5-(2-pyrroyl)-1,2-dihydro-3h-pyrrolo(1,2-a)-pyrrole-1-car- boxylic acid derivatives

The invention relates to 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid compounds of the general formula (A):

in which R and R¹ each independently represents hydrogen or a C_1-4Alkyl group, and the individual (l) - and (d) acid isomers same and their phramazeutisch acceptable, non-toxic C_1-12Alkyl esters and salts.

The invention further provides a process for the preparation of these compounds and their use as drugs, especially for the treatment of inflammation, Pain, pyrexia and to delaying the onset of Contractions in pregnant women.

The alkyl groups represented by R and R¹ are preferably straight-chain, ie methyl, ethyl, n-propyl and n-butyl.

The above erfindungegemäßen, and described in more detail below Compounds exclusively of (d) acid isomers and the derivatives thereof, exhibit anti-inflammatory, analgesic and antipyretic efficiencies and are suitable Therefore for the treatment of inflammation, pain and Pyrexia in humans and mammals, as described in more detail below executed. Further, they are a means of relaxing the smooth Muscles.

As used herein, "pharmaceutically acceptable, non- toxic esters and salts "refers to" alkyl esters "derived from branched or straight chain hydrocarbons having 1-12 Carbon atoms are derived and the acceptable pharmaceutically, derived non-toxic, inorganic or organic bases Salts.

Typical alkyl ester groups are, for. Example, the methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopentyl, Hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl esters.

comprise derived from inorganic bases salts among others, the sodium, potassium, lithium, ammonium, Calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, Ferric or Manganisalze. Particular preference the ammonium, potassium, sodium, calcium and magnesium salts. The pharmaceutically acceptable organic non-toxic Bases derived salts include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted Amines, cyclic amines and basic ion exchange resins, such as, inter alia, isopropylamine, trimethylamine, diethylamine, Triethylamine, tripropylamine, Ätholamin, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, Lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, Betamin, ethylenediamine, glucosamine, methylglucamine, theobromine, Purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins.

Particularly preferred organic non-toxic bases are Isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, Dicyclohexylamine, choline, and caffeine.

The novel compounds of the formulas (A) and (XI) exist as Pairs of optical isomers (or enantio-), ie as (dl) mixture, and any optical isomers and (dl) mixtures are encompassed by the present invention.

If the new compounds of the invention are used, a physiological response (z. B. an anti-inflammatory, effecting analgesic or antipyretic effect), ie, if they are to be used as drugs, then a preferred sub-group that the compounds of formula (A) and the (l) acid isomers and their esters and pharmaceutically acceptable salts thereof.

to be used in a further subgroup of the drug as Compounds are those of formula (A) and (l) acid isomers of formula (A) and the esters and pharmaceutically acceptable salts, in which R is hydrogen and R¹ is methyl to stand.

The (d) acid isomers of the formula (A) and its esters, and pharmaceutically acceptable salts are useful as intermediates in the preparation of the (dl) -acid of formula (A), as in the following described.

The new (dl) compounds of the invention may for a prepared by the following reaction scheme method shown will:

In the above formulas, R and R¹ have the abovementioned meaning, and R is a lower C_1-4Alkyl group such as methyl, Ethyl, isopropyl and n-butyl.

equimolecular In the implementation of the above process Amounts of ethanolamine (I) and dimethyl-1 0.3-acetonedicarboxylate (II) at a temperature of about 0 ° C at about room temperature reacted, thereby obtaining the vinyl amine of formula (III). To prepare the compound of formula (IV) in which R is hydrogen, a solution of compound (III) is in a suitable inert organic solvent under anhydrous Conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at about 40-100 ° C. For a period of about 30 minutes to about 16 treated hours. Suitable solvents for this reaction are aprotic solvents such as acetonitrile, tetrahydrofuran, Dimethoxyethane, chloroform, dichloromethane, etc. In the preferred Embodiments the reaction takes place in acetonitrile at Reflux temperature for about 1 hour. The 2-bromo- (chloro) -acetaldehydreaktionsteilnehmer are known compounds or can by pyrolysis of the corresponding Diäthylacetale in presence obtained from oxalic acid. To prepare the compounds of formula (IV) in which R for a low, preferably straight chain alkyl group with 1-4 C atoms, is an aqueous mixture of ethanolamine (I) and dimethyl 1,3- acetonedicarboxylate (II) with a compound of formula

in which X represents bromine or chlorine, and R₃ low, preferably straight chain alkyl group 1-4 C-atoms, in particular 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-bromo-2-hexanone, at about -20 ° to about 40 ° C. for a period of about 30 minutes to about 16 hours treated. In the preferred embodiments, the reaction is carried out at about -10 ° C to room temperature for about 1-6 hours. The

are known compounds.

The esterification of a compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine, ie, for example triethylamine, pyridine, optionally in the presence of a co-solvent, such as dichloromethane, at a temperature of about -10 ° C to about room temperature for about 10 minutes to about 2 hours delivers the corresponding mesylate of formula (V), which are accessible by reaction Sodium iodide in acetonitrile at reflux for about 1-10 hours in the ebntsprechende N- (2-ethyl iodide) -pyrrole of formula (VI) is converted.

After reaction of Jodäthylverbindungen of formula (VI) with sodium hydride in a suitable inert, organic solvent, such as dimethylformamide, one obtains dimethyl 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylate and its 6-alkyl-substituted Derivatives (VII). This cyclization is carried out under an inert Atmosphere, ie, under argon or nitrogen atmosphere, at temperatures to about 15-40 ° C for a period of about 15 minutes to about 4 hours. The best results are obtained by the reaction at room temperature is carried out for about 30 minutes, when R = H.

The compounds of formula (VII) can also be by direct cyclization of the mesylate (V) with sodium hydride in dimethylformamide at about -10 ° C to about room temperature for about 30 minutes are produced to about 2 hours.

The basic hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate, such. as sodium hydroxide, Potassium hydroxide, sodium carbonate and potassium carbonate, in an aqueous ,, low, aliphatic alcohol such as methanol or ethanol, at a temperature between room temperature and reflux for about 4-24 hours provides the corresponding free diacid of the formula (VIII), ie 1,2-dihydro-3H-pyrrolo- [1,2-] pyrrole-1,7-dicarboxylic acid and the 6-alkyl derivatives. The Hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at reflux temperature for about 6-10 hours.

Then, the carboxylic acid group is in the C-1 position of the compound (VIII) selectively by treatment with a lower aliphatic Alcohol such as methanol, ethanol, isopropanol or n-butanol, in the presence of hydrogen chloride to form the corresponding Alkyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate 7-carboxylic acid of formula (IX) is esterified. The reaction is carried out at a temperature of about 0-50 ° C for about 1-4 Hours.

The decarboxylation of the monoesterified compounds (IX) to corresponding compounds of formula (X), the substantially Intermediates in the process for preparing the invention Compounds, can be carried out by reacting compound (IX) for a sufficient time to complete the reaction in a elevated temperature heated to about 230-280 ° C. The reaction course can by the rate of carbon dioxide evolution and thin-layer chromatographic analysis are pursued, the decarboxylation is usually completed in about 45-90 minutes. The reaction product, namely, alkyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and the 6-alkyl derivatives (X) can be prepared by chromatograpische Procedures to be cleaned. Further it can be, in particular for decarboxylation small batches of compound (IX), the Reaction product (X) distilled directly from the reaction vessel.

