FI78917C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA SUBSTITUERADE DIPEPTIDER. - Google Patents

Description

1 78917

Method for preparing therapeutically active substituted dipeptides - Förfarande för framställning av terapeutiskt aktiva substituerade dipeptider

Enkephalin is a natural opiate receptor agonist. It is believed to be a mixture of two pentapeptides: H-Tyr-Gly-Gly-Phe-Met-OH (methionine-enkephalin) and H-Tyr-Gly-Gly-Phe-Leu-OH (leucine-encephalin). Hereinafter, the name enkephalin is generically used to cover all such compounds.

Belyzzi et al., Natura, 260, 625 (1976), have reported that the initiation of enkephalin into the cerebral ventricle of rats results in an analgesic state. It is also known in the art that enkephalin is generically affected by a group of enzymes known as enkephalinases. These enzymes also occur in nature and inactivate enkephalin.

European patent application No. 79105015.6, Publication No. 12401, discloses some dipeptide derivatives described as having antihypertensive effects.

European patent application No. No. 81110337.3, Publication No. No. 54862, discloses certain dipeptide compounds having enkephalinase inhibitory activity.

The present invention relates to a process for the preparation of therapeutically active substituted dipeptides of formula I

R 1 C * H-NH-C * H-CONH (CH 2) -C * -COR 6 (I) COR 2 R 3 R 5 or pharmaceutically acceptable salts thereof, wherein: 2,78917

R 1 is phenyl-lower alkyl or diphenyl-lower alkyl, R 2 is hydroxy, -OCl 2 OCO-lower alkyl or the group R 7 is R 8 O 2 I! -och2-ch-ch2 wherein R7 and R8 are independently C1-C8 alkyl or r2 is -O-lower alkyl-O-phenyl, -O-CH2-CHOH-CH2-OH, phenyl-C1-C4-alkoxy or aminophenyl- C 1 -C 6 alkoxy, R 3 is 1-benzyl or phenylbenzyl, R 4 is hydrogen, lower alkyl or hydroxy, R 5 is hydrogen, and

R 9 is hydroxy, phenyl-C 1 -C 4 -alkoxy, -OCH 2 CO-lower alkyl, C 1 -C 6 -alkoxy or the group -OCH 2 -CH-CH 2,

V

R7 r8 wherein R7 and Rq independently of one another denote C1-C8-alkyl.

The asterisks in formula I denote those carbon atoms which may be asymmetric (chiral) centers. According to the invention, all isomers can be prepared in these centers both in pure form and as a mixture.

An interesting group of compounds of formula I are those wherein R 4 is hydroxy or lower alkyl i.e. R4 does not represent hydrogen. Examples of such R4 groups are hydroxy and methyl.

As used herein, and unless otherwise indicated, the terms alkyl and alkoxy refer to groups in which 11 3 78917 is a straight or branched carbon chain of 1 to 6 carbon atoms. The term pivaloyloxymethyl is a trivial name or a common name for a (2,2-dimethyl-1-oxopropoxy) methyl group.

Some compounds of structural formula I form salts with pharmaceutically acceptable acids. Useful include hydrochloric acid, sulfuric acid, acetic acid, maleic acid, fumaric acid and the like.

Compounds of structural formula I in which R 2 and / or R 8 represent hydroxy form salts with pharmaceutically acceptable bases. For this purpose, calcium hydroxide and sodium and potassium carbonate. Also possible are salts formed with pharmaceutically acceptable amines, such as ammonia, N-methylglucamine, benzylamine and morpholine.

The individual compounds of structural formula I within the scope of this invention are as follows: 1. N- [N- [L1- (2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine, (2,2-dimethyl-

1-oxopropoxy) methyl ester; compound B

2. N- [N- [L-1- [phenylmethoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine, (2,2-dimethyl-1-oxopropoxy] methyl ester;

3. N- [N- [L-1-carboxy-2- (4-phenyl) phenylethyl] -L-phenylalanyl] -O-alanine compound J

4. N- [N- [L-1-carboxy-2-phenylethyl] -L- (4-phenyl) phenylalanyl] -O-alanine; compound K

4,78917 5. N- [L-1-carboxy-2-phenylethyl] -1-phenylalananyl-β-alanine, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl ester m.p. 153-8 ° C.

6. N- [N- [L-1-carboxy-2-phenylethyl] -L-phenylalanyl] -L- (rf-methyl) - (3-alanine; compound G

7. N- [N - [(L-1-carboxy-2-phenylethyl)] - L-phenylalanyl] - β-alanine, 2-phenoxyethyl ester; mp. 141-144 ° C, white crystals 8. N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] Β-alanine; mp. 93-95 ° C, white crystals 9. N- [N- [L- [1 - [(2,3-dihydroxy) -1-propoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -O-alanine

white amorphous solid, changes: 85 ° C, decomposes: 180 ° C

10. N- [N- [L- [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-phenylethyl] -L-enylalanyl] - [3- alanine; mp. 80-82 ° C, white crystals 11. N- [N- [L- [1- (2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L - (4-phenyl) phenyl-alanyl] -0-alanine; mp. 138-140 ° C, white solid

12. N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L-α-methyl-O alanine; white prawns, m.p. 79-85 ° C

13. N- [N- [L- [1 - [(2-phenoxy) ethoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, Lo (-methyl-β-alanine; mp 107-111 °) C, white 5,78917 14. N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L- (4-phenyl) -phenylalanyl) -D, L-a-methyl-fl-alanine; mp. 129-130 ° C, white solid 15. N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- [4-phenyl) phenylethyl ] -L- (4-phenyl) phenylalanyl] -D, L-O-methyl-β-alanine, amorphous solid 16. N- [N- [L- [1 - [(2,2-dimethyl-1- oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-enylalanyl 1-o-methylalanine; yellow oil, toU2 ^ = -18.3 ° (DMF, C = 1)

