CS231227B1 - 2,5-pierazindion derivatives - Google Patents

Description

(54) 2,5-Piperazinedione derivatives

The invention relates to 2,5-piperazinedione derivatives of the general formula I

(I), new substances which have shown useful effects in the treatment of animals for the treatment of memory disorders, tardive dyskines and Parkirmon's disease.

The invention relates to 2,5-piperazinedione derivatives of the general formula I

(AND)"

2 wherein R is hydrogen or methyl, n is hydrogen, alkyl of 1 to 9 carbon atoms, hydroxymethyl, phenol, benzyl or trimethylene chain, forming an unfused ring with the nitrogen atom at the 1-position, and an integer from 1 to 3 .

The 2,5-piperazinedione derivatives of formula I, which have not been described so far, have shown an interesting and useful biological activity in pharmacological tests, as described in more detail below »

Some 2,5-piperazinedione tulle derivatives have been previously described (J. Chem. Soc. 2119, 1960; J. Med. Pterm. Chem. 5, 42, 1962; Cen. J. Chem. 40, 2214, 1962; Cooi. Chem. Cornun., 35, 619 (1970). the authors suggest that some of them inhibit tumor growth or have anti-viral activity (No. AO No. 210 383) and theoretical (co-study studies).

In the case of the 2,5-piperazine-hione derivatives of the general formula (I), significant biological activity has been found, especially in steaming experimental animals. As is known, substances with this activity are preferably monitored in the extinction tests of the conditional escape reaction and the duration of the passive evasion reaction in rats (R. Waeter et al., Proc. Natl. Aced. Sci. USA 75, 2493, 1975; ibid. 4180, 1975; J. Krejjc, Op. In these tests, the MS activity factor, the so-called MIF (epithelium), reached the highest activity. In all cases this substance has to be applied subcutaneously, because the enzyme is rapidly activated in the gastrointestinal tract.

For one of the compounds of formula I according to the invention, namely with cyclo (L ^»r l-naphthalen-1" amino-1 - cy01opentankariornluu that Tyl selected for more detailed zkouuení, rearward with překvappenrn found to exhibit high activity in the test of passive avoidance secondly during application No ^P i ^with a drill ^d per minute ^to 3 ° ^{Pla d} retention test in ¹ AVCE ^d ^ jl ^k g ^{p -1} sc ozoruhodné butyloxy the substance Tyl effective even when administered orally, in the long term, even and ²⁰ h ^{Pla d} practicing Neto ^{Pla d} ^ Vrachou ZSTE at ^0, 5 to ¹⁰ mg. ^{kg 1st}

From longer logic tests, it is significant that the substance inhibits the development of tolerance to

Oetaltptic effect after repeated administration of neuroleptics. In the experimental model, which is used as a mmdel for the development of tardive dyskines, it has been applied repeatedly (in five-day doses) for a long-term effect of the non-olefinic isofloxylepin; active substance by ^you. ^ i ^: ^u l ^e of the neck-hammered twice a day ^- VCE ^{be 7.5 m} ^. ^kg ~ ^{1 p} .o., when ^no <MŽ significantly inhibit development of tolerance-Val.

In the same experiment, the compound of the invention significantly inhibited (at a dose of 10 mg.kg per day) a decrease in the concentration of hoic acid in the striatum of rats and an increase in the meximanoic potential of dopamine binding sites (using Jipiptron). při po administration prevented the development of supersensitivity of the dopatergic receptors in the strike of rats. It can be considered to be a substance with possible antioxidant activity. MS-in. The factor of activity (MIF) is only effective under these experimental conditions

s.c.

Accordingly, the advantages of the 2,5-piperazinedione derivatives of formula (I) for their therapeutic ingestion are that, while maintaining activity that is equivalent to or greater than that of the MSI-Inhibition Factor (MIF), their effect is long-lasting, and even by oral administration *

Other dosage forms, such as tablets or gelatin capsules, are suitable for this mode of administration; for parenteral administration, the active ingredient may be administered in the form of a solution for injection (subcutaneously, intramuscularly, or intravenously).

The various types of preparations can be prepared according to conventional pharmaceutical practice by treating the active ingredient with the usual granulating and tableting additives such as lactose, sucrose, starch, polyvinylchloride, calcium stearate, microcrystalline cellulose, etc. The obtained granulate or tablet is then filled either into gelatin capsules or compressed into tablets of the required size in an effective amount

Injectable solutions are prepared *

The 2,5-piperazinedine derivatives of the general formula I according to the invention can be prepared, for example, by reacting a compound of the general formula II

X - NH - CH - COOH (II)

in which R is totéž.co in formula I and X represents a protecting group, for example benzyloxykarbonylkvku, is condensed with a compound of formula III (CH _{2) n} -COOR ³ C (III) ^to structural mechanics ^r1 represents an tot ^ as in formula ^I and ^R3 is not methyl ^b et a l ^y, whereupon ^e ignites ^the lysed ehháničí product after removal of the group X in the cyclized compound of formula I, napříkled by boiling in toluene, acetic acid přítomnkatalytického application rates.

