The invention relates to 4-amino-3-hydroxycarboxylic acid derivatives. It concerns the compounds of formula I

R ₂ X ₃

I 3 I R _l A - NH - CH - CH - CH - CO - BR 4 1 2 1

OH

wherein

A and B independently are a bond or an optionally substituted aminoacyl moiety; Ri is hydrogen; an amino protecting group; or a group of formula R«Y- wherein

Re is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and Y is -CO-; -NHC0-; -NHCS-; -S0 ₂ -; -0-C0-; or -0-CS-;

R ₂ is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl,

2-thienylmethyl or styrylmethyl; R ₃ is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group; R ₄ is a group of formula -OR7 or -NHR7 wherein

R ₇ has the significance indicated above for R$; and X is -S- or -NR ₅ - wherein

R5 is hydrogen, methyl, formyl or acetyl; in free form and, where such forms exist, in salt form, hereinafter briefly named "a compound of the invention".

To date, there is a definite need for finding compounds which effectively inhibit retroviruses in a human infected by such a virus, and thus treat or prevent diseases caused thereby, such as acquired immunodeficiency syndrome (AIDS) .

One approach for effecting retroviral inhibition is the use of an inhibitor of a viral proteinase essential for processing viral polypeptide precursors by proteol tic maturation, e.g. the HIV proteinase.

The compounds of the present invention are antivirally active. They inhibit the HIV proteinase.

Ri preferably is 2-pyridylmethoxycarbonyl, benzyl-CH(OH)-carbonyl, phenoxy ethylcarbonyl or an amino protecting group such as tert-butorycarbonyl or benzyloxycarbonyl; it especially is benzylo ^* sycarbonyl.

A preferably is an optionally substituted aminoacyl moiety, preferably an optionally substituted α-aminoacyl moiety such as alanine, leucine, isoleucine, asparagine, valine, tert-butylglycine, tert-leucine or histidine. It preferably is the optionally protected moiety of a natural α-amino acid, preferably of an amino acid which is a normal constitutive part of proteins. It especially is L-valine.

R ₂ preferably is the side chain of a natural amino acid, preferably of an o-amino acid, preferably of an amino acid which is a normal constitutive part of proteins. It is e.g. isopropyl, aminocarbonylmethyl, methyl, 1-methylpropyl, benzyl, 4-hydroxybenzyl or isobutyl, preferably benzyl.

B preferably is an optionally substituted aminoacyl moiety, preferably an optionally substituted α-aminoacyl moiety, such as phenylalanine, valine, leucine, isoleucine, alanine or asparagine. It preferably is the optionally substituted moiety of a natural o-amino acid, preferably of an amino acid which is a normal constitutive part of proteins. It especially is L-valine.

R4 preferably is a group -NHR7; it preferably is isopropylamino, tert-butylamino, 1- or 2-naphthylmethylamino, or 2-, 3- or 4-pyridylmethyl- a ino; it especially is benzyla ino or benzimidazolylmethylamino, particularly benzimidazol-2-ylmethylamino.

R ₃ preferably is an optionally substituted arylalkyl group, especially benzyl. The aryl part of arylalkyl optionally is substituted by, preferably, alkoxy or 1 to 4 carbon atoms, such as methoxy, or halogen of atomic number of from 9 to 35, such as bromine; it preferably is monosubstituted, preferably in 3 or 4 position; it especially is monosubstituted in 3 or 4 position by methoxy.

X preferably is a group - R5- as defined above. It especially is the imino group.

R« preferably is an optionally substituted alkyl, arylalkyl or heteroarylalkyl group, especially alkyl; when it is optionally substituted heteroarylalkyl it preferably is pyridylalkyl, especially 2-pyridylmethyl; when it is optionally substituted arylalkyl it preferably is benzyl-CH(OH)-; when it is substituted alkyl it preferably is phenoxymethyl.

Y preferably is -CO- or -O-CO-, especially -CO-.

R7 preferably is an optionally substituted alkyl, arylalkyl or heteroarylalkyl group, preferably phenylalkyl of altogether 7 to 10 carbon atoms such as benzyl, or a pyridylalkyl, indolylalkyl or benzimidazolylalkyl group of 1 to 4 carbon in the alkylene part; it

preferably is benzyl, 2-, 3- or 4-pyridylmethyl or benzimidazolylmethyl, especially benzyl or benzimidazolylmethyl, particularly benzimidazol-2-ylmethyl.

Rs preferably is hydrogen or methyl, especially hydrogen.

A salt is e.g. an acid addition salt such as a hydrochloride.

The compounds of formula I normally have several chiral centers and can therefore exist in a variety of stereoisomers. The invention provides all stereoisomers as well as racemic mixtures. The isomers may b resolved or separated by conventional techniques, e.g. chromatographically.

The carbon atom in 4 position preferably has the S configuration.

An optionally substituted aminoacyl moiety preferably is unsubstituted. When it is substituted it e.g. is substituted by alkyl of 1 to 4 carbon atoms, such as in 0-tert-butyl-L-serinoyl or in 2-aminobutanoyl. It preferably is in the L optically active form. It preferably is an α-aminoacyl moiety, such as valine or tert-leucine.

Optionally substituted alkyl preferably is alkyl of 1 to 5 carbon atoms, preferably of 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or tert-butyl; it is especially of 1 or 4 carbon atoms. The substituent is e.g. phenoxy, hydroxy or optionally protected amino.

Optionally substituted arylalkyl is e.g. phenylalkyl of altogether 7 to 10 carbon atoms, such as benzyl or 2-phenylethyl; it is optionally substituted by e.g. hydroxy, such as in benzyl-CH(OH)- or phenyl-CH(CH ₂ 0H)-, or is e.g. naphthylalkyl of 1 to 4 carbon atoms in the alkylene part.

An amino protecting group preferably is benzyloxycarbonyl or tert-butoxycarbonyl.

Optionally substituted heteroarylalkyl preferably is pyridylalkyl, especially 2-pyridylmethyl.

Aryl, heteroaryl and the aryl parts of arylalkyl or heteroarylalkyl may be mono- or polycyclic, such as e.g. pyridyl, naphthyl, 9-fluorenylmethoxycarbonyl (FMOC) or benzimidazolyl. The alkylene part of

arylalkyl or heteroarylalkyl may be substituted by e.g. hydroxy.

A heterocyclyl group and the heterocyclyl part of a heterocyclylalkyl group is a saturated heterocyclic group having one or more heteroatoms selected from nitrogen, oxygen and sulfur. It preferably has 5 or 6 ring constitutent atoms, and preferably up to 3 heteroatoms.

Cycloalkylalkyl preferably is cyclohexylalkyl; it preferably is of 1 to 4 carbon atoms in the alkylene part.

A subgroup of compounds of formula I is the compounds of formula I wherein A and B independently are a bond, the aminoacyl moiety of a natural amino acid, the D-enantiomer thereof, or tert-butylglycine, and the other substituents are as defined above.

A further subgroup is the compounds of formula I wherein RiA- is an optionally substituted and optionally N-teπninal protected natural aminoacyl moiety, -BR4 is a natural aminoacyl moiety optionally esterified or amidated at the C-terminus , R ₂ is the side chain of a natural amino acid, R ₃ is an alkyl, alkenyl, cycloalkyl, aryl or arylalkyl group such as naphthylmethyl and X is as defined above.

A further subgroup is the compounds of formula I wherein Ri is benzylyoxycarbonyl, 2-pyridylmethoxycarbonyl, phenyllactoyl or phenoxymethylcarbonyl, A is L-valine or L-tert-leucine, R ₂ is benzyl, X is -NH-, R3 is benzyl, 3- or 4-methoxybenzyl or 4-bromobenzyl, B is L-valine and R4 is benzylamino or benzimidazol-2-ylmethylamino, and the carbon atom in 4 position has the S configuration.

A further subgroup is the compounds of formula Is

R ₂ , X,R ₃ .

I 3 I R _lβ A, - NH - CH - CH - CH - CO - B _S R ₄ , Is

4 1 2 1

OH

wherein

i _a is hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atoms; quinolylcarbonyl or quinolylsulfonyl; pyridylmethoxycarbonyl; aminocaproyl optionally protected by tert-butoxycarbonyl; 9-fluorenylmethoxycarbonyl (FMOC) ; phenyllactoyl; isovalerianoyl; phenoxymethylcarbonyl; palmitoyl; or 4-hydroxyphenylpropionyl; A _s is a bond; a natural o-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; O-tert-butyl-L-serine; or L-2-aminobutanoyl; R _2a s alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to

9 carbon atoms; X _a is -S- or -NR5,- wherein s. is hydrogen or methyl; R ₃ , is alkyl of 3 to 5 carbon atoms; cycloalkyl of 5 to 7 carbon atoms optionally monosubstituted by hydroxy; phenyl; phenylalkyl of altogether 7 to 9 carbon atoms optionally monosubstituted in the pheny ring by hydroxy, alkoxy of 1 to 3 carbon atoms, halogen of atomic number of from 9 to 35, or phenyl; a pyridylalkyl, indolylalkyl or naphthylalkyl group of 1 to 3 carbon atoms in the alkylene part; or phenylalkenyl of 2 to 4 carbon atoms in the alkenylene part; B _s is a bond; a natural o-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-1-carbonyl; R _β is hydroxy; an alkoxy or alkylamino group of 1 to 5 carbon atoms; phenylalkyla ino of altogether 7 to 9 carbon atoms optionally monosubstituted in the phenyl ring or in the alkylene part by hydroxy, or monosubstituted in the phenyl ring by halogen of atomic number of from 9 to 35; benzimidazolylalkoxy or benzimidazolylalkyla ino of 1 to 3 carbon atoms in the alkylene part optionally mono- or disubstituted in the aryl part by halogen of atomic number of from 9 to 35 or nitro; or an indolylalkyla ino, pyridylalkylamino or morpholinylalkylamino m> .3ty of 1 to 3 carbon atoms in the alkylene part; and the configuration in 4 position is S, in free form and, where such forms exist, in salt form.

