SI7711721A8 - Process for obtaining 5-aroyl-1,2 dehydro-3h-pyrrolo (1,2-a)pyrrol-1-carboxylic derivatives - Google Patents

Description

jv SIHTEX (U.S # A.) 180., Falo Alt ο, Calif ornia

SAP

Inventors

Joseph K «Muohovski Arthur F« Servants

KTfiBIiTtiflKl SKHIYA21 I POSUJPAA & A HJIHOVO IXffiI? AKJE

The present invention relates to an exemplary pyrrole-1-carboxylic acid compound 1 to a process for their preparation.

By definition, the present invention relates to novel 5-aroyl-1H-hydroxy-1H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid represented by the formula-2-

1 to the individual (1) -isoaers of acids 1 (d) -isoaers of acids as well as to their pharmaceutically acceptable «non-toxic • str« 1 salts «where B represents hydrogen or a lower alkyl group which I has from 1 to 4 carbon atoms a B1 represents hydrogen, a niche alkyl group having from 1 to 4 carbon-crusts, a niche alkyl group having from 1 to h carbon atoms, chloro, fluorine or bronze in the case of H * eupsti-tooi in ort o "Target or vapor position There is an aroyl group" as well as the procedure for obtaining these compounds and new intermediates.

The compounds of the present invention say that the above and complete niche "easy Jude Judi (d) -iaomer kieeline and its derivatives" have anti-inflammatory "analgesic and anti-pyrethric activity, and in coriander is treated with inflammation, white and / or or pyrexia in sla ar a, as described in detail hereinafter later «also in smooth muscle relaxants. lermln " pharmaceutically acceptable «non-tocaid esters and salts " as used herein refers to " alkyl esters " which are derived from branched or straight-chain hydrocarbons having from one to twelve carbon atoms «or to pharmaceutically acceptable ns-toxic salts with inorganic and organic bases«

Typical rings! tartar groups au, for example, methyl, style, propyl, isopropyl, butyl, t-butyl, isosmyl, pentyl, ispentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldeoyl and dodeoyl esters

Salts derived from inorganic bass include sodium, potassium, lithium, ammonium, calories, magnesium, faro, zinc, copper, manganese, alualnium, ferrous, manganese salts and the like. "Ammonium, potassium and sodium are particularly preferred. Magnesium * salts "Salts derived from pharmaceutical infusions of organic non-tokeic bases include salts of primary, secondary and tertiary amines," substituted amines, including substituted naturally occurring amines, cyclic amines and basal ionic names. such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, α-distylaminootsnol, trometaine, diolclohexylamine, lysine, arginine, histidine, kalein, procaine stilsndiamine, glucosamine, mstilglucaine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, resin polyaines and the like «Certain preferred organic non-toxic agents are isopropylamine, diethylamine, ethanolamine , piperldln, trometaine, diolclohexylamine, choline and caffeine «

A new one is formulas (A) and (Al) which are described below as pairs of bird isomors (or enantiomorphs), t «j«, as (dl) zaeSa «Kedjutlm, each optical isomer as well as their (dl) the compositions are included in the present invention. "

When the novel compounds of the present invention are to be used to exhibit a physiological response (e.g., anti- »- inflanatory, analgesic« 111 anti-pyro pending activity), t * jM when the «tape« d «aa carlate as drugs, po & alnja pod »grupa« a jadlnjonja JPoraul «(A) 1 their (l)» isom «ri ki- •• lina as 1 their faraaooutically acceptable asters 1 salts ·

Further "sub-group from the poor who are trying to benefit" like a bow! salts of formula (A) 1 (l) -acid iso-norils iodine Formula «(A) as 1 their farnaooutskl acceptable sharp 1 salts gd« wl H 1 81 hydrogen · (d) * Acid isoaor formula «(A) 1 njagovl The pharmaceutically acceptable asters of the salt are used as intaraodiorl with the pro-hydrochloride formula (A), as described below.

Owl (dl) jadlnjonja and sodadnjag invention can make a procedure which illustrated alodadon raakolonon sakvanooai (. CH. CH.

OH: d JCOOCH COOCH. (III)

COOR (XI)

COOH - 5 - v ** / gde RIB * im ju gore aasaačsa * ω «ϋΐο« 9 ij «niža» im grupa od X do 4- ugljenlkora «ton» n «pr«, «stil, stil, iaopropil 1 n- butyl.

When carrying out the process described in the above formulation (It) where "R is hydrogen", "k" viaolecular "amounts of otanolaal (X) and diaotl l, J-neetox > -dlcarfeoksilata (II) ) react at a temperature of about 0 ° to about the room «t« apparatus «, so that they are easily decorated with a solution of vinilaalaa Formi« (IH) «when they are but the third track, most« in situ, in podoanm inortnoa organic « raatvamchu, under an-bidrovania oslovim, with 2-bronoaootaldohido «or 2-hloro-aoetaldehidoa,« and from about 40 ° to about 100 ° C about the flow of vroaonakog period from about 30 minutes to about 16 hours «Podom raatvarači sa ova roakoi ju o «such aprotic raotvaradl as Sto on« eetoaitril, totrahydrofuras, dimtoksletan, hlorofora, dichloroaetan 1 similar # O posoljni «rsaliaaoljam reaction with jugs n aootonitrilno« solution on roflux toaaparaturi * 2 flow h * ** ac «taldehyde reagonsl sil posneta jodinjonja or s« «egu get pyrrolisoa correspond-rajudlh diotilaootala n the presence of ocal acid dihydrate« £ a making Pomol (IT) compounds wherein a lower alkyl group, preferably a straight niche, which treats 1 to 4 carbon atoms in the waters with otanolaal (I) 1 diaothyl 1,5-aoethonedicarboxylate (II) is treated with a compound of formula B ^ -C-CH ^ *

O wherein X is bromo lyl chloro a is a lower alkyl group, preferably a straight niche, from 1 to 4 carbon atoms, 1 most preferably with 1-broaaethane, 1-bromo-2-butanonoa, 1-broao-2-penta-7 nonoa 1 l-broao-2-hekeanon © · t at from about 40 ° to about 100 ° C during the Vrenoas period from about JO nlnata to about 16 S or sofTo * In the pedestrian realimaeijl reaction with Trši to teape-raturl from about · 1Ο ° 0 to about oobna teaperature a toka about 1 dara to about 6 daoova · roagonal ou known compounds · 0 žaterlfikaeija JedlnJanJa (IT) «a aotanaulfonylchloridom in prieuetvu teraljarnog« mine, & «pr ·, trietllaaina 1, pyridine , opioao a prieuetvu mekog koraitvarada kao Ste Jo dlhloroaetaa, na temperaturi od oko -10 ° C do oko aobna teaperature, a toka Oko 10 nizata do oko 2 Sasa, proizvodi pripada & i aaailat penole (T), ko ji »o translates in odgevarmjudi H »(2» Jedeetil) plrel Joraule (71) reakcijo® ra natri Jo »-jodldoa n aootonitrllnoa ra« tvoru, na refluks teaperaturi od oko Jedaeg do oko doaot darova «M reakeiji Jodootll Iodine Foraola (71) aa sodium-Jua-hydrlden a nakoa podaonoa inortnoa organskoa raetvaraču kao Sto Jo diootlforaaaid gets ao diaat il-1,2-dihydro-jB-pyroleA, 2-a / pyrrol-1,7-dicarbokeylat and its 6 -alkyl-substituted derivatives ”(711). This oxidation occurs in an inert atmosphere, tJ ·, under argonaco or acetoaphor, at temperatures of the order of about 15 ° to about 40 ° C, for a period of about 15 ° to about 40 ° C, during the heather period of some period from about 15 series to about t hours · The best results will be obtained by re & keijoa at room temperature, during about JO ainuta where it is hydrogen. - 8 -

An alternative to the formula (TU) is to make a sodium molecular (▼) solution of sodium chloride-dinotylformamtrtna raster, at about -10 * C to about room temperature, from about 30 minutes to about 2 ladies. ·

Batna hldrollta JadinJanja formula · (ΤΠ) aa hydroxide tli kaabonaton alkalnag motala, n «pr», natri jum-feldrokaldoa, kaliJu »· hidroksidon, natri jttm« »ksrboaaton, kalijum-karbonate i slično a vodnom milom alfa ·, »· Tarnal or ethanol, aa tomparaturi ismodja sobno toaporataro and roflucoa, a toka ad about 0 to about 20 ladies, give the corresponding alabodam dikisolina formula (TIH), t * Jf 1,3, * * hydrohyd-5B-pyrroloA , aa / -plrel ^ 1,7-dicarbenic kiaolin and its 6-alkyl derivatives · Bidroliaa with longitudinal trii use «aqueous aethanol potassium Jra-Mdrokald a, on roflaka toaporaturi and a flow of about 10 daaova«

Casbocaic acid grapes in the Q ~ 1 position of the Compound (TIH), but aoloctively etherifies the treatment of "aa with some of them" aliphatic alcohol, e.g., nataaol, otanoloa, iaapropanolone, D-butanolo-a slidaro, and the presence of , so that aa produces the corresponding alkyl 1, N-dihydro-N-pyrrolo A # 2-a [pyrrole-1-carboxylate] -7-carboxylic acid formula (H), and reacts at a temperature of about 0 ° up to about 50 ° C., o flow about 1 to about d Sasa «

Oacarboxylaols of the monoastarphlated Compounds (XX) to the corresponding Compounds of formula (X), key intromodiers in the process for the preparation of the compounds of the present invention, are fastened by heating (IX) at an elevated temperature of the order of about 2 ° C to about 280 ° 0. sufficient time period to complete the reaction «The course of the reaction can be monitored 9 brsinos development of carbon dioxide 1 soil analisob, dr Sasu a« decarboxylation usually ends uimtar about 49 to about 90 synet · Bo «koioni product, naise, alkyl 1,2- dihydro-5S-pyreles / 1,2-yl (pyrrole-1-carbekeylate and its 6-alkyl derivatives (X) leg 8) predispose by chromatographic techniques · Alternatively, and especially with decarboxylation of the test compounds of compound (H), (X) knives a · deatilize directly from reacolon soda ·

Condensation of the compound (X) * a anidoa forraule - »· gives the corresponding alkyl 5-aroyl-1,2-dihydr-1H-pyrrolo [1,2-a] -pyrrol-1H-carboxylate (XI) · This reaction so vrSi n nekos iner-taos organsko * aprotlčnon rastvarsftn i u prisuetvu fosfor-okalhlorlda, aa refluks tesporaturi od oko 1 do oko 175 dišava, pod inortaos atnoeferoa, i Batin daljin reflukson u prieuatvu natri jus-aoetata, 10 δ hours »Alternatively, use expensive kiaoline chlorides such as phosgene or oxalyl chloride with the foafovoxychloride foot. In preferred embodiments, this condensation is added by adding a solution of compound (X) to a soluble solvent of a pre-refluxed acetate of 1 to 1 solar equivalents and the desired acid and phosphorus-chloride chloride in the same solution, refluxing until also obtained. about 72 hours under the argon atmosphere and then adding about 3 to about 10 solar equivalents of sodium acetate, and satisfying the reflux period for another 4 to about 6 days. 10

Makvntai raatrarndi m vn rnktije au halogaaovmni ugljovodoniei kao λ to m rtlMoroaatan, lti * -dihlor © atanf hliHftnii ugljantetr »chloride i sli & ai, diaatakniataa 1 tatrahidrofuraa · Foiallo 1at-rad 4

Examples of S »B-dimethylarylaal da ko ji ao aogu koriatiti nus StMiMti > 9 * teauaiA | 5 tS-dimethyl-tolthaaid, 8 t-dimethyl-tolyl, H tB-dimethyl-opttoluenide »H 9S-dimethyl-p ^ tll-bensanidt Π, Β-dimethyl-o-propyl-banjsaaid in H ^ li-Hliaatil ^ m-Butyl-bonaaBid * H, S * diaetyl ^^ aatokai ^ banaaaid f H, 3-dia * tyl-pa toxo-banaaaid v 8 (MaitilrHaera ^ Biaaid! 8 ^ tt-dimatyl ^ a-chloro-banaaaid, H 98-diaotil ^ p * kleso »boxiBaaia 9 H» S-diaet ii-pI luore ~ kensaaid t H9fl - dlnetilH »-bromo ~ baaftaBt & 1 B, SUdiaetil-p ~ broao ~ bensaaid ·

Oti amides au poanata koaareijalno prietupa & aa jodiajenja ili so aogu napraviti na konvencionna nadin is appropriate-dik acid, t «j«, konvarsijoa u kieolinaka chloride i tretiranjaa sa diaatilasinoa · u - M alkalnoj hldrolisl alkilestarsnje Zrug ) dobita m odgorermjude elobodne kieelina 7oml «(A) · On hldioUu ae vril n knvrnieuln mIIb, • a hydroxide« or carbonates * alkaline »steel, n« pr ·, aa sodium hydroxide, potassium ju »-hydrexidoa, sodium jua- carbonate, potassium-carboaato * and the like, in a "born" "lower" aliphatic bottom of "alcohol, e.g.", aatanal, ethanol and elidno ", at a temperature of about 15 nimates to about 2 days, under inert »atoo-afero ·« TJ poseljnia realiste! jaaa, ora hidroliaa so trši sa sedmin netanelnin kalijun-karbonate », na refluka teape-raturi a toku oko JO» inata ·

The compounds of the root (s) of the legs are inherited, the thoracic post-poiaa which are recorded and found, so that their corresponding individual isses are obtained "laoneri (l > -kl * eline and isoaori (d) -kieelin · compounds of Formi" ( A) leg are obtained to bring "recorded techniques · weekly chroaategraphy under high pressure" (HFLO) on eCr * Phenethyl diaetereoisomeric "ethers of the Compound Foroule (A), hours" ki-selinakia raakidaajea "Such, for example, Compounds of Formula (A) where m H and H1 both rodonik, aogu with podrrdl further »tre-tiranja according to aladedaa floe-diagrena and 12 -

A more detailed description of this procedure is given in Example 12 B below ·

Slobodne klMliM Fermule (A) m ga e «preveati u drug · alkll« stara kaji laaju «d 1 do 12 ugljtaiknlh atoma koavear-olomalnlm poatupoima, iupr *, tretlranjea so (s) alkoholom ji ji odgorara deljeno * oatru u prieuatru jako mineralne acids, (b) etaraki * dlasoalkamom or (e) divided by * alkll-iodide in primustvm lltlju »» carbonate · Iaomers (l) -cleolino can be salted with their alkll «str · according to the procedure (b) and (e) above · ·

