CA1100140A - 5-(2-furoyl)-,5-(2-thenoyl)-,5-(3-furoyl)-and 5-(3- thenoyl)-1,2-dihydro-3h-pyrrolo ¬1,2-a|pyrrole-1- carboxylic acid derivatives and process for the production thereof - Google Patents

Abstract

5-(2-FUROYL)-, 5-(2-THENOYL)-, 5-(3-FUROYL)- AND
5-(3-THENOYL)-1,2-DIHYDRO-3H-PYRROLO[1,2-a]PYRROLE-PRODUCTION THEREOF

Abstract of the Disclosure Novel 5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a]pyrrole-1-carboxylic acid compounds repre-sented by the formulas (A) (B) and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein X is oxygen or sulphur, R
is hydrogen or a lower alkyl group having from 1 to 4 carbon atoms and R1 is hydrogen, methyl, chloro or bromo, the R1 substitution being at the 3, 4 or 5 positions of the furan or thiophene ring in the com-pounds of Formula (A), and process for the produc-tion thereof; 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid and 5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid are representative of the class. These com-pounds are useful as anti-inflammatory, analgesic and antipyretic agents and as smooth muscle relaxants.

Description

~3~
- The pres~nt invention relates to certain novel pyrrole-l-carboxylic acid compounds and to a process for the production thereof.
More particularly, this invention relates to novel 1,~-dihydro-3H-pyrrolo[1,2-a]pyrrole l-carboxylic acids substituted at the C-5 position by a 2-furoyl, 2-thenoyl, 3-furoyl or 3-thenoyl group, represented by ~he formulas ~, ~ coo~ [~C~O~

(A) ~B) - 15 and the individual (l~-acid isomers and the (d~-acid isomers thereof and ~he pharmaceutically acceptable, non-toxic esters and salts thereof, wherein X is oxygen or sulphur; R is hydrogen or a lower alkyl group having from 1 to 4 car-bo~ ato~s a~d Rl is hydrogen, methyl, chloro ox bromo, the ~1 substitution in the compounds of Formula (A) bein~ a~ the 3, 4 or 5 positions of the furan or thiophene ring, and to the m~tho~ f or the production thereof.
The compounds o the present invention as described above~ and more fully below, exclusive of the (d)-acid isomers anddexivatives thereof, exhibit anti-infl~ma-tory, analgesic and anti-pyretic activities and thus are us~ful ~n the treatment of infla~mation, pain and/or pyrexia in mammals, as described hereinafter in detail. They are also smooth mu~cle relaxants.
The term "pharmaceutically acceptable, non-~ ~ .

- 2 -0~

toxic esters and salts" as used herein r~fers to "alkyl esters" d~rived from hydrocarbons of branched or strai~ht chain having from onc to twelve carbon atoms and salts derived ~rom pharmaceutically accept.able non-toxic in~rganic and orqanic base~, respectivcly.
Typical alkyl ester ~roups are methyl, ethyl, propyi, isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl esters.
Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous~ a7uminum, ferric, manganic ~alis ana ~he li~e. ~articularly pre~erred are the ammonium, potassium, sodium, calcium and magneSium salts. Salts deriv-ed from pharmaceutically acceptable organic non-toxic bases include salts of primaryl secondary, and tertiary amines, substituted amines including naturally occuring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, die hylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-di-ethylaminoethanol, tromethamine, lysine, arginine, histidine, ¢affeine, procains, hydrabamine, choline, betaine, ethylene~
diamine, glucosamine, methylglucamine, theobromine, purine~, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like . Par~icularly pre~erred organic non-toxic bases are isopropylamine, diethylamine, ethanolaminel piperidine, tromethamine, choline and caf ~eine .
The novel compolmds o~ Formulas (A) and (B~, and Formulas (XI) and (XII) depicted below exist as pairs of optical isomers (or enan~iomo~phs), i.e., a (dl) mixture.

.
: - 3 -However, each optical isomer as well as the (dl) mi~ure~
thereo~ are included within the present invention.
When the novel compounds of this inve~tion ; are to be used to elicit a physiological respo~se (e.g., anti-inflammatory, a~algesic or anti-pyretic activity), i.e., they are to be used as medicinals, a pre~erxed sub-grouping is that of the compounds o~ Formulas (A) and ~B), and the (l)-acid isomers thereof ~nd the esters and phaxma-ceutically acceptable salts thereof.
A still -further sub-gxouping, ~or compounds to be used as medicinals are the compounds of Formula (A) and the (l)-acid isomPr of Formula (A) and the esters and pharmaceutically acceptable salt~ thereof, and this sub-grouping may be divided into two further sub-groupings made up of (a) ~he compound of Formula (A), i.e., the (dl)-com-pound wherein R and Rl are both hydxogen and X is sulfur and : (bi the (l)~acid isomer of Formula ~B) wherein R and Rl are both hydrogen and X is sulfur and the esters and pharmaceuti-. cally acceptable salts thereo~. ;
The (d)-a~id i~omer of Formulas (A)~nd ~B) : ~ and the esters and pharmaceutically acceptable sal~s thereo~
are useful as intermedia 2S for the preparation of the (dl)-acid of Formulas (A) and (~), as described more fully below.
: The novel (dl) compounds of the present invention can be prepared by a process illustrated by the ~llowi~g reaction sequence:
`~
`: :

`;
`' ' -:: :

.

3~

2 COOC}J3 COOC1~3 C~32 ~COOCH3 ~ CCOOCH3 (I) (I~)~c~2 n , COOC~3 ~, COOCH3 `~ ~ ~r--I ~

~ ,~COOCH 3 ~ ~ ~COOC~ 3 1 j2 , \, ~I2C--C~I

1~2 ~V) \ ~ t ~
oSo2cH3 .

~I.~T~COOCH3 ~ ~t~COOCH3 - - ! N CC(~CR 3 ~ ~ ~coo~ll3 Ç132 , .
(VI ) ~Vï X
~, .... ,,, , . ' ' . ~
. ,COOE~ OOH

~N ~ ; ~ ~ CooE~

X~ . . . tVIIX ) . .
' 1 :' ' ~_ I~OOR2 n; ~COOR

tXI I:) ~

R~3~
~ Coo:l .. O , ,~

-- 5 .--(x) C ~ CG~

~XII) ~ I ~COOH

. ~B) wherein X, R and Rl have the above-indicated meaning and ~2 is a lower alkyl group of 1 to 4 carbon atoms, e~g., methyl, ethyl, isopropy1 or n-butyL.

In practicing the process outlined above, or the pre-paration of the compound of Formula (IV) wherein R is hydrogen, .equimolecul~r amounts of ethanolamine ~I) and dimethyl l,3-acetonedicarboxylate (II) are reacted at a temperature of from about 0 to about room ~emperature, to readily form a solution of the vinylamine.. o~ Formula (III), which is - then treated, preferably in situ, in a suitable .inert organic solvent, under anhydrous conditions, with 2-b-omoacetaldehyde o.r 2-chloroacetaldenyde, at from about 40~ to about 100C
for a period of tlme of from a~out 30 minutes to about lG
hours. Suitable solvents for this reaction are the aprotic solvents such as acetonitrile, tetrahvdrofuran, dimethoxy-ethane, chloroform, dichloromethalle and the like. In the preferred embodimen~s, .he reac~on is conducted in aceto-nitrile solution, a~ reflux temperature ~or about 1 hour.
The 2-bromo-(chloro)-acetaldehyde reagents are ]snown com-pounds, or can be obtainea by pyrolysis of ~he corres2on-. --6~
.

ding diethyl ace~als in the presence of oxalic acid dihy-drate.
To prepare the compounds o~ Formula (IV) wherein R
is a lower alkyl group, pref~rably straight chain, hav-ing 1 to 4 carbon a~oms, an aqueous mixture of e~hanolamine (I~ and dimethyl 1,3-acetonedicarboxylate (II) is treated with a compound of the Lormula R3-~-C~2X, wherein X is bromo or chloro and R3 is a lower alkyl group, prefera~ly straight chain, of from 1 to 4 carbon atoms, and most pre-ferably l-bromoace~.one, 1-bromo-2-butanone, 1-bromo-2-pen-tanone, and l~bromo-2-hexanone, at from about 40 to a~out 100C or a period of time from about 30 minutes to about 16 hours. In the preferred embodiment the reaction is con-ducted at a temperature of from about -10C to about room temperature for from about 1 hour to about 6 hours. The 3 ~
R - -CH2X reagents are known compounds.
Esteri~ication o~ compound ~IV) with methane-sulfonyl chloride in the presence of a tertiary amine, i.e., triethylamine, pyxidine and the like, optionally in the pres-~o ence of a cosolvent such as dichloromethane, at a temperature of from about -10C to about room temperature, for about 10 minutes to about 2 hours produces the corresponding mesylate of Formula (V), which is converted into ~he corresponding N~(2-iodoethyl3pyrrole of Formula (VI) by reaction with sodium iodide in acetonitrile solution, at reflux temperature for from about one to about ten hours.
Upon reaction o~ the io~oe~hyl compounds of Formula (VI) with ~odium hydri.de in a suitable inert organic solvent such as dimethylformamide there are obtained dimethyl-1,2-dihydro 3H-pyrrolo[1,2-a]pyxrole-1,7-dicarboxylate and the 6-aI~yl substituted deriva~ives thereof (VII). This cyclization is conducted under an inert atmosphere, i.e., under argon or nitrogen atmosphere, at temperatures of the order o~ from about 15 to about 40C, for a period of time S of from about 15 minutes to about 4 hours. Best results are obtained conductin~ the reaction at room temperature, for about 30 minutes when R is hydrogen.
Alternatively, the compounds of ~ormula ~VII) ~` can be prepared by direct cyclization of the mesylate (V), 1~ with sodium hydride in dimethylformamide solution ~ at from about -10C to about room temperature, ~or ~rom about 30 minutes to about 2 hours.
Basic hydroLysis of a compound of Formula ~VII) with an alkali metal hydroxide or alkali metal carbon-`~ 15 ate, e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like in an aqueous lower aliphatic alcohol, e.g., methanol or ethanol, at a temperature of between room temperature and reflux, for from about 4 to about 24 hours, a~fords the corresponding free diacid of Formula (VIII~, i.e., 1,2-dihydro-3E-pyrrolo~1,2-a~-pyrrole-1,7-dicarboxylic acid and the 6-alkyl derivatives t~ereof. q~ne ny~rolysis is pre~erably carried out using a~ueous methan~lic potassium hydroxide, at reflux temperature for abou~ lOhours.
The carboxylic acid group at the C-1 posi~
t~on in compound ~VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g., methanol, - ethanol, isopropanol, n butanol and the like in the presence o~ hydrogen chloride, to produce the corresponding alkyl 1,2-~` 30 dihydro~3~-pyrrolo~1,2-a]pyrrole-1-carboxylate-7 carboxylic , _ ~ _ acid of ~'ormuia ~l~j. Tne reaction is conducted at a temper-ature of from about 0 to about 50C., for about 1 to about

4 hours.
Décarboxylation of the monoestérified com-pounds (IX) to the corresponding compounds of Formula (X), the key intermediates in the process for obtaining the com-pounds of the present invention, is achieved by heating (IX) at an elevated temperature, of the order of from about 230 to about 280C, for a period of time sufficient to complete the reaction. The course of the reaction can be followed by the xate of carbon dioxide evolution and t.l.c. analysis, de carboxylation being generally completed within from about 45 to about 90 minutes. The reac~ion produc~, ~amely, alkyl 1,2-dihydro-3H-pyrrolo~1,2-a~pyrrole-1-carboxylate and the 6-alkyl derivatives thereo~ ~X) can be purified ~y chromato-graphic techniques. Alternatively, and particularly for the decarboxylation of small batches of compound (IX), the reac-tion product (X~ can be distilled directly from the reaction vessel.
Condensation of a compound (X) with an amide o~ the formulas 1 ~ CON(CH3) ~ ON(CH3)2 wherei.n X and R have the above indicated meaning, affords the corresponding alkyl 5-substituted-1,2-dihydro-3H-pyrrolo-- 25 ~1,2-a]pyrrole-l~carboxylates of Formulas (XI) or (XII~
- respect~vely.
This reaction i5 co~ducted in an inert organic aprotic solvent and in the presence of phosphorous o~ychloride, at reflux temperature for from about 1 to about 72 ~ours, under an inert atmosphere, followed by further .:

:' ' . ~, ' u~

reflux in the presence of sodium acetate, ~or ~rom about 2 to about lO hours. Alternatively, instead of phosphorous oxy-chloride other acid chlorides such as phosgene or oxalyl chloride may be used.
In the preferred embodiments, this condensa-tion is carried out by adding a solution of compound (X) in a suitable solvent to a previously refluxed mixture of 1.1 to 2 molar equivalents of both the desired amide and pnosphorous oxychloride in the same solvent, refluxing the reaction mix-ture thus obtained for from about 2 to about 30 hours under an argon atmosphere and thereafter adding thereto from about 3 to about lO molar equivalents of sodium acetate, followed by an additional reflux period for from about 4 to about 6 hours.
Adequate solvents for this reaction are the halogenated hydrocarbons such as dichloromethane, 1,2-dichloro-ethane, chloroform, carbon tetrachlcride and the like, di-~; methoxyethane and tetrahydrofuran. The preferred solvent i~
1,2-dichloroethane.
Representative of the N,N-dimethyl amides which ~an be used are: N,N-dimethylthiOphene-2-carboxamide, : NIN-dimethyl~uran-~-carboxamide, N,N-dimethyl-3-methylthiophene-2-carboxamide, N,N-dimethyl-4-methylthiophene-2-Carboxamide, N,N-dimethyl-S-m~thylthiophene-2-carboxamide, N,N-dimethyl-4-chlorothiophene-2-carboxamide, N,N-dimethyl-5-chlorothiophene-2-carboxamide, N,N-dimethyl-3-bromothiophene-2-carboxamide, N,N-dimethyl 5-bromothiophene-2-carboxamide, N,N-dimethyl-3-methylfuran-2-carboxamide, N,N-dimethyl-4-methyl~uran-Z-carboxamide, ~,N-dimethyl-4~chlorofuran-2-carboxamide, N,N-dimethyl-5-chloro~uran-2-carboxamide, N,N-dimethyl-4-bromofuran-2-carboxamide, N,N-dimethyl-5-bromofuran-2-carboxamide, N,N-dimethylthiophene-3-carboxamide and N,N-dimethyl~uran-3-carboxamide.
Thece amides can be prepared in a conven-tional manner from the ccrresponding thiophene- or furan-2-~3)-carboxylic acids i.e., by conversion into the acid chlorides ~ollowed by trcatment wi~h dimethylamine.
Upon alkaline hydrolysis of the alkyl ester group in a compound o~ Pormulas (XI) or (XII) there are ob-tained the corresponding free acids of Formulas (A) or ~B), respectively. The hydrolysis is effected in a conventional - manner, with an alkali metal hydroxide or alkali metal carbon-ate, e.g., sodium hydroxide, potassium hydroxide, sodium carbonate~ potassium carbonate and the like, in an aqueous - lower aliphatic alcohol, e.g., methanol, ethanol and the like, at a temperature o~ ~rom about room temperature to reflux, for from about 30 minutes to about 4 hours, under an inert a~mosphere. In~the preferred emkodiments, this hydrolysis is e~ected with aqueous methanolic potassium hydroxide, at reflux temperature for about 2 hours~
~ The aompounds o~ Fo m ula~ (A) and (B) can be resolved, according to method~ known in the art, to obtain ~he ; correæponding individual isomers thereo~. Thuq, ~or example, the compound of Formula (A) wherein R and Rl are both hydrogen and X i~ sulfur can be suhjected to ~urther trea~ment in : .

:. - . , , , ", .': ', . :

accordance with the following flow diagram:

~ ~ COOH
~ ~ _ l . .
resolution ~ , ' .

~ \
A~-tl)-acid isomer-(d)-amphetamine ¦ salt .

A ~ acid isomer .

` .

Mixture of ~ A ~(d)-acid isomer~(d) amphetamine salt ( A~ acid isomer-(d)-amphetamine salt ~
A more detailed~description of this procedure is set ~orth in ~x~mple 10 B-l b~low.
~ Alternatively, the (l)-acid isomers and (d1-acid isomers o~ the compounds of Formulas (A) and (B~ can be obtained by applying the known technique of high pressure :~ liquid~chromotography (~PLC) ~o the ~-phenethyl dia~ereo-i omeric es~ers of the compounds of Formulas (A) and (B), `' ' .

:` ~

~ollowed by acid cleavage. Thus, for example, the compounds of Formula tA) whersin R and Rl are both hydrogen and x is suflur can be subjected to ~urther treatment in accordance with the following flow diagram:

~Cool~ ~

10(Al) several steps C (A~ acid isomer-(l)-a-phenethyl ester 15~ixture ~ ~ 1 ( (A )-(d)~acid isomer-(l)-a-phenethyl ester~

separate using ~PLC

~ \

(Alj-tl)-acid isomer-tl)-phenethyl este . \~

~ 25 (A )-(d)-acid isomer (l)-phene~,hyl ester ~ / ' ' I
(A~ .)-a~id isomer (Al)-(d)-acid isomer _ ~ more de~ailed description of this procedure is set orth in Example 10 B-2 below.

~ he free acids o~ Formulas (A) and (B~ can be con-verted into o~her alkyl es~ers having ~rom 1 to 12 carhon atoms by conventional methods, e.g., by treatment with (a) the alcohol corresponding to the desired ester in the pre-sence 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 ~e converted into their alkyl esters by the methods of (b) and (c) above.

The salt derivative~ of the compounds of Formulas (~) and ~B) a~d the (l)-acid isomers thereof are prepared by treating these free acids with an appropriate amount of a pharmaceutically ~cceptable base. Representative pharma-ceutically acceptable bases ~re sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrou~ hydroxide, zinc hydroxide, copper hydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide, manganic hydroxide, isopropyl-amine, trimethylamine, diethylamine, triethylamine, tripropyl-amine, ethanolamine, 2-dimethylaminoe~hanol, 2-diethylamino-ethanol, tromethamine,~lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosami~e, methylglucamine, theobromune, purines, pipera-zine, piperidine, N-ethylpiperidine, pol~amine resins and the like. The reaction is conduc~ed in water, alone or in combination with an inert, water-misible organic solvent~
a~ a temperature of from about 0C. to about lOO~C, pre-ferably at room tempera~ure. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, ac2tone, dioxane or ~e~rahydrofuran. The molar ratio o~ compound3 of Formula~ (A) or (B) or the (1)~ acid isomer~ thereof to base used are chosen to provide the ratio ~ `

desired forany particular salt. For preparing, for example, the calcium salts or magnesium salts of th0 compounds of Formula (A) or (B) or the (1)- acid isomers khereof~ the free acid starting material can be treated with at least one-half molar equivalent o~ pharmaceutically acceptable base to yield a neutral saltO When the aluminum salts of the compounds of Formulas (A) or (B) or the (1)- acid is~mers 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 proceaure, the calcium salts and magnesium salts of the compounds of ~ormulas (A) and (B) and (l)-acid~isomers thereof can be prepared by treating the corresponding sodium or potassium salts thereof with at leas~t one-half molar equivalent of calcium chloride or mag-nesium chloride, respectively, in an aqueous solution, alone or in combination with an inert water-miscible organic sol-vent, at a temperature of ~rom about 20C to about 100C. .
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, such as aluminum triethoxide, aluminum tripropoxide and the like, in a hydrocarbon solvent, such as ben~ene, xylene, cyclohexane and the like, at a temperature of from about 20C to about 115C. SLmilar procedures can be used to prepare salts of lnorganic bases which are not su~ficiently : soluble for easy reaction.
It is to be understood that isolation of the compounds described herein can be effected, if desired, by any suitable separation or purification procedure, such as, : - 15 -, for example, extraction, ~iltration, evaporation, distilla-tion, crystallization, thin-layer chromatography or column chromatography, high pressure liquid chromotography (HP~C) or a combination of the~e procedures. Illustrations of suitable separation and isola~ion procedures can be had by reference to the Examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
While the (d)-acid isomers are not used as medicinal agent~ per se, they can, i~ 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 isomexs to their pharmaceutically acc~p~able, non-toxic es~ers and salts thereof.
The compounds of Formulas (A) and (B) and the (l)-acid isomers thereof and the pharmaceutioally accept-able non-toxic esters and salts thereof, are useful as a~ti-inflammatory agents, analgetic agents, platelet aggregation inhibitors, fibrinolytic agents, and as smooth muscle relax-ants. These compounds can be used both prophylactically and therapeu~ically.
The compositions containing these compounds are thus useful in the treatment and elimination of inflam-mation such as inflammatory conditions of the muscular skel-etal system, skeletal joints and oth~r tissues, ~or example~
; in the t~eatment of inflammatory conditions such as rheuma-tism, concussion, laceration, arthritis, bone ~ractures, post-traumatic conditions, and gout. In those cases in which the above conditions include pain and pyrexia coupled with inflammation, the instant compounds are useful for the relief of these conditions as well as the inflammation.
Aaministratlon o~ the active compounds o~
Formulas (A) or (B) or the (l)-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters a~d salts thereof, in an appropriate pharmaceutical composition can be via any o~ the accepted modes of administration o~ ayents ~or the treatment of inflammation, pain or pyrexia, or the prophylaxis thereo~. Thus, administration can be for xample, orally, parenterally or topically, in ~he form of solid, seml-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments or the like, preferably in unit dosage ~orms suitable ~or simple administration of precise dosages. The compositions will include a co~ventional pharmaceutical carrier or excipien~
and a~ active compound of Formulas (A) or (B) or the (l)-acid isomers thereof and the pharmaceutically acceptable non-toxic esters and sal~s the~eof, and, in addition, may include.other medicin~l agents, pharmaceutical agents, carriers, adjuva~
etc.
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 de~ree of affliction. Generally, a daily dose of from 25 mg.
to 500 mg. of the active compound of Formulas (A) or (B) or the (l)-acid lsomers thereof and the pharmaceu~ically accept-~ able, non-koxic esters and salts thereo~ is used. Most con-.~ ditions respond to treatmen~ comprising a dosaye level of the - order of 0.5 mg. ~o 6 mg. per kilogram of body weight per day.
For such oral administration, a pharmaceutically acceptable, ~: `

non-toxic composition is formed by the incorporation o~ any of the normally employed excipients, such as, for example, pharmaceutical grade~ of mannitol, lactose, starch, magnesi-um stearate, sodium saccarine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. such compositions take the form of solutions, suspensions, tablets, pills, capsules, powdexs, qustained release formulations and the like.
The active compounds of Fo~mulas (A) or tB) or the (l)-acid isomers thereo~ and the pharmaceutically acceptable, non-toxic esters and salts ~hereo~, may be formu-lated into a suppository using, for example, polyalkylene glycols r or example, polypropylene glycol, as the carrier.
Liquid phaxmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound ! as described above, and optional pharmaceu-; tical adjuvants in a carrier, such as, ~or example, water, saline, aqueous dextro~e, glycerol, ethanol and the like, to thereby folm a solution or suspension. If desired, the phar-maceutical composition to be administered may al~o contain mlnor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH bufering agents and the like,:such as ~or example, sadium acetate, sorbitan monolau-rate, triethanolamine oleate, etc.

~ Actual methods of preparing such dosage : forms are ~nown, or will be apparent, to those skilled in . this art; ~or example, see Remington's Pharmaceutlcal Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th. Edition, 1970. The composition to be administered will, in any event, .

contain a quanti~y o~ ~he active compound(s~ in a pharma-ceutlcally effective amount or relief of the particular con-dition being treated in accordance with the teachings of this invention.
Th~ co~pounds o~ Formulas (~) and tB) and the (l)-acid isomers thereo~ and the non-toxlc, pharmaceuti-cally acceptable esters and qalts thereof, described above, are also uterine smooth muscle relaxants and thus are useful as agents ~or maintaining the pr~gnanc~ of pregnant mammals~
for the benefit of the mother and/or fetus, until tenmination of ~he pregnancy is considered, from a medical poin~ of view, to be favorable, or more f~vorable, for the mother and~or the fetus. It should be understood, howe~er, that in certain in~tances, for e~ample where parturition has already begun (i.e., the mother is expexie~cing uterine contractions, especially near full term), that administration of the com-pounds herein described may not maintain the pregnant state for an indefinite period of time. Rather, in such instances, the pregnancy will, most probably, be slightly "prolonged", a ~actor which may be advantageous to either the mother and/or tAe fetu~.
particular, the compounds of Formulas (A) and (B) and the (l)-acid isomers thereo~ and the phaxmaceuti-cally acceptable, non-toxic es~ers and salt~ thereo~, are used as agents ~or delaying the o~set of, or for postponing, ~arturition. As used in this application, the phrase "to delay the on~et o parturition" is intended to cover that delay i~ parturition caused by the administration o~ the com-pounds o~ Foxmulas (~) or (B) or the (l)-acid isomers thereof and ~he pharmaceutically acceptable, non-toxic esters and sal~s ~ -- 19 --thereof, at any time before uterine muscle contractions have begun. Thus, it is intended that the aforemenkioned phrase couer abortion prevention early in pregnancy (i.e., before the fetus i9 "viable") as well as delaying premature parturi-tion, 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 administratio~ tends to prevent the onset of parturition.
This administration is particularly useful in the treatment o women having a history o~ spontaneous abortion, miscarri-age or premature delivery (i.e., delivery prior to ~ull term).
Such administration is also useful where there are clinical indications that the preynancy might be t0rminated prior to that time and i5 considered favorable to the mother and/or ~etus.
With respect to animals, this treatment can ~` also be utilized to synchronize the deliveries ~rom a group -- of pregnant animals to happen at or about the same time, or to happen at or about a desired time and/o~ place, when the births can be handled with greater facil~ty.
As used in this application, the phrase "postponing parturition" is intended to covex that delay in parturitian caused by the administration of the c~mpounds o~
Form~la3 (A) or (B) or the (l)-acld isomers thereof and the ~- ph~rmacoutically acceptable, non-toxic esters and salts - thereo~ a~ter uterine muscle contractions have begun. The condition o~ the patient, including the time within khe ge~ta-tion period when the contractions have begun, the severity of the contractions and how long the contractions have taken ', ~- - 20 -.
- , .