The condensation of a compound (X) with an amide of formula

in which R¹ has the above meaning, yields the corresponding Alkyl-5- (2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI). This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for about 15-70 hours under an inert atmosphere, followed by further reflux in Presence of sodium acetate for about 20 minutes to about 1 Hour. Instead of phosphorus oxychloride, other acid chlorides, such as phosgene or oxalyl used.

In the preferred embodiments, this condensation is carried out, by reacting a solution of compound (X) in a suitable solvent to a previously refluxing mixture of 1.1-2 molar equivalents of both the desired amide and the phosphorus oxychloride in the same solvent adding that so resulting reaction mixture is about 17-50 hours under an argon atmosphere heated to reflux and then about 3-10 molar equivalents Sodium acetate, and then adding about a further 30 Minutes heated to reflux.

Appropriate solvents for this reaction are the halogenated Hydrocarbons, such as dichloromethane, 1,2-dichloroethane, Chloroform or carbon tetrachloride, dimethoxyethane and Tetrahydrofuran, wherein 1,2-dichloroethane is preferred.

Suitable amides are N, N-dimethylpyrrole-2-carboxamide, N, N-dimethyl 1-methylpyrrole-2-carboxamide, N, N-dimethyl-1-äthylpyrrol- 2-carboxyamide, N, N-dimethyl-1--propylpyrrole-2-carboxamide and N, N-dimethyl-1-butylpyrrole-2-carboxyamide.

These amides can in the usual manner from the corresponding Pyrrole-2-carboxylic acids, that is, by conversion to the acid chlorides followed by treatment with dimethylamine can be prepared. The N-alkylpyrrole-2-carboxylic acids are known or can be prepared from the corresponding N-alkylpyrroles according to in Liebigs Ann. Chem. 721, page 105 (1969) described methods are made.

After alkaline hydrolysis of the alkyl ester group in a compound of the formula (XI) is obtained the corresponding free acid of formula (A). This hydrolysis is carried out in a conventional manner with an alkali metal hydroxide or carbonate, such as sodium hydroxide, Potassium hydroxide, sodium carbonate or potassium carbonate, in a aqueous lower aliphatic alcohol, such as methanol or ethanol, at a temperature of about room temperature up to the Reflux for about 15 minutes to about 2 hours under an inert The atmosphere. takes place in the preferred embodiments this hydrolysis with aqueous methanolic potassium carbonate at Reflux temperature for about 30 minutes.

The compounds of formula (A) can be by conventional methods the corresponding individual isomers aufgetrennt be.

The (l) acid isomers and (d) acid isomers of the compounds of Formula (A) as obtained by conventional methods, eg. By applying the known high-pressure liquid chromatography (HPLC) on the <i>α</i>-phenäthyldiastereoisomeren esters of the compounds of Formula (A), followed by acid cleavage. Thus, for. Example, the Compounds of the formula (A) in which R is H and R¹ Is methyl, by conventional known methods in accordance with the following flow chart to be further discussed:

The above (A¹) - (l) and -Säure- (A¹) - (d) are acid isomers (l) -5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carbonsä acid and (d) -5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

The free acids of formula (A) can be prepared by customary methods be converted into other alkyl esters having 1-12 carbon atoms, z. B. respective by treatment with (a) the the desired ester Alcohol in the presence of a strong mineral acid, (b) a ethereal diazoalkane or (c) the desired alkyl iodide in The presence of lithium carbonate. The (l) acid isomers can by the above methods (b) and (c) is converted into its alkyl esters will.

The salt derivatives of the compounds of formula (A) and the (L) - are acid isomers by treatment of the free acids with a corresponding amount of a pharmaceutically acceptable base produced. Suitable pharmaceutically acceptable bases include Sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, Calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, Copper hydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide, Manganihydroxid, isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, Caffeine, procaine, Hydrobamin, choline, betaine, ethylenediamine, Glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine or polyamine. The reaction is carried in water, alone or in combination with an inert, with miscible water, organic solvent at a temperature of about 0-100 ° C, preferably at Zimmertempertur. Typical inert, water-miscible organic solvents include methanol, Ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of the compounds of formula (A) or its (l) acid isomers to base is selected so that one achieved the desired for any particular salt ratio. to Preparation of the calcium or magnesium salts of the compounds of can the formula (A) or its (l) acid isomers z. B. Free Acid starting material with at least one-half molar equivalent pharmaceutically acceptable base to form a neutral Salt to be treated. In the preparation of aluminum salts the Verbindungn of formula (A) or its (l) acid isomers is at least one third molar equivalent of the pharmaceutically acceptable Base used if a neutral salt product is desired becomes.

In the preferred method, the calcium and magnesium salts may of the compounds of formula (A) and its (l) made acid isomers be by the corresponding sodium or potassium salts same with at least one-half molar equivalent Calcium or magnesium chloride in an aqueous solution, alone or in combination with an inert, water-miscible, organic solvent at a temperature of about 20-100 ° C. treated. The aluminum salts of the compounds of the invention can preferably be prepared by reacting the corresponding free acids with at least one third molar equivalent an aluminum such. B. Aluminiumtriäthoxid or Aluminiumtripropoxid, in a hydrocarbon solvent, such. as benzene, Xylene or cyclohexane, at a temperature of about 20-115 ° C treated. Similar methods can in preparing the salts of inorganic bases are used for a light reaction are not enough soluble.

Of course, the isolation of the compounds of the invention where appropriate by any suitable separation or Purification methods as described, for. Example, extraction, filtration, evaporation, Distillation, crystallization, thin layer or column chromatography, High pressure liquid chromatography or a Combination thereof. Suitable separation and isolation procedures can be found in the following examples, it being understood but any other equivalent separation or Isolation procedures can be applied.

Although the (d) acid isomers not per se as drugs are used, they can optionally after the conversion the (l) acid isomers in their pharmaceutically acceptable, non-toxic esters and Slaze method described in pharmaceutically converted acceptable, non-toxic esters and salts will.

The compounds of formula (A) and (l) acid isomers and their pharmaceutically acceptable, non-toxic esters and salts are valuable antiinflammatory and analgesic agents, inhibitors an aggregation of red blood cells, fibrinolytic Means and means for relaxing smooth muscle. The connections Both prophylactic and therapeutic be used.

Thus, these compounds are compounds containing for the treatment and elimination of inflammation, eg. as the muscle Bone system, the joints and other tissues, such as in the case of rheumatism, contusions, lacerations, arthritis, Bone fractures, post-traumatic conditions and gout. Where the said diseases pain and pyrexia associated with inflammation include compounds of the invention are also to facilitate these states.

Administration of the active compounds of the formula (A) or its (l) acid isomers and the phramazeutisch acceptable, non-toxic esters and salts thereof, in a corresponding pharmaceutical preparation may be in the for agents for treating or prophylaxis of inflammation, pain or pyrexia usual take place as such., orally, parenterally or topically, in the form solid, semi-solid or liquid dosages, for. example, as tablets, Suppositories, pills, capsules, powders, solutions, suspensions, Emulsions, creams, lotions or ointments, preferably in a for simple administration of precise dosage form suitable. The preparations include a conventional pharmaceutical carrier or an extender and an active compound of formula (A) or the (l) -Säureisomeres and their pharmaceutically acceptable, non-toxic Esters and salts and may further comprise other medical Aids, pharmaceutical agents, carriers and adjuvants include.

