalent separation or isolation procedures could, of course, also be usad.

· While the (d)-acid isomers are not used as medicinal agents per se, they can, if desired, be converted to their pharmaceutically acceptable, non-toxic esters and salts thereof according to the methods described for the conversion of the (l)-acid isomers to their pharmaceutically acceptable, non-toxic esters and salts thereof.

The compounds of Formula (A) and . the (l)-acid isomers thereof and the pharmaceutically acceptable non-toxic esters and salts thereof, are useful as anti2o inflammatory agents, analgetic agents, platelet aggregation inhibitors, fibrinolytic agents, and as smooth muscle relaxants. These compounds can be used both prophylactically • and therapeutically.

The compositions containing these compounds are thus useful in the treatment and elimination of inflammation such as inflammatory conditions of the muscular skeletal system, skeletal joints and other tissues, for example, in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, bone fractures, 30 post-traumatic conditions, and gout. In those cases in which the above conditions include' pain and pyrexia coupled with inflamination, the instant compounds are useful for the relief of these conditions as well as the inflammation.

Administration of the active compounds of Formula (a) os the (1)- aoid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, in an appropriate pharmaceutical composition can ba via any of the accepted modes of administration of agents for (die treatment of inflammation, pain or pyrexia, or the prophylaxis thereof. Thus, administration can be for example, orally, parenterally or topically, in the form of- solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, solutions, or suspensions, emulsions, creams, lotions./ointments, - preferably in unit dosage forms suitable for simple administration ©f precise dosages. Ths compositions will include a conventional pharmaceutical carrier or excipient and an active compound of Formula (A) or the (1)- acid isomer, thereof and the pharmaceutically acceptable non-toxic esters and salts thereof, and, in addition, may include other and medicinal agents, pharmaceutical agents, carriers /adjuvants.

The preferred manner of administration, for the conditions detailed above, is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Generally, a daily dose of from 25 rag. to 500 mg. of the active compound of Formula (A) or tha (l)-acid isomer thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof is used. Most conditions respond to treatment comprising a dosage level of the order of 0.5 mg. to 6 mg. per kilogram of body weight per day. For such oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccarine, talcum, cellulose, glucose, and gelatin, sucrose / magnesium carbonate. Such compositions take the form of solutions, suspensions, tablets, and pills, capsules, powders /sustained release formulations.

The active compounds of Formula (A) or the (l)-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, may be formulated into a suppository using, for example, polyalkylens glycols, for example, polypropylene glycol, as the carrier. Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound, as described above, and optional pharmaceutical adjuvants i„ a carrier, such as, for example, water, . or saline, aqueous dextrose, glycerol /ethanol, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as and wetting or emulsifying agents /pH buffering agents, such as for .example, sodium acetate, sorbitan menolauand rate /triethanolamine oleate.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th. Edition, 1970. The composition to be administered will, in any event, contain a quantity of the active compound(s) in a pharmaceutically effective amount for relief of the particular condition being treated in accordance with the teachings of this invention.

• She compounds of Formula (A) and the (l)-acid isomers thereof and the non-toxic, pharmaceutically acceptable esters and salts thereof, described above, are also uterine smooth muscle relaxants and thus are useful as agents for maintaining the pregnancy of pregnant mammals, for the benefit of the mother and/or fetus, until termination of idle pregnancy is considered, from a medical point of view, to bo favorable, or more favorable, for the mother and/or tha fetus. It should be understood, however, that in certain instances, for example where parturition has already begun (i.e., the mother is experiencing uterine contractions, especially near full term), that administration of tiie compounds herein described may not maintain the pregnant state for aa indefinite period cf time. Rather, in such instances, the pregnancy will, most probably, be slightly ’’prolonged'', t a factor which may be advantageous to either the mother and/or the fetus. la particular, the compounds of Formula- (A) and the (1)- .acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, are used as agents for delaying the onset of, or for postponing, parturition. As used in this application, the phrase to delay the onset of parturition is intended to cover that delay in parturition .caused by the administration of the compounds of Formula (A) or the (1)- acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, at any time before uterine muscle contractions have begun. Thus, it is intended that the aforementioned phrase, cover abortion prevention early in pregnancy (i.e., before the fetus is viable) as well as delaying premature parturition, a term which sometimes is used with reference to that premature labor experienced later in the pregnancy when the fetus is considered to be viable. In either case, the agents are administered as prophylactic agents in that such administration tends to prevent the onset of parturition.

This administration is particularly useful in the treatment of women having a history of spontaneous abortion, miscarriage or premature delivery (i.e., delivery prior to full term). Such administration is also useful where there are clinical indications that the pregnancy might be terminated prior to that time and is considered favorable to the mother and/or fetus.

With respect to animals, this treatment can also be utilized te synchronize the deliveries from a group of pregnant animals to happen at or about the same time, or to happen at tr asout a desired time and/or place, when the births can be handled with greater facility.

As used in thie application, the phrase postponing parturition is intended to cover that delay in parturition caused by the administration of the compounds of Formula (A) or the (lj-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof after uterine muscle contractions have begun. The condition of the patient, including the time within the gestation period when the contractions have begun, the severity of the contractions and how long the contractions have taken place will affect the results achieved with the administration of the compounds hereof. For Example, the effect can be to reduce the intensity and/or the duration of the contractions (the actual abt of parturition being prolonged), or to stop the contractions altogether. Xn either case, the effesfe will ba to prolong the gestation period although, depending upon the conditions of the patient as described above, the effect may either fco/islight or, under appropriate circumstances, somewhat greater. Such administration may be to prevent spontaneous abortion, to cause the delivery to ba more easily accomplished and/or less‘painful to the mother, or to occur at a more appropriate time and/or place.

Sn all cases, administration of the compounds of Formula {&) cr the (1)-acid isomers thereof and the pharmaceutically acceptable,‘ηόη-toxic esters and salts thereof, for the purposes set forth herein should be consistent with best and/or accepted msdieal (or veterinary) practices so as to maximise ths benefits to the mother and the fetus. For example, administration should not be continued se long past full term that the fetus dies in utero* ' In tho practice of the methods of the present invention, a therapeutically effective amount of a compounds of Formula (A) or the (l)-aeid isomers thereof and the pharmaceutically acceptable, non-toxic asters and salts thereof, or a pharmaceutical composition containing Same, is administered io ths pregnant mammal via any of the usual and acceptable methods known in the art. The compound can be administered either singly or in combination with another compound or compounds, as defined above, or other pharmaceutical agents, carriers, adjuvants, ets. Such - 20 10 45353 compound(s) or compositions can be administered orally, parenterally. either in the form of solid, semi-solid, or liquid dosage forms. Typically, administration is by a pharmaceutical composition containing the pharmaceutically active compound and one or more pharmaceutical carriers or adjuvants.

The administerable . pharmaceutical composition may take the form of oral tablets, vaginal cr uterine tablets cr suppositories, pills, capsules, liquid solutions or suspensions , preferably in unit dosage forms suitable for simple administration of precise dosages. Conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, gelatin, and sucrose /magnesium carbonate. The active compound as defined above may be formulated as suppositories using, for example, poiyalkylene glycols, for example, polypropylene glycol, as the carrier. Liquid pharmaceutically administerable compositions can, for exaaple, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, or glycerol /ethanol, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying and agents / pH buffering agents , for example, sodium acetate, sorbitan mor.olaurate, triethanolamine oleate.

Actual'methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example. see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition, 1970. The com·» position or formulation to be administered will, in any event, contain a quantity of the active compound(s) in an amount effective to delay the onset of parturition or to postpone parturition if uterine contractions have already begun.

Generally a daily dose of from 0.5 mg. to about 25 mg. of the active compound per kilogram of body v/eight v/ill be administered, v/ith administration being a single daily dose ©r up to three or four smaller dosages regularly given throughout the day. The amount of active compound administered v/ill, of course, depend on its relative activity.

. The follov/ing . Examples illustrate the invention but are not intended to limit its scape. The abbreviation t.l.c. refers to thin-layer chromatography and all mixture ratios used v/ith regard to liquids refer to volume ratios. Also v?here necessary, examples are repeated te prepare additional material for subsequent : examples? and unless otherwise 'specified the reactions are barriedoat at roost tsmperaturg..(20°C to 30°C). . Examples 1 to 5, 13A and 13B, 17 and IS relate to intermediate steps in preparing compounds of the invention.

’EXAMPLE 1.

. A 250 ml* 3-necked round bottomed flask containing a magnetic stigring bar and fitted with a calcium chloride filled drying tuba is connected directly {via one of the outer necks) by means of a receiver adapter and short (3) water condenser to the acetal pyrolysis apparatus. This latter apparatus consists of a 100 ral. round bottomed flask [previously charged with 15.S g. of oxalic acid dihydrate and 11.82 g. of bromoacetaldehyde diethyl acetal, prepared - 22 45253 from vinyl acetate, as described by P.Z. Bedoukian, J. Am.

Chem. Soc. SS, 651 (1344jJ, topped with a 6 Vigreux column, bearing a thermometer, connected to the above mentioned condenser.

The 3-necked flask is charged with 3.36 g. of ethanolamine cooled in an ice bath at 0°-10°C and treated dropwise, with stirring, with 8.7 g. of dimethyl 1,3-acetonedioarboxylate· Methyl 3-carbomethoxymethyl-3(2’-hydroxyethyl) amino acrylate (ill) forma immediately. When the addition is completed, the ice bath is removed and 100 ml. of dry acetonitrile is added. The pyrolysis part of the apparatus is placed in an oil bath and the temperature thereof is raised to 15O-lGOeC. The bromoacetaldehyde solution which forms is distilled (b.p. 8O-83°C/58C· mm) directly into the magnetically stirred solution of the vinylamine (III). When the distillation temperature drops below 80°G, the pyrolysis apparatus is disconnected and replaced by a reflux condenser fitted with a drying tube containing calcium chloride. The solution is heated at reflux temperature for 1 hour, the solvent is removed under reduced pressure and then 200 ml. of methanol and 20 g. of silica gel are added to the residue.

This mixture is evaporated to dryness in vacuum and placed on top of a column of 200 g. of silica gel packed in hexane.