Derivatives of salts of the compounds of form · (A) and their (1) -isomeric acids make m treatment of ore free acids with a higher amount of * some pharaoeutic nutrients boso · Examples of pharaaseutakl nutritious bass are sodium »· hydroxide, potassium-hydrocaldene hydroxide, ammonium »hydroxide, kalel jum-hldrokeid, magmesljua-hldrokald, ferro-hydroxide, elnk-hldrokaid, copper-hydrokeid, sangano-hydrokaldn alualnljum-hldrokaid, feri-hi & rokald, mangani-hldrekalal, lgani-hldrekalal, l triothylanine, tri-propylamine, otanolaine, 2-dlaethylaminettanol, 2-diethyl * ino- • tannol, treaetaaim, liain, arginia, hiatidine, caffeine, pro-xin, hydrabaine, choline, botain, «tiloadlanln, glucoamine, aotylglucan obleain, purini, piperaain, piperidin, B- · tilpiporidin, poliaainske amole and the like · & · akcija ao ▼ rdi u rodi, 1 to eaoo u rodi or in combination aa inertnim, organakiB rastraračem ko ji ·· noda aa rodom, na at a temperature of about 0 ° C to about 10 ° C, at room temperature raturi. Typical inert, organic disintegrants which by birth include methanol, ethanol, isopropanol, butanol, acetone, diocane or tetrahydrofuntane · Molar ratio of the compounds of formula · (A) 111 or (1) -Id. se linslcih izosera prema kariddenaj basi bira se tak · da »a efeesbedjujt deljeni oda ·· sa nakon odradjana sa · Ha priaer, sa previjanja kal-« 1 jmsvlh tali ili eagnasijuaevih tali jadinjanja Varnole (A) 111 njihove (l) -kiaal laikih laoaara «Slobodan kisella» skl polarni aster * jel aola ea tre tirati aa najaaaje pola Dolaaaog ekvivalenta faraaoaatakl prthvatljlvs basa da s «dobijo neutralaa aa * Sada at prava aluainljuaske soli je * din jen ja Porasla (A) 111 their (l) isoaara used with at least # jsdaa tradiaa aolaraog akvivalanta faraaoaatakl acceptable bana aka with gave neutral pr © · l «vod * ao · 0 desired procedure, kalei joasvs salt 1 aagnasi juaova salt yodlajta ja? arattla (A) 1 their (l) -kiealinaki laoaarl leg so make tratiranjsa appropriate sodium jnaavlh 111 kali juaovih aali ovlh jadinjanja aa najasnja jadnoa paleviaoa aolaraog akvivalanta kalel jua-hlorida ili aagne-sljuo-hlorlda, a vodanoa rastrom, ili sasa u vodi ili agabina akia rastvaredaa koji sa aada aa vodas, na tasparatori od aka 20 ° C da oko 100 ° 0, Pošaljilao sa aluainljuaske soli jadinjanja aogn napraviti tratiranjaa appropriate slednih kisa lina sa najasnja jadnoa tradiaoa aolaraog akvivalanta nskog aluadni jua-alkox-sida » aluainium-trietoxide, aluainium »* tripropok-sid 1 sequentially, in a solution of hydrocarbons, such as benaol, xylene, oichlohecane and the like, at a temperature of about 2 ° 0 to about 115 ° ^ · The following processes can be used with making salts of non-inorganic basses that are not sufficiently soluble with a light reactor ·

It should be clear that with the isolation of the compounds described herein, "go and dry", the millet consumes "bil · kojls podse"! · The process of separation or prodiddavanjo "k ··

Sto 4 * · M prinor «ekatrakoija« filtration, evaporation «, distillation, kriatalisaoija, tonkoalojno chronography 111 chronographs on the column« weeks of chronographs under high · pressure «· (HFLG) 111 koablsaoijo of these procedures« Ilnstrooijo lalovanje podacnib aadl n Pvl — risa ko Ji sleda niže «Modjutln« COURSE that eo aogu to use drugs okvirvalentai postupal sa odvajar nje 1 isoloranje ·

Hode ae (d) ~ lsoaerl klselina ne koris · aani po avbi kao aedialnaks sredstva, oni a · noga, prema treba t prevesti o njihove farmaaeutaki prlžrratljlve, ne-toksid & ee etre 1 soli proso poatopoina ko Ji sn «pisani a« kosvoraiju (1) -isoaaro kloollno n their · farnaaeutski prihvmtljlve, non-toxic oxide eatre 1 salt ·

The compounds of Porsule (k) 1 and their D-acid isonors and their pharmaceuticals are suitable for non-tocaid ethers and seles, kerlsal au as anti-inflammatory agents, analgesics, inhibitors of aggregates of fertile thaladaoa, fibrino-glycidal agents and · This Jedi-n Jon I foot eo use 1 profllaktldno and tarapeutaki.

Preparations containing JddinJenJa are so useful in the treatment and elininaaijn burning as dto au lnflaaater-na states of the muscular acalatine slatina, akelat aglobov and other tissues «on prisor« with tre tiran Is inflasatomih states such as Sto au reunatlasn «contusion« lao arthritis «bone fractures Ju« poet-traunatiSna states and gout · In those cases when the above conditions include pain and pyrex- 16 sija «» jedno m »spaldenjea, eadainda d ^^ lnJondA koriana ια 1 in pcpuitanje ovili atanda ^ oo 1« s «Arrest ·

Devmaje of the active compounds * Formula (A) or their C 1) -iseln * kih lsomars and their farmseeutaki prlhvmtlji-vih, oo ^ okiitell «« taro 1 salts, t ebliku appropriate & eg farmaosutskog preparation »modo biti bilo kodi · od prikradenih način devanja srodatava a »trotiraad ·» apal jenja, bol »ili \ plrekeije, Hi ndihava profllaks # · Sako, n» primer, davanje aožo biti oralno, parantoralno ili lokalno, u oblić solid, pol * -čvrtih ili tednih doanih form, kao which au, for example, tablets, suppositories, pills, capsules, powders !, raetveri, suspenslje, emalside, kreaovi, loeioni, aaoti or similar obliei; Preferably in a single right-hand formulation and in combination with "simple melting of precursors", the preparations will include conventional nasal pharmaceuticals or ingredients and active dodindondo of Formula (a) or its (1) -acetic acid or other pharmaceutically acceptable acceptables. and, further, may include other intermediates, pharmaceuticals, carriers, excipients, etc.

The preferred method of davanda, aa atanda code and described in detail above, is given by using a given interval of daily dose codes to be adjusted according to the condition of the condition · Generally, it is used with daily homes from 25 mg · to 5QQ mg · active dedindenda Formula (A) or Many atandas respond to the treatment code include a right level of 0.5 mg · de 6 mg · per kilogram of body weight per day · For such oral administration, pharmaoeutaki acceptable, - 17 - non-tokaid preperet foreuliše m iakorperlranjen any kojtg ®d aemlM korlSdenih saatojaka, such as, n «priner, famaeeutaki dist sani tol, lactose, starch, aagne-sijua-etearat, natri jun-a , cellulose, glucose, gelatin, secharesis, magnesium carbonate 1 and the like. Such preparations take the form of solvents, suspensions, tablets, pills, capsules, powders, formulations, and the like.

The active compounds of formula (A) 111 its (1) -k ± seli »-skl Isoaerl 1 its taraaoeutskl acceptable, non-tokaic esters 1 salts, aogu are forsulisatl in the suppository using, on the printer, pollalkl lanskih gllkola, on the printer, polypropylene- gllkola, kao nasada «Tedni faraaoeutskl acceptable preparations foot with, on priner, make raatvaranjen, dispargovanjen, etc.«, some aktlvnog jedlnjonja, as described above, and © peionih farnaoeutsklh additions in nekon noaadu, such as I, on priner, water , salt solution, aqueous dextroa, glycerin, ethanol and the like, difficult to form a solution or suspension. "If necessary, the phase preparation product can be administered in a form which also contains non-toxic pollutants such as wetting agents and emulsifying agents. , pH buffering agents and the like, such as, for example, sodium acetate, sorbitan aonolaurate, triethanolanin d elaate, etc.

The actual procedures for making such dosage forms are known or to be clear to experts in this field of science, see Canington * s Phamaoeutsioal Sciences,

Mačk Publishing Companjr, E as ton, Pennajlvania, 14th Edition, 1970 · The preparation which is to be given, in any case contains a total active ingredient in f & rcaaeutrfc. aflkasaoj amount s «oalobadjaaje od edredjeneg stanje ko je m trt tire prtu udenjioa la ovog pronalaaka ·

The iodines of formula (A) and their (1) -acid-acid injectors are toxic, pharaoaeutskl prlfcvatljlvl sharp 1 salts * which are all described above »he also relaxants of smooth notorious aldides and all so korianl as means of maintaining® pregnant * do gravidnlh mammals, aa dobrobit najke i / ili fetusa · dok st sa Bediolaskog stanoviSta no ustanovi da 4® završovanje trud * node povoljno, lil povelja! jo sa eajku i / ili fetus «Medjutin, treba je jasno, da u Isvesnin sludajeviaa, sa prlaor, kada je porodja ved sapodeo (tj ·, Bajka ved ina uterusae kentrakelje, naredite blisu kraj trudnode), davanjo jedi · n jen ja who have since been described aoida nodo maintain a pregnant state during the unborn Vreoen period · Kadijo, in such cases, pregnant & and to most likely be " slightly prolonged " · and this is a factor that can be favorable either with the mother and / or fetus ·

Certainly, Foroule (A) and their (1) -acid acid isoaers and phase-sensitive "non-toxic esters and salts" are used as a means of delaying the birth, or of delaying childbirth. In this application, the phrase "postponement of the beginning of childbirth" is intended to cover the postponement of childbirth due to the administration of a single formula (A) or its (1) -acid isosers and pharmaceutically acceptable non-toxic esters and salts, at any time. before the contraction of the uterine muscles * although the intention is to use the phrase "to cover the prevention of abortion at an early stage - 19 pregnancies (ie, the fetus than the fetus is" capable of life *) as 1 delay of premature birth, which is a topic that ee poaakaA used in resi sa prerreaenia trudovisa ko ji so ispoljavaju u kasni jo j trudnodi koda so fetus considers " viable · " · D in any case, the means are given as a prophylactic agent at the right takro giving gives tends to spread the data of childbirth I · Oro daraaje jo narodito korieno u tretiranju žena ko je iaaju istorlju spontanih pobadaja, taškog nožen ja ili prerreaenog povod ja ja (i.e. · porod ja ja pvo kraja trudnode). On the other hand, I also use the clinic where the clinical indology becomes, so that the pregnancy of the knife is perfect for the person with whom I want to work with the shark and / or the fetus. "In the case of animal pits, the treatment of the table and" also used with synchronisation. ју породјаја у групи граридних живо тиinjaа којл тробе да са демо у оприлика лато рроно или или отпрлике у vrtat i / lli na ne s tu, kada porodjaji aogu da se sprevodu sa vedo * лакодоа «како со користи у овој пријави, фраса " delivery delays ”is intended to include the administration of compounds of Formula (a) or their (1) -acid acids and pharaeoa-utakl acceptable non-toxic ethers 1 salt before the onset of contarration of atheroidal algae · Condition of the patient, including the period of use sapodsu kontrakoi je, osblljnost kontrakoija 1 koliko dugo kontrakoijo traja, uticado na rosultate kojl ao poetižu davanjea ovih jedinjenja. & a example, the effect may be dreaming Intensity and / or mam lasting j * contrakoia (in dama aa a trami act of childbirth " prolongs "), or that with contrakoia completely »a» · a tar ·· In any case, the effect The effect may be prolonged, although, as described above, the effect may be significant or, under appropriate circumstances, not relevant. "Such administration may prevent miscarriage, result in miscarriage. ji ea lekše vrči i / ili ko ji ja nanj · bolan aa majku, ili kojl moda da s · daal u podesnijea vrijeme i / ili na podaanijam mjesto «U avla alludjtvima, daranj · jadinjanja formula (A) ili njagovih (l) - kiealinakih iaoaara 1 farmaoeutski prthvatlji-vik, na-toksidnih aatara i soli, sa »vrha koji prikaaana gora, traba ja ja komaiatantno sa n & jboljim i / ili pra & am & amp & amp & medical medical (ili veterinarski ^ praksa tako da sa poatignu maximum Benefits Fairy Tale and Fetus * For example, giving should last so long that the fatus dies in the mate rlol *

In carrying out the methods of the present inventor, a therapeutic amount of the compound of formula (A) or its (1) -acetic isomer and its pharmaceutically acceptable, non-toxic aatars 1 salt, 111 of the pharmaceutical preparation which aadryl lata gives aa pregnant aiaaru any of the acceptable 1 common peatupaka in nauol · Jadinjanja aa can be given either individually or in combination aa with other jedlnjenjam or jadinjanjima, as ato is defined above, or aa other farmaoeutakim aradatvlma, carrying, added ima, etc. «Such jedinjenja (a) or the preparations may be administered orally, parenterally, or in the form of δ species ib, semi-d or weekly dosage forms. "Typically, a pharmaceutical composition is given which retains pharmaceutically active administration and one or more pharmaceutical carriers, or add aka «

Acceptable pharmaceutical preparation of the knife takes the form of oral tablets, vaginal or notorious tablets or suppositories, pills, capsules, exact solutions, suspensions or the like, best of all iodine dolanin oblioina for easy delivery of conventional doses · Conventional nocotoxic for example, pharmaceutically pure mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, oolnlose, glacose, gelatin, sucrose, nag * zium * carbonate and the like. An active compound such as a defined mountain can be formulated in a suppository using, for example, polyalkylene * glycol, for example, polypropylene glycol, as a carrier «Liquid tanaoantskl acceptable preparations of the foot, for example, make reconstitutions, dispargo * vanj en , etc. «active compounds as defined above and other pharmaceutical additives in the post-carrier, such as, for example, veda, saline, solution, aqueous decatrose, glycerin, ethanol and the like, so that a solution or suspension is formed. If necessary, the pharmaceutical composition to be administered may also contain Binary amounts of non-toxic excipients such as wetting agents or emulsifying pH buffering agents 1 similarly, for example, sodium acetate, sorbitan monolaurate, triethanolain oleate, etc. "The actual procedures for making such dosage forms are known, or will be clear to experts, for example, see Remington * s Phareaoeu" Tichal Sciences, Mack Publisbing Company, Caston, Pannsjlvania 14 th Kdition, 1970 · The preparation or formulation to be administered will, in any case, contain an amount of the active compound - 22 - in an effective amount to delay the onset of labor or to delay childbirth if au aatarid contraceptive vision has begun, Mainly 6a g # dava «! dmavna daaa from 0.5 mg »to about 25 mg * of the active compound per kilogram ta laena weight, at Sesa sa daj« jsdna daily doia ill da aa regularly give three to ten aanja daaa a during the day * We want the amount of active compounds that aa daj # depend on its relative activity *

