CS208724B2 - Method of making the 5-(2-furoyl)-,5-(2-thonoyl)-,5-(3-furoyl) a 5-(3-thenoyl)-1,2-dihydro-3h-pyrrol/1,2-a/pyrrol-1-karboxyl acid derivatives - Google Patents

Abstract

Carboxylic acid esters of the formula <IMAGE> are prepared by condensation of a compound of the formula <IMAGE> with an amide of the formula <IMAGE> In the formulae, X represents oxygen or sulphur, R represents hydrogen or C1-C4-alkyl, R<1> represents hydrogen, methyl, chlorine or bromine and R<2> represents C1-C4-alkyl. Hydrolysis of the carboxylic acid esters results in the corresponding carboxylic acids and their salts. The compounds are novel and exhibit an anti inflammatory, analgesic and antipyretic action. They are suitable in particular for treating inflammations, pain and febrile conditions.

Description

The invention relates to a process for the preparation of novel pyrrole-1-carboxylic acids.

In particular, the present invention relates to novel 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids substituted at the C-5 position with 2-furoyl, 2-thenoyl, 3-furoyl or 3-thenoyl which have the general formula I,

(I) and especially the 1-isomers and d-isomers of the acid and the pharmaceutically acceptable non-toxic esters and salts. X is oxygen or sulfur, R1 is hydrogen, methyl, chlorine or bromine. R ¹ -substitution in the moiety 9 is 3,4 or 5 of the furan or thiophene ring. When the carbonyl is bonded at the 3-position of the furan or thiophene ring, R 1 is hydrogen. R is hydrogen or (C1-C4) -alkyl.

The compounds of the invention described above and in more detail below, with the exception of the d-isomers of acids and derivatives thereof, have anti-inflammatory, analgesic and antipyretic effects and are therefore useful in the treatment of inflammation, pain and / or pyrexia (long-lasting fever) described in detail below. They are also smooth muscle relaxants.

The term "pharmaceutically acceptable non-toxic esters and salts" is used herein to refer to alkyl esters derived from linear or branched hydrocarbons having from one to twelve carbon atoms and salts derived from pharmaceutically acceptable non-toxic inorganic and organic bases.

Typical alkyl esters are formed using the residues methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isosyl, pentyl, isopentyl, hexyl, octyl, noryl, isodecyl, 6-methyldecyl and dodecyl.

Salts derived from inorganic bases include potassium, sodium, lithium, ammonium, calcium, magnesium, ferrous and ferric salts, zinc salts, media, manganese, aluminum. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary and tertiary amines, substituted amines, including naturally occurring ^4- substituted substituted amines, cyclic amines, and basic ion exchange resins such as, for example, iso. βθ,,, diethylamine, triethylamium, uripoopylamine, ethanolamine, 2-dimethylamine 181-4% 0-8,2,2-diethylaminomethanol, Uromeamine, lysine, arginine, histidine, caffeine, procaine; hydrabamine, choline, betaine, ethylenediamine, glucosamine, methanol / glucamine, purines, piperazine, piperidine, N-thypiperidine, amine resins and so on. Particularly preferred are isopropylamine, diethylamine, ethane-4-piperidine, Uromethamine, choline and caffeine.

The novel compounds of formula (I) described below are present as pairs of optical isomers (or as a mixture of 1- and d-isomers. Each of these two isomers as well as a mixture thereof fall within the scope of the invention.

When the novel compounds of the present invention are used to elicit a physiological response (e.g., an anti-inflammatory, anelgesic or allutetric effect) when used as medicaments, the compounds of formula (I) are preferred. I, their 1-isomers and their esters and pharmaceutically acceptable sele.

The essence of the process for the preparation of 5- (2 - [(3-furoyl)] and 5- (3-thnoyl) -1,2-SihtSro-3H-ωtroO / 1,2-a / ptrrcll1- acid derivatives of the general formula I

(I), or individual isomers 1 and d isomers and pharmaceutically nontoxic pijatelrých est ^er s ^with di and wherein X is sulfur ^{Neto, R1} is hydrogen ^with methyl ^yl CHLC Neto ^b ^ ^{rom price R1} -substituce it is at position 3,4 or 5 of a furan or thiophene cycle, with the proviso that R ^{1 is a} hydrogen when in ^ AN ^ furan cradle ^{3 Star} it Neto t ^ o ^ lcfonov cykl'u, and ^R is hydrogen or alkyl having 1 to 4 carbon atoms according to the invention, characterized in that they condense the compounds of the general formula X

(X) o

wherein R is as defined above and R is C 1 -C 4 asylum, with an amide of formula XIII,

R ¹ - ^ JJ-CON (CH _{3) 2} (XIII), X and k d ^e R * ^ in maj výwiam DENY above to ignite disconnects ^ Daiichi otocrého composite. formula XI,

COOR1 (XI)

Wherein R, R, R and X are as defined above. The alkyl ester groups are hydrolyzed to give the free acid of formula I. Optionally, the free acids of formula I are separated into their 1-isomers and d-isomers, or optionally the racemized d-isomer of acids or salts thereof to the corresponding compounds of formula I. For example, the carboxyl group of the compounds of formula (I) is esterified, or the carboxyl group of the 1-isomer or the d-isomer of formula (I) is esterified, or each is converted into a pharmaceutically acceptable non-toxic salt. Optionally, salts of formula I or salts of individual isomers of formula 1 are converted to the corresponding free acids.

The d-isomers of acids of formula I and their esters and pharmaceutically acceptable salts are also useful as intermediates in the preparation of dl-acids of formula I, as described in more detail below.

The novel dl-compounds of the invention can be produced as illustrated by the following reaction sequence:

OH

.___ COOCH3

ДХ. / ^С00Сн з

AND

H ₂ C-CH 3

I OH (IV) ^R .____> COOCH ₃ чД ^ соосиз

AND

CH ₂

AND

1H ₂ C

Wherein X, R, and R are as defined above and R is a lower alkyl group having from 1 to 4 carbon atoms, i.e., for example, methyl, ethyl, isopropyl or n-butyl.

In the process described above, for the preparation of a compound of formula IV wherein R is hydrogen, the reaction of etavimoococular amounts of ethanolamine and dimethyl 1,3-acetone dicarboxylate is carried out at a temperature of about 0 ° C to the ambient temperature to give a vinylamine solution. of formula (III), which is then treated, preferably in situ, in a suitable inert organic solvent, under anhydrous conditions, with 2-broccacetaldehyde / d 2 or 2-chloroacetyl aldehyde at a temperature of about 40 to 100 ° C for about 30 minutes to about 16 hours. Roozpolšёdla which are suitable for this reaction are aprotic solvents such as 610X11 ^ ^ 11 tetral'yгlrsflran, dim tho ^ ^^ ^{(^,} ^ han, chloroform, dichloromethane and the like. The reaction is preferably carried out in solution acetsnitri0ovéž The 2-bromo (Clhor) acetaldehyde reagents are known compounds or can also be prepared by pyrolysis of the corresponding diethyl acetals in the presence of scalic acid hydrate.

For the preparation of compounds of formula (IV) wherein R is a lower alkyl group, preferably straight chain, having 1 to 4 carbon atoms, an aqueous mixture of ethanolimine and dimethyl 1, 4-acetone / carboxy is treated with the compound. of the general formula

R ³ - $ - CH ₂ X wherein X ^j e bromo or chloro and ^R3 is it ^{harder for} asylum with ^LPIN, with an effluent ^p i ^'my řetěícem, žciÍíc! from 1 to 4 carbon atoms, most preferably 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-bromo-2-hexanone, at a temperature of about 40 ° C to about 100 ° C to from about 30 minutes to about 16 hours. Preferably, the reaction is carried out at a temperature of from -10 ° C to room temperature for about 1 hour to about 6 hours. Reagents

R ³ -C-CH, X ft ² .

are known compounds.

Esterification of compounds of formula IV with methanesulfonyl chloride in the presence of a tertiary amine, i.e. triethylamine, pyridine, etc., optionally in the presence of a cosolvent such as dichloromethane, and at a temperature of -10 ° C to room temperature for about 10 minutes to about 2 hours The corresponding mesylate of formula V is formed, which is then converted to the corresponding N- (2-iodoethylpyrrole of formula VI by reaction with sodium iodide in acetonitrile solvent at reflux for one to ten hours.

Reaction of the iodoethyl compounds of formula VI with sodium hydride in a suitable inert organic solvent such as dimethylformamide affords dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate and its 6 -alkyl substituted derivatives of formula VII. The cyclization is carried out under an inert atmosphere, i.e., under argon or nitrogen, at a temperature of the order of about 15 ° C to about 40 ° C for about 15 minutes to about 4 hours. Best results are obtained when the reaction is carried out at room temperature for about 30 minutes when R is hydrogen.

Alternatively, compounds of formula VII can be prepared by direct cyclization of the mesylate of formula V with sodium hydride in dimethylformamide solution at a temperature of from -10 ° C to room temperature, for a period of from 30 minutes to about 2 hours.

Basic hydrolysis of compounds of formula VII with an alkali metal hydroxide or carbonate such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate and the like in an aqueous lower aliphatic alcohol such as methanol or ethanol at a temperature from room temperature to reflux temperature to from about 4 to about 24 hours gives the corresponding free dibasic acid of formula (VIII), i.e., 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and its 6-alkyl derivatives. The hydrolysis is preferably carried out with aqueous methanolic potassium hydroxide at reflux for about 10 hours.

The carboxylic acid group is then selectively esterified by treatment with a lower aliphatic alcohol, such as methanol, ethanol, isopropanol, n-butanol, and the like, in the presence of hydrogen chloride to give alkyl-1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid of formula IX. The reaction is carried out at a temperature of about 0 ° C to about 50 ° C for 1 to 4 hours.

The decarboxylation of the monoesterified compound of the formula IX to the corresponding compound of the formula X is carried out by heating the compound of the formula IX to a temperature of about 230 ° C to 280 ° C for a sufficient time to complete the reaction. This reaction represents a key site for the preparation of the compounds of the invention. After the reaction, carbon dioxide evolution and thin layer chromatography can be performed, and the reaction is usually complete in about 45 to 90 minutes. The reaction product, alkyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and its 6-alkyl derivatives of formula (X), can be purified by chromatographic techniques. It is also possible, especially in the case of small batches of the compound of the formula IX, to distill the reaction product of the formula X directly from the reaction vessel.

Condensing a compound of formula X with an amide of the formulas'<Д * CON (CH _{3) 2} or

wherein X and R 1 are as defined above, gives the corresponding alkyl 5-substituted-1,2-dihydro-3H

-pyrrole- (1,2-a) pyrrolecarboxylate of formula XI or XII.

This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride, at reflux for 1 to 72 hours, under an inert atmosphere, followed by an additional reflux in the presence of sodium acetate for about 2 to 10 hours. Instead of phosphorus oxychloride, another chlorinated acid such as phosgene or oxalyl chloride may be used.

Preferably, the condensation is carried out by adding a solution of the compound of formula X in a suitable solvent to a mixture of 1.1 to 2 molar equivalents of the desired amide and phosphorus oxychloride in the same solvent previously distilled at reflux temperature and then distilled at reflux for about 2 to 80 hours in an argon atmosphere; about 8 to 10 molar equivalents of sodium acetate are then added and distilled at reflux for about 4 to 6 hours.

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

Representatives of Ν, Ν-dimethylamides that can be used are:

N, N-dimethylthoeen22-arbloxamide, N, N-dimethylethane-4-carboxamide,

N, N-ddmeethl-3-methoxyhthiophene-2-carboxamide, _ч

4-Ineetylthiophene-2-carboxamide,

N, N-dSmeetyl-5-meetylthiophene-2-carboxamide, N, N-dSiethyl ---- hhlsthisfen-2-carboxamide,

N,] Ndiûeteyh-5 - ihosthiof e-2-carboxamiS,

N, N-Dimethyl-3-bromothiophene-2-carboxamide, N, N-dSmeeth ^r -Bromothiophene-2-carboxamide, N, N-Dimethyl-3-meetylfuran-2-carboxamide, Ν-Ν - Ηπ ^ 1 ^ 1- 4-meetylfuran-2-carboxamide, N, N-dSmeeth114-chlorofuran-2-cabboxamide,

-2-carboxamide,

N, N-di-methyl-4-bromofural-2-carbsxamide,

N, N-dimethyl-bromofuran-2-carboxamide,

N, N-dimethythiophene-1-carboxamide,

N, N-Dimethylfuran-J-carboxamide.