D

17. N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy] methoxy] carbonyl] -2- (4-methoxy) phenylethyl] -L-phenylalanyl-D, La- methyl / i-alanine benzyl ester, clear oil, [X] 26 = -19.5 ° [DMF, C = 1.3]

D

18. N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-methoxy) phenylethyl] -L-phenylalanyl-β-alanine , colorless viscous syrup 19. N - [(D1-carboxy-2-phenylethyl-1-L-leucyl-L-phenylalanine, mp 191-192 ° C, colorless solid 20. N- [N - [(S) - [1 - [(R, S) - (2,2-dimethyl-1,3-dioxalan-4-yl) -methoxy] carbonyl] -2-phenylethyl] - (L) -phenylalanyl] - (R ) -2-hydroxy- [3-alanine, mp 125-128 ° C, white crystals 21. N- [N - [(S) - [1 - [(R, S) - (2,2-dimethyl- 1,3-dioxalan-4-yl) -methoxy] carbonyl] -2-phenylethyl] - (L) -phenylalanyl] - (S) -2-hydroxy-4-alanine methyl ester, mp 78-82 ° C, white solid

The invention also includes pharmaceutically acceptable salts of the individual compounds listed above.

6,78917

The analgesic activity of the compounds of structural formula I can be utilized in many dosage forms known in the art, such as tablets, capsules or helixes for oral administration or sterile solutions or suspensions for parenteral administration. In addition to the compound of this invention, pharmaceutically acceptable and compatible excipients, binders, preservatives, stabilizers, falsifiers, and the like are preferably used in the preparation of these pharmaceutical dosage forms. In each dosage form, the active compound is administered in a dose range of about 1 to 100 mg / kg. Doses are given every 3-8 hours. However, the amount and frequency of dosing will depend on such factors as the severity of the pain, the general physical condition of the patient, including the age and weight of the patient, and other factors known to those skilled in the art.

The compounds of this invention can be prepared using reactions and reagents well known in the art of polypeptide.

In general, the compounds of formula I are prepared by any of the following suitable methods (in the following formulas, p, R 1, R 2, R 3, R 4, R 5 and R 8 are as defined above, including the exclusionary meanings of the above condition and including possible protection of reactive groups); (a) reduction of a compound of formula XX in a C = N-double bond Τ ’

R1-C = N-CH-CONH (CH2) -CR4R5COR6 - * I

cor2 (XX)

II

7 78917 b) an amino acid of formula VIII is coupled with an amino acid of formula V.

R1-C-NHCH-CO2H + H2N (CH2) -CR4R5CORg - »I

COR2 (VIII) (V) is then deprotected and then, if desired or necessary, converted into a compound of formula I or another compound of the general formula I as defined above and / or a salt thereof and, if desired, the preferred isomer is isolated.

The various intermediates used in the methods described above can be obtained directly by following the European patent application, Publication No. 54862, or methods analogous thereto.

A number of intermediates required for the preparation of the compounds of this invention are commercially available or can be readily prepared by methods known to those skilled in the art. Many of the intermediates required in the preparation of many of the compounds of this invention have been described or included in publications and works on peptide chemistry. Examples are e.g. J. H. Jones, "Comprehensive Organic Chemistry", Vol. 2, D. Barton and W.D. Ollis, ed. Pergamon Press, 1979, pp. 819 to 823 and references 2, and 29 to 31. The relevant sections of this publication are incorporated herein by reference.

The following examples illustrate the preparation of the compounds of the invention.

78917

Example 1 N- [N- [L-1-carboxy-2- (4-phenyl) phenylethyl] -L-phenylalanyl] -3-alanine benzyl ester.

A. 4-Phenylphenylpyruvic acid 40 g of potassium t-butoxide were added in small portions and with stirring 150 any diethyl oxolate. Initially, after the exothermic reaction subsided, the reaction mixture was heated in a steam bath under nitrogen to dissolve the solid. After cooling to room temperature, 79 g of 4-biphenylacetic acid methyl ester were added in one portion. The mixture was stirred for 2 hours at 65-70 ° C while removing low boiling in vacuo. After cooling to room temperature, the viscous residue, 200 ml of ether and 350 ml of water were stirred under cooling. The ether layer was separated and extracted once with 10 ml of water. The aqueous layers were combined, extracted once with ether, acidified with concentrated hydrochloric acid (cooled) and extracted twice with 300 ml of ether. Some of the solid did not dissolve in the ether layer and these were separated by filtration. The ether layer was then evaporated to dryness and the semi-solid residue was combined with the solid previously obtained. To a mixture of the solid and the semi-solid residue was added a mixture of 160 ml of concentrated hydrochloric acid and 350 ml of acetic acid, and the resulting mixture was heated at reflux for 2.5 hours. Upon cooling to 50 ° C, a solid precipitated which was filtered and washed with 150 ml of water. The wet solid was stirred with 150 mL of acetonitrile for 50 min. then filtered and dried under high vacuum at room temperature for 3 hours. 42 g of the title compound were obtained, melting point 215-218 ° C, B. N- [N- [κ-tert. -butyloxycarbonyl] -L-phenyl.anyl-N-β-alanine benzyl ester, in a mixture bathed in an ice bath containing 7523 ml of dry N., Kt-dinethylformamide containing 0.023 moles of each of the following 9,78917 compounds; di-t-butyl dicarbonate, L-phenylalanine, galalanine benzyl Tester n-t-toluenesulfonate f. hydroxybenzotriazole and N-dimethylaminopropyl-N, N-ethylcarbodiimide, 5 ml of N, N-ethylmorpholine were added and the mixture was stirred for 3 hours. at room temperature, then poured into 600 ml of ice water and extracted 3 times with 150 ml of ether. The ether layers were combined and extracted once with 150 ml of 0.3N hydrochloric acid, then twice with 300 ml of water and then dried over sodium sulfate, filtered and evaporated to dryness in vacuo at 28 ° C. 9.0 g of a gummy solid were obtained.