In a subgroup of compounds of formula Is, when A ₉ or B _a is a natural o-aminoacyl moiety it is valine, tryptophane, phenylalanine, asparagine, isoleucine, glutamine, leucine, alanine or histidine; in a further subgroup, when Rι _s is phenylalkyloxycarbonyl it is benzyloxycarbonyl.

A further subgroup is the compounds of formula Ipi

R ₂ XR _3p

I 3 I R _lp A - NH - CH - CH - CH - CO - BR _4p Ipi

* 4 I 2 1

OH

wherein

A, B, R and X are as defined above;

Rip with the exception of hydrogen has the significance indicated above for Ri; R _3P with the exception of optionally substituted cycloalkyl has the significance indicated above for R ₃ ; and R _4P is hydroxy or a group of formula -OR ₇ or -NHR ₇ as defined above; in free form and, where such forms exist, in salt form.

A further subgroup is the compounds Ip ₂ , i.e. the compounds of formula I as defined above with the exception that R4 is hydroxy or a group of formula -OR ₇ or -NHR ₇ as defined above.

The compounds of the invention may be prepared by a process whic comprises a) submitting an epox-ide of formula II

R ₂

I Ri A - NH - CH - CH - CH - CO - BR

\ / I

0 wherein the substituents are as defined above, to ring opening in the presence of a compound of formula III

H - XR ₃ II wherein the substituents are as defined above, where indicated in a further reactive form; or

b) for the preparation of the compounds of formula I wherein -BR ₄ is other than hydroxy [bi], or Ri is other than hydrogen or HY- [b ₂ ], appropriately substituting a corresponding compound of formula I where -CO-BR4 is carboxy or Ri is hydrogen or HY-, e.g. t>ι) substituting a corresponding compound of formula la

R ₂ XR ₃ R _l A - NH - C IH - CH - CIH - COOH l wherein the substituents are as defined above, or b ₂ ) substituting a corresponding compound of formula lb

R ₂ XR ₃

Rj A - NH - C IH - CH - CIH - CO - BR4 l

I OH wherein Ri' is hydrogen or HY- and the other substituents are as defined above;

and where indicated deprotecting or saponifying a resultant compound of formula I in protected or esterified form,

and recovering the resultant compounds of formula I in free form or, where such forms exist, in salt form.

The process of the invention can be carried out in conventional manner.

Process variant a) is effected e.g. in an inert solvent such as an ether, e.g. tetrahydrofuran, or acetonitrile. The temperature preferably is between about -50°C and the boiling temperature of the reaction mixture, preferably between about -20°C and about 80 ^β C. The compound of formula III is an appropriate amine or mercaptan. A further reactive form preferably is a salt of a mercaptan, e.g. an alkali metal salt such as the potassium salt.

Process variant b) is effected using conditions known for coupling amino acids. The reaction preferably is effected in an inert solvent, such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran. The temperature preferably is between about room temperature and the boiling temperature of the reaction mixture, preferably about room temperature.

Deprotection conveniently is effected by hydrolysis, preferably under acidic conditions for removing e.g. a hydroxy or amino protecting group such as tert-butoxycarbonyl, preferably with trifluoroacetic acid, or hydrogenolytically for removing e.g. benzyloxycarbony1. Saponification is effected preferably with aqueous sodium hydroxide solution for removing e.g. alkoxy. The temperature preferably is between about -20°C and about 60°C, it conveniently is about room temperature. An organic solvent such as dichloromethane or tetrahydrofuran conveniently is used.

The resultant compounds of formula I can be isolated from the reaction mixture and purified according to known methods, e.g. chromatographically.

The compounds of formula II can be prepared e.g. in accordance with the following reaction scheme:

R ₂

I H ₂ N - CH - CH ₂ 0H III

acylation

R ₂

I R _l A - NH - CH - CH ₂ OH IV

oxidation

R ₂

R _X A - NH - CH - CHO V

Wittig reaction

V

R ₂

I R _l A - NH - CH - CH - CH - C00C ₂ H ₅ VI

saponification epoxidation + coupling

V R ₂

I R _l A - NH - CH - CH - CH - CO - BR

VII epoxidation

R ₂ R ₂

I R _l A - NH - CH CH - CH - COOC ₂ H ₅ R _l A - NH - CH - CH - CH - CO - BR ₄

\ / \ /

0 Ha 0 II

In the above reaction scheme the substituents are as defined above The single reaction steps may be carried out according to reaction conditio conventionally employed in such reactions, whereby the various intermediate can, where appropriate, be reacted further without isolation.

Insofar as they are not particularly described above or in the Examples, the starting materials and intermediates are either known or can prepared according to known methods or analogously to known methods or methods described in the Examples.

The following Examples illustrate the invention. The carbon atom i the 4 position in formula I has the S configuration. All temperatures are degrees Centigrade. The abbreviations for amino acids follow the international (IUPAC) rules. All NMR spectra are in CDC1 ₃ unless indicated otherwise; the shifts are in ppm relative to trimethylsilane.

Other abbreviations have the following meaning:

BOC = tert-butoxycarbonyl; Bu = n-butyl; Bz = benzyl; ch = hydrochloride; cHex ■ cyclohexyl; d. - decomposition; dch - dihydrochloride; depr. - deprotection;

Et - ethyl; Ex. = Example;

FMOC = 9-fluorenylmethoxycarbonyl; iBu = isobutyl - 2-methylpropyl; iPr = isopropyl;

Me = methyl; m.p. - melting point;

OEt ^» ethoxy; OMe - methoxy;

Ph » phenyl;

Phe - a phenylalanine moiety;

Pr - n-propyl; s. = sublimation; sap. » saponification;

Su * the N-hydroxysuccinimide ester moiety; tBu ^■ tert-butyl; tch - trihydrochloride; tLeu - a tert-leucine moiety -NHCH[-C(CH ₃ ) ₃ ]CO-;

Z - benzyloxycarbonyl.

Rτam ie 1; 2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-valinoyl)amino]-

3-hydroxy-5-phenylpentanoic acid ethyl ester

[Formula I: Ri = Z; A - L-Val; R ₂ , R ₃ ^■ Bz; X - -NH-; B = a bond; R ₄ - OEt]

[Process variant a) , ring opening]

400 mg of 4(S)-[(N-benzyloxycarbonyl-L-valinoyl)aιaino]-2,3-epoxy-

5-phenylpentanoic acid ethyl ester (an intermediate of formula II; compound A hereafter) are dissolved in 6 ml of tetrahydrofuran. 185 μl of benzylamine (an intermediate of formula III) are added and the solution is kept at 60° for 2 days. The solvent is evaporated and the residue chromatographed on silicagel (solvent: toluene/ethyl acetate 2:1). The title compound is obtained (m.p. 52-55°) .

Exj-ππgle La: 4(S)-[(N-tert-Butoxycarbonyl-L-valinoyl)amino]-

2-benzylthio-3-hydroxy-5-phenylpentanoic acid ethyl ester

[Formula I: Ri - BOC; A = ^• L-Val; R ₂ ,R ₃ - Bz; X - -S-; B - a bond; R ₄ -OEt]

[Process variant a) , ring opening]

1.15 g of benzylmercaptan (an intermediate of formula III) potassium salt are dissolved in 20 ml of acetonitrile and cooled to -50°. 2 g of 4{S)-[{H-tert-bπtc^carbonyl-L- ^y alin^l)aιιino]-2,3-epαry-5-phe3Byl- pentanoic acid ethyl ester (an intermediate of formula II; compound C hereafter) dissolved in 10 ml of acetonitrile are added and the mixture is kept at -20° for 48 hours. After neutralization with acetic acid the mixture is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: toluene/ethyl acetate 4:1). The title compound is obtained (sirup) : iH-NMR: 1.27 (t,3H); 1.42 (s,9H); 2.67-3.15 (AB,2H); 3.24 (d,lH); 3.47

(d,lH); 3.70 (AB,2H); 3.84 (dd,lH); 4.17 (q,2H); 4.22 (q,lH); 4.78 (q,lH); 7.15-7.40 (m,10H);

^•g τraτπpie 2z N-{[2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-valinoyl)amin o] 3-hydroxy-5-phenyl]pentanoyl)-L-valine benzylamide

