GB2127807A

GB2127807A - 2,5-Piperazinediones

Info

Publication number: GB2127807A
Application number: GB08324683A
Authority: GB
Inventors: Evzen Kasafirek; Jiri Vanzura; Ivan Krejci; Jiri Krepelka; Antonin Dlabac; Martin Valchar
Original assignee: Spofa Spojene Podniky Pro Zdravotnickou Vyrobu; Spofa Vereinigte Pharma Werke
Current assignee: Spofa Spojene Podniky Pro Zdravotnickou Vyrobu; Spofa Vereinigte Pharma Werke
Priority date: 1982-10-01
Filing date: 1983-09-14
Publication date: 1984-04-18
Also published as: DE3335891A1; JPH0526782B2; IT8323058A0; GB8324683D0; GB2127807B; BE897843A; HU193047B; CS231227B1; YU44751B; ATA336683A; SE8305157D0; IT1171091B; SE8305157L; SE466654B; FR2533919A1; AT388161B; FR2533919B1; CH655929A5; JPS5989671A; DE3335891C2

Abstract

Novel 2,5-piperazinedione derivatives of the general formula I <IMAGE> wherein R<1> is hydrogen, or alkyl with 1 to 5 carbon atoms, R<2> is hydrogen, alkyl with 1 to 9 carbon atoms, hydroxymethyl, benzyl or phenyl or a trimethylene or tetramethylene chain that forms a ring with the adjacent nitrogen atom and n is an integer of 1 to 3. The compounds show effect on the memory of experimental animals and inhibit the development of tolerance to the cataleptic effect after repeated administration of neuroleptics; they are expected to find use in the treatment of memory disturbances, tardive dyskinesias and Parkinson disease.

Description

SPECIFICATION Piperazinedione derivatives, a process for the preparation thereof and pharmaceutical compositions containing same The present invention provides biologically active 2,5-piperazinedione derivatives of the general formula I

wherein R' is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms, R2 is a hydrogen atom an alkyl group having from 1 to 9 carbon atoms, a hydroxymethyl group, a phenyl group or a trior tetra-methylene chain which forms a ring with the adjacent nitrogen atom and n is an integer of 1 to 3.

The 2,5-piperazinedione derivatives of the general formula I defined above, which are novel compounds, have revealed in pharmacological tests interesting and valuable biological properties.

Certain 2,5-piperazinediones have already been described in the pertinent literature (J. Chem.

Soc. 2119, 1960; J. Med. Pharm. Chem. 5, 42, 1962; Can. J. Chem. 40, 2214, 1962; Coll.

Czechoslov. Chem. Commun. 35, 619, 1970). These compounds attracted some pharmacological interest, which was based on the antitumorous or antiviral properties of certain related compounds (Czechoslovak certificate of authorship No, 210 383), and also were involved in theoretical studies of the conformation of the molecules.

The 2,5-piperazinedione derivatives of the general formula I show remarkable and surprising biological effects, especially on the memory of experimental animals. As is known in the art, substances of similar properties are evaluated pharmacologically by a test for extinction of a conditioned escape reaction and in a test for the duration of the passive avoidance response in rats (R.

Walter et al., Proc. Natl. Acad. Sci. USA 75,2493, 1975; ibidem 72,4180, 1975; J. Krejci et al., Neuropeptides and neutral transmission, A. Ajmone Marsal and W. Z. Traczyk (ed.) Raven Press, New York 1980). Maximum activity in these tests was observed in the MSH (melano-stimulating hormone inhibiting factor) MIF, melanostatin). This substance, however, must be administered parenterally (preferably subcutaneously) since, on oral application, it undergoes rapid enzymatic inactivation in the gastro-intestinal tract. It has unexpectedly been found that, e.g., cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl), a typical compound of the present invention, is highly active in the passive avoidance test. The substance was administered at a dose of 1 mg/kg subcutaneously (s.c.), either immediately after the training or 30 minutes before the retention test.Now it is most surprising that this compound is similarly active even on peroral administration of doses of the same order of magnitude and, in addition to this, that its effect (at a dosage level of 0.5 to 10 mg/kg orally (p.o.) is protracted over as much as 20 hours before the training or the test.