These amides can be prepared from the corresponding thiophene or furanedd (3) - ‘carboxylic acids in a conventional manner, i.e. by conversion to the acid chloride followed by treatment with dimethylamine. .

Alkaline hydrolysis of alkyl ester groups in compounds of formulas

XI or XII are obtained by deposition of free acids of formulas I or Ia. The hierolysis is carried out in a conventional manner, i.e., with an alkali metal or alkali metal hydroxide, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous lower aliphatic alcohol such as methanol, ethanol and the like at about room temperature to about room temperature. of reflux temperature, for about 30 minutes to 4 hours and in an inert atmosphere. Preferably, the hydrolysis is carried out with aqueous methanolic. potassium hydroxide at reflux for about 2 hours.

The compounds of formulas I and Ia may be resolved by methods known to those skilled in the art to obtain de-oxidizing optical isomers. For example, compounds of general interest.

^VZO r ^ce I kd ^e R and R ¹ are both hydrogen and X is sulfur, tyt processed by ff ^ TO, THE ^- smb diagram:

split

N-1-isomer-d-amphetamine salt ⁱⁿ N-1-isomer

Mixture

Д-d-isomer-d-amphetamine salt <>

N, N-1-isomer-d-amphetamine salt,

A more detailed description of this procedure is given below in Example 10 B-1.

Similarly, the 1-isomers and d-isomers of acids of formulas I and Ia can be obtained using the known high pressure liquid chromatography (HPLC) technique for alpha-phenethyldiastereoisomeric esters of compounds of formulas I and Ia, followed by acidic resolution. For example, compounds of formula I wherein R ¹ and R ¹ are hydrogen and X is sulfur may be treated as follows:

A more detailed description of this procedure is given below in Example 10 B-2.

The free acids of formulas I and Ia may be converted to alkyl esters having from 1 to 12 carbon atoms by conventional methods, for example by treatment with (a) an alcohol corresponding to the desired ester in the presence of a strong acid, (b) an ethereal diazoalkane or (c) the desired alkylthody in the presence of lithium carbonate. The 1-isomers can be converted into your alkyl esters by the above methods (b) and (c).

The derivatives of the compounds of the formulas I and Ia, which are salts and their 1-isomers, are prepared by treatment with an appropriate amount. pharmaceutically acceptable bases to the free acids of formulas I and Ia. Preferred pharmaceutically acceptable bases are sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, alumina, manganese, M-initium, selesium, istortoylamine, irimittyltine, lithium, irppoopylamine, ethanol. dimetbylaminethinol, 2-dimethylaminoltinol, lysine, arginine, histidine, caffeine, provin, hydrnbamine, betain, ethylenediamine, glucose-trimethylglucaine, paraffin, piperazine 'N-Ethylpiperidine polyamine resins' and so on.

The reaction is conducted in water, either alone or with an inert water komminaci mísitenným or anickým RTZ ^{g of} ousia ^{EI hem p} s at about ⁰ ° C to about ¹⁰⁰ ° C, preferably ^p s míssnoosi temperature. ^Ype ical inert, water msi availably iitltΘtlnO solvent is ethanol, ittortotnol, butanol, acetone, or n-dÍLox ittrahyirtfuгtn. The molar ratio of the compounds of the formulas I or Ia or their 1-isomers relative to the same base is chosen so as to achieve the ratio required for the lithium salt.

For example, in the manufacture of salts. of the calcium or magnesium compounds of the formulas I or Ia or their 1-isomers, the starting free acid may be treated with at least one-half of the equivalent of a pharmaceutically acceptable base to obtain the neural salt. In the production of aluminum salts, at least one-third of the pharmaceutically acceptable base must be used to achieve the neuronal salt.

In the preferred process, the calcium and magnesium salts of the compounds of formulas I and Ia and their 1-isomers may be obtained by treating at least one half molar equivalent of calcium chloride or sodium chloride on the sodium or potassium salts of the compounds of formulas I or Ia or their 1- t ^ mery, either in the water, either alone, or in СппЬпвс! with an inert water-miscible organic solvent at a temperature of from 20 ° C to ¹⁰⁰ ° C. Aluminum with ^about ye ^e Uve ^ NYCHA composites can be the winnings obtained by the action of at least one third m ^ oi ^ irní ^ h ^ o equivalent alcoholate hliniéého, lacO is aluminum irOptootxii alumina and the like., To tdiooíditjcí free acids of formulas I or Ia or L-isomers, in a hydrocarbon solvent Цп-benzene, xylene, cyklthtxnn, ^ ^p ^ s from a temperature ^of from ²⁰ ° C to about 115 ° C. Pldo ^b n ^{e o y} axes ^and the CS may ^b YT prnžKy for producing show. inorganic bases which are not sufficiently soluble to carry out an easy reaction.

It will be appreciated that i.a. depressions of the compounds described herein may be performed by a separation or purification process, such as extraction, filtration, evaporation, distillation, crystallization, thin-layer or thin-film chrtiatigge, high-pressure liquid itroatography or a combination thereof. . Illustrations of suitable separation and isolation procedures can be found in the examples below. Other equivalent separation or isolation procedures can also be used coolantly.

While the i-isomers are not themselves used as medicaments, they can, if necessary, be converted into their pharmaceutically acceptable non-toxic esters and salts by the methods described for converting the 1-isomers into their pharmaceutically acceptable non-toxic esters and salts.

The compounds of formulas (I) and (Ia) and their 1-isomers and their pharmaceutically acceptable toxic esters and salts are used as anionic agents, and anaagetic agents, blood clotting inhibitors, fibrinolithic agents, smooth muscle cells. These compounds can be used both prophylaxisally and therapeutically. .

Compositions containing these compounds are thus useful in the treatment and elimination of inflammation. Such as, for example, those of the muscular skeletal system, joints, and other tissues, for example in the treatment of inflammatory conditions such as rheumatism, concussions, arthritis, cosmic fractures, posttraumatic conditions, and diny. In those cases where pain and pyrexia are associated with the above conditions, fast-acting compounds are useful for alleviating these conditions as well as inflammation.

The administration of the active compounds of the formulas I and Ia or their 1-isomers and their pharmaceutically acceptable non-toxic esters and salts in a suitable pharmaceutical composition can be carried out by any of the methods used in the treatment of inflammation, booessia or pyrexia or prylactic use. For example, administration may be by oral, parenteral or topical administration, in the form of a solid, semi-liquid or liquid, for example, as tablets, suppositories, pills, powders, solutions, suspensions, emulsions, creams, lotions, maasi and the like. in a dosage form suitable for simple administration of precise dosages. They will contain conventional pharmaceutical carriers and the active compound of formula (I) or (Ia) or its 1-isomer or a pharmaceutically acceptable non-toxic ester or salt, and may additionally contain other pharmaceutical or therapeutic agents, carriers, excipients, etc.

A preferred method of administering ppi above conditions is oral administration of a suitable daily dosage, which may be adjusted to one degree. Usually, a daily dose of from 25 mg to 500 mg of an active compound of the formula I or Ia or a 1-isomer thereof is used and is used pharmacologically in conjunction with nontoxic esters and salts thereof. In most cases, it is used in the treatment of a daily dose of the order of 0.5 to 6 mg per kioogaam body mass per day. For such oral administration, the pharmaceutically acceptable non-toxic mixture is formed using conventional excipients, such as any of the pharmaceutical types of mannitol, lactose, starch, magnesium stearate, sodium saccharin, chalk, cellulose, glucose, sucrose gelatin, magnesium carbonate, and the like. The compositions are administered as solutions, suspensions, tablets, pills, powders, and the like.

The active compounds of the formulas I or Ia or their 1-isomers and their pharmaceutically acceptable non-toxic esters and salts may be administered in the form of suppositories, wherein the preparation comprises either p-n-ololyl alkyl glycols, for example polypropylene glycol, as carriers. Liquid compositions for general use may be prepared, for example, by dissolving or dispersing the like, the active compound as described above, and optionally using a pharmaceutical agent as a carrier, for example, water, saline, aqueous dextrose, glycell, ethanol, and the like. to form a solution or suspension. If desired, the formulation to be administered may also contain small amounts of nontoxic excipients such as wetting or emulsifying agents, buffering agents, and the like, for example, sodium acetate, sorbitol, trithinone oil, and the like.

Specific methods of making such dosage forms are known or apparent to the art; Reference may be made to Reunton's Pliarmacetical Sciences, Mack Chemicals Commeny, Easton, Perennial, 14th Editin, 1970. They are intended to administer, in any event, a number of active compound (s) in the form of an effective amount sufficient to alleviate the condition. as described in the application. *

The compounds of formulas (I) and (Ia) and their 1-isomers and the non-toxic aromatic esters and salts described above are also smooth muscle relaxants. and as such are useful for controlling pregnancy in pregnant mammals, in favor of the mother and / or fetus, until termination of the pregnancy is medically advantageous or advantageous for the mother and / or fetus. It will be appreciated, however, that in some instances, for example, when birth has already begun (i.e., when uterine contractions are observed), administration of the agents described herein may not result in the maintenance of a pregnancy condition indefinitely. Rather, in these cases the delivery is likely to be slightly prolonged, which may be a benefit factor for the mother and / or the fetus.

In particular, the compounds of formulas I and Ia and their 1-isomers and pharmaceutically acceptable non-toxic salts may be used as agents to delay or delay the onset of labor. In these applications, the postponement delivery phrase is intended to indicate a postponement delivery caused by the administration of compounds of formulas I and Ia or their 1-isomers and non-toxic pharmaceutically acceptable esters and salts in any of the oceans prior to the onset of uterine contraction. Thus, the above formulation is intended to express the prevention of abortion moonnosi early in pregnancy (i.e., before the fetus is visible) as well as to prevent premature labor later in pregnancy when the fetus is already considered to be visible. In both cases, the drugs are administered as prophylactic agents such that administration is intended to prevent the onset of labor. Such administration is particularly effective in women who have already had spontaneous abortion or preterm labor (i.e., labor before full pregnancy). Such subclinosis is also useful when there are clinical indications that pregnancy may end prematurely and although administration of the above-mentioned substances is judged to be beneficial to the mother and / or her fetus.

With respect to animals, the administration of the compounds of formula I or Ia or their 1-isomers and their pharmaceutically acceptable non-toxic salts and esters may be used to synchronize births in a group of pregnant animals such that these births occur at approximately the same time or and / or location, if it is possible in this way to easily control the beginning of the intended birth.

The postponement delivery formulation in these applications is intended to express the postponement of labor caused by the administration of compounds of formulas I or Ia or their pharmaceutically acceptable non-toxic esters and salts after the uterine contractions have already begun. The patient's condition, which includes the time during contraction, the contraction rate, the contraction rate, and the duration of contraction, affects the results of the undercutting of the substances described above. For example, the effect may remain limited to reducing the intensity and / or duration of the contractions (whereby the delivery itself is prolonged) or may mean total contraction arrest. In both cases, the effect caused by administration means an increase in delivery time, but depending on the condition of the patient as described above, the effect may be small or large under appropriate ambient conditions. Such administration may be carried out to prevent spontaneous abortion or to delay delivery so that it may be performed in a lighter manner and / or with less pain and / or at a more appropriate time and / or location.

In all cases, the administration of the compounds of formulas I or Ia or their 1-isomers and their non-toxic pharmaceutically acceptable esters and salts for the purposes described above should be consistent with best and / or accepted medical (or veterinary) procedures to achieve the best result for mother and fetus. For example, administration of the aforementioned substances should not take place for as long as the full time of the pregnancy is such that the fetus would die in utero.

