SA90110168B1 - amino acid derivatives. - Google Patents

Abstract

COMPOUNDS OF THE GENERAL FORMULA@@(FORMULA 1)@@WHEREIN R REPRESENTS BENZYLOXYCARBONYL OR 2-QUINOLYLCARBONYL, AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS INHIBIT PROTEASES OF VIRAL ORIGIN AND CAN BE USED AS MEDICAMENTS FOR THE TREATMENT OR PROPHYLAXIS OF VIRAL INFECTIONS. THEY CAN BE MANUFACTURED ACCORDING TO GENERALLY KNOWN PROCEDURES.

Description

Y

Amino Acid Derivatives Full Description Background This invention relates to amino acid derivatives. The amino acid derivatives provided by this invention are compounds of the general formula: a 0 m hass 0 | 0! 0 12.

NH, NHC (CH) 5 ; and its salts in addition 2-quinolylcarbonyl or benzyloxycarbonyl R Jud where 0 pharmaceutical accepteable acids addition salts Compounds of formula 1 and its salts - in addition to pharmaceutically acceptable acids - are new protease compounds with valuable properties. In particular, they inhibit the proteolytic enzyme of viral origin and can be used in the prevention or treatment of viral infections and, in particular, infections caused by HIV (human immunodeficiency virus) and other viruses. The aforementioned retroid viruses and their aforementioned salts T The purposes of this invention are the compounds of the formula itself. And using them as therapeutic and practical active materials for the manufacture of the aforementioned compounds and intermediate compounds used in the aforementioned process; Medicines that contain the aforementioned deadly compounds and salts, and the use of compounds and salts to control or prevent disease, especially in the treatment or prevention of viral infections, and the use of the aforementioned compounds and their salts to manufacture drugs for treatment or prevention of viral infections. Pharmacologically acceptable salts - in addition to with acids - For compounds of formula 1 they are salts of eg inorganic acids formed with inorganic acids © or hydrobromic acid or hydrochloric acid ~~ Jw hydrohalic acids

+ xl phosphoric acid sl nitric acid | sulfuric acid or with organic acids ¢ for example citric acid 4 acetic acid or methanesulphonic acid J tartaric acid 4 fumaric acid 4 maleic acid p-toluene-sulphonic acid Jf etc. 0 GENERAL DESCRIPTION OF THE INVENTION According to the process provided by the present invention, the aforementioned compounds of Formula 1 and their pharmaceutically acceptable salts are made - in addition to an acid - by means of. 0) Complex reaction: 2-[(3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl- ; decahydro-(4aS,8aS)-isoquinoline-3( S)-carboxamide Ve « With the formula: (s] [8] and 8 ENTS) OH 7 [s) is] 0 NHC (CH 3 ) 3 with acid of general formula: i Less a C~=—=0H 111 0 NE, where WR is the prior meaning or a reactive derivative thereof; Ve or (b) a compound shorthand of the general form: es 9 © N 51 x [5] 3 3 11 i 5 p Q 5 51 0 0 NHC(CH,) 5 and

¢ where +1 has the aforementioned meaning co S3 and a similar separation of the desired 2-(R)-hydroxy isomer from the resulting mixture; or Jeli (—) compound 2-[(3(S)-[(L- asparaginyl) amino]-2(R)- hydroxy-4- phenylbutyl]-N- tert.butyl- decahydro-( 4aS,8aS)-isoquinoline-3(S)-carboxamide 0 « with the formula: ddr aE )5[ )#805 i L TT v | o=="TsTTs 0 NH, NHC (CH) 5 Melis with group 1 agent 2-quinolylcarbonyl sl benzyloxycarbonyl and (3) as desired conversion of the resulting compound of formula A to its pharmaceutically acceptable salt plus an acid. Detailed Description 01. A complex reaction can be carried out Formula IT with acid ITT according to embodiment embodiment 0 of the process and according to methods known by themselves in peptide chemistry then when using acid with formula IT it is preferable to complete Jeli) in the presence of a hydroxy condensing agent benzotriazole Jia and dicyclohexylcarbodiimide This reaction is usually carried out in an inert organic solvent Jie ether (such as tetrahydrofuran diethyl ether 0_etc) or dimethylformamide at a low temperature, preferably between about 50 degrees below zero And ** Celsius above zero, especially at zero Celsius. anhydrides etc. Ya When using a reactive derivative, the reaction usually takes place in an inert organic cule (dichloromethan Ji) halogenated aliphatic hydrocarbon Jie (& ( ether diethyl ether Ji) | or tetrahydrofuran &) and as necessary in the presence of Diisopropylethylamine (§N-ethylmorpholin Ji) organic base (3) in pH