As to further pharmacological assays, it is remarkable that the compound inhibits the development of tolerance to the cataleptic effect after repeated administration of neuroleptics. In the standard experimental model that is used for approximating the development of tardive dyskinesias, this compound, when administered twice daily in doses of 7.5 mg/kg p.o., significantly inhibited the tolerance after the application of the long-acting neuroleptic isofloxythepin drug dosaged repeatedly over six days.

In a similarly arranged experiment, the same compound of the invention, at a dosage level of 10 mg/kg p.o. in one day, significantly inhibited the decrease of the homovanillic acid content in the corpus striatum of rats and the increase of maximum counts of the dopamine binding sites (with the use of 3 H-spiperone). The substance, administered perorally, also prevented the development of supersensitivity of the dopaminergic receptors in the rat striatum. Consequently, the compound under test can be expected to have an anti-dyskinetic effect. The MSH-inhibiting factor (MIF, melanostatin) was active, under equal experimental conditions, only after subcutaneous administration.

As it follows from the foregoing, the major advantage of the 2,5-piperazinedione derivatives of the invention resides in the fact that their action, at an equal or higher level of activity compared with that of melanostatin, is substantially more protracted, even on peroral administration. The compounds of the invention are therefore expected to find use in the treatment of memory disturbances, tardive dyskinesias and Parkinson disease. For this purpose, they can be formulated into suitable common peroral or parenteral pharmaceutical dosage form such as, e.g., tablets, coated tablets, gelatin capsules or injection solutions for subcutaneous, intramuscular or intravenous application.

The peroral dosage forms can be manufactured in accordance with the common practice by the formulation of the active ingredient with usual granulating and/or tabletting auxiliaries such as, e.g., lactose, saccharose, starch, polyvinylpyrrolidone, stearin, calcium stearate, ultraamylopectin, micro crystalline cellulose and the like. The obtained granulation or tabletting powder is then filled into gelatin capsules or pressed to tablets of the desired size and weight with the required content of the active ingredient. Similarly the parenteral solutions and dosage forms can also be manufactured by the common method of drug formulation.

The 2,5-piperazinedione derivatives of the present invention can advantageously be prepared by a process that comprises reacting a compound of the general formual II

wherein R2 is as defined in formula I and X is a protective group, preferably a benzyloxycarbonyl group, with a compound of the general formula III

wherein R' and n are as defined in formula I and R3 is a methyl or an ethyl group, and subsequently eliminating the protective group X and cyclising, preferably by boiling in toluene in the presence of a catalytic amount of acetic acid.

Another process for the preparation of the compounds of the invention comprises reacting a compound of the general formula IV

wherein R' and n are as defined in formula I and X is as defined in formula II, with a compound of the general formula V

wherein R2 is as defined in formula I and R3 is as defined in formula III, and subsequently eliminating the protective group X and cyclising, preferably by the above-mentioned method.

It is understood, however, that the compounds of the invention can also be prepared by any other suitable process known in the art, especially in the preparative chemistry of peptides.

The invention will now be described by way of illustration in the following Examples: Example 1 Cyclo (L-alanyl-1 -a mi no-i -cyclohexanecarbonyl) A solution of benzyloxycarbonyl-L-analine (11.2 g, 50 mmoles) in dimethylformamide (100 ml) containing N-ethyl-piperidine (7 ml) cooled to 20or is treated with ethyl chloroformate (5 ml). After 20 minutes of stirring at --100C, a dimethylformamide (100 ml) solution of ethyl 1 -amino-1 -cyclohexanecarboxylate, liberated from its hydrochloride (10.6 g, 50 mmoles) by the addition of N-ethylpiperidine (7 ml), is added. After 1 hour of stirring at OOC and 2 hours at room temperature, the reaction mixture is evaporated under reduced pressure, the residue is dissolved in an ethyl acetatewater mixture, the organic phase is successively shaken with 1 M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated to give a noncrystalline residue. Drying is completed by azeotropic distillation with tetrahydrofuran-benzene mixture; the residue is then treated with a 35% hydrogen bromide solution (50 ml) in glacial acetic acid and, after 1 hour of standing at room temperature, the noncrystalline ethyl L-analyl-1 -amino-1 -cyclohexanecarboxylate hydrobromide is precipitated with petroleum ether (500 ml).

Rf=0.52/S1, 0.68/S2. S: n-butanol-acetic acid-water 4:1 :1, S2: n-butanol-acetic acidpyridine-water 15:3:10:6.