place ~ill afrect the resul~s achieved with the administra-tion of the compounds hereof. For Example, the e~ect can be to reduce the intensity and/or the duration of the con-tractions (the actual act of parturition being "prolonged"), or to stop ~he contractions altogether. In either case, the e~fect will be ~o prolong the gestation period although, depending upon the co~ditions of the patient as descri~ed above, the effect may ei~her by slight or, under appropriate - circumstances, omewhat greater. Such administrati~n may be to prevent spontaneous abortion, to cause the delivery to be more easily accomplished and/or less pain~ul to the - mother~ or to occur at a more appropriate time and/or place.
In all cases, administration of the com-pounds of Formulas (A) or (B) or the (1) acid isomers thereo~
and the pharmaceutically acceptable, non-toxic esters and salts thereof, for the purposes set forth herein should be consistent with best and/or accepted medical (or veterinary) practices so as to maximize the benefits to the mother and the fetus. For example, administration should not be con-tinued so long past ~ull term that the fetus dies in utero.
In the practice of the methods of the pre-sent invention, a therapeutically effective amount of a com-pound o~ Formulas ~) or (B) or the (l)-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereo, or a pharmaceutical composition containing same, is administered to the pregnant mammal via any of the usual nd acceptable methods known in the art. The compound can be admi~istered ei~her singly or in combina~ion with ; another compound or compounds, as de~ined above, or other pharmaceutical agent~, carrierQ, adjuvants, etc. Such `'`' : ' "'''' ' '' `' ' ` ' ' 4~

compound(s) or compositions can be admini~tered orally, parenterally, either in the form of solid, semi-solid, or liquid dosage forms. Typically, administration is by a pharmaceutical composi~ion containing the pharmaceutically active compound and one or more pharmaceutical carriers or adjuvants.
The administera~le pharmaceutical composi-tion may take the form o~ oral tablets, vaginal or uterine tablets or suppositories, pills, capsules, liquid solutions~
suspensions, or the like, preferably in unit dosage forms suitable ~or simple administration of precise dosages.
Conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium sacsharin, talcum, cellulose, ylucose, gelatin, sucrose, magnesium carbonate, and the like. The active com~
pound as de~ined above may be formulated as suppo-citories using, for example, polyalkylene glycols, for example, polypropylene gl~col, as the carrier. Liquid Pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above a~d optional pharmaceutical adjuvants in a carrier, ~uch as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. I de~ired, the pharmaceutical composition to be admin:istered may al=o contain minor amounts of non-toxic auxlIiary substances such as wetting or emulsifying age~ts, pH buffering agents and the like, or example,sodium acetate, ~orbitan monolaurate, triethanolamine oleate, etc.
Actual methods o~ preparing such dosage ~orms are known, or will be apparent, to those skilled in this art; ~or example, ~ee Remington's Pharmaceutical sciences, Ma~k Publishing Company, Easton, Pennsylvania, 14th Edition, 1970. The com-posi~ion 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 parturitio~ or to postpone partu-ition i~ uterine contractions have already begun.
Generally a daily dose o~ from O.S mg. to about 25 mg. of the active compound per kilogram of body weight will be administered, with administra~ion being a single daily dose or up to three or four smaller dosages regularly given throughout the day. The amount of active compound adminis~
tered will, of course, depend on its relative activity.
The following Preparation and Examples il-lustrate the invention but are not intended to limit its scope. The abhreviation t.l.c. refers to thin-layer chroma-tography and all mixture ratios used with regard to liquids refer to volume ratios. Also where necessary, examples are repeated to prepare additional material ~or subsequent examples; and u~less otherwise specified the reac~ions are carried out at room temperature (20C to 30C).

PREPA~ATION
A mixture of 23 g. o~ 4-chlorothiophene-2-carboxylic acid ~J. Iriarte et al., J. ~eterocyclic Chem. 13, 393) and 80 ml. of thionyl chlorids is heated to reflux, un-der anhydrous con~itions for 4 hours. The excess thionyl chloride is eliminated and the residue distilled under re-duced pressure (60C/Z mm), to afford 18 g. of 4-chlorothio-phe~e-~-carboxylic acid chloride.
A solution of 10.5 g. o~ 4 chlorothiophene-2-carboxylic acid chloride in 500 ml~. of anhydrous benzene is cooled in an ice water bath and dimethylamine is slowly bubbl-ed through the solution for 30 minutes. The ice water bath is removed, maintaining the stream of dimethylamine or 15 ~dditional minutes. The reaction mixture is then diluted with lOO ml. o~ lO~ sodium chloride ~olution and stirred for ; S minutes at room temperature, the organic phase is separat-ed, wa hed with lO~ hydrochloric acid, saturated sodium bi-carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under xeduced pressure, to produce N,N-dimethyl-4-chlorothiophene-2-car~oxamide.
In a similar manner the thiophene and furan-2-carboxylic acids listed below under I are converted into the N,N-dimethyl amides listed undar II:

~ I II

Thiophene-2-carboxylic acid N,N-dimethylthiophene-~-car-boxamide furan-2-carboxylic acid N,N-dimethylfuran-2-carboxa-mide 3-methylthiophene-2-carboxylic N,N-dimethyl-3~methylthio-acid phene-2-carboxamlde 4-methylthiophene-2-carboxylic N,N-dimethyl-4-methylthio acid phene~2-carboxamide

5-methylthiophene-2-carboxylic N,N-dimethyl 5-methylthiophe-acid ne-2-carboxamide S-chlorothiophene~2-ca~oxylic N,N-dimethyl-5-chlorothio-acid phene-2-carboxamide 3-bromothiophene-2~carboxylic N,~-aimetnyl-3-bromothiophene-acid 2-carboxamide 4-bromothiophene~2-carbo~ylic N,N-dimethyl-4-bromothiophene-acid 2-carboxamide 5-bromothiophene-2-carboxylic N,N~dimethyl-5-bromothiophene-acid 2 carboxamide 3-methylfuran-2-carboxylic N,N-dimethyl-3-methylfuran-2-acid carboxamide 4-m thylfuran~2-carboxylic N,N-dimethyl 4-methyl~uran-2-acid carboxamide 5-methylfuran-2-carboxylic N,N-dimethyl-5-methylfuran-2-acid carboxamide .~ .
3-chlorofuran-2-carboxylic N,N-dimethyl-3-chlorofuran-acid 2-carboxamide 4-chlorofura~-2-carboxylic N,N-dime~hyl-4 chloro~uran-acid 2-carboxamide 5-chlorofuran-2-carboxylic N,N-dimethyl-5-chlorouran-acid 2-carboxamide 4-bromofuran-2-carboxylic N,N-dimethyl-4-bromofuran-acld 2-carboxamide 5-bromofuran-2-carboxylic N,N-dimethyl-5-bromofu~an-acid 2-carboxamide thiophene-3 carboxylic N,N-dimethylthiophene-3-acid carboxamide ~uran-3-carboxylic acid N,N-dimethylfuran-3-carb~
oxamide ~X~MPLE 1 A 250 ml. 3-necked round bottomed flask con~
taining a magnetic stirring bar and fitted with a calcium - chloride filled drying tube 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 ~atter apparatus consistq of a 100 ml. round bottomed flask [previou~ly ch~rged with 15.6 g~ o~ oxalic acid dihydrate and 11. 82 g. o~ bromoacetaldehyde diethyl acetal, prepared from vinyl acetate, as de~cribed by P.Z. Bedoukian, J. ~m. Chem.
Soc. 66, 651 (1944)], topped with a 6" Vigreux column, bear-ing a thenmometer, connected to the above mentioned condenser.

- 2~ ~

The 3-necked flas~ is charged with 3.36 g.
of ethanolamine cooled in an ioe ba~h at 0-10C and treated dropwise, with stirring, with 8.7 g. of dimethyl 1,3-acetone-dicarboxylate. Methyl 3-carbomethoxymethyl-3(2'-hydroxy-ethyl)amino acrylate (III) forms immediately. When the ad-dition is completed, the ice bath is removed and 100 ~1. of dry acetonitrile is added. ~he pyrolysis part of the ap-paratus is placed in an oil bath and the temperature thereof is raised to 150-160C. The bromoacetaldehyde solution which forms is distilled (b.p. 80-83C/580 mm) directly into the magnetically stirred solution of the vinylamine (III). When the distillation temperature drops below 80C, the pyrolysis apparatus is disconnected and replaced by a re~lux 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 o~ 200 g. of silica gel packed in hexane.
The column is then eluted with hexane:ethyl acetate ~80:20;
500 ml.~ and hexane:ethyl acetate (1:1; 9 x 500 ml.). Frac-tions 2 and 3 contain less polar impurities and dimethyl 1,3-acetonedicarboxylate; fractions 4-8 a~ord 4.1 g. o~ methyl N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R=H), which upon recrystallization ~rom ether-hexane has a meltin~
point o 52-54C.

To a stirred solution o~ 4.1 g. o~ methyl .

N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate in 35 ml.
of dry dichloromethane cooled to -10C, are added 2.65 ml.
of triethylamine and thereafter, in a dropwise fashion, 1.46 ml. of me~hanesulfonyl chloride, maintaining the temper-ature o~ the reaction mixture at -10 to -5~C. The course o the reaction is followed by t.l.c. analysis using chloro-form:acetone (90:10). When the reac~ion appears to be com-plete ~about 30 minutes after t~e addition of the methane-sulfonyl chloride is terminated) there is added slowly 10 ml.
of water. The organic phase is separated, washed with water ~3 x ~0 ml.), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the,residue from di-chloromethane-hexane affords 4.75 g. (77.7%) of methyl N-(2- -mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 99-lOl~C.

~XAMPLE 3 A solution of 785 mg. of methyl N-(2-mesyl~
oxyethyl)-3-~arbomethoxypyrrole-2-acetate and 1.83 g. of sodium iodide in 10 ml. of acetonitrile is refluxed for 1 hour. The coole~ reaction mix~ure is evaporated to dryness under reduced pressure and the residue is triturated with watex. The i~soluble material is separated by filtration and alr dried, thus obtaining 840 mg. (97~) of methyl N-(2-iodoeth~ 3-carbomethoxypyrrole-2-acetate ~VI, R - H), m.p.
137-138C.

EX~MPLE 4 A solution o~ 1 g. o~ methyl N-(2-iodoethyl)_ 3-carbomethoxypyrrole-2-acetate in 5 ml. of dry dimethyl-formamide 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 tempera~ure and then quenched with 100 mlO of water. The product is extract~
S ed with ethyl acetate (3 x 50 ml.), the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography o~ the residue on silica yel (20 g.) usiny hexane~ethyl ace~ate (4:1) as eluant a~fords 500 mg. (80~) of dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a]pyrrole-1,7-dicarboxylate ~VII, R = H) m.p. 70-71C.
A solution of 1.80 g. of dimethyl 1,2-di-hydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate in 20 ml. of methanol is ~rea~ed with a solu~ion of 4.48 g. of potassium - hydroxide in 20 ml. of water, and the reaction mixture is lS re~luxed for 6 hours. I'he cooled solution is evaporated to dryness and the residue is treated with 50 ml. of satu~ated sodium chloride solution. The resultant solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3 x 50 ml.). The combined extrac~s are dried over 2~ magnesium sulfate and evaporated to dryness under reduced pressure, to yield 1.51 g. (95~) of 1,Z-dihydro-3H-pyrrolo-~1,2-a]pyrrole-1,7-dicarbo~ylic acid (VIII, R = H), m.p.
220C, with decomposition.

EXA~PLE 5 A solution of 1.34 g. o~ l,Z-dihydro 3H-pyrrolo[L,2-a]pyrrole-1,7-dicarboxylic acid in 50 ml. o~ iso-propanol, cooled in an ice bath is saturated with gaseous hydrogen chloride, malntaining the temperature of the reac-; 30 tion mixture below 50C. The ice bath is then removed and '' the reaction mixture is stirred for 1.5 ~ours at room temp~r-a~ure, and evaporated to dryness under reduced pressure;
10 ml. of ~enzene is added to the residue and th~ 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. (96%) of isopropyl 1~2-dihydro-3H-pyrroloC1~2-a]pyrr~le-l-carboxylate-7-carboxy-lic acid (IX, R = H, ~ ~ iC3~7), which upon crystallization from methanol-e-thyl acetate has a melting point of 144-145C.
In a similar manner but substituting methan-ol, ethanol, propanol, and n-butanol for isopropanol in the above procedure there are respectively ob~ained:
methyl 1,2 dihydro-3H-pyrrolo[1,2-a~pyrrole-1-carboxylate-7-carboxylic acid, ethyl 1,2 dihydro-3H-pyrrolo~1,2-a]pyrrole-1-carboxyl-ate-7-carboxylic acid, propyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate 7-caxboxylic acid, and butyl 1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxyi-ate-7~carboxylic acid.

1.054 G. of i~opropyl 1,2-dihydro-~H-pyrrolo-~1,2-a]pyrrole-1-carbo.Yylate-7-carboxylic acid is heated to 240-250C~in a dry 10 mlO round bottomed flask, distilling direc~ly the reaction product from the reaction vessel. Xn this manner there is obtained 745 mg. (87%) o~ isopropyl lt2-dihydro-3H-pyrrolo[1,2-a]pyrrol~ carboxylate (X, R = H, R2 = iC3H7), a pale yellow oil , having the ~ollowing MeOH ' physical constants: U.V.: A max ;~15 nm (~ 6020); I .R.:

v max 1725 cm ; N.M.R.: ~TMS 1.22 (d, J = 7 Hz, 6H), .
2.40-2.90 ~m, 2H), 3.60-4.20 (m, 2~), 4.65-5.2 ~m, lH), 5.73-5.92 (m, lH), 6.10 (t, J = 3 Hz, lH), 6.43-6.53 (m, lH).