The column is then eluted with hexanesethyl acetate (80s 20; 500 ml.) and hexanesethyl acetate (1:1; 9 x 500 ml.). Fractions 2 and 3 contain less polar impurities and dimethyl 1,3acetor.edicarboxylate; fractions 4-8 afford 4.1 g. of methyl N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV,R = Η), which upon recrystallisation .from ether-hexane has a melting point of 52-54 °C. - 23 5 EXAMPLE 2 To a stirred solution of 4.1 g. of methyl N-(2-hydroxyethyl)“3-sarbomethGxypyrrele-2-aeetate in 35 ml. of dry dichloromethane cooled to -1O°C, are added 2.65 ml. of triethylamine and thereafter, in a dropwise fashion,1.46 ml of methanesulfonyl chloride, maintaining the temperature of tha reaction mixture at -10° to -5BC. The course of the reaction is followed by t.l.c. analysis using chloroform:acetone (90:10). When the reaction appears to be complete (about 30 minutes after the addition of the methanesulfonyl chloride is terminated) there is added slowly 10 ml. of water. The organic phase is separated, washed with water (3 x 30 ml.), dried over oodium sulfate and evaporated under reduced pressure. Crystallisation of the residue from dichloromethanehexane affords 4.75 g. (77.7¾) of methyl N-(2-mesyloxyethyl)M3-earbemathoxypyrrole-2-acetatG (V..R => H), m.p. 99-101,°C.

EXAMPLE 3 A solution of 785 mg. of methyl H-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate and 1.83 g. of sodium iodide in 10 ml. of acetonitrile is refluxed for 1 hour. She cooled reaction mixture is evaporated to'dryness under reduced pressure and the residue is triturated with water.

The insoluble material is separated by filtration and air dried, thus obtaining 840 mg. (97%) of methyl N-(2-iodoathyl)-3-carbomofchoxypyrrole-2-acetato (VI, R = B), m.p. 137138°C.

EXAMPLE 4 A solution of 1 g. of methyl N-(2-iodoethyl)24 3-carbomethoxypyrrole-2-acetate in 5 ml. of dry dimethylformamide is stirred, under an atmosphere of argon, with 137 mg. of 50% sodium hydride in mineral oil. The reaction mixture is maintained for 30 minutes at room temperature and then quenched with 100 ml. of water. The product is extract5 ed with ethyl acetate (3 x 50 ml.), the combined extracts are 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 eluant, affords 500 mg. (80¾} of dimethyl 1,2-dihydro-3B1θ pyrrolo[l,2-a]pyrrole-l,7-dicarboxylate (VII, R = TS.} m.p. 7O-71eC.

A solution of 1.80 g. of dimethyl 1,2-dihydro-3H-pyrrole[l,2“ajpyrrole~l,7-dicarbcxylate in 20 ml. of methanol is treated with a solution of 4.48 g. of potas1 c sium hydroxide in 20 ml. of water, 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 resultant solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3 x SO ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to yield 1.51 g. (95%) of l,2-aihydro-3Hpyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid (VIII, R => Η), m.p. 22O°C, with decomposition.

EXAMPLE 5 ' A solution of 1.34 g. of l,2-dihydro-3Iipyrrclo(1,2-a]pyrrole-1,7-dicarboxylic acid in 50 ml. of iso30 propanol, cooled in an ice bath is saturated with gaseous - 25 4«»*’ hydrogen chloride, maintaining the temperature of fhe reaction mixture below 50°C. The ice bath is then removed and the reaction mixture is stirred for 1.5 hours at room temperature, and evaporated to dryness under reduced pressure; ml. of bensene is added to the residue and the solution is evaporated under vacuum once again, repeating this process a total of three times to completely remove the excess hydrogen chloride, thus obtaining 1.58 g. (96C) ef isopropyl 1.2- dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxyIste-7-carboxy» lie acid (IX, R = E, Ra = iCgH?), which upon crystallisation Ιθ from methanol-ethyl acetate has a-melting point of 144-145SC.

In a similar manner but substituting methanol ethanol, propanol and n-butanol for isopropanol in the above procedure there are respectively obtained; methyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxyl15 ate-7-carboxylic aeid, ethyl l,2-dihydro-3E-pyrr©lo[l,2-a)pyrrole-l-carboxylatc-7-carboxylic acid, propyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylafee-7-earboxylic aoid, and ?0 • -butyl l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxyl ata-7-carboxylic acid.

EJMSSS δ ‘ * 1.054 G. of isopropyl l,2-dihydro-3K-pyrrolo [1,2-a]pyrrole-l-carboxylate-7-earboxylic aeid is heated to 24O-25O°C in a dry 10 ml. round bottomed flack, distilling directly the reaction product from the reaction vessel. Xn this manner there is obtained 745 mg. (87%) of isopropyl1.2- dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate (X, R =» H, 4SS53 R = iC-H_), a pale yellow oil, having tha following physical J MeOH CHC1, constants: U.V. :1 max 215 nm (ε 5020}; I.R.: v max J CCC 3. 1725 cm”1; N.M.R.: 6TMS 1.22 (d, -J = 7 Ka, SH), 2.40-2.90 (in, 2H), 3.60-4.20 (m, 2H) , 4.65-5.2 (m, IH) , 5.73-5.92 (m, IH), 6.10 (t, J « 3 Hz, ,1H), 6.43-6.53 ppm. (m, IH).

EXAMPLE 7 A ICO ml. 3-necked round bottomed flask equipped with a condenser, nitrogen inlet tube and a gas bubbler is charged with S.O g. of isopropyl l,2-dihydro-3Hpyrrolo[l,2-a3pyrrole-l-carboxyIate-7-carboxylic acid. The apparatus is thoroughly flushed with nitrogen and then the nitrogen flow is stopped. The apparatus is immersed in an oil bath heated at 27G°C and the reaction is followed by the rate of carbon dioxide «volution (gas bubbler) and by t.l.c, on silica gel, using benzene:dioxan:acetic acid (90:10:1) as developing solvent. After 45 minutes the reaction is almost complete. After one hour, the vessel is removed from the oil rath and the contents of the reaction flask are transferred to a round bottomed flask with 500 ml. of 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) afford 2.77 g. (685) of isopropyl 1,2-aihydro-3H-pyrrolc(1,2-a]pyrrola-l-carboxylate (X, R » H, R iC^H?), an oil, whose physical constants are identical to those obtained ir. Example 6.

EXAMPLE 8 A solution of 179 mg. of N,N-dimethyl-p- 27 toluamide and 0.11 ial- of phosphorous oxychloride in 2 ral. of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 193 mg. of isopropyl 1,2-dihydro3H-pyrrolo{l,2-a]pyrrole-l-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 a further 5 hours. The resultant mixture is then evaporated to dryness aad ths residue is chromatographed on 12 g. of silica gel,eluting with hexane: 1Q ethyl acetate (3:1), thus obtaining 208 mg. {65%) of isopropyl 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-11 2 Carboxylate {Xl, R = H, R = p-CH,, R. -- iC-di,), an oil, * -5 ' MeOH having the following physical constants: U.V.: Iraax 256, film . 312 am, (sS700, 19500)? 2.R.: vraax 17-35, 1620, 1605 cm x; CSCl, ls N.H.R.: 6TMS 1.23 {d, J = 7 Hs, 6E) , 2.38 (s, 3H) ,2.5-3.0 {ra, 2H), 3.75-4.10 (m, IH), 4.2-4.50 (a, 2H), 4.85-5.20 {ra, IH), 5.95 {d, 3=4 Hz, IH), S.70 {d, 3 « 4 Hz, IH), 7.10 {d, 3 = 8 Hs, 2H), 7.60 ppm.(d, 3 = 8 Sz, 2K).

SWIRLS 9 A solution of 336 rag. of isopropyl 5-ptoluoyl-l ;2-dihydre-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ral. of methanol is treated with a solution of 690 rag. of potassium carbonate in 5 ml. of water. The reaction mix25 ture is refluxed under 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 resultant mixture extracted with ethyl acetate {2 x 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. - 28 A Κ r .«· * «* U d Crystallization cf the residue from ethyl acetate-hexane affords 238 mg. (89%) of 5-p-toluoyl-l,2-dihydro-3H-pyrrolo (1,2-ajpyrrole-l-carboxylic acid ((A), R = H, R^ = p-CH^], m.p. 182-133°C.

EXAMPLE 10 A solution of 250 mg. of isopropyl 5-ptoluoyl-l ,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in ml. of metfc&aol is treated under an atmosphere of nitrogen, with a solution cf 200 mg. of sodium hydroxide in 1 ml. of water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with ml. of water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 15 % hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 5-p-toluoyl-l,2-dihydro3H-pyrrolo[l,2-a]pyrrole-l-carboxylic aoid, identical to the product obtained in Example 9.

EXAMPLE 11 By following the methods Of Example S or 7, the remaininc compounds obtained in Example 5 are converted 25 respectively into: methyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-lcarboxylate, ethyl 1,2-dihydro-3H-pyrrolo(1,2-a]pyrrole-l3q carboxylate, propyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-lcarboxylate and butyl 1,2-“dihydxc“3H-pyrrolo [1,2-a] pyrrole-1carboxylate.

Upon condensation of these compounds with NfU-dimethyl-p-toluamide, in accordance with the method of Example 8 there are respectively obtained! methyl 5-p-toluoyl-l»2-dihyd.ro-3H-pyrrolo [L»2-a]pyrrole-l-earboj^ylate, ethyl 5-p-toluoyl-l,2-dihydro-38-pyrrole[l,2-a]pyrrole-l-carboxylate, propyl 5-p-toluoyl-l,2-dihydro-3H-pyrrolo El,2-a] pyrrole-l-carboxylate and butyl 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]15 pyrrole-l-carboxylate.