Pale Examples illustrate the invention but are not intended to limit its scope. Skradenloa t * l * o «refers to thin layer chromatography and avl used relations snsfia xa accuracy refers to aapremlnske relations« Also when necessary «examples and repeated aa making additions. of material from kaanija example #} and if it is not drocdija specifically raakolja sa vrda at room temperature (20eC to 30 * 0), PRIMES 1 3-Throat balloon of 250 al, with a round bottom «which is washed with magnetic modalioon and kojl i equipped with kaleijun-hlorldnom oavi with judging the occasion is directly (via one of the sex poor throat) pomada adapts 1 short water (5 ”) kondanaatorm with apparatus with pyrolis aeetala, Oraj last apparatus consists of from balloons with round! bottom of 100 ml, / which was pre-filled with 15 * 6 g * oxalic acid dihydrate and 11 * 82 g, brooacataldehyde diethyl & cetala, which I made with vinyl * acetate, as I opioao P, Z, Bedoukian, J.Am, < 3bea, Soo * 66 »651 (1944) /» at the top of which is a Vigreuac column of 6 * t which I have a thermometer, connected to the above-mentioned condenser * 5-Throat talon sheršlra m oo 3 * 36 g * ethanolamine ehla & Je-nog no lodonon bath no Qe-10®0 and treatment by instillation, with neioajen, om 8 * 7 8 dimethyl 1,3-aeethonedylcarboxylate · Currently will be decorated with 3-kartasetQksinetil «» 5 (2Mildroksletll) -aminoakrylat (ZU), Koda Je dedovanje savrlene, ledeno kupo-tile so © dvoji i doda bo 100 ml «euvog acetonitrila · Piroli-tldki deo aparata eo otavi na ul Jano kup & tilo i njegovo temperatra pone na 150-160 ° ^ Bronoaoetaldehldnl ras tvor ko Ji bo obrasuje doatilujo so (t »klj · 80-83 * 0/580 na) direktno u nagnetao neSani raetvor vinilaalna (III) · Koda deatilaoiona temperature padao iapod 8Q ° Qy aparat na pirolisu se raetavl 1 seed eo with reflex condeaseteron ko Ji Is equipped oa potassium-chloride eevi with sitting · Bastvor eo heated to reflux temperature 1 Sas, raotvarad eo © dvoji under saanjenia pressure and then add 200 ml «methanol and 20 g. sllik * »gel« This bold bo lep ari to dry in a vacuum and put on top of a column of 200 g · sllikorgela packed in fees · The column is eluted with bold beksanietilaoetat (80i20j 500 ml «) and bold taksen tet ilaoetat ( lil) 9 * 500 ml ·) · frakolje 2 15 containing polar nellsted and dimethyl 115-acetonedicarboxylate \ fractions 4-8 give 4 · 1 g · methyl B- (2-hydroxyethyl) -5-carbomethoxypyrrole-2-eoetate (IVf R * H) t ko Ji after recristaHseoiJe is smele etar-beksaa has a melting point of 52-54 ° C, PHIK £ R 2

Melanoma solution of 4 · 1 g of methyl B- (2-biaroxyethyl) -3-cartamethoxypyrrole-2-acetate in 35 ml of eu-dichloromethane cooled at -10 [deg.] C. is added to 2 * 65 ml of triethylamine and after addition of IM al · aotanaalfenllhlorlda, as odršarsnjo tesparatsr «rsakoioao« mši as -10 # do -5β0 · Sok roaksljo so pasti posod «tlo ksrlddoajos «sodo hlorof oratoootoa (about 30 slinita job of adding aatansulfonylchloride roakaija so safzUnra) (90il0) ·? aia e« add lightly 10 sl »sodo · Organic hair with odfojif isporo so with soda» (5 with 50 ml ·), suit so the practice of sodium ouifate and iaparam with under aaaajonlB pressure · Kristaliaaalja ostafcka is saodo dichloronotan-haksaR give 4 · 75 g «(77 * 7 $) sotil H- (2-» asilokeethyl) -3-carboaetote ·· sipirol »2 " Osota (Tf B · B) ft * t * 99 * 101®0 # FH1MSH 3

Raatror 785 ag · aotil «- (£ ►» · sil oxlotil) -3-carbo »e tokei-pyrrol-2-ao« tata 1 1 * 85 g · sodium Jo »-iodide a 10 al · neotoni-trila roflnksujo so 1 das · Ohlsdjoaa roakeioaa saoda with evaporates to oura under saanjonin pressure 1 the rest is isitni with radon · Beraatroroi »atsrijal with odra ji filtration« and dried with rasdulm so that it dates 800 ag «(97 #) aotil Β · · (2- iodootH) ~ 3 ~ carboaethoxypropyl ~ 2-ae «tata (ΥΙ, H« H) f tt, 157-158 ° 0 · P & IHER 4

Raatror 1 g · aotil B - (& * iodootil) ~ 3 ** carbo «otekeipirel-2-aootata a 3 al · stsrog diaotilfornaaida aoda no, pod atnosfo-rea argona, sa 137 ®g · 5 ° ^ natri ju» -bidrida n oinoralnoa ulj «· Boakoiona saoda so odrim 30 minuta na sobnoj to» »poraturi i toda so prokia · oa 100 al · roda · Proiarod so ek * strahuj« sa otilaootatoa (3 * 5 ° ni ·), spojoni ekstrakti s «Wash aa rodea, soda with over nagaoaijtta-eulfata 1 lep are bo do sura« Hroaatografljos residue on 20 g · silica gel, used- 25 - šdenjen hours «(4 * 1) as elueata, gets a · 300 ag, ( 80 $ 0 dlnetll 1, 2-dihydre-3B * pyrroloA, 2-a / pyrrole- 1.7-41kaM «U« ta (Til, Rrf), mp 70-71 * 0.

Baotvor 1 «80 g · dlnetll l, < y-dihydro-3B ^ pyrrolo A, 2-α-pyrrole-1H7-dlk8rboxylate in 20 ni · methanol is treated with aa raatvoron 4 * 48 g« potassium hydroxide in 20 ni · Water, 1 reafc-oiona aaeda ae refluksuje 6 daaova * The cooled solution is evaporated to euva 1 oetatak aa trativa aa 50 al · saaldenog raatvora sodium »-chlerida · Collected raatvor aa saklaali aa 6H hlorovod onifino · klaaletaa 1 extrah »Ton (3 x 50 al ·) · Combined extracts aa aude over forced jum-aulfate 1 lapara aa to owls under ananjenia pressure, so aa gets 1 * 51 g · (95 $) 1,2-dihydro-3H« * pyrroloA, 2-α / pyrrole-1,7-dicarbonate of kiaaline (VIII, B «H), mp 220 ° C, aa decomposition · PRIKER 5

Raatvor 1 * 34 g · 1,2-dihydro-3ii-pyrroloA, 2-e / pyrrole-177-dicarboxylic acid in 50 ml · isopropanol, cooled in an ice bath, aaalti aa aa gaaovltin hlorovodoz | pcon, while maintaining the reaction temperature below 50 ° G. Ice bath and then remove 1 reaction anaSa aa our 1 * 5 fiaa at aobaoj temperature, 1 iaparl do euva under emanjenin pressure; 10 [mu] l of benzene was added to the mixture and the solution was evaporated in vacuo once, and this procedure was repeated three times to completely remove excess blorohydrogen, so that 1 * 58 S * (96 $) of isopropyl 1,2-dihydro was obtained. -3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid (IX, H «11, «Cl2Hr;), which after crystallization from ethanol-ethyl acetate has a melting point of 144-Χ45 * ® · M «in a similar manner or senono * laoprepanol and the above * according to the procedure m * et« nele * 9 ethanol, propasolo * 1 ab * tenolcm obtained methyl 1,2-dilxidro-3ii-pyrrolyl, 2-a / pyrrole-1 -carboxylate-7-carboxylic acid, tyl X t2-dihydro-5B-pyrrole-2-pyrrolyl-1-carboxylic acid-7-carboxylic acid, propyl 1,2-dihydro-pyrrole-pyrrole, N- [pyrrole-1-carboxylate-7-carboxylic acid, 1-butyl 1,2-dihydro-3S-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid. P8ZKSB 6 1,054 g of isepropyl 1,2-dihydre-3 ' -pyrrolo [1,2-a] pyrrole-1-carboxylate-boxylic acid is heated from 240 to 250 DEG C. in a 10 ml dry flask. «M round * dso * v deatilujudi dl» rectum 1 * reakeionog «ud * r ·« column product. In this way I obtained m 745 * g «(87%) of iaepropyl 1,2-dihydro-3B-pyrrolo [1,2-a] pyrrole-1-carboxylate (Zt R» Hf B2 · iC ^ H ^) ^ light Suto oil when in «the following fox constants with ϋ, V. t X as * 215 n * 0801 «n ** β & β1χ (L 6020) | IBi / me * * 1725 «μΓ1» Β.Μ.Η.ιίϊΗΒ 5 1.22 (d, J · 7 Ha, 6H) t 2.40-2.90 (n * 28) t 3.60-4,20 (m, 28), 4.65 -5.2 (*, 1H), 5.75-5.92 (*, ») * 6.10 (t, J» 3 Ha, 1H), 6.43-6.53 PP »* C ·· 1H). EXAMPLE 7 3-Gvli bales * of 100 ml. e «ofcrutli® dno * ko JI It is equipped with a condenser, inlet for asot 1 aa tube with bubbling gene, it is charged aa 5.0 g. isopropyl 1,2-dihydro-3 & - 27 pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid. The apparatus was filled with oil and then the flow of asot iioitcrl was carried out. The apparatus was immersed in an oil bath heated to 27 ° e0 and the earthenware was washed with carbon dioxide (gamma bubbling apparatus) and the soil was swept with gel. , using benaolidlokaanialrtatna klselina (90il0il) as a means of developing · Foala 45 minutes of reaction with almost aavrSon «Poale one daaa, aud aa oda ji ea oils-ziog bathroom and aadaržaj raakoioaog« uda ae prosta «in a balloon with a round 500 vi · acetone »RaatvaraČ at otara pod smer * njeni · pressure, 1 oatatak at prodiati chromatography * on a column on 100 g #« ilika-gel, Fraction which au oluirana aa aaežoa bekaanibanaol (70 * 50) and aaoftoa bakaantbanaol (50 * 50 ) give 2 * 77 g · (68 $) of ioopropyl Ι, ^ - ΛϋιΙάΓΟ-ϊΗ-'ρΙροΙο / Ι, ^ ο / -pyrrole-1-carbocaylate (1, H »H, B2» iC ^ H ^), one oils «longer au fisidke kosatanta identical aa those obtained in Example 6. PRIMKH 8

Baatrar 179 «β · H, B-dimethyl * p-toluene and 0.11 ml« phoaphor-okaichloride in 2 al · 1,2-dichloroa tana ref reflux is «30 minutes · Oran raatraru a« add raatrar 195 mg · ioopropyl 1 t2-Dihydro-3S * > pyrrolo [1,2-a] pyrrole-1-carbocaylate in 2 ml · 1,2-dichloroethane «Be« column bothers aa raf lux i under argon atmospheres 8 hours »f treats ao aa 405 mg. sodium acetate and reflux for 5 days, the mixture is evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane; ethyl acetate (3 * 1) to give 208 mg. ($ 66) ioopropyl 5-p-toluoyl-1,2-dihydro-3,11-CII, H 'H, B1. p-OBj, B2 m 10-B-), ulj ·, which iaa aladada flslSka constant UTi vNc € H -, JU * A «« 256, 312 na, 8700, 19500), IBi * nax 1735i 1620, 1605 β · " 1, Β.Μ, Β.ι 1 * 23 Cd, J · 7 £ s, 6H), 2 * 38 (e, 5H), 2 * 5-3 * 0 (a, 2 »), 3.75- d.10 (a, 1H), 4.2-4.60 (a, 2H), 4.85-5 * 20 (a, 1H), 5 * 95 (d, J · 4 H *, 1H), 6.?0 (d , J »4 Ha, IB), 7.10 (d, I« SHs, 2B), 7 * 60 ppa. (d, J »8 Ha, 2H). JPHIHEB 9

Baatvor 336 mg. isopropyl 5 * β-toluene-1,2-dihydro-3B-. pir9l «/ ly2-u / 9irolr > l-cartexyl« t · u 10 ul. methanol is treated with a solution of 690 mg. potassium carbonate in 5 ul «vod ·. The reaction honey is relaxed under an acetole atmosphere for 30 hours, cooled to 1 liter and evaporated to 10 hours. The residue is taken up in 10 ml. 10 $ TOdaaa hlorovodonizhoe ki — lin »1 50 al. water 1 the resulting mixture M ectracheates aa ethyl acetate (2 * 50 al). The combined extracts are dried over nagseal jum-aulfate 1 and pressed to sura ped pressure. Krlstallaaoijoa residue la with mixed ethyl acetate-hexane gets ae 238 ag. (89h) 5-p-toluoyl-1,2-dihydro-3B-pyrrolo [1,2-a] pyrethyl-1-carboxylic acid (U), H · H, B1 · p-CH2 /, m.p. 182-183 ° 0. PBIMSB 10

Baatvor 250 ag. Laopropyl 5-β-toluene-1,2-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 8 [mu] l of methanol was treated under an atmosphere of 200 [mu] l of sodium chloride. -drokaida in 1 al «vodo, us odrdavanje reakoiona aaaSa aa sobno j tempera turi 1.5 Sasa. the ethanol was then removed under reduced pressure with 1 basin solution which was diluted with 5 ul. water 1 ektrahuje aa with ether so that at removes 29 bil · kakar ampmlfltoTMil proisrod. Vodeni rastror eo sakiseli aa 10 £ hlororodoalchmoa kleellnoa 1 ekstrahuj «so tri. times with ethyl acetate "The combined extracts are dried and evaporated to dryness under said pressure and the residue is crystallized from ethyl acetate-hexa" so as to give 5-P-toluoyl-1 * 2-dihydro- * 5B "pyrroloA" 2a > a / plrol »l« * carboxylic acid, ko Ja Ja identical aa proiarodoa ko ji Ja obtained in Example 9 «phimsr u

Precursors and Example 6 or 7 The remaining compounds of the gene age in Example 5 were recovered from methyl 1,2-dihydre-3a-pyrrolo [2] a [pyrrole-1-carboxylate] • tyl 1 [beta] 2 * dihydro-3B-pyrrolo. (1H-pyrrole-1-carboxylate $ propyl) 11-Hydro-N-pyrrolo [1,3-a] pyrro-11-carboxylic acid butyl 1,2-dihydro-3H-pyrrolo [2-a] piro ll-carbox and lat ·

When co-ordinating orlb Jedla Janja with H, N-dimethyl-p-toluamide, he agreed to the procedure with Primor 8 «obtained Ju set methyl 5-p-toluoyl-1 * 2-dihydro-3H-pyrrolo [2-a / -pyrrole -1-Carboxylate, • til 5 'P * toluene-1,1'-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate t propyl- [beta] -p-toluene-1 ta-dihydro- * 9B- pyrrolo [1 H] -pyrrole-1-carboxylate 1-butyl 5-p-toluene-1. "2- * dihydro-5H-pyrrolo [1- (e) -pyrrole-1-carboxylate"

