SE466654B - BIOLOGICALLY ACTIVE 2,5-PIPERAZINDION DERIVATIVES, PREPARED FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents
BIOLOGICALLY ACTIVE 2,5-PIPERAZINDION DERIVATIVES, PREPARED FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEMInfo
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- SE466654B SE466654B SE8305157A SE8305157A SE466654B SE 466654 B SE466654 B SE 466654B SE 8305157 A SE8305157 A SE 8305157A SE 8305157 A SE8305157 A SE 8305157A SE 466654 B SE466654 B SE 466654B
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- C—CHEMISTRY; METALLURGY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
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Description
466 654' 10 15 20 25 30 35 även teoretiska studier av bildningen av molekyler. 2,5-piperazindionderivaten med den allmänna formeln I visar utomordentligt överraskande, biologiska effekter i synner- het på minnet hos försöksdjur. Såsom är känt enligt tek- nikens ståndpunkt bedömes substanser med liknande egen- skaper farmakologiskt i testet för undertryckande av den be- tingade flyktreaktionen och vid testet av varaktigheten för den passiva undvikande reaktionen hos råttor [_R. Walter et al., Proc. Natl. Acad. Sci. USA lä, 2493, 1975; ibidem lå, 4180, 1975; J. Krejëï et al., Neuropeptides and neutral transmission, A. Ajmone Marsal och W. Z Traczyk (ed.) Raven Press, New York 1980]. 466 654 '10 15 20 25 30 35 also theoretical studies of the formation of molecules. The 2,5-piperazinedione derivatives of the general formula I show extremely surprising biological effects, in particular on the memory of experimental animals. As is known in the art, substances with similar properties are evaluated pharmacologically in the test for suppression of the conditioned escape reaction and in the test of the duration of the passive avoidance reaction in rats [_R. Walter et al., Proc. Natl. Acad. Sci. USA lä, 2493, 1975; ibidem lå, 4180, 1975; J. Krejëï et al., Neuropeptides and neutral transmission, A. Ajmone Marsal and W. Z Traczyk (eds.) Raven Press, New York 1980].
Maximal aktivitet noterades i dessa försök vad gäller den MSH (melanostimulerande hormon)-inhiberande faktor (MIF, melanostatin). Denna substans måste emellertid administre- ras parenteralt (företrädesvis subkutant), då den vid oral administrering snabbt undergår enzymatisk inaktivering i gastrointestinalområdet. Det har oväntat visat sig, att t.ex. cyklo(L-alanyl-1-amino-1-cyklopentankarbonyl), en typisk förening enligt föreliggande uppfinning, är mycket aktiv i testet vad gäller passivt undvikande; substansen administrerades i en dos av 1 mg/kg s.c., antingen omedel- bart efter övningen eller 30 minuter före kvarhållnings- testet. Det är nu i hög grad överraskande, att denna för- ening är lika aktiv även vid peroral administrering av doser i samma storleksordning och att vid sidan av detta dess effekt (vid en doseringsnivå av 0,5 - 10 mg/kg p.o.) är ut- sträckt över så lång tid som 20 timmar före övningen eller testet.Maximum activity was noted in these experiments regarding the MSH (melanostimulatory hormone) inhibitory factor (MIF, melanostatin). However, this substance must be administered parenterally (preferably subcutaneously), as during oral administration it rapidly undergoes enzymatic inactivation in the gastrointestinal tract. It has unexpectedly turned out that e.g. cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl), a typical compound of the present invention, is very active in the passive avoidance test; the substance was administered at a dose of 1 mg / kg s.c., either immediately after exercise or 30 minutes before the retention test. It is now very surprising that this compound is equally active even with oral administration of doses of the same order of magnitude and that in addition to this its effect (at a dosage level of 0.5 - 10 mg / kg po) is - stretched over as long as 20 hours before the exercise or test.
Beträffande ytterligare faramakologiska bestämningar är det anmärkningsvärt, att föreningen inhiberar framkallandet av tolerans för den kataleptiska effekten efter upprepad admini- strering av neuroleptiska preparat. I den experimentella standardmodellen, som användes för att efterlikna utveck- landet av tardiv dyskinesi, hämmade denna förening, när den administrerades två gånger dagligen i en dos av 7,5 ;oo 10 15 20 25 30 35 I/.x 466 654 mg/kg p.o., signifikant toleransen efter administreringen av det långtidsverkande neuroleptiska preparatet isofloxy- tepin, doserat upprepade gånger under loppet av 6 dagar.With regard to further pharmacological determinations, it is remarkable that the compound inhibits the induction of tolerance to the cataleptic effect after repeated administration of neuroleptic preparations. In the standard experimental model used to mimic the development of tardive dyskinesia, this compound, when administered twice daily, was inhibited at a dose of 7.5 I /. 466 654 mg / kg po, significant tolerance after administration of the long-acting neuroleptic drug isofloxytepine, dosed repeatedly over the course of 6 days.