EXAMPLE 12 a Following the procedure of Example 8 using 1.1 to 5 molar equivalents of Ν,Ν-dimethyl-banzanide, NfN-dimethyl-o-toluamide, N, N-dimethyl-n-toluamide, H jN-dimsthyl-p-ethyl-bensaiaide, Ν, N-dimethyl-o-propyl-ben2aiaide, N,Ν-dimathy1-m-butyl-bensamide, NfM-dimethyl-o-aethoxy-benzasiide, N, N-csiiaethyl-p-msthoxy-benzamide, N jN-dimethyl-p-ethoxy-benzamidep N,N-dimethyl-p-isopropoxy-ben2amide, NfN-dimathyl-o-chloro-bensamids, K,N-dimethyl-m-chloro-beasamide, 4SSS3 H ,N-dimethyl-p-chloro-benzamide, N,N-dimethyl-o-fluoro-benzamide, f Ν,N-dimethyl-p-fluoro-ben samide, N ,N-dimethyl-m-bromo-benzamide and N,N-dimethyl-o-bromo-benzamide, in place of Ν,Ν-dimethyl-p-tcluamide, and monitoring the course of the reaction by t.l.c., there are obtained respectively: isopropyl 5-benzoyl-l,2-dihydro~3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, a light yellow oil, having the folMeOH lowing physical constants: U.V.: /.max 245, 311 nn (ε 7230, CHC1, τ CDC1, 17800); I.R. vmaX J 1735, 1620 cm'*; N.M.R: fiTMS 1.24 [d, 6H, {CH3)2CH], 2.SC-3.13 (m, 2H; H-2); 3.97 (dd, IH, H-l), 4.18-4.70 (m, 2H, H-3), 5.00 (sept., IH, (CH3)2CH), 6.00 (d, IH, H-7), 6.86 (d, IH, H-6), 7.10-7.90 ppm (m, 5H, 4· phenyl protons); M.S.: m/e 297 (M ), isopropyl 5-o-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, an oil, having the following physiMeOH cal constants: U.V.: Amax 252, 303 nm (ε 4460, 19100); CHC1, . CDC1, I.R.: vmax J 1735, 1620 cm ; N.M.R.: δ TMS 1.18 [d, 6H, (CH3)2CH), 2.28 (s, 3H-, o-CHj), 2.50-3.13 (m, 2H, H-2), 3.92 (dd, IH, H-l), 4.17-4.70 (m, 2H, H-3), 4.98 (sept. IH, (CH3)2CH), 5.92 (d, IH, H-7), 6.43 (d, IH, H-6), 6.97-7.45 ppm (m, 4H, phenyl protons). isopropyl 5-m-toluoy1-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, an oil, having the following physical MeOH constants: U.V.: /.max 250-251, 310-312 nm (e 6460, 17400); CHC1 . CDC1, I.R.: vmax j 1735, 1620 cm ; N.M.R.: STMS J 1.25 [d, 6H, (CH3)2CH), 2.27 (s, 3H, CH3), 2.52-3.13 (m, 2H, H-2),3.92 (dd, IH, H-l), 4.13-4.70 (m, 2H, H-3), 4.95 [sept. IH, (CH3)2CHb 5.95 (fi, IH, E-7), S.S7 (fi, IH, H-6), 7.03-7.57 ppm. (m, 4H; phonyl protons), isopropyl S-p-sthylbensoyl-l,2-fiihyfiro-3E“pyrrolo[1,2-aJ pyrrole-X-cazboxylate, , ioogregyl 5-o-progylbensoyl-l,2-fiihyfiro-3H-pyrrolo5 ' [X,2=a3gyrreXQ-X-earbo3sylate, isopropyl S-B“butylben2cyX-l,2-fiihyfiro«3H-pyrrolo[X,2-a]pyrreXe=X-sarfco;;yXate, isopropyl S-o-iastho.’iyaensoyX-l, 2-fiihyfiro-3S-pyrrolo[1,2-a]pyrrole-l-carboxylate, “ isopropyl S-p-methoxybensoyl-l,2-fiihyfiro-3H-pyrrolo“· [1,2-a]pyrrole-X-carboxylate, having the following physical jieOH Constanta; C.V., *®as 218, 270-284 (shoulder), 314 nm (a 9780, 9320, 22400); CHCX ,» I.R. 'fosr. 3 1730, ISOS om“X> cool. 0.U.R. °THS 3 1.24 [fi, 5H, J = 6 Hz) (CH^CH-J, 2.50-3.10 fo, 2B) H-2), 3.78 (S, 3H) eSgO), 3.93 (fid, IH, ffjy, - ί Βί, ϋΞχ 7 Hs; S-1J, 4.13-4.SO fo, 2E? H-3), 4.S3 [sept., IH, σ a G HZ? (CS3)2CS], 5.9S (s, IH, 20 d a 4 Hss E-7), 6,68 (fi, IH, J 4 Hz) H-6), ' 0,70=7.90 ppm. fo, 4E; phenyl protons); M.S. m/s 327 (/'}. isopropyl S-p-ethoxybensoyi-l,2-fiihyfiro-3H-pyrrolo[1,2-aJpyrzole-l-earborylate, m.p. 94-95°C., isopropyl 5-p-isoproposybeazoyX“l,2-fiihyfiro-3H-pyrrolo[I,2-a]pyrrole-1-carboxylate, isopropyl 5-o-chlorobensoyl-l,2-fiihyfiro-3H-pyrrolo[l,2-a]gyrrole-l-sarbas5ylatQ, an oil, having the following KsOH physical constants; O.V.: Imax 251, 306 nm (s 5750, 13600); CHCl, . CDC1, I.S.; vmaX 1735, 1625 om s N.M.R.; άΤΝΕ d 1.22 [fi, 6H, - 32 45353 (CHgJgCH·, 2.55-3.OS (m, 2H; H-2), 3.97 (dd, IH, H-l), 4.17-4.70 (m, 2H, H-3), 4.97 [sept., IH, (CH^CH], [5.93. (d, 2/3H), 6.00 (d, 1/3H) H-7],[6.42 (d, 2/3H), S.67 (d, 1/3H), H-6], 7.07-7.80 ppm.(m, 4H; phenyl protons), isopropyl 5-m-chlorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, an oil,having the following MeOH physical constants: U.V.: Imax 241, 3i3 nm (e 6S0G, 15100),CHCl, , CDCl, Ϊ.Κ.; wsat 1735, 1S2O, 1570 cm ; N.M.R.s 6TMS J 1.27 id, 6H, (CH3]2CH], 2.SC-3.13 (m, 2H, H-2), 3.93 (dd, IH, H-l), 4.10-4.S3 (m, 2H, K-3), 4.99 [sept., IH, (CH^CK], 5.98 (d, IK, H-7), 6.67 (d, IH, H-6), 7.07-7.78 ppm.(m, 4K, phenyl protons); M.S.s m/e 331-333 (M+), isopropyl 5-p-chlorobensoyl-l,2-dihydro-SH-pvrrolo[1,2-a]pyrrole-l-carboxylata, m.p· 8O.5-81°'C., isopropyl 5-o-fluorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-oarboxylate, isopropyl S-p-rlaorobenzcyl-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-cj.rboxyiate, m.p. 72-72.5®C., isopropyl 5-m-bromobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate and isopropyl 5-p-bromobenzoy1-1,2-dihydro-3H-pyrrolot1,2-a]pyrrole-l-carboxylate.

Upon hydrolysis of the isopropyl ester group, in accordance with the methods of Examples 9 or 10, there are obtained tha corresponding free acids, namely: -benzoyI-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-lcarboxylic acid, m.p. 160-161®C, -o-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1carboxylic acid, an oil, having the following physical ΜθΟΗ constants; C.^.s Xmas: 253, 307 na (s 3310, 16920}; I.S.3, CHC1., ίτϊ'ΐ CDC1vinas; 3 1720, 1620 ca ; H.M.R.s .SMS 2.32 (S, 3E, CHg}, 2.53-3.03 (®, 23, H-2), 3.97 (fid, IH, H-l), 4.17-4.67(m, 2B, H-3), 6.92 (d, IS, S-7), 6.40 (d, IH, H-6), 6.83-7.37 ta, 4H, phony! protons), 8.60 ppm. (b.s, IH, 0008), S-at=toluoyl-l,2-dihydro-3H-pyrreloEl,2-a]pyrrole-lcazbessylic aeid, -p-ethylbensoyl-l,2-dihydro-3H-pyrroloEl,2-a)pyrrolc1-earborylic aeidj S-o-propylbenseyl-l,2-dihydro-3H-pyrrolo £1,2-a]pyrrole10 l-earfeossylie acid, S“m-butylbsnsoyl-l,2-dihydrs-3K-pyrroIeEl,2-a]pys's©lel-carbozylic acid, S-o-asthoxybenzoyl-l,2-dihydzo-3H-pyrrolo(1,2-a]pyrrolel-eazbossylic acid, S-p-sathenybenzoy 1-1,2-dihydro-3H-pyrrolo [ 1,2-a ] pyrroleX-eazbaxylie aeid, B.p. 187-187.3°C., S-p-ethoxybenzoyl-I,2-dihydzo-3H-pyzzoloEl,2-a]pyrroleX-eazbossylie acid, m.p. 1S9.5-17O°C., -p-isopropoxybensoyl-l,2-dihydro-3H-pyrrolo[1,2-a]20 . pyrzolG-X-csrbojsylie acid, S-o-chlorobBnsoyl“l,2-aihydro-3H“pyEKolo(1,2-a]pyzzola-l-earbo^lie aeid, having tho following physical MeOH constants: O.V. Ama;: .230, 307.S na (e 4360, 17400); CHC1., X.R. · vma;: 1715, 1620 cm·1·? CBC1H.M.S. δϊί-JS J 2.60-3.15 te, 2H; H-2), 4.02 (dd, IS, 6^« 7 Hz; H-l), 4.20-4.70 ta, 28? H-3), 5.98 (d, IH, J ° 4 Hs; H-7), 6.42 (d, IH, J = 4 Hz; H-6), 7.00-7.77 (m, 4H; phenyl protons), &-S7 ppm [s, (br), lH? COOH], - 34 4S233 3-m-chlorobenzoyl-l,2-dihydro-3H-pyrrolo(1,2-a]pyrrole-l-carboxylic acid, m.p. 180-181’C, -p-chlorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, m.p. 201.5-202.5’C, -o-fluorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]-pyrrolel-carboxylic acid, -p-fluorobenzoyl-l,2-dihydro-3H-pyrroio[1,2-a]pyrrolel-carboxylic acid, m.p. 179.5-130.5’C., S-m-bromofcenzoy1-1,2-dihydro-3H-pyrrclc[l,2-a]pyrrolel-carboxylic acid and -p-bromobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrolel-carboxylic acid.