PRIMES 12 A

The accompanying procedure is in Example 8 using 1 «1 to 5 * aolar ecriralents of N, N-dimethyl-benzamide, B» N-difflethyl-o-thioluamide, H, N-difflethyl-toluamidate 30 K, »- diBethyl-p- «Til-beiiz amide, H f2MJjMtll ~ < Kp70piI * b6nzamide, H .B-diaethyl-o-butyl-ben * amide, N, N-diaethyl-o-aetokei-benzaaide, K, H-diBatyl-p-methokei -benzaaiaa, H, H-di »ethyl-p-“ ethoxy * -benzaaide, H jN-dlaethyl-p-isopropokai-beii * amide, K, jf ~ dlaetilr ^ hlara-baasaal & a, K, B-diaethyl ~ »» Chloro-b «ri * aa ± da, H, B-diaethyl-p- * chloro-benaaaida, H, I4-diaatyl-o ~ fluoro- * b« naa »ida, H, IWLiaethyl-p ~ fluoro ~ bensaadda, H, g-dlaatii ^ a »broaa» ban taalda 1 Η, Η-diaatll-o-broaa-baiisaalda, uaeata H .IMLiaatil-p-toluaaida, i ragiatroranjaa toka reakcija peaodu tle ·, dobirajn sat iaopropil 5-ben * oiH, 2-dibiaro-3H-pyrrolo [19a-a] -pyrrole-1-kaifcocaylate, rnretle Sata oil, which laa aladada physical v MtCE. kobstantai H.T.i / max »5 * 511 na (* 7230, 1780Q); I.R. Vaaxl5 173 $, 1620 ea " 1 * H.M.R »1.24 / d, 6H, (CH ^ CH /, 2.50-3.13 U, 2H; E-2) | 3 * 97 (d, 1H, Hl), 4.18-4.70 (a, 2H, 2-3), $ .00 (sept ·, 1H, (CH5) 2CH), 6.00 (d, 1H, H-7) , 6.86 (d, 1H, H-6), 7.10-7.90 ppa (a, 5H, phenyl protons); KSs a / a 297 (O, Iaopropyl 5-o-toluoyl **! * 2-dihydro-JH-pyrrolo / 1,2-a-pyrrole-1-carboxylate, an oil which has the following physical constants. MeOH 0H01 - ϋ.Υ.ι Anax 2 $ 2, 303 na (* 4460, 19100); IR * ^ max 7 1735, < 0201 * 1620 ca x; NM £. {$ MS 7 1.18 / d, 6H, (OH ^ CH 2, 2.28 (s, 3Β-, o-CBj), 2 * 50-3.13 (»* ΛΒ * H-2), 3 * 92 (< M, IB, Hl), 4,17-4. 70 (*, aflf B-3). * · 9β / Mpt * 1H, (CH 2 OH /, 5.92 (d, 1H, H-7), 6 * 43 (d, 1H, B ~ 6) t 6 * 97-7 * 45 PP »(* · da, phthalic protons)» ioopropyl 5 - »- tolerosyl-1,2-dichloro-3H-pyrrole [1,2-s] pyrrole-1-carboxylic acid .uldo. code Im slodsds tisldks konstsntei in HoOH - CH01 * li.V.iAuz 25O-25I. 310-512 n »(* - 6460, 17400) * I, R, / ae 0 ^ 0001« 1735, 1 «0 O «'1! ®WB 5 1.25 / d, 6H, (OH2) 20H /, 2.2? (», I, 0H?), 2.52-J.lJ (a, 2H, a-2), 3, 92 (dd, IB, Bl), 13 .13-4.70 («, 2B, aJ), 4.95 / M» t. 1H, (OHj) ^ OH /, 5.95 (d, 1H, H-7) ), 6.6? (D, 1H, B-6), 7.03-7.57 ppa (a, 4B | phenyl protons), ioopropyl 5-P- «tilbon * oil-1,2-dihydro-3B-pyrroloA» 2 N-pyrrole-1-caspheoxylate, ioopropyl 5-o-propylbonzoyl, 2-dihi dro-5B-pyrrolo [2,2-a] -pyrrole-1-carboxylate, ioopropyl 5-yl] tylfconacene. 2-dihydro-5B-pyrrolo [1,2-a] pyrrole-1-carboxylate, ioopropyl 5-o-ethylcarbonyl-1,2-dihydro-3H-pyrrolo-A, 2-a N-pyrrole-1-carboxylate, ioopropyl 5-β-aoxyxyconsole-1,2-dihydro-3B-pyrrolo [1,2-d] pyrrole-1-carboxylic acid, code 1 »» Fluid constant 1

\ KoOH U.V, A * a * 218 ^ 284 (wire). 314 nn (t 9780, 9320, 22400) | I.H. y / »0x 3 1730, 1605 oa * X | N. M. H JS IMS * 5 1.24 / d, 6H, J. 6 Hs | (C 6 H 18 OB- /, 2 * 50-3.10 (a, 2B * H-2), 3.78 (e, 3H | < 1 ^ 0), 3.93 (dd, 1H, a 6 Hs, J3i a 7 Ha j Hl), 4.13-4.60 (o, 2H | H-3) j 4.95 (sept. 1H, J. 6 Ea; (CH 2 CH /, 5.95) (β, 1H, J »4 Ha j H -7), 6.68 (d, 1H, J a 4 Hz * H-6), 6.70-7.90 ppm, (m, 4Hj feail proton ©) | MS n / o 32? (H *), - 32 izopylpyrrole-1-carboxylate9 mp · 94 ~ 95 ° C ·, ioopropyl Sp-isepyloxyBibenaoll-liS-dihydro-SH ^ irol © - / 1,2-a / pyrrole-1-carboxylate, ioopropyl 5 * * o -chlo: roben3oil-1,2 «dihydro — 5H-» pyrrolo / 1,2-a / - pyrrolo 1-1-carboxylate, oil. ko jo iit sledeh · £ iai5ke kooetsh M «OH, 0» C1 * te * UVt Xmaz 341, 306 na (* 5750, 16600) | IB, < / o * x 7 n -.0501 * 1735 »1625 e» -1 * ΓϊΜ8 5 1.22 / d, 6 », (CH ^ gCH /, 2.55-3.05 (n, 2H | E-2), 3.97 (dd, 1H, H1), 4.17-4.70 (a, 2H, H-3) »4.97 / Wt.# 1H,, (CH 2 CH /, / ^ (d, 2 / 3H), 6.00 (d, 1 / ¾ H ^ 7 /, /6.42 (d, 2 / 3H), 6.67 (d, 1/3 »), H-6 /, 7.07-7.80 ppm. (a, 4Hj ftnil protons), iaopropyl 5-a-chlorob «n * 0ilrl, 2 * dihydro-3H-pyrro Wl, 2-a / - p Irol-l-carbokailat, oil ko j · ina« lododo flsldk «Constant« »<

MfGK 0H01 * U.T.iVm »231, 313» · (¢ .6600, 15100) 1 IA1 / 10 5 1735, * _ 0501 * 1620, 1570 e · " 1! fl .MHI S ΪΗΒ 5 1.27 / 4, 6H, (OB ^ gOH /, 2.50-5.18 (n, 2B, H-2), 3.93 (44, IB, H1), 3.10-4.63 (», 2H, H- 3), 3.98 (opt., 1H, (OH 1) aCH 2), 5.98 (4, 1H, H-7), 6.67 (d, 1H, B-6), 7.07-7.78 ppa. (*, 3H, tonil protons) HSI 3 O 331-333 (1 *). Iaopropyl 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 80.5-81 ° 0, ioopropyl 5-o-fluorobenzoyl-1,2-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ioopropyl 5-p-fluorobenzoyl-1,2-dihydro-3B -pyrrolo [2- (1-pyrrole-1-carboxylate, mp 72-72.5 ° 0), isopropyl 5 - b-bromobenzene-1,2-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate and Iaopropyl 5-p-baoobenzyolyl-1,2-dihydro-5yl-pyrrolo [1,2-a] pyrrole-1-carboxylate.

After hydrolysis of the isopropyl group, millet of po-stupoin from Prinara 9 or 10 obtained with "burning free acid, 1 to 5" bansoyl-1,2-dihydro-3B-pyrroleA, 2-a / pyrrole-1 " carboxylic acid, m.p. 160 * 161®0e 5-o-tolnoyl-1,2-dlkldro »3B-pyrroleA t2-a / pireX-1-cartak» ilic acid, uide, code and malt physical constant with MeCfl OBOI · UVi Xaaz 253 » 307 on (£. 3310 * 16980) | I.B.1 Vmex p • ^ ODCIl, 1720 »1620 ae * 1! H »M.K« s 0TM8 9 2.32 (s, 3 **, OHj), 2.53-3.03 Ca »2H. H-2) »3 * 97 (44» IB »BD * 4A7-4.67 (a * 20 * B-3) * 6 * 92 (4 * IH, B -?) * 6.40 (d * IH, B-6 ) * 6.83-7.37 (a »4H, phanyl protons), 8.60 ppa« (8ir «s, 1H, COGB), 5-« toluene-1,2-dihydro-5H-pyrrole, 2-a / pyrrole ~ l-carboxylic

Id salt, 5-p-atylbansoyl-1,2-dihydro-3H-pyrroloyl, 2-α-pyrrole-1-carboxylic acid, 5-propylbenzoyl-1H-2-dihydro-3H -pyrrole [1 * 2-a] pyrrole-1-carboxylic acid, 5-α-butylbansoyl · ·! * 2-dihydro-5H-pyrrolo [1 * 2-a] pyrrole-1-carboxylic acid [5-o- * nethoxy] -soyl-1,2- * dihydro-$ H-pyrrolo [1,2-e] pyrrole- 1-carboxylic acid, 5-p-Bethoxybansoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 187-187 * 5 ° 0, 5-p-atoxybansoyl ~ 1 * 2-dihydro-3 * methyl, 2-α-pyrrole-1-carboxylic acid * m.p. 169 "5" 170 ° 0, 5-p-isopropoxybenzoyl * 1,2-dihydro-3B-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, 5-o-chlorobenaoyl-1,2- diiiidr o- 3 ^ -p 1 o / 1,2-a / -pyrrole-1-carboxylic acid, which has the following physical constants: D * V. λ

ΟΒβΟΒ βαχ 250. 30y * 5 at 4360, 17400) | , ,Ί, I.H. ^ box 5 1715 * 1620 ob S 0DO1 5 2.60-3.15 (a, 2H; H-2), 4.02 (d4, 1H t

Jty 6 K ,, JRy- «7 H * | Hl) «4.20-4.70 U, 2Ej H-3), 5.96 (α, 1H, J - 4 Hz * B * 7), 6.42 (d * IH * J m 4 Est H-6), 7 * 00-7.77 C ». 4Hj phenyl protons), 8.67 ppm / e, (fat), 1H COOg [5-D-blorobanzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 180-181 D, 5,5-p-Chlorobenzoyl-1,2- * dihydro-3H-pyrrolo [1,2-a] pyrrole-N-carboxylic acid, mp 201.5-202.5 ° Q.5 -o-flaorobenaoyl-1,2-dihydro-1H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [1,5-p] phenylobenzoyl-1,2-dihydro-3H-pyrrole / 1, 2-α-pyrrole-1-carboxylic acid, m.p. 179 * 5-160.5 ° 0, 5-hydroxybenzoyl-1,2-dihydro-3S-pyrrolo [1,2-e] pyrrole-1-carboxylic acid and 5-p-broobenzoyl 1-1, 2-dihydro-3H-pyrrolo [1,2-e] pyro-1-carboxylic acid.

JPEIHER 12 B

Raster 300 mg. 5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 25 L. of dry benzene, 0 * 56 s * of trifluoroacetic acid anhydride * was added. The mixture was filtered with suction at room temperature for 10 minutes and the resulting solution was cooled to 0-5 [deg.] C. and 1.4 g was added. triethylaraine, and odeah zatia 0.5 g. (1) - ^ phenylethyl alcohol. although the resulting reaction solution was stirred at room temperature for 15 minutes and poured into 20 ml. water that contains! 1 ml. triethylamine, and is then extracted with ethyl acetate. The etlleoet & tiii extract is dried over sodium Jun-sulfate «and hours · ae removes raetmrad 1 excess (1) - -phenylothyl alcohol in the raccoon so that ** yields 0.42 g · smode (l) -5 ** ben * eil-lt2- dihydro-5B-pyrrolo-N-3-α-pyrrole-1-carboxylic acid (1) -4-phenathanyl ester of (d) -5-benzoyl-1- (2-dihydro-3H-pyrrole-A) 2-α-pyrrole-1-carboxylic acid - * (1) -U-phenethyl ester was obtained by weekly chromatography under high pressure (using a mixture of 44 EtOAc / hexane at 11 at · x 50 on * 10 [mu] m * Liobroaord 31-60 columns) so as to obtain 180 ag. polar ester -145 * 7 °) and 178 mg · aanje of polar ester + 128 ^ 6 °) · 148 mg »of polar ester ras is formed in 8 Figs. dry benzene * Hastvor se Iliadi at 15-20 * 0 and add 5 ni «tri-fluorosirdetne ki se line ps se raetvor seda na sobno J teaperaturl 1 das 1 10 minuta * Heakeioai raetvor is poured into 60 ml« dry benzene and rastmradi ee removed under mkunon at obidnoj teaperaturl · Predidamnje se vrdi weekly · broma-tografljea under rieokia pressure (use * column described above »isusev dte 354 EtOAc / hexane in 1/2 * aircetnoj kieelini» «changes 44 EtOAe / beksaa) so that ee gets 63 mg. (i) -5-Bonsol-1,1'-dihydro-33-pyrrolo [1,2-a] pyrrolo [1-carboxylic acid] iaa * ^ 101} -155.7®, and melted I 155-155 ° 0 .

Similarly, the spread of polar sharpness according to the procedure described above with polar eatar yields 85 mg, (d) -5-benzoyl-1t2-dihydro-3B "Pirolo / 1,2-a / pyrrole-1- carboxylic acid lino ko Ja ΙλαΦ ^ Η + 155 * 1 ° · and melting point 154-156 ° C «Thus obtained (d) -acid acid isonar knives with« as needed, racemize (and reoyclonate) according to the procedures known in science «

Similarly, ee and other (dl) Compounds can be translated into the corresponding (l) -isooere and (d) ~ i3omere · PKIESR 13 ▲ dal · »of 230 Ml« o «3 heads which Jo equipped with aa magna * tnoa stirrer 1 aa calcium- chloride oevi aa drying «, šeršlra« a oa 3 · 36 g · ethanol! »«, cool n aa cold bath at 0 »10 ° 0 1 treats ao instillation * i ua mixing« aa 8.7 g «dime til 1, 3-Aoetone dicarboxyflylate. Jfretunnm ao forms a motil > »carb * aetoksimetll» 3 ~ (2 * -hldroksietll) «mino-akrilat (111) · Koda jo dedovanj« aavršeao, ledeno kupatilo ao odvojl i doda ao 80 ml «euveg aootoaitrila · Boakoiona aaoša a treated by digging 6 «73 e« broaoaoetaldohida in 20 ml · aootonitrlla 1 poalo toga ao heated on ratluka temperature 2 daaa # Bastvarač eo then remove under «dream pressure» and to the rest with add 200 ml «methanol and 20 g« ailikargol * Ova aaeša and "1 was evaporated to sura in vacuo and aged on top of a column of 200 g" of silica gel packed in hexane, and the column was oluted with a mixture of hexane-ethyl acetate (ltl) to give methyl H ~ (2-hydrobethyl) -3 ~ carbomethoxyBi-plrol-2-acetate (IV, B * H) which is identical to the product obtained in Example 1 «

PHIKK8 13 B

Dissolve 6 ml of ethasolamine in 5 ml of water, add 1 · 4 g of dimethyl 1, 3 acetone diacarboxylate. The resulting mixture is rapidly cooled to 11Q ° C and treated dropwise for 13 minutes with stirring. , with 1.67 ml of 1-bromoaeetone, is reacted with the reaction mixture at a temperature not exceeding 40 ° 0. The code is added to complete the dark reaction mixture with the mixture for another hour at room temperature, and for * * e pour in the hydrochloric acid-ice-ice, saturate with solid sodium chloride 1 extract with ethyl acetate (3 with 100 sl ) »Binding organic extract are j. washed with broad water to neutrality, dried with the practice of anhydrous sodium sulfate and evaporated to sulfur under said pressure. * Chromatography * of the residue on 30 g of silicate gel using emea haxaniothyl acetate (70130) as oluent, obtained with 390 g of crystal N- (2-Hydroxyethyl) -3-carbonaethoxy-4-methylpyrrole-2-acetate which, after recrystallization from the acetyl chloride-bexane mixture, melts at 7 ° C and has the following analysis.