A 100 ml. 3-necked round bottomed ~lask equipped with a condenser, ~itrogen inlet tube and a gas bub~ler is charged with 5.0 g. of isopropyl 1,2-dihydro-3H-pyrrolo[l,2-a~pyrrole-1-carboxylate-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 270C and the reaction is ollowed by the rate of carbon dioxide evolution (gas bubbler) and by t.l.c.
on silica gel, u ing benzene:dioxan:acetic acid t90:10:1~ as developing solvent. After 45 minutes the reac~ion is almost complete. A~ter one hour, the vessel is removed from the oil ; bath 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 sîlica gel.
The fractions eluted with hexane:benzene (70:30) and bexane:
benzene~(SO:S0) afford 2.77 g. (68%) of isopropyl 1,2-di-~hydro-3H-pyrrolo[1,2-a]pyrrole l-carboxylate (X, R - H, R a-~ iC3~7), an oil, whose physical constants are identical ` to those obtained in Example 6 710 Mg. of a 50% suspension o~ sodium hydride in mineral oil i5 washed with anhydrous h0xane under an atmosphere of nitrogen, and then suspended in 50 ml. of dimethylformamide. The suspension is cooled to -5C and 4.5 g. of methyl N-(2-mesyloxyme~hyl)-3~carbomethoxypyrrole-2-acetate are added, stirring the reaction mixture a~ -5 to O~C for 1 hour. It is then poured into iced sodium chlcride solution and extracted several times with benzene.
The combined extracts are washed with water, dried and evaporated to dryness under xeduced pressure. The solid residue is crystallized from ether, thus obtaining dimethyl 1,2-dihydro-3~-pyrrolotl,2-a]pyrrole-1,7-dicarboxylate (VII, R = H) identical to the produc~ obtained in Example 4;

A solution o~ 232.5 mg. of N,N dimethylthio-phene-2-carboxamide and 0.15 ml. of phosphorous oxychloride in 2 ml. of 1,2-dichloroethane is re~luxed for 30 minutes.
To this solution is add~d a solution of 181 mg. of isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carhoxylate in 2 ml.
of 1,2-dichloroethane. The reaction mixture is refluxed under an argo~ atmosphere ~or 8 hours, treated with 450 mg.
of sodium acetate and refluxed for a further 5 hours. The resultant mixtuxe is then evaporated to dryness and the residue is chromatogr~phed on 12 g. of silica gel, eluting wi~h hexane:ethyl acetate (3:1), thus obtaining isopropyl 5-(2-~henoyl)-1~2-dihydro 3~-pyrrolo[1,2-a]pyrrole=~1-carboxyl-ate (XI, R and Rl = H, R = iC3H7, X = S).
; EX~MP~E 10 A
: :~ A solution of 300 mg. of isopropyl 5-(2-the~oyl) 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate .~
in 30 ml. of 50~ aqueou9 methanol containing 1% of potassium hydroxide is refluxed under an atmosphere o~ nitrogen ~or 2 hours~ The methanol is then removed under redused pressure ' " ' ' . " ~

and t~e basic solution which remains is diluted with water and extracted with chloroform to remove any unsaponifiable product. The aqueous alkaline phase is acidified with 20~
hydrochloric acid and extractad three times with e-thyl ace-tate. The com~ined extracts are dxied over sodium sul~ate and evaporated to dryness under reduced pressure, thus ob-taining 250 mg. of crude 5-(2-thenoyl)--1,2-dihydro-3H-pyrrolo-~1,2-a]pyrrole-1-carboxylic acid, [(A), R and Rl = ~, X - S~, having a melting point of 145-148C, which upon recrystalliza-tion from ethyl acetate melts at 152-153C, with decomposi-tion.

EXAMæLE 10 B-l -410 Mg. o~ 5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo-[1,2-a]pyrrol0-l-carboxylic acid and 212.3 mg. of (d)-; amphetamine are dissolved in 15 ml. of absolute methanol and heated at reflux for 15 minutes, followed by removal of the me~hanol u~der vacuum. The resulting diastereoisomeric-(d)-amphetamine salt mixture (612.3 mg.) is dissolved in a mini-mum volume of hot (55C) acetone, cooled ko room temperature, filtered and washed with 2 ml. of cold (-10C) acetone. ThiC
recrystallization procedure was repeated three additional times to yield 247 mg. of (1)-5-(2-thenoyl)-1,2-dihydxo-3H
pyrrolo-[1,2-a]pyrrole-1-carboxylic acid-(d)-amphetamine salt having an ~ HC13 -181.3 and a melting point of 168 170C.
The (l)-acid isomer~(d)-amphetami~e salt, ob ained immediately above, is added ~o 30 ml. of methylene chloride and shaken three times with 1~ ml. of O.lN a~ueous hydrochloric acid. The methylene chloride solution is washed ` 30 three times with 15 ml. of saturated sodium chloride/waker ; - 32 -` " ` ~. `

(2:1/V:V) and dried over anhydrous sodium sulfate. Fil-tration and r~noval of the organic solvent under vacuum yields 90 mg. of (1)-5-2-(thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid, which has an ~ HC13 -1i7 and a melting point of 134-135.5C.

The acetone mother liquors resulting from the resolution (i.e., the multiple crystallizations) of the diastereoisomeric-(d)-amphet~nine salt mixture, descxibed 1o above, are combined and converted, using the hydrochloric acid cleavage procedure as described above, to yield 245 mg.
of a mixture enriched in ~d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-~1,2-a]pyrrole-1-carboxylic acid and con~aini~g (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-car-is boxylic acid. This mixture is racemized (recycled) back to ~ a 1:1 mixture of the (d)-and (l)-isomers of 5-(2-thenoyl)-- - 1,2-dihydro-3~-pyrrolo-~1,2-a]pyrrole-1-car~oxylic acid as follows: The 245 mg. of the mixture enriched in the (d)-isomer and containing the (l)-isomer J described above, is dissolved in 15 ml. of methanol. 1.5 Ml. of me~hanol and 350 mg. of sodi~n hydroxide are added and the solution is heated at re~lux, under nitrogen, for one hour. The metha-nol is removed under vacuum, 2.5 ml. of water is added and the solution acidified to pH 2 with 10~ aqueous hydrochloric acid. ~he mixture is extracted with three 10 ml. portions ; of methylene chloride and the methylene chloride extrac~s are combined and back-washed to neu~rality (pH 7~, dried ov~r anhydrous ~odium sulfate and concentrated in vacuo to ~yield 230 mg. of a crude crystalline product, which upon recry~alliza~ion from ethyl acetate-hexane yields 180 ms-,: ~
. ~ ., of 5-(2-thenoyl)~1,2-dihydro-3H~pyrrolo-~1,2-a]pyrrole-l-carboxylic acid having an aDMeH 0 0 and a melting point o~ 152~-154C.
In like man~er other (d)-optically active bases may be substituted ~or (d)-amphe~amine in the above process. Particularly ~uitable are:
(d)-p-bromo a-phenethylamine, - (d)-a-phenethylamine, (d~--l-naphthethylamine, and (d)-a-2-naphthethylamine, wi~h (d)-p-bromo-a-phenethylamine being mast preferred after (d)-amphetamine.
Similarly, the (d)-acid isomers e.g., - (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-~1,2-a~pyrrole-1-carboxylic acid, are obtained by substituting th~ (l)-opti-cally active bases for the (d)-optically active bases~ e.g., the suhstitution of (l)-amphétamine for (d)-amphetamine.

To a solution of 118 mg. of 5-~2-thenoyl)-1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 8 ml. of dry benzene, 0.234 g. of trifluoroacetic ~nhydride is added. The mixture is stirred at room temper-ature for 10 minutes and the resulting solution is cooled to 0-5C and 0.55 g o~ dry triethylamine is added, ~ollowed immediately by the addition of 0.2 g o (l)-~-phenyl ethyl alcohol. The thus-obtained xeaction solution is stirred at room temperature for 15 minutes and poured into 20 ml.
of watex containing 1 ml. of triethylamine, ~ollowed by - 30 extraction with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate, ~ollowed by removal of the i' solvent and excess (l)-a-phPnyl ethyl alcohol under vacuum to yield 0.166 g.of a mixture of (1)~5-12-thenoyl)-1,2-dihydro-3H-pyrrolo-[l~2-a]pyrrole-l-carboxylic acid-(l)-a-phenethyl ester and (d)-5 (2-thenoyl)-1,2-dihydro-3H-pyrrolo-~1,2-a]pyrrole-l-carhoxylic acid-(l)-a-phenethyl ester which is separated by high pressure liquid chromatography (using 4% EtOAc/hexane on a 11 mm. x 50 cm., 10~m. Lichrosorb Sl-60 column) to give 68 mg. of a more polar ester (aMeH
-149.1) and 73 mg. ~f a les~ polar ester (aDIeOH +105.2).
62.1 Mg. o~ the more polar ester is dissolved in 3 ml. of dry benzene. The solution is cooled to 15-20C and 2.5 ml. of tri~luoroacetic acid is added and the solution stirred at room temperature for 1 hour and 40 minutes. The reaction solution is poured into 6G ml. o~
dry benzene 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 acid is substituted fox 4% EtOAc/hexane) to give 41 mg. (1)-5-(2-thenoyl)-1,2 dihydro-3~-pyrroIo-[1,2 a]pyrrole-l-car-boxylic acid having an aDeH -144, and a melting point of 130-132C.
Similarly, cleavage of the less polar 25~ estex t according to the method described above ~or, the clea~age of the m'ore polar ester, yields (d)-S-(2-thenoyl)-1,2-dihydro-3H-pyrrolo~1,2-a]p,yrrole~l-caxboxylic acid ha~ing an aMeH ~142.4, and a meltiny point of 127-129C.
The thus-obtained (d)-acid isomer may, if desired,be racemized ~ .
~`

(and recycled), according to methods known in ~he art.

Similarly other (dl) compounds may be converted to their respectlve (l)-isomers and (d)-isomers.

solution o 336 mg. of isopropyl 5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ml. of methanol is treated with a solution of 690 mg.

o~ potassium carbonate in 5 ml. o~ water. The reaction mix~
ture is refluxed under nitrogen atmosphere for 2 hou~s, 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 mixturè extracted with ethyl acetate (2 x 50 ml.). The combined extracts are dried over magnesium ; sulfate and evaporated to dryness under reduced pressure.
; Crystallization of the residue from e~hyl acetate affords 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carbo~y-lic aoid, identical to the product obtained in Example 10A~

By following the methods of Examples 6 or 7, the remaining compounds obtained in Example 5 are conver~ed respectively into:
methyl 1,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-1- -caxboxylate, ethyl 1~2-dihydro-3H-pyrrolo[l~2-aJpyrrole ca~boxylate, propyl 1,2-dihydro-~H-pyrrolo[1,2-a]pyrrole-1 c~rboxylate and butyl 1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Upon condensation of these compounds with N,N-dimethylthiophene-2-carboxamide, in accordance ~Jith the method of Example 9 there are respectively obtained:
methyl 5-~2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylate, ethyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-Me~H
pyrrole-l-carboxylate, ~max 265, 328 nm (~ 7580, 17780), propyl 5-t2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylate and butyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylate.

.

Following the procedure of Ex~mple 9, using 1.1 to 2 molar equivalents of ~` ~ N,N-dimethylfuran-2-carboxamide, N,N-~imethyl-3-methylthiophene-2-carboxamide, N,N-dimethyl-4-methylthiophene-2-carboxamide, N,N-dimethyl-5-methylthiophene-2-carboxamide, N,N-dimethyl-4-chlorothiophene-2-carboxamide, :
NjN-dimet~yl-5-chlorothiophene-2-carboxamide, N,N-dimethyl-3-bromothiophene-2-carboxamide, 25~ ~ N~N-dimethyl-4-bromothiophene-2-carboxamide~
N,N~dimethyl-5-bromothiophene-2-carboxamide, N,N-dimethyl-3-methylfuran-2-carboxamide, N,N-dimethyl-4-methyl~uran-2-carboxamide, N~,N-dimethyl-S-methylfuran-2-carboxamide, 3~ N,N-dimethyl-3-chlorofuran-2-carboxamide~
. ~ .
' N,N-dimethyl~~-chlorofuran-2-carboxamide, N,N-dimethyl-5-chlorofuran-2-carboxamide, N,N-dimethyl-4-bromofuran-2-carboxamide and N,N-di~e-thyl-5-bromofuran-2-carboxamide, in place of N,N-dimethylthiophene-2-carboxamide, and - monitoring the course of the reaction by t.l.c., there are obtainea respectively:
isopropyl 5-(2 ~uroyl)-1,2-dih~dro-3~-pyrrolo[1,2-a]-pyrrole-l-carboxylate, an oil, having the following physical constants: - -MeOH
U.V~ ~max 27S, 332.5 nm (~ 8900, 17800);
CHCl I.R. vmax 3 1735, 1685, 1605 cm CDCl N.M.R~ ~TMS 3 1.23 [d, 6H, J = 6 Hz; (CH3~2CH], 2.60-3.00 (m, 2H), 3.90 (dd, lH, JAX- 6 Hz;
JBX = 7 Hz; H-l), 4.10-4.67 (m, 2H), 4.95 [sept., lH, J = 6 HZ; (CH3)2CH],

6.00 (d, lH, J = 4 Hz; H-7), 6.40 (m, lH~,

7.10 (m, lH), 7.23 (d, lH, J s 4 Hz; H-6), :: .
7.43 ppm (m, lH);
~.S. m/e 287-~M ), .
isopropyl 5-(3-methyl-2-thenoyl)-1,2-dihydro-3~-pyrrolo~l,2-a~pyrrole-1-carboxylate, isopropyl 5-(4-methyl-2-thenoyl3-1,2-dihydro-3H-pyrrolo[l,2-~Jpyrrole-l-carboxylate, isopropyl 5-(5-methyl-2-thenoyl)-1,2-dihydro-3~-pyrrolo[l,2-a~pyrrol~-1-carboxylate, having a melting point o~ 82-82.5C, isopropyl 5~(4~chloro-2-thenoyl-1,2-dihydro-3H
pyrrolo[l,2-a~pyrrole-1-carboxylate, ::
:', . . .
~ - 38 -.~ .... .
- .. : .,, " , . . .