In practicing the methods of the invention, a therapeutically effective amount of a compound of Formula I or Ia, or a 1-isomer thereof, or a pharmaceutically acceptable non-toxic ester and salt thereof, or a pharmaceutical composition comprising any of these is administered to a pregnant patient or pregnant mammalian female by a conventional and acceptable method known to those skilled in the art. The compound (s) may be administered either alone or in combination with the other compounds (or compound) described above or with other pharmaceutical agents, ingredients, additives, etc. Such compounds (compounds) or mixtures may be administered orally, penterally, in a solid, liquid or liquid. Typically, administration of a pharmaceutical composition comprising a pharmaceutically active compound and one or more pharmaceutical carriers and excipients.

The usable pharmaceutical form can be administered in the form of oral tablets, vaginal or divided tablets or suppositories, pills, liquid solutions, suspensions and the like, preferably in a unitary dosage form suitable for single administration of precise dosages.

1

Nutoxické Conventional solid carriers include, for example, pharmaceutical types of mannitol, lactose, starch, stearauu hořečuatáho, sodium saccharin, the ^one to, cellulose ^y glu ^{OZ y} želatiu ^{y, y} sucrose, magnesium carbonate, and the like ^é it. The active compounds o ^{p p s} san above may be ^{p y} odáván in Forni suppositories formulated using ^p olytlky1eiglykolй example polyprofylen glycol, as the carrier. Liquid active pharmaceutical compositions may be prepared, for example, by dissolving, forming dispersions and the like, the active compounds described above, and optionally using the pharmaceutical agent as a carrier, for example, water, saline, aqueous duxtrose, glycerin, ethanol, and the like.

If desired, the pharmaceutical compositions to be administered may also contain a small amount of nutoxic excipients such as formulations, urnifying agents, pH adjusting agents and the like, for example, sodium acetate, toronite, olujan nrUnlhonoaauiou etc. Specific methods for making such pharmaceutical compositions and their shapes are well known in the art; reference may be made to Remunton's Pharmacological Sciences, Mack R. Commany, Easton, Pennstlvania, 14th Edition, 1970.

The nubo dose compositions to be administered should in any case contain the active nubo compound in an amount sufficient to delay the onset of delivery or delay it if the uterine contractions have already begun. Typically, a daily dose of 0.5 mg to 25 mg of active compound per body weight will be administered to the patient. It is administered either as a judges dose, nubo distributed over up to three nubo four smaller doses, given regularly throughout the day. The amount of active compound administered depends on its reactive activity.

The examples illustrate the invention without limiting it. The abbreviation t. 1. c. In all examples will mean thin-layer chromutobraphies (tlin-lt ^y er chromatograph /) and all ratios given when mixing the kappain of the relationship! to volume. If necessary, the examples are repeated to prepare excipients for the following examples; after ^k u ^ ^d Nunia SOLUTIONS well ^Л о пп ^г, REA ^for the Cu horsefly ^ ^ i ^ ^P P .plotě locally-Si ^{(20 and} 3 ^{0 0} C).

Example

A mixture of 23 g of 4-chlorobutyl-2-carbiboxoic acid (J. Irarte ut al., J. Heerocyclic Chum. 13,393) and 80 ml of nibuyl-hybrid was heated to reflux under anhydrous conditions for 4 hours. Excess nlibn ^y llllbridu it is removed and rutdduím deutilováno under reduced pressure to yield 18 g of acid chloride of ^{4-chlbrtlioUen-2-yl} ktribx lbvé.

A solution of 10.5 g of 4-bromobutyl-2-carboxylic acid chloride in 500 ml of anhydrous benzene was cooled in an ice-water bath and the solution was stirred for 30 minutes. The oily bath was then removed while the bubbling of dimlyllauin continued for 15 minutes. The reaction mixture is then diluted with 100 ml of 10% sodium chloride solution and stirred for 5 minutes at room temperature, the organic phase is separated, washed with 10% sodium bicarbonate solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. under reduced pressure to give N, N-dimethylamino-4-ylbenzonyl-2-oxiboxamide.

In a similar manner, the 11-furan-2-carboxylic acids listed in column I can be converted to the .alpha.,. Beta.-di-diethyl acids listed in column II:

Thiophene-2-carboxylic acid furBn-2-carboxylic acid

3-Methylliophene-2-carboxylic acid

4-Methylthiophene-2-carboxylic acid

5-Methylthiophene-2-carboxylic acid 5-chlorothiophene-2-carboxylic acid

3-bromothiophene-2-carboxylic acid

4-bromothiophene-2-carboxylic acid

5-bromothiophene-2-carboxylic acid

3-yl meehh ^{r ura-2-carboxylic} acid meetvyfuran ^ ^ -carboxylic acid-Meeth-furan ^ -carboxylic acid

3-chlorofuran-2-carboxylic acid

4-chlorofuran-4-carboxylic acid

5-chlorofuran-2-carboxylic acid

4-Bromoan-2-carboxylic acid

5-bromoan-2-carboxylic acid thiophene-3-carboxylic acid furan-3-carboxylic acid

II

N, N-2-dimeehyythiofen kabboxamid N, dimeethyfuran-2-carboxamide _s Ν Ν-dimethyl-3-methylthbofen22 kabboxamid Ν, Ν-4-dimethll methylthbofen22 krbboxaeid-N, N-5-dtmettyl eettylthtbfen- 2-Rarboxamide N, N-Dimethyl-5-chlorophenyl-2-Rarboxamide N, N-Dimethyl-3-bromothiophene-2-carboxamide N, N-Diethyl-4-bromothiophene-2-carbonyl-N, N-imethyl 5-bromothiophene-2-carboxyamide, N, N-dimethyl-3-methylfuban-2-carboxylic acid, N-dimethyl-1-4-methyl-N, N-dimethyl-5-ethyl-furan-2-carboxyamide N, N-Dichloro-3-chlorofuran-2-carboxamide N, N-Dimethyl-4-chloro-furan-2-carboxamine N, N-imethyl-5-chlorofuban-2-carboxaeth N, N-Dimethyl-4-bromo-urane-2- N, N-bromomethyl-5-bromofuran-2-carbamic acid

N, N —- let's Lhy! thi of en-3-carboxylate N _> N-dbmeehylfuгan-3-cabboxambd

Example 1

A 250-neck three-necked round-bottomed flask equipped with a magnetic stirrer and equipped with a calcium chloride drying tube is directly connected (via one of the outer throats) via a feed duct and a short water cooler with an acetal pyrolysis apparatus. This apparatus is Vvořena tolatou toňkouo ^ emu about ¹⁰⁰ ml ^{(per g of p} flax B5,6 ^dihydro DR ^and the ^acid; n ^Y lavelové) and 1'1,82 bromraetaldehydu g diethyl acetal, prepared from vinyl acetate, as described in CA Bedoukian, J. Am. Chem. Soc. 66,651 (194-4), together with a Vigbeux column carrying a thermometer connected to the aforesaid water cooler.

Three necked flask was charged with 3.36 g of ethanolamine, chilled in an ice bath to 0-10 ° C, which was treated under stirring 8.7 g of ^{1,3-dimethyl-Val-yl} methacrylate acetbndikarbbx dropwise addition. Okammžtě is created of manufacture & ^mettyl-3-yl kabromethox meetyl-3- ^(2'-yl tyirbx ettyl) aeinoakrylát formula III. When the addition is complete, remove the ice bath and add 100 mL of dry acetonntril. The pyrolysis portion of the apparatus is placed in an oil bath and the temperature is raised to 150-160 ° C. The bromobetaetaldehyde solution that is formed is distilled (boiling point 80-83 ° C) directly into a meggneierl stirred vinylamine solution. When the distillation temperature drops below 80 ° C, the pyrolysis apparatus is disconnected and replaced by a reflux condenser equipped with a drying tube containing calcium chloride.

The solution is refluxed for one 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. The mixture was evaporated to dryness in vacuo and loaded onto the top of a column of 200 g silica gel in hexane. The column is then washed with hexane, ethyl acetate (80:20, 500 m) and ethyl hexane (1: 1, 9x500 mL). Fractions 2 and 3 contain mmnší minoství polar impurities and dimethyl 1,3-c € ^y tbndikarbbx methacrylate; Fractions 4 to 8 gave 4.1 g of methyl N- (2-hydroxymethyl) -3-carbomethylbenzoicroacetate, which after recrystallization from ether-hexane had a melting point of 52-54 ° C.

Example 2

To a stirred solution of 4.1 g mmttyl N- (2-hydroxylethyl) -3-rarroeeehobχlylrrb-2-acetate in 35 ml of dry-chloromethane ^to esters is cooled to rt-te ^ at - ¹⁰ ° ^C with 2 pHfó ⁶ 5 ^m tr ^ i ^ ehylaminu and then, dropwise, 1.46 ml eeehannuUfobylchlbriiu while maintaining the reaction temperature at -10 ΐ to -5 ° C. The reaction is carried out by t. 1. c. Analysis using chloroform: acetone (90:10). When it is determined that the reaction has already taken place (about 30 minutes after the addition of methanesulfuryl chloride), 10 ml of water are added slowly. The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue in dichloromethane-hexane gives 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate, m.p. 99-101 ° C.

Example 3

A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is distilled at reflux for one hour. The cooled reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with water. The insoluble component was separated by filtration and air drying to give 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate, mp 137-138 ° C.

Example 4

A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of anhydrous dimethylformamide was stirred under argon with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept at room temperature for 30 minutes and then quenched with 100 ml of water. The reaction product is extracted with ethyl acetate (3 x 50 mL), the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue on silica gel (20 g) using hexane: ethyl acetate (4: 1) as solvent gives 500 mg (80%) of dimethyl 1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1, 7-dicarboxylate, m.p. 70-71 ° C.

A solution of 1.80 g of dimethyl 1,2-dihydro-3H-pyrrole- (1,2-a) pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of potassium hydroxide in 20 ml of water, the reaction mixture was distilled at reflux for 6 hours. The cooled solution is evaporated to dryness under reduced pressure and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution was acidified with 6N hydrochloric acid and extracted with ethyl acetate (3 x 50 mL). The combined extracts were dried over magnesium sulphate and evaporated to dryness under reduced pressure. 1.51 g (95%) of 1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1,7-dicarboxylic acid are thus obtained, m.p. 220 DEG.

Example 5

A solution of 1.34 g of 1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1,7-dicaphoxylic acid in 50 ml of isopropanol, cooled in an ice bath, was saturated with hydrogen chloride gas, keeping the reaction temperature below Deň: 32 ° C. The ice bath was then removed and the reaction mixture was stirred for 1.5 hours at room temperature, then evaporated to dryness under reduced pressure. 10 ml of benzene are added to the residue and the solution is evaporated again under vacuum; this process is repeated three times to completely remove excess hydrogen chloride. 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate-7-carboxylic acid are thus obtained which, after crystallization in a mixture of methanol-ethyl acetate, is obtained. mp 144-145 ° C.

In a similar way, but substituting methanol, ethanol, propanol or n-butanol instead. isopropanol in the above-described process to give the following corresponding compounds: ₍ methyl-1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate-7-carboxylic acid, ethyl-1,2-dihydro-3H) -pyrrole (1,2-a) pyrrole-1-carboxylate-7-carboxylic acid, propyl 1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate-7-carboxylic acid, butyl -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate-7-carboxylic acid.

Example 6.

