FR2533919A1 - DERIVATIVES WITH BIOLOGICAL ACTIVITY OF 2,5-PIPERAZINEDIONE, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

DERIVATIVES WITH BIOLOGICAL ACTIVITY OF 2,5-PIPERAZINEDIONE, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM; THESE COMPOUNDS MEET FORMULA I: (CF DRAWING IN BOPI) IN WHICH R IS AN ATOM OF HYDROGEN OR AN ALKYL WITH 1 TO 5 ATOMS OF CARBON, R IS AN ATOM OF HYDROGEN OR AN ALKYL WITH 1 TO 9 ATOMS OF CARBON, A HYDROXYMETHYL, A PHENYL OR A TRIMETHYLENE OR TETRAMETHYLENE CHAIN FORMING A CYCLE WITH THE ADJACENT NITROGEN ATOM AND N IS A WHOLE OF 1 TO 3; METHODS FOR THEIR PREPARATION ARE ALSO DESCRIBED; THESE COMPOUNDS ARE USEFUL AS MEDICINAL PRODUCTS, ESPECIALLY IN THE TREATMENT OF MEMORY DISORDERS, LATE DYSKINESIA AND PARKINSON'S DISEASE.

Description

The present invention relates to derivatives having a biological activity of 2,

  5-piperazinedione of general formula I:

CH 2 CO-NH

1 1

(CH 2) CH -R

CH NH CO (I)

  in which R 1 is a hydrogen atom or an alkyl having 1 to 5 carbon atoms, R 2 is a hydrogen atom, an alkyl having 1 to 9 carbon atoms, a hydroxymethyl, a phenyl or a chain trimethylene or tetramethylene forming a ring with the adjacent nitrogen atom and N is an integer of 1 to 3 The invention also relates to processes for the preparation

  of these compounds and pharmaceutical compositions

  ing. The 2,5-piperazinedione derivatives of general formula I, as above, which are new compounds, have exhibited interesting and useful biological properties in pharmacological tests.

  Some 2,5-piperazinediones have previously been

  in the corresponding literature (J Chem Soc 2119, 1960, J Med Pharmo Chem 5, 42, 1962, Can J Chem 40, 2214, 1962 Coil Czechoslov Chemo Commun 35, 619, 1970) They aroused a certain pharmacological interest resting sure

  the antitumor or antiviral properties of certain

  related statements (Czechoslovak author's certificate No. 210 383), and also figured in theoretical studies of

conformation of the molecules.

  The 2,5-piperazinedione derivatives of general formula I exhibit remarkably surprising biological effects,

  especially on the memory of laboratory animals

  As is known in the art, substances with similar properties are the subject of pharmacological evaluations in the quenched leak test and in the passive avoidance response test in the rat (R Walter et al., Proc Natl Acad Sci USA 75, 2493, 1975, ibidem 72, 4180, 1975; J Krejc et al, Neuro-peptides and

2 2533919

  neural transmission A Ajmone Marsal and W Z Traczyk) ed.

  (Raven Press, New York 1980) In these trials, human activity

  ximal has been observed for melanostatin (MIF; melanocyte stimulating hormone inhibiting factor (MSH)). However, this substance must be administered parenterally (preferably subcutaneously) because it is orally

  rapid enzymatic inactivation in the gastrointestinal tract.

  It has been unexpectedly found that cyclo (L-alanyl)

  amino-1-cyclopentanecarbonyl) which is a typical compound of the present invention, is very active in the passive avoidance test The substance was administered at the dose of 1 mg / kg subcutaneously or immediately after training ,

  30 minutes before the retention test. It is particularly important

  surprisingly that this compound has a similar activity, even peroral administration at doses of the same order of magnitude and that, moreover, its effect (at a dose of 0.5 to 10

  mg / kg per os) is prolonged for up to 20 hours.

before training or testing.

  With regard to subsequent pharmacological tests, it is remarkable that the compound inhibits the development of

  tolerance to the cataleptic effect after repeated administration

  neuroleptics in the standard experimental model

  used to mimic the onset of tardive dyskinesia

  ve, this compound, when administered twice daily at a dose of 7.5 mg / kg per os), significantly inhibits the tolerance

  after repeated administration for 6 days of the neu-

  long-acting role of isofloxythepine.

  In a similarly designed experiment, the same compound of the invention, at the dose of 10 mg / kg per os, in one

  day, significantly inhibited the decline in

  to homovanillic acid in the striated body of rats and increased maximum counts of

  dopamine (with the use of H-spiperone) The controlled substance

  administered perorally also prevented the development of dopaminergic receptor hypersensitivity in the striated body of rats.

  The compound under study has an anti-dyskinesic effect.