isopropyl 5-(5-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-1-carboxylate, isopropyl 5-t3-bromo-2-the~oyl)-1,2-dihydro-3~-pyrrolo~1,2-a]pyrrole-1-carboxylate, S isopropyl 5-~4~bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a~pyrrole-1-carboxylate, isopropyl 5-(5-bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl-5-(3-methyl-2-furoyl)-1,2-dihydro-3~-pyrrolo~l,2-a]pyrrole-1-carboxylate, isGpropyl-5-t4-methyl-2-furoyl)-1,2-dihydro-3H-pyrrolo[l,2-aJpyrrole l-carboxylate, isopropyl 5-(5-methyl-2-furoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-1-carboxylate, isopropyl 5-(3-chloro-2-furoyl)-1,2-dihydro~3H-pyrrolo[l,2-a]pyrrole-1-carboxylate, - isopropyl 5-(4-chloro-2-furoyl)-1,2-dihydro~3H-pyrrolo[l,2-a]pyrrole-1-carboxylate, isopropyl 5-(5 chloro-2-furoyl)-1,2-dihydro-3H-pyrrolo~l,2-a]pyrrole-1-carboxylate, isopropyl 5-(4-bromo-2-furoyl)-1,2-dihydro-3H-pyrxolo[l,2-a]pyrrole l-carboxyla~e and isopropyl 5-(5~bromo-2-furoy~ 2-dihydro-3H
pyrrolo[l,2-a]pyrrole-1-carboxylate.
. ~ Upon hydrolysis of the isopropyl ester group, i~ accordance with the methods of Examples lOA or 11, there ; are o~ai~ed the corresponding free acids, namely:
5-~2~furoyl)-1,2-dlhydro-3~-pyrrolo[1,2-a]pyrrole-1 carboxylic acid, having a melti~g point of 184-184.5C, :, :

:
: - 39 -.,, ~

5-(3-methyl-2-thenoyl) 1,2-dihydro-3H-pyrrolo[1,2-a]-pyrxole-l-carboxylic acid, 5-(4-methyl-2-thenoyl)-1,2.-dihydro-3H-pyrrolo[1,2-a]-pyrrole 1-carboxylic acid, 5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyxrole l-car~oxylic acid~ havi~g a melting paint of 169~-170C, 5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid, 5-~5-chloro-2-thenoyl)-1,2-dihydro-3H-pyrro~o[1,2-a]-` 10 pyrrole-l-carboxylic acid, 5-~3-bromo-2-thenoyl)~1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l~carboxylic acid, 5-(4-bromo-2-thenoyl)-1,2~dihydro-3~-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid, 5-(5-bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, 5-(3wmethyl~2-furoyl)-l,Z-dihydro-3H-pyrrolo~1,2-aj-pyrrole-l-carboxylic a d d, 5 (4-methyl-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l carboxylic acid, 5-(5~methyl-2-furoyl~-1,2-dihydro-3~-pyrrolo[1,2-a]-pyrrole l-carboxylic acid, 5-(3-chloro-2-furoyl)-1,2~dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid, 5-(4-chloro-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l carboxylic acid, 5-(5-chloro-2 ~uroyl)-1,2-dihydro~3~-pyrrolo~1,2-a]-pyrrole-1-car~oxylic acid, 5-(4-bromo~2~furoyl)-1,2-dihydro-3~I-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid, and 5-(5-bromo-2-~uroyl)-1,2-dihydro-3H-pyrrolo~1,2-a]-pyrrole-l-carboxylic acid.
, A 250 ml. 3-necked round bottomed flask con-taining a magnetic stirring bar and ~itted with a calcium chloride filled drying tube, is charged with 3.36 g. of ethanolamine, cooled in an ice bath at 0-10C and treated dropwise, with stirring, wLth 8.7 g. of dimethyl 1,3-acetone-dicar~o~yl~t~ ethyl 3-carbomethoxymethyl-3-(2'-hydroxyethyl) amino acrylate (III) forms immediately. When the addition is ~`~ complete, the ice bath is removed a~d 80 ml. of dry aceto-nitrile is added. The reac~ion mixture is then trcated drop-wise with 6.75 g. of bromoacetaIdehyde in 20 ml. of aceto~
nitrile and thereafter heated at reflux temperature for 2 ; h~urs. The solvent is then removed under reduced pressure ~ ~and Z00 ml. of methanol and 20 g. of silica gel are added to , t~e residue. This mixture is evaporatsd to dryness i~ vacuum ~` and placed on top of a column o~ 200 g. of silica gel packed 20 ~ ~ in hexane, eluting the column with hexane:ethyl acetate mix-tur~s. The fractions eluted witX hexane:ethyl acetate (1:1) a~ord methyl N-(2-hydroxyethyl)-3-Garbomethoxypyrrole-2-acetate (IV, R = H) identical to the product obtained in Example 1.
25~
EXAMP~E 14 B
To a ~olution o~ 6 ml. o~ e~hanolamine in 5 ml. o~ water there i~ added 1.74 g.o~ dimethyl 1,3-acet-. ~
~- onedicarboxylate. The resultant mixture i~ rapidly cooled to 30 ~ ~ -10C and t~eated dropwise, over a lS minute period, with : ::

:

:

.

.

stirring, with 1.67 ml. of l-bromoaceto~e, whilst maintain-ing the reaction mi~ture at a temperature not higher than 40C. When the addition is completed the dark reaction mix-ture is stirred for an additional hour at room temperature, and then poured into a mixtura of hydrochloric acid-ice, saturated with solid sodium chloride and extracted with ethyl acetate (3 X lO0 ml.). The comhined organic extract is washed with cold water to neutrality, dried with anhy-drous sodium sulate and evaporated to dryness under re-duced pressure. Chromatography of the residue on 30 g.

of silica gel, using hexane: ethyl acetate (70:30) as.eluant, a~fords 890 mg. o~ crystalline methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate which upon recrystal-lization from methylene chlorlde-hexane melts at 78C and has the following analysis:

calculated for C12Hl7N5 C, 56-45; H, 6-71 Found: C, 56.41; H, 6.73.
In a similar manner but using a stoichio-metric egui~alent of l-bromo-2-butanone, 1-bromo-2-pentanone and l-b~omo-2-hexa~one in place of l-bromoacetone there are respectively obtained:
methyl N-(2-hydroxye.thyl)-3-carbomethoxy-4-ethyl-pyrrole-2-acetate, methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-propyl-pyrrole-2-acetate and methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-butyl-pyrrole-2-acetate.

By following the method of Example 2, meth~l . - 42 -N~(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH3) is converted into methyl N-t2-mesyloxyethyl)-3-carbomethoxy-4-methylpyrrole 2-acetate and then cyclized with sodium hydride in ~imethylformamide, in accordance with the method of Example 8, to a~ord dimethyi 1,2-dihydro-6-methyl-3H-pyrrolo~1,2-a]pyrrole-1,7-dicarboxyl~te.
Upon hydrolysis of the latter compound with potassium hydroxide, in accordance with the method of Example 4 followed by selective esterification at C-l and decarboxy-lation at C-7, in accordance with ~he methods of Examples 5 and 7, respectively, there are successively obtained 1,2-di-: hydro 6-methyl-3H-pyrrolo~1,2-a]pyrrole~1,7-dicarboxylic acid, isopropyl 1,2-dihydro-~-methyl-3H-pyrrolo~1,2-a]-lS pyrrole l-carboxylate-7-car~oxylic acid and isopropyl 1,2-di hyd.ro 6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (X, R = C~3, R = iC3H7).
In a similar manner, subsli~ffl i~g ~ chy;
N-~2-hydroxyethyl)-3-carbomatho~y-4-ethylpyrrole-2-acetate, methyl N-(2-hydroxyethyl~-3-carbomethoxy-4-pro~ylpyrrole-2-acetate and methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-butyl-pyrrole-2-acetate for methyl N-(2-hydroxyethyl)-3-carbo-methoxy-4 methylpyrrole~2 acetate there are respectively obtained as final products:
isopropyl 1,2-dihydro-6-ethyl-3H-pyrrolotl,2-a]-pyrrole-l-carboxylate, isGpropyl l~2-dihydro-~-propyl-;}I-pyrroio~l~2 &J-pyrrole-l-carboxylate and : isopropyl 1,2-dihydro-6-butyl-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylate.

~. :

EXA~LE 1 6 In accordance with the method of Example 9, . ~ isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethylthiophene-2-car-boxamide to produce isopropyl 5- (2-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo~1,2-a]pyrrole-1-carbo~ylate (XI, ~ = CH3, ~- Rl = H, R = iC3~7, X - S), haviny a melting point of lOZ.5C.
In a similar manner but using the N,N-di-methylthiophene- or ~uran-2-carboxamides listed in Example 13 in place of N,N-dimethylthiophene-2-carboxamide, there are respectively obtained:
isopropyl 5-(2-furoyl)-1,2-dihydro-6-methyl-3H-; pyrrolo~l,2 a]pyrrole l-carboxylate, - isopropyl 5-(3-methyl-2-thenoyl)-1,2-dihydro-6-methyl-3H~pyrrolo[1,2-a]pyrrole-1-carboxylate, .
isopropyl 5-(4-me~hyl-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyxrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-(5-methyl-2-thenoyl)-1,2-dihydro-6-methyl~
: 3H-pyrrolo~1,2-a]pyrrole-1-caxboxylate, 2 isopropyl 5-(4-chloro-2-thenoyl)-1,2-dihydro 6-methyl-3H-pyrrolo r 1,2-a]pyrrole-1-carboxylate, isopropyl 5-(5-chloro-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-(3-bromo-2-thenoyl)-1,2-dihydro-6-methyl-~H-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-~4-bromo-2-thenoyl)-1,2-dihydro-6-methyl-~-- 3H-pyrrolo[1,2-a]pyrrole l-carboxylate, isopropyl 5-~S-bromo-2-thenoyl~-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a~pyrrole-1-carboxylate, i~opropyl 5-(3-methyl-2-~uroyl)-1,2-dihydro-6-methyl-' ~ .

3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-(4-methyl-2-~uroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-(5-methyl-Z-furoyl)-1,2-dihydro-6-methyl-3H=pyrrolo[1,2-a]pyrrole l-carboxylate, isopropyl 5-(3-chloro-2-furoyl)-1,2-dihydro-6-methyl-3~-pyrroloC1,2-a]pyrrole-1-carboxylate, isopxopyl 5-(4~chloro-2-furoyl)-1;2-dihydro-6-methyl-3~-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-(5-chloro-2-furoyl)-1,2-dihydro-6 methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, isopropyl 5-(4-bromo-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a~pyrrole-1-carboxylate and i~opropyl 5-~5-bromo-2-furoyl)-1,2-dihydro-6 me~hyl-3~-pyrrolo~1,2-a~pyrrole-1-carboxylate.
Likewise, the remaining final compounds obtained in Example 15 are converted into the corresponding 5-furoyl or thenoyl substituted derivativ~s. R~presentative compounds thus obtained are:
isopropyl 5-(2-thenoyl)-1,2-dihydro-6-ethyl-3H
py~rolotl,2~a]pyrrole~1-carboxy:late, isopropyl 5-(2-furoyl)-1,2-dihydro-6-propyl-3H-pyrrolo~1,2-a]pyrrole-l-carboxylate, isopropyl 5-(3-methyl-2-thenoyl)-1,2-dihydro-6-butyl~
3H-pyrrolo E 1,2 a]pyrxole-1-carboxylate, isopropyl 5-~4-chloro-2-thenoyl)-1,2-dihydro-6-ethyl-~H-pyrroloC1,2-a]pyrrol0-l-carboxylate, isopropyl 5-~5-methyl-2-~uroyl)-1,2-dihydro~6-propyl-3H-pyrrolo~1,2-a~pyrrole-l~carboxylate and isopropyl 5-(3-chloro-2-~uroyl) 1,2~dihydro-6-butyl-3~-pyrrolo[1,2-a]pyrrole-1-carboxylate.

A solution of SOO mg. of isopropyl 5-(2-thenoyl)~l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a~pyrrole-1-carboxylate in 15 ml. o~ methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. o~ water. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporat~d to dryness. The residue is taken up in lO ml. of lO~ aqueous hydrochloric acid and :50 ml. of water and the resultant mixture extracted with ethyl ac~tate (3 x 50 ml.). The combined extracts are dried over mag~esium sulfate and evaporated to dryness undex reduced pressure, to give 5-(2 thenoyl~-1,2-dihydro-5-methyl~
3H-pyrrolo~1,2-a]pyrrole-1-carboxylic acid [~A), R = CH3, Rl = H, X = S], having a melting point of 166C.
In a similar manner, or alternatively by the hydrolysis method of Example 10 A, the xemaining isopropyl ester compounds obtained in Example 16 are converted into the corresponding free acids, namely:
5-(2-furoyl)-1,2-dihydxo-~-methyl-3H-pyrxolo~1,2-a]-pyrrole-l-carboxylic acid, 5 (3-methyl-2-thenoyl)-1,2-dihydro-6-methyl-3H-: 25 pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5~(4-methyl-2~thenoyl)-1,2-dihydro-6-methyl-3H-. pyrrolo~l,2~a]pyrrole-1-carboxylic acid, 5-~S methyl-2-thenoyl)~-1,2-dihydro-6 methyl-3H-pyrrolo~l,2-a]pyrrole-1-car~oxylic acid, ; 30 5-~4-chloro-2-.thenoyl)-1,2-dihydro-6-methyl-3H-.

pyrrolo~l,2-a]pyrrole-1-carboxylic acid, 5-(5-chloro-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole~ carboxylic acid, 5-(3-bromo-2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5-(4-bromo-2-~henoyl)-1,2-dihydro-6-methyl-3~1-: pyrrolo[l,2-a~pyrrole-1-carboxylic acid, 5-(5-bromo-2-thenoyl)-1,2-dihydro-6-methyl-3~-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5-(3-methyl-2-~uroyl)-1,2~dihydro-6~methyl-3H-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5-(4-methyl-2-furoyl)-1,2-dihydro 6-methyl-3H-pyrrolo[l,2-aJpyrrole-l-carboxylic acid, 5 t5-methyl-2-furoyl)-1,2-dihydro-5 methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, 5-(3-chloro-2-furoyl)-1,2-dihydro-6-methyl~3H-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5-(4-chloro-2-furoyl)~1,2-dihydro-6-methyl-3~-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5-(5-chloro-2-furoyl)-1,2-dihydrG-6-m~thyl-3H-pyrrolo[l,2-a~pyrrole-l~carboxylic acid, 5-(4-bromo-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrxolotl,2-a]pyrrole-1-carboxylic acid, : 5-(5-bromo-2-fuxoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5--(2-thenoyl)-1,2 dihydro-6-ethyl-3H-pyrrolo~1,2-a]-: pyrrole-l-carboxylic acid, ~:: 5-(2-~uroyl)-1,2-dihydro-6-propyl-3H-pyrrolo[1,2~a]-pyrrole-l-carboxylic acid, ~ .