EXAMPLE 12 B . To a solution of 300 mg. of 5-bensoyll,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid in 25 ml. of dry benzene, 0.58 g. of trifluoroacetic anhydride is added. 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 triethylamine is added, followed immediately by the addition of 0.5 g. of (l)-a-phenyl ethyl alcohol. The thus-obtained reaction solution 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)-β-phenyl ethyl alcohol under vacuum to yield 0.42 g. of a mixture of (l)-5-ber.zoyl-l,2-dihydro-3H-pyrrolo-[l,2-a]pyrrole1-carboxylic acid-(1)-α-phenethyl ester and (d)-5-benzoy1-1,2dihydro-3H-pyrrolo-[1,2-a]pyrrole-l-carboxylic acid-(1)-a35 phenethyl ester which is separated by high pressure liquid chromatography (using 4% EtOAc/hexane on a 11 mm. x 50 cm., (Trade Mark) lOjua. Liehrosorfe' £1-60 column) to give 180 mg. of a more polar ester (α^θ0Η -145.7°) and 178 fag. of a less polar ester (c^e°a +128.6°). 148 Mg. of the more polar ester is dissolved in 8 ml. of dry bensene. She solution is cooled to 15=2Q°C and 5 mi. of trifluoroacetic acid is added and the solution stirred at room temperature for 1 hour and 10 minutes. The reaction solution is poured into SO ml. of dry bensene and the solvents are removed under vacuum and at ambient temperature. Purification is effected by high pressure liquid chromatography (using a column as that , described above, except that 35% EtOAc/hexane in 1/2% acetic aeid is substituted for 4% BtOAc/hexane) to give 63 mg. (1)5-bensoyl-l,2-dihydro-3H-pyrrolo-(1,2-a]pyrrole-l-carboxylic aeid having an ¢^30½ -153.7°, and a melting point of 153- 155°C.

Similarly, cleavage of the less polar ester, according to the method described above for the cleavage of the more polar ester, yields §S mg. of (¢3.)-5bensoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylia acid having an <2gHC13 +155.1°, and a melting point of 154- 156°C. The thus-obtained (d)-acid isomer may, +- desired, be raeemised (and recycled), according to methods known in the art.

Similarly other (dl) compounds may be converted fco their respective (1)-isomers and (d)-isomers. - 36 45353 EXAMPLE 13 A A 250 ail. 3-necked sound bottomed flask containing a magnetic stirring bar and fitted with a calcium chloride filled drying tube, is charged with 3.36 g. of ethanolamine, cooled in an ice bath at 0o-10“C and treated dropwise, with stirring, with 8.7 g. of dimethyl 1,3-aeetonedicarboxylate. Methyl 3-carbomethoxymethy1-3-(2'-hydroxyethyl} amino acrylate {III) forms immediately. When the addition is completed, the ice bath is removed and 80 ml. of dry acetonitrile is added. The reaction mixture is then treated dropwise with 6.75 g. of bromoacetaldehyde in 20 ml. of acetonitrile and thereafter heated at reflux temperature 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 vacuum and placed on top of a column of 200 g. of silica gel packed in hexane, eluting the column with hexane:ethyl acetate mixtures. The fractions eluted with hexane:ethyl acetate (1:1) afford methyl N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R = H) identical to the product obtained in Example 1.

EXAMPLE 13 B To a solution of 6 ml. of ethanolamine in 5 ml. pf water .there is added 1.74 g. of dimethyl 1,3-acetonedicarboxylate. The resultant mixture is rapidly cooled to -10’C and treated dropwise, over a 15 minute period, with 3tirring, with 1.67 ml. of 1-bromoacetone, whilst maintaining the reaction mixture at a temperature not higher than 4O’C. When the addition is completed the dark reaction mix- 37 •I furs io stirred for an.additional hoqr at room temperature, and then poured into a mixture of feydroshloric asid-ico, saturated with solid sodium chloride and extracted with ethyl acetate (3 X 100 ml.). She combined organic extract g is washed with cold water ts neutrality, dried with anhydrous sediraa sulfate and evaporated to dryness under reduced pressure. Ghrematography of the residua on 30 g. of silica gel, using hexane: ethyl acetate,(70:30) as eluant, affords 820 mg. of crystalline methyl H-{2-hydrsxyethy1)-310 earbffiaethoxy“4-iaethylpyEK'3le2-aeetate which upas reerystalli2Stiea -from methylene ehlssidc-hejsaaa malts at ?3°C and has ths following analysis: Calculated for 7N0g: C, 56.45? 3, S.71 Founds G, 56.415 S, 6.73. s In a similar maanor but using a atoichiosssferie equivalent of l-broao-2-butanonQ, l“brema“2-'psntai!0ne»i and l-bromo-2-hexaaone in place of l-bremeacetone there are respectively obtained: aathyl H= (2-hydro3^ethyl) -3-carbarnsthoxy—S-ethyl20 pyrrole-2-acetatQ, methyl Εϊ- (2-hydroxy ethy I) -3-csrbomathoxy-4-propylQyrrole-2-aeetatQ and methyl ET- (2-hydroxyethyl) -3-carbomethoxy-4-butvl25 pyrrola-2-acafcate.

EXAMPLE 14 By following the methods of Examples 2, 3, 4, 3 and 7 methyl ΕΪ- (2-hydroxyethyl)-3-carbosnethoxy-4~methyl pyrrole-2-aeetats (IV, S = CH^) is converted successively into: - 38 43283 methyl U- (2-mesy loxy ethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, methyl N-(2-iodoethyl)-3-carbo»ethoxy-4-methylpyrrole2-acetate, dimethyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a)pyrrole1,7-dicarboxylate, 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a) pyrrole-1,7-dicarboxylic aoid, isopropyl 1,2-dihydro-S-meth.yl-3E-pyrrolo (1,2-a] pyrrole-l-carhixylate-7-carboxylic aoid and isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo-[I,2-a]pyrrole-l-earboxylate (X, R = - iC-jH?). in a similar manner substituting methyl N-(2hydxoxyethyl)-3-carbomethoxy-4“ethylpyrrole-2-acetate, methyl N-(2-hydroxyethyl)-3-earbomethoxy-4-propylpyrrole-2aoetate and methyl N-(2-hydrcxyethyl)-3-carbomethoxy-4-fcutylpyrrole-2-acetate for methyl N-(2-hydroxyethyl)-3-carbomethoxy4-methylpyrrole-2-asetate there are respectively obtained as final products: isopropyl I,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, isopropyi 1,2-dihydro-S-propyl-3H-pyrrolo[1,2-a]pyrrole-l-earboxylate and isopropyl 1,2-dihydro-6-butyl-3H-pyrrolo[ 1,2-a] pyrrole-l-carboxylate.

EXAMPLE 15 In accordance with the method of Example 8, isopropyl l,2-dihydro-S-methyl-3H-pyrrolo[1,2-a]pyrrole-lcarboxylate is condensed with N,N-dimethyl-p-toluamide, to - 39 5 produce isopsopyl-S-p-toluoyl-l,2-dihydro-6-Eaefhyl-3H-pyrrolo [1,2-a] pyrrole-l-earbossy la to (X£, s = GH3, R1 = p-CHg, R2aiC3H7).' is In a similar manner but using the N,E-dimethyl axylaraides listed in Example ]2Α·ϊη place of H»N-dimsthyl-p-toluamide, there are respectively obtained: isopropyl S-benzoyl-l,2-fiihydro-S-ffiathyl“3H-pyrroIo[1,2-a] pyrrole-X-carbo3Eylat2, isopropyl S-p-toluoyl-1,2-dihydro-6-mathyl-38-pyrrolo(1,2-a]pyrrole-l-earboxylate, isopropyl S-m-toluoyl-1,2-dihydro-S-methyl-3H-pyrrolo[1,2-a]pyrrole-l-carborylate, isopropyl S-p-efhylhensoyl-X,2-dihydjfO-S-Bisthyl-3Spyrrola [1,2-a] pyrrole- X-carbossy late, isopropyl S-o-propylbcnsoyl-1,2-dihydro“6-methyl-3I!pyrsolo[1,2-a]pyrrole-1-earboxyXate, isopropyl 5-m-butylbenssyl-l,2-dihydro-6-jaethyl-3Kpyrrol© El,2-a]pyrrole-l-carbsxylate, isopropyl S-o-Kieti.c::ybeasoyl-i, 2-dihyfiro-S-sc2thyl-3Hpyrrolo[1,2-a]pyrrole-l-carbexylate, isopropyl S-p-methoxybensoyl-l,2-dihydro-S-methyl-3Hpyrrolo[1,2-a]pyrrole-l-earboxyiate, isopropyl 5-p-ethoxybensoyl-l,2-dihydro-S-methy1-3Hpyrrol© El,2-a]pyrrole-X-carboxylate, isopropyl 3-p-isopropo^/bensoyl-l,2-dihydro-6-mefchyl3H-pyrrols El,2-a]pyrrole-l-cerborylate, isopropyl 5-o-chiorobenzoyI-X,2-dihydro-6-methyl-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate, isopropyl 5-m-chlorobenzoyl-l,2-dihydro-S-methyl-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate, 4S2S 3 isopropyl 5-p-chlorobenzoyl-l,2-dihydro-6-methyl-3Hpyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-o-fluorobenzoyi-1,2-dihydro-6-jnethyl-3Hpyrrolo[1,2-a]pyrrole-l-carbcxylate, isopropyl 5-p-fluorobenzoyl-l,2-dihydro-6-methyl-3Hpyrrolo[l,2-a]pyrrole-l-carboxylate, having the following physical constants; U.V. Imax 250, 315 nm (s 6170, 14,100), CHCl χ, F.« 'wf.ax 3 1734, 1605, 1593 cm”1; CDC1N.M.R. 5TMS 1.25 (d, 6H, J = 6 Hz; dster CHg), 1.83 (s, 3H; ring CHg), 2.49-3.00 (a, 2H; CH2), 3.90 (t, IH, 2j a 7.4 Hz; CHCO), 4.10-4.23 (m, 2H; H-CHg), 4.98 (sept., IH, J = 6 Hz; ester CH), 5.84 (s, IH, H-3), 7.00 (t, 2H, JQrtho = 8.4 Hz, a 8 Hz; H-3',5'), 7.55 (q, 2H, Jortho = 8.4 Hz, Jgj. » 5.5 Hz; H-2,6'5; M.S. m/e 1% 329 25 M+ 2i2 100 M+-C02CH(CHg)2 123 36 P-CgH4CO , isopropyl 5-m-b romobenzoyl-1,2-dihydro-6-methyl-3H· pyrroloil,2-a]pyrrole-1-carboxylate and isopropyl 5-p-bromobenzoy1-1,2-dihydro-6-methyl-3Hpyrrolo[1,2-a]pyrrole-1-carboxylate.