[Formula I: Ri = Z; A,B = L-Val; R ₂ ,R ₃ - Bz; X - -NH-; R ₄ = NHBz]

[Process variant bi), substitution]

230 mg of compound of Example 4a are dissolved in 5 ml of dimethylformamide- 87 mg of L-valine benzylamide (an intermediate of formula H-BR ₄ ), 57 mg of hydroxybenzotriazole and 104 mg of dicyclohexylcarbodiimide are added at room temperature. After 24 hours stirring at room temperature the solution is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: gradient toluene/ethyl acetate 1:1 to 1:3). The title compound is obtained (amorphous; m.p. 81-84°) .

j ^* amgle_2a: H-{ [2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-valinoyl)- amino]-3-hydroxy-5-phenyl]pentanoyl)-L-leucine benzylamide

[Formula I: Ri * Z; A - L-Val; R ₂ ,R ₃ - Bz; X = -NH-; B ^» L-Leu; R ₄ - NHBz]

[Process variant bi), substitution]

220 mg of compound of Example 4a in 10 ml of a mixture of dry tetrahydrofuran and dimethylformamide (1:1) are protected from light and stirred at room temperature in the presence of 195 mg of 1-benzotriazolyl- oxy-tris-(dimethylamino)phosphonium hexafluorophosphate and 49 μl of N-methylmorpholine for 15 minutes. 106 mg of L-leucine benzylamide (an intermediate of formula H-BR ₄ ) are then added and the reaction mixture is stirred at room temperature overnight. The solvent is removed, water is added and the crude product extracted with ethyl acetate. The organic layers are dried, the solvent evaporated and the residue chromatographed on silicagel (solvent: gradient toluene/ethyl acetate 3:2 to 1:1). The title compound is obtained (m.p. 190-201°).

Bτam ie 3: N-{ [Benzylamino-4(S)-[ (N-benzyloxycarbonyl-O-tert-butyl- L-3erinoyl)amino]-3-hydroxy-5-phenyl]pentanoyl}-L-valine benzylaπride

[Formula I: Ri - Z; A = 0-tBu-L-Ser; R ₂ ,R ₃ = Bz; X - -NH-; B = L-Val; R ₄ = NHBz]

[Process variant b ₂ ), substitution]

0.35 g of N-benzyloxycarbonyl-O-tert-butyl-L-serine-M-hydroxy- succinimide ester (an intermediate of formula RiA-Q wherein Q is N-hydroxysuccinimidyloxy) are added to a solution of 0.1 g of compound of Example 119 in 4 ml of dioxane. The mixture is stirred for 6 days at room temperature, the solvent is evaporated and the residue is chromatographed on silicagel (solvent: cyclohexane/ethyl acetate 1:1). The title compound is obtained (m.p. 59-63°) .

Example 3a: N-([2-Benzylamino-4(S)-[(N-benzyloxycarbonyl-L-valinoyl)amin o]- 3-hydroxy-6-methyl]heptanoyl)-L-phenylalanine methylester

[Formula I: Ri - Z; A = L-Val; R ₂ - iBu; X - -NH-; R ₃ - Bz; B = L-Phe; R ₄ - OMe]

[Process variant b ₂ ), substitution]

96 mg of compound of Example 118 are dissolved in 2 ml of tetrahydrofuran. 82 mg of N-benxyloxycarbonyl-L-valine-p-nitrophenyl ester

(an intermediate of formula RiA-Q wherein Q is p-nitrophenyloxy) and 200 mg of K ₂ C0 ₃ are added and the reaction mixture is stirred for 3 days. The solution is filtered and the solvent evaporated. The residue is dissolved in ethyl acetate; the solution is washed with aqueous 0.1 N HC1, saturated

NaHC0 ₃ solution, dried and the solvent evaporated. The residue is chromatographed on silicagel (solvent: toluene/ethyl acetate 1:1), the title compound obtained (oil) : ⁱ H- MR: 0.90-1.00 (2d,12H); 1.20-1.40 (m,lH); 1.50-1.80 (m,2H); 2.20 (oct,lH); 3.05-3.20 (m,3H); 3.55 (bs,lH); 3.75 (s,3H); 3.84 (d,lH); 3.97 (dd,lH); 4.08-4.17 (m,lH); 4.90 (dd,lH); 5.08-5.20 (ra,2H); 6.60 (d,lH); 7.10-7.38 (m,15H); 8.10 (d,lH);

^p .Tampie 3b: N-{ [2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-histidinoyl)- amino]-3-hydroxy-5-phenyl]pentanoyl}-L-valine benzylamide

[Formula I: Ri - Z; A = L-His; R ₂ ,R ₃ = Bz; X - -NH-; B = L-Val; R ₄ = NHBz]

[Process variant b ₂ ), substitution]

300 mg of N-benzyloxycarbonyl-L-histidinoyl hydrazide (an intermediate of formula RiA-Q wherein Q is -NHNH ₂ ) are added at 5° to 4 ml of 1 N HC1 solution. A solution of 80 mg of sodium nitrite in 2 ml of water is added at 5°, the mixture is stirred for 5 minutes and quenched with 8 ml of saturated Na ₂ Cθ ₃ solution. The resulting white solid is washed twice with water, dissolved in 4 ml of dimethylformamide and added to a solution of 150 mg of compound of Example 119 in 3 ml of dimethylformamide. The mixture is stirred for 6 hours at room temperature, the solvent is evaporated and the residue is chromatographed on silicagel

(solvent: ethyl acetate). The title compound is obtained (resin):

^X H-NMR (DMSO): 0.88 and 0.89 (2d,J-6Hz,6H) ; 2.04 (oct,J-6Hz,lH) ; 2.61-2.68 (m,lH); 2.73-2.90 (m,3H); 3.42-3.56 (m,3H); 4.22-4.38 (m,5H); 5.03 (s,2H); 5.13 (b,lH); 6.72 (S,1H); 7.10-7.35 (m,20H); 7.39 (d,J-9Hz,lH) ; 7.48 (S,1H); 7.65 (d,J=9Hz,lH) ; 8.26 (t, J-6Hz,lH);

Examgle_3c: N-([2-Benzylamino-3-hydroxy-5-phenyl- (S)-[(H-2-qninolyl- carbonyl-L-asparaqinoyl)amino]]pentanoyl}-L-valine benzylamide

[Formula I: Ri ■ quinolin-2-ylcarbonyl; A - L-Asn; R ₂ ,R ₃ - Bz; X - -NH-; B - L-Val; R - NHBz]

[Process variant b ₂ ), substitution]

55 mg of diphenylphosphoryl azide and 20 mg of N-methylmorpholine are added to a solution of 100 mg of compound of Example 119 and 57 mg of H-(2-quinolylcarbonyl)-L-asparagine (an intermediate of formula RχA-Q wherein Q is -OH) in 3 ml of dimethylformamide. The mixture is stirred for 2 days at room temperature, the solvent is evaporated and the residue is chromatographedon silicagel. The title compound is obtained:

^X H-NMR: 0.92 and 0.95 (2d,6H); 1.70 (b,lH); 2.16-2.24 (m,lH); 2.82 (dd,2H); 2.92 and 3.01 (ABX,2H); 3.34 (d,lH); 3.57 and 3.66 (AB,2H); 3.86-3.90 (m,lH); 4.26 (dd,lH); 4.31-4.46 (m,3H); 4.89-4.95 (m,lH); 6.68-6.72 (m,lH); 6.95-7.00 (m,lH); 7.09-7.30 (m,17H); 7.65-7.68 (m,lH); 7.79-7.82 (m,lH); 7.86-7.93 (m,2H); 8.16-8.21 (m,2H); 8.31 (d,lH); 8.73 (d,lH);

Example 4: N-[2-Benzylamino-4(S)-(H-benzyloxycarbonyl-L-serinoyl)amino- 3-hydroxy-5-phenylpentanoyl]-L-valine benzylamide

[Formula I: Ri - Z; A - L-Ser; R ₂ ,R ₃ ^» Bz; X - -NH-; B - L-Val; R ₄ - NHBz]

[Deprotection]

2 ml of trifluoroacetic acid are added to a solution of 55 mg of compound of Example 3 in 2 ml of dichloromethane. The mixture is stirred for 16 hours at room temperature, the solvent is evaporated, toluene is added and evaporated (twice) , the residue is solved in dichloromethane, washed with 0.1 N NaOH, dried over MgSθ ₄ , concentrated in vacuo and chromatographed on silicagel (solvent: cyclohexane/ethyl acetate 1:2). The title compound is obtained (m.p. 76-81°) .

Example 4a: [2-Benzylamino-4(S)-(H-benzyloxycarbonyl-L-valinoyl)amino]- 3-hvdroxy-5-phenylpentanoic acid

[Formula I: Ri - Z; A » L-Val; R ₂ ,R ₃ ^* ■ Bz; X - -NH-; B - a bond; R ₄ - OH]

[Saponification]

330 mg of compound of Example 1 are dissolved in 3 ml of tetrahydrofuran. 627 μl of IN aqueous sodium hydroxide solution are added and the reaction mixture is stirred for 10 hours at room temperature. Neutralization with dilute aqueous HC1 solution leads to a white precipitate which is filtered off and dried. The title compound is obtained (m.p. 187-193°) .