The preferred mode of administration for the diseases listed above is oral using suitable daily doses, which are set according to the extent of the disease can. Usually, a daily dosage of 25-1000 mg of active compound of formula (A) or its (l) acid isomers and their pharmaceutically annhembarer, non-toxic esters and salts used. Most diseases speaking to treatment with doses of about 0.5-15 mg / kg body weight per day. For a such oral administration, a pharmaceutically acceptable, non-toxic preparation by incorporating a conventional Extender formed such. B. pharmaceutical types of mannitol, Lactose, starch, magnesium stearate, sodium saccharin, talcum, Cellulose, glucose, sucrose or magnesium carbonate. The Preparations may, for. Example, the form of solutions, suspensions, tablets, take pills, capsules, powders or sustained release formulations.

The active compounds of formula (A) or their (l) acid isomers and their pharmaceutically acceptable, non-toxic ester and salts can be formulated into suppositories by z. B. polyalkylene glycols such as polypropylene glycol, used as a carrier. Liquid pharmaceutically administrable compositions can z. B. be prepared by one of the above active compounds and optional pharmaceutical adjuvants in a Carrier such as water, saline, aqueous dextrose, glycerol or ethanol, dissolves or disperses to form a solution or suspension. Optionally, the administered pharmaceutical Preparation also contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, z. B. Sodium acetate, sorbitan or Triäthanolaminoleat contain.

The methods of preparing such dosage forms are known or apparent to the artisan (see., "Remington's Pharmaceutical Sciences "Mack Publishing Comp., Easton, Pa, 14th ed., 1979). The preparation to be administered in each case contains a for the treatment of specific diseases effective amount of active compound (s).

The compounds of formula (A), its (l) acid isomers and the non-toxic, pharmaceutically acceptable esters and salts are also means of relaxation of uterine smooth muscle and thus suitable for the maintenance of pregnancy in favor of the mother and / or fetus, until the completion of the Pregnancy from the medical point of view as for mother and / or the fetus is considered cheap or cheaper. In particular Cases, however, z. B. when the contractions have already begun, ie the mother has uterine contractions, especially in almost full strength, then the administration of the present invention Compounds the pregnancy is not maintained indefinitely. In these cases, the pregnancy is usually somewhat "Extended", which may be advantageous for the mother and / or fetus.

In particular, the compounds of the formula (A) and their l-acid isomers and the pharmaceutically acceptable, non-toxic Esters and salts as agents for delaying the onset or used to postponing childbirth. The term "to delay the commencement of birth "means that delay birth, by administering the compounds of the Formula (A) or its l acid isomers and pharmaceutically acceptable, non-toxic esters and salts thereof, at any time causes before the contractions of the uterus muscle becomes. Thus, should the above expression the prevention of abortion in early stages of pregnancy, that is, before the fetus "viable" is, and include the delay of premature birth. The latter term is also sometimes called the premature Wehen applied that occur in later stages of pregnancy, when the fetus is considered "viable". In each Case be administered the agent as a prophylactic agent by can prevent the beginning of the birth of their administration. This administration is particularly useful in the treatment of Women who have been spontaneous abortions, miscarriages or premature Births have occurred. Such administration is also useful if there are clinical indications that the Pregnancy might be terminated prior to that date and if the administration considered beneficial for mother and / or fetus becomes.

In animals, this treatment can also be applied to the synchronize births in a group of pregnant animals, so that they at the same time or about the same time occur or desired in a particular time and / or or the same place near happen if they treated better can be.

As used herein, "the postponement of childbirth" is intended to include the delay of birth, by administering the compounds of formula (A) or its l acid isomers and pharmaceutically acceptable, non-toxic esters and salts by Beginning of the contractions of the uterus muscle caused. Of the Condition of the patient, including the time within pregnancy at which the contractions have begun, their seriousness and their current duration, affecting by the administration of the present compounds obtained results. The effect may be, for. Example, consist in the intensity and / or duration of the contractions is reduced (whereby the "Extended" actual birth process) or that the contractions be ever ended. In any case, there is a Effect is to extend the pregnancy, although the Effect according to the condition of the patient, as mentioned above, low or may be slightly larger in appropriate circumstances. Such administration can serve a spontaneous to prevent miscarriage, the birth easier and / or less painful to make for the mother or to the occurrence of birth create a more convenient time and / or place.

In each case, the administration of the compounds of formula should (A) and its l-acid isomers and pharmaceutically acceptable, non-toxic esters and salts for the above purposes with the best and / or accepted medical or veterinary Practice match to the benefits for mother and optimize fetus. For example, the administration should not be so long be continued beyond the due date beyond that of fetus dies in the uterus.

In the practice of the process of the invention a therapeutically effective amount of a compound of formula (A) or its l acid isomers and pharmaceutically acceptable, non-toxic esters and salts thereof or a pharmaceutical preparation, which this contains, the pregnant human or mammal administered in a customary, accepted way. The connections can be used individually or in combination with another compound or other compounds of the type defined above or with other pharmaceutical agents or auxiliaries be administered. The compound (s) or compositions can be administered orally or parenterally in the form of solid, semi-solid or liquid Dosage forms are administered. Usually, the administration is means a pharmaceutical preparation comprising the pharmaceutically active compound and one or more pharmaceutical containing carriers or excipients.

The pharmaceutical preparations can be administered eg., In the form tablets for oral administration, tablets or suppositories for insertion into the vagina or uterus, pills, capsules, liquid solutions or suspensions, preferably in Dosage forms for simple administration precisely Doses are also suitable. Ordinary, non-toxic solid carriers are z. B. pharmaceutical types of mannitol, lactose, starch, magnesium stearate, Sodium saccharin, talcum, cellulose, glucose, gelatin, Sucrose or magnesium carbonate. The above-mentioned compounds can be formulated as suppositories, by z. B. polyalkylene glycols, such as polypropylene glycol, used as a carrier. Liquid pharmaceutically administrable compositions can, for. Example, be prepared by reacting a compound of the above Type and usual pharmaceutical adjuvants in a carrier, such as z. B. water, saline, aqueous dextrose, glycerol or ethanol, dissolved or dispersed as a solution to form or suspension. Optionally, the administered pharmaceutical preparation also contain minor amounts of nontoxic auxiliary substances, such as wetting agents, emulsifying agents, or pH buffering means, z. B. sodium acetate, sorbitan or Triäthanolaminoleat, contain. Processes for preparing such dosage forms are known or obvious to the skilled person (see. eg. B. Remington's Pharmaceutical Sciences ", Mack Publishing Comp., Easton, Pa., 14th ed., 1970). The preparation to be administered or the formulation comprises in each case an effective amount of the or the drugs that delay the onset of parturition or Birth postpone, if the contractions of the uterus already have begun. In general, a daily dose of 0.5 to about 25 mg of active compound administered per kg body weight, wherein the administration is in the form of a single daily dose or in up to three or four smaller doses at regular Intervals are given during the day is done. The administered amount of the active compound depends, of course its relative activity.

The following experiment and examples illustrate the present Invention. The abbreviation "tlc" means "TLC" and all used in relation to liquids Mixing ratios are volume ratios. If necessary, examples are repeated to additional material prepare for subsequent examples; unless otherwise stated, the reactions at room temperature (20-30 ° C) performed.

try

A. A solution of 10 g of N-methylpyrrole-2-carboxylic acid in 20 cc of anhydrous benzene was treated with 11.5 cc of thionyl chloride and the reaction mixture for 16 hours under anhydrous conditions heated to reflux. Benzene and excess thionyl chloride were distilled off and the residue under reduced Pressure distilled to give 7.88 g of N-methylpyrrole-2-carbonyl chloride with a Kp._5mm79.84 ° C received.