C. H- (L-Phenylalanyl) -g-alanine benzyl ester hydrochloride 4.0 g of the product of Example 1B in 25 ml of ethyl acetate were stirred for 10 minutes at 0 ° C with gaseous hydrogen chloride. After stirring at 0 ° C for 1.5 hours, 30 minutes at 10 [deg.] C. Excess hydrogen chloride was removed by passing a stream of nitrogen gas into the solvent, the solution was poured into 200 ml of ether with vigorous stirring, the precipitated solid was collected by filtration and then dried at room temperature under high vacuum for 2 hours to give 3.35 g of product. .

D. N- [N- [1-1-carboxy-2- (4-phenyl) phenylethyl] -L-phenylalanyl] -3-alanine benzyl ester.

A mixture of 9.10 g of H- (L-phenylalanyl) -3-alanine-benzyl ester hydrochloride and 8.40 g of the compound of Example IA in 500 ml of a mixture of tetrahydrofuran and ether (9: 1) was treated with triethylamine to pH 6.6 and stirred at room temperature for 1.5 hours, over 2 hours a solution of 2.0 g of sodium hydroxyborohydride in 100 ml of tetra, atabolir of hydrofuran and a mixture was added dropwise with stirring. Stirring was continued overnight at room temperature. The reaction mixture was concentrated to 75 ml in vacuo at 40 ° C. The residue was stirred with 400 ml of 0.5H hydrochloric acid and 400 ml of ether for one hour. The ether layer was dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give a yellow viscous syrup. 78917 which was dissolved in 25 ml of ethanol. On cooling overnight, a solid formed which was filtered off, washed with cold ethanol (4.2 g} and chromatographed on a column containing 30 g of silica gel using CHCl 3 as a solvent mixture. H (2QQ; 1Q; 21. The effluent was divided into fractions which were evaporated to dryness in vacuo to give 600 mg of a solid product consisting of the title compound, m.p. 192-194 ° C.

Example 2 β- [β- [β-carboxy-2- (4-phenyl] phenylethyl] -L-phenylalanyl-1 H -alanine.

A suspension of 590 mg of the product of Example 1 in 100 ml of ethanol was shaken overnight with 200 mg of 10% M / C catalyst in a Parr apparatus. The resulting mixture was diluted with 40 mL of ethanol and 10 mL of water, then briefly heated on a steam bath until the white precipitate was completely dissolved. After cooling, the catalyst was filtered off, the filtrate was evaporated to 5 ml at 50 ° C in vacuo. The solid was filtered off, washed with ethanol and dried at room temperature under high vacuum for 6 hours to give 155 ml of the title compound, m.p. 226-228 ° C.

26 α j = 16.8 (C = Q, 5, DMFl.

Analysis, calculated; C 174.040 H, 6.13; M, 6, Q8,

Found; C, 70.54; H, 6.26; N, 5.97,

Example 3 N- (N- [N- [1- [pivaloyloxy-1-methoxy] carbonyl [% 2-phenylethyl)] -; L-phenylalanyl ±] -β-alanine, pivaloyloxymethyl ester.

A. N- (tert-butyloxycarbonyl) -β-alanine, pivaloyloxy-11,789 7 methyl ester.

Triethylamine (32.4 mil was added to N-tert-butyloxycarbonyl β-alanine in 4 g of K, N, N-dimethylformamide at room temperature under nitrogen in a 1 liter round bottom flask. The solution was stirred for 15 minutes and at 0 ° C was added dropwise chloromethyl 6 g) M. Rasmussen & NJ Leonard, J. Amer. Chem. Soc., 89, 5439 (1967) The solution was stirred at room temperature overnight, then diluted with ethyl acetate, filtered, washed with water and then brine and evaporated. 70 g of crude material which was chromatographed (silica gel) eluting with 15% ethyl acetate-hexane gave 62.5 g of product.

B. S-alanine, pivaloyloxymethyl ester, trifluoroacetate.

Trifluoroacetic acid (10 ml) was added to a solution of the product of Example 3A (62 g) in methylene chloride (180 ml) at 0 ° C. The mixture was stirred at room temperature for 2 hours and the solvent was removed in vacuo to give 100 g of product as a pale yellow oil, C, N- [L-1- (phenylmethoxy) carbonyl-2-phenylethyl)] - L-phenylalanine.

L-phenylalanine benzyl ester hydrochloride was suspended in 190.4 g (0.652 mol in 96 96 ml of absolute methanol, 6.7 liters of dry (3A sieves) tetrahydrofuran was added and the slurry was stirred while about 5Q ml of triethylamine was added to adjust the pH to 6. .5 7.0, pH was checked with EM Reagents Coloj? PHast indicator strips, a, read pH 5-10, moistened with water before use., 200 g (0.98 mol) of sodium phenylpuruvate »hydrate ( Sigma) followed by 24Q g of crushed 3A m ° molecular sieve, (The sieve can be ground in a mortar and does not have to be fine, If it is too fine it is difficult to separate by filtration).