The following further compounds of the invention (formula I) are obtained in analogous manner:

Ex. Process No. Ri R ₂ x R ₃ B R variant m.p.

98-103° 127-130° sirup;NMR ^h >

162-170°

79-84°

59-66°

72-80°

79-82° oil; NMR ^h > oil; NMR ^h >

114-130°

159-168° 83-86°

a) b) oil; NMR ^h >

a) b) 78-82°;NMR ^h > ch 128-131° a) b) oil; NMR ^h > a) b) 55-62° a) b) a NMR ^h > ; methylamino b 77-82°;NMR ^h >

Ex. Process No. Ri R ₂ X Ra B Ri variant m.p.

Ex. Process Ho. Ri R ₂ R ₃ B Ri variant m.p.

77 BOC bond Bz -NH- Bz bond OEt a) sirup; NMR ^h > 78 Z L-Val Bz -HH- Ph bond OEt a) b) NMR ^h > 79 Z L-Val Bz -NH- cHex bond OEt a) b) 55-65° 80 Z L-Val Bz -HH- Bu bond OEt a) b) 63-67° 81 Z L-Val Bz -NH- 1-napbthyl- bond OEt a) b) NMR ^h » methyl

82 L-Val Bz -] NH- 2-(indol-2-yl)- bond OEt a) b) resin; NMR ^h) ethyl

83 Z L-Val Bz -1 NH- 3-pyridyl- bond OEt a) b) resin; NMR ^h > methyl

84 Z L-Val Bz NH- 2-(2-pyridyl- bond OEt a) b) NMR ^h > ethyl

85 Z L-Val Bz ^■ NH- 4-MeO-Bz bond OEt 82-89° 86 z L-Val Bz ^• HH- 4-Cl-Bz bond OEt 88-96° 87 z L-Val Bz ^■ NH- 2-phenylethyl bond OEt 90-96° 88 z L-Val Bz ^■ NH- biphenyl bond OEt 66-72° 89 z L-Val 2-Ph- ^•■ HH- 4-Cl-Bz bond OEt 90-96° ethyl

90 z L-Val Bz -NH- 3-MeO-Bz bond OEt 93-99° 91 z L-Val Bz HMe- 3-phenylprop- bond OEt oil; NMR ^h >

2(E)-enyl

92 L-Val Bz -HH- 2-(4-OH-phenyl)- bond OEt 50-57° ethyl

93 BOC bond Bz -S- Bz bond OEt sirup; NMR ^h >

94 2-pyridyl- L-Val Bz -NH- Bz bond OEt methox carbonyl

Ex. Process

No. Ri A R ₂ R ₃ B R variant m.p.

Ex. Process Ho. Ri R ₂ X R ₃ B R variant m.p.

Ex. Process HO. Ri R ₂ X R ₃ B R4 variant m.p.

Ex. Process No. Ri R ₂ X R ₃ B R4 variant m.p.

a)

See Example la; b) See Example 3a; o) See Example 3b; d) See Example 3c; ^β ) Two stereoisomers designated a and b are obtained; f) Two diastereoisomers designated a and b are obtained; 9 ⁾ A mixture of both stereoisomers is obtained; h) NMR:

Example 25:

¹ H-NMR: 0.75 (d,6H); 0.86 (2d,6H); 1.97 (sext,2H); 2.45-2.80 (m,4H); 3.10 (d,lH); 3.80-3.90 (m,2H); 4.00-4.15 (m,2H); 4.40 (dq,2H); 5.10 (AB,2H); 5.18 (d,2H); 6.85-7.40 (m,19H); 7.20 (d,lH); 7.36 (d,lH); 7.78 (d,lH); 8.50 (t,lH);

Example 29: ⁱ H-NMR: 0.70 (d,3H); 0.82 (d,3H); 0.87 (d,3H); 0.92 (d,3H); 1.80 (sext,lH); 2.01 (sext,lH); 2.97 (d,2H); 3.22

(d,lH); 3.55 (AB,2H); 3.72 (s,3H); 3.75-3.90 (m,2H); 4.15-4.23 (m,2H); 4.40 (dq,2H); 5.10 (bs,3H); 6.45 (bd,lH); 6.63 (bt,lH); 6.82 (d,lH); 7.08-7.40 (m,19H); 8.18 (d,lH);

Example 31: ⁱ H-MR: 0.72 (d,3H); 0.78 (d,3H); 0.84 (d,3H); 0.90 (d,3H); 2.08 (m,2H); 2.85 (AB,2H); 3.24 (d,lH); 3.62

(dd,2H); 3.84 (m,2H); 4.40 (AB,2H); 4.61 (dd,lH); 5.08 (bs,3H); 6.28 (d,lH); 6.52 (t,lH); 6.64 (d,lH); 7.12-7.41 (m,20H);

Example 32 (CDCI ₃ /CD ₃ OD 9:1): ⁱ H-NMR: 0.87 (d,3H); 0.93 (2d _/ 6H); 0.97 (d,3H); 2.2-2.3 (m,2H); 2.83-2.96 (m,2H); 3.33 (d,lH); 3.88 (dd,lH); 4.25-4.33 (m,3H); 4.52 (s,2H); 6.94-6.99 (m,lH); 7.08-7.18 (5H); 7.2-7.36 (5H); 7.6-7.7 (m,2H); 7.8-7.85 (m,lH); 7.91 (dd,lH); 8.14 (dd,lH); 8.36 (d+m,2H); 8.60 (d,lH); ,

¹³ ONMR: 17.55, 17.695, 19.27, 19.353, 29.98, 30.07, 37.18, 44.32, 51.89, 52.4, 58.813, 59.36, 63.506, 71.78, K 118.59, 122.26, 122.36, 126.18, 127.21, 127.634, 128.146, 128.178, 128.283, 128.389, 129.013, 129. ^ 368, 129.69, 130.226, 137.13, 137.61, 137.76, 138.75, 146.38, 148.59, 148.67, 156.88, 165.11, 171. 59, 171.66, 173.67;

Example 36: ⁱ H-MR: 0.73, 0.86, 0.89 and 0.95 (4d, J=6Hz,12H); 2.07 and 2.23 (2oct, J=6Hz,2H); 2.96 (d,J=6.7Hz,2H); 3.25 (d,J=8Hz,lH); 3.59 (q,J=12Hz,2H); 3.84-3.93 (m,2H); 4.16-4.22 (m,2H); 4.35 and 4.45 (ABX, J _AB =15Hz,J _A χ=J _B χ=6Hz,2H); 4.92 (b,lH); 5.19 and 5.24 (AB,J=13Hz,2H); 5.21-5.26 (m,lH); 6.50-6.62 (m,2H); 7.15-7.35 (m,17H); 7.68 (t,J=6Hz,lH); 8.09 (d,J=9Hz,lH); 8.53 (d,J=5Hz,lH);

Example 37: ⁱ H-HMR: 0.86 (s,9H); 1.86 and 1.94 (2d,J=7Hz,6H); 2.00 (b,lH); 2.25 (oct,J=7Hz,lH); 2.97 (d,J=8Hz,2H); 3.29 (d,J=8Hz,lH); 3.52-3.63 (m,2H); 3.73 (d,J=8Hz,lH); 3.90 (d,J=6.4Hz,lH); 4.12 (q,J=7Hz,lH); 4.29

(dd,J=7 and 9Hz,lH); 4.33 and 4.51 (ABX,J _AB =15Hz,J _AX =5.4Hz,J _BX =6Hz,2H); 5.01 and 5.10 (AB,J=12Hz,2H);

5.08 (b,lH); 5.31 (d,J=8Hz,lH); 6.48 (d,J=7Hz,lH); 6.90-7.03 (m,lH); 7.08-7.39 (m,20H); 8.13

(d,J=9Hz,lH);

Example 38: ⁱ H-HMR: 0.91 and 0.97 (2d,J=7Hz,6H); 1.23 (t,J=6Hz,3H); 1.72 (b,lH); 2.32 (oct,J=7Hz,lH); 2.86 (m,2H); 3.30

(d,J=8.5Hz,lH); 3.56 and 3.71 (AB,J=13.6Hz,2H); 3.74 (dd,J=2 and.16Hz,lH); 4.12-4.22 (m,2H); 4.34-4.49

(m,2H); 6.58 (d,J=9Hz,lH); 6.96-7.18 (m,HH); 7.60-7.65 (m,lH); 7.78-7.96 (m,2H); 8.15-8.38 (m,3H);

8.63 (d,J=8.6Hz,lH);

Example 40 : ⁱ H-NMR: a) diastereoisomer a: 0.69 (d,3H); 0.82 (d,3H); 0.88 (d,3H); 0.94 (d,3H); 1.70 (m,IH exchangeable) ; 2.03 (m,lH); 2.30 (m,lH); 2.90-3.00 (2dd,2H); 3.30 (d,lH,J=6.7Hz) ; 3.65 (dd,2H); 4.15 (m,lH); 4.25