I ett på liknande sätt arrangerat försök inhiberade samma förening enligt uppfinningen, vid en doseringsnivå av 10 mg/kg p.o. per dag,sigfifflæmt sänkningen av homovanillin- syrahalten i corpus striatum hos råttor och ökningen av det maximala antalet impulser av dopaminbindningsställena (med användning av 3H-spiperon). Substansen förhindrade även, när den administrerades peroralt,utvecklandet av överkänslighet för dopaminreceptorerna i råttans striatum.In a similarly arranged experiment, the same compound of the invention inhibited, at a dosage level of 10 mg / kg p.o. per day, due to the decrease in homovanillic acid content in the corpus striatum in rats and the increase in the maximum number of impulses of the dopamine binding sites (using 3H-spiperone). The substance also, when administered orally, prevented the development of hypersensitivity to the dopamine receptors in the rat striatum.
Den undersökta föreningen kan således förväntas ha en dyskinesihämmande effekt. Den MSH-inhiberande faktorn (MIF, melanostatin) var under likvärdiga experimentella beting- I elser aktiv endast efter subkutan administrering.The test compound can thus be expected to have an anti-dyskinesia effect. The MSH inhibitory factor (MIF, melanostatin) was active under equivalent experimental conditions only after subcutaneous administration.
Såsom framgår av det föregående ligger den väsentliga för- delen med 2,5-piperazindionderivaten enligt uppfinningen i -det faktum, att deras verkan, vid en likvärdig eller högre aktivitetsnivå jämfört med den för melanostatin, är väsent- ligt utdragen även i samband med den perorala administreringen.As can be seen from the foregoing, the essential advantage of the 2,5-piperazinedione derivatives according to the invention lies in the fact that their action, at an equivalent or higher level of activity compared to that of melanostatin, is substantially extended even in connection with the oral administration.
Föreningarna enligt uppfinningen förväntas därför finna användning vid behandlingen av minnesrubbningar, tardiv dyskinesi och Parkinsons sjukdom. För detta ändamål kan de formuleras till lämpliga, sedvanliga,perorala eller paren- terala, farmaceutiska doseringsformer, som t.ex. tabletter, dragëer, gelatinkapslar eller injiceringslösningar för sub- kutan, intramuskulär eller intravenös injicering.The compounds of the invention are therefore expected to find use in the treatment of memory disorders, tardive dyskinesia and Parkinson's disease. For this purpose, they may be formulated into suitable, conventional, oral or parenteral, pharmaceutical dosage forms, such as e.g. tablets, dragees, gelatin capsules or injection solutions for subcutaneous, intramuscular or intravenous injection.
De perorala doseringsformerna kan tillverkas i enlighet med sedvanlig praxis genom kombinering av den aktiva bestånds- delen med vanliga granulerings- och/eller tablettillverk- ningshjälpmedel, som t.ex. laktos, sackaros, stärkelse, polyvinylpyrrolidon, stearin, kalciumstearat, ultraamylo- pektin, mikrokristallin.ceLhflosa etc. Det erhållna granu- lerings- eller tablettillverkningspulvret fylles sedan i gelatinkapslar eller pressas till tabletter av önskad stor- lek och vikt med det erforderliga innehållet av den aktiva 466 654 10 15 20 25 30 35 beståndsdelen. På liknande sätt kan även de parenterala lösningarna och doseringsformerna tillverkas med hjälp av de sedvanliga metoderna i samband med läkemedelsbe- redning. 2,5-piperazindionderivaten enligt föreliggande uppfinning kan lämpligen framställas med hjälp av ett förfarande, som innefattar omsättningen av en förening med den all- männa formeln II I--NH--ffi--COOH 32 (II) där R2 har samma betydelse som i formel I enligt ovan och X är en skyddande grupp, företrädesvis en bensyloxikarbo- nylgrupp, med en förening med den allmänna formeln III GHz /@Sâ\n /////T--COOR5 (111) CH NH 11 2 B där R1 och n har samma betydelse som i formel I och R3 be- tecknar en metyl- eller etylgrupp, och efterföljande eli- minering av den skyddande gruppen X och cyklisering, före- trädesvis genom kokning i toluen i närvaro av en katalytisk mängd ättiksyra.The oral dosage forms can be manufactured in accordance with customary practice by combining the active ingredient with conventional granulation and / or tablet making aids, such as e.g. lactose, sucrose, starch, polyvinylpyrrolidone, stearin, calcium stearate, ultraamylopectin, microcrystalline cellulose, etc. active 466 654 10 15 20 25 30 35 component. In a similar way, the parenteral solutions and dosage forms can also be manufactured by means of the usual methods in connection with drug preparation. The 2,5-piperazinedione derivatives of the present invention may conveniently be prepared by a process which comprises the reaction of a compound of the general formula II I - NH - f fi-- COOH 32 (II) wherein R 2 has the same meaning as in formula I as above and X is a protecting group, preferably a benzyloxycarbonyl group, with a compound of the general formula III GHz / @ Sâ \ n ///// T - COOR5 (111) CH NH 11 2 B where R 1 and n have the same meaning as in formula I and R 3 represents a methyl or ethyl group, and subsequent elimination of the protecting group X and cyclization, preferably by boiling in toluene in the presence of a catalytic amount of acetic acid.