12 7891 7

The slurry was stirred at ambient temperature while 61.6 g (0.98 mol / l of sodium cyanoborohydride, 40 ml of methanol and 300 ml of dry tetrahydrofuran) were added dropwise over 5 hours. The reaction mixture was stirred at ambient temperature. -72 hours while monitoring the disappearance of the benzyl ester by thin layer chromatography, "The molecular sieve was removed from the reaction mixture by filtration and washed with very hot methanol as some of the product precipitated on them.

The filtrate was concentrated on a rotary evaporator to a syrup at 50 ° C. This syrup was dissolved in 2.4 liters of ether in a 12 liter round bottom flask and stirred in an ice bath while adding 2.4 liters of 2.5% aqueous hydrochloric acid. The large amount of HCN formed was passed to a sodium hydroxide trap. The mixture was stirred for 2.5 to 3 hours, at which time a white solid gradually formed on the interface and the cyanogen boiling ceased.

The 2-phase mixture was filtered (most of the aqueous phase can be removed in a separator before filtration because the product remains on the interface) and the solid was washed well with ether and dried in vacuo below 50 ° C; yield 80-90 g, melting point 175-180 ° C. This material was 90-95% pure L, L isomer based on thin layer chromatography. The crude product was redissolved in about 10 liters of boiling absolute methanol, a small amount of white inorganic insoluble matter was separated by filtration, and the filtrate was concentrated to 5 liters at the boiling point to form fluffy white crystals. The product was allowed to slowly cool to room temperature and then to 0 ° C over 2-3 hours. The solid was collected and dried in vacuo at 50 ° C; yield 57-60 g, m.p. 185-186 ° C, [α] 25 D 5.9 τ · 6.3 ° * (DijSQ, C = 1). The product contained more than 98% of the L, L isomer based on thin layer chromatographic assay and high pressure liquid chromatography. (results of several runs).

i3 7891 7 D. H- (Lrl, benzyl) cyclocarbonyl-2-phenyl-yl) -L-phenyl-α1α-n-i-p-yloxymethyl ester.

A solution containing 4.03 g (10 moles). The product of Example 3C and 1.5 ml (11 moles of triethylamine in 20 ml of dimethylformamide) were treated at ambient temperature with 1.6 ml (11 moles) of chloromethyl pivalate, stirred for 24 hours at 50-6 ° C and the resulting solution was poured into water. and extracted 3 times with 100 ml of ether A small amount of insoluble matter was filtered off with a pad and the ether phase was washed with water, dried and concentrated to an oil, yield 4.8 g, NMR consistent with the structure of the title compound.

E. N- (L-carboxy-2-phenylethyl) -L-phenylalanine, pivaloyl oxymethyl ester.

The crude diester of Example 3D was hydrogenated in a Parr apparatus 2 at 4.2 kp / cm for 3 hours in a mixture of 50 ml of methanol and 5 ml of water in the presence of 0.4 g of 10% Bd / C catalyst. The resulting reaction mixture was filtered and concentrated to a wet solid which was then recrystallized from methanol / water. The white light needles were filtered and dried in vacuo; yield 3.0 g, melting point 122-124 ° C. TLC showed substantially one spot, Rf 0.2, CHCl 3 / MeOH / HOAc 100: 1: 0.0.5.

F. H-L-1-pivaloyloxymethylcarbonyl-2-phenylethyl) -L-phenylalanine-g-alanine, pivaloyloxymethyl ester.

A mixture of 1.0 g (2.3 moles) of the product of Example 3E and 0.89 g (2.3 moles) of the product of Example 3B in 25 ml of dimethylformamide was treated with 1.01 ml (8 mole allyl-retyl-raorpholine followed by 352 mg (2.3 moles mole) of 1-hydroxyhento-triazole-jxydr.a.att and 439 mg (2.3 moles mole of 1 - (3-dimethylamino) The mixture was stirred at ambient temperature overnight, the starting material was still present by TLC, the reaction mixture was heated at 40-50 ° C for 6 hours and allowed to stand at room temperature overnight. was extracted several times with ether 784. 791. The ether phase was then washed well with water, dried and concentrated to an oil (1.2 g), the oil was chromatographed on thin layer chromatography on silica gel 6Q-G to give 0.9 g of an oil which formed one spot, 0.4, in an EtOAc / Hexane 1: 2 system (the same system was used for column chromatography). Calculated for C33H44N2O9: C, 64.69; H, 7.24; H, 4.57. Found: C, 64.47; H, 7.20; N, 4.29 [α] D 26 - 21.7 ° (DMF, 01.0).

Example 4 il- [n- [1- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-phenyl) phenylethyl] L-phenylalanyl-5-alanine.

A. N- [D, L-1-carboxy-2- (4-phenyl) phenylethyl] -L-phenylalanine, benzyl ester.

The stirred suspension of 4-phenylphenylpyruvic acid (24.0 g) and L-phenylalanine benzyl ester hydrochloride (23.2 g) in one liter of tetzahydrofuran / ethanol (9: 1) was adjusted to pH 6.6 by gradual addition. triethylamine. During the adjustment, all solids dissolved. The resulting solution was stirred for 2 hours at room temperature, after which a solution of sodium cyanoborohydride (3.5 g) in the same solvent was added dropwise with stirring. The reaction mixture was stirred overnight at room temperature.

The reaction mixture was then concentrated to 200 ml under reduced pressure. The residue was poured into 600 ml of 0.3N hydrochloric acid while cooling and stirring. This gave a gummy solid. The aqueous solid was separated by decantation and the resulting solid was mixed with 120 mL of ethanol. * The resulting solid was filtered off, and the wet solid was mixed with 1 mL of fresh ethanol. After standing overnight, the solid was filtered off and dried to give 22.3 g of solid product.

is 78917 E. R- [D, L- [1- (2,2-dimethyl-1 * -oxopropoxymethoxy-3 * -carbonyl] -2- (4-phenylphenylethyl) -L-phenylalanine, benzyl ester.