1.054 g of isopropyl-1,2-dihydro-3H-pyrrole- (1,2-a) pyrrole-1-carboxylate-7-carboxylic acid is heated to 240 DEG-250 DEG C. in a dry, 10 ml round-bottom flask. The vaccine product was distilled immediately from the reaction vessel. In this way 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrole-1,2-kilo-pyrrole-1-kkoroxylate, a pale yellow oil, having the following physical constants were obtained:

u. x MeOH max 215 nm ( ε 60; 20); I WANT., 1 I. R. v 3 msx 1 725 i CH - 1 i; NMR _with CDC1-. ^with TMS ³ 1, 22 (d, j = 7 Hz , 6H) 2.40 to 2.90 (m, 2H) 3.60 to 4.20 (m, 2H) 4.65 to 5.2 (m, 1H) 5.73 to 5.92 (m, 1H) 6.10 (t, J = 3 H z, 1H 6.43 to 6.53 (m, 1H)

Example 7

100 ml three-necked round-bottomed flask with condenser, nitrogen inlet to the bubbling apparatus, is charged with 5.0 g of isopropyl-1,2-dihydro-3H-ylroO (1,2-j) pyrrole-1-caoroxylate-7- carboxylic acid. The instrument is purged thoroughly with nitrogen: then the nitrogen flow is interrupted. The apparatus is immersed in an oil bath heated to 270 ° C and reacted by t. 1. c. Analysis on silica gel using benzene: dioxane: acetic acid (90: 10: 1) to produce carbon dioxide.

After 45 minutes, the reaction is almost complete after one hour, and the reaction vessel is removed from the oil bath and transferred to a round-bottomed flask containing 500 ml of acetone. The solvent was removed under reduced pressure to the settlements and purified by column chromatography on 100 g of silica gel. Fractions eluting with hexane: benzene (70:30) to hexane: benzene (50:50) gave 2.77 g (68%) of isopoopyl-1,2-ihliro-3H-oxo-1,2,2-a) pyrrole-1 -carboxylate, an oil whose physical constants are identical to those obtained in Example 6.

Example 8

710 mg of a 50% suspension of sodium hydride in mineral oil is washed with anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension was cooled to -5 ° C, to 4.5 g of methyl N- (2-meeyloxyyetetyll kakbroθthoxyplУ --- · rol-2 - jeeátu, oeakčn ^s míctá mixture for ^{1 h} at Odin ^P H - ^fifth ° C to ^Z 0 ° C. ^p Otom pour ^d of sodium chloride, cooled in an ice bath and extoahuje with někooikrát benzene. the combined extoakty with poopeoou water, dried the concentrated to dryness under reduced pressure. the residue solid state crystallized in Ethyme to give a 1,2-dihydro-3H-ylro-O- (1 H -a) pyrrole-1,7-dicarroxylate dimension identical to the product of Example 4.

Example 9

A solution of 232.5 mg of N ₁ N-dimethylthiophene-2-carboximide to 0.15 ml of phosphorus trichloride in 2 ml of 1,2-dichloroethane is distilled at reflux for 30 minutes. To this solution was added a solution of 181 mg of isopoopyl-1,2-iodo-3H-yyo-O (1,2-a) pyrrole-1-cacboxylate in 2 ml of 1,2-dichloroethane. the mixture was distilled for 8 hours in an aogon atmosphere at reflux, then treated with 450 mg of sodium acetate - distilled at reflux for an additional 5 hours. The mixture was stirred. it is then evaporated to quench the roside by chromatography on 12 g of silica gel, the solvent used being hexane: ethyl acetate (3: 0) to give isopropyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrole (1: 1). 2-a) pyrrole-1-carboxylate of the formula XI, wherein R = H, R 6 = H, R ² = γΟ, γ, X = S.

Example 10 A

A solution of 300 mg of isopropyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate in 30 ml of 50% aqueous methanol containing 1% potassium hydroxide was distilled. at reflux under a nitrogen atmosphere for 2 hours. Methanol is then removed under reduced pressure and basically the solution that remains is dissolved with water and extracted with chloroform to remove any unsaponifiable product. The aqueous alkaline phase was then acidified with 20% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. 250 mg of crude 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic acid of formula I, R and R5 = Η, X = S are thus obtained. having a melting point of 145-148 ° C; after recrystallization in ethyl acetate, this acid melts with decomposition at 152-153 ° C.

Example 10 B-1

410 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole- (1,2-a) pyrrole-1-carboxylic acid and 212.3 mg of d-amphetamine are dissolved in 15 ml of pure methanol and heated to reflux for 15 minutes. The methanol was then removed in vacuo. Then, the mixture of diastereoisomeric d-amphetamine salt (612.3 mg) was dissolved in a minimum volume of hot (55 ° C) acetone, cooled to room temperature, filtered and washed with 2 mL cold (-10 ° C) acetone. This γ recrystallization procedure was repeated three more times to give 247 mg of 2-thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic acid-d-amphetamine salt, giving a ^CHCl3. M.p. 168-170 ° C.

The D (1) -isomer of the d-amphetamine salt obtained above is added to 30 ml of methylene chloride and shaken three times with 10 ml of 0.1 N aqueous hydrochloric acid. The flow was washed three times in 15 mL of saturated sodium chloride / water (2: 1 / V: V) and dried over sodium sulfate. Filtration and removal of the organic solvent in vacuo gave 90 mg of one isomer of 5-2- (thenoyl) -1,2-dihydro-3H-pyrrolo (1,2-a) pyrrole-1-carboxylic acid having ^{a HC1} ° M.p. 134-135.5 ° C.

Acetone mother liquors resulting from the dissolution (i.e., multiple crystallization) of the diastereoisometric-d-amphetamine mixture described above are combined and converted using a hydrochloric acid purification procedure as described above. 245 mg of a mixture enriched in the d-isomer of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic acid containing the 1-isomer of 5- (2- thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic acid. This mixture was racemized back to a 1: 1 mixture of the 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic acid d- and 1-isomers.

The procedure is as follows: 245 mg of the d-isomer-enriched mixture containing the 1-isomer described above are dissolved in 15 ml of methanol. 1.5 ml of methanol and 350 mg of sodium hydroxide are added and the solution is refluxed under nitrogen for one hour. The methanol is then removed in vacuo, water (2.5 ml) is added and the solution is acidified to pH 2 with 10% aqueous hydrochloric acid. The mixture is extracted three times with 10 ml of methylene chloride, the extracts are combined and neutralized to pH 7, dried over anhydrous sodium sulfate and concentrated under vacuum. 230 mg of a crude crystalline product are obtained which, after recrystallization in ethyl acetate-hexane, yields 180 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic acid. having α α ^β θ ^Η 0.0 ° and a melting point of 152 to 154 ° C.

In the same way, other d-optically active bases can be substituted for d-amphetamine using the procedure described above. Particularly suitable are:

I D-isomer of p-bromo-l ^ f ^ and - ^ ^ r ^ i ^ etyy ^of divided ^ ia ^ nu. _The d-isomer of alpha-eenetlylamine, the d-isomer of β-1-nifthethylamine, the d-isomer of β-2-niftethylamine, with the d-isomer of the β-bronm-1-phenettrinamine being the most preferred compound after d-amphetamine. Analogously, d-isomers nappíklad d-isomer of 5- (2-ttenool) -1,2-3H-ditydro - prroo- / _1> 2-i / pyrrol- 1 kabboxylové substituting 1-optically active bázf d space optically active bases, for example by substituting 1-.alpha.-amine instead of d -amphetamine.

Example 10 B-2

To a solution of 118 mg of 5- (2-thienosr) -1,2-di-nitro-3H-yyrro-1H-pyrrole-1-carboxylic acid in 8 ml of dry benzene was added 0.234 g of triflolceelentrdoidb. The mixture is stirred at a temperature ^of inclu after ESET ^d min and the mites ^to the algorithm as at ^0-5 ° C. and ^adding 0.55 g of dry treθtlylaminu, whereafter okamižtě followed by adding 0.2 g of 1-alpha-isomer Fento -ethyl alcohol. The reaction mixture thus obtained was stirred at room temperature for 15 minutes and poured into 20 ml of water containing 1 ml of treelhylamine. Extraction was then carried out with ethyl acetate.

The extract obtained with ethyl acetate is dried over sodium sulfate, then the excess solvent and the 1-isomer of α-alpha-phenyl ethyl alcohol are removed in vacuo to give 0.166 g of a mixture of the 1-isomer of 5- (2-thienyl) -1,2-dihldro-3H 1-itsomer of alpha-phenethyl ester and the d-isomer of the 5- (2-thienol-1,2-dihldro-Z, 2-hexyl-1,2-dihydroxy-1,2-dihydroxy-1,2-dihydroxy-1,2-dihydroxy-1,2-dihydroxy-1-carboxylic acid) -1-kaoboxylové kysseiny L-ssoier llfl-fenettll-etteob which are separated using liquid vytoko01lké chromaaografie (pouuitíi with 4% EtOAc / hexane on a 11 mm x 50 cm, 10 ^<60 microns Lochrosorb sl- column) ^of COMES ^from SE z ^ ka ^68mg olárnějšího ^yl ester ^{(a 'e0ÍI} -149.1 °) and 73 mg of the less ol ^{y ry ¹H} esters 0 «^ ^ ^{e8R +} 5.2 °).

62.1 mg of the more polar ester were dissolved in 3 ml of dry benzene. The solution was cooled to ¹ 5 to ²⁰ ° C and ^P s ^can be ^2, 5 mL of trifluoroacetic uooccSové ^b k ^r n ^{r i} phone -ao ^ ^ o ^for the Animal Welfare stirred ^y s ^y te iístnoosi ture for 1 hour and 40 minutes. The reaction solution is poured into 60 ml of dry benzene and the solvents are removed in vacuo at a temperature of 0 ° C. Purification was by high pressure liquid chromatography (using the column described above except that 35% EtOAc / hexene in 1/2% acetic acid was used in place of 4% EtOAc / hexane) and 41 mg was also obtained. 1-isomer of 5- (2-ttenoyl) ^-1,2-ro-d Ditl ЗH-pprroS- (1.2-L) · 1kaarbsxrl ylrosl-oic acid iaiíčfaM ^ (H _44 ° θ ^for counting from 130 to 132 ° C .

Similarly, cleavage of the less polar ester by the method described above for the cleavage of the more polar ester yields the 5- (2-thienol-1,2-di-dipro-3H-prroS (1,2-l) yprosyl-1-carboxylic acid di-isomer) ^. iaaící ₊ H2,4 ° and the temperature T ^and E27 and 9 ^{of the 12} ° C. thus, a ^ ^d ~ kanyā isoier can, if desired, oacemizován (a rec ^ k ^ rate) pouuitíi conventional methods.

In a similar manner, other compounds may be decomposed into the sidisodic 1-itsomers and d-isomers.

Example 11

A solution of 336 mg itsyrsy ^yl-5- (2-thensrl) -1,2-dihrdrs pylrol-3H- (1, 2 L) yprrsl 1-klobsxplátb mmehanolu in 10 ml was reacted with 690 mg oozookei uiličiaanu potassium 5 ^y i- water.

the mixture was distilled at reflux temperature for 2 hours in a nitrogen atmosphere, cooled and evaporated to dryness. The residue was taken up in 10 L of 10% aqueous hydrochloric acid and 50 L of water and extracted with ethyl acetate (2 x 50 L). The combined extracts were dried over magnesium sulphate and evaporated to dryness under reduced pressure. Crystallization of ethyl acetate in ethyl acetate yields 5- (2-thiolol-1,2-dihydro-3H-yyro-1,2,3-aplooS-1-sulfonic acid, identical to that obtained in Example 10a).

Example 12

Following Example 6 or 7, the other compounds obtained in Example 5 are converted to the following compounds obtained in Example 5 into the following compounds:

methyl 1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate, ethyl 1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate, propyl- 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, butyl 1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate,

Condensation of these compounds with N, N-dimethylthiophene-2-carboxamide according to the example gives the following compounds:

methyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ethyl 5- (2-thenoyl) -1,2-dihydro-3H- pyrrole (1,2-a) pyrrole-1-carboxylate, ^λ has ^{λ 265} ' ^{328 nm (ε 7 580} ' ^{17 7805} propyl-5- (2-thenoyl) -1,2-dihydro-3H- ^K pyrrole) 1,2-a) pyrrole-1-carboxylate and butyl 5 / (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Example13

Following the procedure of Example 9, wherein from 1.1 to 2 molar equivalents of the following compounds are used.