  MSF (MIF, melanostatin) has been active under conditions

  similar experimental conditions only after

  It is apparent from what has just been said that the main advantage of the 2,5-piperazinedione derivatives of the invention lies in the fact that their action, at activity levels equal to or greater than those of melanostatin, is considerably prolonged even after peroral administration.

  may therefore provide that the compounds of the invention are

  in the treatment of memory disorders, dyskinesia and

  late-onset and Parkinson's disease For this purpose,

  they can be presented in pharmaceutical forms of admi-

  Common parenteral or parenteral administration, such as, for example, tablets, coated tablets, gelatin capsules or injectable solutions for use

  subcutaneously, intravenously or intramuscularly.

  The forms of peroral administration can be manufactured

  in accordance with current practice by combining the

  active ingredient with usual granulating and / or tableting auxiliaries, such as, for example, lactose, sucrose, starch, polyvinylpyrrolidone, stearin, calcium stearate, ultra-amylopectin, cellulose

  microcrystalline and the like are then filled with

  The granules thus obtained can be granulated or pressed into tablets of the desired size and weight having the required active ingredient content. In a similar manner, it is also possible to produce drugs, solutions and

  other forms of parenteral administration.

  The 2,5-piperazinedione derivatives of the present invention are

  can advantageously be prepared according to a

  which comprises reacting a compound of the general formula

the II

X-NH-CH COOH (II)

  R 2 R in which R has the same meaning as in formula I

  and X is a protecting group, preferably a benzyloxy-

  -carbonyl, with a compound of general formula III: CH 2

(CH 2) C COOR (III)

CH NH 2

  in which R 1 and N have the same meaning as in formula I and R is methyl or ethyl, followed by elimination

  of the protecting group X and cyclisation, preferably by boiling

  toluene in the presence of a catalytic amount

of acetic acid.

  Another process for the preparation of the compounds of the invention

  The invention comprises reacting a compound of the general formula IV: ## STR2 ##

H C-COOH

  NH-X R in which R and N have the same meanings as in formula I and X has the same meaning as in formula II, with a compound of general formula V

NH 2 -CH COOR 3 (V)

  R 2 in which R 2 has the same meaning as in formula I and R has the same meaning as in formula III, then removal of protecting group X and cyclization, as a rule

  general according to the aforementioned method.

  It should be noted, however, that the compounds of the

  may also be prepared in accordance with any other

  appropriate method known in the art, particularly in the pre-

chemical parsing of the peptides.

  Other features of the preceding advantageous processes

  described for the preparation of the compounds of the invention

  as well as for their transformation into forms of admi-

  Pharmaceutical administration is illustrated by the following non-limiting examples. The nature and purity of the products

  have been verified by the elementary analysis, the values

  corresponding to the theoretical values with limits of

narrow tolerances.

EXAMPLE 1

  Cyclo (L-alanyl-l-amino-l-cyclohexanecarbonyl)

  A solution of 11.2 g (50 mmol) of benzyloxy-

  -carbonyl L-alanine in 100 ml of dimethylformamide containing 7 ml of Nethylpiperidine cooled to -20 ° C. with 5 ml of ethyl chloroformate After stirring for 20 minutes at -10 ° C., a solution in 100 ml of dimethylformamide is added, 6 g (50 mmol) of ethyl 1-amino cyclohexanecarboxylate liberated from its hydrochloride by addition of 7 ml of N-ethylpiperidine. After stirring for 1 hour at 0 ° C. and 2 hours at room temperature, the reaction mixture is evaporated under reduced pressure, the residue is dissolved in a mixture of

  ethyl acetate and water, the resulting organic phase is stirred

  With 1 M hydrochloric acid, water, 5% sodium hydrogen carbonate and water, it is dried over anhydrous sodium sulphate and evaporated to give a residue.

  non-crystalline product. Drying is completed by azeotropic distillation.

  eg with a mixture of tetrahydrofuran and benzene; the residue is then treated with 50 ml of a 35% hydrobromic acid solution in glacial acetic acid and, after 1 hour of residence at room temperature, the lanalyl-1-amino-1-cyclohexanecarboxylate hydrobromide is precipitated. non-crystalline ethyl with 500 ml of petroleum ether Rf = 0.52 / 51, 0.68 / 52% n-butanol / acetic acid / water: 4/1/1,

  52: n-butanol / acetic acid / pyridine / water: 15/3/10/6.

  The hydrobromide salt thus obtained is suspended in ml of a solution of chloroform saturated with OC ammonia and, after standing for 20 minutes at 5 ° C., the precipitate of ammonium bromide is filtered off and the chloroform solution is evaporated off. and dried by azeotropic distillation with a

  mixture of tetrahydrofuran and benzene.