Triethylamine (3.05 ml) was added to a solution of N, N-D, L1-carboxy-2- (4-phenylphenylethyl) -L-phenylalanine, benzyl ester (9.6 g) in 30 ml of dimethylformamide, and the mixture was stirred at room temperature for 20 minutes. and then chloromethyl pivalate (3.15 ml) was added, the resulting mixture was heated for 4 hours at 45-55 ° C in a bath with stirring, and then stirred at room temperature overnight, the resulting mixture was diluted with 300 ml of water and extracted with 3 ml of water. 150 ml of ether, the combined ether layers were extracted twice with 100 ml of water and the ether solution was dried over anhydrous sodium sulfate, and filtration and evaporation in vacuo gave 7.5 g of a syrupy product.

This material was chromatographed on 135 g of silica gel eluting with a mixture of ethyl acetate and cyclohexane (85:15). Fractions containing the desired diastereomeric mixture of products were identified by thin layer chromatography, combined and evaporated to dryness in vacuo to give 5.9 g of a syrupy product.

C. K- [D, L- [1 - [(2,2-Dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanine.

A solution of the product obtained above (5.9 g) in 175 ml of ethanol was hydrogenated for two hours at 1.05 to 2.1 kp / cm at 750 mg of 10% Pd / C catalyst over two hours. The reaction mixture was diluted by adding 250 ml of ethanol and heated to 45 ° C to dissolve the precipitated product. The catalyst was filtered off from the warm solution and the filtrate was evaporated to give a total of 4.4 g of product D. N - ([N- [1- [1- (] (2- Dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanine-S-alanine, benzyl ester.

16,789 7 N-Ethylmorpholine (1.2 ml) was added to a stirred mixture of the product prepared above (3.25 g), X- (H, H-dimethylaminopropyl) -K'-ethylcarbodiimide hydrochloride (1 , 7 g), hydroxybenzotriazole (1.3 g) and 3-alanine benzyl ester p-toluenesulfonate (3.0 g) in 25 ml of dimethylformamide. The mixture was stirred at room temperature for 3 hours, diluted with 200 ml of ice water and extracted twice with 125 ml of ether. The combined extracts were washed with 250 ml of water and dried over anhydrous magnesium sulfate. Filtration and evaporation gave 5.25 g of residue. The main products of thin layer chromatography (silica gel CHCl 3 / EtOAc - 10: 1) were two, R f = 0.36 and R f = 0.32 (partially overlapping). This material was chromatographed on 350 g of silica gel (thin layer chromatography grade) eluting with CHCl 3 -EtOAc (100c 5). Fractions containing pure individual components were identified by thin layer chromatography, pooled and evaporated. In this way, 650 mg of the faster moving component (L, L-diasterioisomer) and 590 mg of the L, D-diasterioisomer were obtained.

The final product was obtained by hydrogenating a solution of 650 mg of the L, L-diasterioisomer obtained above in 50 ml of ethanol over a period of 3 hours at a pressure of 1.05 to 3.15 kp / cm at 50 mg of 10? Fd / C catalyst. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo at 30 ° C. The residue was chromatographed on 50 g of TLC silica gel, eluting first with 300 ml of CHCl 3 / EtOAc (10: 1) and then with CHCl 3 / CH 3 OH / AcOH (600: 10: 2). Fractions containing pure product were identified by thin layer chromatography (silica gel) CHCl 3 / CHCl 3 / CH 3 OH / AcOH (600: 10: 2), Rf = 0.31. These fractions were combined, evaporated and the residue dried at room temperature overnight under high vacuum. The residue was recrystallized from ether and the product was dried under high vacuum for 3.5 hours. 250 mg of solid product were obtained, m.p. 101-10 ° C, λ max] D 26-22 ° (c = 0.5, DMF).

17 7891 7

Example 5 N- [N- [1- [1- (2,2-dimethyl-1-oxopropoxy] methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine

A mixture of 0.9 a (2.1 moles) of H- (L1-carboxy-2-phenylethyl) -L-phenylalanine-pivaloyloxyethyl ether (Example 3E) and equal molar amounts β-Alanine benzyl ester p-toluenesulfonate (73 mg), 1-hydroxybenzotriazole hydrate (321 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (401 mg) were dissolved in 20 ml: dimethylformamide containing 0.8 ml (6.3 moles) of K-ethylmorpholyl. The mixture was stirred overnight at ambient temperature.

The yellow solution was poured into water (150 ml) and extracted three times with 100 ml of ether. The ether phase was washed with water, dried and concentrated to an oil, 1.1 g. In thin layer chromatography, the product formed. one spot and contained little impurity.

The whole product was chromatographed on 150 g of silica gel eluting with ethyl acetate / hexane (30:70). The fractions were combined and concentrated to an oil [α] D 26-20.0 ° (DMF, c = 1).

2

The product described above (1.5 g) was hydrogenated at 2.8 kp / cm for 3 hours in 100 ml of absolute ethanol using 0.2 g of 10% Pd / C as catalyst.