Ett annat förfarande för framställning av föreningarna en- ligt uppfinningen innefattar omsättningen av en förening med den allmänna formeln IV /H2 (Iv) fw of 10 15 20 25 30 35 5 466 654 där R1 och n har samma betydelse som i formel I och X har ovan i samband med formel II angiven betydelse, med en förening med den allmänna formeln V NH2-- cH-_-coo1z3 (V) åz där R2 har samma betydelse som i formel I och R3 har ovan i samband med formel III angiven betydelse, och efterföljande eliminering av den skyddande gruppen X och cyklisering, som regel medelst ovannämnda metod.Another process for the preparation of the compounds according to the invention comprises the reaction of a compound of the general formula IV / H 2 (Iv) fw or 10 15 20 25 30 35 5 466 654 wherein R 1 and n have the same meaning as in formula I and X has the meaning given above in connection with formula II, with a compound of the general formula V NH 2 - cH -_- coo1z3 (V) åz where R 2 has the same meaning as in formula I and R 3 has the meaning given above in connection with formula III , and subsequent elimination of the protecting group X and cyclization, usually by the above method.
Föreningarna enligt uppfinningen kan emellertid givetvis även framställas med någon annan lämplig förut känd metod, i synnerhet inom den preparativa peptidkemin.However, the compounds of the invention may, of course, also be prepared by any other suitable prior art method, particularly in the preparative peptide chemistry.
Ytterligare detaljer beträffande de ovan beskrivna, för- delaktiga förfarandena för framställning av föreningarna enligt uppfinningen liksom beträffande deras formulering till farmaceutiska doseringsformer illustreras med hjälp av följande exempel. Produkternas identitet och renhet veri- fierades bl.a. genom elementaranalys och de funna värdena motsvarar de beräknade värdena med snäva toleransgränser.Further details regarding the advantageous processes for the preparation of the compounds according to the invention described above as well as regarding their formulation into pharmaceutical dosage forms are illustrated by means of the following examples. The identity and purity of the products were verified, among other things. by elemental analysis and the values found correspond to the calculated values with tight tolerance limits.