(q,lH); 4.40 (dd,2H); 4.65 (p,lH exchangeable) ; 5.09 (s,2H); 5.13 (d,lH exchangeable) ; 6.59 (d,lH exchangeable); 7.10-7.40 (m,16H); 7.6 (ddd,lH); 8.08 (d,lH exchangeable); 8.43 (dd,lH,J=3.6Hz) ; 8.49

(d,lH,J=1.7Hz); b) diastereoisomer b: 0.78 (d,3H); 0.79 (d,3H); 0.88 (d,3H); 0.94 (d,3H); 1.70 (m,IH exchangeable) ;

1.90 (m,lH); 2.25 (m,lH); 2.92 (m,2H); 3.10 (d,lH); 3.54 (AB,J _AB =12.5Hz,2H) ; 3.62 (d,lH); 3.80 (t,lH);

4.28 (dd,lH); 4.40 (d,2H); 4.60 (dd,lH); 5.15 (AB,J _AB =12.5Hz,2H) ; 5.45 (d,lH exchangeable) ; 6.50 (d,lH exchangeable); 7.05 (m,IH exchangeable) ; 7.10-7.40 (m,16H); 7.59 (ddd,lH); 8.45 (dd,lH); 8.50 (d,lH); Example 42: ⁱ H-NMR: a) diastereoisomer a: 0.73 (d,3H); 0.87 (d,3H); 0.98 (s,9H); 1.70-2.00 (m,H exchangeable); 2.00-2.18 I

(m,lH); 2.85-3.00 (m,2H); 3.25 (d,J=8.5Hz,lH) ; 3.56 (s,2H); 3.88 (m,lH); 3.90-4.10 (m,lH); 4.10-4.50

(m,4H); 5.05 (s,2H); 5.22 (d,lH exchangeable) ; 6.44-6.54 (t,lH exchangeable) ; 6.80 (d,lH); 7.10-7.45 ^< J ^D

(m,20H); 8.34 (d,IH exchangeable) ; b) diastereoisomer b: 0.72 (d,3H); 0.79 (d,3H); 1.05 (s,9H); 1.80-2.00 (m,lH); 2.80-3.00 (m,2H); 3.12

(d,J=9.4Hz,lH); 3.54 (s,2H); 3.66 (d,lH); 4.00-4.10 (dd,lH); 4.40-4.55 (m,4H); 4.70-4.95 (dd,2H); 5.21

(d,lH exchangeable); 7.00-7.40 (m,20H); ¹³ C-NMR: diastereoisomer b: 17.65, 19.42, 26.81, 31.05, 35.5, 38.36, 43.58, 51.32, 53, 60.92, 64.5, 66.97, 72.5,

77.2, 126.38-129.34 (C aromatic), 136.02, 137.86, 138.01, 138.73, 156.38, 169.91, 171.43, 174.14; Example 43: ¹ H- MR: [0.8(d,diastereoisomer a); 0.90 (d, diastereoisomers a+b), 0.95 (d, diastereoisomer b) , 6H]; [1.23 (s, diastereoisomer a), 1.38 (diastereoisomer b), 9H]; 2.10-2.20 (m,lH); 2.70-2.80 (m,2H); 3.20-4.60 (8H) ;

7.00-7.30 (m,HH); 7.55-7.70 (m,lH); 8.35-8.45 (m,2H); Example 44:

¹ H-NMR (DMSO): 0.88 (d,3H); 0.94 (d,3H); 1.33 (s,9H); 2.20-2.30 (m,lH); 2.80-2.90 (m,2H); 3.30 (d,lH); 3.60-3.80 ^'

(2d,2H); 3.80-3.90 (m,lH); 3.90-4.10 (m,lH); 4.40 (m,lH); 4.50 (m,2H); 7.00-7.40 (m,12H); 7.60 (ddd,lH);

8.45 (m,lH);

Example 45: ¹ H-NMR: 0.85 (d,3H); 0.93 (d,3H); 1.28 (s,9H); 2.20-2.30 (m,lH); 2.80-3.00 (m,2H); 3.38 (d,lH); 3.50-4.60 (m,8H) ;

7.10-7.40 (m,12H); 8.50-8.60 (m,2H);

Example 46: ⁱ H-NMR: 0.96 (s,9H); 1.39 and 1.42 (2s,9H); 2.80-3.00 (m,2H); 3.12 and 3.24 (2d,lH); 3.50-4.10 (m,8H); 4.30-4.40

(m,2H); 7.10-7.50 (m,15H); Example 51: ⁱ H-NMR: 0.73 (s,9H); 0.95 and 0.98 (2d,J=7Hz,6H) ; 1.65 (bs,lH); 2.30 (oct,J=7Hz,lH) ; 2.89 and 3.15 (ABX,

J _AB =14Hz,J _AX =4Hz,J _BX =7.5Hz,2H); 2.94-3.08 (m,3H); 3.29 (d,J=7.5Hz,lH) ; 3.60 (d,J=7.5Hz,lH) ; 3.60 and 3.65 (AB,J _AB =12.5Hz,2H); 3.89 (dd,J=3.5Hz,J=7.5Hz,lH) ; 3.95-4.01 (m,lH); 4.22-4.33 (m,3H); 4.52-4.58 (m,lH); 5.13 (b,lH); 5.95 (bm,lH); 6.79 (t,J=6Hz,lH); 6.88 (d,J=7.5Hz,lH) ; 7.14-7.33 (m,20H); 8.01

CO (d,J=9Hz,lH); c Example 53: ra ^X H-NMR: 0.63, 0.89, 0.93, 0.95 (4d,J=7Hz,12H) ; 2.05 (dsp, J=3Hz,J=7Hz,lH) ; 2.19 (oct,J=7Hz,lH) ; 2.91-3.02 (X (m,2H); 3.20 (d,J=8Hz,lH); 3.55 and 3.58 (AB,J _AB =13Hz,2H) ; 3.88 (d,J=8Hz,lH) ; 3.91 (d,J=3Hz,lH) ; 4.18 I i (dd,J=6Hz,J=7Hz,lH); 4.35 (q,J=7.5Hz,lH); 4.42 (dd,J=2Hz,J=6Hz,2H); 6.45 (t,J=6Hz,lH); 7.03 -

3 (d,J=10Hz,lH); 7.18-7.35 (m,15H); 8.08 (d,J=8Hz,lH); _f 2 Example 56: i ¹ H-NMR: 0.78 (d,3H); 0.83 (d,3H); 0.97 (d,3H); 1.00 (d,3H); 1.98 (sext,lH); 2.35 (sext,lH); 2.95 (ABX,2H); 3.38 lϊ (d,lH); 3.65-3.76 (m,2H); 3.79 (s,3H); 3.84 (m,lH); 3.99 (m,lH); 4.17 (m,lH); 4.24 (dd,lH); 4.62 (ABX,2H); 5.11 (AB,2H); 5.19 (d,lH); 6.80-7.41 (m,20H); 7.96 (d,lH); 8.20 (bs,lH);

■ Example 59: ffj ⁱ H-NMR (CDCI ₃ /CD ₃ OD 9:1): 0.76 (d,3H); 0.83 (d,3H); 0.97 (2d,6H); 1.94 (sext,lH); 2.20 (sext,lH); 2.78-2.92 m (m,2H); 3.38 (d,lH); 3.58 (AB,2H); 3.79 (s,3H); 3.84 (d,lH); 3.90 (m,lH); 4.22 (d,lH); 4.25 (dd,lH);

H 4.61 (AB,2H); 5.10 (AB,2H);.6.82 (d,2H); 7.02-7.60 (m,16H);

Example 66 (DMSO): ⁱ H-MR: 0.75 (d,6H); 0.87 (d,3H); 0.90 (d,3H); 1.80-2.00 (m,lH); 2.00-2.15 (m,lH); 2.50-2.70 (m,lH); 2.70-2.85

(m,lH); 3.00-3.20 (d,lH); 3.30-3.50 (m,2H); 3.50-3.60 (m,lH); 3.83 (t,lH); 4.20-4.40 (2m,2H);

4.40-4.65 (2dd,2H); 5.00-5.15 (AB,J _AB =12.4Hz,2H); 5.35 (d,IH exchangeable); 7.00-7.45 (m,19H); 7.52

(d,IH exchangeable); 7.60 (d,lH exchangeable); 7.90 (d,IH exchangeable);

¹³ C-NMR: 17.85, 18.25, 19.3, 29.92, 30.38, 37.04, 51.3, 51.8, 58, 60.75, 63.79, 65.5, 71.06, 74.1, 11??.2,

118.35, 121.1, 121.8, 124.8-129.16 (C aromatic); 136.9, 138.9, 140.1, 151.8, 156.2, 170.78, 171.3,

173.2;

Example 67 (DMSO) :

¹ H-NMR: 0.74 (d,6H); 0.87 (d,3H); 0.89 (d,3H); 1.80-2.20 (m,2H); 2.40-2.70 (m,lH); 2.70-2.95 (m,lH); 3.10 (d,lH); 3.30-3.50 (m,2H); 3.50-3.60 (m,lH); 3.75-3.85 (t,lH); 4.20-4.40 (m,2H); 4.40-4.65 (m,2H);