Low temperature, preferably at about 501 degrees below zero to 20 degrees Celsius, especially at ial | Celsius. © The reduction of the compounds of formula 17 according to embodiment (b) of the process of the invention may be completed by methods known by itself to reduce the carbonyl group to a hydroxy group © and then the reduction may be completed”; For example, using alkali Jw complex metal hydride metal borohydride, especially sodium borohydride 4, as a suitable organic solvent; Jia propanol i ethanol s methanol Ji) alkanol or isopropanol etc.) and is usually reduced at room temperature. It is almost possible to complete the separation of the desired homolog 2(R)-hydroxy isomer } from the resulting mixture according to Lali processes such as adsorption chromatography 0 and the like. © According to embodiment (c) of the process of the invention, the appropriate agent that gives the benzyloxy carbonyl group is the appropriate Jd sell .benzylchloroformate which gives a 2-quinolylcarbonyl ic sens the corresponding acid (corresponding acid) or its reactive derivatives such as (acid chlorides Jw) corresponding to acid halides acid mixed anhydride anhydride 00 or esters 20072160_etc. A compound of formula 7 is reacted with the aforementioned agents in such a manner as the foregoing described according to embodiment (i) of the process of the invention. This compound is made in a conventional way using an inorganic acid; Ja hydrochloric acid Jw hydrohalic acid i.e. hydrobromic A or &I phosphoric acid sl nitric acid 4 sulfuric acid or using an organic acid such as fumaric maleic acid J citric acid 4 acetic acid tartaric acid J acid or J methane sulphonic acid p-toluenesulphonic acid etc. The compound of formula Yo [1] used as a starting material in embodiment (a) of the process of the invention is a new compound and also constitutes an object purposes of this invention.

: A compound of formula TT can be prepared, for example, by a compound reaction of the general formula: vi 1 Nx 51 X 8 H 0 an representing dc gana Rl is protective of the amino (tert.butoxycarbonyl Ji) or (benzyloxycarbonyl, X representing a chlorine atom or bromine, reacting with the compound N-tert.butyl- “decahydro-(4aS,8aS)isoquinoline-3(S)-carboxamide 0 has the formula: Z NG) [STs] vii ) Den NHC (CH) 4 z and reducing the resulting compound with the general formula: / \ 1 R Ne) GE] | VIII : 0 . Omer” [5[ > ]5] NHC (CH, ) 3 y cua | Rl represents the prefix co S3 and the desired separation of the 2(R)-hydroxy cognate from the mixture 0 i output; And separate the RT group from the resulting compound with the general formula: Ra 1 [R] 6 51 Ix H i" ome” Iss] NHC (CH 3 ) 3 where RI has the previous meaning to give a compound It is possible to complete the reaction of a compound of formula VI, preferably a compound where Rl represents cbenzyloxycarbonyl with a compound of formula VII in a known manner in an organic solvent (Jala v) and in (& dichloromethane J) halogenated aliphatic hydrocarbon >. etc.) and usually at room temperature. triethylamine such as trialkylamine the presence of a base (eg, hence the chapter TX) A compound of formula [1711] can be reduced to give a compound of formula ide with respect to embodiment (b) of SU Desired as previously 2(R)-hydroxy similar to the desired 2(R)-hydroxy hepasim and chapter IV of the invention; i.e. the reduction of the compound of formula 0 of the resulting mixture.