B. Under an argon atmosphere were added 7.88 g of N-methylpyrrole-2- carbonyl chloride and 400 cc of anhydrous benzene mixed. The Solution was cooled in an ice-water bath to 5 ° C and anhydrous Dimethylamine was slowly bubbled through the solution. was allowed the temperature of the reaction mixture slowly to room temperature rise and headed dimethylamine by a further 5 minutes. Then, the reaction mixture was diluted with water, the organic Phase was separated and washed with 50 cc of 10% aqueous Hydrochloric acid, 50 cc of saturated sodium bicarbonate solution and twice washed with 50 cc of saturated sodium chloride solution. Of the organic extract was dried with anhydrous sodium sulfate, decolorized with animal charcoal and concentrated under reduced pressure to dryness evaporated, yielding 8 g of N, N-dimethyl-1-methylpyrrole-2-carboxamide as an oil having the following physical constants received:UV <i>λ</i> 221, 226 nm (<i>ε</i> 6900, 9300); IR<i>ν</i> 1610 cm^-1;NMR <i>δ</i> 3:08 (s, 6 H), 3.70 (s, 3 H), 5.87-6.05 (m, 1 H), 6:17 to 6:35 (m, 1 H), 6.47-6.65 ppm (m, 1 H). By repeating the above procedure using N-Äthylpyrrol-2-carboxylic acid, N--propylpyrrole-2-carboxylic acid and N-butylpyrrole-2-carboxylic acid as starting materials there was obtained N, N-dimethyl-1-äthylpyrrol-2-carboxyamide, N, N-dimethyl-1-propylpyrrol- 2-carboxamide or N, N-dimethyl-1-butylpyrrole-2-carboxyamide.

N -propylpyrrole-2-carboxylic acid and N-butylpyrrole-2-carboxylic acid were prepared by reacting N -propylpyrrole or N-butylpyrrole with Trichloroacetyl chloride to form the corresponding 2-Trichloracetylpyrrole and prepared by subsequent basic treatment (See. Lieb. Ann. Chem. 721, page 105 (1969)).

Following the procedure of Part B, which was described in J. Org. Chem. 41, Page 3050 (1976) obtained pyrrole-2-carbonyl chloride in N, N-Dimethylpyrrol- 2-carboxymid converted with an F. from 100.5 to 102 ° C.

example 1

A 250 cc three-necked round bottom flask, a magnetic stir bar contained and with a container filled with calcium chloride drying tube was provided, was directly (via one of the outer necks) by an adapter plate and a short (7.5 cm) water cooler connected to a Acetalpyrolysevorrichtung; latter consisted of a 100-cc Rundkolben (the previously 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethylacetal prepared of vinyl acetate according to J. Am. Chem. Soc. charged 66, 651 (1944) was), mounted a 15-cm Vigreux column to the was that a device connected to the radiator above Thermometer contained.

The three-necked flask was charged with 3.36 g of ethanolamine, the in an ice bath was cooled to 0-10 ° C, and charged with stirring treated dropwise with 8.7 g of dimethyl-1,3-acetonedicarboxylate. An immediate methyl-3-carbomethoxymethyl-3 (2'-hydroxyethyl) - aminoacrylate (III). After complete addition, the ice bath was removed and added to 100 cc of dry acetonitrile. The Pyrolyseteil the apparatus was placed in an oil bath and its temperature increased to 150-160 ° C. The forming Bromacetaldehydlösung was directly in the magnetically stirred solution of the vinyl amine (III) is distilled (bp. 80-82 ° C / 580 mm). When the distillation temperature fell below 80 ° C, the pyrolysis was removed and replaced by a reflux condenser equipped with a Calcium chloride-containing drying tube fitted. The Solution was heated to reflux temperature for 1 hour, solvent removed under reduced pressure, and then, the Residue 200 cc of methanol and 20 g of silica gel was added. These Mixture was evaporated under vacuum and to the head Trochne a column of 200 g of silica gel, which was filled in hexane, out. The column was then washed with 500 cc of a 80: 20-mixture of hexane: ethyl acetate and 9 x 500 cc of a 1: 1 mixture of Hexane: ethyl acetate eluted. Fractions 2 and 3 contained less polar impurities and dimethyl 1,3-acetonedicarboxylate; fractions 4-8 yielded 4.1 g of methyl N- (2-hydroxyethyl) -3- carbomethoxypyrrol-2-acetate (IV; R = H), which after recrystallization of ethane / hexane had a F. of 52-54 ° C.

example 2

To a solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrol- 2-acetate in 35 cc of dry dichloromethane (to -10 ° C. cooled) with stirring, 2.65 cc of triethylamine and then dropwise 1.46 cc methanesulfonyl, the maintained the reaction mixture temperature at -10 ° to -5 ° C has been. The reaction progress was monitored by TLC analysis using 90: 10 chloroform: acetone followed. When the reaction seemed completed (about 30 minutes after completed addition of methanesulfonyl chloride), 10 cc of water was added slowly. The organic Phase was separated, washed three times with 30 cc of water, dried over sodium sulfate and concentrated under reduced pressure evaporated. After crystallization of the residue from dichloromethane / hexane there was obtained 4.75 g of methyl N- (2-mesyloxyäthyl) -3- carbomethoxypyrrol-2-acetate (V; R = H) with an F. of 99-101 ° C.

example 3

A solution of 785 mg of methyl N- (2-mesyloxyäthyl) -3-carbomethoxypyrrol- 2-acetate and 1.83 g of sodium iodide in 10 cc acetonitrile was heated to reflux for 1 hour. The cooled reaction mixture was evaporated under reduced pressure to dryness and the residue triturated with water. The insoluble material was filtered off and air dried, yielding 840 mg of methyl N- (2-ethyl iodide) -3-carbomethoxypyrrol-2-acetate (VI; R = H) with a F. of 137-138 ° C was given.

example 4

A solution of 1 g of methyl N- (2-ethyl iodide) -3-carbomethoxypyrrol- 2-acetate in 5 cc of dry dimethylformamide under an Argon atmosphere with 137 mg of 50% sodium hydride in mineral oil touched. The reaction mixture was 30 minutes at room temperature held and then quenched with 100 ml of water. The product wu RDE extracted three times with 50 cc of ethyl acetate, and the combined Extracts were washed with water, over magnesium sulfate dried and evaporated to dryness. chromatography of the residue on 20 g silica gel using 4: 1 Hexane: ethyl acetate as eluant afforded 500 mg of dimethyl-1,2-dihydro 3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate (VII; R = H) with a F. of 70-71 ° C.

A solution of 1.80 g dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] - pyrrole-1,7-dicarboxylate in 20 cc of methanol was added a solution treated from 4.48 g of potassium hydroxide in 20 cc of water and the reaction mixture heated to reflux for 6 hours. The cooled Solution was evaporated to dryness and the residue with 50 cc treated saturated sodium chloride solution. The resulting solution was acidified with 6 N hydrochloric acid and three times with 50 cc of ethyl acetate extracted. The combined extracts were dried over magnesium sulfate dried and evaporated under reduced pressure to dryness. This gave 1.51 g of 1,2-dihydro-3H-pyrrolo [1,2-a] - pyrrole-1,7-dicarboxylic acid (VIII; R = H) with mp of 220 ° C u. dec.

example 5

A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1,7- was dicarboxylic acid in 50 cc of isopropanol, (cooled in an ice bath) saturated with gaseous hydrogen chloride, maintaining the temperature the reaction mixture was kept below 50 ° C. Then the Ice bath was removed and the reaction mixture for 1.5 hours at room temperature stirred and evaporated under reduced pressure to dryness; to the residue 10 cc of benzene were added and the Solution evaporated again under vacuum, said method total of three times to completely remove the excess Hydrogen chloride was repeated; so obtaining 1.58 g isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX; R = H; R² = iC₃H₇) which, after crystallization from methanol / ethyl acetate an F. of 144-145 ° C had.