Calculated for ^ 2 ^ 17 ^ 51 ® * 56 ** 5 | H »6 * 71 B & djemos C * 56» 41 | H, 6 * 7? ·

Km in a similar way, but using the stachyanotric equivalent of 1-bromo-2-butone, 1-brsao-2-pontanone and 1-bormo-2-heccanone instead of 1-brooaootone, the salt methyl H- (2-hydroxyethyl) -3- Carbomotoxy-4-ethylpyrrole-2-acetate, methyl K- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrroch-2-acetate methyl K- (2-hydroxyethyl) -3-carbomethoxy-4-butyl-pyrrole -2-aoetate * EXAMPLE 14

The preceding procedures of Examples 2 * 3, 4, 5 and 7 methyl H- (2-hydroxyethyl) -3-carboaethoxy-4-nitro-pyrrole-2-acetate (IV, R m CH 2) are translated successively into methyl N- (2-Razeloxyethyl) -2-carboaethoxy-4-oethylpyrrole-2-acetate, methyl N- (2-iodoethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, * “dloethyl 112-dihydro-6 -a «tyl-3E-pyrrolo [t2-a] pyrrolidine, 7 > dicarboxylate, 1 [beta] -dihydro-6-ybethyl-5-yl-pyrrolo [2,1-a] pyrrole-1,7-dikerboxylic Idsellane, Isopropyl 1 # 2-dihydro-6-aeyl-3H- * pyrrolo A, 2-α-pyrrole-1-carboxylate-T-carboxylic acid and isopropyl 1,2-dihydro-6-rathyl-pyrroxy -olo- [1,2-a] pyrrole-1-carboxylate (X * R «OH ^,

The method is shown by substituting methyl H- (2-chloroquinethyl) -2-carboethyloxy-4-ethylpyrrole-2-acetate for anethyl S- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl H- (2-hydroxy-ethyl) -5-carbomethoxy- * -propyl-nitro-2-acetate and ethyl N- (2-hydroxyethyl) -N-carboethoxy: 3-4-butylpyxole-2-acetate gave the final products * isopropyl [1,2-dihydro-6-ethyl-3β-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl 1,2-dihydro-6-propyl-5H-pyrrolo [1,2-a] α-β-troll-1-carboxylate and isopropyl 1β-dihydro-N-butyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate · EXAMPLE 15

According to the procedure of Example 8, isopropyl [2H-dihydro-6-methyl-3B-pyrrolo [1,2-e] pyrrole-1-carboxylate was condensed with Hβ * -di®ethyl-p-toluene to give isopropyl-5-p -toluoyl-1,2-dihydro-6-methyl-N-pyrrolo [1,2-a] pyrrole-1-carboxylate (Xit 1-CH 2 P-CB 2), - 39 - H «91S & 9M aa & ia «11 korlš6« nj · »H f a-dim« tilarila »ida navtdtnlh« Fsiatjni 12 A usest «M, dla-dlae til-pt» ltta «l & m, dobiTa ^ u ni isopropll f-benaoll- l g2HLihldro ~ 6 * «* til« -3B < -pyrroloA * 2- «A plrol-Mrekbekeilmt t isopropyl ^ -o-toliiell-1 ^ S-dihydro-e-alkyl-N-pyrroloA, ^« / - pyrrole -1-carboxylate, isopropyl 3 - * »toluene-1t2-dichloride» «- 6« α «tyl-3B - n) irole [1 * 2-α] -pyrrole-1-carboxylate» fluopropyl $ -yt 11 » btnmollA »a-dlhidro-6» · —til-jB ^ pirolo ^ A f 2 »« ^ lxol ** lptesb «) Eeilat« iaopropil 5 »« »p» epllbensal2 ^ 1t2-dlhld3? o-6 »metll» 3B * e9irolo »A iS- ^ pyrrol-l-kmkbokeilmt v

Isopropyl 5- [butylb] ii * © yl-1t2-dihydro-6-yl] tyl-3H-pyrrolo [N] -2-pyrroyl-1-carboxylic acid totopropyl 5 * o-Bethoxybeii * oil ·! % 2-dihydro-N-yl-3H-pyrrolo [2-yl] pyrrol-1-yl] carboxylic acid propyl 5-N- [tokeiben] oil-1H-ethylhydroxy-pyrroloyl-pyrrolo -A f2- * e / pyrrole-l ~ k «Fboxylate thiaopropyl 5-p-Hrphoxibone» oll «» l t2-dlhiAro-6 ~ B «tyl-3H-plrolbAta-e / pyrrole-1-carboxylate, ioopropyl 5 ~ P * l * < ^ rojK > k «iben» ell ^ 1,2 »-diMdxo-» 6-methyl-3H- * pyrroloA * 2 - «/ pir © ll-carbokailatt iaopropyl 5-o ** blorob« aaeil-1H-dihydro ^ -aethyl-N'-p1 · ®! ® ”A * 2» α / pyrrole-1-carbaylate, ioopropyl 5 < ^ chlorob «naoylHLt2 * 4ihydbro-6-wtil-3B ~ pyrrolo [1,2-a] pyrrole-1-carboxylate, ioopropyl 5-p-chlorobenzoyl-1H-dihydro-6-aethyl-3H-pyrrolo-N, 2-a [pyrrole-1-carboxylate] isopropyl 5- Hydrofluorohydro-6-ethyl-3H-pyrrole-2-a / pyrrole-1-carboxylate isopropyl 5 * P * fltta * obenaoyl-1,2-dihydro -6 - «ethyl-3B-pyrrolo-A * 2-a / pyrrl- * carboxylate, k» ji la «smoothing fiaic kenatan-tat 0.». \ mm * 250, J15 na (6170, 14,100) t OBOI * 1 IJU Jma 9 1734, 1605 * 1593 e * l NMR *? fHS 1.25 (d * 6Hf J · 6 Haj «« tarski GH ^), 1.Θ3 (s * 3H | pretanaates OH ^), 2.49-3.00 (μ, 2H) OHg), 3.90 (tt IH * & ·?. * Ha j CHCO), 4.1 < V 4.23 (a * 2 »! B- CHg), 4.98 Ceapt., IH * 2 · 6 Ha} aatarski OB) * 5 * 84 (a * IH * S- *),?, 00 (t * 2Ht Jarta - β · 4 H «f · 8 Hs * Β-3 ·, 5 ·), 7.55 (q * 21

Jorts * 8 · 4 * ·% * * · * H * l Μ.6 * > | a / «l * 329 25 8 * 242 100 H * -CO2CB (GHj) 2 123 36 * -06B4COe isopropyl 5-a-troeobsBaoyl-l *; & -dihydr © -6 - ^» atyl- 3 &-p irolo-A.2-α-pyrrole-1-carboxylate and isopropyl 5-membered benzyl-1,2-dihydro-6-ethyl-3H-pyrrolo-A * 2-α / pyrrole-carbocarlate. H «alical way prsaatala final compounds obtained in friaar 14 are translated into odgerarajud« 5-aroyl substituted derivatives, fax obtained vepresentative compounds «ut isopropyl 5“ ben * ayl ^ l * 2-dihydro- & ^ atyl-3H-pirpla- N, N-pyrrole-1-carboxylate, isopropyl 5-benzoyl-1,2-dihydro-N-propyl-3-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-benzene -S-dihydro-e-butyl-N-pyrrolo- , 2-aβ-propropyl 5T-toluene-1-ylpropyl-6-ethyl-1-pyrrole-2-a-2-pyrrole-1-carbexylate and iseprepyl 5-pyrroloyl -1,9 Dihydro-6-propyl-pyrrolo [1-S] pyrrole-1-carboxylate 9 isopropyl 5-e-ethocabenzoyl-1,9-dihydro-butyl-5H-pyrrolo- / 192- * / pyrrole-1-bocailate in isopropyl 5r-ethoxyben * oil-1 * ** lihydride -6-ethyl * 3H-pyrrolo [1 t2-a] plrol-1-carbocaylate 9 isopropyl 5 - ^ chlorobensoyl-l92 ** lihydro-6-propyl-3Ii ~ pl ~ r < > 1 < > · " (1,2 * -e) Pyrrole-1-carboxylate 9-propropyl 5-D-jaroben * oil-192-dihydro-butyl-5H-pyrrolo [1-an] pyrrole-1-carboxylate 9 iseprepyl 5- ^ flu © rob «njK > iVlt & " dihydro-6 ^ 1dl ~ 3B-pyroXo- / I, 3-a / pyrrole ~ l ~ carbocallat9 iaopropyl $ -p-fl» erobenaeil ~ l92-dlbldpo-6-propyl- 5H-pyrrolo [1-a] pyrrolo [1H] carboxylate 1 iseprepyl 5 ' p * breebenaoyl ~ 192 * dihydro-6-butyl-5H-pyrrolo / 192-a / pyrrolo [1-yl] bekaylate * PRDCSH 16 Phiaat. * iaopropyl $ "p ~ * olttoyl-1-92-dihydro-6-aethyl-3 & -pyrrolo / l92-a / pyrrole-1-carboxylate in 1 $ al *« ethanol treats ae aa raatvero * 1 * 0 $ g « potassium carbonate in 6 ml · water * Beaksiena amoeba reflukeuja ped aaotsoa atmosphere «$ Q minutes * cool ae 1 1 sp ari ae de sura · ^ statak ae collect in 10 al * 10% aqueous chlorohydrogen acid and $ 0 ml · water and the resulting amoeba was extracted with ethyl acetate ($ x $ 0 ml ·) · The combined extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 5-p-toluoyl-1% 2-dihydro-6-me. t il-3H-p irolo / 1 * 2 ~ a / p irol- 1-carboxylic acid (* (A), B - C8 ^ B4 · p-CB ^). B «iU8a nadia, lli alUastttM UAtvUmb kao u poatnpku ls Ivlam 10y iaapropil ictrnka jadiajaaja dablTena« Trlaam X5 praT * d »mu odgevarajuA ·» loboda · klsalia · «oaia # i 5-b * a * d-oil-l2 - »ethyl-5B-pyrrolo [t2-a] plrol-1-castooxylase [X1 & af < ^ - teluall'-lv2 ^ 1hldarow6» aethyl-5H-plroleA »2-a / pyrrol-l-IrliralliMg > * a »tol] iaiX» Xf2-dilkldza * G * aatll ^ 3B «pixelaAtB *« / - plzolrl- ide «Xi2Mu > p ^ tilbensoil * lt2wdihldra- ^ wwtllw3DwplroXeA, 3 * Ι 0 -ίλ &; pgoplXbinioil »Xta» dllildw ^ »» til ^ ffi ^ irolo »A t2- · / -pirol ~ l ~ kaAokailaa klefXiBA · ^ p-btttiXbanaol3 ^ 1f2 * dihydr» -6 «M6tll ^ B-plrolo-AgŽ- · / -pix «ll» kaxt > ok * ikUwXlBt | 5iweweetakeibe »soiX» X f 2-dihldra-6 - * # t ll- ^ pirolo- A »2-aA pirol-l-ka * bokailna kiaallna, > p * wtek» ibeosoili-Xt2e ^ iMd »e ^» ethyl »9B« plroXo ^ At2 »· / -pyrrole-XHwort > © Jc» iliwi ki »« lina, 5-p-atokeibanaoil-l t2 ^ Llhi43ro-6-eetlX ^ 3B * pirelo · A · 2 »a / ~ p irol ~ l ~ carbo kalina kla «llnaf ^ -p-ikopropokaibanaoil-l f2-dilyl < Jro-6-, o» til-5B * > piroX < > ~ A * 2-a / · pyrol-l-kaibokailaa acid, 5- * o-chlorobenaoyl-1,2-dihydro-6-ethyl-3B-pyrazole-2- [pyrrole-1-carboxylic acidal-chloro-banoban-1-yl-chlorobanaol-1-yl-dibold. 6 ^ * tlX »5BwplroXe-A [2-a] -pyrrole-1-carboxylic acid, 5-p-bloxobenzol-1,2-yl] -apo-e-» et 11- 3H-pyrrole »/ l, 2 - «/ - p Iral ^ I-carboxy ln > klMllaa9 9 - «- fle» * eb # ii * oil »lf2-dilildjp * -6« * eethyl-3H * piJpeld- / lf2 ·· / -pyrrole-l ^ carboxylic acid ** linat > ^ nnorob * fuwil » lt2-dihydro * o-6- ^ tyl ~ 3H ^ pyrrole ~ A 92 · * / · * pyrrole-1-carbacaine kiaalin *, t «t · 204 ° Ct Sa ^ broeobensoll- ^ iS-dihydan-G-ethyl JB -pyrrolo-A 92 »* A pyrrole-1-carboxylic acid, 5-p-brp * ob« n * oil ~ l 9 S ^ ihidro-6 · »« tlX-5 &-p trole · A 92-a / -pyrrole-carbocarbide clathyl * '' Hm & mII-I 9 2- ^ Llhydro-6- «tll-3B« plrolo A f3 - * / pyrrole-l · »carbochaln * kiaallna, 5» b «a» oll-l # 2-dlbiaro-6-pwpll »5B-plrole / I * 3W * -plrel-1-carbocalic acid *, 5-beaaoyl-l 92-dlhldro-6-butyl-? HpirelaA f £ - * / pyrrole-1- carboxylic acid «lizia9 5 - ^^ olu © il ~ l92-dihi4r © - ^« til ~ 5B »pir © loA92 ** / ^ lrol-1-ksrbnksiln * kleellaa9 5 ^ -ttHbaa * oll ^ X 9 JMlkldre ^ pjfopil- JB-pyrrolo-A 9 ^ - · / -pyrrole-1-carboxylane klatyla *, 5-P ^ Betokaiben * oll * ·! 92 ^ 1-Hydro-6-pyrrolyl-3H-pyridin-3-yl-pyrrole-1β-carbecaic acid, 5-p-tokalbey oil * *! 92-dihydro - ^ * € til «, 5H-ptrolo - A, 2» aA pyrrole-l-carboxylic acid lin «, 5“ 0 »hlopoben2oH-l 92-Λ11ιΐ4Γβ“ 6-ρΓορ11 · 5Β, · ρΐΓθ1 ·, [1,2,2] * - pyrrolo-1-carboxylic acid [5 * 5-[beta] chlorobenaoyl- [beta] 2-dihydro-6-butyl [b] pyrrolo [alpha] -pyrro-1- Carbokeyl klaalin *, 5-o-fluoroben * oil-192-dihydro-6-yl-3S, -pyrelo- [92-a] -pyrrole-1-carboxylic acid, 5-p-fluorobenzoyl [2] dihydro -O-propyl-3B-pyrrolo [2-a] -pyrimidin-ethyl] -acid, and 5-p-brone-benzoyl [1,2-a] hydro-6-butyl-3B-pyrrolo [2-a] -pyrrole-1 Carboxylic acid * PRIMES 17 710 A suspension of sodium hydride in mineral oil is washed with anhydrous hexaazoate under ataoeferon asota and fcatia salt is suspended in $ 0 ml. diaethyliormamide * The suspension is cooled to -5 ° σ 1 and 4 * 5 g of methyl K- (2-aesyl-oxyaethyl) -3-carboxyethoxypyrrole-2-yl are added. ° to 0 ° 0 during 1 Now. Zatia «o lily in ice cold raster? sodium chloride and extracted with some »like pot with benselon» 3po jeni extracts with delivery with water · »kind with and lsparo to sura under saanjonia pressure * solid sharp tak kristalile is 6ra so so gets diaotyl 1,2-dihydro-JB -pyrroleA * 2-a / pi »ol ~ l« 7 * dicarbexylate (TU «E · H) which is identical to the product obtained in Example 4 · U 3 ~ 250 ml halon with a round lady who is equipped * -ljoa sa ulaono-islasnim rontiloa sa suri asott sa nagnetnoa nodalioon 1 sa lorkoa sa dodaranj «sa sovi sa is jodnachsranjo tlaka« ko ji sadri! 10 * 08 g of "otaaolanine" are added to the solidified "1 us with Sanjo" 26 * 1 g of diaothyl 1, p-acetonedicarbocaylate for 50 minutes at a sliding temperature below 30 ° C * Kotil 3 * carboaotoxoxotyl-5- (2 > -hydroxyotyl) -aglwooacrylate (III) when treated with dilutions with 20 sl «aootonitrlla 1 added with chloroaeetaldehld« previously made heating sseše 45 27 * 4 g * hloroaootaldahld diethyl eetal m 46 * 8 g · oxalic acid Oe da 160 ° 0, #a mešanjem a toka 2 minuta Soatalona smeša a «reflnksuje 5 do X0 minuta, posla Sega ao nalaai da S · reakoija perfect, kao Sto ja odredjeno posoda tlo analna use of a mixture of acetonihlorolorm (10i90) as eluent * Hastvaraš at otera under reduced pressure ekon 1 oatatka ee add 250 ml * bensol and 250 ni «heptane, and then distillation is performed under reduced pressure * Oily residue remaining lag distillation with eacpeaftuj 5 ° ml * of methylene chloride and add 20 g * of silicate gel. Methylene chloride saucepan containing 200 g * of silica gel made in the form of acetylate acetate (20t80) * The column is first alluvized with 6 liters of the mixture acetylate acetate (2§ * 80) 1 satia with 4 liters of anaSs attilaate 50) · That fraction which I as elnlrajn with saaSom atilaoatat tksksan (50 * 50) with compound and koneantrujfl so that with gets 12 * 8 g * oil which I with ieitnl with 20 al * patzolstra (35O-60 ° 0), so with satia tends to dissolve under pressure under pressure so as to obtain 11 * 89 s * (32.9 ^ of theoretical) motyl B- (2 * -hydrocyanyl) * 3-carboB »toxipyrrole-2-acetate (It * H · H) which has a melting point of 51-54 ° C, and this is the same product as the salt obtained in Example 1 * EXAMPLE 19