4.90-5.10 (AB, J _AB =12.5Hz,2H); 5.36 (d,IH exchangeable) ; 7.05-7.25 (m,9H); 7.25-7.6 (m,9H+lH exchangeable); 7.86 (d,lH exchangeable) ; 8.65 (t,lH exchangeable) ; 12.17 (s,lH exchangeable) ; ¹³ C-NMR: 17.84, 18.29, 19.26, 19.3, 29.86, 30.33, 37.04, 50.37, 51.73, 58.05, 60.75, 63.6, 65.5, 70.96,

111.19, 118.35, 119.68, 121.07, 121.86, 125.825, 127.7, 127.765, 127.99, 128.31, 129.15, 130.31, 130.87, 134.11, 136.93, 138.9, 139.56, 143, 151.8, 156.2, 162.3, 170.7, 171.3, 173.2; Example 73: ^-NMR: 1.80 (bs,lH); 2.99 (d,J=8Hz,2H) ; 3.16 (d,J=9Hz,lH) ; 3.41 and 3.50 (AB,J=13Hz,2H) ; 3.78 (d,J=10Hz,lH) ;

4.12 (q,J=8Hz,lH); 4.33 and 4.40 (ABX,J _AB =14Hz,J _AX =J _BX =6Hz,2H) ; 5.00-5.28 (m,3H); 5.40 (d,J=10Hz,lH) ;

6.98-7.42 (m,20H); 7.84 (t,J=5.5Hz,lH) ; Example 74: ⁱ H-NMR: 0.92 (d,6H); 1.20-1.38 (m,2H); 1.40 (s,9H); 1.53-1.72 (m,lH); 3.01-3.22 (m,2H); 3.10 (d,lH); 3.45 and

3.60 (AB,2H); 3.75 (d,lH); 3.78 (s,3H); 3.80-3.95 (m,lH); 4.80-4.95 (m,lH); 7.02-7.38 (m,10H); Example 76: ⁱ H-N R: 0.92 (d,6H); 1.30 (t,3H); 1.30-1.41 (m,2H); 1.65 (sept,lH); 3.35 (dd,lH); 3.65 and 3.85 (AB,2H);

3.67-3.73 (m,lH); 3.80-3.92 (m,lH); 4.22 (q,2H); 4.65 (d,lH); 7.20-7.35 (m,5H);

Example 77: ⁱ H-NMR: 1.28 (t,3H); 1.38 (s,9H); 1.72 (bs,lH); 2.80-3.03 (m,2H); 3.33 (d,lH); 3.60 and 3.80 (AB,2H); 3.72

(d,lH); 4.04 (q,lH); 4.18 (q,2H); 4.80 (d,lH); 7.15-7.40 (m,10H); Example 78: ⁱ H-NMR: 0.82 (2d,6H); 1.08 (t,3H); 2.10 (sext,lH); 2.95 (m,2H); 3.90 (m,2H); 4.05 (d,lH); 4.10 (q,2H); 4.28

(dt,lH); 5.12 (s,2H); 6.65 (d,2H); 6.78 (t,lH); 7.08-7.42 (m,15H); Example 81: ⁱ H-NMR: 0.64 (d,3H); 0.82 (t,3H); 1.85 (sext,lH); 2.61-2.83 (m,2H); 3.24 (d,H); 3.62-3.80 (m,2H); 3.94 (d,lH)

4.21 (q,2H); 4.25-4.41 (m,2H); 5.07 (d,lH); 5.10 (s,2H); 5.97 (d,lH); 7.00-7.61 (m,14H); 7.78 (m,lH);

7.81 (d,lH); 8.24 (d,lH); Example 82: ⁱ H-NMR: 0.78 (d,3H); 0.84 (d,3H); 1.21 (t,3H); 1.95 (sext,lH); 2.60-3.08 (m,6H); 3.10 (d,lH); 3.62 (dd,lH);

3.75 (dd,lH); 4.17 (q,2H); 4.23 (dq,lH); 5.12 (s,2H); 5.17 (m,lH); 6.17 (d,lH); 6.95-7.40 (m,14H);

7.58 (d,lH); 8.39 (bs,lH);

Example 83: ⁱ H-NMR: 0.75 (d,3H); 0.87 (d,3H); 1.26 (t,3H); 2.17 (sext,lH); 2.84 (AB,2H); 3.22 (d,lH); 3.43-3.81 (m,3H);

3.90 (dd,lH); 4.18 (q,2H); 4.45 (dd,lH); 5.10 (s,2H); 5.20 (d,lH); 6.41 (d,lH); 7.08-7.40 (m,HH);

7.69 (d,lH); 8.50 (m,2H);

Example 84: ⁱ H-NMR: 0.78 (d,3H); 0.85 (d,3H); 1.22 (t,3H); 2.00 (sext,lH); 2.75-3.00 (m,5H); 3.12 (dd,lH); 3.28 (d,lH);

3.65 (dd,lH); 3.91 (dq,lH); 4.08 (dd,lH); 4.18 (q,2H); 5.10 (s,2H); 5.38 (d,lH); 7.10-7.39 (m,12H);

7.64 (dt,lH); 8.15 (d,lH); 8.22 (m,lH);

Example 91:

¹ H-NMR: 0.80 (d,3H); 0.92 (d,3H); 1.34 (t,3H); 2.15 (m,4H); 2.82-3.22 (m,5H); 3.84 (m,2H); 4.23 (dq,2H);

4.70 (dd,lH); 5.10 (s,2H); 5.20 (d,lH); 6.01 (dt,lH); 6.40 (d,lH); 7.00-7.40 (m,16H); Example 93: ⁱ H-NMR: 1.27 (t,3H); 1.42 (s,9H); 2.67-3.15 (AB,2H); 3.24 (d,lH); 3.47 (d,lH); 3.70 (AB,2H); 3.84 (dd,lH); 4.17 (q,2H); 4.22 (q,lH); 4.78 (q,lH); 7.15-7.40 (m,10H); Example 97: ¹ H-NMR: 0.72 (d,3H); 0.80 (s,9H); 0.87 (d,3H); 2.18 (sext,lH); 2.88-3.16 (m,5H); 3.62 (AB,2H); 3.76 (d,lH); 3.81 (s,3H); 4.00 (dd,lH); 4.45 (bq,lH); 5.11 (s,2H); 5.08-5.18 (m,lH); 6.58 (d,lH); 6.83 (d,2H); 7.15-7.40 (m,12H); 7.80 (bt,lH); Example 98: ⁱ H-NMR: 1.27 (s,9H); 2.80-3.12 (m,2H); 3.38 (d,lH); 3.63 (d,lH); 3.69 (s,3H); 3.81-3.94 (m,lH); 4.46 (bq,lH); . 4.90 (d,lH); 7.03-7.40 (m,10H); Example 106:

¹ H-NMR: 0.83 (s,9H); 0.95 and 1.01 (2d,J=7Hz,6H); 1.59 (bs,lH); 2.32 (oct,J=7Hz,lH); 2.96-3.06 (m,2H); 3.31 (d,J=7.5Hz,lH); 3.61 and 3.65 (AB,J=14Hz,2H); 3.77 (d,J=7.5Hz,lH); 3.92 (d,J=7.5Hz,lH); 4.06-4.12 (m,lH); 4.28 (dd,J=6Hz and 9Hz,lH); 4.35 and 4.58 (ABX,J _AB =15Hz,J _AX =6.5Hz,J _BX =5Hz,2H); 4.40 and 4.47 (AB,J=15Hz,2H); 4.98 (bs,lH); 5.98 (d,J=7.5Hz,lH); 6.73 (t,J=6Hz,lH); 6.90-6.97 (m,3H); 7.02-7.07 (m,lH); 7.13-7.37 (m,17H); 8.09 (d,J=9Hz,lH);

Example 108: ⁱ H-NMR: 0.84 (s,9H); 0.85 (s,3H); 0.88 and 0.92 (2d,6H); 1.20-1.41 (m,25H); 1.48-1.62 (m,lH); 1.92 (bs,lH); 2.01-2.21 (m,2H); 2.28 (oct,lH); 3.00 (d,J=8.5Hz,2H); 3.26 (d,J=8Hz,lH); 3.58-3.65 (m,2H); 3.83-3.98 (m,2H); 4.02-4.18 (m,lH); 4.23-4.39 (m,2H); 4.48-4.60 (m,lH); 5.03 (bs,lH); 5.90 (d,J=7Hz,lH); 6.32 (d,J=7.5Hz,lH); 7.03 (t,lH); 7.10-7.37 (m,15H); 8.08 (d,J=9Hz,lH);

Example 114: ⁱ H-HMR: 0.83 (s,9H); 0.92 and 0.97 (2d,J=7Hz,6H); 2.24 (oct,J=7Hz,lH); 2,95 and 3.01

(ABX,J _AB =14Hz,J _AX =7Hz,J _BX =8Hz,2H); 3.23 (d,J=8Hz,lH); 3.56 and 3.63 (AB,J _AB =13Hz,2H); 3.92