N, N-dimethylfuran-2-carboxamide,

N, N-dimethyl-3-methylthiophene-2-kerboxamide,

N, N-dimethyl-4-methylthiophene-2-carboxamide,

N, N-dimethyl-5-methylthiophene-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-4-bromothiophene-2-carboxamide,

N, N-dimethyl-5-bromothiophene-2-carboxamide,

N, N-dimethyl-3-methylfuran-2-carboxamide,

N, N-dimethyl-4-methylfuran-2-carboxamide,

N, N-dimethyl-5-methylfuran-2-carboxamide,

N, N-dimethyl-3-chlorofuran-2-kerboxamide,

N, N-dimethyl-4-chlorofuran-2-carboxamide,

N, N-dimethyl-5-chlorofuran-2-carboxamide,

N, N-dimethyl-4-bromofuran-2-carboxamide,

N, N-dimethyl-5-bromofuran-2-carboxamide, instead of N, N-dimethylthiophene-2-carboxamide and monitoring the progress of the reaction by t-1c analysis, gave the following corresponding compounds:

isopropyl-5- (2-furoyl) -1,2-dihydro-3H-pyrrole- [1,2-a] pyrrole-1-carboxylate, oil having the following physical constants:

^υ ' ^ν · ^λ ma ™ ²⁷⁵ > ³³² ' ^{5 (c 8,900} « ^7,800)

IR '' ™ ^ 3 '735, 1 665, 1 605 cm ^-1 ,

NMR δ δ 1.23, d, 6H, J = 6 Hz, (CH ₃ ) ₂ CH],

2.60 to 3.00 (m, 2H)

3.90 (dd, 1H δ = 6 Hz, J _BX = 7 Hz, H-1)

4.10 to 4.67 (m, 2H),

4.95 / sept., 1H,. J = 6 Hz, (CH3 JCH2),

6.00 (d, 1H, J = 4Hz, H-7),

6.40 (m, IH); 7.10 (2m, 1H), 7.23 (d, 1H, J = 4Hz, H-6); 7.43 ppm (m, 1 H),. M. S. m / e 287 (M) J

isopropyl-5- (3-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isoproopl-5- (4-meetyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 1,8-propl-5- (5-methyl-2-thennol) -1,2-dihydro-3H-proprole [1,2-a] pyrrole-1-carboxylate, having m.p. 82-82.5 ° C, 18-β-oplo-5- (4-chloro-2-t-enol) -1, β-dihydoop 3 H -pyrido [1,2- a] proproo-1-carboxplate, isopropyl-5- (5-chloro-2-thenoyl) ) -1,2pdihydro ppyroO-3H- / 1,2-a / ^{ppггoO-1pkaobo2yУ.á,} t isopropplp5p (3-bromo-2-thenopl) P1.2-dhhldoop3H-ppyooO / 1, 2-a / ppyy ' o-1-carbohydrate, isopoopplp5p (4-boom-22-thennol) -1,2-dihydyo-3H-ppyo10 / 1,2-aolololp1-carboxylate, isopoopyl 5- (5-bromo-2-thenopl) p1 1,2-dihydro-3H-ppyloo [1,2-a] yyrylo-1-cyclooxylate, isopropyl (2-methyl-2-fuoyl) -1,2-dihydro-3H-pyrido [1,2-a] pyyoO- Isopropo-5- (4-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopyoopl-5- (5-methyl) -22 (fluoro) -1,2-di-di-3H-pyrrolo [1,2-a] pyrrole-1-carboxyylate, isopropyl-1 (5) - (3-1-di-1-di-1-yl) - 1,2-dihydyo-3H-pyrrolo [1,2-a] pyrrolidine-5- (4-oxo-2-fuyoyl) -1,2-dihyde 0-3 1-X-1,2,2-ayyrroO-p-aroxyoxyate, sopylooyl-55 (5-chloy-2-fluorooyl) -1,2-dihydyo-3H-pyrrolo [1,2-a] pyrrole-1-ol isoproopy-S- (4-bromo-2-fluoro) -1,2-dihydyo-3H-ppyo [1,2-a] pyrrole-1-carboxylate, isocyanate, isopropiate i ^ · (5-bromo-2-fluoro-дyool) -1,2-dihydyo-3H-pyyroO / 1,2-a / _f yyyyoO-1pkarboxylát tydyolýzou isopoopylesterové group as described in EXAMPLE 11 or 10A were obtained free odppoídaaící acids, listed longer:

5- (2-: Uooll · -1,2-dhùdOooзЗHppyrrol / 1,2-aУpyyyol- · aayboelic acid melting point

184-184.5 ° C,

5- (3-Methyl-2-thenoyl) -1,2-dhhyao-3 H -pyrrolo [1,2a] -1-ca] -benzoic acid, 5- (4-methyl-2-thenoyl) p 1,2,2-dhhydoop 3 H -pyrido (1,2pa) -1-polyacetic acid, 5- (5-methyl-2-thenoyl) p1,2-dhlydoop 3 H -pyrido [1,2- a] pyylo) -1-caoboic acid, m.p. 169-170 ° C C,

5- (4-chloro-2-thenoyl) -1,2-dihydro-3 H -pyloo [1,2- a] pyrrole-1-aroyoylic acid; 5- (5-ch-or-2-thienoyl) · -1,2-dhУddгoзЗH-ylrrol / 1,2-appyyroP- · -aryboxylová acid, 5- (3ρbooш thenool-P) _P1) 2paihyaoop3H-pylroO / 1,2-a / 1-yyrroO - aoУoyylová acid 5- (4-chloro-2-thenool) -1,2-dihydro-3H-pyrrolo [1,2-a] yyro-1β-azooylic acid, 5- (5-chloro-22-thenool) -1,2-dihydyo-3H-pyro (1,2-a) pyrimido-1-acetylic acid, 5- (3-methyl-2-fluorooyl) -1,2ddhydrohydro-3H-pyrrolyl) / 1,2-a) pyrimidyl-5- (4-methyl) -2-furol) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrido-1-aoboyyl cellulose, р (5рМ ^ У1 ^ У1) ^ Р ^ - ^ Р ^ 1 ^] ^ < (1,2-aylamino) -3H-pyrrolo [1,2-a] pyrido-1-arboyyloic acid, 5- (3-chloro-2-fuoyl) -1,2-dihydro-3H-pyrazole-3H -ppyro011,2-a / p1oro1-1-kayoic acid, 5- (4pco-oop2pзUlool -) - 1, P-dhhydro-3H-pyro [1,2-a] pyyoO-1-azoyoyl acid, 5р (5рсУЗ) 1-P-diidyl-3H-pyrrolo [1,2-a] pyrrolido-1β-azooylic acid, 5d (4promo-PP-1-olol) -1 2-dihydyo-3H-yyroO [1,2-a] yrrol-1-yl] oxoic acid, 5- (5-chloro-p-furoyl) p1,2-dihydrop3H-pyrrolo [1,2a] yloool-1-carboxylic acid other acid.

Example 14 A

A three-ml 250 ml round-bottom flask containing a magnetic stirrer and equipped with a calcium chloride-containing drying sponge is charged with 3.36 g of ethanolamine, cooled in an ice bath to 0-10 ° C and then dropped into it dropwise with stirring 8.7 g of _3-l dimettyrlp1 acetonaikarУoзy1Létu. Methyl 1-3- (2-hydroxyethyl) -acrylic acid III is formed immediately. After the addition was complete, the ice bath was removed and 80 ml of dried acetone was added.

The reaction mixture, to which 6.75 g of bromoacetyl aldehyde in 20 ml of ketone Otoil is then added dropwise, is refluxed for 2 hours, then the solvent is removed under reduced pressure and 200 ml of methanol and 20 g of brine are added. g ^ el ^ u. This mixture evaporates to dryness - under vacuum and monks! 200 g of silica gel in hexane were added to the top of the column. Wash the column with hexane: ethyl acetate. Fractions eluted with hexane: ethyl acetate (1: 1) gave methyl (2-hydroxy-pyrrole) -3-carbonyl] -dodo-2-acetate IV, R = H identical to the material obtained in the precursor Example 1.

Example 14 B

To a solution of 6 mL of ethanolamine in 5 mL of water was added 1.74 g of dimethyl 1,3-amino-3-carboxylic acid. ^The Zn ^{n KL} pruclce mixture was cooled to - ¹⁰ ° C and treated with ^p o and ^{the PKA} c ^{h runs} through ¹⁵ minutes and stirring 1.67 ml of 1-bromoacetone, přččemž the temperature is maintained, - that does not exceed ⁴⁰ ° C. When the ^REA-EU no ^{C CNA} t ^ MAV ^and REA ^ the mixture was stirred ^{and P} for further one hour at místnoH and then poured into a mixture of hydrochloric acid and ice, n ^ j ^ s ^ l ^ children is sodium chloride and extracted with ethyl acetate (3 x 100 mL).

The combined organic extracts are washed in cold water until neutralized, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. a residue on 30 g of silica gel, with hexane: ethyl acetate (70:30), gives 890 mg of crystalline methyl N- (2-hydroethyl) -3-methylhexyl-3,4-methylpyrrone-2-acetate, which after rčrrlstalinkei in methyleoeh ^l or ^i-du-hexane is at 7 ^{to 8} ° ^C and ^from the analysis of V ^{and W, and} the following results obtained by ^^

For C ₁₂ H ^ NO ^ calc: found:

C 56445

C 56.1 1

H, 65.71

И 6.33

In a similar manner, but using the equivalents of 1-bromo-2-butene, 1-bromo-2-pentone, 1-bromo-2-hexone to one hundred 1-bromo-2-one, the following compounds were obtained:

Methyl-N- (2-hydrooyl-ethyl) -3-carbomeehony-4-ethylproro-2-acetate, methyl-N- (2-idoyl-ethyl) -3-carbonyl-4-pronylpylro-acetate and methyl 1-N- (2- hydroxyethyl) -3-carboxylic acid methyl-2-acetyl-3-carboxylic acid;

Example 15

Methanol - (2-hydroxyethyl) -3-carbonyl-4-methylpropyl-2-acetate IV, R = CH3 is converted to methyl (2-phenyllooyl) -3-carbonyl-14-methylheptlool-2 by the method described in Example 2 acetate, which is then cyclized with sodium hyUoidem dimethylOormkmidu method described in example 8, to afford the 1,2-dihydro ^Uimethl, o-6-I] mtčphlЗ3 p-rlo0nl-122- / pylron-1, 7-dicarboxylate.

Analysis of the latter product with potassium hydroxide according to the method described in Example 4 and subsequent selective esterification in C-1 and Uecarbooylation in C-7 according to the procedures of Examples 5 and 7 yielded successively 1,2-ethyl-6-chloro-3-propyl. (1,22-Apploo-1, 1-dicarboxylic acid, isopropyl-1,2-iodo-6-iodo-6H-p-oxo-1,2-k) pyrrole-1-carbonyl-1-carboxylic acid and isopropyl-1,2- iihlUro 6-ieehhl-ЗH-pprro0 / 1,2-a / pyrool 1-carboxaldehyde with R = CH, R ² = H iC ^j ?.

In a similar manner, instead subblituujíeč íečOhl --- (2-hlUrnxpethll) з rkabnoíčthoxρ-4-iečhhlpyrrol-2-acetate íeeOhl ^'- (2-hydrooylethl) -3-4-kaobnmiehhoy eehhlρploon-2-keetáO and meethrl- -208724

- (2-hydroxyetlhfl) -3-carbomethoxy-4-butyl-pyrrol-2-8Cetát and meth'yl-N- (2-hydroxyetbyl) - 3-karbomtei ° xy "4", ^R 4 opylpyrrol-2-acetate obtained ,, st the following final substances:

isopropyl-1,2-dihydro-6-ethyl-3H-2-yiro [1,2-a] pyrrole-2-carboxylate, isoorppyl-1,22-diidro-6-propyl / 33-pyriol / 1,222Ciroiro-12-carboxylate c isoorooyl-2 1 _> 2 • 2-di-dolo-6-butyl- (3H-20lrol) 1,2-ayryrol-2-carboxylate.