A solution of 200 mg of * 5-banaoll-1,2HLihydro-3 & -pyrrole [1,2-a] -pyrrole-1-carboxylic acid in 5 ml * of dibloroaethane is triturated with excess atar dlanematene, and the reacolon mixture is maintained at room temperature. at a temperature of 30 minutes * Haatvar ^ aSi and the excess reagent are eliminated by the said pressure and the rest of the crystallisate and the mixture of ethyl acetab-aethanol, so that 46 * nttl 5-benzoyl-1,2-dihydro-3H-pyrroloA, 2- « / pixol-l ^ car-bokailat. In the 11th way, using di & zoethane «and diaao» »propane« useate diasoaotans give a «« tyl 5-benzoyl-1, <? - dihydro-JB-pyrroloA, 2-α / -pyrrole-Mcarboxylate 1 propyl 5-benzoyl-1,3-dihydro-3B-pyrrolo A, 2-α-pyrrole-1-carboxylate ·

In a similar way, the remaining "free" acid "line" obtained in Prisers 12A (1 12B) and acid is Priaerm 16 translation "s" in the corresponding "ethyl," til 1 propyl ester · PHIMBH 20

Saotver 300 ngv Jp-tolooil-1,2-dihydro ~ 5H " 'pi * oloA, 2 ~ a / -pyrroll-carbecaline ktealin «u $ al · iaoanilalkohola saeitl a« sa hlorovedonikoa · Posl «24 chasa, vlšak alkohol oe odo -at linj «u Takso» i oatatak a «prečisti hroaatografijo» na aloslnljan-ekelda, tako Aa m gets isoasdl 5-p-tolooil-1 t2-dihidzoa-3H-piroleA »^» a / pirol-l-karbokailat · H «Similar way with« get 1 expensive «strl, n« pr ·, pentyl, hekeil, okt 11, netil, dodeeil and similar 5-p-toluoyl ~ 1,2 ~ dihydrates »5H / pyrrole« -A, a-eZ -pyrrole-l-kerboke line kiaeline seneno »Isotodlalkohola sa drogi · alkoholi» «, n * pr., aa pentil, heksil, okt11, nenil i dodeoilalkoholo».

The free acid compounds The compounds obtained from Priaerina 12 1 and 16 are etherified with the reaction ether, and thus the ethers are obtained, for example, 5 ~ ben * oil ~ l, 2-dlhidxo ~ 5i ~ piroloA, 2-a p-pyrrole-1-carboxylate, pentyl 5-n-tolooyl-1,2-dihydro-3H-pyrrolo, 2-aβ-pyrrole-1-carboxylate, hokayl 5-p-tylbonyl-oil-1,1-diisoxy 3B-pyrrolo [2-pyrrole] -alkyl-carboxylate isolaalline-pyrrolidin-5H-pyrrolo [2-pyrrole-1-carboxylate] octyl 5-p-aetocaibonzoyl [2-o] Lihydro-5α-pyrrolo [3- [pyrrole-1-carboxylate] nonyl < - from peroxybonyl} -1H-1,2-dihydro-3H-pyrrolo [2-a] -pyrrole-1-carboxylate * dodeoyl 5 N < HtHorob «tt * oiZ-1 t2-dihydro * 3B-pyrrole-2-e] -pyrrole-1-carboxylate in isoaall Ca ^ chlorobonzoyl · ·! t2-dihydro-5 ^ pixttXo ** A92 ** e / * · pir «ll * carbokailat f dodeoll 5-o-fluorob« nzoyl-l f a-dihydro-JH- ^ pyrroloA t3 ** A plr®l »» l ~ kajpboksilabt bokali 5 * P * llttorobonzoil-l f a-dihldro-JS-plroloA t2 · ** / - plrol-l ~ karbokeilAt% nonil 5 ** p-bro®obefiaoil-l, a-dilii.dr © - 3H-pyrro-N-pyrrolo-1-pyrrole-1-carboxylate isoa [5-dihydro-1H-dihydro-N-methyl-3-yl] -N-pyrrole-1-pyrrole-1-carboxylab. N-Hydro-d-aothyl-1H-pyrelo-N-pyrrolo-pyrrole-1-carboxylate nonyl 5-acetoxybaraoyl-1,2-chloro-6-yl-3H-pyrrolo [2-s] pyrrole-1-carboxylate. dodeoll 5 * N-tyl-Orobenzoyl-1,2-b-dihydro-3-ethyl-3H-pyrrolo-N-a-alkyl-1-carboxylate f nonyl 5-benzoyl-1H-dihydro-6-ol-3H-pyrrolo, 2 ** a / -pyrrole-1-carboxylate isolaall 5-P, isobenolyl-1 * 2-dihydro-6- * thi '3B-pyrrolo [1,1-a] pyrrole-1-carboxylate t 48-pontyl 5-yl-fluoroben-1,2-dihydro-6-propyl-5H-pyrrolo-1-yl-pyrrole-m-carboxylate, hekayl < -i ** lilorob «nBoil-l , 2-dihydro-G-butyl-3B-pyrrolo [1] aβ / pyrro-1-carboxylate 1 dodeoyl 5-T < yl-1t2-dihydro-N-ynyl-5B-pyrelo- [X] a / pyrrolyl] -cartocailate · PHIMEH 21

To a solution of 300 ag »5rP« teluoyl »lf ^ dilildro» 3B - pyrelo [1,2-a] · plrol-1-carboxyla yl · acid · in 3 sl «» ethanol was added with «1 molar equivalent of n & trlduB- hldrokei & au oblito * O.lH ra »tvora« Raat-vor a · tafta ispari pod snanjenia pritiakos 1 ostatak eo eakupi m 2 a! «» ethanol, pa ao © nda precipitates aa etrea so that eo gets crude sodium jo * 5 -P "toluene" 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate crystals which crystallize.

Na ali & aa naftia so pravo i drugo soli »n« pr ·, aaeniJUB i kaliJonove soli 5 ^ * toluoil- > le ^ -dihidro-3H «pirolo / lt2« a / -plrol ~ l ~ karfcokallBe klas lino sanonoa natri Juar-hydrocaida aaonluj ^ bidroxyftoa 1 potassium-hydroxydone ·

In a similar manner, salt-substituted-1H-dihydro-3N-pyrrolo [1,2-a] pyrrole-1-carboxylic acid compound was obtained in Frinoriaa 12 A (and 12 B) and 16. sodium, potassium and aaonium salts «

The jacket is obtained on the representative compounds of sodium 3 "© -toluoyl-1,2-quihydro-3H-pyrrolo # 2-a [pyrrole-1-carboxylate sodium 5 * benzoyl-1,2-dihydro-3H-pyrrolo] * 2-α-pyrrole-1-carboxylate »- - sodium» (1) - ^ benzo: U.-1,2,2-hydrohydro-5H-pyrrole-pyrrole-1-carboxylate and potassium p- «tilbensoH-1, J £ * dihydro-3H-pyrrolo- [1,2 * t] - * pyrrole-1-carboxylate * potassium» 5 < 0-butylbexyl-oil-1H-dihydro-1H-pyrrolo] / 1H-pyrrole-1-carboxylate, sodium 3H-ethylene-1,2-dihydro-3β-pyrrolo [1,2-a] pyrrole-1-carboxylate, aaonium 5 * p-chloro-obenaol-1-yl-dihydro-5-pyrrole-α * 2- · [- pyrrolo-1-carboxylate, ammonium »5-0” yltro-benzene-X-t2-dihydro-5H-plroXo-A ^ 2 * '· / - · pyrrole-1-carboxylate, potassium »5 ^ bro» ob «n * oil - 1,2-dibiaro-3H * -pyrrolo *' / 1,2-aA pyrrole-1-sodium carboxylate 5-Benzoyl-1,2-dihydro-6-ethyl-5H-pyrrolo [1,3- [1-pyrrole-1-potassium carboxylate] 5-toluoyl-1% 2-dihydro-1- oe tyl-3H-pyrrolo-A, 2- * a [-pyrrole-1-carboxylate] alpha-o-methoxybenzoyl-1H-dihydro-e-methyl-1H-pyrrolo [1,2-a] pyrrole- l ~ carboxylate , natri jun * 5-p * f luorobtnz ο11 · »1,2- ^ ULhidre-6-propyl- * 5H-» pyrrolo · A, 2-a / pyrrolo-1-carbocaylate and potassium »^ - ^ - chlorobenzoyl- 1HS-dihydro-e-butyl-JH-pyrrolo-A, 2-α / pyrrole-1-carboxylate · PHDOSR 22

Rautvor 175 ®β · 5 “P ~ toluoilr · !, 2 '^ ihldΓo, ·· 3H- * pyrrolo · * A, 2-a / pyrrol-1-carboxylic acid in 5! · Methanol is added at 1 mo lam equivalent of potassium jua-hydroxide in the form of a 0.1 N solution, so that st receives a solution containing potassium Jp-toluoyl-1, a-dlhldro-: ia-p3 rtilo / Χ tS > e / -plrol-l-karl > ekstlata . Baatnr 40 «g, kaloijne-karbonate rutnmeg a ninlnalnoj kalldlni IH hlarovodanlSne klaallne koja je treba da iavrSl raatvaraaja kaloi jna-karbonate, buferoja aa aa 100» g · Svretog aaenljna ^ hlarida, 1 onda a · dalje doMvan bufereran kaleijuaov raatvor aa toda doda rastvoru kalijo · 5 ^ tob »ll-lf3 ^ 1hto * 3B ^ l» Wlf3 ·· / · pirol ~ l ~ karbokailata i talog ko ji aa obranaja aakupi aa dalja filtracijo ·, iapere aa aa voda · 1 aafii on vaadolni so that sa gets calcium · 5 * P ~ taluoil-lf2, -dihldro, - ^ - pyrrolo / l «JS-a / -pird-l-carbakallat«

Ha alidan nadin pravi aa aagoaslju · 5 * -p ~ toluoil ~ lft2 * dihidro »5S * i * piroloA, 3, i * a / plrol *, l“ karbokailat sasanaa kalciju »-karbonate aa aagnasi jua * karbanaton ·

Similar to aaaasos 5-p-toluoyl-1 # 2-dihydro- * 3H-pyrrolo [1 t2-a] -pyrrole-1-carboxylae kisslins aa 5-banzoyl-1'S-dihydro ^ JB-pyrrolo [f 2 * -e (pyrrole-1-carbacayl) lino «, (l) -5 " banaoil-1 t2-dihydro-3H-pyrrolo- A t2-a / -pyrrole * l *» carboxylic acid · kleallno · '5-p -blorocarbonyl-1H-dihydro-3H-pyrrolo-N2-a [pyrrole-1-carboxylic acid] -5-o-methoxybenzoyl-1,2-dihydro-3S-pyrrolo-N2-a / pyrrole-1-carboxylic acid 5- * p-methoxybensoyl-1,2-dihydro-5H-pyrrolo-1,2-apyrrole-1-carboxylic acid 5-benz oil-1,2-dihydro -6-methyl-3H-pyrrole-N- 2- [alpha] pyrrole * 1-carboxylic acid 1 5-fluorobenaoyl-1H-2-dihydro-6-ethyl-5H-pyrrolo [alpha] -2-α-pyrrole -1-carboxylic acid · 9 51 get m edgovarmjude kaloljsaov »and magnasijueova salts · PEIHEB 25

Baatvavi 200 ag · 5-p-toluoyl ^ lt2 ^ hixiro ~:? I-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid in 5 [mu] l of methanol add aa 1 aelar equivalent of potassium hydroxide in form of O.lli raster. The solution is dissolved in 5 .mu.l and if the resulting aqueous solution is potassium "5" P-toluoyl-1t2-dihydro-3-pyrroloAt2-e / pyrrole-1-chloroboxes: Lata is added to rafltvor 150 mg * cupri-nitrate trihydrate in 5 ml · water · Educational precipitate aa collected, washed aa aa water · and audi, so that aa gets copper 5 ~ P " talaoil-lv2i »dihydro * 3H ~ pyral- / 1,2 -α / pyrrole-1-carboxylate «

On a similar planting aa alobodoa acid jadlnjenja obtained * vena in Fzimerlma 121 (and 12 B) 1 16 legs right in odgcnrara-juda bakaraa aali · EXAMPLE 21

Baatvor 200 mg, 5-p-toluoyl-1H-dihydro-3-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 60 ng of isopropyl amine. The mixture was allowed to cool to room temperature and the product was filtered, washed with ether and dried to give isopropylamine with 5-p-toluene-1,2-dihydro-5-pyrrolo [1,2-a] pyrrole-1- carboxylic acids.