By using methanol, ethanol, propanol and n-butanol instead of isopropanol in the above process was obtained in a similar Wise:Methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carbonsäur-eEthyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acidPropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carbonsäur-e or.Butyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid.

example 6

1.054 g of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic-äure was in a dry 10-cc round bottom flask heated to 240-250 ° C, the reaction product from Reaction vessel was distilled .. This gave 745 mg of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H; R = iC₃H₇) as a pale yellow oil having the following physical constants:UV: <i>λ</i>Kn 1725 cm^-1;NMR: <i>δ</i> 1.22 (d, <i>J</i> = 7 Hz, 6 H), 2.40 to 2.90 (M, 2 H), 3.60 to 4.20 (m, 2 H), 4.65 to 5.2 (m, 1 H), 5.73 to 5.92 (M, 1 H), 6.10 (t, <i>J</i> = 3 Hz, 1 H), 6.43 to 6.53 ppm. (M, 1 H).

example 7

One with a condenser, nitrogen inlet tube and gas blower (bubbler) PROVIDED 100 cc three-necked round bottom flask was charged with 5.0 g of isopropyl 1,2-dihydro- 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid charged. The apparatus was flushed with nitrogen gründlicch, then the nitrogen flow was interrupted. The apparatus was immersed in a heated oil bath at 270 ° C and the ROUP by the rate of carbon dioxide evolution (gas fan) as well as by TLC on silica gel using 90/10/1 benzene: dioxane: acetic acid as the developing solvent tracked. After 15 minutes the reaction was almost completed. After one hour, the vessel was removed from the oil bath and the contents the reaction flask converted acetone in a round bottom flask with 500 cc. The solvent was removed under reduced pressure and the residue purified by column chromatography on 100 g Silica gel purified. The 70/30 hexane: benzene and 50/50 Hexane: benzene eluted fractions yielded 2.77 g of isopropyl 1,2- dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H; R² = iC₃H₇) as an oil, whose physical constants with those of Example 6 were identical.

example 8

A solution of 204 mg of N, N-dimethyl-1-methylpyrrole-2-carboxyamide anhydrous in 10 cc of dichloromethane 307 mg of phosphorus oxychloride acid was 30 minutes under an argon atmosphere heated to reflux. To this solution, a solution of 193 mg of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate added in 15 cc of 1,2-dichloroethane. The reaction mixture was 50 hours under an argon atmosphere was heated to reflux on cooled room temperature and, with a solution of 1.36 g of sodium acetate dissolved in 15 ml of water, treated. The resulting mixture was further heated for 30 minutes under reflux, cooled, the organic phase was separated and the aqueous phase extracted with chloroform extracted. The combined organic solutions were washed twice with 10 cc of saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced Pressure evaporated to dryness. The oily residue was purified by TLC using 3: 97 ethyl acetate: methylene chloride as the Eluant afforded 253 mg of purified and isopropyl-5- (N-methyl-2- pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI; R = H; R = CH₃; R = iC₃H₇) as a pale yellow oil having the following physical constants:UV <i>G</i> 260-275 (Shoulder), 330 nm (<i>ε</i> 4790, 19500); IR<i>ν</i> 1735, 1600 cm^-1;NMR <i>δ</i> 1.27 (d, 6 H <i>J</i> = 6 Hz), 2.50 to 3.10 (m, 2 H), 3.85 (s, 3 H), 3.92 (dd, 1 H, <i>J</i>_<i>AX</i>= 6 Hz, <i>J</i>_<i>BX</i>= 7 Hz; H-1), 4.17 to 4.60 (m, 2 H), 4.95 (sept., 1 H, J = 6 Hz), 5.85 to 6.20 (M, 2 H), 6.60 to 7.87 ppm (m, 3 H), MS <i>m / e</i> 300 (M⁺).

example 9

A mixture of 1.2 g of isopropyl-5- (N-methyl-2-pyrrole) -1,2-dihydro- 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 1.1 g of potassium carbonate and 25 cc of a 4: 1 methanol: water mixture was under a Nitrogen atmosphere, heated for 30 min at reflux, cooled and evaporated to dryness. The residue was dissolved in 50 cc of water was added and extracted three times with 10 cc ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and ten times extracted with 15 cc of ethyl acetate. The combined extracts were washed with saturated sodium chloride solution with anhydrous Sodium sulfate and dried under reduced pressure to Dryness. After crystallization of the residue from Methylene chloride-ether-hexane to give 636 mg of 5- (N-methyl-2- pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [(A); R = H, R¹ = CH₃] F. with a 161 to 161.5 ° C from.

example 10

According to the method of Example 6 or 7, the other, in Example 5 obtained compounds converted to:Methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylateEthyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylatePropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate andButyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

After condensation of these compounds with N, N-dimethyl-1-methylpyrrole 2-carboxyamide in Example 8 to give the following compounds:Methyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate Ethyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylatePropyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole carboxylate andButyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate.

example 11

Example 8 was to using 1.5 molar equivalents ofN, N-dimethylpyrrole-2-carboxamideN, N-dimethyl-1-äthylpyrrol-2-carboxamideN, N-dimethyl-1--propylpyrrole-2-carboxamide andN, N-dimethyl-1-butylpyrrole-2-carboxamiderepeated in place of N, N-dimethyl-1-methylpyrrole-2-carboxamide and delivered as:Isopropyl-5- (2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate; F. 131.5 to 132.5 ° C.Isopropyl-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-- 1-carboxylateIsopropyl-5- (N-propyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate andIsopropyl-5- (N-butyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-- 1-carboxylate.

After hydrolysis of the Isopropylestergruppe by the method of Example 9 yielded the corresponding free acids, namely:5- (2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid; F. 217-218 ° C5- (N-ethyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-propyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid and5- (N-butyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

example 12

A 250 cc three-necked round bottom flask, a magnetic stir bar contained and with a container filled with calcium chloride drying tube was was charged with 3.36 g of ethanolamine (in an ice bath cooled to 0 ° C) and charged dropwise with stirring 8.7 g of treated dimethyl-1,3-acetone-dicarboxylate. It formed immediately methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) - aminoacrylate (III). After complete addition, the ice bath was removed, and there were added 80 cc dry acetonitrile. Then the reaction mixture was treated dropwise with 6.75 g of bromoacetaldehyde treated in 20 cc of acetonitrile and then for 2 hours heated to reflux. The solvent was reduced pressure removed, and the residue was added 200 cc Of methanol and 20 g of silica gel added. This mixture was evaporated to dryness under vacuum and in the head Column added of 200 g of silica gel, which filled in hexane was, eluting the column with hexane: ethyl acetate eluted mixtures has been. The 1: 1 hexane: ethyl acetate eluted fractions yielded Methyl-N- (2-hydroxyethyl) -3-carbomethoxypyrrol-2-acetate (IV; R = H) identical to the product obtained in Example 1 is.

example 13

To a solution of 6 cc of ethanolamine in 5 ml of water was in an amount 1.74 g was added dimethyl 1,3-acetonedicarboxylate. The obtained mixture was quickly cooled to -10 ° C and dropwise within 15 minutes while stirring with 1.67 cc treated 1-bromoacetone, while the reaction mixture on an Temperature was not kept above 40 ° C. After completion of the addition was the dark reaction mixture an additional hour at stirred room temperature and then poured into a mixture of hydrochloric acid and poured ice, saturated with solid sodium chloride and extracted three times extracted with 100 cc of ethyl acetate. The combined organic Extracts were washed neutral with cold water, with dried anhydrous sodium sulfate and concentrated under reduced Pressure evaporated to dryness. After chromatography of the residue on 30 g of silica gel using 70: 30 Hexane: ethyl acetate as eluant to give 890 mg of crystalline Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV; R = CH₃), which after recrystallization from methylene chloride / hexane an F. of 78 ° C had.