(d,J=8Hz,lH); 4.23 (dd,J=3Hz and 9Hz,lH); 4.29 (q,J=8.5Hz,lH); 4.42 and 4.45

(ABX,J _AB =14Hz,J _AX =J _BX =6Hz,2H); 5.10 (bs,lH); 6.72 (bm,lH); 7.18-7.36 (m,15H); 8.05 (d,J=9Hz,lH);

Example 116:

¹ H-NMR: 0.58 and 0.87 (2d, =7Hz,6H) ; 1.28 (t,J=7Hz,3H) ; 1.50 (b,3H); 2.09-2.24 (m,lH); 2.97 (d,J=8Hz,2H) ;

3.08 (d,J=4Hz,lH); 3.22 (d,J=8Hz,lH) ; 3.54-3.83 (m,4H); 4.23 (dq,J=3 and 8Hz,2H); 7.08-7.38 (m,10H);

7.51 (d,J=8Hz,lH); Example 118: ⁱ H-HMR: 0.88 (d,6H); 1.38 (t,2H); 1.70 (sept,lH); 3.00-3.20 (m,2H); 3.20 (d,lH); 3.22-3.35 (m,lH); 3.58

(AB,2H); 3.67 (dd,lH); 3.71 (s,3H); 4.82 (dd,lH); 7.15-7.35 (m,10H); 7.90 (d,lH); Example 120: ¹ H-NMR (CDCI ₃ /CD ₃ OD 9:1): 0.97 (d,3H); 1.04 (d,3H); 2.26 (sext,lH); 2.48-2.81 (AB,2H); 3.21 (m,lH); 3.43

(d,lH); 3.69 (d,2H); 3.74 (dd,lH); 4.30 (d,lH); 4.42 (AB,2H); 7.08-7.38 (m,12H) Example 130: '

^! H-N R (DMSO): 0.68 (d,3H); 0.76 (d,3H); 1.87 (sext,lH); 2.70,2.80 (2dd,2H); 4.34 (q,lH); 5.07 (s,2H);

7.08-7.60 (m,15H); 7.70 (d,lH); ,

Example 138 (DMSO) : ⁱ H-NMR: 0.79 and 0.81 (2d,J=8Hz,6H) ; 2.02-2.18 (m,lH); 2.64-2.86 (m,2H); 3.80-4.16 (m,3H); 4.24-4.58 (m,2H);

6.90-7.03 (m,lH); 7.04-7.30 (m,4H); 7.30-7.54 (m,5H); 7.70-7.82 (m,lH); 7.82-7.98 (m,lH); 8.12-8.39

(m,4H); 8.58-8.70 (m,lH); ¹³ C- MR: 18.27, 19.24, 30.06, 37.46, 50.34, 51.28, 61.12, 62.32, 65.68, 70.98, 74.2, 120.6, 126, 127.9, 128.2, 128.4, 129.3, 130.9, 131.16, 136.9, 137.24, 138.8, 156.23, 171.56, 173.3;

The compounds used as starting materials can be prepared e .g. as follows :

A: 4(S)-[(N-Benzyloxycarbonyl-L-va inoyl)amino] -2,3-epoxy-5-phenyl- pentanoic acid ethyl eater

[Formula II: Ri = Z; A ^« L-Val; R2 - Bz; B - a bond; R = OEt; configuration at 4 position: S]

a) Acylation:

3.2 g of L-phenylalaninol (an intermediate of formula III) are added to a solution of 7.44 g of H-benzyloxycarbonyl-L-valin-p-nitro- phenylester (an intermediate of formula RχA-0. wherein Q is p-nitrophenyloxy) in 50 ml of dimethylformamide. 2 g of triethylamine are added and the reaction mixture is stirred at room temperature for 3 days. After evaporation of the solvent the residue is dissolved in dichloro¬ methane and carefully washed repeatedly with 0.1 N NaOH, then once with water and dried. The solution is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: dichloromethane/methanol 95:5). N-Benzyloxycarbonyl-L-valinoyl-L-phenylalaninol (an intermediate of formula IV) (m.p. 154-156') is obtained.

b) Oxidation and Wittiq reaction:

3.12 ml of oxalylchloride are dissolved in 40 ml of dry dichloromethane and cooled to -55°. 2.81 ml of di ethylsulfoxide are carefully added dropwise and then 6.98 g of product of step a) dissolved in 40 ml of dichloromethane and 3.125 ml of diaetliylsulfoxide are added at -50°. The reaction mixture is stirred at -60* for one hour, reacted with triethylaaine and stirred until it reaches room temperature. After dilution with 200 ml of dichloromethane the mixture is washed with aqueous IN HC1 solution, dried and the solvent evaporated. The residue is dissolved in toluene, 6.32 g of etho^caι±onylιnethylenetripheι ^** ylphθ3phorane are added and the reaction mixture is heated to 80° for 1 hour. After evaporation of the solvent the residue is chromatographed on silicagel

(solvent: toluene/ethyl acetate 4:1). 4(S)-[(N-Benzyloxycarbonyl- L-valinoyl)amino]-5-phenylpent-2(E)-enoic acid ethyl ester (an intermediate of formula VI) (m.p. 161-165°) is obtained.

c) Epoxidation:

3 g of product of step b) are dissolved in 30 ml of dichloromethane. 1.373 g of m-chloroperbenzoic acid are added and the reaction mixture is stirred for 5 days. After evaporation of the solvent the residue is chromatographed on silicagel (solvent: toluene/ethyl acetate 4:1). The title compound (compound A) (an intermediate of formula Ila) is obtained (m.p. 164-167°) .

The following intermediates of formula II are obtained in analogous manner (the configuration in 4 position is S) :

1

^a)χ H-NMR: 0.97 (2d,6H); 1.29 (t,3H); 1.44 (s,9H); 1.40-1.53 (m,2H); 1.63-1.80 (m,lH); 3.25 (bs,lH); 3.35 (bs,lH); 4.10 (bq,lH); 4.22 (dq,2H); ^f c^H-N R: 0.87 (d,3H); 0.98 (d,3H); 1.28 (t,3H); 1.82-2.06 (m,2H); 2.20 (sext,lH); 2.60-2.78 (m,2H);

3.21-3.37 (m,2H); 3.95 (dd,lH); 4.21 (q,2H); 4.38-4.50 (m,lH); 5.07-5.20 (m,3H); 5.92 (d,lH); 7.10-7.42 (m,10H); ^β ' ⁱ H- MR: 0.70 (d,3H); 0.76 (d,3H); 1.70-1.90 (m,lH); 2.60-2.90 (m,2H); 3.00-3.15 (m,lH); 3.18-3.20 (m,lH); 3.60-4.30 (m,2H); 5.10 (s,2H); 7.00-7.50 (m,HH); 7.86 (d,lH) .

G: D,L-tert-Leucine benzylami.de

[Formula H - BR : B - D,L-tLeu; R ₄ = NHBz]

a) To a solution of 1 g of N-(tert-butoxycarbonyl)-D _r L-tert-leucine in

60 ml of dichloromethane are added at room temperature 980 mg of dic clohexylcarbodii ide, 550 mg of N-hydroxysuccinimide, 0.53 ml of

N-methylmorpholine and 0.57 ml of benzylamine. After 24 hours stirring at room temperature the solution is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: toluene/ethyl acetate 5:1).

N-(tert-Butoxycarbonyl)-D _f L-tert-leucine benzylamide is obtained (solid):

^X H-NMR: 0.98 (S,9H); 1.4 (s,9H); 3.89 (d,lH); 4.3-4.6 (2dd,2H); 5.35 (d,lH); 6.55 (m,lH); 7.2-7.4 (m,5H).

b) 1.7 g of product of step a) are dissolved in 50 ml of dichloro¬ methane , 10 ml of trifluoroacetic acid are added, the mixture is stirred for 4 hours and the solvent is removed. The residue is dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate, then brine. The organic layer is dried, the solvent removed and the title compound (compound G) is obtained (oil) :

^X H-NMR: 0.98 (s,9H); 3.05 (s,lH); 4.4 (s,2H); 7.2-7.4 (m,5H); ¹³ C-NMR (CDC1 ₃ + drops CD ₃ OD): 26.35, 34.05, 63.87, 127.3, 127.74, 128.5,

138.04, 173.7.