  100 ml of toluene are added, 0.2 ml of glacial acetic acid are added and the solution is refluxed for 1 hour. After cooling the solution to room temperature and

  a stay for 2 hours at 0 C, the cris-

  tallin and washed with petroleum ether The desired product is obtained in 38% yield. A sample is crystallized with a mixture of dimethylformamide and 2-

  propanol and it then melts at 319-320 C.

  The following compounds are similarly prepared:

  N-benzyloxycarbonyl-L-seryl-l-amino-l-cyclopentanecarboxy-

  Methylate, from N-benzyloxycarbonyl-1-acid

  amino-1-cyclopentanecarboxylic acid and methyl ester of L-serine, yield 74%, mp 117-118, mId = 5.4

(c = 0.9, methanol).

  Cyclo (L-seryl-1-amino-1-cyclopentanecarbonyl), yield

  18%, mp 267-2690 C, al 2 = + 24.4 (c = 1.3, acetic acid).

  N-benzyloxycarbonylglycyl-l-amino-2-methyl-l-cyclohexane

  Methylcarboxylate, 43% yield (non-crystalline substance)

  line); Rf = 0.63 / 54, 54: chloroform / methanol: 9/1; spec-

mass, m / z: 362.

  Cyclo (glycyl-1-amino-2-methyl-1-cyclohexanecarbonyl), 26% yield, mp 333-334 ° C (dec); spectrum of

Mass: m / z: 196.

EXAMPLE 2

  Cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl)

  A solution of 2.25 g (10 mmol) of benzyloxy-

  -carbonyl-L-alanine in 20 ml of chloroform cooled to -10 ° C. with 15 ml of a chloroform solution of 1.8 g (10 mmol)

  methyl 1-amino-1-cyclopentanecarboxylate released at

  shot of its hydrochloride with 15 ml of an ammonia solution

  in chloroform and 2.3 g of N, N'-dicyclohexyl-

  -carbodiimide After 1 hour stirring at 0 C and 12 hours

  at room temperature at 3 ° C., N, N'-dicyclohexyl-

  precipitate, the filtrate is evaporated under reduced pressure,

  the residue is dissolved in ethyl acetate and stirred well.

  the organic phase is successively added with 1M hydrochloric acid, water, 5% sodium hydrogen carbonate and water, dried over anhydrous sodium sulphate and evaporated to obtain a non-crystalline residue, DalD = 17.6 (c = 1.46;

  methanol); Rf = 0.74 / 53.53: chloroform / methanol / acetic acid

tick: 14/2/1.

  The non-crystalline dipeptide derivative obtained is dissolved in 30 ml of methanol, 0.1 ml of acetic acid is added and

  about 250 mg of palladium black and introduced

  gas in the reactor with stirring for 1 hour.

  The catalyst is then separated by filtration, the methanolic solution is evaporated and the residue is dissolved in 20 ml of toluene. After 1 hour of reflux and then cooling to room temperature and 2 hours of residence at OC, the crystalline substance is separated off. wash with petroleum ether; the

yield is 39%.

  Crystallization with dimethylformamide and 2-propanol gives the title product, mp 279-281 ° C.

  ID = -8.4 (c = 1.12, acetic acid); Rf = 0.76 / 53.

  The following compounds are similarly prepared: methyl benzylcycarbonyl-valyl-1-amino-1-cyclopentanecarboxylate 255 o 2, yield: 62%, mp 139-140 ° C; D 17.5

(c = 1.2, methanol); Rf = 0.68 / 53.

  cyclo (L-valyl-1-amino-1-cyclopentanecarbonyl) Yield: 31%, mp 3210 ° C; rcd 25 = + 4.6 (c = 2.1 acetic acid;

Rf = 0.87 / 53.

  methyl benzyloxycarbonyl-D-valyl-1-amino-1-cyclopentanecarboxylate, yield: 63%, mp 139-140 ° C; ll 5 = + 17.30

(c = 1.3, methanol); Rf = 0.68 / 53.

  cyclo (D-valyl-1-amino-1-cyclopentanecarbonyl), Yield: 29%, mp 3200 ° C; ν = -4.7 (c = 2.1, acetic acid);

Rf = 0.87 / 53.

  benzyloxycarbonyl-D-phenylglycyl-1-amino-1-cyclopentane

  methylcarboxylate, yield: 49%, mp 156-158 ° C;

  lalD 5 = 68.8 (c = 0.96, methanol); Rf = 0.71 / 53.