Exempel 1 Cyklo(L-alanyl-1-amino-1-cyklohexankarbonyl) En lösning av bensyloxikarbonyl-L-alanin (11,2 g, 50 mmol) i dimetylformamin (100 ml) innehållande N-etylpiperidin (7 ml) och kyld till -ZOOC behandlades med etylkloroformat (5 ml). Efter 20 minuters omröring vid -10OC tillsattes en di- metylformamidlösning (100 ml) av etyl-1-amino-1-cyklohexan- karboxylat, erhållet från dess hydroklorid (10,6 g, 50 mmol) genom tillsättningen av N-etylpiperidin (7 ml). Efter 1 tim- mes omröring vid OOC och 2 timmars vid rumstemperatur av- drevs reaktionsblandningen under reducerat tryck, varefter återstoden löstes i en etylacetat-vatten-blandning och den 466 654' " 6 10 15 20 25 30 35 organiska fasen skakades sedan successivt med 1M klorväte- syra, vatten, 5 % natriumvätekarbonat och vatten, torkades sedan över vattenfritt natriumsulfat och avdunstades, så att enzkïe-kristallin återstod erhölls. Dess torkning slut- fördes genom azeotrop destillation med en tetrahydrofuran- -bensen-blandning. Återstoden behandlades sedan med en 35 % vätebromidlösning (50 ml) i isättika och efter 1 timmes förvaring vid rumstemperatur utfälldes den icke-kristallina etyl-L-alanyl-1-amino-1-cyklohexankarboxylat-hydrobromiden med petroleumeter (500 ml). R = 0,52 /S1, 0,68/S2. S f 1* -butanol-ättiksyra-vatten 4:1:1, S2: n-butanol-ättiksyra- n_ -pyridin-vatten 15:3:10:6.Example 1 Cyclo (L-alanyl-1-amino-1-cyclohexanecarbonyl) A solution of benzyloxycarbonyl-L-alanine (11.2 g, 50 mmol) in dimethylformamine (100 mL) containing N-ethyl piperidine (7 mL) and cooled to -ZOOC was treated with ethyl chloroformate (5 ml). After stirring for 20 minutes at -10 ° C, a dimethylformamide solution (100 ml) of ethyl 1-amino-1-cyclohexanecarboxylate, obtained from its hydrochloride (10.6 g, 50 mmol) was added by the addition of N-ethylpiperidine (7 ml). ml). After stirring for 1 hour at 0 DEG C. and 2 hours at room temperature, the reaction mixture was evaporated under reduced pressure, after which the residue was dissolved in an ethyl acetate-water mixture and the organic phase was then shaken successively with 1M Hydrochloric acid, water, 5% sodium bicarbonate and water, then dried over anhydrous sodium sulphate and evaporated to give the enzyme crystalline, its drying was completed by azeotropic distillation with a tetrahydrofuran-benzene mixture and then treated with the residue. a 35% hydrogen bromide solution (50 ml) in glacial acetic acid and after 1 hour storage at room temperature the non-crystalline ethyl L-alanyl-1-amino-1-cyclohexanecarboxylate hydrobromide precipitated with petroleum ether (500 ml) R = 0.52 / S1, 0.68 / S2, S f 1 * -butanol-acetic acid-water 4: 1: 1, S2: n-butanol-acetic acid-n--pyridine-water 15: 3: 10: 6.
Den erhållna hydrobromiden suspenderades i en kloroform- ' ammoniaklösning, mättad vid OOC (50 ml) och efter 20 minuters förvaring vid 500 filtrerades ammoniumbromidutfällningen av, varefter kloroformlösningen avdunstades och torkades azeo- tropiskt med en tetrahydrofuran-bensen-blandning. Åter- stoden löstes i toluen (100 ml), isättika (0,2 ml) till- sattes och lösningen kokades under återlopp 1 timme. Efter kylning av lösningen till rumstemperatur och förvaring i 2 timmar vid OOC avskildes den kristallina produkten och tvättades med petroleumeter. Den i rubriken angivna pro- dukten erhölls i ett utbyte av 38 %.Ett prov kristalliserades ur dimetylformamid-2-propanol och smälte därefter vid 319 - 32o°c.The resulting hydrobromide was suspended in a chloroform-ammonia solution, saturated at 0 ° C (50 ml) and after 20 minutes storage at 500, the ammonium bromide precipitate was filtered off, after which the chloroform solution was evaporated and azeotropically dried with a tetrahydrofuran-benzene mixture. The residue was dissolved in toluene (100 ml), glacial acetic acid (0.2 ml) was added and the solution was refluxed for 1 hour. After cooling the solution to room temperature and storing for 2 hours at 0 ° C, the crystalline product was separated and washed with petroleum ether. The title product was obtained in a yield of 38%. A sample was crystallized from dimethylformamide-2-propanol and then melted at 319 DEG-32 DEG.
Följande föreningar framställdes på likartat sätt: Metyl- -N-bensyloxikarbonyl-L-seryl-1-amino-1-cyklopentankarboxylat, av N-bensyloxikarbonyl-1-amino-1-cyklopentankarboxylsyra och L-serinmetylester, utbyte 74 %, smp. 117 - 11800, ¿@7š5 = -5,4° (C = 0,9, metanol).The following compounds were prepared in a similar manner: Methyl-N-benzyloxycarbonyl-L-seryl-1-amino-1-cyclopentanecarboxylate, of N-benzyloxycarbonyl-1-amino-1-cyclopentanecarboxylic acid and L-serine methyl ester, yield 74%, m.p. 117 DEG-11800 DEG-7.5 DEG--5.4 DEG (C = 0.9, methanol).