~ , .

~, . ..
- : , 5-(3-methyl-2-thenoyl)-1,2-dihydro-6-butyl~3~-pyrrolo~l,2-a]pyrrole-l~carboxylic acid, 5-(4-chloro-2-thenoyl)-1,2-dihydro-6-ethyl-3~-pyrrolo[l,2-a]pyrrole-1-carboxylic acid, 5-(S-methyl-2-furoyl)~1,2-dihydro-6-propyl~3H-pyrrolo~l,2-a]pyrrole-1-carboxylic acid and 5-(3-chloro-2-~uroyl)~1,2~dihydro~6-hutyl-3H-pyrrolo[l,2-a]pyrrole-1-carboxylic acid.

., BXAMPLE lt3 A solution of 232.5 mg. of N,N-dimethylthio-phene-3-carboxamide and 0.15 ml. of phosphororus oxychloride in 2 ml . o~ 1,2-dichloroethane is refluxed for 30 minutes.
To this solution is added a solution of 181 mg. of isopropyl 1,2-dihydro-3~-pyrrolol1,2-a]pyrrole-1-carboxylat~ in 2 ml.
of 1,2-dichloroethane~ The reaction mixture is refluxed under an aryon atmosphere for 8 hours, treated with 450 mg.
of sodium aceta~e and refluxed for a further 5 hours. The resultant mixture is then.evaporated to dryness and the residue is chromatographed on 12 g. o~ silica gel, eluting wi~h hexane:ethyl acetate (3:1), thus ob~aining isopropyl 5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1 carboxylate (XII, ~ = H, R2 = iC3H7, X = S).
In a ~imilar manner isopropyl 1,2-dihydro-6-methyl-3H-pyrrolotl,2-a]pyrrole-1-carboxylate and isopropyl 1,2 dihydro-6-propyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate are converted re~pectively into i~opropyl 5-(3-thenoyl)-1,2-dihydro-6-methyl-3~-pyrrolo~1,2-a]pyrrole-1-carboxylate and i~opropyl 5-(3-thenoyl)-1,2-dihydro-6-propyl-3H-pyrrolo-30 . ~1,2-aipyrrole-1-carboxylate.

v ~ y the same me~hod, substitu~ing N,M-di-methylfuran-3-carboxamide for N,N-dimethylthiophene-3-carboxamide there are obtained the corresponding 5-(3-fur~yl) derivatives, namely:

isopropyl 5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate, an oil, ha~lng the ~ollowing ~hysical constants~

U.V. ~MaeH 222, 244-277 (shoulder), 314 nm (~ 6750, 4250, 14800);
I.R~ Vm~aXC13 1730, 1610, 1560 cm 1;

N.M.R. ~CMDcl3 1.23 [d, 6H, J = 6 ~z; (CH3)2CH], 2.50-3.00 (m, 2H)~ 3.92 (dd, 2~, J~X = 6 Hz, JBX = 7 ~7 H-l~, 4.10-4.60 (m, 2~), 4.95 [sept., 1~, J = 6 Hz; (C~3)2CH], 5-95 (d~ lH~
J = 4 ~æ; H-7), 6.78 (m, 1~), 6.83 (d, lH, J = 4 Hz; ~-6), 7.30 (m, lH), 7.83 ppm (m, lH);
M.S. m/e 270 (M ), ~ isopropyl 5-(3-furoyl)-1,2-dihydro-6-methyl-3H-: 2~ pyrrolo[1,2-a]pyrrole-l-carboxylate a~d : isopropyl 5~(3-furoyl~-1,2-dihydro-6-propyl-3H-py~rolo[1,2-a]pyrrole-l carboxylate.
, ~ .

EXAMPLE l9 A:.solution o~ 300 mg. o isopropyl 5~(3-the~oyl)-1,2-dihydro-3H-p~rrolo~ -a]pyrrole-l-carboxylate in 30 ml. o~ 50% agueous me hanol containing 1~ of potassium hydroxide i9 re~luxed under an atmosphere of nitrogen for 2 ~^ hours. The methanol is then removed under reduced pressur~
and the ~as~c solution which remains is diluted with water ~' .

:
and extracted with chloroform to remo~e any unsaponifiable produ~t. The aqueous alkaline phase is acidiied with 20~
hydrochloric acid and extracted three times with ethyl ace-tate. The combined extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure, thus ob-taining 250 mg. of crude 5-~3-thenoyl)-1,2-dihydro-3H-pyrrolo~l,2-a]pyrrole-1 carbo~ylic acid, [(B), R = H, X - S].
By the ~ame method, the remaining compounds obtained in Example 18 are converted into the free acids, namely:
5-(3-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]~
pyrrole-l-carboxylic acid, 5-(3-thenoyl3-1,2-dihydro-6-propyl-3H-pyrrolo[1,2-a~-; pyrrole-l-carboxylic acid, 5-(~-~uroyl)-1,2-dihydro-3H-pyrroloEl,2-a]pyrrole-1 carboxylic acid, having a melting point of 156~C, 5-(3-furoyl)-1,2~dihydro-6-methyl-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid and 5-(3-furoyl)-1,2-dihydro-6-propyl-3H-pyrrolo~1,2-a]-pyrrole l-carboxylic acid.

A solution of 200 mg. of 5-(2-furoyl~-1,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-l~carboxylic acid in 5 ml.
o~ dichloromethane is treated with an excess o~ ethereal di-azomethane, and the reaction mixture is mai~tained at room temperature for 30 minutes. The solvents and excess reayent are eliminated under reduced pressu~e and the residue cry~-tallized from ethyl acetate-methanol, to yield methyl 5-~2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-~carbo~ylate.

.4~
Likewise but using diazoethane and diazo-propane is place of diazomethane there are respectively obtained ethyl 5-(2-furoyl)-1,2-dihydro-3H~pyrrolo~1,2~a]
pyrrole~ arboxylate and propyl 5-(2-~uroyl)-1,2~dihydro-3H~
pyrrolo~l,2-a]pyrrole-1 carboxylate.

In a similar manner, the remaining free acids obtained in Ex2mples 10 A, 10 B-l (and 10 B~2), 13 and the acids of Examples 17 and 19 are converted into the corresponding methyl, eth~l and propyl esters. Representa-tive compounds thus-obtained are:
methyl 5-(2-thenoyl)-1~2-dihydro-3H-pyrrolo-[1,2-a]
pyrrole-l-carboxylate, e~hyl 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo-tl~2-a]
; pyrrole-1-carboxylate, . propyl 5-(2-~henoyl)-1,2-dihydro-3H-pyrrolo-[1,2~a]
pyrrole-l-carboxylate, and the methyl ethyl and propyl Psters o~ 5-(Z-thenoyl)-1,2-dihydro-3H~pyrrolo-~1,2-a]pyrrole~l-carboxylic acid.

~XAMP~E 21 A ~olution of 300 mg. of 5-(2-theno~1)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml.
of isoamyl alcohol is saturated with hydrogen chloride.
After 24 hours, the excess alcohol is distilled off in vacuum and the residue purified by chromatography on alumina to yield isoamyl 5-(2-the~oyl)-1,2-dihydro-~H-pyrrololl,2-a]
pyrrole-l-carboxyl~e.
Likowise other esters, e.g., pentyl, hexyl, : octyl, nonyl, dodecyl and the like, of 5-(2-thenoyl)-1,2-:` :

. . . . . . .

dihydro-3~-pyrrolo[1,2-a]pyrrole~l-carboxylic acid ar~
obtained by substituting other alcohol~, e.g., pentyl, hexyl, octyl~ nonyl, dodecyl alcohol and the like, for lsoamyl alcohol.
: 5 By the same method the free acid compounds obtained in Examples 10 B-l, 13, 17 and 19 æe esterified with the appropriate alcohol to produce the corresponding asters, e.g., isoamyl 5-(2-furoyl~-1,2-dihydro-3R-pyrrolo[1,2-al-pyrrole~l-carboxyiate, pentyl 5-(4-methyl-2-thenoyl~-1,2-dihydro-3H-pyrrolo-- [1,2-a~pyrrole-1-carboxylate, hexyl 5-(5-chloro~2~thenoyl)-1,2-dihydro-3H-pyrrolo-~1,2-a]pyrrole-1-carboxylate, isoamyl 5-(4-bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo-tl~2-a]pyrrole-l-carboxylate~
ccty~ 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-car~oxylate, . nonyl 5-(3-methyl-2-furoyl)-1,2-dihydro--~H-pyrrolo a]pyrrole-l-carboxylate, dodecyl 5-(3-chloro-2-furoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a~pyrrole-1-carboxylate, hexyl 5 (4-chloro-2-thenoyl)-1,2-dihydro-6-methyl-3H-:~ pyrrolo~lr2-a]pyrrole-1-carboxylate, isoamyl 5-(2-thenoyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-11,2-a]pyrrole-1-carboxylate and octyl S-(3-f~royl)-1,2-dihydro-3H-pyrrolo~1,2-a~-~ .

pyrrole-l-carboxy~ate.

To a solution of 300 mg. of 5-~2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-alpyrrole-1-car~oxylic acid in S ml. o~ methanol is added 1 molar equivalent o~ sodium hydroxide, in the form o~ a O.lN solu~ion. The solvent is then evaporated under reduced pre~sure and the residue taken ; up in 2 ml. of methanol, followed by precipitation with ether, to yield crude sodium 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-Zl,2-a]pyrrola-1-carbo~late which can be crystalli~ed from isopropanol~
Likewise other salts, e.g., ammonium and po tassium,of 5-[2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2 a]-pyrrole-l-carboxylic acid are prepared by substituting am-monium hydroxide and pota~sium hydroxide for sodium hydroxyde.
In a similar manner, the 5-substituted 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid compounds obtained in Examples 10 B-l (and 10 B-2) 13, 17 and 19 can be converted into the correspo~di~g sodium, potassium a~d ammonium salts.
Representative compound~ thus obtained are:
sodium ~ 5-~2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole--1-carboxylate, sodium 5-~2-~uroyl)-1,2-dihydro-3H-pyrrolo[1,2-a]
pyrrole-1-carboxylate, sodium 5-(4-methyl-2-thenoyl)~1,2-dihydro-3H-pyrrolo-~1,2-a]pyrrole~l~carboxylate, ; potassium 5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a~pyrrole-l~carboxylate, , ~ 53 -potassium 5-(5-bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrxole-1-carboxylate, sodium 5-(3-methyl~2-furoyl)-1,2-dihydro-3H-pyrrolo-~1, 2-a] pyrrole-l-carboxylate, ammonium 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2~a]-pyrrole-l-carboxylate, ammonium 5-~3-chloro-2-furoyl)-1,2-dihydxo 3H-pyrrololl,2-a]pyrrole-1-carboxylate, sodium 5-~4-mathyl-~-thenoyl)-1,2-dihydro-6-ethyl-3~-pyrrolo[l,2-a]pyrrole-1-carboxylate, potassium 5-~5-chloro;2-thenoyl)~1,2-dihydro-6-methyl-3H-pyrrolo~1,2-a]pyrrole-1-carboxylate, ammonium 5-~3~thenoyl)-1,2-dihydro 3~-pyrrolo~1,2-a]-pyrrole-lrcarboxylate and sodium 5-~3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-~ pyrrole-l-car~oxylate.
,~;

To a solution of 237 mg. o 5-(2-thenoyl)-~ 1,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-1-carboxylic acid in

8~ml. of methanol is added 1 molar equivalent of potassium hydroxide, in the form of a O.lN solution to yield a solu~
tion containing potassium 5-(2~thenoyl)-1,2-dihydro-3H-pyrrolo~l,2-a]pyrrole-1-carboxyla e. A solution o~ 50 mg.
of~alciu~ carbon~te dissolved in the minimum amount o~ lN
hydrochlorLc acid necessary to eect solut~on o the calcium carbonate, is bufered with lOO mg. of solid a~nonium chloride, followed ~y the further addition of S ml. of water.
The thus o~tained bu~ered calcium solution is then added to 30; the 501ution 0~ potassium 5-~2-thenoyl)-1,2-dihydro-3H-~::

~ : :
` ~ - 54 -:

. ~ .. .
:: :

pyrrolo[l,2-a]pyrrole-1-carboxylate and the precipitate which forms is collected by filtration, washed with water and air dried, to yield calcium 5-~2-thenoyl)-1,2-dihydro-3~-pyrrolo~
[1,2-a~pyrrole~l-carboxylate.
~ 5 Likewise magnesium 5-(2-thenoyl)-1,2 dihydro-`~ 3H-pyrrolo[1,2 a]pyrrole~l-carboxylat~ is prepared by subs-tituting magnesium carbonate for calcium carbonate.