Other amine salts, such as diethyl amine, ethanolamine, piperidine, tromethamine, choline and caffeine, can be formed in an alkyl manner with 5-p-toluene-1,2-dihydro-1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid with o- 52-prepylasin seed with the corresponding amyl

In a steel manner, the free acidic compounds obtained by Priorities 12 A (and 12 B) and 16 are converted into the corresponding isopropylamine, diethylaine * ethanolamine kef pipsridine, trometaaine, choline 1 caffeine salts * EXAMPLE 25

Baatvor 77 © sg * 5-o-teluoyl ^ 1,2- < l] iidx ^ 3H-pyrrolo [1,2-a] - · pyrrole-1-carboxylic acid in 10 sl »benzene 360 sag · diolklohekallaaina «Reakoioaa onesa ea meča 10 minuta * i solidna ko ja sa obrezuje separates with filter-oil and marl« with anhydrous etron so that the salt receives 963 sg «dioiklohokailnainsk» salt of 5-o-toluoyl-lt2-dihydro -JH-pyrrolo, 2-α-pyrrole-1-carboxylic acid, mp * 161-163® ° *

In a similar manner, the remaining free acid iodine was obtained in Priaeris 12 A (and 12 B) and the compounds in Examples 9 and 16 were converted into the corresponding diecyclobexylanine salt, e.g., dioichloxyxylamine to 3-o-chlorobenaoyl-1,2- dihydro-N-pyrrolo, 2-α-pyrrole-1-carboxylic acid, mp 173-175 DEGREE EXAMPLE 26 5-Benzoyl-1,2-dihydro-5H-pyrrolo [1,1-a] -pyrrole-1-carboxylic acid Maize starch Lactose, spray-dried magnesium juateaerate 25 20 153 2

The above ingredients are completely isolated and compressed into individual tablets · PRIHEB 27

SiBSaJH no tablets, »g. 5-Benzoyl-1,2-dihydro-5? -Pyrrolo- [1,2-a] pyrroyl-1-carboxylic acid 200 corn starch 5 ° lactose 1 * 5 magnesium stearate 5

The above ingredients are mixed thoroughly and compressed into individual tablets of "100 mg, (1) -5-ben" oil-1f 2-dihydro-5H-pyrrolo-A, 2-m-pyrrole-1-carboxylic acid. gg · (dl) of the compound and of the above preparation · PRIKBE 28

SajitO.IOl KflllžlB »M kgpaull. BK. Sodium 5-beasoyl-1H-dihydro-3H-pyrrolo [2-a] -pyrrole-1-carboxylate 108 lactose 15 Maize starch 25 Reagnes 2-Stoarate 2

The above saetojci are anointed and introduced into gelatin capsules with a hard shell · weight 5 $

Saato.lcl PQ krnili, ag. potassium 5-benzoic acid-diffidre-3-pyrrolo * A f 2 - * - - pyrrole-1-carboxylate 115 lactose 95 corn starch 40 magnesium etearate 2

The upper saetojoi are foamed and arranged in a gelatin capsule with a hard shell · example 30 3aato.1al proximity to the tablet ^ m. 24 $ 75 175 5 Isopropylammonium β · 5-benaoxy-1,2-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate corn starch lactose magnesium jua etearate

The upper saatojei are intimately mixed and converted into individual tablets "PRIHLR 31 S — talai K.HŽ1". m tablrtl. on. methyl 5H > enzoyl ~ 1 f 2-dihydro-3-pyrrolo-AtS-eZ-pyrrole-carboxylate 25 lactose 123 the above constituents are pooled and introduced into a No # 1 gelatin capsule aa hard Ijuokor «EXAMPLE 32 * · M * 300 300 5-Benzoyl-1H-2-dihydro-3E ”pyrrolo- [1 * α] -pyrrole-1-carboxylic acid eacharose - 55

The above ingredients are "completely excreted and processed into individual tablets, with which the tablet is eaten" and gives three to four tablespoons · FKIMEB 33

Bastoicl Quantity per tablet »^ g. Isoamyl 5-benzoyl 1% 2-dihydro-3H-pyrrolo [1-iva] -pyrrole-1-carboxylate 254 imTroyHK ^ 4 starch 50 lactose 190 magnesium atearate 6 The above constituents are intimately separated from each other. »Single tablets« PHDtEH 34 Saatoial Kaii * i «i pft nff. 3-Benzoyl-1H-dihydro-N-pyrrolo- N-pyrrolo-1-pyrrole-1-carboxylic acid 100 lactoma 148 dex trosa 2

The burning ingredients are eaten and placed in a gelatin capsule with a hard shell of "50 mg" (li - ^ - benaoll-ltS-dihydro - ^ - pyrrolo ^ / ltS- · / · pyrrole-1-carboxylic acid is replaced by 100 mg · (dl) j edin je iz gornjes preparata «56 primer 55 netil 5 ^ 000011-112-4 ^ 1170-5 ^ -917010- / lf2-a / -plrol-l-karb < > xylat 158 laktosa 92

Gornji aastojei s «poaeftaju 1 uradu ee u gelatineku kap tulu ea trrdea ljuakon« EXAMPLE 56

Santoi «l

Kollžln «τλ fcmrnll. no. 12? 91 25 2 5 lsoaail 5 ~ to «n2oH * l9 &» dlhllvo-3B * " PlTOlo-A, ^ a / -pyrrole-1-carboxylate Lactose corn maize ekrob nasnezijus-etearat gelatin

EXAMPLE 57 frafedal 6oH81b «t», | y calcium »5-benaoyl-l * 2“ 4ihilro-3H ^ irolo- / l 12-a / -pyrrole-l -carboxylate 250 corn starch (paste) 40 corn starch 50

Bagnesius-atearate 2 lactose 1? 8

The above ingredients are taken up and compressed into individual tablets. 57 EXAMPLE 38

Sftutatel

Quantity oo tablets, atu 217 50 2 226 5 sodium »5 * to« wsoll-lt2-dlhldre-3Si-piro3x > - corn starch sagneziua-etearate gelatin lactose

Upper breath that is intimately excreted and transformed into individual tablets «PSIMER 39

Gastodol

Kollžlrm pa tabl.tl. ag. 122 30 98 Isopropylathioabenzoyl * le2-dihydro · 3B-pyrrolo-N-2-α-pyrrole-1-carboxylate corn starch lactose

The upper consisted of an exit and an introduction into a gelatin capsule with a hard shell «PKIMEB 40 £ ftgtoioi ŠMŠtito M9 tegiUAa. Isoanyl ^ benzoyl-1H-E-dihydro-1H-pyrrolo [1H-2H-pyrrole-1-carboxylate 52 Lactose 101 Maize starch 15 Magnesium stearate 2

The above ingredients are mixed and introduced into a hard shell gelatin capsule · PRIMES 41

Sepwli # n 4 · Preparation with pH-buffered fluorine containing 5-benzyl-1β-dihydro-JB-Pyrrolo- [1,2] · · pyrel-1-carboxylic acid 0.2 g buffer (0.4 M r & atvor) 2 al «SOB (1H) qa to pB7

Water (deatilized) q * s. up to 20 ml. 0.1 g. (1) ~ 5-Benzoyl-1H-dihydro-3H-pyrrolo [2 * -α-pyrrole-1-carboxylic acid] 0.2 g. (dl) compounds of the preparation. PRIHEH 42 made a suppository of a total of 2.8 graaa colors laa alededi aaatavi 5-bensoil-1 # 2— & i hidro — J ^ pirolo · - /! .2-N-pyrrole-1-carboxylic acid 25 mg.

Witepaol H-15 (trlglioerides of saturated vegetable fatty acids; products of Biehee-Nelsea Inc.,

Htv Torkv ST) residue 12.5 mg · (l) -5 * ben * cil — lf2-dihydro * »3H-pyrrolo- / l * 2» a / ·· pyrrole-1-carbocane · acidic acid 23 mg · (dl) compounds from the upper vapor & ta * PBIKEB 43

An oral suspension * e podiatry was made using fcoja has Bledeči eaetavs 59 59 5-benaoll-l | a-dihydre-3ii-pyrrolo- / l t2-a / ~ pyrrole-l ^ cartoxylic acid 0 * 1 g * fuisama acid 0.5 6 sodium chloride * ~ chloride 2.0 g * metallparaben 0 * 1 g. grammed Sugar 25.5 S «sorbitol (7056 solution) 12.85 6 · Veegum K (VanderMlt Co.) 1.0 g * odor 0.035 ol color 0 * 5 mg * distilled water ς * 8 · up to 100 sl * 0 * 05 δ · (l) -5-Benzyl-1H-dihydro-3S-chloro-N-3- [1H-pyrrole-1-carboxylic Idylcelline] 0.1 g. (dl) Compounds of the above preparation * rnm & L 44-45 H performed in the practice of veterinary use which ΈΕη JfcS 0 * 1 g · 1 * 2 g * 5 ·? S · 5 * 7 S »0.3 5. 0 * 3 g. 5a-Benol-1H-2-dihydro-3H-pyrrolo [1S-a] -propyl-1-carboxylic acid sucrose Polyvinyl pyrrolidone 0.05 β · (1) -benzoyl-1H-dihydro-3H-pyrrolo ~ A 2-α-pyrrole-1-carpheoic acid replaces 0.1 g. (dl) Compounds of Prepara la Primera 44.0 * 6 g * (1) -5 "benzoyl-1,2-diyldro-5H-pyrrolo- [2 -" - pyrrole-1-carboxylic acid kite 1 * 2 z · Compounds and preparations of Primera 45 * PHIHEB 46

BJ.OPOOAOI A «Analgstaka preb * (against cramps) na« izhavina

Proplat ftrobni saterijal e · daje oralno n vodoaoa nasada u ivni 0 Sutas-kobster iiitriM od 18 * 20 grsMu Bvadosot minuta kasnija inktira m 0.25 ni. 0.02 * phenyl-binan solution intraparitoneally · Baatvor sucks ugly ve. The animals are then observed from Trta · for the next 10 minutes.

Ultimate points Total number of nicks that make ugly 1 average number of ugly per mile.

Karlldenjan gosake transcription determined that 5 ** benzoyl-1 2-dibidre ~ 3B “pyrrolo * 2-a / pyrrole-1-carboxylic acid laa approximately 450 times the water analgesic activity of aspirin) and (l) ~ i ^) (beiisoil ) -4f2 »dihydre-3H-ireloA * 3» a / pyrrole-1-carboxylic acid iaa approximately 700 times the water asalgative activity of aspirin. B. Acute oral toxicity (LD ^)

Propia »The test sater is suspended in an aqueous vehicle in which carboxynatatyl oalulose is suspended. Concentrations are given in such a way that they reach 10 ni · / kg with sapraninafla. wave melt. Aorists are stack groups (which contain six Swiae ** Webater cats and nothing in each group) of eds. Miževiata 99 give one oral dose. pomolu ateaadna osti. per kilogram of body fat, was from 200 mg ·. 400 mg., 800 mg ·. 111 1200 mg., 5- (benzoyl) -1,2-dihydro-3H-pyrrole-2-yl] -propyl-1-carboxylic acid. (Pota group is used as a control). After administration, the milk is observed for a period of three weeks.

Using the above transcript, acute oral ΙΌ50 5- (benzoyl 1,2-dihydro-'5E-pyrrolo [1,2-a] - 'pyrrole-1-carboxylic acid is approximately 200 mg / kg.

Claims (8)