Likewise, the remaining final compounds obtained in Example 14 are converted into the corresponding -aroyl substituted derivatives. Representative compounds thus obtained are: isopropyl 5-benzoyl-l,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, isopropyl 5-benzoyl-l,2-dihydro-6-propyl-3H-pyrrolo- 41 [1,2-a]pyrrols-l-carbcxylate, isopropyl 5=bensoyl=l, 2-dihydro-5-feutyl-3S?-gyrrols[1,2-a 3pyrrole-l-carboxylate, isopropyl 5-p-toluoyl-l, 2-dihydro-C-ethyl“3H-pyrrolog [l,2-a]pyrrole-l-earboxylate, isopropyl 5-p-ethylbenzoyl-l,2-dihydro-S-propyl-3Hpyrralo[1,2-a]pyrrole-l-carboxylate, isopropyl S-c-methcxyhensoyl-l, 2-dihydra-S-liutyl=3Hpyrrolo[1,2-a]pyrrole-l-carboxylate, isopropyl 5-p-ethoxybenzoyl-l,2-dihydro-6-cthyl-3Hpyrrolo £1,2-a]pyrrole-l-carboxylate, isopropyl S-o-chlorobenzoyl-l,2-dihydE0-S-gropyl-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate, isopropyl 5-n=ehlorobenzoyl-lf 2-dihydro-S-buty1-382_g pyrrole [ 1,2-a ] pyrrole-1-carboxylate, isopropyl 5“0-fluorobenzoyl“l,2-dihydro-6-ethyl-3Hpyrrols(1,2-g]pyrrole-l-earbexylato, isopropyl 5-p-fluorofeensoyl-l,2-dihydro-S-propyl-3Hpyrrole[1,2-a]pyrrole-1-carboxylata and 2o isopropyl 5-p-bromobeRsoyl-I,2“dihydro-g-butyl-3Heyrrolo[1,2-a]pyrrole-l-carboxylate.

EXAMPLE IS A solution of 500 mg. of isopropyl 5-p25 toluoyl-1,2-dibydro“S-methyl“3H-pyrrolo[1,2-a]pyrrole-lcarboxylate in 15 al. ©S methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and - 42 45253 ml. of water and the resultant mixture extracted with ethyl acetate (3 x 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-p-toluoyI-l,2-dihydro-6-methyl3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid [(A), R » CH3, R1 = p-CHj].

In a similar manner, or alternatively by the hydrolysis method of Example 10, the remaining isopropyl ester compounds obtained in Example 15 are converted into the corresponding free acids, namely; -benzoy1-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrolel-carboxylic acid, -Ο-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo(1,2-a]pyrrole-l-carboxylic acid, -n-toluoyl-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, -p-ethvlbenzoyI-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, -o-propylbenzoyl-1,2-dihydro-6~methyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, -ra-butylbenzoyl-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-aJpyrrole-l-carboxylic acid, -o-methoxybenzoyl-l,2-dihydro-6-raethyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, -p-methcxybenzoyI-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, -p-ethoxybenzoyl-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxy1ic acid, -p-isopropoxybenzoy1-1,2-dihydro-6-methyl-3H-pyrrolo(1,2-a]pyrrole-l-carboxylic acid, 6»* -o.-chlorsbensoyl— l,2-dihydrc-6-Kiethyl-3H-pyrrolo[1,2-aJpyzrols-l-carberylic acid, S-ni-ehlorabonssyl-l, S-dihydze-S-msthyl-SK-pyrrolo(1,2-a]pyzrela-X-eaEboxylic aeid, -p~chlosobenaoyl-l,2-dihydro-S-;pethyl-3H-pyrrolo[ 1,2-a] pyrroXe-l-cazborylie aeid, S-o-Sluorobanzeyl-l,2-dihydro-g~saathyl-3H-pyrrolc(1,2-a]pyrrole-l-carbo::ylie acid, -p-fluorobsnzayl-1,2-dihydro-6-msthyl-3H-pyrroloig. tl,2=ajpyrrole-l=carbosylie acid, Ξ.ρ. 204°G., S-si-bromobenzoyl-l, 2-dihydro- 6-mefchy 1- 3H-pyrrolo[1,2-a] pyrrole-l-carbo:sy Xie acid, -p-bromobensoyl-X, a-dihydro-S-tnethyl-SH-pyrro loti, 2-a] pyrroXe-l-earboxylie aeid, S-bensoyl-1,2-dihydrO“S-efhyX-3H:=pyrrolo [1,2-a] pyrrole 1-earborylic acid, -banzoyl-l,2-dihydre-S-»ropyl-3H-pyrrolo[1,2-a]pyrrole-X-earboxylie acid, S-bensovl-l, 2-dihydra-S-butyl-3Ii-pyrrolo [1,2-a] pyrrole 20 1-carboxylic acid, S-p-toluoyl-X,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]pyrrole-X-carboxyXie acid, S-p-Gfehylbanzoyl-l,2-dihydro-6-propyl-3H-pyrrolo[1,2-a]pyrrole-i-earboxylie aeid, 2® S-o-'Tisthorybcnsoyl-l, 2-dihydra-6-butyl-3H“pyrrolO[1,S-alpyrzele-l-cazbos-ylie acid, S-p-ethoxybensoyl-l,2-dihydro-6-ethyl-3H-pyrroloE1,2-a] pyrrols-1-earboxylic acid, S-o-chlorobonsoyl-l,2-dihydro-6-propyl-3H-pyrrolo30 [l,2-a]pyrrole=l-carbo5ylic acid, - 44 45283 -ffi-cblorobenzoyl-l,2-dihydro-S-butyl-3H-pyrrolotl,2-a]pyrrole-l-carboxylic acid, -o-fluorobenzoyl-l,2-dihydro-6-ethyl-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid. 's'5-p-fluorobensoyl-i, 2-dihydro-6-propyl-3H-pyrrolo• [l,2-a]pyrrolQ~I“Carb©:£ylie acid and -p-bromobensoyl-l,2-dihydro-S-butyl-3H-pyrrolo[1,2-a] pyrrole-l-carboscy lie acid.

EXAMPLE 17 71Θ Mg. of a 505 suspensien of sodium hydride in mineral oil is washed with anhydrous hexane under aa atmosphere of nitrogen, and- then suspended in 50 al. of dimathylformamide. The suspension is cooled to -5 °C and 4.5 g. of methyl N-(2-sesylo3cym2thyl3-3-carbomethoj:ypyrrole2-acetate are added, stirring the reaction missture at -5° to 0°C for 1 hour. If is then poured into iced sodium chloride solution and extracted several times with bensene. The IS combined extracts are washed with water, dried and evaporated ts dryness under reduced pressure. The solid residue is crystallised from ether, thus obtaining dimethyl 1,2-dihydre-3S-pyrrole El, 2-a] pyrrole-1,7-diearbo::y late (VIS, R = H) identical to the product obtained in SsssmalG 4.

EXAMPLE1 18 To a 250 ml. 3-necked round, bottomed flask, fitted with a dry nitrogen inlet-outlet valve, a magnetic stirrer bar, and a pressure equalised addition funnel, eon25 taining 10.08 g. of ethanolamine, there is added dropwise, with stirring, 26,1. g. os dimethyl 1,3-acetonedicarboxylate over a period of 30 minutes .whilst maintaining the temperature below 30°C. The methyl 3-earbomsthQ3tyKet-hyl-3-(2,“ hydrassyet hyi J -aminoacrylate (III) which is formed is diluted with 20 ml. of acetonitrile and chloroacetaldehyde, previ. 46 43353 ously prepared by. heating a mixture of 27.4 g. of chloroacetaldehyde diethyl acetal with 46.8 g. of oxalic acid dihydrate at 150’ to 160“C, is added with stirring over a 2 minute period. The reaction mixture is refluxed for 5 to 10 minutes, after which time the reaction is found to be complete, as measured by t.l.c. analysis using acetone:chloroform (10:90) as eluant. The solvent is removed under reduced pressure and to the residue is added 250 ml. of benzene and 250 ml. of heptane, and distillation is then carried out under reduced pressure. The oily residue remaining, following distillation, is suspended in 50 ml. of methylene chloride and 20 g. of silica gel is added thereto. The methylene chloride mixture is poured onto a column containing 200 g. of silica gel made up 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). Those fractions eluted with ethyl acetate:hexane (50:50) are combined and concentrated to give 12.8 g. of an oil which is triturated with 20 ml. of petroleum ether (30®-60’C), followed by removal of the solvent under reduced pressure to yield 11.89 g. (32.9% of theory) of methyl N-(2'hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R = H) having a melting point of.51-54eC, the same product obtained in Example 1.

EXAMPLE 19 A solution of 200 mg. of 5-benzoyl-l,2-dihydro- 3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid in 5 ml. of dichloromethane is treated with an excess of ethereal diazo30 methane, and the reaction mixture is maintained.at room temperature for 30 minutes» The solvents and excess reagent are eliminated under reduced pressure and the residue crystallised from ethyl acetate-methanol, to yield methyl Sbenzoyl-1,2-dihydro-3H-pyrrclof 1,2-a]pyrrole-1-carboxylate.

Likewise but using diasoethsne and diazopropane in place of diazomethane there ere respectively obtained ethyl 5-benzoy1-1,2-dihydro-3E-pyrroloI1,2-a]pyrrole-l-carbesqflate and propyl S-bensoy1-1,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate. la a similar manner, the remaining free acids obtained in Examples 12A (and 123) and the acids of Example IS are converted into the corresponding methyl, ethyl and propyl esters.

EXAMPLE 20 A solution of 300 mg. of -5-p-toluoyl-l,2-dihydro-3H-pyrroloil,2-a]pyrrole-l-earboxylie 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 purified by chromatography on alumina, to yield isoamyl 5-p-toluoyl-l,2-dihydrs-3H-gyrrolo[1,2-a]pyrrole-lcarboxylate .

Likewise other esters, e.g., pentyl, hexyl, and octyl, nonyl /dodecyl, ' ' of S-p-toluoyl-l,2-dx25 hydro-3H-pyrrolo[l,2-a]pyrrole-l-cssbaxylis aoid are obtained by substituting other alcohols, e.g., pentyl, hexyl, octyl and nonyl /dodecyl alcohol, for isoamyl alcohol.