The catalyst was filtered off and the residue was concentrated to an oil which crystallized on drying overnight under high vacuum. On standing under hexane, fine colorless crystals were obtained, which were filtered and dried to give 1.2 g of product, m.p. 93-95 ° C, [α] D 26 - 27.3 ° (DMF, C = 1) -K

Following the methods of the previous description and examples and using suitable intermediates, the compounds 1 · * · 63 listed above can be prepared.

ie 7891 7

In the following table, the abbreviations and ^ 7 ^ 7 denote benzyl groups. means a phenyl group. Using the methods described above, the following compounds of the invention were prepared by way of example. Unless otherwise stated, all compounds have absolute L-stereochemistry at the center of chirality and are hydrogen.

i9 7891 7 ^ ^ ^ • h SR u- · lu u. x +) ^ S 2: g 0

Q Σ 0 O O O

g Σ • H LO O O O »O r— r—> -

CO - * -> - - OI t I

- - I I I

o 00 o 0 q · · · r- I — 1 LO r- ro 0

Ö CM CM CM CM CO

L_l I I I I I

0 0 r— lo

• III

Λ> 1 <- o · ο

lo (7 '7. -. «O-00CM, -H

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Example 6 A. H (L-1- (Phenylmethoxycarboxyl) -2H-phenylethyl) -L-phenylalanine, cyanomethyl ester,

To a solution of 4.03 g (10 mmol) of the product of Example 3C and 2.1 mL (15 mmol) of triethylamine and 150 mL of acetone were added dropwise 0.95 mL (15 mmol) of chloroacetonitrile at room temperature. The resulting solution was heated to reflux overnight. The solution was evaporated to dryness and extracted with water and ether. The fet teriphasic phase was washed several times with water, dried and evaporated to an oily residue. This gave 4.5 g of material which was used directly in the next step.

B. (L-1- (Phenylmethoxycarbonyl) -2-phenylethyl) -L-phenylalanine, 2,2-dimethyl-1,3-dioxolan-4-yl methyl ester.

The product of the step from Fd (4.4 g, 10 mmol) and 25 mL (20 mmol) of 2,2-dimethyl-1,3-dioxolan-4-yl methanol (Aldrich Chemical Co.) were combined and then triethylamine (1 , 4 mL, 10 mmol) and N, N-dimethyl-4-aminopyridine (20 mg).

The mixture thus obtained was stirred under a nitrogen atmosphere at 55-60 ° C for 16 hours. The reaction mixture was then poured into water and extracted several times with ether. The combined ether fractions were washed several times with water, dried and evaporated to give 5.7 g of an oily product. The product was chromatographed on 400 g of Merck silica gel 60G, eluting with ethyl acetate-hexane. The fractions which were found to be pure by thin layer chromatography were combined and evaporated to dryness to give 4.2 g of oil, [α] D = -6.2 ° (c 1.3, DMF).

C. N- (L-1- (2,2-dimethyl-1,3-dioxolan-4-yl methoxycarbonyl) -2R-phenylethyl) -L-phenylalanine.

The product from the previous step was dissolved in 50 mL of tetrahydrofuran and hydrogenated on a Parr apparatus using 0.4 g of 10% Palladium on carbon at room temperature and 60 psig for 4 hours.

22 7891 7

The catalyst was filtered off and the filtrate was evaporated in vacuo to give a waxy residue (3 g) which was recrystallized from ethyl acetate to give 2.6 g of crystals, m.p. 140-2 °.

D. N- (N- (L- (1- (2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -β-alanine, bent-syvliesteri.

Product from previous step (2.5 g, 5.8 mmol), 2.2 g (6.4 mmol) β-alanine benzyl ester p-toluenesulfonate, 887 mg (5.8 mmol) 1-hydroxybenzotriazole hydrate, 1.1 g (5 1.8 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 23 ml (18 mmol) of N-ethylmorpholine and 20 ml of dimethylformamide were stirred at room temperature overnight.

The yellow solution thus obtained was poured into water and extracted several times with ether. The combined ether fractions were washed repeatedly with water, dried over anhydrous potassium carbonate and concentrated to an oily product (3.3 g). The product obtained was chromatographed on 300 g of Merck silica gel 60, eluting with hexane-ethyl acetate (2: 1). The fractions which were found to be homogeneous by thin layer chromatography (silica gel • 254 'ethyl acetate-hexane (1: 1)) were combined and the solvent evaporated to give 2.7 g of an oily product which was used directly in the next step.

E. H- (N- (L- (1- (2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -β- alanine.

The product from the previous step (2.2 g) was dissolved in 50 ml of absolute ethanol and hydrogenated on a Barr apparatus using 0.2 g of 10% palladium / carbon at 50 ° C for 4 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to give an oily product. (1.9 g) which solidified. Recrystallization from ether at -eo yielded 1.8 g of a solid with a melting point of 80-2 °, λmax = -22.7 ° (c 1, DMF).

23 7891 7

TLC gave a single spot, Rf = 0.35 (chloroform-methanol-acetic acid 500: 25: 2.5).

F. N- (N- (L- (1- (2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -10-alanine, maleate (1: 1).

The product of the previous step (5.0 g) was dissolved in 200 ml of ether and treated with a solution of maleic acid (1.16 g) and 200 ml of ether. After standing overnight in the refrigerator, crystals slowly formed at 5-10 °. These were filtered and dried to give 4.7 g of salt, m.p. 127-9 ^ 6 = -16.3 ° (c 1, DMF). Calculated for C31H38N2O11: C; 60.58, H, 6.23, N; 4.55. Found C; 60.33, H; 6.31, N; 4.48.

The compounds of structural formula I inhibit the activity of enzymes called enkephalinases. These compounds can be particularly useful in inhibiting enkephalinase A, which is obtained from the striated muscles of both rats and humans. Certain compounds of structural formula I have been found in in vitro tests to inhibit the activity of the above enzyme by 50% or more in the concentration range of 10 "® - 10 ~ ®M.

The following experimental method was used to determine the enkephalinase A enzyme inhibitory activity of the compounds of structural formula I.