Cyklo(L-seryl-1-amino-1-cyklopentankarbonyl), utbyte 18 % smp. 267 - 269°c; ¿a7š5 = +24,4° (C = 1,3, ättiksyra).Cyclo (L-seryl-1-amino-1-cyclopentanecarbonyl), yield 18% m.p. 267 DEG-269 DEG C .; ¿A7š5 = + 24.4 ° (C = 1.3, acetic acid).
Metyl-N-bensyloxikarbonylglycyl-1-amino-2-metyl-1-cyklo- hexankarboxylat, utbyte 43 % (icke-kristallin substans); Rf = 0,63/S4, S4: kloroform-metanol 9:1; masspektrum, m/z 362.Methyl N-benzyloxycarbonylglycyl-1-amino-2-methyl-1-cyclohexanecarboxylate, yield 43% (non-crystalline substance); Rf = 0.63 / S4, S4: chloroform-methanol 9: 1; mass spectrum, m / z 362.
I t'>. f) 10 15 20 25 30 35 “H 466 654 Cyklo(glycyl-1-amino-2-metyl-1-cyklohexankarbonyl), utbyte 26 %, smp. 333 - 334OC (sönderfall); masspektrum, m/z 196.I t '>. f) 15 H 256 654 Cyclo (glycyl-1-amino-2-methyl-1-cyclohexanecarbonyl), yield 26%, m.p. 333 - 334 ° C (dec.); mass spectrum, m / z 196.
Exempel 2 Cyklo(L-alanyl-1-amino-1-cyklopentankarbonyl) En lösning av bensyloxikarbonyl-L-alanin (2,25 g, 10 mmol) i kloroform (20 ml), kyld till -10oC, behandlades med en kloroformlösning (15 ml) av metyl-1-amino-1-cyklopentan- karboxylat, erhållet från dess hydroklorid (1,8 g, 10 mmol) med hjälp av en kloroformammoniaklösning (15 ml), och N,N'- -dicyklohexylkarbodiimid (2,3 g) tillsattes. Efter 1 timmes omröring vid OOC och 12 timmars förvaring vid 3oC filtre- rades den utfällda N,N'-dicyklohexylkarbamiden av, varefter filtratet avdunstades under reducerat tryck och återstoden ' löstes i etylacetat, varefter den organiska fasen succes- sivt skakades med 1M klorvätesyra, vatten, 5 % natriumväte- karbonat och vatten, torkades över vattenfritt natrium- sulfat och indunstades så att en icke-kristallin återstod erhölls, ¿@7š5 = -17,6° (c = 1,46, metanol), Rf = 0,74/53.Example 2 Cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) A solution of benzyloxycarbonyl-L-alanine (2.25 g, 10 mmol) in chloroform (20 mL), cooled to -10 ° C, was treated with a chloroform solution ( 15 ml) of methyl 1-amino-1-cyclopentanecarboxylate, obtained from its hydrochloride (1.8 g, 10 mmol) with a chloroformammonia solution (15 ml), and N, N'-dicyclohexylcarbodiimide (2, 3 g) was added. After stirring for 1 hour at 0 DEG C. and storing for 12 hours at 30 DEG C., the precipitated N, N'-dicyclohexylurea was filtered off, after which the filtrate was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, after which the organic phase was successively shaken with 1M hydrochloric acid. water, 5% sodium bicarbonate and water, dried over anhydrous sodium sulphate and evaporated to give a non-crystalline residue, δ @ 7š5 = -17.6 ° (c = 1.46, methanol), Rf = 0, 74/53.
S3: kloroform-metanol-ättiksyra 14:2:1.S3: chloroform-methanol-acetic acid 14: 2: 1.