The obtained hydrobromide is suspended in a chloroform ammonia solution saturated at O C (50 ml) and, after 20 minutes of standing at 50C, the ammonium bromide precipitate is filtered off, the chloroform solution is evaporated and dried azeotropically with a tetrahydrofuran-benze mixture. The residue is dissolved in toluene (100 ml), glacial acetic acid (0.2 ml) is added and the solution is refluxed for 1 hour. After cooling of the solution to room temperature and standing for 2 hours at O C, the crystalline product is separated and washed with petroleum ether. The target product is obtained in a yield of 38%. A sample is crystallized from dimethylformamide-2-propanol and melts then at 31 9-3200C.

The following compounds are prepared similarly: Methyl N-benzyloxycarbonyl-L-seryl-1 -amino-1 -cyclopentanecarboxylate, from N-benzyloxycarbonyl-1 -amino-1 -cyclopentanecarboxylic acid and L-serine methylester, yield 74%, m.p.

117--118 C, [a125=-5.40 (c=0.9, methanol).

Cyclo(L-seryl-1 -amino-1 -cyclopentanecarbonyl), yield 18%, m.p. 267-2690C; [α]D25=+24.4 (c=1.3, acetic acid).

Methyl N-benzyloxycarbonylglycyl-1 -amino-2-methyl- 1 -cyclohexanecarboxylate, yield 43% (noncrystalline substance); Rf=0.63/S4, S4: chloroform-methanol 9:1; mass spectrum, m/z 362.

Cyclo (glycyl-1 -amino-2-methyl- 1 -cyclohexanecarbonyl), yield 26%, m.p. 333-3340C (decompn.); mass spectrum, m/z 196.

Example 2 Cyclo (L-alanyl-1-amino-1 -cyclopentanecarbonyl) A solution of benzyloxycarbonyl-L-alanine (2.25 g, 1 0 mmoles) in chloroform (20 ml) cooled to -100C is treated with a chloroform (15 ml) solution of methyl 1-amino-1-cyclopentanecarboxylate liberated from its hydrochloride (1.8 g, 10 mmoles) by a chloroform ammonia solution (15 ml), and N,N'dicyclohexylcarbodiimide (2.3 g) is added.After 1 hour of stirring at O C and 12 hours of standing at 30C, the precipitated N,N'-dicyclohexylurea is filtered off, the filtrate is evaporated under reduced pressure, the residue is dissolved in ethyl acetate and the organic phase is successively shaken with a 1 M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated to give a noncrystalline residue, [α]D25=--17.60 (c=1.46, methanol); Rf=O.74/S3. S3: chloroform-methanol-acetic acid 14:2:1.

The obtained noncrystalline dipeptide derivative is dissolved in methanol (30 ml), acetic acid (0.1 ml) and palladium black (approx. 250 mg) are added and hydrogen gas is introduced into the reaction vessel under stirring for 1 hour. The catalyst is then filtered off, the methanolic solution is evaporated and the residue is dissolved in toluene (20 ml). After 1 hour of refluxing, subsequent cooling to room temperature and 2 hours of standing at OOC, the crystalline substance is separated and washed with petroleum ether; the yield is 39%. On crystallization from dimethylformamide-2-propanol, the title product melts at 279-281 C [a]20--8 4C (c=1.12, acetic acid); Rf=O.76/S3.

The following compounds are prepared similarly: Methyl benzyloxycarbonyl-L-valyl- 1 -a m ino- 1 -cyclopentanecarboxylate, yield 62%, m.p.

139--140 C; [aj25--1 750 (c=1.2, methanol); Rf=0.68/S3.

Cyclo (L-valyl-1-amino-1-cyclopentanecarbonyl), yield 31%, m.p. 321 0C; [a']D25=+460 (c=2.1, acetic acid); Rf=0.87/S3.

Methyl benzyloxycarbonyl-D-valyl-1 -amino-1 -cyclopentanecarboxylate, yield 63%, m.p.

139-1 400C; [α]D25=+17.3 (c=1.3, methanol); Rf=0.68/S3.

Cyclo (D-valyl-1-amino-1-cyclopentanecarbonyl),yield 29%, m.p. 320 C; [D25--470 (c=2.1, acetic acid); Rf-0.87/S3.

Methyl benzyloxycarbonyl-D-phenylglycyl-1-amino-1-cyclopentanecarboxylate, yield 49%, m.p.