Mie in a known manner IX from a compound with the formula RD also split a group (Sa) or a strong organic acid (such as hydrohalic acid Jie) using a strong inorganic acid: at a temperature of zero Celsius to a temperature of sale ( &) trifloroacetic acid _chamber acid. Sls is present in an organic solvent or solvent mixture (palladium-on-carbon eg Je catalyst or J isopropanol or ethanol Ji alkanol is inert under reaction conditions (eg etc.) and usually in Room temperature ethylacetate Ju alkane carboxylic acid ester approximately 0. First of all, the reaction of a compound of the formula IT includes an additional method for preparing a compound of the general formula: b x ye above, usually in the same solvent VII The previous groups with a compound of the formula RI where it represents vo or dimethylformamide J etc.) methanol (such as an inert organic alkanol such as C and 1710 C approximately and then split “01” more like at elevated temperatures ; Usually between the aforementioned) as before. TX in the reaction product (compound of formula 8! de sana used as starting materials in embodiment (b) TV The compounds of formula can be prepared

R1 amino-protecting group The process of the invention, for example, by separating the protective group of the amine (0 Yo

A

interacting with it. Fide enables a compound of formula 17111 to be reacted with an acid of formula ¥ or to complete this reaction in a manner similar to that previously described for embodiment () of the process of the invention. c) From the process, a new compound, such as V, is prepared for the compound of formula (Kay) from the purposes of this invention. AT and constitutes a purpose 0

R from a compound of formula 1, where benzyloxycarbonyl (R) represents the example by separating the tert.butoxycarbonyl de sess group or by separating the benzyloxycarbonyl group, and the last compound can be prepared as tert.butoxycarbonyl (R) corresponding to formula 1 But it is represented according to N-(tert. butoxycarbonyl)-L-asparagine with II by a compound reaction of the formula Ja d the aforementioned when speaking Ba of the embodiment (a) of the invention process. The aforementioned division is done in the manner of 0 0

The starting materials of formula VII [11] and their reactant derivatives, as well as the aforementioned compounds of formula RI, can be prepared as long as they are not known compounds or similar to known compounds VII «VI in a manner similar to known compounds or as Described in the following examples or in a similar manner. Moreover, the agents used in embodiment (c) of the process of the invention are generally ve known compounds. As aforementioned, the compounds of formula 1 and its salts, together with acceptable pharmacological acids, inhibit proteolytic enzymes of viral origin and are useful in Treatment or prevention of 0 1117 viral infections, especially infections caused by HIV

Aga) Clay a lags To

HIV The process of inhibition of the proteolytic enzyme of viral origin can be demonstrated in the laboratory by the compounds of this invention through the following test: For the proteolytic enzyme of gene expression, the gene expression was carried out from the bacterial extracts by fraction Wis and pure 15. Coli in any coli HIV virus. The activity of the enzyme (ZY = sia) ammonium sulphate was compromised using ammonium sulfate ve succinyl-Ser-Leu-Asn-Tyr-Pro - protein analysis using the protected hexameric peptide succinyl-Val-Ser-Gln-Asn- or the seven-protected peptide Ile isobutylamide (S 1) csubstrate was identified as the tested substance Phe-Pro-Ile- isobutylamide 82

The tested substance quantitatively (uly) production of isobutylamide -11-010-116 with a proline N hall titration spectrophotometric assay. 09 mmol of the tested substance was dissolved in VYO mmol of a buffered lemon solution pH) citrate buffer 0.0) containing *1.10mg/mL of Tween 01©20; add 10µL of a solution of various concentrations of test compound (dissolved in dimethyl sulphoxide si methanol and diluted with water It contains 70.1 tween (Yr) and 10 microliters of protein analysis enzyme, Ard microliters of the tested material and the aforementioned pH regulation. Mixed at Agha OF for a specified period of time and finished by adding 1 ml of a color reagent, Yr) μg/mL of gisatin 0.5 mg/mL of 2-(4-chlorobenzoyl) benzoic acid in 701 acetone in ethanol (vol/v); the solution was heated in a water bath and returned Dissolve pigmented residues in Ja) of pyrogallol 71 in 7277 water in acetone (w/v/v); the optical density of the solution was measured spectrophotometrically at 094 nanometers (nm) compared to H- Pro-lIle isobutylamide in the presence of 0 test compound with controls and determine the concentration of the required test compound to give an inhibition percentage I 790 by using a plotted graph of the different concentrations of the test compound used. The activity of Formula 1 compounds against viruses in test tubes in vitro can be demonstrated in the following titration: Efficacy against HIV: v. This titration uses [1111-17-11 (strain RF) grown in C8166 Wa (a human 0047 T lymphoblastoid line) using 1640 'gs RPM1 medium, bicarbonate buffer, antibiotics, and 0079 foetal bovine serum. of the virus and the adsorption was allowed to continue for 90 minutes at 51 C. The cells were washed three times with medium. The test was done in tissue culture tubes of capacity dal and each tube contains 017 infected cells in (da). From the medium The test compounds were dissolved either in an aqueous medium or in dimethyl sulphoxide according to the solubility and a solution of 101 microliters of the substance was added.