Were used instead of 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone, 1-bromo-2-hexanone, or the corresponding 1-chloro derivative used, was obtained in a similar manner:Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-äthylpyrrol-2-acetateMethyl-N- (2-hydroxyethyl) -3-carbomethoxy-4--propylpyrrole-2- acetate andMethyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate.

example 14

To a solution of 7.7 g of methyl N- (2-hydroxyethyl) -3-carbomethoxy 4-methylpyrrole-2-acetate in 200 cc of dry dichloromethane (Cooled to 0 ° C) were added while stirring 4.24 cc of triethylamine and 2.4 cc of methane-sulfonyl chloride added. The reaction mixture for 15 minutes kept at room temperature and then with water diluted. The organic phase was separated, washed three times with washed per 30 cc of water, dried over anhydrous sodium sulfate and at reduced pressure evaporated to dryness. After crystallization of the residue from methanol gave 9.04 g of methyl N- (2-mesyloxyäthyl) -3-carbomethoxy-4-methylpyrrole 2-acetate (V; R = CH₃) with an F. of 81 ° C.

A solution of 9.067 g of methyl N- (2-mesyloxyäthyl) -3-carbomethoxy 4-methylpyrrole-2-acetate in 250 cc of dry acetonitrile was treated with 20.23 g of sodium iodide and the mixture obtained heated to reflux for 8 hours. The solvent was then vermindetem evaporated under pressure to dryness and the residue was added to 100 cc of dichloromethane. The organic Solution was washed twice with 40 ml of water, with anhydrous Sodium sulfate and dried under reduced pressure to Dryness. After crystallization of the solid residue from hexane-ether gave 9.13 g of methyl N- (2-ethyl iodide) -3- carbomethoxy-4-methylpyrrole-2-acetate (VI; R = CH₃) with a F. of 103 ° C.

example 15

To a suspension of 660 mg of sodium hydride in 250 cc dry Dimethylformamide (cooled to 0 ° C and under a nitrogen atmosphere kept) were added with stirring 9.13 g of methyl N- (2-ethyl iodide) -3-carbomethoxy-4-methylpyrrole-2-acetate was added. The reaction mixture was stirred for 3 hours at room temperature and then quenched with 250 ml of water. The product was extracted three times with 100 cc of benzene, the combined extracts washed twice with 100 cc of water, over anhydrous sodium sulphate dried and evaporated under reduced pressure to dryness. After chromatography of the residue on 200 g silica gel using 70: 30 hexane: ethyl acetate as Eluant gave 4.56 g of dimethyl-1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate (VII; R = CH₃), which by Recrystallization from ether-hexane had a F. of 71 ° C.

A solution of 3.81 g dimethyl-1 .2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole- 1,7-dicarboxylate in 30 cc of methanol was treated with treated a solution of 8.96 g of potassium hydroxide in 15 cc of water and the reaction mixture heated to reflux for 8 hours. Then the methanol was removed under reduced pressure, the aqueous Solution was cooled to 0 ° C and with 20% hydrochloric acid acidified. The precipitate formed was filtered off, with water washed, dried in an oven and recrystallized from methanol; This gave 2.55 g of 1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = CH₃) with a F. 200-230 ° C u. Dec.

example 16

A solution of 3.8 g of 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1,7-dicarboxylic acid in 100 cc of freshly distilled isopropanol was cooled to -10 ° C and with gaseous hydrogen chloride saturated. Then, the ice bath was removed and the reaction mixture stirred for 3 hours at room temperature and under reduced Pressure evaporated to dryness. The residue was dissolved in 100 cc Ethyl acetate and the solution saturated with twice 100 cc sodium chloride solution, dried over anhydrous Sodium sulfate and dried under reduced pressure to dryness evaporated. After crystallization of the residue from acetone-water there was obtained 3.74 g of isopropyl 1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, R = CH₃; R = iC₃H₇) with an F. 160 ° C.

8 g of isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1- carboxylate-7-carboxylic acid was dissolved in a distillation apparatus heated for about 1 hour at 240 ° C. During the decarboxylation distilled a light yellow oil and delivered as 4.61 g isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X; R = CH₃; R² = iC₃H₇). This substance is in the air at room temperature very unstable and should be immediately in the next stage be used; They had the following physical constants:UV <i>λ</i> 226, 250 (shoulder) nm. (<i>ε</i> 4900, 2240); IR<i>ν</i> 171 cm^-1;nmr <i>δ</i> 1.22 (d, 6 H, <i>J</i> = 6 Hz; Ester CH₃) 2.03 (s, 3 H; ring CH₃), 2.42 to 2.93 (m, 2 H; CH₂), 3.55 to 4.17 (m, 3 H; NCH₂, CHCO), 4.92 (sept., 1 H,<i>J</i> = 6 Hz; CH of the ester) 5.66 (s, 1 H; H-3), 6.25 (s, 1 H; H-5);

example 17

According to Example 8 Isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole was 1-carboxylate with N, N-dimethyl-1-methylpyrrole 2-carboxamide condensed and delivered isopropyl-5- (N-methyl-2- pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI; R and R = CH₃; R² = iC₃H₇).

Were used instead of N, N-dimethyl-1-methylpyrrole-2-carboxyamide those mentioned in Example 11, N, N-dimethylpyrrole-2-carboxamide used, was obtained in a similar manner:Isopropyl-5- (2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -pyrro-l- 1-carboxylateIsopropyl-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate Isopropyl-5- (N-propyl-pyrroyl) -1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate andIsopropyl-5- (N-butyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate.

example 18

Following the procedures of Examples 14, 15 and 16 were obtained by Using methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-äthylpyrrol- 2-acetate, methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4- -propylpyrrole-2-acetate and methyl N- (2-hydroxyethyl) -3-carbomethoxy 4-butylpyrrole-2-acetate as starting materials instead of Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate the following end products:Isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylateIsopropyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate andIsopropyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

example 19

According to Example 8, the compounds obtained in Example 18 were with N, N-dimethyl-2-pyrrolamidreaktionsteilnehmern of Examples 8 and 11 is condensed and supplied the corresponding . 5-Pyrroylderivate, such as, inter alia:Isopropyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2 - a] pyrrole-1-carboxylateIsopropyl-5- (2-pyrroyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole - 1-carboxylateIsopropyl-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-butyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate Isopropyl-5- (N-propyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylateIsopropyl-5- (N-butyl-2-pyrroyl) -1,2-dihydro-6-propyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylateIsopropyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-butyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate andIsopropyl-5- (2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrol-- 1-carboxylate.

example 20

A solution of 500 mg of isopropyl-5- (N-methyl-2-pyrroyl) -1,2- dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 15 cc Methanol was in with a solution of 1.05 g of potassium carbonate treated 8 cc of water. The reaction mixture was under a Nitrogen atmosphere, heated for 30 min at reflux, cooled and evaporated to dryness. The residue was dissolved in 10 cc was added 10% aqueous hydrochloric acid and 50 cc of water and the mixture obtained extracted three times with 50 cc ethyl acetate. The combined extracts were dried over magnesium sulfate dried and evaporated under reduced pressure to dryness and yielded 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid [(A); R and R¹ = CH₃].