Example 16

Using the methods described in Example 9, isopropyl 1'-diidro-6-methanol (BH-pyrrolo [11a] -a) pyrrole-1-carboxylate is coupled with Ν-, Ν-dimethylthiophene-4-carboxamide to give isopropyl 5 ^{( (-} - ^AO tnoyl) ²¹ s ^d ro26 ^{-2-di-Me th} of ^{L / 2 H L} 1 _t -ρyolol 222 YRO ^C p ^{p O} l (12 ^to CR ^b oxylate XI ^R = CHP ^R1 = H, ^R = iC ^ Hy, X = S, ^{m /} m ^ 2.5 ° C ·

Analogous method st at pouUití njn dimetOyláOioftnů ntbo-NN-2dmmtholl ^-1 determination of an - in 2kcrbox2 ćmíd vyjmenovanýeO příklcdu 1H ncmísho _N> N ^{d 2} imethyltOio.ftn2- carboxamide are obtained with the following / oučtninl:

isopropyl 5 - (- furoyl) -1'-diolldro-6-methanol-HH-pplroo [1,1-c] pyrrole-1-carboxylate, isopropyl ² 5- (3-methyl / 2-) (tOtnoyl) -1 - diOldro o-menthol-lH-pplroo / l - c / pylroo 1-kcoboxxl / t, S ^2-isopropyl (4 ^{2 2} 2-methyl áOenoyl) -1 -2diOldro ² 6 ² MeOH-2H ^2- pyrrole / 112-acro-1-carboxylic acid, isopropyl 1-5- ( ^2- methyl- ² -enoyl) -2,2,2-diol-6-ol (6-methyl-2H- ² -carboxylic acid) ² -Chloro-1-carboxylic acid, isopropyl (5- (4-chloro-oenool) -1,2-diol- ^2- ol ² 6 ^2- methanol ² 3H ² POro / 1, a) pylroo-1-carboxylate, isopropxl-S - ^ - eO / or - ^ - OeenolD-l 2 ^{2 2} 6 ² dOhydro metOxl Pplrol ^2-32/1 - ² C / 1-pprrol kcrboxxlát, islpropχl-5- ^{(3-bromo-2-2 2} tOtnoll) ² 1, - diOydro ² 6-methχУ ² ЗH ² ppyrrO / 1, - a / pxlroo ² 1-kcrboxxlate isopropχl ² 5- (42brom ² 2-2honelll ² (12 ² dihχddΌo66methol-ЗH ² 2-oyorOl , 2-ac / plrro / (2-ccrboxxlate, islpropχ122 5 ² (52-bromo-2-halo) ² (12-dihχldO122621ethχl-ZH-oyo00112-2 / polrol ² l-kcrblxyltt, isopyoppl-5 ² (3-methOl / 2) -furophyl) ² 1, - ² Sulfur-6-methyl ² 32 - Oro / 1> 2-c / pprol-1-kcrbo xxlát, islprlpχl ² 5- (4-methχl ^2-2 furoyl) (1 - (- 6-dOhydro - metOyl ^pOУrol-32/2 1 t c / pyryol2 12kcrbo2xl / t isopropyl-5- (5 (meeholl2 -furool) 1 ² - ^{2 2} 6 diOydro-mee-O ^'r l ² ЗH polУoO ^2/1 --C / Py RNL ^{2-1-kcoblxχlát,} isoproppl ² 5 ² (3 ² 2 ² chOor furoxl) ² 1, - ² diOydro-6-methoУ ² ZH-poly (1, - a / pylroo ² 12-ketboxxl / t, isopropyl ² 5 ² (4-chloro- ^2- furoyl) -1, - ² SiOydrl ² 6-methanol / ЗH poyyrO ^2/1 - and / pylyoo-12kcrboxxlát, isopropxl ^S-2 (52ehloy2- furoxl ^{2) 2} 1 - diOydro O ² nm Thol ² 2H 2 oyorOl12-2c / 0lroO-12kcrboxylát, isooropχl ² 52 (4-brlm - 2fuuolll ² 1 - ² 6 ² diOydr0 meehol-23-2-oyol / 112-2Cp0lroO l2kcrboxχltá ^2> and isooropyl-5- ^(5-bromo-2 2 ϊfιroyl) -1 - ² dihydroxy (66) (mthol-2H- ^2- yoyloxy ⁾ -12-α / pyrrole ^2-1 -carboxylate.

In a similar manner, the remaining final compounds obtained in Example 15 can be converted. nc deyivtál ». substituted with 5-furoll or htropyl groups. The following are:

isopгópyl ² 5 ² (--áOteoχl) ² 1 - SiOydyo 6-etOyl-32 - pyrrole / 1 - c / plУrl / -1-kcrboxylát, isopyoppl ² 5- (2-furoyl) ² 1 » - »diOydro ² 6-popoool-23-2yplol112-2C / OlroO122coblxylate, isopropy 1-5- (3 ^ 6 ethyl-2-thenoeno) -1, - ² diOydd0126bbthl / ЗH ² pyolol ² / 112- (c'ppyгoO- L-kcoblxylát, isoproppl-S- (4-ehloг --'- áOteopl) -1 »- ^{2 2} 6 ² diOydУl táOyl ppyroO-32/1 --C / pplyoo-12kcrboxxl / t islprlpyl ² 5 ² ( 5-Methanol / 22fuyoyl) ² 1 »- diOydrl ² 6 - opyopollЗH ² pyyol / 112-a / polУol-1-chlorobutyl with isopУoppl-5- (3-eO1oг-furoyl) ² 1, - ² SiOydгo- 6-Butyl-32-olroO (1-a) pylgol-1-crboxylate ·

Example 17

A solution of 500 mg of isopropil 5 '(- [alpha] -oyoyl) -1, - (- dihydro-6 (methyl-32-pyrrolo [1,1-a] pylol-1-carboxylate) in 15 ml of methanol cannot be recycled with solution 1. 0.05 g of carbonate-carbonate in 8 ml of water. The reaction mixture is distilled through a flask at room temperature in a nitrogen chloroamer after cooling, cooling until finally evaporating into the residue. The residue is poured in 10 ml of 10% aqueous solution. The combined mixture was dried by suction (H x 50 ml). The combined extracts were dried in sulfuric water and evaporated to dryness. This gave 5 - (- toluoyl) ² 1, - SiOydro-6. -meehol-ZH-prroO / 112-a / oyrгll ² 1 · kCabboxy / lithium acid wall sample I, R = C- ₃ , r '= Η, X 2 S, soap and melting 166 ° C ·

In a similar manner or, if appropriate, by the hydrolysis method of Example 10A, the remaining isopropyl ester compounds obtained in Example 16 are converted to the corresponding free acids, namely 5- (2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrole / l. 2- (a) pyrrole-1-carboxylic acid, 5- (3-methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (4-chloro-2-thenoyl (-1,2-dihydro-6-methyl)) -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5-chloro-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrole [1,2-a] pyrrole-f-carboxylic acid 5- (3-bromo-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrole [1,2-a] pyrrole-1-carboxylic acid 5- (4 -bromo-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5-bromo-2-thenoyl) -1,2 -dihydro-6-methyl-3H-pyrrole [1,2-a] pyrrole- 1-carboxylic acid, 5- (3-methyl-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-methyl) 2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5-methyl-2-furoyl) -1,2-dihydro 6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (3-chloro-2-furoyl) 1,2-dihydro-6-methyl-3H-pyrrole / 1,2 - (a) pyrrole-1-carboxylic acid 5- (4-chloro-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5 - (5-chloro-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -1-carboxylic acid, 5- (4-bromo-2-furoyl) -1 2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5-bromo-2-furoyl) -1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (2-furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (3-methyl-2-thenoyl) -1,2 -dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (4- chloro-2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (5-methyl-2-furoyl) -1,2- dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (3-chloro-2-furoyl) -1,2-dihydro-6-butyl-3H-pyrrole / 1 , 2-a] pyrrole-1-carboxylic acid.

Example 18

A solution of 232.5 mg of N, N-dimethylthiophene-3-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is distilled at reflux for 30 minutes. To this solution was added a solution of 181 mg of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 mL of 1,2-dichloroethane. The reaction mixture was distilled at reflux under argon for 8 hours and then treated with 450 mg of sodium acetate and distilled at reflux for a further 5 hours. The resulting mixture was then evaporated to dryness and the residue chromatographed on 12 g of silica gel. Hexane: ethyl acetate (3: 1) is used as the eluting solvent. There was thus obtained isopropyl 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate XII, R = H, R ² = IC 2, ^x = ^s ·

In a similar manner, isopropyl 1,2-dihydro-6-methyl-3H-pyrrole (1,2-a) pyrrole-1-carboxylate and isopropyl 1,2-dihydro-6-propyl-3H-pyrrole are converted, 2-a) pyrrole-1-carboxylate to isopropyl 5- (3-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrole [1,2-a] pyrrole-1-carboxylate and isopropyl-5- ( 3-thenoyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

By the same method, substituting N, N-dimethylfuran-3-carboxamide instead of N, N-dimethylthiophene-3-carboxamide, the corresponding 5- (3-furoyl) derivatives are obtained, i.e. the following compounds: isopropyl-5- (3-furoyl) - 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil having the following physical constants:

222, 244 to 277 (upper part of the characteristic), 314 nm (6 750, 4 250, 14 800),

730, 1610, 1560 cm ',

u.v.

max

CHCl ₃ max ^J

I.R <

AND.

1.23 / a, 6H, J = 6 Hz,

2.50 to 3.00 (m, 2H)

MS. me

3.92 (dd, 2H, J _AX = 6Hz, _JBX = 7Hz,

4.10 to 4.60 (m, 2H)

4.95 / sept, 1 H, J = 6 Hz, (CH 2 CH,

5.95 (d, 1H, J = 4, H-7) ’

6.78 (m, IH);

6.83 (a, 1H, J = 4Hz, s-6),

7.30 (m, IH);

7.83 ppm (m, 1 H),

270 (M ⁺ h)

H-1), isopropyl-55 (3-oyl .fu _{R-1,2-dihydro} (d? O-6-meehyl-3H-pyrrolo / 1,2-а / ругго1-1 кагЪоху1ё1 ai-isopropyl-5- (3pfUr orl) -4, β-detridro-6-propi-3 H -propyl [1,2-a] proprole-1-carboxylate m.p.

Example 19

A solution of 300 mg of 18-propro [1,5-a] (3-thenool) -1,2-dihydro-3H-ppiroo [1,2-a] pyiroo-1-carboxylate in 30 ml of 50% aqueous methanol containing 1% potassium hydroxide was de-refluxed under nitrogen. for 2 hours. The methanol was then removed under reduced pressure and the basic solution, which was diluted with water and extracted with chloroform, was removed in an insoluble matter. The aqueous alkaline phases were acidified with 20% hydrochloric acid and extracted three times with ethyl acetate, the combined extract was dried over sodium sulfate and evaporated to dryness under reduced pressure. In this way, 250 mg of crude (5 ^, p (3-thenpyl) p1,2-dihldrp-3H-pprool) 1,2a (α) p-palo-1-paloocaproic acid of formula Ia, R = Η, X = S. is obtained.

In the same manner, the other compounds obtained in Example 18 were converted to. o ^ ^ d ^ povcí djjíc free kyselinl ^ i, may thus be placed on nássedující compound 5- (3-1 Casinos!) - 1, ^l pudiyU rP-6-pyrrol-rethylp3H / 1,2-1-aPpyopoP kaъOoxyPovpu, klsePinu 5- (3-thenpyP) (-1,2udihydrp-6-prppl1-3H-prprp1,21a) PlyoolP-1-caucic acid 5- (3p1Urlrl (· ,, Pudirydrp-Z1pprpropool / 1,2-a)) 156 [deg.] C., 5- (3 [beta]: [alpha] -1r1) -1, p-glutyrp-6-methyl-3H-ppligol / 1,2-a] pyrogol-1 [beta] -cycloyl, and 5- (3 [beta]: UrllP ( p1, Pudirudop-6ppo-pplpl-ZHpplropl / 1, Pa / trans-1-capsule.