ve: an hour in the middle of a humid atmosphere with 70 VY gas and 00 VY C for a period of FY, and the cultures were incubated with aliquot sds floating in air, then the cultures were centrifuged and subjected to titration to capture the Nonidet antigen. p40 using the viral supernatant and the YE system using a primary antibody that has specific reactivity against the all protein; antigen Spectral measurement color generation Measurement of color generation. horseradish peroxidase discovery 0

LA 750 was photographed and drawn against the concentration of the test compound, and the concentration that gives the dye was determined on the basis of taking the dye cytotoxicity assay. A radio- or cellular toxicity assay was performed, or the inclusion of the radiolabeled amino acid metabolism and uptake. Along with the above titration to determine the selectivity of Lis labeled amino acid incorporation (efficacy against the virus. 0 The following table shows the results of previous tests using Formula 1 compounds as a test compound. Table [Z compound] micromol) (nmol) HIV protease Z. 0 Use of Formula 1 compounds and their salts prepared in addition with Sa acids (Sa) as medicines (eg in the form of pharmaceutical preparations). Acceptable Waa ve preparations may be administered orally (in the form of tablets, coated tablets or OMe in the pharmacy) Intestinal route; tablets, solid or soft gel capsules, solutions, lozenges, or suspensions) or intranasally (eg in the form of a nasal spray) or rectally (in the form of suppositories) however parenteral administration is possible For example, intramuscularly or intravenously (eg in the form of solutions for injection). ad Y. For the manufacture of tablets, coated tablets, pills, or hard gel capsules; compounds of Formula 1 and their pharmaceutically acceptable salts may be synthesized together with acids with inert organic or inorganic excipients Pharmacologically acceptable, lactose or cornstarch can be used

11 As excipients for tablets or Sle or its salts etc. stearic acid or tale its derivatives or: pills or hard gel capsules. Suitable excipients for soft gel capsules are for example semi-solid and liquid vegetable oils etc. Polyols, fats, polyalcohols, waxes, waxes, for example water, syrups, suitable excipients for solutions, syrup °, glucose, etc., invert sugar, invert sugar, saccharose, polyalcohols, and sucrose © Suitable excipients for solutions Injections are, for example, water, alcohols, polyurethane, vegetable oils, etc. Suitable excipients for suppositories are alcohol and glycerol: liquid or polyols, for example natural or thickening oils, waxes, fats, semi-liquid polyalcohols, etc. Preserving In addition, pharmaceutical preparations may contain preservatives. or stabilizing agents or viscosity-increasing agents or solubilizers or solvents 5

Lai or emulsifying agents or wetting agents Adan flavoring agents or salts or coloring agents or sweetening agents or buffers or osmotic pressure regulating solutions ‎ . 1 The antioxidants or coating agents of pharmaceutical preparations may also contain substances of other therapeutic value. According to the invention, the compounds of Formula 1 and their salts may be used in combination with the acids, Pharmaceutically acceptable Tacorifla 0 in the treatment or Prevention of viral infections, especially recurrent infections The dosage can vary in a wide range and will of course agree with individual requirements in a given daily dose of about all is sufficient. Generally in the case of administration by Ua approximately each (eg about 10*mg per person) aa) “mg to g and preferably about 10mg to g can be for example in the same dose units (Dy) 9-1 Divided at best into quantity; however, it is clear that the above-mentioned upper limit can be exceeded when necessary. The following examples are to illustrate the invention by way of example, but not limited to. [3(S)-amino-2(R)- hydroxy-4- chilled solution of 1+#2mg of phenylbutyl]-N- tert.butyl- decahydro-(4aS, 8aS)- isoquinoline-3(S)- In + “ml N-(benzyloxycarbonyl)-L-asparagine of aaa¥VY and carboxamide salt. Added 8901 mg [mB] in tetrahydrofuran lad mixture of 0 mg”17 and N -ethylmorpholine from asad), hydroxybenzotriazole, then the mixture was diluted with asad 116 sad and the mixture was stirred with dicyclohexylcarbodiimide sodium bicarbonate filtrated using Jue's solution and filtered. ethyl acetate using chromatographed and the solvent was removed by evaporation and sodium adsorbed aqueous chloride AA and solution 74 to strip off the (4:1) dichloro methane/methanol residue on a silica gel using 0 2-[3-(S)-[[N- (benzyloxycarbonyl)-L- asparaginyl] amino] - mg of 2(R)- hydroxy-4-phenyl butyl]-N- tert. butyl- decahydro-(4aS,8aS)-methanol/ diethyl as white solid of isoquinoline-3(S)-carboxamide «MS: m/e 650 [M+H] tether