Det erhållna icke-kristallina dipeptidderivatet löstes i metanol (30 ml), ättiksyra (0,1 ml) och palladiumsvart (ungefär 250 mg) tillsattes och vätgas infördes i reaktions- kärlet under omröring i 1 timme. Katalysatorn filtrerades därefter av, den metanolhaltiga lösningen indunstades och återstoden löstes i toluen (20 ml). Efter 1 timmes kok- ning under återlopp och efterföljande kylning till rums- temperatur samt 2 timmars förvaring vid OOC avskildes den kristallina substansen och tvättades med petroleumeter; utbytet uppgick till 39 %. Vid kristallisering ur dimetyl- formamid-2-propanol smälte den i rubriken angivna produkten vid 279 - 2s1°c. ¿Q7š0= -s,4° (C = 1,12, ättiksyra; Rf = 0,76/S3.The resulting non-crystalline dipeptide derivative was dissolved in methanol (30 ml), acetic acid (0.1 ml) and palladium black (about 250 mg) were added and hydrogen gas was introduced into the reaction vessel with stirring for 1 hour. The catalyst was then filtered off, the methanolic solution was evaporated and the residue was dissolved in toluene (20 ml). After 1 hour of refluxing and subsequent cooling to room temperature and 2 hours of storage at 0 DEG C., the crystalline substance was separated and washed with petroleum ether; the yield was 39%. Upon crystallization from dimethylformamide-2-propanol, the title product melted at 279 DEG-21 DEG. ¿Q7š0 = -s, 4 ° (C = 1.12, acetic acid; Rf = 0.76 / S3.
Följande föreningar framäfiflldes på likartat sätt: 4656 10 15 20 25 30 35 654' Metylbensyloxikarbonyl-L-valyl-1-amino-cyklopentankarboxylat, utbyte 62 9, smp. 139 - 14o°c; ¿@7š5 = -17,5° (c = 1,2, metanol); Rf = 0,68/S3.The following compounds were prepared in a similar manner: 4656 Methylbenzyloxycarbonyl-L-valyl-1-amino-cyclopentanecarboxylate, yield 629, m.p. 139-140 ° C; Δ @ 7š5 = -17.5 ° (c = 1.2, methanol); Rf = 0.68 / S3.
Cyklo(L-valyl-1-amino-1-cyklopentankarbonyl), utbyte 31 %, emp. 321°; ¿97š5 = +4,6° (e = 2,1, ättikeyre); Rf = 0,87/s3.Cyclo (L-valyl-1-amino-1-cyclopentanecarbonyl), yield 31%, emp. 321 °; ¿97š5 = + 4.6 ° (e = 2.1, acetic acid); Rf = 0.87 / s3.
Metylbensyloxikarbonyl-D-valyl-1-amino-1-cyklopentankarboxy- let, utbyte 63 %, smp. 139 - 14o°c; ¿u7š5 = +17,3° (e 1,3, metanol); Rf = 0,68/S3f Cyklo(D-valyl-1-amino-1-cyklopentankarbonyl), utbyte 29 %, smp. 32o°c; ¿@7š5 = -4,7° (e = 2,1, ättikeyre); Rf = o,s7/s3.Methyl benzyloxycarbonyl-D-valyl-1-amino-1-cyclopentanecarboxylate, yield 63%, m.p. 139-140 ° C; ¿U7š5 = + 17.3 ° (e 1.3, methanol); Rf = 0.68 / S3f Cyclo (D-valyl-1-amino-1-cyclopentanecarbonyl), yield 29%, m.p. 32 ° C; ¿@ 7š5 = -4.7 ° (e = 2.1, acetic acid); Rf = o, s7 / s3.
Metylbensyloxikarbonyl-D-fenylglycyl-1-amino-1-cyk1opentan- karboxylat, utbyte 49 %, smp. 156 - 158°C; [QYÉS = -68,80 (c = 0,96, metanol); Rf = 0,71/S3.Methyl benzyloxycarbonyl-D-phenylglycyl-1-amino-1-cyclopentanecarboxylate, yield 49%, m.p. 156 DEG-158 DEG C .; [Α] D = = 68.80 (c = 0.96, methanol); Rf = 0.71 / S3.
Cyklo(D-fenylglycyl-1-amino-1-cyklopentankarbonyl), utbyte 35 t, smp. 285 - 2a7°c; ¿u7å5 = -s,7° (e = 0,23, ättikeyre); Rf = 0,89/S3.Cyclo (D-phenylglycyl-1-amino-1-cyclopentanecarbonyl), yield 35 h, m.p. 285 - 2a7 ° C; ¿U7å5 = -s, 7 ° (e = 0.23, acetic acid); Rf = 0.89 / S3.
Metylbensyloxikarbonyl-D-fenylalanyl-1-amino-1-cyklopentan- kerbexylet, utbyte 59 9, smp. 99 - 1o1°c.Methyl benzyloxycarbonyl-D-phenylalanyl-1-amino-1-cyclopentanecerbexyl, yield 599, m.p. 99-110 ° C.
Cyklo(D-fenylalanyl-1-amino-1-cyklopentankarbonyl), utbyte 36 %, smp. 256°c; ¿u7š5 = -6a,1° (e = 0,3, ättikeyre).Cyclo (D-phenylalanyl-1-amino-1-cyclopentanecarbonyl), yield 36%, m.p. 256 ° C; ¿U7š5 = -6a, 1 ° (e = 0.3, acetic acid).