Another possible way is to. The compound of formula (IV) may be condensed by condensing a compound of formula IV * -ch _2x (CH ₂ ) _n C-CCGH 1 h ⁴ hx

(IV), in which the formula V and ⁿ denote the ^same as in the formula:!

I and X the same as in formula II, with the compound

NHg - CH

COO r3 (A),

R ²

Wherein R is the same as in Formula I and the product, after deprotection X, cyclizes as a rule as described above.

^{R 3 t} o ^t ^ ^Ez as in formula III, whereafter the resulting compound represented by formula I

Of course, any other processes known in particular in peptide chemistry are useful for the preparation of 2,5-piperazinedione derivatives of formula (I).

The details of the process for preparing the compounds of the invention and their formulation into dosage forms are apparent from the following Examples.

Example 1

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

To a solution of benzyloxycarbonylalanine (11.2 g; 50 mmol) in dimethylformamide (100 mL) and N-ethylpiperidine (7 mL) cooled to -20 ° C was added ethyl chloroformate (5 mL). · After 20 minutes of stirring at -10 ° C was added to the reaction mixture a solution of 1-emino-1-cyclohexanecarboxylic acid ethyl ester in dimethylformemide (ml0 mL), released from the corresponding hydrochloride (10.6 g; 50 mmol) by addition of N-ethylpiperidine (7 mL). After stirring at 0 ° C for 1 h and at room temperature for 2 h, the reaction solution was evaporated in vacuo, the residue was dissolved in ethyl acetate-water, the organic phase was shaken successively with 1 M hydrochloric acid, water, 5% sodium bicarbonate and water. , dried over anhydrous sodium sulfate and evaporated in vacuo. A non-crystalline residue was obtained, which was dried by azeotropic distillation with tetrahydrofuran-benzene; a 35% solution of hydrogen bromide in glacial acetic acid (50 ml) was added to the non-crystalline residue. After standing at room temperature for 1 h, the non-crystalline L-elanyl-1-amino-1-cyclohexanecarboxylic acid ethyl ester hydrobromide was precipitated by addition of ether (500 ml);

0.52 / S _t ; 0.6B / S ₂ .

Sj: n-butanol - acetic acid - water (4: 1: 1),

S ₂ : n-butanol-acetic acid-pyridine-water (15: 3: 10: 6).

The prepared hydrobromide was suspended in aminiacal chloroform saturated at 0 ° C (50 ml) and after standing at +5 ° C for 20 minutes the precipitated ammonium bromide was filtered off, the chloroform solution was evaporated in vacuo, dried with tetrahydrofuran-benzene *. The residue was dissolved in toluene (100 mL). After glacial acetic acid (0.2 mL) was added, the solution was heated at reflux for 1 h. After cooling the reaction solution to room temperature and standing at 0 ° C for 2 h, the precipitated crystalline product was filtered off and washed with petroleum ether. The product was obtained in 38% yield. The sample for analysis was crystallized from dimethylformemide and 2-propanol; mp 319-320 ° C.

For C _1q H ₁₆ N ₂ O ₂ (196.3) calculated: 61.20% C, 8.22% H, 14.27% N; Found:% C, 60.76;% H, 8.38;% N, 14.25.

Example 2

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

To a solution of benzyloxycarbonyl-L-alanine (2.25 g; 10 mmol) in chloroform (20 mL) cooled to -10 ° C was added a solution of 1-amino-1-cyclopentanocarboxylic acid methyl ester in chloroform (15 mL), released from the corresponding hydrochloride (1.8 g; 10 mmol) with a solution of ammonia in chloroform (15 mL); then N, N'-dicyclohexylcarbodiimide (2.3 g) was added. After stirring at 0 ° C for 1 h and standing at 3 ° C for 12 h, the precipitated N, N'-dicyclohexylurea was filtered off, the filtrate was evaporated in vacuo, the residue was dissolved in ethyl acetate and the organic phase was successively shaken with 1 M hydrochloric acid solution. , 5% sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and evaporated in vacuo · Non-crystalline residue was obtained; (A) a ^ = -17.6 ° (c = 1.46, methanol) _Rf »0.74 / ₃ S Sy: chloroform - methanol - acetic acid (14: 2: 1).