The following intermediates of formula H - BR ₄ , which may suitably be in protected form, are obtained in analogous manner:

Compound B Ri m.p. benzimidazol- oil; NMR* ⁾

2-ylmethylamino 2-(4- H-phenyl)- oil; NMR ^f > ethylamino 2-(4-morpholinyl)- oil; MR9> ethylamino benzimidazol- oil; NMR ^h >

2-ylmethoxy 5-NO2-benziaidazol- oil; MR ¹⁾

2-ylmethoxy 5,6-diCl-benzimid- Oil; MRΪ' azol-2-ylmethoxy 2-(indol-3-yl)- 81-86° ethylamino

•J ⁱ H- MR: 0.82 (d,J-7Hz,3H); 1.00 (d, J«7Hz,3H) ; 2.30-2.50 (m,lH); 3.31

(d,J-3.6Hz,lH); 4.40-4.60 (ddd,2H); 7.25-7.35 (m,2H); 7.60-7.70 (ddd,lH); 7.80-7.90 (m,lH); 8.53 (dd,J-4.8 and 1.6Hz,lH); 8.55 (d,J-2.25Hz,lH); ^b ^H- MR: 0.88 (d, J»7Hz,3H) ; 0.99 (d, J»7Hz,3H) ; 2.00-2.20 (m,lH); 3.30 (d,J»4.8Hz,lH); 4.54 (s,2H); 7.10-7.40 (m,2H); 7.60-7.70 (ddd,lH); 8.20-8.30 (m,lH); 8.30 (d,lH); c)l _H . •NMR: 0.88 (d,J-7Hz,3H); 0.95 (d, J-7Hz,3H) ; 2.10-2.30 (m,lH); 3.23 (d,J»4.6Hz,lH); 4.46 (s,2H); 7.25 (d,2H); 8.45 (d,2H); )l _H . NMR: 0.75-0.90 (m,2H); 1.45-1.55 (m,2H); 4.40-4.50 (d,2H); 7.20-7.40 (m,5H); 7.90-8.10 (bs,lH); ^β )l _H - ^• NMR (DMSO) 0.80 (d,3H); 0.89 (d,3H); 1.85-2.10 (m,lH); 3.06 (d,lH); 4.51 (s,2H); 7.10-7.20 (m,2H); 7.45-7.55 (m,2H); 8.50 (bs,lH); ^f)x H-NMR (DMSO) 0.74 (d,3H); 0.81 (d,3H); 1.82 (sext,lH); 2.58 (t,2H);

2.88 (d,lH); 3.14-3.30 (m,2H); 6.67 (d,2H); 7.00 (d,2H); 7.82 (bt,lH); g'iH- 'NMR (CDCI ₃ /D2O) : 0.78 (d,3H); 1.84 (sext,lH); 2.31-2.42 (m,6H); 2.95

(d,lH); 3.18-3.31 (m,2H); 3.54-3.62 (m,4H); h)l _H . NMR: 0.84 (d,3H); 0.89 (d,3H); 1.80-2.00 (sext,lH); 3.00-3.50 (d,J-4.6Hz,lH); 5.30 (s,2H); 7.00-7.20 (m,2H); 7.40-7.60 (m,2H); i ⁾ l _H - NMR: 0.84 (d,3H); 0.89 (d,3H); 1.80-2.00 (m,lH); 3.26 (d,J-5.4Hz,lH); 5.37 (s,2H); 7.74 and 7.67 (2d,J-9Hz,lH); 8.00-8.20 (2dd,lH); 8.40 and 8.47 (2d,lH);

^■ JJ ⁱ H- R: 0.83 (d,3H); 0.89 (d,3H); 1.80-2.00 (m,lH); 3.24 (d,J-5.4Hz,lH) ; 5.36 (s,2H); 7.74 (s,2H);

T: N-Benzyloxycarbonyl-L-tert-leucine-N-hydroxysuccinimide ester

[Formula R _A A - Q: Ri = Z; A = L-tLeu;

Q = N-hydroxysuccinimid-2-yloxy]

2.6 g of N-hydroxysuccinimide and 4.6 g of dicyclohexylcarbodi- i ide are added to a solution of 6 g of N-benzyloxycarbonyl-L-tert-leucine in 70 ml of dioxane. The mixture is stirred for 12 hours at room temperature, the solvent is evaporated, the residue is suspended in ethyl acetate, the urea is removed by filtration and the solvent is evaporated.

The title compound (compound T) is obtained:

^-H-NMR: 1.10 (s,9H); 2.84 (s,4H); 4.52 (d,J-10Hz,lH) ; 5.03-5.12 (m,2H); 5.34 (d,J=10Hz,lH); 7.26-7.40 (m,5H) .

The following intermediate of formula R _A A - Q is obtained in analogous manner:

Compound Ri A Q m.p.

U 2-pyridyl- L-Val Su white solid; methox carbonyl NMR*>

»> ¹ H-NMR: 1.09 and 1.11 (2d, J-7Hz, 6H) ; 2.38 (oct, J»7Hz, IH) ; 2.82 and 2.84 (2s,4H); 4.62 (dd, J-5Hz, J-7.5HZ, IH) ; 5.28 (s,2H); 7.25-7.42 (m,3H); 7.72-7.81 (m,lH) .

The compounds of formula I in free form and, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, possess interesting pharmacological properties. They are therefore indicated for use as pharmaceuticals. In particular, they exhibit antiviral activity, especially HIV-1 protease inhibiting activity, whereby they show only low or inexistent inhibiting effect against human proteases such as renin or pepsin.

This activity can be shown in the following tests:

1. HIV-proteinase inhibition

Inhibition of peptide cleavage by HIV-proteinase is measured as described in A.Richards et al., J.Biol.Chem. 265 (1990) 7733-7736 and L.H.Philip et al., Biochem.Biophys.Res.Commun. 171 (1990) 439-444. Briefly, the peptide H-Lys-Ala-Arg-Val-Leu-Nρh-Glu-Ala-Nle-NH ₂ (where Nph is p-nitrophenylalanine and Nle is norleucine) is used as substrate for recombinant HIV-1 or HIV-2 proteinase. Cleavage, occurs between the Leu and Nph residues. The reaction is followed spectrophotometrically by the decrease in extinction at 300 n which is observed upon cleavage.

In this test the compounds exhibit Ki values of from about 3 nM to about 1 μM for HIV-1, and of from about 30 nM to about 10 uM for HIV-2.

2. Inhibition of cellular HIV-induced cytopathic effect

Inhibition of the HIV-1 (HTLV III _B )-induced cytopathic effect is measured in MT4 cells as described in R.Pauwels et al., J.Virol.Methods 20 (1988) 309-321. Briefly, an HTLV-1 transformed T4 cell line, MT4, which has been shown previously to be highly susceptible to HIV infection, serves as the target cell line. Inhibition of HIV-induced cytopathic effect is used as the end point. The viability of both HIV- and mock-infected cells is assessed spectrophotometrically via the in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) . The comparison of the effects of various concentrations of the compound on HIV- versus mock-infected cells allows the determination of minimum toxic (MTC) and minimum virus-inhibitory (MIC) concentrations.

In this test the compounds exhibit IC50 values of from about 5 nM to about 350 nM. Thus the compounds of Examples 56 and 59 exhibit IC5 ₀ values of, respectively, 49 nM and 12 nM against HIV-1 strains, and the compound of Example 37 is effective with an IC ₅₀ value of 150 nM.

The compounds of the invention in free form and, where salt forms exist, in pharmaceutically acceptable salt form are therefore indicated for use as pharmaceuticals, particularly as agents against HIV-proteinase, e.g. in the prophylaxy and treatment of retroviral infections. For this use the effective dosage will, of course, vary depending on the particular compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.02 mg/kg to about 50 mg/kg animal body weight, suitably given in divided dosages two to four times daily. For most larger mammals the total daily dosage is from about 1 mg to about 3500 mg, e.g. from about 1 mg to about 500 mg or about 10 mg to about 100 mg. The compounds may be administered in similar manner to known standards for use in such indications.

The compounds are also indicated for use in treating non-human animals infected with a retrovirus, such as cats infected with feline leukemia virus, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chla ydia. Exact dosages, forms and modes of administration of the compounds to non-human animals would be apparent to one of ordinary skill in the art, e.g. a veterinarian.

The compounds of Examples 29, 36, 37, 51, 56, 59, 66, 67 and 106, especially of Examples 56 and 59, i.e. N-{ [4(S)-[ (N-benzyloxycarbonyl- L-valinoyl)amino]-3-hydroxy-2-(3-methoxybenzylamino)-5-pheny l]pentanoyl)- L-valine-N-(methyl-2-benzimidazolyl)amide and, respectively, the corresponding 4-methoxy position isomer are the preferred compounds as anti HIV-proteinase agents. It is indicated that for this indication these compounds may be administered to larger mammals, for example humans, by

similar modes of administration at similar or lower dosages than employed with standards for such indications.

The invention therefore also concerns a method of treating retroviral diseases, especially diseases caused by HIV which comprises administering to a subject in need of such treatment a prophylactically or therapeutically effective amount of a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, as well as a compound of formula I in free form-or, where salt forms exist, in pharmaceutically acceptable salt form for use as a pharmaceutical, especially as an agent against HIV-proteinase.

The compounds may be admixed with conventional pharmaceutically acceptable diluents and carriers and, optionally, other excipients and administered e.g. orally in such forms as tablets or capsules. The compounds may alternatively be administered parenterally or intravenously. The concentrations of active substance will, of course, vary depending i.a. on the compound employed, the treatment desired and the nature of the form.

The invention thus also includes a pharmaceutical composition comprising a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent.

It further concerns a process for the preparation of a medicament against retroviral diseases which comprises mixing a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, together with a pharmaceutically acceptable carrier or diluent, and the use of such a compound in the manufacture of a medicament against retroviral diseases.

It further concerns a compound of formula I in free form or, where salt forms exist, in pharmceutically acceptable salt, e.g. acid addition salt form, for use as a pharmaceutical, particularly for use in the treatment of retroviral diseases.