Metylbensyloxikarbonyl-L-pro1yl-1-amino-1-cyklopentan- kerbexylet, utbyte 72 %, emp. 126 - 127°c; ¿@7š5 = -4o,5° (c = 1,0,metanol).Methylbenzyloxycarbonyl-L-propyl-1-amino-1-cyclopentanecerbexyl, yield 72%, emp. 126-127 ° C; ¿@ 7š5 = -4o, 5 ° (c = 1.0, methanol).
Cyklo(L-prolyl-1-amino-1-cyklopentankarbonyl), utbyte 36 %, smp. 127oC; [@]š5 = -122,80 (c = 1,4, ättiksyra).Cyclo (L-prolyl-1-amino-1-cyclopentanecarbonyl), yield 36%, m.p. 127 ° C; [@] š5 = -122.80 (c = 1.4, acetic acid).
Metylbensyloxikarbonylglycyl-1-amino-1-cyklobutankarboxy- let, utbyte 42 9, smp. 83 - se°c; Rf = o,73/s3.Methyl benzyloxycarbonylglycyl-1-amino-1-cyclobutanecarboxylate, yield 429, m.p. 83 - se ° c; Rf = 0.73 / s3.
Cyklo(glycyl-1-amino-1-cyklobutankarbonyl), utbyte 74 %, emp. 277 - 27s°c; Rf = 0,50/s3.Cyclo (glycyl-1-amino-1-cyclobutanecarbonyl), yield 74%, emp. 277 DEG-27 DEG C .; Rf = 0.50 / s3.
Exemgel 3 Tablettformulering: Cyklo(L-alanyl-1-amino-1-cyklopentankarbonyl) 25,0 mg laktos 300,6 mg sackaros 44,0 mg majsstärkelse 192,0 mg polyvinylpyrrolidon 12,0 mg stearin 2,4 mg ultraamylopektin 24,0 mg 4,9 4bb (3234 7 Den aktiva beståndsdelen blandades successivt med laktos, sackaros och majsstärkelse, varefter blandningen granu- lerades och det torra granulatet homogeniserades med stea- rin och ultraamylopektin, varefter tabletter med en dia- meter av 13 mm och 600 mg vikt pressades i en roterande tablettstansningsmaskin.Example gel 3 Tablet formulation: Cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) 25.0 mg lactose 300.6 mg sucrose 44.0 mg maize starch 192.0 mg polyvinylpyrrolidone 12.0 mg stearin 2.4 mg ultraamylopectin 24, 0 mg 4.9 4bb (3234 7 The active ingredient was successively mixed with lactose, sucrose and maize starch, after which the mixture was granulated and the dry granulate was homogenized with stearin and ultraamylopectin, after which tablets with a diameter of 13 mm and 600 mg weight was pressed in a rotary tablet punching machine.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS827012A CS231227B1 (en) | 1982-10-01 | 1982-10-01 | 2,5-pierazindion derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| SE8305157D0 SE8305157D0 (en) | 1983-09-23 |
| SE8305157L SE8305157L (en) | 1984-04-02 |
| SE466654B true SE466654B (en) | 1992-03-16 |
Family
ID=5418454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8305157A SE466654B (en) | 1982-10-01 | 1983-09-23 | BIOLOGICALLY ACTIVE 2,5-PIPERAZINDION DERIVATIVES, PREPARED FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5989671A (en) |
| AT (1) | AT388161B (en) |
| BE (1) | BE897843A (en) |
| CH (1) | CH655929A5 (en) |
| CS (1) | CS231227B1 (en) |
| DE (1) | DE3335891C2 (en) |
| FR (1) | FR2533919B1 (en) |
| GB (1) | GB2127807B (en) |
| HU (1) | HU193047B (en) |
| IT (1) | IT1171091B (en) |
| SE (1) | SE466654B (en) |
| YU (1) | YU44751B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS277405B6 (en) * | 1986-06-12 | 1993-03-17 | Vyzk Ustav Farm Biochem Sp | Peptides with 1-amino-1-cycloalkane carboxylic acid |
| US5182285A (en) * | 1986-11-07 | 1993-01-26 | Spojene Podniky Pro Zdravotnickou Vyrobu | Cell-protective composition for preventing or treating of peptic ulcer |
| GB8822674D0 (en) * | 1988-09-27 | 1988-11-02 | Tate & Lyle Plc | Preparation of acylated sucrose derivatives |