The non-crystalline dipeptide was dissolved in methanol (30 mL); after the addition of acetic acid (0.1 ml) with palladium black (esi 250 mg), hydrogen was introduced into the reaction vessel with stirring. After 1 h, the hydrogenolysis was complete, the catalyst was filtered off, the methanolic solution was evaporated in vacuo, and the residue was dissolved in toluene (20 mL). After heating at reflux for 1 h and cooling the solution to room temperature and standing at 0 ° C for 2 h, the precipitated crystalline product was filtered off and washed with petroleum ether. The product for analysis was crystallized from dimethylformamide and 2-propanol, mp 279-281 ° C; (a) 2- ⁰ = -8.4 ^(c - ^l ^ 12j acetic acid R _f 0.76 / S _3rd

For C ₉ H ₄ N ₂ O ₂ (180-, 2) calculated: 59.33% C, 7.75% Η, 15.38% N;

Found: 58.77 ° C, 72.72H, 15.63

Example 3

Mtyyester btnzyls · .χyklrbosyyl .valyl-L-L-L-amino-acid amide cyklopenterkerbsxylové 'was prepared obdobrým manner as bacon derivative, described in Example 2, yield ⁶² · temperature ^Ta n ^{e 1} 39 and ¹ 4 ° ^{C (} a) = = -n ^{1 (} c ^1, 2 ^; m ^ ^ r r ^ r) ^{; R} t = 0.68.

Calcd for C20 H20 N3 O (376.5): C 63.80; H, 7.50; N, 7.44. found: 63'1% c, 7.42% H, 7/9% N.

Cyyio (L-valyl-1-amino-cyclopentanecarbonyl)

Eyl prepared in a similar manner as bacon derivative, described in Example 2, ^1% 3 ^mined; mp 3 ²¹ ° C. ⁽ +4 ^, ° C ⁽ c = ^2.1; acetic acid) ^Rf * ^0.8 7 / Sy)

For (210.3) calculated: 62.83% C, 8.63% H, 13.32% N; Found: C, 62.45; H, 8.38;

EXAMPLE 4 ^ bei bei bei bei bei bei: lo lo: lo:: lo lo ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ am acid

Prepared in analogy to the alanine derivative of Example 2 in 63% yield; mp EŽ ¹ 39 ¹ 4 ° ^{C (} «) + 17 N ^{5, 3 (c - 1,} 3; me ^{an s} H 8 ^{NO), R} _f" 0.68 / S ^3rd

• For 020¾¾ (376.5) calculated: 63.80% C, 7.50%, H, 7.44% N;

. Found:% C, 63.69;% H, 7.39;% N, 7.28.

Cyclo (D-valyl-1-amino-1-cyclopentanlarbnyl).

tulle prepared in a similar manner to that described in Example 2, in a yield of 29%; mp 320 ° C. ( «) ^ ⁵ = -4, ⁷ ° ^(c = ^2.1; acetic tyselina) R. = ^^ 78 ^third

For C _n H ₁₈ N ₂ O ₂ (210.3) calculated: 62.83% C, 8.63% H, 13.32% N; Found: C, 62.41; H, 8.28; N, 13.06.

Example 5

Benzyloxycarbonyl-D-phenylglycyl-1-mineralno-1-cyclopentanecarboxylic acid methyl ester

It was prepared in a similar manner to the bacon derivative shown in Example 2 in a yield of 49%; mp 56-158 ° C. (A) p ^ = -68.8 ° (c = 0.96, methanol): B _f = 0.71 / Sj.

For ^C 23 ^H 26 ^N 2 ^O 5 U ¹⁰ · C calculated: 67.30% C, 7.38% H, 6.82% N; Found: 67.21% C, 6.56% II, 6.75% N.

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

It was added analogously to the bacon derivative in Example 2 in a yield of 35%, mp 285-287 ° C. [.alpha.] D @ ²⁰ = -8.7 DEG (c = 0.23; acetic acid); _Bf = 0.89 / S4.

For C ₁₄ H ₁₆ N ₂ O ₂ (244.3) calculated: 63.83% C, 6.60% H, 11.47% N;

Found: 68.13 »C, 6.33% H, 11.25% N.

Example 6

Benzyloxycarbonyl-D-phenylellyl-1-amino-1-cyclopentanecarboxylic acid methyl ester

It was prepared in a similar manner to the alanine derivative shown in Example 2 in a yield of 59%; mp 99-101 ° C.

For C ₂₄ H ₂₈ N ₂ O ₅ (424.5) calculated: 67.19% C, 7.38% H, 6.82% N; Found: C, 67.85; H, 6.47; N, 6.42.