Enkephalin (ENK) degrading activity was separated into the following three fractions by the method of Gorenstein and Snyder, Life Sci., 2-5, 2065 (1979): Enkase A (Gly 2 -Phe 2), Aminopeptidase, (AP) (Tyr Gly2) and Enk'ase B (Gly2 -Gly3).

24 7891 7

Enzyme activity was separated by taking brain tissue (minus cerebellum) from Sprague-Dawley rats and homogenizing it with a Brinkmann Polytron in 30 volumes of 50 mM Tris buffer pH 7.4. The resulting homogenate is centrifuged for 15 minutes (50,000 xg). The pellet consisting of the membrane-bound enzyme material is washed by resuspending it in Tris buffer and centrifuging four times.

After washing, the membrane pellet is dissolved by incubating for 45 minutes at 37 ° C in the presence of 15 volumes (based on the original weight of brain tissue) of 50 mM Tris-1% Triton X-100 buffer, pH 7.4. Insoluble material is removed by centrifugation for 60 minutes (100,000 xg), after which the Triton-soluble supernatant is applied to a 1.5 x 30 cm DFAF Sephacel column already equilibrated with 50 mM Tris-0.1% Triton buffer, pH 7.4. The material is eluted from the column using a 1 liter linear HCl gradient from 0.0 to 0.4 M. The eluent is recovered in seven fractions, each of which is assayed for enkephalin degrading activity. Under these conditions, Enkase A activity is observed to elute between 120 and 200 ml, followed by elution with AP activity (260-400 ml) and finally Enkase B activity between 420 and 450 ml.

Enkephalin-degrading activity is monitored by radiometric assay. The substrate is 1 H-Met 2 -ENK (50.1 Ci / mmol, New Englands Nuclear diluted in 0.05 M Tris buffer, pH 7.4, so that the concentration of the finished reaction mixture is 40 nM. with enzyme and substrate is 250 μι Incubation is performed for 90 minutes at 37 ° C. The reaction is stopped by transferring the tubes to a boiling water bath for 15 minutes.

25 7891 7 The products to be determined are separated using thin-layer chromatography. A 4 μl aliquot of the reaction mixture is run on a Baker-flex Silica Gel 1B plate (20 x 20 cm) together with unlabeled standards (Met 2 - ENK, tyrosine, tyrosylglycine, tyrosyl-glycyl-glycine) and the components are co-chromatographed with isopropanol: ethyl acetate: 5% in an acetic acid-solvent system (2: 2: 1) capable of separating Met 2 -ENK from its decomposition products. The total driving time is about 17 hours. The TLC tanks are treated with nitrogen before starting the run. After the run, the markers are visualized with a nin-hydrogen spray. These spots are cut from the plate together with the remaining areas of the plate and the corresponding radioactivities are determined on a liquid scintillation counter. IC50 values are determined by linear regression.

This method gave the following concentrations of said compounds in nanomoles (nM) which inhibited enkephalinase A activity by 50% (IC50).

26 7891 7 '- - - - ,, .. “m I I ------ - I' 1 - (

TABLE A

Compound Enkephalinase A.

Inhibition IC ^ g n M

A N.A.1 B N. A.1 C N.A.1 0 N.A.1 E 230 F 580 G 6.4 H N.A.1 J 2.5 K 0.9 L N.A.1

^ No activity at a dose <i ° 5 nM

The following experimental method was used to determine the extent to which said compounds potentiated the analgesic effects of (DA1a-Met) -encephalinamide (DAEAM). The background to the use of this method is given in: Chipkin, R.E., Iorio, L.C., Barnett, A., Berger, J., and Billard, W., Regulatory Peptides * From Molecular Biology to Function, ed. E. Costa and M. Trabuccbi, Raven Press, New York, 1982, pp. 235-242.

27 7891 7 Used in CFI male mice (19-23 g), Charles River Breeding Labs, Mass., (N = 10 / dose or as a combination of doses). The tail jerk test is performed in the same manner as Dewey and Harris, Methods in Narcotic Research, eds., S. Phrenpreis and A. Neidle, pp. 101-109, Marcel Dekker, Inc., New York, 1975, using a harmful thermal wave stimulus. After determination of reference latency times (typically 2-3 seconds), mice are first injected (either or not) with either vehicle or drug and then at appropriate intervals intracereproventricularly (icv) with either vehicle (10 μΐ saline) or DABAM according to Haley and MacCormic,

Br., J. Iharmacol., 12, 12 (1957) As the tail twitch, latency times are re-determined to be 30 min. as this has previously been shown to be the peak of the analgesic effect of DAEAM. During the cut-off, 10 seconds are used.

This method gave the following EDr „50 values (dose at which half of the experimental animals experienced analgesia) for said compounds.

28 7891 7

TABLE B

DAEAM enhancing effect

Compound, ^. .

E [) (route of administration) 50 A 155 mg / kg (po) B 37 mg / kg (po) C 100 mg / kg (po) D 100 mg / kg (po) E 30-60 mg / kg (po) F 100 mg / k (se) 1 G SOyMS (icv) H 100 mg / k (po) K 50 (icv) 1 L 100 mg / k (po) ED100

It is noteworthy that compounds A, B, C, F and H are ester derivatives; compound H is an ester derivative of compound G and compound L is an amide derivative. Such derivatization has been found to confer oral activity to the parent compound f, which is poorly absorbed from the gastrointestinal tract. to the site of action of the central nervous system (see Table B).