| US7202279B1 (en) * | 1998-02-11 | 2007-04-10 | Georgetown University | Cyclic dipeptides and azetidinone compounds and their use in treating CNS injury and neurodegenerative disorders |
| US7119091B2 (en) | 1999-12-03 | 2006-10-10 | Ono Pharmaceutical Co., Ltd. | Triazaspiro[5.5]undecane derivatives and pharmaceutical compositions comprising thereof, as an active ingredient |
| KR20030093248A (en) | 2001-03-19 | 2003-12-06 | 오노 야꾸힝 고교 가부시키가이샤 | Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient |
| JP4047365B2 (en) | 2006-01-11 | 2008-02-13 | 生化学工業株式会社 | Cycloalkanecarboxamide derivative and method for producing the same |
| ATE509941T1 (en) * | 2006-01-11 | 2011-06-15 | Seikagaku Kogyo Co Ltd | CYCLOALKYLCARBONYLAMINOSIC ACID ESTER DERIVATIVE AND PROCESS FOR PRODUCTION THEREOF |
| JP3975226B2 (en) | 2006-01-11 | 2007-09-12 | 生化学工業株式会社 | Cycloalkylcarbonylamino acid derivative and process for producing the same |
| WO2013020527A1 (en) | 2011-08-11 | 2013-02-14 | University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy | Utilization of alaptide as transdermal penetration modifier in pharmaceutical compositions for human and veterinary applications containing anti-inflammatory drugs and/or antimicrobial chemotherapeutics |
| WO2014019556A1 (en) | 2012-08-02 | 2014-02-06 | University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy | Alaptide : methods of effecting its solubility, membrane permeation and pharmaceutical compositions for human and/or veterinary applications |
| CN107903303B (en) * | 2017-11-20 | 2021-06-04 | 陕西慧康生物科技有限责任公司 | Liquid phase synthesis method of cyclopeptide Alaptide |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1459488A (en) * | 1974-03-19 | 1976-12-22 | Wyeth John & Brother Ltd | Piperazinedione derivatives |
-
1982
- 1982-10-01 CS CS827012A patent/CS231227B1/en unknown
-
1983
- 1983-09-14 GB GB08324683A patent/GB2127807B/en not_active Expired
- 1983-09-21 AT AT0336683A patent/AT388161B/en not_active IP Right Cessation
- 1983-09-23 SE SE8305157A patent/SE466654B/en not_active IP Right Cessation
- 1983-09-26 CH CH5208/83A patent/CH655929A5/en not_active IP Right Cessation
- 1983-09-27 BE BE0/211589A patent/BE897843A/en not_active IP Right Cessation
- 1983-09-29 YU YU1952/83A patent/YU44751B/en unknown
- 1983-09-29 IT IT23058/83A patent/IT1171091B/en active
- 1983-09-30 FR FR8315599A patent/FR2533919B1/en not_active Expired
- 1983-09-30 HU HU833419A patent/HU193047B/en not_active IP Right Cessation
- 1983-10-01 JP JP58181834A patent/JPS5989671A/en active Granted
- 1983-10-03 DE DE3335891A patent/DE3335891C2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| HU193047B (en) | 1987-08-28 |
| GB2127807A (en) | 1984-04-18 |
| GB2127807B (en) | 1987-02-25 |
| FR2533919B1 (en) | 1986-10-03 |
| SE8305157D0 (en) | 1983-09-23 |
| SE8305157L (en) | 1984-04-02 |
| YU195283A (en) | 1986-10-31 |
| IT8323058A1 (en) | 1985-03-29 |
| CH655929A5 (en) | 1986-05-30 |
| BE897843A (en) | 1984-01-16 |
| DE3335891A1 (en) | 1984-04-05 |
| GB8324683D0 (en) | 1983-10-19 |
| JPS5989671A (en) | 1984-05-23 |
| CS701282A1 (en) | 1984-01-16 |
| IT1171091B (en) | 1987-06-10 |
| AT388161B (en) | 1989-05-10 |
| JPH0526782B2 (en) | 1993-04-19 |
| FR2533919A1 (en) | 1984-04-06 |
| ATA336683A (en) | 1988-10-15 |
| YU44751B (en) | 1991-02-28 |
| CS231227B1 (en) | 1984-10-15 |
| IT8323058A0 (en) | 1983-09-29 |
| DE3335891C2 (en) | 1993-11-11 |
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