NMR: (ds CH30H, 400 MHz ): vo 7.33 (5H, m, PhCH,0 ) , 7.25 (2H, m) , 7.18 (2H, m) , 7.09 (1H, m ), 5.05 (2H, s, PhCH,0) , 4.42 (1H, dd, Asn a. J = 7.8, 6.1 ) , 422 (1H, m, -CH,CHCH(OH) - J = 10.7, about 4, about 4 ) , 3.85 ( 1H, m, - .CHCH(OH)CH, - 1 = 8.0, 6.2, about 4 ) , 3.02 (1H, dd, PhCH(H)CHJ = -13.9, about 4 , for 3.02 (1H, dd, le J = -12.0, small ) , 2.69 (1H, dd, 0

PhCH(H) CH- J = -13.9, 10.7), 2.63 (1H, dd, -CH(OH) CH(H) N- J = -12.6, 8.0) , 2.62 (1H, dd, 113. J = about 11, small ) , 2.57 (1H, dd, Asn

B;J=-152,6.1),238(1H,dd, Asn B,J=-15.2,7.8),2.19 (1H, dd, -

CH(OH)CH(H) N- J = -12.6, 6.2 ) , 2.17 (1H, dd, 1 J = -12.0, 3.2), 2.07 (1H, m, H4,, J = -12.7, about 11, about 11.5 ), 1.78 (1H, m, H4a 0

Jsadax = about 11.5, Lomdopa - small , Jyo8,= small ), 1.63 ( 1H, m, 1188 yul, tax = 3.2, Jgarteq = small, Jyool small ( , 1.35 (1H, m, H4, q J = -12.7, small , small ( , 1.30 (9H, s, t-butyl ) , 2.0-1.2 (8H, m ) .q.

VY : 2-[3(S)-[(L-amino]-2(R)-) The starting material hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS) was prepared as follows. )-isoquinoline- 3(S)-carboxamide of carbon on rhodium 76 above 040 gradients at 580 °C under atmospheric pressure (V): 1,2,3 4-tetrahydro- acid ( dso suspension of 71,1776 g (1,1 ml delat oo) in (Chem. Pharm. Bull. 1983, 31,312) 3 (S)-isoquinolinecarboxylic acid. The mixture was left to cool to room temperature and then filtered. 9180 01 ml of ethyl acetate was dissolved in gum and the filtrate was evaporated to give a vigorously stirred catalyst lial.This resulted in a precipitate of diisopropyl ether which was added slowly to 100 ml of ethyl and the precipitate was extracted using resin decantation. The supernatants were removed by 0 Jalon decantation. The hot solution was poured over a vigorously stirred mixture of pals acetate to give by filtration a solid of (0:1) diethyl ether / diisopropyl ether and dried. diethyl ether b Glues Cal gal) mainly from (approximately 710) 58 decahydroisoquinoline-3(S)-carboxylic acids (Z¥e (approximately 4aR (8aR) isomer together with cognate 42S 885; isomer _ similar to 0