Example 20

A solution of 200 mg of 5- (2-furyl) -1,2-trifluoromethyl-3H-propyl [1,2-a] pylrpP-1-pyrazoxic acid in 5 ml of dichloromethane is treated with a sufficient amount of ethereal diazomethane and the reaction mixture is maintained at room temperature. !.! for 30 minutes. The residue and the excess reagent were removed under reduced pressure and the residue was crystallized in ethyl acetate and methaopPu to give methyl 5 - (2-fluoropyrrole-1,2H-pyrrolo-3H-pploo [1,2-a] pyrrole-1-carboxy).

In a similar manner, using avtak Uiazptthaou diazopropane and place diazprethaou obtained ethli (5ρ (2-Uupyl (· _1> PudlhyUгlp3H-pyrrolo / 1,2-a / plrop1-1 k6гЪρyylát and prop-S- (pfuro ^ ^ l) -1,2-dh-yrp-3H-pprooP (1,2pa) pyrrpP-1 pcarboxylate.

In the old manner, the remaining free acids obtained in Examples 10. A, 10 Bp1 (and 10 B-2), 13, and the acids of Examples 17 and 19 are converted to the deprotecting metal, ethyl and propyl esters.

Rettyl-5- (2-thtooyl) -1,2-urofiro-2 H -pyrrolo [1,2- a] pylrpP-1-carboxylate, Ethyl-5- (2-itenool) -1,2-dihydro-3H- oгrrt / 1,2-a / ρoУгotl1-CtrioxχУáá, propoУι-5- _{(2-thtncoУl-1>} 2-pyrrol-iihydiOtЗH / 1,2-L-anpoУΓΌt kaгitxylá ηηΠ · ta ^ ^ Ι, ethyl and propyl-oic esters of 5- (2-itenool) -1,2-nitro-2 H -pentyl] -1-1-pyrrole-1-carboxoxylic acid 1-isomer.

Example 21.

A solution of 5- (2-thenyl) -1,2-diphtydri-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (300 mg) in 5 ml was treated with hydrogen chloride. After 24 hours, excess alcohol is vacuumed and the granulated is purified by grinding. There was thus obtained isoaxyl (2-thennyl) -1,2-dihydroxy-3H-piperidine (1,2-a) -1-Cethoxylate.

Similarly, other esters are obtained, i.e., downyl, hexyl, octyl, nonnyl, dotdealkyl, etc., 2- (2-trifluoromethyl) -1,2-dihydro-3H-pogol / 1,2-a. The fatty acids are replaced by substitution of other alcohols, such as peenyl, hexyl, octyl, nonnl, iode, alcohol, etc.

By the same method, the free acids obtained in cases 10B-1, 13, 17 and 19 are eaten with a suitable alcohol so as to form esters, e.g.

isoaIml-5- (22-utotУ) -1, 2-ditydďOoЗ3 pyoюl / ^l, 22atpoггc0l·l-CaгitxyУát, pennyl 5- (4-meihУι2 ittnotl) -1, 2-iihydiOtЗ3 pyoюl / 1-L 122eap0lгot -Ctigitxylate, hexyl 5- (5-chloro-2-benzenol) -1,2-dihydro-2H-pyrrole / 1,22-eno-p-oxyl-1'-Ca-thioxylate, iso 811x1-5- (4-broccin-1-ol) (2-Chloro-1,2-nitro-2 H -pyrrole / 1,2-n ^- pyrrole-1-carboxylic acid, α, α) - (2 ^^ гц 2.) - 1,2 -dihydiOtЗ3-pyrrole / 1,22aapolyl-1-Ctitoxilate, nornl-5- (3-xethhl-22i-irooy) -1,2-ditldgo-ZH-ppггrt / 1,2-a / ppyroo-1 -Carb ^ a 4-Chloro-1- (3-chloro-2-trifluoromethyl) -1,2-dihydro-2 H -pyrrole [1,2-a] pyrimidine-1-carbonyl 4-Chloro-1- (4-chloro-2-thenosyl) -1,2-ditydro-33-6-methyl-1 H -porol 1, 2-a-piperidine-1-Cetitoxide, ββ Ι --- ^ ^m op op!! D O!!!!!!!!!!! 2 122 122 122 122 122 122 122 122 122 122 122 122 122 122 <^ - ^ - ^ b ^ H? p ^ ^] rrol '1,2-a / ppiroo-1-Спг ^ ху ^ Ъ

Example 22

To a solution of 300 mg of (2'-hexanol) -1,2-dihydro-3H-pplolo [1,2-a] ppyrotl-1-carioxylic acid in ml of methanol is added molar equivalent of sodium hydroxide in form 0, 1 N solution. The solvent was then evaporated under reduced pressure, and the residue was taken up in 2 ml of methanol, then triturated in ether to give crude - (2-thunool) -1,2-lithium-3H-oyrgt / l, Sodium 2-propyl-1-trioxide, which may still be fed in isopropanol.

Similarly, other salts, such as ammonium and potassium salts of (2-trifluoromethyl) -1,2-dhhydro-3H-pyrrolo [1,2-a] pyrido-1-nitro-ethylsulphonic acid, or ammonium hydroxide, or potassium hydroxide.

In a similar manner, the substituted 1,2-nitro-3H-piperidine / 1,2-n-olro-1H-nitro-biboxylic acid obtained in tadtit 10 B-1 (and 10 B-2), 13, 17 and 19, it converts into sodium, potassium and ammonium salts.

The antititanium compounds of the inCit compounds obtained are:.

1- (2-nitro) -1,2-dimethyl-3H-poly (1,2-a) sodium-1-sodium nitroxylate, - (- furoyl) -1,2-ditydiOtЗ3-pygyl / 1122 Sodium-1-Cetogitxylate sodium.

- (4-Sodium-2-thienol-1,2-dihydro-1,2-diol-3-pyrrole / 1122-npolгot-1-Cagitxylate sodium,

- Potassium (4-nitro-2-thienyl) -1,2-dihydro-3-pyrazole- / 112-anthiol-1-nitrite,

- (- iInt-2-thennoll-1,2-ditydrotЗ3-pyrrole / 1122anpolгot-l-ktгio: yУ.at potassium,

- (3-methyl-2-furoto) -1,2-dihydroxy-3-yyolol-1,22-n ^from sodium pylrol-1-octoxylate,.

- (2-furoyl) -1,2-dihyldi-3-pyrogol / [1,2-a] n -polrr)t-l-Ctrit:JyjИ.á t amoraný,

- (4-chloro-1,2-diol-3H-ol) 1,2-nolyl-1-carboxylate;

Sodium 5- (4-methyl-2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 5- (5-chloro-2-hheolyl) -1,2 Ammonium and 5- (3-furoyl) dihydroxy-3H-piperidine (1,2-apolyolpolylpolyxyl ether), 5- (3-phenool) -1,2-dihrdro-3H-pprool [1,2-a] pplol-1-carbonylxylate 11,2-dihldrlp3H-pplroO [1,2-a] pplol-1-propyl carboxylate.

Example 23

To a solution of 237 mg of 5- (2-chloro) -1,2-dihrdro-3H-proprole / 1,2pt / propanol-10-tasboxryl acid in 8 ml of methanol was added one molar equivalent of potassium hydroxide as a 0.1 N solution, thereby to give a solution containing 5- (2-henool) β 1, 2-dihydro-2 H -pyrrole [1,2- a] -proprolp potassium salt. A solution of 50 mg of calcium carbonate is dissolved in the minimum amount of 1N hydrochloric acid necessary to form a calcium carbonate solution; the solution is buffered with 100 mg of solid ammonium chloride, followed by the addition of 5 ml of water. The solution thus obtained is then added to a solution of 5- (2-henoxyl) -1,2-dihydroxy-3H-pplro (1,2pt) prrrl-1-trichloro-potassium and the precipitate which is formed is collected by filtration, washed with water and dried. in air to give 5- (2- · thenool) -1,2-dihydrol-1,3-proprole / 1,2-tyrrole-1-carboxylate

Similarly, magnesium 5- (2-henool) p1,2pdihldrl-3H-pplroO / 1,2-t-pyrrole-1-pyropoxylate is prepared by drying magnesium carbonate instead of calcium carbonate.

5- (2phhloool) p1,2pdihldolp3H-pilool (1,2pt) irorole-1-carbonyl, 1-isomer of 5- (2-furoyl) -1,2-dihldolp3H-pilool (1,2-a) 5- (4-Chloro-2-pyrrolidin-1-yl) -1,2-dihydro-3H-proprolo [1,2-a] pilool-1-carboxylic acid; dihdrl-3H-pplrole / 1,2-a] pilolol-1-carboxylic acid, 5- (5p-brm-P-Purool) p *, 2pdihrdrlp6pmeltlyl-3H-pprrole / 1,2pa / pyrrole-1-aabboxramic acid and 5- (3- Chloro-2-follol-1-yl-3 H -pyrrolo [1,2- a] pirool-1-carboxylic acid, instead of 5- (2-phenoxyl) -1,2-dihydro-3H-pilool [1,2-a] pilool-1-carboxylic acid, yielding calcium precipitates and magnesium salt.

Example 24

One copper solution was added to a solution of 237 mg of 5- (2-hexanol) -1,2-dihydro-3H-propro [1,2-a] pyrrole-1-aabboxrboxylic acid in 8 ml of methanol. equivalent of potassium hydroxide as a 0.1 N solution. Remove the roastener and dissolve the resdduum in 5 ml of water. The thus obtained aqueous solution of 5- (2-thiolol) p1,2pdihldolp3H-piloo [1,2-a] pyrimidine-1-iodine was added to a solution of 110 mg of copper nitrate in 5 ml of water. Wow! is collected, washed with water and dried OA 'air to give 5 -. (2-hhlnoll) -1,2pdihldro-ЗH-pprroO / 112-a / ^s lxyl yrrllp1pkéo ^{i s} t ^ me notes.

In a similar manner, the free acids obtained in cases 10B-1 (and 10B-2), 13, 17 and 19 can be converted into the corresponding copper salt.

Example 25

A solution of 237 mg of 5- (2-theoolyl) -1,2-dihrdro-3H-proprolo [1,2-a] pilool-1-carboxylic acid in 15 ml of hot benzene was treated with 59 mg. The solution was allowed to cool to room temperature and The product was washed with ether, washed in ether and dried to give the 5- (2-thiolol) p1,2-dihydro-3H-pplool / 1,2-t-pilool-1-carboxylic acid itolinylplamine salt.

Similarly, daltic amine salts are obtained, such as diethyllemium, ethanol, pipuridium, tromethamine, choline and caffeine 5- (2-hheolyl) p1,2pdihldrlp3H-ppyrrole / 1,2pt / iloril-11-tasboxrl amine tester, for example, with amine tastes.

In a similar manner, the free acids obtained in Examples 10B-1 or (10B-2), 13, 17 and 19) can be converted into the corresponding salts of isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine.

Example 26

Ingredients Quantity per mg tablet

5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid25 corn starch10 lactose, spray-dried153 magnesium stearate2

The above ingredients are carefully mixed and compressed into tablets.

Example 1 a d 27

Folders

Quantity per 1 tablet in mg

5- (2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole

-1-carboxylic acid 200 maize starch 50 lactose 145 magnesium stearate 5

The above ingredients are mixed and compressed into one notch tablets.

200 mg of the dl-mixture of 5- (2-thenoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid) can be replaced by 100 mg of the 1-isomer of the above compound.

Example 28

Folders

Amount per capsule in mg

5- (2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole

Potassium -1-carboxylate 108 lactose 15 maize starch 25 magnesium stearate 2

The above ingredients are mixed and placed in gelatin capsules.