Claims (8)

29 7891 7 A process for the preparation of therapeutically active substituted dipeptides of the formula I or R 4 C * H-NH-C * H-CONH (CH 2) -C * -COR 8 (I) COR 2 R 3 R 5 or pharmaceutically acceptable salts thereof, wherein : R 1 is phenyl-lower alkyl or diphenyl-lower alkyl, R 2 is hydroxy, -OCH 2 OCO-lower alkyl or a group -OCH 2 -CH-CH 2 wherein r 7 and R 7 are independently C 1 -C 6 alkyl or R 2 is -O-lower alkyl -O-phenyl, -O-CH2-CHOH-CH2-OH, phenyl-C1-C4-alkoxy or aminophenyl-C1-C8-alkoxy, R3 is 1-benzyl or phenylbenzyl, R4 is hydrogen, lower alkyl or hydroxy, R 5 is hydrogen, and R 6 is hydroxy, phenyl-C 1 -C 4 -alkoxy, -OCH 2 CO-lower alkyl, C 1 -C 6 -alkoxy or the group -CX: H 2 -CH-CH 2, V * r 7 r 8 wherein R 7 and R 8 independently of one another mean C 1 -C 6 alkyl, characterized in that the compound is prepared by one of the following methods, wherein R 1, 1 * 2, R 3, R 4, R 5 and R 8 have the same meanings as defined above. including protection of any reactive groups, a) reducing the compound of formula XX ON in a double bond R1-C = N-CH-CONH (CH2) -CR4R5COR6 - * I cor2 (XX) b) coupling an amino acid of formula VIII to an amino acid of formula V with f3 R1-C-NHCH-CO2H + H2N (CH2) -CR4R5COR5 -> I COR2 (VIII) (V) after which any protecting groups are removed and then, if necessary, its salt is formed. Process according to Claim 1, characterized in that the compound of the formula (I) is prepared by process variant b) of claim 1. Process according to Claim 1 or 2, characterized in that a compound of the formula I is prepared in which at least one of R 2 and R 6 is CH 3 CH 3 O 'OII -o-ch 2 -ch-ch 2 31 7891 7 or (2,2-dimethyl- 1-oxopropoxy) methoxy, and the other is selected from the groups defined above, and in the starting materials R 2 and R 8 represent groups defined according to this requirement. Process according to Claim 1 or 2, characterized in that a compound is prepared in which R 1 is paraphenylbenzyl, R 2 is hydroxy, CH 3 CH 3 O * O-O-ch 2 -ch-ch 2 or (2,2-dimethyl-1-oxopropoxy ) methoxy and in the starting material the groups R 1 and R 2 are defined according to this requirement. Process according to Claim 4, characterized in that a compound is prepared in which R 4 is methyl and R 5 is hydrogen and in the starting materials R 4 and R 5 have the corresponding meaning. Process according to Claim 3, characterized in that a compound is prepared in which R 1 and R 3 have the same meaning as in Claim 4, R 4 is hydrogen or methyl and in the starting materials R 1, R 3 and R 4 have the corresponding meanings. Process according to Claim 6, characterized in that R 4 is hydrogen. Process according to Claim 1, characterized in that the compound prepared is: N- [N- [L1- (2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl)] - 2-phenylethyl] -L-phenylalanyl θ-alanine, (2,2-dimethyl-1-oxopropoxy) methyl ester; 32 7 8 9 1 7 N- [N- [L-1- (phenylmethoxy) carbonyl 3-2-phenylethyl] -1-phenylalanyl] -β-alanine, (2,2-dimethyl-1-oxopropoxy) methyl ester; N- [N- [L-1-carboxy-2- (4-phenyl) phenylethyl] -L-phenylalanyl] - β-alanine; N- [N- [L-1-carboxy-2-phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine; N- [N- [L-1-carboxy-2-phenylethyl] -L-phenylalanyl] -L- (n-methyl) -A-alanine? N- [N- [L1-carboxy-2-phenylethyl] -L-phenylalanyl] - [3-alanine, 2-phenoxyethyl ester, N- [N- [L- [1 - [(2,2-dimethyl-1- oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine, N- [N- [L- [1 - [(2,3-dihydroxy) -1-propoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] - [5-alanine, N- [N- [L- [1- [2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2 -Phenylethyl] -L-phenylalanyl] -N-alanine, N- [N- (L- [1 - [(2,2-dimethyl-1-oxopropoxy] methoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L-phenylalanyl] -β-alanine, N- [N-CL-Cl-C (2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L- (4- phenyl) phenylalanyl] -N-alanine, 33 7891 7 N- [N- [L- [1 - [(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy] carboxylate] methyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine, N- [N- [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] 2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenylalanyl] -β-alanine, N- [N-1L- [1 - [(2, 2-dimethyl-1-oxopropoxy) methoxycarbonyl] -2-phenylethyl] -L-phenylalanyl] -D, L - # - methyl / 2-alanine, N- [N- [L- [1 - [(2 -phenoxy) ethoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, Lo (-methyl- / 3-alanine, N- [N- [L- [1 - [(2,2-dimethyl-1- oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L- (4-phenyl) phenylalanyl] -D, L - # - methyl- / 5-alanine, N- [N- [L- [1 - [(2 , 2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-phenyl) phenylethyl] -L- (4-phenyl) phenylalanyl] -D, 10- (methyl-N-alanine, N- [N - [L- [1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] - <X-methylalanine, N- [N- [L-tl- [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -D, La-methyl- / i-alanine benzyl ester, N- [N- [L- [ 1 - [(2,2-dimethyl-1-oxopropoxy) methoxy] carbonyl] -2- (4-methoxy) phenylethyl] -L-phenylalanyl / 5-alanine, wherein the starting compounds are selected to form the desired end product. 34 7891 7