MS: m/e 184 [M+H]T ¢trans isomers corresponding isomers 701 and about a mixture of oe acids (mmol) ia Gb £3.3) solvent, g (Y) mM or) Jeon aforementioned in decahydroisoquinoline-3(S)-carboxylic 0 0 and the resulting solution was cooled to zero (IM) 1 molar (NaOH) of a benzyl solution of benzyl chloroformate (se) was added dropwise 4./ml (1.87*mL ge © 1 concentration NaOH wala/# dmL (7:/*mM_g) of chloroformat solution in a period of one hour with heat preservation by refrigeration between 0 to 20 C. Then (IM) molar the mixture was stirred for two additional hours. During this time the mixture was left to warm to a temperature and the mixture was filtered as the iso-1808 non-diethyl ether was removed from the room. 100 ml of By adding dissolved 1-7* acid. The aqueous layer of the filtrate was separated and the pH was adjusted ve ethyl twice using 100 ml of guid as an oil precipitate. Extract Xe HCI sodium each time. The organic extracts were washed together with water and dried above ethyl acetate ml of Yo anhydrous and evaporated to give oil.dissolve that oil in © q.

V¢ the precipitate gaa .cyclohexylamine (molecule) of Gl YO) Ja¥,A0 was added, and fractional from the fractional recrystallization Cie white by filtration to give after a number of “methanol / ethyl acetate from 385 2 -(benzyloxycarbonyl)- cyclohexylamine acid g of salt

MS: m/e 318 ¢decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid 0

JMET

2-(benzyloxycarbonyl)- cyclohexylamine acid from p2¥,¥VE salt p2¥,¥VE (Y) ethyl partition between +© mL decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid The organic layer was separated and washed with water 7201 citric acid from a solution of Jeo + 5 acetate 1 2-(benzyloxycarbonyl)-decahydro- from acid aa), AY, filtered and evaporated to give 0

MS: m/e in transparent gum form; (4aS,8aS)-isoquinoline-3(S)-carboxylic acid 318 [M+H]* gram) of Bi de Y acid) 174,.;g Meat ae (§) 2-(benzyloxycarbonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)- gram)sia JLY) p20, YY with diethoxyethane from Jal in carboxylic acid re (mol) of JY) and 0417 g N-hydroxy sccinimide of h. VA. Stir the mixture at room temperature for 1 hour. dicyclohexylcarbodiimide of N-hydroxy sccinimide ester of ant, AY? The mixture was filtered and the filtrate was evaporated to give 0 mol (GY) pan ATA the aforementioned acid in the form of a pale yellow oil. A solution of in © ml of SA Gills N-hydroxy sccinimide ester (g) of 0” was stirred, cooled to 0°C, and treated with 7191 g (*mM dichloromethane µmol) of ©1.601010(7127(10:10): © The mixture was stirred at zero degrees Celsius for two hours, its concentration ? HCL, then at room temperature for £.0 an hour, then the mixture was washed using anhydrous acid and evaporated. of aan IY and filtered. The filtrate was evaporated to give the remaining diethyl ether in 10ml_ of ve 2-(benzyloxycarbonyl)-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-

MS: m/e 373 [MHH]*.as a white solid; 3(S)-carboxamide q.l.

yo) mole (0,85) aA Ga solution zm (0) 2-(benzyloxycarbonyl)-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline- palladium 701 of ane) In the presence of ethanol L01 in 3(S)-carboxamide at room temperature and atmospheric pressure for 81 hours. The catalyst was removed by carbon filtration over N-tert.butyl-decahydro- quantitative ZU at a rate of (chad) and the solvent was removed by evaporation 0

MS: m/e 239 as pure oil; (4a8,8aS )-isoquinoline-3(S)-carboxamide - which was used in the next step without further purification. ([MHH]T

N-tertbutyl-h solution of 460 mg of sad; inverted at 10°C (1) 3(S)- and 9mg of decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide ethanol in mL (benzyloxy-formamido)-1,2(S)-epoxy-4-phenylbutane 00 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4- added another 54 mg of The solvent was removed by evaporation at 11 sad C oY and the solution was stirred at phenylbutane diethyl on a wire gel using chromatography and the residue was separated by chromatography 2-[3 (S)- mg of YY) «at-d/atta(7/,5:47,5;:) _to extract methanol (benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl-N-tert.butyl- 00 as a decahydro-colored solid -(4aS,8aS)-isoquinoline-3(S)-carboxamide white; MS: m/e 536 [M+H]" © 2-[3(S)-benzyloxyformamido)-2(R)- Hydrogenate a solution of 7;amg of (71 hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline- 0 carbon on palladium 701 over ethanol from Jef: in 3(S)-carboxamide C under atmospheric pressure for ½ hours The catalyst was removed by filtration and oY evaporation at 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]- N-5011 mg to be given as solid tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Smoke color Use in the next step without purification. Ex: 2-[3(S)-[(L-asparaginyl)-amino]-2(R)- cold solution of 1594 mg of hydroxy-4 -phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-