By the same method the free acid compounds obtained in Sxamples 12A and 16 are esterified with the ap30 propriate alcohol thus obtaining the corresponding esters, -484 G 2 g 3 e.g., isoamyl 5-benzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrolel-carboxylate, pentyl 5-m-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, hexyl 5-p-ethylbenzoyl-l, 2-dihydro-i3H-pyrrolo(l, 2-a] pyrrole-l-carboxylate, isoamyl 5-o-propylbenzoyl-l,2-dihydro-3K-pyrrolo[1,2-a]pyrrole-l-carboxylate, octyl 5-p-methoxybenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, nonyl 5-p-isopropoxybenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, dodecyl 5-o-chlorobenzoy1-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, isoamyl 5-m-chlorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, dodecyl 5-o-fIuorobenzoyl-1,2-dihydro-3H-pyrrolo £1,2-a]pyrrole-l-carboxylate, hexyl 5-p-fluorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, nonyl 5-p-bromobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, isoamyl 5-benzoyl-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, hexyl 5-p-ethylbenzoyl-l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, nonyl 5-o-methoxybenzoyl-l,2-dihydro-6-methyl-3Hpyrrolo[1,2-a]pyrrole-1-carboxylate, dodecyl 5-o-fluorobenzoy1-1,2-dihydro-6-methy1-3H- 49 pyrrole[1,2=a]pyrrole-l-carboxylate, nonyl 5-benzoy1-1,2-dihydra“6-ethyX“3H=gyrrolo[1,2-a]pyrrole-X-earbo^late, isoamyl 5-p-ethoxybensoyl-l,2-dihydro-e-ethylr3H5 pyrr©lo[l,-2“£]pyrrole-l-carbaxylate, parity 1 5-p-fluorobensoyl-1, 2-dihydro-6-prOpyl-3Hpyrrolo [1,2-a] pyrrole-l-carbojsylate, hexyl S-m-ehlorobanscyl-l^-dihycro-S-biityl-Sii-pyrsoiQ[X,2-a]pyrrole-l-carboxylate and dodecyl 5-p-broH!oben2ayl-l,2-dihydro=6“bufeyl-3Hgyrrolo[1,2-a]pyreols-l-&arb©«ylafce.

ESMSLE 21 To a solution of 300 mg. of S-p-toluoyl-1,213 dihydro-3a-pyrrole[X,2-a]gyrrolG-l-carboxyXie acid in S ml. of methanol io added 1 molar equivalent of sodium hydroxide, in tho -fora of a O.lii solution. The solvent is then evaporated undar rafiueod pressure aad the residue taken up in 2 ml. of methanol, followed by precipitation with ether, to yield osudo sodium S-p=toluoyl=l,2“dihydro-3H“pyrroio-[1,2-a]pyrsele-l-earboxylate whieh can be crystallized from ethyl acetate-hexane.

Likewise other salts, e.g., ammonium and , salt potassium/of 5-p-toluoyl-l,2-dihydso-3H-pyrrols[1,2-a]pyrrole 1-carbo^lie aoid are prepared by substituting ammonium hydroxide and potassium hydroxide for sodium hydroxide.

In a similar manner, tiie 5-substituted-l,2dihydra“3B=£yrroXo[l»2~a]pyrrole“l-carbojsylic acid compounds obtained in Examples 12A (and 12B) and 16 can ba converted into the corresponding sodium, potassium aad ammonium salts. “ 50 = Representative compounds thus obtained are; 43253 sodium 5-o-toiuay1-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylata, sodium 3-benzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole5 l-oarboxylate, sodium (1)-5-benzoy1-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, potassium 5-p-ethylbenzoyl-l,2-dihydro-3H-pyrrolo(1,2-a]pyrrele-l-carboxylate, potassium 5-c-butylbenzoyl-l,2-dihydro-3H-pyrrolot1,2-a]pyrrole-l-carboxylate, sodium 5-p-methoxybenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a] pyrrole-l-carboxylate, ammonium 5-p-chlorobenzoyl-l,2-dihydro-3H-pyrrolo15 [l,2-a]pyrrole-l-carioxylate, ammonium 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, potassium 5-p-bromobenzoyl-l,2-dihydro-3H-pvrroΙοί 1,2-a]pyrrole-l-carboxylate, sodium 5-benzoy1-1,2-dihydro-6-ethyl-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate, potassium 5-toluoyl-l,2-dihydro-5-methyl-3S-pyrrolo[1,2-a]pyrrole-l-carboxylate, ammonium 5-o-methoxybenzoyl-l,2-dihydro-$-methyl-3H25 pyrralo [1,2-a] pyrrole-l-carboxylate , sodium 5-p-fluorobenzoyl-1,2-dihydro-G-propyl-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate and potassium 5-m-chlorobenzoyl-l,2-dihydro-6-butyl-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate. - 5t EXAMPLE 22 So a solution of 175 mg. of 5-p-toluoyl-l,2dihydro-3H-pyrrolo£l,2-a]pyrrola-l~carboxyiic acid in 5 ml. of methanol is added 1 molar equivalent of potassium hydroxide, in tho form of a O.li’ solution, thus yielding a solution containing potassium 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole- 1-carhojsylate. A solution ef 40 mg. of calcium carbonate dissolved in the minimum amount of 111 hydrochloric acid necessary to effect solution of the calcium carbonate, is buffered with 100 mg. of solid ammonium chloride, followed by the further addition of 5 ml. of water. The thus obtained buffered calcium solution is then added to the solution of potassium 5-p-toluoyl-l,2-dihydro-3S-pyrsola[1,2-a]pyrrolel-carboxylate and the precipitate which forms ia collected by filtration, washed with water and air dried, to yield calcium 5-p-tsluoyl-l, 2-dihydre-3i’-pyrrole [1,2-a] pyr role- i-caraoxylate.

Likewise, magnesium 5-p-toluoyl-l,2-dihydro3H-pyrrolo£l,2-a]pyrrole-I-earboxylate is prepared by substituting magnesium carbonate for calcium carbonate.

Similarly, by substituting 5-ben2oyl~l,2-dihydsa-3H-pyrrolo(1,2-a]pyrrols-1-earborylie acid, (1)-5-bonsoyl-l,2-dihydsc~3H-pyrrolo£1,2-a]pyrrole-l-carboxylic acid, =p=ehlorobea2oyl-l,2-fiifcydro-33-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, S-o-methexybansoyl-l,2-dihydre-SH-pyrrolo£1,2-a] pyrrole-l-carbosqplie acid, -p-msthoxybensoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylie acid. 452S3 -benzoyl-l, 2-dihydro-6-mefhyl-3K-pyrrolo[1,2-a]pyrrole-l-carboxylic acid and -o-£luorobenzoyl-l,2-dihydro-6~ethyl-3Hpyrrolofl,2-a]pyrrole-l-carboxylic acid for -p-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid there are obtained the corresponding calcium and magnesium salts.

EXAMPLE 23 To a solution of 200 mg. of 5-p-toluoyl-l,2dihydro-3E-pyrrolo[l,2-a]pyrrole-l-carboxylic acid in 5 ral. of methanol is added 1 molar equivalent of potassium hydroxide in the form of a 0.1N solution. The solvent is stripped and the residue is dissolved in 5 ml. of water. The thus obtained aqueous solution of potassium 5-p-toluoyl-l,2dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is added to a solution of 150 mg. of cupric nitrate trihydrate in 5 ml. of water. The formed precipitate is collected, washed with water and air dried, thu3 obtaining copper 5-p-toluoyl-l,220 dihydrc-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.

In a similar manner the free acid compounds obtained in Examples 1?A (and 12B) and IS can be converted into the corresponding copper salts.

EXAMPLE 24 A solution of 200 mg. of 5-p-toluoyl-l,2-dihydro-3H-pyrrolo(l,2-a]pyrrole-l-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 filtered off, washed with ether and dried to yield the' isopropylamiae salt oS S-p-teIuoyl-l,2-dihydro-3H-pyrrolo [1,2-a]pyrrole-1-carboxylic acid.

Likewise other amine salts, a.g., diethylamine, ethanolaaine, piperidine, tromethamine, choline and caffeine salts of 5-p-toluoy1-1,2-dihydro-3H-pyrrole[1,2-a]pyrrols-1-carboxylic acid are prepared by substituting each of the respective amines for isopropylamine.

In similar manner the free acid compounds obtained ia Examples ISA (and 12S] and Xu can be converted iO into the corresponding iaopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts.

EXAMPLE 25 A solution of 770 ag. of 5-o-toluoyl-l,2-di“ hydro-3E-pyrsolo [1,2-a]pyrrole-l-carbo:sylic acid ia 10 ml. of benzene is treated with 5S0 mg. of dicyclohexylamine.

The reaction mixture is stirred for 10 minutes, and the solid which forms is separated by filtration and washed with anhydrous ether thus obtaining SSS ag. of the dicyclohoxylesiine salt of 5-o-teiuoyl-l,2“dihydro-3H-pyrrolotl,2-a]pysrolo“l=earbo:^lio aeid, a.p. 1G1-163°C. ϊη a similar manner the remaining free acid oompounds obtained in Examples 12A (and 12B) and the compounds of Examples 9 and 16 can be converted into the corresponding dieyelohexylaisine salts, e.g., the dicyelohexylamine salt of S-0“chlorobaagoyl-l,2-fiihyaro-3H“pyrrolo [1,2-a] pyrrole-l-sarbejsy lie acid, m.p. X73-175°C. - 54*s3S3 EXAMPLE 26 Ingredients Quantity per tablet, mgs. -benzoyl-1,2-dihydro3H-pyrrolo-[1,2-a]pyrrole5 1-carboxylic acid 25 cornstarch 20 lactose, spray-dried 153 magnesium stearate 2 The above ingredients are thoroughly mixed 10 and pressed into single scored tablets.

EXAMPLE 27 Ingredients Quantity Far tablet, mgs. -beazoy1-1,2-dihydro- 3H-pyrrolo [l,2-a]pyrrole1-carboxylic acid 200 cornstarch 50 lactose 145 magnesium stearate 5 The above ingredients are mixed intimately and pressed into single scored tablets.. 100 Mg. of (1)-5-benzoyl-l,2-dihydropyrrolo 3H-j|fi, 2-a] pyrrole-1-carboxylic acid is substituted for the 200 mg. of the fdl) compound of the above composition.