Cyclo (I) -phenylalanyl-1-amino-1-cyclopentanecarbonyl)

Similarly, the alanine derivative of Example 2 was prepared in a yield of 36%; mp 256 ° C. [.alpha.] D = -66.1 DEG (c = 0.3, acetic acid).

For C ₁₅ H ₁₈ N ₂ O ₂ (258.3) calculated: 69.75% C, 7.02% H, 10.85% N; Found:% C, 69.31;% H, 6.62;% N, 10.68.

EXAMPLE 7 Benzyloxycarbonyl-1-L-propyl-1-eraino-1-cyclopentarboxylic acid methyl ester

It was prepared in a similar manner to the bacon derivative shown in Example 2 in a yield of 72% ^; lota ^p te mp 126-127 ° C. [.alpha.] D @ ²⁰ = -40.5 DEG C. ( ^c = 1.0; recrystalline).

For C 20 ^H 26 ^N 2 ° 5 (374.4) calc. H, 7.00; N, 7.48. Found:% C, 63.79;% H, 6.89;% N, 7.13.

Cyllo (L-propyl-1-amino-1-cyclopentanecarbonil) tulle was prepared analogously to the bacon derivative mentioned in Example 2, yield 36, mp 127 ° C. [.alpha.] D @ 20 = -122.8 DEG C. (c = 1.4; acetic acid).

For C ^ HH ^C ^ (208.3) calculated: 63.43% C, 7 H / 4% H, 13.45% N;

Found:% C, 62.95;% H, 7.48;% N, 13.1%.

Example 8

MeSylestsг ^{benzyloxykerbonyl-1-amino-1-L-R} cyllopsntaokθrborO ssrinu

Ethyl was prepared from benzyloxycarbonol-disodium 1-8mino-1-cyclopropanecarboxylic acid and methyl ester of Example 1 in 74% yield, m.p. 117-118 ° C. (A) 2 3 ⁴ -4.4 ° ^(c = ^0.9; raeeenoD.

For C 6 8¾¾¾^^ (364.2) Calculated: C, 49.33; H, 6.64; N, 7.69. Found:% C, 48.66;% H, 7.00;% N, 7.87.

Cyclo (L-seryl-1-amino-1-cyclopsoУaokarbooy1)

Prepared in analogy to Example 1 in 18% yield, mp ^267-269 ° ^{C. [.alpha.] D @ 20} = +24.4 DEG ⁽ c = ^1.3; acetic acid).

Example 9

Methylbenzylcarbonyl-1-amino-1-cyllobutocarboxylic acid

Prepared in analogy to the derivative mentioned in Example 2 in a yield of 42%; mp 83-86 ° C; R _f = 0.73 / S ..

Cyclo (glycyl-1-amino-1-cyclobutanecarbonyl) -yl was prepared analogously to the derivative mentioned in Example 2 in 74% yield; mp 277-278 ° C; R _f = 0.50 / _r

Benzyloxycarbonylglycyl-1-amino-2-methylcyclohexanecarboxylic acid methyl ether prepared. analogously to the bacon derivative of Example 1, in a yield of 43% (non-crystalline); R _f χ 0.63 / S 2

S ^: Chloroform-methanol (9: 1)

The NMR spectrum of 362.

Cello (glycyl-1-amino-2-methylcyclohexarcarbonyl)

It was prepared in a similar manner to the corresponding derivative shown in Example 1, in a yield of 26%, mp 333-334 ° C (dec.);

For ^ ₀ Η ₁₆ Ν ₂ 0 ₂ (196.2), the hmoonoot spectrum m ^ z 196.

Example 11

Tablets

Cclo (L-altoyl-1-azioo-1-cyclopentottolecyl) Ofl) 25.0 mg lactose 300.6 mg sucrose 44.0 mg cornstarch 1912.0 mg polyvioylpyrllidlo 12.0 mg steario 2.4 mg ultraam lop®Уtio 24.0 mg

The active ingredient is gradually mixed with lactic acid, sucrose and corn starch and the gramilate is prepared. To the dry granulate is added steario and llraaoylpectio, and tablets of mm 13 mm and Ιβο ^ ο ^ Ι 600 mg are prepared on a rotary tablet.

Claims (1)

SUBJECT OF THE INVENTION 2,5-Piptrazinedione derivatives of the general formula I ch ₂ , co - k Τ H H Hk X> - k CH ^X Ы NH ЫУ In which R @ 1 denotes a hydrogen atom or R @ 1 ₍ R @ 1 hydrogen atom, alkyl of 1 to 9 carbon atoms, Oydro: ethynyl, feoyl, benzyl or triottyl chain forming an uncondensed ring with the nitrogen atom at position 1) number from 1 to 3.