. .in + mL of quinaldic and mg of 3(S)-carboxamide acid 41 hr Tf dry in ice/salt mixture. Add and stir for a mixture of tetrahydrofuran and 46 mg of N-ethylmorpholine Yo 5 mg of hydroxybenzotriazole mg of

Jue and filtered. ethyl acetate Dilute the mixture with dicyclohexylcarbodiimide 0. The residue by Glad then evaporate aqueous NaCl and filtrate NaHCO3 with a solution of 0 to remove 00 mg of (1:8) CH30H /0112012 Chromatography on silica gel using

N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolyl-carbonyl)-L-asparaginylJamino]-butyl}(4aS,8aS )-isoquinoline-3(S)-

MS: m/e 671 [MAH] as a white solid;

NMR : 6 (d4 CH;OH, 400 MHz ) : 8.52 (1H, m ), 8.18 (1H, m ) ,8.14 0 (1H, m), 802 (1H,m),7.84 (IH, m), 7.69 (1H,m), 7.18 2H, m), 6.90 2H, m), 6.72 (1H, m), 4.93 (1H, dd, Asna CHJ = 6.6, 6.8 ( 4.27 ( 1H, m, -CH2CHCH(OH) - J = 3.8, 3.8, 11.0 ) , 3.89 (1H, m, -

CHCH(OH)CH,;-J=7.2,6.4,3.8),3.06 (1H, dd, Hleq J =-12.0,3.0) , 3.02 ( 1H, dd, PhCH(H) CH- J = -14.0,3.8 ) ,2.77 (1H, dd, Asn B; J = d -15.6, 6.6 ) , 2.68 (1H, dd, Asn B, J = -15.6, 6.8 ) , 2.68 ( 1H, dd,

PhCH(H)CH- J = -14.0, 11.0 ) , about 2.68 (1H, dd, -CH(OH)CH(H) N-

J = -12.0,72), 2.63 (1H, dd, H3,, J = 11.0, 2.2 ) , 2.22 (1H,dd, - ~~ CH(OH)CH(H)N- J = -12.0, 6.4) , 2.18 (1H, dd, Hl, J=-12.0,22), 2.06 (1H, m, H4,, J=-11.0,11.0,11.0), 1.78 (1H, m, 4a Jsauax= 11.0, 0

Jiaaeq = about 4, J4og,= about 4) , 1.65 (1H, m, 8a snool = 2.2 Jgar1eq = 3.0 Jga4a= about 4), 1.37 (1H, m, H4,, J = -11.0, 2.2, about 4 ) , 1.30 (9H, s, t-butyl ( , 2.0-1.2 (8H, m ) ). 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4- The compound phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)- Yo used as a starting material was prepared as follows: 0056

Ve mg 01 h over 18 pH at room temperature and atmospheric pressure for 2-[3(S)-[[N-(benzyloxy-ame}i¢) palladium-on-charcoal solution