EXAMPLE 2S Quantity per capsule, mgs. sodium 5-benscyl1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-cartosylate lactose cornstarch magnesium stearate 108 IS The above ingredients are missgd and intro duced into a hard-shell gelatin capsule. iO SX&MPLB 29 Ingredients Quantity per capsule, calcium S-bonsoyl1,2-dihydro-3H-pyrrola[1,2-ajpyrrole-l-carbsjjylats US lactose _ S3 cornstarch 40 - magnesium atoarate 2 The above ingredients are mixed and intro· duced into a hard-shell gelatin capsule. - 56 4 S g 8 3 EXAMPLE 30 Ingredients Quantity per tablet, mgs. isopropylammcnium 5- benzoyl-1,2-dihydro-3Hpyrrolo [l,2-a]pyrrole1-carboxylate 245 cornstarch 75 lactose 175 magnesium stearate 5 The above ingredients are mixed intimately and pressed into single scored cablets. EXAMPLE 31 Ingredients Quantity per capsule, mg3. methyl 5-benzoyl-l,2dihydro-3K-pyrrolo [1,2pyrrole-l-carboxylate •a] 23 lactose 125 The above ingredients are mixed and introduced into a No. I hard-shell gelatin capsule.

EXAMPLE 32 Ingredients Quantity per tablet, mgs. -ber.zoyl-l,2-dihydro3H-pyrrole Ε1,2-a]pyrrole1-carboxylie acid 300 sucrose 300 The above ingredients are thoroughly mixed and processed into single scored tablets, one tablet being administered every three to four hours. - 57 isoamyl S=bonsoyl—lf2= dihydro-3K-pyrrole [1,2-a] EXAMPLE 33 pyrrole-l-carboxylate . 254 eornstareh SO Xaetoce 19Θ magnesium stearate 6 She above ingredients are nixed intimately and pressed into single scored tablets.

IS EXAMPLE 34 Ingredients Quantity psr capsule, mgs.

S-benaoyl-l,2-dihydroSS-pyrrolo [1,2-a] pyrrole• X-esrbossylie aoid X00 laetasQ 148 dextrose 2 She above ingredients are mixed and introduced into a hard-shell gelatin capsula.

SO Mg. of (l)-S-ben2oyl-l,2-dihydro'3H-pyrrolo [1,2-a]pyrrole-1-carboxylio acid is substituted for tha lOOmg. of the (dl) compound of the above composition. .Λβ.·^ίΡ “ 4s35'3 EXAMPLE 35 Ingredients Quantity per capsule, mgs. methyl 5-benzoyl-l,2- . dihydro-3H-pvrrolo - [1,2-a] pyrrole-1-carboxylate 158 lactose 92 The above ingredients are mixed and intro- duced into a hard-shell gelatin capsule.

EXAMPLE 36 Ingredients Quantity per tablet, mgs. isoamyl 5-benzoyl-1,2dihydro-3H-pyrrolo [1,2-a] pyrrole-i-carboxylate 127 lactose 91 cornstarch 25 magnesium stearate 2 gelatin 5 The above ingredients are mixed and pressed scored into single/tablets.

EXAMPLE 37 IS IS Ingredients Quantity per calcium 5-aensoyl-l,2- dihydro-3H-pyrrolc [1,2-a] pyrrole-1-carboxylate 230 cornstarch (paste) 40 cornstarch SO magnesium staarate 2 lactose 173 The above ii ijrediants are thoroughly and pressed into single scored tablets. Bsas©as 38 lacsGdioBts QUSLSfci vl? J3QS? fefiJ&Xofe f SJSJJ sodium 5“ban3oyX-l,2dihydre-SH-gyrrolo [1,2-a] pyrrole-l-carboxylate 217 cornstarch . se nagsGsiua stearate 2 226 lactose 5 Tho above ingredients are mixed intimately and pressed into single scored tablets. 45353 EXAMPLE 39 Ingredients Quantity per capsule, mgs. isopropylanunonium 5benzoyl-1,2-dihydro-3Hpyrrolo (1,2-a]pyrrole5 · 1-carboxylate 122 cornstarch 30 I lactose 98 The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

EXAMPLE 40 Ingredients Quantity per capsule, mgs. isoamyl S-benzoy1-1,2- dihydro-3H-pyrrolo -(1,2-a] pyrrole-l-carboxylate 32 lactose l‘01 cornstarch 15 magnesium stearate 2 The above ingredients axe mixed and introduced into a hard-shell gelatin.capsule.

EXAMPLE 41 An injectable preparation buffered ts a pH of 7 is prepared' having the following composition: S-benseyl-l,2-dihydroSK-pyrrolo [1,2-a]pyrroleI-earaoxylic acid 0.2 g KgHPOjj suffer (0.4 M solution) 2 ml.

SOS (IN) water (distilled sterile) q.s. to pH? g.s. to 20 ml. 0.1 G. of (l)5be-i'joyi-l,2“dihydso -33-pyrroio-(1,2=a3 pyrrole-l-earbo2£ylis asid is substituted for the 6.2 g.· of the (fil) compound of the above composition. · · EXAE-SLS 42 & suppository totaling 2.3 grams is preparad having tho following compositions S-bonsoy1-1,2-difeyeroSS-pyrrol© tif2-s]eyrrvi25,-earbouylis acid . 25 ag, iiitapeal H-15 (Trade Mark) (triglycerides of saturated vegetable fatty acids; a product of Hiches-Nelson, 2nc., New York, N.Y.) balance 12.5 Mg. of (1)“5-bansoyl-l,2-dihydroSHrgyrrelo [1,’2-aJpyrrole-1-carboxylic acid is substituted for the 25 mg. of the (dl) compound of the above composition.

EXAMPLE 43 An oral suspension for pediatric use is prepared having the following composition: -62 5-benzoyl-l,2dihydro-3H-pyrrolo[l,2-a]pyrrole-l-car- °&33 boxylic acid 0.1 g. fumaric acid 0.5 g. sodium chloride 2.0 g. methyl paraben 0.1 g. granulated sugar 25.5 g. sorbitol (70% solution) 12.85 g. Veegum X (Vanderbilt Co .) (Trade Mark) i.o q. flavoring 0.035 ml. colorings 0.5 mg. distilled water g.s. to 100 ml. 0.05 G. of (l)-’5-benzoyl-l,2-dihydro3H-pyrrolo [1,2-ajnyrroie-l-carboxylic acid is snhs*i*u*ed for the 0.1 g. of the (dl) compound of the above composition. · ' EXAMPLES 44-45 Powdered top dressings for veterinary use are prepared having the following compositions: Ex. 44 Ex, 45 -nenzoyl-l,2-dihydro3H-pyrrolo [1,2-a]pyrrale- l-carboxylic acid o.i g. 1.2 g. sucrose 5.7 g. 3.7 g. polyvinyl pyrrolidone 0.3 g. 0.3 g. 0.05 G. Of (1)-5-benzoy1-1,2-dihydro- 3H-pyrrolo [1,2-a]pyrrole-l-carboxylic acid is substituted for the 0.1 g. of the (dl} compound of the composition of Example 44. 0.6 G. of (1)-5-benzoy1-1,2-dihydro- 63. <5 3H=pyrrolo il,2-sjpyrrole-l-carboxyiic acid is substituted for fche 1.2 g. of fche (dl) compound of fche composition of Example 45. 54EXAMPLE 46 BIODATA A. Mouse Analgesic (Anti-writhing) Assay Protocol: The test material is administered orally S by gavage in an aqueous vehicle at time 0 to 18-20 gram male Swiss-Webster mice. Twenty minutes later 0.25 ml. o£ a 0.02% solution o£ phenyIguinone is injected iniraperitoneally. This solution induces writhing. The animals are then observed during the next 10 minutes for welthing.

End point: The total number of mice that writhe and the average number of writhes per mouse.

Using the above protocol it is determined that 5benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid has approximately 430 times the analgetic activity of IS aspirin; and (1)-5-(benzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole1-carboxylic acid has approximately 700 times the analgetic activity ox aspirin.

B. Mouse Acute Oral Toxicity (LDS0) 20 Protocol: The test material is suspended in an aqueous carboxymethyl cellulose suspending vehicle. Concentrations are adjusted so that doses can be given in volumes of 10 ml./kg. body weight. Five groups (comprising six Swiss-Webster male mice in each group) of mice are used.

A single oral dose, by stomach tube, per kilogram of body weight, of either 200 mg., 400 mg., 800 mg., or 1200 mg. of 5-(benzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylie acid is administered to the mice. (The fifth group is used as a control.) After administration the mice are observed _ 65 _ for a three wash period.

Using ths above protocol, ths acute oral W-θ of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [ 1,2-a] pyrrolc-l-car boxylie aeid is approximately 200 sg./kg.