Similarly, the remaining were Isopropylesterverbindungen of Example 17 and the compounds of Example 19 in converted the corresponding free acids, namely:5- (2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid 5- (N-propyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrol-- 1-carboxylic acid5- (N-butyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (2-pyrroyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-propyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-butyl-2-pyrroyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid and5- (2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid

example 21

A solution of 200 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6- methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 cc of methylene chloride was treated with excess ethereal diazomethane and the reaction mixture 30 minutes at room temperature kept. The solvent and the excess reagent was eliminated under reduced pressure and the residue from ethyl acetate / methanol crystallized to give methyl 5- (N-methyl-2- pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate received.

By using diazoethane and diazopropane instead of Diazomethane was obtained in a similar manner ethyl 5- (N-methyl-2- pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate or propyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate.

In similar manner there were the remaining, obtained in Example 20, free acids into the corresponding methyl, ethyl and propyl converted.

example 22

A solution of 300 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 cc of isoamyl alcohol was saturated with hydrogen chloride. After 24 hours, the excess Alcohol distilled off under vacuum and the residue purified by chromatography on alumina to yield isoamyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrro lo [1,2-a] pyrrole 1-carboxylate obtained.

Similarly, were using other alcohols, such as pentyl, hexyl, octyl, nonyl or dodecyl alcohol, instead of isoamyl alcohol other esters such as the pentyl, hexyl, Octyl, nonyl or Doedcylester, the 5- (N-methyl-2-pyrroyl) - 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

Under the same procedure were in Examples 11 and 20 obtained, esterified free acids with the corresponding alcohol and so afforded the corresponding ester such. B.Pentyl-5- (2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-- carboxylate Hexyl-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylateOctyl-5- (N-propyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylateDodecyl-5- (N-butyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylateIsoamyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylateNonyl-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyr-rol-1 carboxylateIsoamyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylatePentyl 5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] py-rrol- 1-carboxylateHexyl-5- (N-propyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] py-rrol- 1-carboxylate andDodecyl-5- (N-butyl-2-pyrroyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate

example 23

To a solution of 300 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro- 3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 cc of methanol was 1 molar equivalent of sodium hydroxide in the form of a 0.1 N solution added. Then, the solvent was evaporated under reduced pressure evaporated and the residue taken up in 2 cc of methanol and precipitated with ether; This gave crude sodium 5- (N-methyl- 2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, which can be crystallized from ethyl acetate-hexane.

instead of by use of ammonium hydroxide and potassium hydroxide of sodium hydroxide were other salts, for. example, the ammonium and Potassium salt, of 5-N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

Similarly, the other, obtained in Examples 11 and 20 can 5-substituted 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid compounds into the corresponding sodium, potassium and ammonium salts are converted such. B.Sodium-5- (2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1- carboxylateSodium-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylatePotassium 5- (N-propyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-- carboxylateAmmonium-5- (N-butyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrol-- 1-carboxylateSodium-5- (2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -pyrrol-- 1-carboxylateSodium 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a -] - pyrrole 1-carboxylateAmmonium-5- (N-ethyl-2-pyrroyl) -1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] - pyrrole 1-carboxylatePotassium-5- (2-pyrroyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylateSodium-5- (N-propyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] - pyrrole 1-carboxylatePotassium 5- (N-butyl-2-pyrroyl) -1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] - pyrrole 1-carboxylate andAmmonium 5- (2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] -pyrrol-- 1-carboxylate.

example 24

To a solution of 175 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 cc of methanol was added 1 added molar equivalent of potassium hydroxide in the form of a 0.1 N solution and so provided a potassium 5- (N-methyl-2-pyrroyl) -1,2- dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate containing solution. A solution of 40 mg of calcium carbonate in the same to solve necessary minimum quantity of 1 N hydrochloric acid was fixed at 100 mg Ammonium chloride buffered, and then 5 ml of water were added. The calcium solution thus obtained, which was then buffered to a Solution of potassium 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylates were added and the precipitate formed filtered, washed with water and air dried. So was obtained calcium-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate.

By using magnesium carbonate instead of the calcium carbonate was obtained in a manner similar magnesium-5- (N-methyl-2- pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.By using5- (2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid5- (N-ethyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-propyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-butyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrol-- 1-carboxylic acid 5- (N-propyl-2-pyrroyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acidinstead of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid gave the corresponding Calcium and magnesium salts.

example 25

A solution of 200 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 15 cc of hot benzene was treated with 60 mg of isopropylamine. The solution was Room temperature allowed to cool and the product filtered off, washed with ether and dried; so to give the isopropyl the 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

By using the corresponding amines instead of isopropylamine can Similarly, other amine salts, eg. as the Diäthylamin-, Ethanolamine, piperidine, tromethamine, choline and Caffeine salt, of the 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid are prepared.

Further, the obtained in Examples 11 and 20 in this manner, free acid compounds into the corresponding isopropylamine, Diäthylamin-, ethanolamine, piperidine, tromethamine, Choline and caffeine acid are converted.

example 26

A solution of 770 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 10 cc of benzene was treated with treated 580 mg Dicyclohexamin. The reaction mixture was stirred for 10 minutes and the dye formed was filtered off and washed with anhydrous ether; so obtaining 965 mg of Dicyclohexaminsalzes the 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

Similarly, those obtained in Examples 11 and 20, free acid compounds into the corresponding dicyclohexylamine being transformed.

example 27

The following ingredients were thoroughly mixed and single scored tablets pressed:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">5- (2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole - 1-carboxylic acid</entry><entry align="right">25</entry><row><entry align="left">cornstarch</entry><entry align="right">20</entry></row><row><entry align="left">Lactose (spray dried)</entry><entry align="right">153</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row></tbody></tgroup>

example 28

The following ingredients were thoroughly mixed and single scored tablets pressed:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid</entry><entry align="right">200</entry><row><entry align="left">cornstarch</entry><entry align="right">50</entry></row><row><entry align="left">lactose</entry><entry align="right">145</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">5</entry></row></tbody></tgroup>

100 mg of (l) -5 - (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole- 1-carboxylic acid was used in place of 200 mg of (dl) Compound the above preparation used.