Similarly~ by substituting 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-aJp~rrole-l-carboxylic acid, 5-(2-furoyl)-1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboyxlic acid, 5-(4-chloro~2 thenoyl)-1,2-dihydro-3H-pyrrolo~1,2-a]-pyrrole-l-carboxylic acid, ~` 5-(3-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-l-carboxylic acid, ` 5-(5-bromo-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid, and 5-(3 chloro-2-~uroyl)~1,2-dihydro-6-ethyl-3H-pyxrolo-1,2 a]pyrrole-1-carbo~ylic acid, for 5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo~1,2-a]pyrrole-l~carboxylic acid there are obtained ~he corresponding calcillm and magnesium salts~
.

To a solution of 237 mg. of 5-~2-thenoyl) - I,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-1-carboxylic acid in 8 ml. o methanol i added 1 molar equivalent o~ potassium hydroxide, in the form of a O.lN solution. The solvent is stripped and the residue i~ dissolved in 5 ml. o~ water. The ' ~hus obtained aqueous solution of po~assium 5-~2-thenoyl~-1,2-dihydro 3~-pyrrolo[1,2-a]pyrrole l-carboxylate is added to a solution o~ 110 mg. of cupric nitrate trihydrate in 5 ml.
of water. The formed precipitate is collected, washed with water and air dried, thus obtaining copper 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-l~carboxylate.
In a similar manner the free acid compounds obtained in ~xamples 10 B-l (and 10 B-2~, 13, 17 and 19 can be converted into the corresponding copper salt-q.

A solution of 27 mg. of 5-(2-thenoyl)-l,Z-dihydro-3H-pyrrolo[1,2~a]pyrrole-1-carboxylic acid in 15 ml.
of hot benzene is treated with 59 mg. of isopropylamine.
The solution is allowed to cool to room temperature and the pxoduct filtered o~f, washed with ether and dried,to yield the isopropylamine salt of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l~carboxylic acid.
Likewise other amine salts, e.g., diethyl-amine, ethanolamine, piperidine, tromethamine, choline and caffeine salts of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-- 11,2-aJpyrrole-l-carboxylic acid are prepared by su~s~itut- -ing each of the respective amines for isopropylamine~

In similar manner the free acid compounds obt~ined in Examples 10 B-l (or 10 ~-2), 13, 17 and l9 can be converted into the corre~ponding isopropylamine, diethylamine, ethanol~mine, pipqridine, tromethamine, choline and caffeine ; ~alts.

:
' nqredientsQuantity_per tablet, mgs.
5-(2 thenoyl)-1,2-dihydro-3~-pyrrolo-~1,2-a]pyrrole-l-carboxylic acid25 cornstarch ~o lactose, spray-dried 153 magnesium stearate 2 The above ingredients are thoroughly mixed and pressed into single scored tablets.
.
EX~MPLE 27 IngredientsQuantity per tablet, mgs.
5-(2-thenoyl)-1,2 dihydro-3H-pyrrolo-[1,2-a]pyrrole-; l-carboxylic acid 200 cornstarch 50 lactose 145 ; magnesium stearate 5 The abo~e ingredients are mixed intimately and pressed into single scored tablets.
100 ~g. o~ -5~(2-thenoyl)-1,2-dihydro-3H-pyrr olc~[l,2-a~pyrrole-1-carboxylic acid is substituted for the 200 mg- of the (dl) compound of the above composition.

_~
i , ~ 30 ; - 57 - -4~
EXAMPLE: 2 8 In~redients Quantity per capsule, mgs.
potassitlm S- (2-thenoyl) -1, 2-dihydro- 3H-pyrrolo-11, 2-a] pyrrole l-car-bc~xylal:e 108 lactose 15 cornstarch 25 - magnesium stearate 2 The above ingredients are mixed and intro-duced into a hard-shell gelatin capsule.

~XAMPLE 29 Tn~rf~ nt~sQllantit~v per capsttJ.e, mgs~
calcium 5- ( 2-thenoyl) -1, 2-dihydro-3X-pyrrolo-[1,2-a]pyrrole-1-car-boxyl Ite 115 lactose 93 cornstarch 4 magnesium s tearate 2 The above ingredients are mixed and intro-deced into a hard-shell galatin capsule.
.._ ~', /

. ' /~
/

~ .

~ ~ .
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~ 58 --In~redientsQuanti_~ E~ let ! mgs.

isopropylammonium 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyxrole-l-carboxylate 245 cornstarch 75 lactose 175 magnesium stearate 5 The above ingredients are.mixed intimately - and pr ssed into single scored tablats~

Quantitv per ca~sule, mgs.

methyl 5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo-[1/2-a]
pyrrole l-carboxylate 25 lactose 125 The above ingredients are mixed and intro-duced into a ~o. 1 hard-shell gelatin capsule.

Qua~tity per tablet, m~s.
5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo-[1,2-a]pyrrole-l-carboxylic acid 300 sucrose 300 ; The above ingredients are thoroughly mixed and processed into single scored tablets, one tablet being administer~d every three to four hours.
3~
`' .. . .
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EX~MPLE 33 IngredientsQuant_~c~ tablet, m~s.
isoamyl 5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo-[1,2-a]
pyrrole-l-carboxyla~e 254 cornstarch 50 lactose 190 magnesium stearate Ç
The above ingredients are mixed intimately and pressed into single scored tablets.
'10 IngredientsQuantity per capsule, mgis.
5-(2)-the~oyl-1,2-dihydro-~-~ 3H-pyrrolo-~1,2-a]pyrrole-1 l-c2rboxylic acid 100 lactose 148 - dextrose 2 ~: The above ingredients aremixed and intxo-duced into a hard-shell gelatin capsule.
50 Mg. of (1)-5-(2-thenoyl)-1,2-dinydro-3~-pyrroloo~1,2-a]pyrrole-1-carboxylic acid is substituted for the lOOmg. o~ the ~dl) compound of thie above composi-tion.

: 25 .

~, /

~.
, ~ , , ~ .

: - 60 -..

InqredientsQuantity per capsule, m~s.
- methyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo~[1,2-a]
pyrrole-l-carboxylate158 : lactose 92 The above ingredients are mixed and intro-duced into a hard-shell gelatin capsule.

EXAMPT~ 36 IngredientsQuantity_~er tablet, mgs isoamyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]
pyrrole-l carboxylate 127 lactose 91 corn~tarch 25 magnesium stearate. 2 gelatin 5 The above inyredients are mixed and pressed into single ~cored tablets.

.

.

~X~MPL~ 37 In~redientsQuantity per tablet, mys.
calcium 5-(2-thenoyl)-l,2-dihydro-311-pyrrolo-[l,2~a]
pyrrole-l-carboxylate 230 cornstarch (paste)40 cornstarch 50 magnesium stearate2 lactose 178 The above ingredients are ~horol~ghly mixed and pressed into single scored tablets.

EX~MPLE 38 InqredientsQuantit~_eer tablet, mgs potassium 5-(2-thenoyl)-l,.2-dihydro-3H-pyrrolo-~l,2-a]
pyrrole-l carboxylate 217 cornstarch 50 magnesium stearate 2 gelatin 226 lactose Tn,e above ingredients a~e mixed intimately and pressed into single scored tablets.
.. ..... ....
//

,: 25 , ~

- : /

~

~ 62 -l4~

Ingredients Quantity per c~
isopropylammonium 5-(2-thenoyl) -1, 2-dihydro-3H-: pyrrolo-~1,2 a]pyrrole-l-carboxylate 122 cornstarch 3 o lactose 98 The above ingredients are mixed and introduced into a hard-shell gelatin capsule.
1~
EXA~PLE 40 ?ngredientsQuantity per capsule, mqs.
isoamyl 5- ( 2-thenoyl) -1, 2-dihydro-3EI-pyrrolo- ~1, 2-a]
pyrrole-l carboxylate32 lactose 101 cornstarch 15 mag~esium stearate 2 .
The above ingredients are mixed and intro-duced into a hard-shell gela~in capsule.
`---~

, / .

~' ' /
~ : ~ 25 .~ ~
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~. 30 .
~ - 63 -o~

An injectable preparation buffered to a - p~ of 7 is prepaxed having the followirlg composition:

5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo-[1,2-a3pyrrole-l-carboxylic acid 0.2 g K2ElPO4 bu~fer (0.4 M
solution) 2 ml.
KOH (lN) q.s. to p~7 water (distilled sterile) q.s. to 20 m}.
0.1 G. of (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrralo-[1,2-a~pyrrole~l-carboxylic acid is ubstituted for the 0.2g. of the (dl) compound of the above composi-tion.

EX~MPLE 42 A suppo~itory totaling 2.8 grams is pre-pared having the ~ollowing composition:

5-(2-~henoyL)-1,2-di~ydro-3H-pyrxolo-[1,2-a]pyrrole-l~carboxylic acid 25 mg.
Witsps~l ~-15 (triglycerides of satu-rated vegetable ~atty acids; a product of Richeq-Nelso~, Inc., New York, N.Y.) balance ~ 12.5 ~g. of (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid is substituted for the 25 mg. of the (dl) cornpound of the above compo-sition.

~X~PLE 43 An oral su~pensio~ for pediatric use is prepared having the following composition.

5-(2-thenoyl)-1,2-dihydro~3H-pyrrolo-[1,2-a]pyrrole-1-car-boxylic acid O~l 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 K (Vanderbilt Co.) 1.0 g.
fla~orins 0.035 ml.
colorings 0.5 mg.
distilled water ~.s. to 100 ml.
0.05 G. o (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid i5 sub~tituted for the 0.1 g. of the (dl) compound of ~he above compo-~; sition.

. ~ :
:
EX~PLES 44-45 Powdered top dressings for veterinary uie are prepared having the ~ollowing compositions:
~. i Ex. 44 Ex. 45 5-(2-thenoyl)-1,2-dihydro-3~-pyrrolo-[1,2-a]pyrrole-l-carboxylic ac-d 0.1 g. 1,2 g.
` :25 suc~ose 5.7 g. 3.7 gO
polyvinyl pyrrolidone 0.3 g. 0.3 g.
0.05 G. o~ 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-~1,2-a]pyrrole-1-carboxylic acid i~ substituted ~or the 0.1 g. of the (dl) compound of the compo~ition of Example 44.
0.6 G. of (1) 5-~2-thenoyl)-1,2-dihydro-::
~ ~5 --~ [l 2-alpyrrole- = acid ~s sub tltUt d .- .
. .

EXA~PLE 46 BIODATA
A. Mouse Analgesic (Anti-writhing) Assay Protocol: The test material is administered orally S by gavage in an a~ueous vehicle at time 0 to 18 20 gram male Swiss~Nebster mice. Twenty minutes later 0.25 ml. o~ a 0.02% solution of phenylquinone i9 injected intraperitoneallyO
This solution induces writhing. The animals are then observed during the next 10 minutes for writhing.~
End point: The total number o~ mice that writhe and the average number of writhes per mouse.
Using The above protocol i.t is determin~d tha-~ 5-(2-thenoyl~-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid has approximately 350 times the analgetic activity of aspirin; and ~ 5-(2-thenoyl)-1,2-dihydro-3~-pyrrol~[1,2-a]
pyrrole-l-carboxylic acid has 670 times the analgetic acti-vity o~ aspixin.
B. Test ~or A~i-Infl = atory Activity Utilizing Carra-. . .
~geenin Indu~ed Paw Inflammation in the Rat Protocol: Simonsen ~emale rats weighing 80-90 grams :
are used. The test materials are given at hour 0 orally by gavage in l ml.~ of aqueous vehicle. At hour 1, 0.05 ml. of a l~;soIution (in 0.9~ NaCl) of carrageenin is injected into the right hind pawO This injection causes an inflammation o~ the paw. The~ rats are sacrificed at hour 4, at which time both hind paws are removed and weighed separately.
End point: % increase in paw size calculated as follows:

~ ~30 Wt O~ Le~tpPaw-Wt. o~ Left Paw X l00 ; -6~-;

; Using ~he above protocol it is determined that 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-car-boxylic acid has 48 (95~ confidence limits:32-72) times the anti~inflammatory activity of phenylbutazone.
- 5 C. Test for Anti-Pyretic Activity Protocol: Simonsen ~emale rats weighing 90-100 grams - are used. The "normal" rectal ~emperature of the rats i5 recorded at hour 0, followed by the injection of 2 ml. of a - yeast suspension subcutaneously (1 ml. dorsally, 1 ml. ven-trally). The injectio~ sites are massaged to spread the suspenion beneath the skin. The yeast injec~ion induces elevated body temperature (pyresis). At hour 17 the rats -; are massaged again to stimulate a further increase in body temperature. At hour 18 the second rectal temperature is recorded, after which the test material is administered - orally by gavage in 1 ml. aqueous ~ehicle. The third rectal temperature is obtained 2 hours after administration of the test material.
End point: The reduction in temperature (F) from ~ the second to the third temperature readings.
Using ~he above protocol it is determi~ed that 5-(~2-thenoyl)-1,2~dihydro-3H-pyrrolo[1,2-aJpyrrole-l-carbox-- ylic acid has 17 times the anti-pyretic activity of aspirin.
D. ~ouse Acute Oral Toxicity (LD50) Pxotocol: The test material is suspended in 2%
agueous starch. Concentration~ are adjusted so t~at doses can be given in volumes of 0.1 ml./10 g. body weight. Six groups (comprising six Swiss-Webster ~emale mice in each group) of rnice are used. A single oral dose, by stomach tube, per kilogram of body weight, of either 50 mg., 100 mg., 200 mg., 400 mg., 800 mg., or 16Q0 mg. of 5-(2-thenoyl)-1,2-dihydxo-3~-pyrrolo[1,2-a~pyr~ole-1-c æboxylic acid is ad-ministered to the mice. A~ter adminictration the mice are - observed 4Or a two week period.
Using ~he above prot w ol, the acute oral LD50 of 5-~2-thenoyl)~1,2-dihydro-3~-pyrrolo~1,2-a~pyrrole-1-carboxylic acid is esti~ated to be 631 mg./kg. with a 95% confidence e~ of~4~0~,4~,!tu;99~