Claims

CLAIMS 1. A compound of the general formula: or a pharmaceutically acceptable, non-toxic ester 5 or salt thereof, wherein R represents hydrogen or a lower alkyl group having from 1 to 4 carbon atoms and R X represents hydrogen, a lower alkyl group having from 1 to 4 carbon atoms, a lower alkoxy group having from 1 to 4 carbon atoms, chloro, fluoro or bromo, the R X ’substitution being at the ortho, 10 meta or para positions of the aroyl group. 2. A compound of Claim 1 wherein R is hydrogen. 3. A compound of Claim 1 wherein R is methyl. 15 4. The carboxylic acid compound of Claim 2 wherein R 1 is hydrogen, 5-benzoy1-1,2-dihydro-3H-pyrrolo11.2- alpyrrole-l-carboxylio acid. 5. The isopropyl ester of the compound of Claim 4, isopropyl 5-benzoyl-l,2-dihydro-3H-pyrrolot1,2-a]20 pyrrole-l-oarboxylate. 6. The carboxylic acid compound of Claim 2 wherein R 1 is o-methyl, 5-o-toluoyl-l,2-dihydro-3H-pyrrolo11.2- a]pyrrole-l-carboxylic acid. 7. The isopropyl ester of the compound of Claim 6, isopropyl 5-o-toluoyl-l,2-dihydro-3H“pyrrolc£l,2-a]pyrrole-l-earbexyiate. 8. .The carboxylic acid compound of'Claim 2 . 1 . wherein R is m-methyl, 5-m-toluoyl-l,2-dihydro-3B-pyrrolo5 (1,2-aJpyrrole-l-carboxylic acid.
2. The isopropyl ester of the compound of Slain 3, isopropyl 5-m-toluoyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate. 10. The carboxylic acid compound of Claim 2 . 1 10 wherein R“ is g-methyi, 5-p-toluoyl-l,2-dihySro-3H-pyrrolo£l,2-a]pyrrole-l-carboxylie acid. 11. The isopropyl ester of ths compound of Claim 10, isopropyl 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyirole-i-uarboxyiate. 15 . 12. The carboxylic acid compound of Claim 2 whosein is p-methoxy, 5-p-methoxybenzoyl-l,2-dihydro“3Hpyrrolo[1,2-a]pyrrole-l-carboxylic acid. 13. The isopropyi ester of the compound of Claim 12, isopropyl S-p-methoxyben2oyl-l,2-dihydro-3H-gyrrolo20 £1,2-a]pyrrole-l-carboxylate. 14. The carboxylic acid compound of Claim 2 therein S is o-chloro, 5-o-ehlerobenssyl-l,2-dihydro-3Hpyrrol©[l,2-a]pyrrole-l-earboxylic acxd. 15. The isopropyl ester of the compound of 25 Claim 14, isopropyl 5-o-chlorobensoyl-i,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate. 15. The carboxylic acid compound Of Claim 2 wherein R is m-chloro, 3-m-chlorobanzoyl-l,2=d3.hydro-3Hpyrrele [1,2-aJpyrrole-l-sarboxylie acid. 30 17= The isopropyl ester of the compound of = 68· Claim 16, isopropyl 5-m-chlorobenzoyl-l,2-dihydro-3K“pyrrolo[1,2-a)pyrrole-l-carboxylate. 18. The carboxylic acid compound of Claim 2 wherein R^ is p-chloro, 5-p-chlorobenzoyl-l,2-dihydro-3H5 pyrrolo[1,2-a]pyrrole-1-carboxylie acid. 19. The isopropyl ester of the compound of Claim IS, isopropyl 5-p-chlorobenzoyl-l,2-dihydro-3H-pyrrolo11,2-a]pyr ?x le-1-carboxylate. 20. The carboxylic acid compound of Claim 2 10 - wherein R is p-fluoro, 5-p-fluoroben2oyl-i,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-l-carboxylic acid. 21. The isopropv?. ester of the compound of Claim 20, isopropyl 2-p-fluorobenzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. j 5 22. The carboxylic acid compound of Claim 2 wherein R^ - is o-fluoro, 5-o-fluorobenzoyI-l,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-l-carboxylic acid. 23. The isopropyl ester of the compound of Claim 22, isopropyl 5-o-fluorobenzoyl-l,2-dihydro-3H-pyrrolo20 [1,2-a]pyrrole-1-carboxylate. 24. The carboxylic acid compound of Claim 3 wherein R^ is p-fluoro, 5-p-fluorobenzoyl1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1carbcxylic acid. 25 25. a sodium, potassium or calcium salt of the compounds according to Formula (A) of Claim 1. 26. The sodium salt compound of Claim 25 wherein’R and R 1 are both hydrogen, sodium 5-benzoyl-l,'2dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate. * 69 4. 5253 27. The compound of Claim 25 wherein S in methyl and S 1 is p-fluaro, sedium-5~p-£Iuorobensoyl-l, 2-dihydro-6-Eisthyl-3H-pyrrelo [1,2-a] pyrrole1-carbonylate. 28. An (l)-aeid isesior of a compound of Claim 1. 29. The compound of Claim 28 wherein R ana R are both hydrogen, (1}-5-benzoyl-l, 2-dihydro3H-pyrrole[i,2-a]gyrr^ie-l-carbenylic acid. 30. The compound of Claim 28 wherein R is methyl.and R is p-f luoro, (D-S-p-fluosohansoyi-1, i-dihydso-S-iasthyl-SH-pyrselo [1,2-a] pyrrole1-earsopylis acid. 31. A sodium, potassium os calcium salt cf an (l)-aeid isomer of Formula (A) of Claim 1. 32. She sodium salt compound of Claim 31 whosoia S and asQ both hydrogen, sodium (1)-S-bsnsoyl1.2- dihydro-3g=gyrrclo [ 1,2- a j gyrrole-X-earfecsiylate. 33. The compound of Claim. 31 wherein S is methyl and s 3, is p-f luoro, sodium (1)-5- p-fluorobenzoyl 1.2- dihydrs--6-methyl- 3H-pyrrolo [1,2-a] pyrrole- 1-car boxy! ate. 34. A (d)-acid isomer of a compound of Claim 1. 35. A compound of the formula wherein R is hydrogen or a lower alkyl group having from 1 to 4 carbcn atoms and R is a· lower alkyl group having from 1 to i carbon atoms. - 70 4 32ΰ3 ρ 36. A compound of Claim 35, wherein R is hydrogen end R is isopropyl, isopropyl 1^-dihydro-SH-pyrrolo/ - !,2-£7pyrrole-l-carbOxylate. 37. A composition for treating inflammation, pain or pyrexia in mammals consisting essentially of a pharmaceutically acceptable non-toxic excipient 5. And a tnerapeutically effective amount of a compound of Claim 1. 38. A method of treating inflammation, pain or pyrexia in non-human the mammals which comprises administering to/ mammal suffering therefrom a therapeutically affective amount of a compound of Claim 1. 39. A method according to Claim 38, wnerein an (l)-isomar of said 6. 10 compound is used. 40. A composition for administration to a pregnant mammal to delay onset of parturition consisting essentially of a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound of Claim 1. 15 41. A method of prolonging, or delaying the onset, of parturition in a the pregnant non-human mammai, comprising administering to / pregnant non-human mammal a compound of Claim 1. 42. A method according to Claim 41, wherein an (l)-isomer of said compound is used. 20 43. A process for producing a compound of the formula (A) or a pharmaceutically acceptable, non-toxic ester or salt thereof, wherein R represents hydrogen or a lower alkyl group having from 1 to 4 carbon atoms and R 1 represents hydrogen, a lower alkyl group having from 1 to 4 carbon 25 atoms, a lower alkoxy group having from 1 to 4 carbon atoms, chloro, fluoro or bromo, the R 1 substitution being at the ortho, meta or para positions of the aroyl group which comprises one or more of the following steps: -7145853 wherein R is as defined above and R is a lov:ar alkyl group having from 1 to 4 carbon atoms, with an amide of the formula f^'V- =0fl(CK 3 ) 2 u wherein R 1 is as defined above, thereby yielding a corresponding compound of the formula 7. 1 2 wherein R, R and R are as defined above; in an alkyl enter of a compound of formula (A) 10 b) hydrolyzing the alkyl ester group /thereby yielding a free acid of Formula (A); c) optionally esterifying the carboxylic acid function in a compound of Formula (A) or converting it into a pharmaceutically acceptable, non-toxic salt; 8. 15 d) converting a salt of Formula (A) to the corresponding free acid. 44. The process of Claim 43 in which the condensation is effected in the presence of phosphorous oxychloride. 45. The process of Claim 43, wherein the amide used in step a) is N,Ndi methyl-benzami de. 9. 20 45. The process of Claim 43, wherein the amide used in step a) is Ν,Νdimethyl -o-toluami de. -72«3253 47. The process of Claim 43, wherein the amide used in step a) is Ν,Νdi me thyl-m-tol uami de. 48. The process of Claim 43, wherein the amide used in step a) is Ν,Νdime thyl-p-toluami de. 49. The process of Claim 43, wherein the amide used in step a) is N,Ndimethyl-p-methoxy-benzamide. 50. The process of Claim 43, wherein the amide used in step a) is N,Ndimethyl-o-chloro-benzamide. 51. The process of Claim 43, wherein the amide used in step a) is N,Ndimethyl-m-chiorO-benzami de. 52. The process of Claim 43, wherein the amide used in step a) is Ν,Νdi methyl -p-ch1oro-benzami de. 53. The process of Claim 43, wherein the amide used in step a) is N,Ndimethyl-p-f1uoro-benzamide. 54. The process for preparing a compound of Claim 1 which comprises, optionally with one or more of the steps of Claim 43, racemizing a (d)-acid isomer or a salt thereof to the corresponding compound of Formula (A). 55. A process which comprises, optionally with one or more of the steps of Claim 43, separating a free acid of Formula (A) of Claim 1 into its corresponding (1)- and (d)-acid isomers. 56. A process of Claim 43, wherein step (c) is carried out on a (d)or (l)-acid isomer of a compound of Formula (A). 57. A process of Claim 43, wherein in step (d) an individual isomer of a salt of Formula (A) is converted to the corresponding free acid. 58. The process which comprises decarboxylating a compound of the formula wherein R represents hydrogen or a lower alkyl group having 1 to 4 carbon p atoms and R is a lower alkyl group of 1 to 4 carbon atoms; to produce the compounds of the formula -73' 5353 ? wherein R and R' are as defined above. 59. The dicyclohexylamine salt of the compound of Claim 6, dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-SH-pyrrolo/ - ! ,2-a_7pyrrole-l-carboxylic acid. 50. The.dicyclohexylamine salt of the compouno of Claim 14, dicyclohexylamine salt of 5-o-chlorobenzoyl-l ,2-dihydro-3H-pyrrolo,/Ί j2-a7pyrrole1-carboxylic acid. 61, 5-p-ethoxybenzo.yl-1,2-dihydro-3H-pyrrolo/“l ,2-aTpyrrole-l-carboxylic acid. 62. A..(dl)-compound according to Claim 1 as exemplified herein. 63. A compound according to Claim 28 as exemplified herein. 64. A compound according to Clair. 34 as exemplified herein. 65. A compound according to Claim 35 as exemplified herein. 66. A process for producing a (dl)-compound of Claim 1, substantially as described herein. 67. A process for producing an individual (d)- or (l)-isomer of a compound of Claim 1, substantially as described herein. 68. A compound according to Claim 1, whenever prepared by a process according to any one of Claims 43 to 53 and 56. 69. A compound of Claim 1 whenever prepared by a process according to Claim 54. 70. A (d)- or (l)-isoraer of a compound of Claim 1 whenever prepared by a process according to Claim 55, 56, 57 or 67. 71. A pharmaceutical composition comprising a compound according to any one of Claims 2 to 27, 59 to 62 and 68, with a suitable excipient. 72. A pharamceutical composition comprising an (l)-isomaric compound of any one of Claims 28 to 33, 63, 69 and 70 with a suitable excipient. 73. A pharmaceutical composition substantially as exemplified herein, comprising a (dl) compound as defined in Claim 1. -74^S3S3 74. A pharmaceutical composition substantially as exemplified herein, comprising the (l)-isomer of a compound as defined in Claim 1.