l carbonyl)-L-asparaginyl[Jamino]-2(R)-hydroxy-4-phenyl- butyl]-N- tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in ethanol ALLY. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to give 1 mg of 2-[3(S)- [(L-asparaginyl)amino]-2(R)-hydroxy-4- phenylbutyl] -N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)- 0 carboxamide was used in the next step without purification. eg ¥ cooled to *00-C solution of a2aYAY of N-(2-quinolylcarbonyl)-L-asparagine , and 00 mg of 2-[3(S)-amino-2(R) )-hydroxy-4-phenylbutyl]-N- tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide 0 [prepared as in Ex.](71-1)-1 In ?mL of tetrahydrofuran, 167 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 1077 mg of CB .dicyclohexylcarbodiimide were added to the mixture at *001- reconstituted for 2 hours and at + oY lysate for 11 hours. Then diluted with ethyl actate and filtered. Jue filtrate with 1 saturated NaHCO3 solution and 1101 saturated solution and then evaporated. The residue was separated using chromatography on silica gel using 74 (vol) ) methanol on 0112012 to remove 5717 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2- quinolylcarbonyl) )-L-asparaginyl[amino]-butyl]-(4aS,8aS)-isoquinoline- 3(S)-carboxamide which is exactly the same as the product in the first paragraph in Example 7. Ye attended N-(2-quinolylcarbonyl) -L-asparagine used as a starting material is as follows: inverted at *010°C for 976 hours. A mixture of 5460 mg of quinaldic acid succinamde ester and 10 mg of monohydrate pg0p1-2808 in Y. mL .dimethylformamide solvent was removed by evaporation to give a white solid residue; stirred vigorously in 0 mL of 112012 filtered and washed with CHCl then 17 mg of N-(2-quinolylcarbonyl)-L- was obtained. asparagine ve as white crucifixion; 7 [11+11] 288 MS: m/e The following example illustrates the manufacture of a pharmaceutical preparation containing a compound of formula 1 or its salt plus a pharmaceutically acceptable acid as the active substance:

Ya

Pod filtered with sterilization an aqueous solution of the active substance and mixed with heating with a hot sterile gelatin solution containing phenol as a preserving agent; Using quantities such that each 1 milliliter of the resulting solution contains *mg of active substance, 5681 mg of gelatin, £,Y© 5 mg of phenol and the remainder to 1 milliliter of distilled water. Fill the mixture in 1 ml bottles under sterile conditions.

Claims (1)

Claimants 1-1 are amino acid derivatives having the general formula z 1 8 ! 0 0 d h NH, NHC (CH) 5 . R Cua r represents quinolylcarbonyl sl benzyloxycarbonyl -2© and pharmaceutically acceptable ¢ salts thereof. 7?- N-tert.Butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2- quinolylcarbonyl)-L-aspraginyl]amino]butyl ]-(4aS,8aS)- Y isoquinoline-3(S)-carboxamide Y . 2-[3(S)-Amino-2(R)-hydroxy-4-phenylbutyl[N-tert.-Butyl--¥ 1 .decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide Y [3(S)-[(L.-Asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N --¢ -2 tert. Butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide Y 1 *#- amino acid derivative of claim 1 or ? For use as a therapeutically effective substance. 1 “- An amino acid derivative according to claims 1 or Y for use in the treatment or prevention of viral infection Adee virus infection Y. 7 - 1 To manufacture an amino acid derivative according to claims 1 or ? These include: (3(S)- amino-2 (R)- hydroxy- 4-phenylbutyl] -N-tert.Jelly (0 [-2 butyl-decahydro-(4aS,8aS)-isoquinoline-3(S) )-carboxamide .v 4 Formula: 0 7 y (R] ]5( ] In : [75r oH {s] {s] 0 NHC (CH, ) 3 o 1 with aes has the general formula : .that a C=—=0H , 111 NH 2 v .A where the aforementioned ANA IR or a reactive derivative thereof, or 4(b) is a compound reduction having the general formula: 0 wv 51 8 A [5] B : 8 0 N 09 0 NH, NHC (CH, ) 3 0 R Cua 11 has the aforementioned significance and the desired 2-(R)-hydroxy cognate separation "7" of the resulting mixture; or a Vy (c) 2-[3(S)-[(L-asparaginyl) amino]-2(R)- hydroxy-4- phenyl butyl]-N- tert reaction. butyl-decahydro- (4aS,8aS)-isoquinoline-3(S)- Ve carboxamide Vo with the formula: q l 1 0 ae 1 - )5[ 7 206 : o © siN~Ts NH, NHC (CH) 3 4 VY with an agent producing benzyloxycarbonyl or “2-quionlylcarbonyl ic seas YA and 08(d) as desired; Conversion of the resulting compound of formula T into an acidic salt of acceptable 79 pharmacologists. 1 +- a drug containing an amino acid derivative of claim 1 or 1 and an inert excipient .therapeutically inert excipient Ladle Y 1 4- A drug for the treatment or prevention of viral infections that contains an amino acid derivative according to 0 . of protection 1 or ? A therapeutically inert excipient. º-01 1 Using Gide is an amino acid according to claims 1 or 1 to manufacture a drug for the treatment or prevention of viral infection. q