  cyclo (D-phenylglycyl-1-amino-1-cyclopentanecarbonyl),

  35%, 285-287 C, 5 = 8.70 (c 0.23, acetic acid), Rf = 0.89 / 53%

  benzyloxycarbonyl-D-phenylalanyl-1-amino-1-cyclopentane

  Methylcarboxylate, yield: 59%, pof 99-101 Co

  cyclo (D-phenylalanyl-1-amino-1-cyclopentanecarbonyl),

= 661 (c = 0.3 active acid)

  Dement; 36%, mp 256 C lal D = 66.10 (c 0.3 acetic acid)

than.

  benzyloxycarbonyl-L-prolyl-1-amino-1-cyclopentanecarboxyl-

  methylate, yield: 72%, mp 126-127 ° C; l 25 =

-40.5 (c = 1.0 methanol).

  cyclo (L-prolyl-1-amino-1-cyclopentanecarbonyl), yield:

  36%, mp 1270 ° C; lal = 122.8 (c = 1.4 acetic acid).

  benzyloxycarbonylglycyl-1-amino-1-cyclobutanecarboxylate

  methyl, yield: 42%, mp 83-86 ° C; Rf = 0.73 / 53.

  cyclo (glycyl-1-amino-1-cyclobutanecarbonyl), yield:

74%, mp 277-278 ° C; Rf 0.50 / 53.

EXAMPLE 3

  Tablet composition: Cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) 25.0 mg Lactose 300.6 mg Sucrose 44.0 mg Corn starch 192.0 mg Polyvinylpyrrolidone 12.0 mg Stearin 2.4 mg Ultra -amylopectin 24.0 mg The active ingredient is mixed successively with lactose, sucrose and mars starch, the mixture is granulated, the dry granules are homogenized with stearin.

  and ultra-amylopectin and is shaped with a rotating machine.

  in tablet of 13 mm in diameter weighing 600 mg.

Claims (8)

  1 Biologically active derivatives of 2,5-piperazinedione having the general formula I: CH 2 CO-NH _ 1 \ (CH 2) C CH R CH NH-CO   (I) wherein R 1 represents a hydrogen atom or a radical   alkyl having 1 to 5 carbon atoms, R 2 is a hydrogen atom   gene, an alkyl having 1 to 9 carbon atoms, a hydroxyl   methyl, a phenyl or a trimethylene chain or tetra-   -methylene forming a ring with the adjacent nitrogen atom and n is an integer of 1 to 3.   2 New compound characterized in that it consists of the   cyclo (L-alanyl-l-amino-l-cyclohexanecarbonyl).   New compound characterized in that it consists of cyclo (L-alanyl-lamino-1-cyclopentanecarbonyl). New compound characterized in that it consists of cyclo (L-valyl-1-amino-1-cyclopentanecarbonyl). New compound characterized in that it consists of cyclo (D-valyl-1-amino-lcyclopentanecarbonyl). New compound characterized in that it consists of cyclo (D-phenylglycyl-1-amino-1-cyclopentanecarbonyl). 7 New compound characterized in that it consists of the   cyclo (D-phenylalanyl-l-amino-l-cyclopentanecarbonyl).   New compound characterized in that it consists of cyclo (L-prolyl-lamino-1-cyclopentanecarbonyl). New compound characterized in that it consists of cyclo (L-seryl-1-amino-1-cyclopentanecarbonyl). New compound characterized in that it consists of cyclo (glycyl-1-amino-1cyclobutanecarbonyl). Novel compound characterized in that it consists of cyclo (glycyl-1-amino-1-methylcyclohexanecarbonyl). Process for the preparation of compounds according to   claim 1, characterized in that it consists in making   act a compound of general formula II X -NH CH COOH (II) R   in which R 2 has the same meaning as in the   cation 1 and X is a protecting group, preferably a benzyloxycarbonyl, with a compound of the general formula III CH 2 (CH 2) C COOR 3 (III) CH NH   it 2 R in which R and N have the same meanings as in the   claim 1 and R 3 is methyl or ethyl, and then the   protection group X and cyclization.   A process for the preparation of the compounds according to claim 1, characterized in that it comprises the reaction of a compound of the general formula IV CH 2 (CH 2) N C COOH (IV) C 1 NH -X   R in which R and N have the same meaning as in the   claim 1 and X has the same meaning as in the   12 with a compound of general formula V NH 2 CH COOR 3 () R   in which R 2 has the same meaning as in the   cation 1 and R has the same meaning as in the   tion 12, then the elimination of the protecting group X and a cy- clisation.   14 New drugs useful especially for the treatment of   memory disorders, tardive dyskinesias, and   Parkinson's disease, characterized in that they consist of   in a compound according to any of the claims 1 to 11.   15 S Pharmaceutical composition characterized in that   comprises a medicament according to claim 14 with ex-   common pharmaceutical containers, carriers and / or auxiliaries.