- 61 - pintn * T y-AHgKyT X · Jedinlenje iubmo is grupe «sili kola su pretetavllena foronlemi 1 nlegovi poledlnaial (l) -kisolinski izonerl 1 (d) -kise linaki izonerl 1 fuuHataki primalllvi, ne-tokaičnl «etri 1 soli« označeno tiso «it · H pretetavlla vodonlk 1X1 niiu alkyl grupu kola 1 ·· od 1 do 4 ugllenlkova atom a B1 threatens hydrogen, alpha alkyl group has from 1 to 4 carbon atoms, nikou alkokal group of la la from 1 to 4 carbon atoms, chloro, fluorine Ul brooo, at home 1 · B1 substituents in orfco, mata 111 paro poloialima aroll grupo · 2 · Jodinlo & lo proaa Requirement 1 «designated soil, ito le R vodonlk · 3« Jedlnlonl · according to Requirement X «designated tiae« ito le R netil · 4 · Carbocalline claelinako ledlnlenle according to Requirement 2? characterized in that it is H * vodonlk, and only these * H > eanoil ~ 1,2, dihydie-3IHpirole / 1,3 * a / pirel ~ l ~ karl > okailna kleellna · 3 «Izepvepll eetar ledlnlenla according to Claim 4, designated time, ito 1 · to isopropyl $ -benzol-1,2-dihydro-3H-plroXo ~ 1,2,2-a] -pyrrole-1-carboxylate · 62 6 · Carbocarasolaminate »4o4in4o & 4o pv« i 2 «htm 2 gd «4« 8 * mhuAim tiso «Ato 4 · to, 2- dihydro-3 ^ ireloAt2 ^ pyrrole ~ l-carboxallBa kisali« ·. 7 »Iaopropll oster 4 · Α1 & 4« α4 «prosa Zahtaru 6t naenačan tiae9 Sto 4 · to iaopropll 5-o ~ tolaoil-l f a-dlhidre-JS-pirelo- / 1 t2 ^ -pirol ~ l« * karbekeilat · d «karbokail & o kinliaito 4adls4aa4o pr« »a Zahtorvu 2, nacnaSeno tiso * it · 4 · χ1 Motik * pa 4 · t · 5-a ~ tolttoil-1 t3-difcidro ~ 5B - pirolo-A» ^ M ^ irol-l-karbokailaa kisali «« · 9 «Iaapvopll Mtcr 4adlii4o & 4a prosa Zahtar« 8, naraačon tiso, it · 4 · t · iaopropll 5 - »'* toliieiX ~ lt2-dihydro-3B ^ irol · · * A f2 ~ a / ^ irol-l ~ ka * fcok »ilat · 10. Karbokailso ktsaliaako 4odin4oa4 # prema Zabtaru 2, naanaSaso tisa, Sto 4 * S * 1 p ** nBtiXf pa 4 * to 5-p-tol «oil — l« 2 “dihldro ^ B-piroloA # S ^ a / piro3r -l-kaapbokeilaa acid. XX «Iaopropll« «tar 4« di & 4es4 * prosa Zaktaru 10, aaa & aSa «ti» ·, Sto 4 · to Iaopropll 5H ^ tol «oil-l * 2» dlhydro-3H-pyrrole © -A t2-a / ^ irol- * Muart > okeilat. 12 · Kasfeokallao klsolinsko 4odla4o & 4 * prosa Zahtotu 2, aasaaioso tiso, Sto 4o H * p-satokal, pa 4 · to SP-Oatoxy-benaoyl-1,2-hydrochloro-3B-pyrroloA, 2-a / pyrrole-1 --kaj? boksil3 »a kjoolina · 13. Iaopropl oatar 4edin4 »4o pr ·» «Requirement 12, characterized in that Sto 4 · to iaopropll $ -p ~ Batok0lboxiaoil-» l92-dlhidro-3H ~ pyrrolo-Λ, 2-a / pyrrole-l-carboxylate · Carbocailao klaoli & sko 4 © < iia4 # n4 «prosa Zahtovu 2, na» 14. - 63 - »« ^ ίΐΛ tl * · «ito 4 · H1 o-hlore, pa 4e to $ * o * hlorob« iisoil * l92 »Dilkld > 0M5B-plvol« Av ^ a / pivolpl * kasbokallaa kleelina. X5. Isopropyl ester 4e61 & 4 «n4a preaa Requirement 14, containing soil, which isopropyl 5-o-fluorobensoyl-1,2-dihydro-5B-pyrrolo-A, 2'^ pyrrole-1 *" carboxylate · 16 » Carboxylic acid compound presses Requirement 2, 1 naaffoio «o soil ·, ito 4 * aa« -chlero, then 4 · to 5 * »- liloroboiiaotl-1,2 ~ dihydro-5B ', - pyrrolo / 1,2 ~ a / pyrrole-1-carboxylic acid * 17. Isopropyl ether 4edi & 4an4a pa · * · Requires 16 »nasnaien soil ·, ito 4 · to Isopropyl 5 - * ^ ilor © bensoil-1,2- < Hydro-3H-pyrrole-Afa ^ a / pyrrole-1 -carboxylate · 18 «Carboxylic acid compound proaa Requirement 2, designated soil ·, ito 40 a * p-chloro, then 4 · to 5-p * hl®robenzoll ~ 1,2, dlhldro * 3H-plroloA, 2- * a / pl2ol »l * carboxylic acid. 19 «Isopropyl ost ar 4« dlii4en4a proaa Requirement 18, indicated soil ·, ito 4 · to isopropyl 5-p * fcle £ Obeiuoil-lt2-dihldro-5 & -plroloA, 2, * a / ^ lrol-, l ** k «r1boka ilat · 20« Carboxylao acid dedinjen4e preaa Requirement 2, aasaaieao soil ·, ito 4 · p-fluoro, pa 4 · to 5-p ~ * luoroben »oil- 1.2- dihydre-3B'-pyrroloA, 2 * - e / pyrrole * -l ~ carboxylic kleelin «21« Isopropyl ether JedinJenJa preaa Requirement 20, designated tiae, ito 4e to isopropyl ^ p ^ ilaorobensoll ^ lfS- ^ ihldro * · 5a-pyrrolo- / 1,2-e / pyrrole ~ Carboxylate "Carboxylic acid The only process according to Claim 2, indicating soil 4, 4-o-fluoro, then 4-to 5-fluorobenaoyl-1,2-dihydro-3B-pyrrolo [1,2-a] pyrrole. l-carbocaine kleelina · 64 23 * Isopropyl «it» JadlmJonJa Z ^ tm 22 »nasnaion tixt | It · j · to iMpN ^ ll ^ pyrrolo-Zl ^ a / pyrrole-a-carbocaylate · 24 * Carbexyl klsolissko compound according to Claim 5 »nasnaSene soil ·« Ito Is R * p-fluero, so Is > -p * fltterob «juM > ll-1» a-dihydre-e-netyl - ^ - pyrroloA »ae / pyrrole ^ l ^ carpheokeyl ki · * ftifl irt. 25 · Sodium Ion »potassium or potassium salt of the Compound of Formula (A) is Requirement 1 * 26 * Hatriune m J edin J en Ja preaa Requirement 25» planted that »ito with both R and R * aqueous» so Jo to natri Jun 5- ben * oil-1 »2-dihydro-3S- * pyrelol · * A * 2-a / -pyrrole * l ~ carboxylate 27 27 * Compound cease Requirement 25» nasnadeno tiso »Sto Jo R netil a R * Je p - * fluore »pa Je to sodium« · 5-p-fluorobensoyl-le2-dihydro-6-t »ethyl-5B» pyrroloA »2 * aZpirol- * l« * aAolayilat · 28 * (l) -Isonar kUoliao Formulas ( A) is Requirement 1 * 29. Chest Compound Requirement 28 »There are thousands of R * aqueous» so Jo to (l) ~ hei »oil-lf2« ^ tihid »e-3R · pyrroloA» 2-a / pyrrole-l ^ cartekailna acid. 50 «Prana Compound Requirement 28» Nasa & eno tis »Sto Je R netil a R * Je p ~ fluere» pa Je to (1) -5-p ~ * loorobensoil-l »2-dihydrv-e * netil-3H- Pyrrole-2-pyrrole-1-carboxylic acid, 31 · Ionic catalyst Ionic or caloic salt (1) -isomeric acid Formula (a) is Requirement 1 · 32. Ionic catalyst The only requirement is 31 nasnadena 65 - tiiitf it »m U 1 ^ hydrogen, pa 4« t »sodium * (1) · 5 " * ·» ιο11 ~ X, 2-4ihiaj ^ 5B ^ is »l» A «2» a / plrol » l ^ totokailAt · 35 · J * d ± n4 * n4 »millet Requires 31 * naaaaino tl» · * it »4» H »» til a H1 4 «p-fluoro, then 4» t »sodium» (l) - 5-benzoyl-1H-dihydro-6H-ethyl-5H-chloro-1H-pyrrole-2H-carboxylate · 3 *. Jedlnjenj »forms · naana & oao ti »·« it »4» H hydrogen 111 a »ka lower alkyl grape which l» a from 1 to t ugljonlkov * atoaa a E2 4 · al ^ a alkyl grape which i »a» d 1 to 4 ugl4 «Nikov * atoaa« 35 · Jodinjenj «proaa Requirement 2t« aaaaai «< io tiso« it »4 · E water and E2 4 · lsapropll« pa 4 · to iaopropll 1,2-dihydro-3H ^ pyrroloA «EMa / ^ ir »l * -l-karb» kailat · 36 «EPoparat» a trrtiranjo »apaljenja * tola tli pireksije kod» iaara * nasnaion tiai, it »o« oaitinakl oaoto41 od farma-eeuteki prlhvatljivog aa-takalinog oaot »4ka 1 tarapoutskl • fikaoaa koliiia »jadlajoaja presented formula *» or ζl) -kjg »linakog izoaora Formula · (A), and its Saraacoutsi acceptable n * -tokaidnih» stara and salts * gd »4» β hydrogen Hi niche alki! grupa ko ja laa ad l da 4 ugljanlkava atoaa a B * pratatarlja rodamik »niiu alkyl grupu ko ja ima ad 1 da 4 ugljanitarra atoaaf sila alkakal grapa kaja laa ad X da 4 ugljonikava atama, blata, fluora Hi. tewat pri dan »4 · ** mipotitucija a avta, mata 111 pasa positions aroil group. 37, The procedure of tratlranja sapaljanja, bala or pira teši 4 · kod alaara, aasnadan tla ·, Sto obseffta dava »jo aiaaru ko ji pati ad asih etan ja tarapautaki aflkamaa kelidiaa jadiajanja pretatavljasag formulami or (l) ~ klgall & ek * g isoeara formula (A), 1 its pharmaoeut- • ki pritavati jivih, na-tokaidnih eetara l aoli, gda ja H vodo-nik ili aiia alkyl grapa kaja laa ad l da 4 ugljaolkova atoaa a H * pratatavlja vada & ik, aila alkyl grupu koja laa od 1 do 4 ugljanlkava atoaa »nižu alkokai grapa ko ja iaa od 1 da 4 ugljonikova atoaa» hlaro, fluora ili bromo, pri Sesa ja R * sap »tl tnal ja a car, »ata or para position has aroil grapo» 38 »Praparat sa davanj» grsiidso · aiaaru for delaying data birth eggs, nasnadaa team »Ste aa auStianki aaatoji od farmaoeutaki prlkvatljiveg no ~ tokaidnog aaatojka 1 tora-paataki eflkaana kalidina forminjona - 67 - fi ω or Cl) «acids of all isoaers of Foruulo (A) 9 and their pharmaceutically acceptable, non-toxic eotars and salts« where H is an aqueous or lower alkyl group which has from X to 4 carbon atoms and S * represents hydrogen alkyl grapes having iaa X to 4 carbon atoms, lower alkoxy grapa having iaa X to 4 agljoaikova atoms «chlorine, fluorine or chromium« in Sam • I jo H supatituolja in ort o, meta or para poloiajoviaa aroil grupo · 39. A procedure involving the granting of a pregnant elsar to a single person selected for grapple is the only one who opposes formal formalities. or (l) -k ± soline isomors of Formula (A), 1 of their farnaoo »influxes of acceptable * non-tokeic ostra and seli, n & snachon tirno« Sto jo a formula B vodoaik lli lower alkyl grapa having from 1 to 4 carbons atoms a R * represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 4 carbon atoms, chloro, fluorine or chromo, where B * eupetitueija in ort o, mota or a pair of aroyl group bearings. Fostupak according to Claim 39 gdo is poaenuti gravidni 40 · 68 slM * female who does not sing from burning, plrekslje 111 pain «, not strengthened by the fact that poaenuto compound gives a therapeutically effective amount when it is adjusted to delay the onset of labor« 41 « Method according to Claim 40, characterized in that the aforementioned pregnant Sanka has a previously spontaneous abortion, difficult to perform or temporary delivery, which has occurred during the time of normal delivery at or near the end of the full period of carrying · 42 · Promotional procedure Requirement 59 u ko joa jo pomesati gravidnl slsor ženko kojo no poti od sapaljenja, pireksije 111 bolero koji nisu isosronl porodjojes sli kod koje dolosi do kont-trokolje soterlžnlh mlšldo, nesnažen tiso, ito se posenuto jodinjenje daje u terapeutskl efektivni kolik kojo je adapt or the duration of motor countercontrols, whereby the end of the pregnancy is delayed from the moment when it would otherwise have occurred »45« The procedure for obtaining the formula OGH (A) or its individual clover-derived D-clamines and (d) -acid acids and farce-acceptable, non-toxic ethers and salts, where H is a hydrogen or niche alkyl group having from 1 to 4 carbon atoms and R * represents hydrogen, niche alkyl grtqnz which has from 1 to 4 carbon atoms.Bitu grapo * »ja Ua from 1 4ο 4 · carbon atom * chlorine, fluorine» Ul broa », at Sasu jo B1 eapatitueija u ort · * Bet * 111 par »palaiajeviaa asoll grap» · naanaSan tli «, Sto abufcvata Jodu» 111 viSe od aladadlh tarnat a) koadonaaolju jadinjan ja foraule 2 gda ja B kaa Sto ja dafinlaano gora a H jo niia alkll grapa koja Ib »od 1 do * ugljanikov * atoaa9» a amidom formula gda ja H1 as Sto ja defined gara, so »ao get the corresponding compounds of formula b) hydrolysis of alkll aataraka grapa so that ao obtain »slo-bodaa kiaollaa Forsnil · (A) te) separation of Slobodnik klsalina Fermile (A) into their corresponding (l) -klselineke iaoaere 1 (d) -klealineko isomerej d) raoemizacija (d) -klaelinakih iaoaer or their salts in the corresponding compounds? ornule (A) \ 70 e) qpeloxa eatarifikaoiju kasbeksilns IrtullMlt «functions in jedlajonjim Formi · (a) tli their (l) -kiaeli» - • kili iaosera 111 (d) -acid ± Iasers Ul translating each of the wraps into their famaseutically acceptable, non-flow-eic solil f) salt conversion of Formula (1) 1 of their individual Iaosers into the corresponding free-salt salts · «44« Millet process Requirement 43 »designated thus »Sto so ko» · densaoija vrli u primatom phoaphorus-oxychloride * 43 «Postam process The requirement 4J» is indicated by yew »What is the amide used in phase a) H» # - dimtil-ben * aaid · 46 * Claim 43 »designated by the team» Sto jo amide ko ji ao used in the phase a) Ii »H-dimtyl-o-toluaside« 47, Breast process Requirement 43 »designated tiso» ato j · anld which is used in the face a) N »Hkdisetilrte-toluanid · 48 * Millet procedure Requirement 43» indicated tiso »What jo aaid which is used in the face a) H "B-dimethyl-p-toluamide" 49 * The process of millet Claim 43 "is indicated" which is the amide used in step a) N, N-diBethyl-p-methoxy-benzaoid * 30 ". The process presses Claim 43 which is an amide which is used in step a) N »H-diaethyl-β-chloro-benzamide. 51 "The process of the presses of Claim 43" is indicated as "The amide used in step a) N tI * -dlaethyl-α > -t.loro-bonsanide * 32" The process of the presses of Claim 43 "is characterized in that the amide co ji ae used in phase a) H »fl — disethyl — p — chloro — benzamide * 53 * Millet process Requirement« 43t nasnadan tise, Sto ja anid ko ji e * used in fasl o) H, M-diaethyl-p-fluoro -beTiaaBld * 54 * Foetopact nasnaden yew «Which includes dacarboxylation of the compound fornulo where B is placed in the hydrogen IH alkyl group having X to 4 carbon atoms and H2 or alta alkyl group aa X to 4 carbon atoms so as to obtain the only formula CQQR ** wherein Η and E2 are as defined above * 55 * the hydrochlohexylalanine salt of the compound of Claim 6, in addition to the fact that it is also dicyclohekeylamine salt with 5 ′ ′ o-toluoyl-1t2-dihydro-3B-pyrrolo / 1,2-a / pyrrole-1-carbocaliol kioolines * 56 «The diolclohaxylamino salts of the compounds of claim 14, wherein the chlorohexylamine salt is 5-o-chloro-benzoyl-1,2-dihydro-5H ', * pyrrolo (1,2-a) Pyrrole-1-carboxylic acid * 57 * A process for the preparation of a compound of formula A wherein H is hydrogen and R 1 is p-ethoxy, termed tiae, which is > * p- » «Tokaito« & »oiIr'X% 2 ^ 1hldro» 3B ~ pirolo / l * Sa / pircl-l — kar ^ · boktiloi Zmi, 3] fBttf (9 »S« At) Iso «| ^ ground AlfcO, Caliloroia, USA Agent,