Example. 29

Folders

Amount per capsule in mg

5- (2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole

Calcium -1-carboxylate 115 lactose 93 maize starch 40 magnesium stearate 2

The above ingredients are mixed and placed in gelatin capsules

Example 30

Folders Quantity per 1 tablet in mg • Isopropylammonium 5- (2-thenoyl) -1,2-dihydro-3H- -pyrrole [1,2-a] pyrrole-1-carboxylate cornstarch lactose magnesium stearate 245 75 175 5

The above ingredients are mixed and compressed into one notch tablets.

Example 31

Folders

Amounts per capsule in mg methyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate 25 lactose 125

The above ingredients are mixed and placed in No. 1 gelatin capsules

Example 32

Folders

Quantity per 1 tablet in mg

5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid sucrose

300

300

The above ingredients are mixed intimately and compressed into one tablet every three to four hours.

into one-notch tablets, taking

Example 33

Folders

Quantity per mg in mg isoamyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate maize starch lactose magnesium stearate

254

190

The above ingredients are mixed and compressed into one notch tablets

Example 34

Folders

Amount per capsule in mg

5- (2-thenoyl) -1,2-dihydro-2 H -pyrrolo [1,2- a] pyrrole-1-carboxylic acid lactose dextrose

100 ALIGN!

148

The above ingredients are mixed and placed in gelatin capsules.

ч

Instead of 100 mg of dl mixture of 5- (2-Theon ^yl) -1,2-dihydro-3H-pyrrolo / 1,2 "and / pyrrole-1" can be used carboxylic acid 50 mg of 1-ioomeou above compound.

Example 35

Ingredients Mnossos per capsule in mg mehl-5- (2-thenool) -1, (β-β-L11, β-β-propyl-1-caoboxylate) 158 lactose 92

The above ingredients are mixed and placed in gelatin capsules.

Example 36

Components of M ^^ per 1 tablet in mg β-β. 5 - ((2 · (thenool) (1,2-dihydro-2 H -pгgol / 1 12-a) prprl-1-k) oblxplate127 lactose9 'corn starch · 25 magnesium stearate2 gelatin5

The above ingredients are mixed and compressed into one notch tablets.

Example 37

Folders It is limited to 1 tablet in m 5- (2-thenoo-D-1,2-dihydro-3H-i) ρριο1 / 11223 / -ρριγο1- Calcium-1-cobobenzoate 230 Pellet starch (paste) • 40 starch starch · 50 you are / r / o magnesium 2 lactose · 178 The above ingredients are carefully mixed! and press into one-notch tablets. EXAMPLE 38 Folders Quantity per tablet in mg N-R-ynoD-1,2- (rih ^y drO13H-pyrrole) 112-a / pprrole- Potassium -1-k / oblxplate 217 cornstarch 50 ^ θ / ο * / ο magnesium 2 gelatine 226 lactose 5

The above ingredients are mixed and compressed into one notch tablets.

Example 39

Folders

Amounts per 1 capsule in mg of 5- (2- (1-chloro-1,2-dihydro-1H-syrroo [1,2-a])). maize is 6-thio-1-carboxylate

Škrobι ^ οζι starch

122

The above ingredients are mixed and placed in Selatin capsules ad 40

Folders

Polymer per capsule in mg isoamyl 5- (2-thenoyl-1,2-dihydro-3H-psrroo [1,2-a] syrroo-1-carboxylate lactose maize starch ltearao magnesium

101

The above-mentioned ingredients are intact! and placed in a piglet capsule

He said a .d 41

The pH 7 le buffered injection preparation is prepared from the following ingredients:

5- (2-thienyl) -1H-dihydro-4 H -propyl [1,2-a] pyrrole-1-carboxylic acid, 0.2 g 0.2 g

Κ2ΗΡΟ4 buffer (0.4 M solution) 2 mL

KOH (1 N) to pH 7 water (sterile, distilled) to 20 ml

Instead of 0.2 g dl of the 5- (2-thenool) -1,2-dihydro-1H-ppyrolo [1,2-l] pyrrole-1-aabboxylic acid mixture, 0.1 g of the 1-isomer of this compound can be used. ,

Example 42

A 2.8 g suppository is prepared from the following ingredients:

5- (2-thenoyl) -1,2-dihydro-2 H -propro [1,2-a] p -prole-1-carboxylic acid 25 mg

Witepsol Η — 15 (triglyceoidl of saturated plant fatty acids) addition of hmoonnoli

12.5 mg of 5- (2-thenoyl-L-1,2-ditydrooZH-pypyl / 1,2-l) pyrrole-1-carboxylic acid 1- (18-mole) can already be used instead of 25 mg dl of this compound.

Example 43

The oral suspension for the peddatric ponies consists of the following HoSeks:

Fumaric acid 1-loomyl-2-dihydro-HH-ppyrrole [1,2-d] pyrrole-carboxylic acid

0.1 g

0.5 g

2,0 g

O ¹ g

25,5 g

12.85 g> 0 g methylpareben granulated sugar sorbitol (70% solution) Veegum K flavor colorant distilled water

0,035 m

0.5 mg to 100 ml 44 and 45

The powder mixture for veterinary use is obtained from the following. Ingredients:

5- (2-thenool) - ¹ ^ -dihydro - ^ - pprroo / ljZ-and / pprrol-1-carboxylic acid sucrose polyvinyl pyrrolidone

Ex. 44

0.1 g

5.7 g

0.3 g

Ex. 45

1.2 g

3.7 g

0.3 g

Instead of 0.1 g of 5- (2-thenorl) -1,2-dihydro-2H-chloro [1,2-a] pyrrole-1-carbonylbenzyl (dl mixture), 0.05 g of 1- isomer of this compound.

Instead of 1.2 g of 5- (2-thenryl) -1,2-dihydro-2 H -pplro [1,2- a] pyrrole-1-carbonic acid, 0.6 g of the 1-thioene of this compound can be used.

Example 46

Biodata

A. Aialgesic (anti-writhing) experiment on spinal cord,

Procedure: The test substance is administered orally by gavage in an aqueous vehicle at 0-18 to 20 male Swiss-WeebSerl my! After 20 minutes, a 0.02% 0.25 ml / ml solution of 0.25 ml is injected intravenously. Twitching of the animals is observed for the next 10 minutes. The administered solution of quinoline causes jerking.

Results: Total number of twitching mice and twitches per mouse (mean).

Using the above procedure, it was established that:

the anaagetic effect of 5- (2-thienool) -1,2-uihldro-3H-pploor [1,2-a] pploor-1-carirxylic acid is about 350 times greater than the anaagetic effect of aspirin,

Alalgejický ioomeru effect of 1-5- (2-thjnool) -1,2-Uihldro-ЗH-pplror / _1,2-: and / iyrrul-1-carboxylic acid is greater than about 670krát anaagetický effect of aspirin,

B. Assay for Effectiveness Using Carrageenin to Induce Con Inflammation.

Procedure: female Stmnsen rats, weighing! 80 to 90 grams are used in the experiment. The test substance is administered orally by gavage at hour 0 in 1 ml of aqueous vehicle. At hour 1, 0.05 ml of a 1% solution (in 0.9% NaCl) of carrageenin was injected into the right hind leg of the rat. This injection causes inflammation. At hour 4, the rats. Both hind limbs are odoperated and increased.

Result:% increase in limb size calculated as follows:

Haotnoat right limb - weight of left limb. ... Smooth lion? 'Limbs' *

Using the above procedure, it has been determined that the finger-counting effect of 5- (2-nheosyl) -1,2-dihydrs-3H-yrroO- (1,2-a) pyrrole-1-carboxylic acid is 48 times greater (95% confidence limits): 32 to 72) than the anti-inflammatory effect of phenylbutane.

C. Test of α-β-thi-pyrrel-β-β-α (ε-fever) effect

Procedure: Female Simonsen rats of 90-100 grams were used in the assay. Normal rectal temperature of the rats is measured at hour 0, then injected with a 2 m suspension from the subcutaneous injection (1 O-dorsal, 1 O-ventral). The injection sites are massaged to disperse the suspension under the skin. Yeast injection causes a rise in body temperature (pуюsss). At hour 17, rats were re-aspirated to stimulate a further increase in body temperature. At 18, the second rectal temperature is measured and then the test substance is orally administered by gavage in a 10-aqueous vehicle. The third rectal temperature was changed 2 hours after administration of the test substance.

As a result, the temperature is reduced from the second to the third temperature reading.

Using the above procedure it was found that the effect of the acid

5- (2-thenoyl) -1,2-dihydro-3H-pprrol / 1,2-e / ^/ tr ^г гol-1kaθbboxrlové is 171km? Oate greater than that of aspirin.

D. Acute oral toxicity in molluscs (LD ^ _Q )

Procedure: Suspend the test substance in - 2% aqueous starch. The concentrations are adjusted so that doses can be given in volumes of 0.1 ml / 10 g body weight. Six groups of six Swiss-Websseries (females) are used in the experiment. A single oral dose, peculiar to the stomach tube is 50 mg, 100 mg, 200 mg, 400 mg 800 mg, or 1600 mg of 5- (2-thsooyl) -1,2-dihrdro-3H-pprooO / 1,2- e / prrrol-1-fireplaceboxlic acid per kilogrm body weight. These doses are administered to a human being, which is then observed for a weekly period.

Using the above procedure, the acute oral LD-q of 5- (2-thenoyl) -1,2-dihydro-3H-propro [1,2-e] thyrole-1-carboxylic acid is estimated to be - 631 mg / kg and with a 95% probability range from 404 to 991 mg / kg.

Claims (2)

A process for the preparation of derivatives of 5- (2-fluoro) -, 5- (2-fluoro) -1-, 5- (3-fluoro) and 5- (3-theooyl) -1, 2-dihrdro-ЗH-pprroO / 1,2-α / tyrool 1-kabboxrlové of formula I (I) and their pharmaceutically přijateOxých nstoxických sooí esters and wherein X is oxygen or sulfur, ^R, is hydrogen, methyl, chlorine, no ^b of ^b rom ^p -sulfonyl Rice ^{of R u} b ^{s t} i j UCS ^Vol ° p ^-O z ^{with 3.4} N ^SBO tion ^{5 of a furan,} or thiophene ^eh oc KLU ^y, ^ .s proviso that ^R1 is ^hydrogen, when js ^to Ar ^b onyl ^v1z1 ° ⁱⁿ p ^o l ^o from 3 furarnového or thiophene cycle and R js hydrogen or an alkyl group having 1 to 4 carbon atoms, vyzm-bore formed in that kondenzuuí compound of formula X (X) wherein R is as defined above and R is a C 1 -C 4 alkyl group having an amide of formula XIII, (xiii) wherein X and R ¹ are as defined above, wherein R 3 is substituted at the 3, 4 or 5 position of the furene or with the proviso that r 'is hydrogen when the carbonyl is attached at the 3-position of the furan or a thioeen cycle to form the corresponding compound of formula XI, R Wherein R, R, R and X are as defined above and the alkyl ester groups are hydrolyzed to give the free acid of formula I, or optionally esterify the carboxylic function of the compounds of formula I, or optionally convert them to their pharmaceutically acceptable non-toxic salts; If desired, the free acids of the formula I can be converted into their trisoxoisomers. 2. Method according to claim 1 for the preparation of compounds of formula I or their samootatných 1-isomer and p-iюíerů farmaceeuicky ořijaeeerých and their non-toxic esters and SDI, wherein X, ^R1 and ^R should uveěný importance of the ^{DE 1 b,} f ^y z ^ f ^ ^j uj ^classes II thieno ^from an asylum ester skupie ^and 'd ^ compounds of general formula XI is hydrolyzed to form 1-isomer and d-isomer of formula I or their SDI optionally sepoaují vdné kyseeiny formula I on Its 1-isomers and d-isomers, or optionally the d-isomer of the acids or their shares to the corresponding compounds of the formula I, or optionally esterifies the carboxyl function of the l-isomer or the d-isomer of the formula I, or these are converted into a pharmaceutically acceptable non-toxic sdi, and / or are optionally converted into a self-reacting sdi. of formula I to the corresponding free acids.