156-1 58aC; [α]D25=-68.8 (c=0.96, methanol); Rf=O.7l/S3.

Cyclo (D-phenylglycyl-1 -amino-1 -cyclopentanecarbonyl), yield 35%, m.p. 285-2870C; [α]D25=-8.7 (c=0.23, acetic acid); Rf=0.89/S3.

Methyl benzyloxycarbonyl-D-phenylalanyl-1-amino-1-cyclopentanecarboxylate, yield 59%, m.p.

99-101 0C.

Cyclo (D-phenylalanyl-1-amino-1-cyclopentanecarbonyl), yield 36%, m.p. 2560C; [α]D25=-66.1 (c=0.3, acetic acid).

Methyl benzyloxycarbonyl-L-prolyl-1-amino-1-cyclopentanecarboxylate, yield 72%, m.p.

126-1 270C; [a]25=-40.50 (c=1.0, methanol).

Cyclo (L-prolyl-1 -amino-1 --cyclopentanecarbonyl), yield 36%, m.p. 127 C; [α]D25=-122.8 (c=1.4, acetic acid).

Methyl benzyloxycarbonylglycycl-1 -amino-1 -cyclobutanecarboxylate, yield 42%, m.p. 8386a C; Rf=O.73/S2.

Cyclo (glycyl-1-amino-1-cyclobutanecarbonyl), yield 74%, m.p. 277-2780C; Rf=0.50/S3.

Example 3 Tablet formulation: Cyclo(L-alanyl-1 -amino-l -cyclopentanecarbonyl) 25.0 mg lactose 300.6 mg saccharose 44.0 mg corn starch 192.0 mg polyvinylpyrrolidone 12.0 mg stearin 2.4 mg ultraamylopectin 24.0 mg The active ingredient is mixed successively with lactose, saccharose and corn starch, the mixture is granulated, the dry granulation is homogenized with stearin and ultraamylopectin, and tablets of 13 mm diameter and 600 mg weight are pressed on a rotary tabletting machine.

Claims

1. A derivative of 2,5-piperazinedione of the general formula I

wherein R1 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, R2 is a hydrogen atom, an alkyl group having from 1 to 9 carbon atoms, a hydroxymethyl group, a phenyl group or a tri- or tetra-methylene chain which forms a ring with the adjacent nitrogen atom, and n is an integer of 1 to 3.

2. Cyclo (L-alanyl-1 -amino-1 -cyclohexanecarbonyl).

3. Cyclo (L-alanyl-1 -amino-i -cyclopentanecarbonyl).

4. Cyclo (L-valyl-1 -amino-i -cyclopentanecarbonyl).

5. Cyclo (D-valyl- 1 -a mino-l -cyclopentanecarbonyl).

6. Cyclo (D-phenylglycyl-1 -amino-cyclopentanecarbonyl).

7. Cyclo (D-phenylalanyl- 1-amino-i -cyclopentanecarbonyl).

8. Cyclo (L-prolyl-i -amino-1 -cyclopentanecarbonyl).

9. Cyclo (L-seryl-1 -amino-i -cyclopentanecarbonyl).

1 0. Cyclo (glycyl- i-amino-i -cyclobutanecarbonyl).

11. Cyclo (glycyl-l-am ino-2-methylcyclohexaneca rbonyi).

12. A process for the preparation of a compound of general formula I defined in claim 1 comprising reacting a compound of the general formula II

wherein R2 is as defined in claim 1 and X is a protective group, with a compound of the general formula III

wherein R' and n are as defined in claim 1 and R3 is a methyl group or an ethyl group, and subsequently eliminating of the protective group X and cyclising.

13. A process as claimed in claim 12, in which X is a benzyloxycarbonyl group.

14. A process for the preparation of a compound of general foi-mula I defined in claim 1 comprising reacting a compound of the general formula IV

wherein R' and n are as defined in claim 1 and X is as defined in claim 12, with a compound of the general formula V

wherein R2 is as defined in claim 1 and R3 is as defined in claim 1 2 and subsequently eliminating of the protective group X and cyclising.

1 5. Pharmaceutical compositions for the treatment of memory disturbances, tardive diskinesias and Parkinson disease comprising a compound of claim 1 in a dosage form together with a pharmaceutical excipient, carrier and/or auxiliary.