example 29

The following ingredients were mixed and a capsule introduced with hard gelatin shell:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">Sodium 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">108</entry><row><entry align="left">lactose</entry><entry align="right">15</entry></row><row><entry align="left">cornstarch</entry><entry align="right">25</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row></tbody></tgroup>

example 30

The following ingredients were mixed and a capsule introduced with hard gelatin shell:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">Calcium-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">115</entry><row><entry align="left">lactose</entry><entry align="right">93</entry></row><row><entry align="left">cornstarch</entry><entry align="right">40</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row></tbody></tgroup>

example 31

The following ingredients were intimately mixed and single, scored tablets pressed:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">Isopropylammonium-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">245</entry><row><entry align="left">cornstarch</entry><entry align="right">75</entry></row><row><entry align="left">lactose</entry><entry align="right">175</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">5</entry></row></tbody></tgroup>

example 32

The following ingredients were mixed and a capsule introduced with hard gelatin shell no. 1:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">Isopropyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro - 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">25</entry><row><entry align="left">lactose</entry><entry align="right">125</entry></row></tbody></tgroup>

example 33

The following ingredients were thoroughly mixed and single scored tablets processed, all 3-4 Hours one tablet was administered:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid</entry><entry align="right">300</entry><row><entry align="left">sucrose</entry><entry align="right">300</entry></row></tbody></tgroup>

example 34

The following ingredients were thoroughly mixed and single scored tablets pressed:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">Isoamyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">254</entry><row><entry align="left">cornstarch</entry><entry align="right">50</entry></row><row><entry align="left">lactose</entry><entry align="right">190</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">6</entry></row></tbody></tgroup>

example 35

The following ingredients were mixed and a capsule introduced with hard gelatin shell:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid</entry><entry align="right">100</entry><row><entry align="left">lactose</entry><entry align="right">148</entry></row><row><entry align="left">dextrose</entry><entry align="right">2</entry></row></tbody></tgroup>

Instead of 100 mg of (dl) compound of the above preparation 50 mg of (L) -5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid used.

example 36

The following ingredients were mixed and a capsule introduced with hard gelatin shell:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">Methyl-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">158</entry><row><entry align="left">lactose</entry><entry align="right">92</entry></row></tbody></tgroup>

example 37

The above components were mixed and tablets each pressed:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">Isoamyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">127</entry><row><entry align="left">lactose</entry><entry align="right">91</entry></row><row><entry align="left">cornstarch</entry><entry align="right">25</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row><row><entry align="left">gelatin</entry><entry align="right">5</entry></row></tbody></tgroup>

example 38

The following ingredients were thoroughly mixed and pressed into single scored tablets:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">Calcium-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">230</entry><row><entry align="left">Corn starch (paste)</entry><entry align="right">40</entry></row><row><entry align="left">cornstarch</entry><entry align="right">50</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row><row><entry align="left">lactose</entry><entry align="right">178</entry></row></tbody></tgroup>

example 39

The following ingredients were thoroughly mixed and single scored tablets pressed:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per tablet (mg)</entry><entry align="left">Sodium 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">217</entry><row><entry align="left">cornstarch</entry><entry align="right">50</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row><row><entry align="left">gelatin</entry><entry align="right">226</entry></row><row><entry align="left">lactose</entry><entry align="right">5</entry></row></tbody></tgroup>

example 40

The following ingredients were mixed and a capsule introduced with hard gelatin shell:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">Isopropylammonium-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">122</entry><row><entry align="left">cornstarch</entry><entry align="right">30</entry></row><row><entry align="left">lactose</entry><entry align="right">98</entry></row></tbody></tgroup>

example 41

The following ingredients were mixed and a capsule introduced with hard gelatin shell:

<tgroup cols="2"><tbody><entry align="center">ingredients</entry><entry align="center">Amount per capsule (mg)</entry><entry align="left">Isoamyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate</entry><entry align="right">32</entry><row><entry align="left">lactose</entry><entry align="right">101</entry></row><row><entry align="left">cornstarch</entry><entry align="right">15</entry></row><row><entry align="left">magnesium stearate</entry><entry align="right">2</entry></row></tbody></tgroup>

example 42

It was an injectable, buffered to pH 7 formulation of following composition:

<tgroup cols="2"><tbody><entry align="left">5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid | 0.2</entry><row><entry align="left">K₂HPO₄ buffer (0.4 M solution)</entry><entry align="right">2 cc</entry></row><row><entry align="left">KOH (1N)</entry><entry align="left">qs to pH 7</entry></row><row><entry align="left">least. sterile water</entry><entry align="left">qs to 20 ccm</entry></row></tbody></tgroup>

Instead of 0.2 g of (dl) compound of the above preparation was 0.1 g (l) -5 - (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole- 1-carboxylic acid used.

example 43

It was a suppository totaling 2.8 grams with the following Composition was prepared:

<tgroup cols="2"><tbody><entry align="left">5- (N-2-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid | 25 mg</entry><row><entry align="left">Triglycerides of saturated vegetable fatty acids</entry><entry align="left">rest</entry></row></tbody></tgroup>

Instead of 25 mg of (dl) compound of the above preparation 12.5 mg (l) -5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid used.

example 44

It was an oral suspension for pediatric use with the following composition:

<tgroup cols="2"><tbody><entry align="left">5- (N-methyl-2-pyrrolyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid | 0.1 g</entry><row><entry align="left">fumaric</entry><entry align="right">0.5 g</entry></row><row><entry align="left">sodium chloride</entry><entry align="right">2.0g</entry></row><row><entry align="left">methylparaben</entry><entry align="right">0.1 g</entry></row><row><entry align="left">granulated sugar</entry><entry align="right">25.5 g</entry></row><row><entry align="left">Sorbitol (70% solution)</entry><entry align="right">12.85 g</entry></row><row><entry align="left">Modified natural Mg / Al silicate</entry><entry align="right">1.0g</entry></row><row><entry align="left">flavoring agent</entry><entry align="right">0.035 cc</entry></row><row><entry align="left">dye</entry><entry align="right">0.5 mg</entry></row><row><entry align="left">least. water</entry><entry align="left">qs to 100 cc</entry></row></tbody></tgroup>

Instead of 0.1 g of (dl) compound of the above preparation was added 0.05 g (l) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid used.

Examples 45 and 46

For veterinary use powder for topical use ( "Powdered top dressings") of the following composition was prepared:

Instead of 0.1 g of (dl) connection of the preparation of Example 45 was 0.05 g (l) -5-N-methyl-2-pyrroyl) -1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-used 1-carboxylic acid, and in place of 1.2 g of (dl) connection of the preparation of Example 46 0.6 g of (L) -5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid used.

example 47

biodata

A. Analgesic evaluation in mice (anti-Krümmtest)

The test material was administered orally by gavage in an aqueous vehicle for Time 0 administered to male Swiss-Webster mice of 18-20 g weight. 20 minutes later was 0.25 cc of a 0.02% solution of phenylquinone injected intraperitoneally. This solution induces a curving itself. Then The animals were observed during the next 10 minutes to bending. Endpoint was the total number of writhing mice and average Number of writhes per mouse.

Following the above procedure, it was determined that 5- (N-methyl-2-pyrroyl) -1,2- dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 120 times the analgesic has effect of aspirin.

B. Acute oral toxicity (LD₅₀) in mice

The test material was suspended in an aqueous Carboxymethylcelluloseträger suspended. The concentrations were adjusted so that doses in a volume of 10 cc / kg of body weight can be administered. six Groups consisting of 6 male Swisss-Webster mice were used. mice were in single oral dose by gavage 75 mg, 150 mg, 300 mg, 600 mg or 1200 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid administered per kg of body weight. (The sixth group served as Control.) After administration, the mice were observed for 3 weeks.

In the above test, the acute oral LD₅₀ of 5- (N-methyl-2-pyrroyl) -1,2 was dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 900 mg / kg.