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:'.
:

Claims (102)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OF PRIVILEGE IS CLAIMED ARE DESCRIBED AS FOLLOWS:

1. A process for producing a compound of the formulas:

(A) (B) or the individual (1)-acid and (d)-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein X is oxygen or sulphur, R is hydrogen or a lower alkyl group having from 1 to 4 carbon atoms and R1 is hydrogen, methyl, chloro or bromo, the R1-substitution in the compounds of Formula (A) being at the 3, 4 or 5 positions of the furan or thiophene ring, which comprises one or more of the following steps:
a) condensing a compound of the formula:

wherein R is as defined above and R2 is a lower alkyl group of 1 to 4 carbon atoms, with an amide elected from the group of those represented by the formulas:
and wherein X and R1 are as defined above, thereby yielding the corresponding compounds of the formulas:

wherein R, R1, R2 and X are as defined above;
(b) hydrolyxing an alkyl ester group thereby yielding the free acids of Formulas (A) or (B);
(c) separating the free acids of Formulas (A) or (B) into their corresponding respective (1)-acid isomers and (d)-acid isomers;
(d) racemizing the (d)-acid isomers or the salts thereof, to the corresponding respective compounds of Formulas (A) or (B);
(e) optionally esterifying the carboxylic acid function in the compounds of Formulas (A) or (B) or the (1)-acid isomers or (d)-acid isomers thereof or converting each of them into their pharmaceutically acceptable, non-toxic salts;
(f) converting the salts of Formulas (A) and (B) and the individual isomers thereof, to the corresponding free acids.

2. The process of claim 1, in which the condensation is effected in the presence of phosphorous oxychloride.

3. A process of claim 1, wherein X is oxygen.

4. A process of claim 1, wherein X is sulphur.

5. A process of claim 1, wherein R is hydrogen.

6. A process of claim 1, wherein R is methyl.

7. A process of claim 3, for preparing compounds of Formula (A).

8. A process of claim 7, wherein steps (a) and (b), R and R1 are both hydrogen to prepare 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.

9. A process of claim 8 wherein step (e) the prepared compound is esterified to give the isopropyl ester thereof.

10. A process of claim 7, wherein R is hydrogen and R1 is methyl.

11. A process of claim 7, wherein R is hydrogen and R1 is chloro.

12. A process of claim 7, wherein R is hydrogen and R1 is bromo.

13. A process of claim 4 for preparing compounds of Formula A.

14. A process of claim 13 wherein steps (a) and (b), R
and R1 are both hydrogen to prepare 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.

15. A process of claim 14, wherein step (e) the prepared compound is esterified to give the ethyl ester thereof.

16. A process of claim 13, wherein R is hydrogen and R
is methyl.

17. A process of claim 13, wherein R is hydrogen and R1 is chloro.

18. A process of claim 17, wherein steps (a) and (b) the R1-substitution is at the C-4 position of the thiophene ring to prepare 5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid.

19. A process of claim 18, wherein steps (e) the prepared compound is esterified to give the isopropyl ester thereof.

20. A process of claim 17, wherein steps (a) and (b), the R1-substitution is at the C-5 position of the thiophene ring to prepare 5- (5-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid.

21. A process of claim 19, wherein step (e) the prepared compound is esterified to give the isopropyl ester thereof.

22. A process of claim 13, wherein R is hydrogen and R
is bromo.

23. A process of claim 3 for preparing compounds of Formula B.

24. A process of claim 23, wherein steps (a) and (b), R
is hydrogen to prepare 5-(3-furoyl)1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid.

25. A process of claim 4 for preparing compounds of Formula B.

26. A process of claim 25, wherein steps (a) and (b), R is hydrogen to prepare 5-(3-thenoyl)1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid.

27. A process of claim 1, wherein steps (a), (b) and (e) sodium, potassium or calcium salts of the compounds are pre-pared.

28. A process of claim 27, wherein steps (a), (b) and (e) R and R1 are both hydrogen and X is sulfun to prepare 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.

29. A process of claim 27, wherein steps (a), (b), (c) and (e), R and R1 are both hydrogen and X is sulfun to prepare sodium 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate.

30. A process of claim 1 for preparing (1)-acid isomers of Formulas (A) or (B) according to steps (a), (b) and (c).

31. A process of claim 30, wherein steps (a), (b) and (c) R and R1 are both hydrogen.

32. A process of claim 31, wherein steps (a), (b) and (c) wherein X is sulfur for preparing (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1- carboxylic acid.

33. A process of claim 1 for preparing sodium, potassium or calcium salts of an (1)-acid isomer of Formulas (A) or (B) according to steps (a), (b), (c) and (e).

34. A process of claim 33 wherein steps (a), (b), (c) and (e), R and R are both hydrogen and X is sulfur to prepare (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.

35. A process of claim 33, wherein steps (a), (b),(c) and (e), R and R1 are both hydrogen and X is sulfur to prepare sodium (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.

36. A compound selected from the group of those represented by the formulas:

(A) (B) and the individual (1)-acidisomers and (d)-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein X is oxygen or sulphur, R is hydrogen or a lower alkyl group having from 1 to 4 carbon atoms and R1 is hydrogen, methyl, chloro or bromo, the R1-substitution in the compounds of Formula (A) being at the 3,4 or 5 positions of the furan or thiophene ring, when prepared by the process of claim 1.

37. A compound of claim 36, wherein X is oxygen, when prepared by the process of claim 3.

38. A compound of claim 36, wherein X is sulphur, when prepared by the process of claim 4.

39. A compound of claim 35, wherein R is hydrogen, when prepared by the process of claim 5.

40. A compound of claim 36, wherein R is methyl, when prepared by the process of claim 6.

41. A compound of claim 36, Formula (A), wherein X is oxygen, when prepared by the process of claim 7.

42. The compound 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, when prepared by the process of claim 8.

43. The isopropyl ester of the compound of claim 42, isopropyl 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, when prepared by the process of claim 9.

44. A compound of claim 36, Formula (A), wherein R is hydrogen, R1 is methyl and X is oxygen, when prepared by the process of claim 10.

45. A compound of claim 36, Formula (A), wherein R is hydrogen, R is chloroand X is oxygen, when prepared by the process of claim 11.

46. A compound of claim 36, Formula (A), wherein R is hydrogen, R1 is bromo and x is oxygen, when prepared by the process of claim 12.

47. A compound of claim 36, Formula (A), wherein X is sulfur, when prepared by the process of claim 13.

48. The compound 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid, when prepared by the process of claim 14.

49. The ethyl ester of the compound of claim 43, ethyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxy-late, when prepared by the process of claim 15.

50. A compound of claim 36, Formula (A), wherein R is hydrogen, R1 is methyl and X is sulfur, when prepared by the process of claim 16.

51. A compound of claim 36, Formula (A), wherein R is hydrogen, R1 is chloro and X is sulfur, when prepared by the process of claim 17.

52. The compound 5-(4-chloro-2-thenoyl)1,2-dihydro-3H-pyrrolo[1,2 a]pyrrole-1-carboxylic acid, when prepared by the process of claim 18.

53. The isopropyl ester of the compound of claim 52, isopropyl 5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate, when prepared by the process of claim 19.

54. The compound 5-(5-chloro-2-thenoyl)1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, when prepared by the process of claim 21.

55. A compound of claim 36, Formula (A), wherein R is hydrogen, R1 is bromo and X is sulfur, when prepared by the process of claim 22.

56. A compound of claim 36, Formula (B), wherein X is oxygen, when prepared by the process of claim 23.

57. The compound 5-(3-furoyl)1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, when prepared by the process of claim 24.

58. A compound of claim 36, Formula (B), wherein X is sulfur, when prepared by the process of claim 25.

59. The compound 5-(3-thenoyl)1,2-dihydro-3H-pyrrolo(1,2-a]-pyrrole-1-carboxylic acid, when prepared by the process of claim 26.

60. A sodium, potassium or calcium salt of the compounds according to Formulas (A) or (B) of claim 36, when prepared b y the process of claim 27.

61. The compound potassium 5-(2-thenoyl)1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, when prepared by the process of claim 28.

62. The compound, sodium 5-(2-thenoyl)-1,2-dihydro-3H-pyrollo[1,2-a]pyrrole-1-caxboxylate, when prepared by the process of claim 29.

63. An (1)-acid isomer of Formulas (A) or (B) of claim 36, when prepared by the process of claim 30.

64. A compound of claim 36, the (1)-acid isomer of Formulas (A) or (B), wherein R and R1 are both hydrogen, when prepared by the process of claim 31.

65. The compound (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid, when prepared by the process of claim 32.

66. A sodium, potassium or calcium salt of an (1)-acid isomer of Formulas (A) or (B) of claim 36, when prepared by the process of claim 33.

67. The compound potassium (1)-5-(2-thenoyl)-1,2-dihydro-3H pyrrolo[1,2-a]pyrrole-1-carboxylate, when prepared by the process of claim 34.

68. The compound, sodium (1)-5-(Z-thenoyl)1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1 carboxylate, when prepared by the process of claim 35.

69. A process of claim 1, wherein a compound prepared by selected steps (a) through (f) is mixed with a pharmaceu-tically acceptable carrier.

70. A process of claim 3, wherein a prepared compound for X as oxygen is mixed with a pharmaceutically acceptable carrier.

71. A process of claim 4, wherein a prepared compound for X as sulfur is mixed with a pharmaceutically acceptable carrier.

72. A process of claim 5, wherein a prepared compound having R as a hydrogen is mixed with a pharmaceutically acceptable carrier.

73. A process of claim 6, wherein a prepared compound having as methyl is mixed with a pharmaceutically acceptable carrier.

74. A process of claim 7, wherein prepared compounds of Formula (A) are mixed with a pharmaceutically acceptable carrier.

75. A process of claim 8, wherein the prepared compound 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is mxied with a pharmaceutically acceptable carrier.

76. A process of claim 9, wherein the isopropyl ester compound is mixed with a pharmaceutically acceptable carrier.

77. A process of claim 10, wherein the prepared compound is mixed with a pharmaceutically acceptable carrier.

78. A process of claim 11, wherein the prepared compound is mixed with a pharmaceutically acceptable carrier.

79. A process of claim 12, wherein the prepared compound is mixed with a pharmaceutically acceptable carrier.

80. A process of claim 13, wherein the prepared compounds of Formula (A) are mixed with a pharmaceutically acceptable carrier.

81. A process of claim 14, wherein the prepared compound 5(2-thenoyl)1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is mixed with a pharmaceutically acceptable carrier.

82. A process of claim 15, wherein the prepared ethyl ester compound is mixed with a pharmaceutically acceptable carrier.

83. A process of claim 16, wherein the prepared compound is mixed with a pharmaceutically acceptable carrier.

84. A process of claim 17, wherein the prepared compound is mixed with a pharmaceutically acceptable carrier.

85. A process of claim 18, wherein the prepared compound 5(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrollo[1,2-a]pyrrole-1-carboxylic acid is mixed with a pharmaceutically acceptable carrier.

86. A process of claim 19, wherein the prepared isopropyl ester compound is mixed with a pharmaceutically acceptable carrier.

87. A process of claim 20, wherein the prepared compound 5-(5-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is mixed with a pharmaceutically acceptable carrier.

88. A process of claim 21, wherein the prepared isopropyl ester compound is mixed with a pharmaceutically acceptable carrier.

89. A process of claim 22, wherein the prepared compound is mixed with a pharmaceutically acceptable carrier.

90. A process of claim 23, wherein the prepared compounds of Formula (B) are mixed with a pharmaceutically acceptable carrier.

91. A process of claim 24, wherein the prepared compound 5-(3-furoyl)1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is mixed with a pharmaceutically acceptable carrier.

92. A process of claim 25, wherein the prepared compounds of Formula B are mixed with a pharmaceutically acceptable carrier.

93. A process of claim 26, wherein the prepared compound 5-(3-thenoyl)1,2-dihydro-3H-pyrrolo[1,2-a]pyrrolo-1-carboxylic acid is mixed with a pharmaceutically acceptable carrier.

94. A process of claim 27, wherein the prepared salt compounds are mixed with a pharmaceutically acceptable carrier.

95. A process of claim 28, wherein the prepared compound 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxy-late is mixed with a pharmaceutically acceptable carrier.

96. A process of claim 29, wherein the prepared compound 5-(2-thenoyl)-1,2-di,hydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxy-late is mixed with a pharmaceutically acceptable carrier.

97. A process of claim 30, wherein the prepared (1)-acid isomers of Formulas (A) or (B) is mixed with a pharmaceutically acceptable carrier.

98. A process of claim 31, wherein the prepared aompound is mixed with a pharmaceutically acceptable carrier.

99. A process of claim 32, wherein the prepared compound (1)-5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is mixed with a pharmaceutically acceptable carrier.

100. A process of claim 33, wherein the prepared salts of the (1)-acid isomers are mixed with a pharmaceutically acceptable carrier.

101. A process of claim 34, wherein the prepared compound (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is mixed with a pharmaceutically acceptable carrier.

102. A process of claim 35, wherein the prepared compound (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is mixed with a pharmaceutically acceptable carrier.