AU626361B2 - Retroviral protease inhibitors - Google Patents

Description

I

Our Ref: 302079

AUSTRALIA

Patents Act COMPLETE SPECIFICATION FORM

(ORIGINAL)

KAt 'r in Application Number: Lodged: KY ~J Complete Specification Lodged: Accepted: Published: Priority: Related Art: Applicant(s): Address for Service: Ciba-Geigy AG Klybeckstrasse 142 4002 BASLE

SWITZERLAND

ARTHUR S. CAVE CO.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000

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S

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00 Complete specification for the invention entitled "Retroviral protease inhibitors".

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0* The following statement is a full description of this invention, including the best method of performing it known to me:- 0 0 1 5020 la Retroviral protease inhibitors oco 00 00 )0 0 00 0 0 o 00 00 0 0 000 0 0 1 0 0 0 00 0000 0000 0 00 00 0 00 0 00 0 0 0 0000 0 0000 00000 0 0 HIV (human immunodeficiency virus) is a retrovirus that causes the AIDS disease which generally proves fatal in man. While it is today possible to alleviate the effects of AIDS and prolong patients' lives, there have hitherto been no pharmaceutical preparations that effectively combat the cause of AIDS. One possible aim in the treatment of AIDS is to prevent the propagation of HIV without at the same time damaging the still intact cell aggregates of the patient.

The genome of the two types of HIV, HIV-1 and HIV-2, that are known so far has a region that codes for a "gag protease". In addition, both viruses contain a region that codes for the "group specific antigens" (gag). The corresponding genes are expressed as precursor protein and the actual gag proteins are freed proteolytically therefrom by the abovementioned gag protease. Gag protease itself is also excised from a precursor protein from which further viral proteins, such as reverse transcriptase and integrase, originate. This process is presumed to proceed autoproteolytically. It is also known that gag protease cleaves the major core protein (p2 4 of HIV-1 and HIV-2 preferentially N-terminally at proline, for example at Phe-Pro, Leu-Pro or Tyr-Pro. A Pro-terminal p 24 thus shortened is then used together with other viral structural proteins for the synthesis of the nucleocapsid and the virus coat of HIV-1 and HIV-2. It is also known that the HIV-1 gag protease cleaves Leu-Phe, Leu-Ala, Met-Met and Phe-Leu sequences with varying degrees of efficiency. It is clear that, in addition to the amino acid sequence, the conformation contributes to the specificity of gag protease.

If the action of gag protease could be inhibited, neither functional structural proteins nor the necessary viral enzymes would be available to the virus and its propagation would be hindered, if not interrupted alto-

A

1- 2 gether. There is therefore a need for complete or at least partial inhibitors of gag protease. Such compounds would play an important role as antiviral agents against AIDS or other retroviral diseases.

It has surprisingly been found that the compounds according to the invention are suitable as gag protease inhibitors since they are capable of inhibiting gag proteases even in the nanomolar concentration range.

The compounds according to the invention are compounds of the formula R -AAN-

H

-AAC-R'

I I o 0oo 0 00 0 0 o 0o oa o oco o c 00 0 o a -I i wherein AAN is a bivalent radical, consisting of fromii ne to five bivalent a-amino acid residues, which is bonded N-te'-mnally to the radical R 2 and C-terminally to the group NH-, AAC is a bivalent radical, consisting of one or two bivalent a-amino acid residues which is bonded N-terminally to the group -C=O and C-terminally to the radical R 1

R

1 is hydroxy, etherified hydroxy, amino or substituted amino with the exception of an amino radical derived from an a-amino acid, and R 2 is hydrogen or an acyl radical with the exception of an unsubstituted or N-substituted acyl radical of a natural amino acid. Apart from the above-defined compounds of the formula I, the invention also relates to salts of such compounds having salt-forming groups, to processes for the preparation thereof, to pharmaceutical preparations containing those compounds and to the use of those compounds as medicaments or for the manufacture of pharmaceutical preparations, and to intermediates for the preparation of compounds of the formula I.

L01 0. 0 3 The abbreviation AAN denotes the amino acid sequence that is linked to the N-terminus of the central (2S,4S,5S)-5-amino-6-cyclohexyl- 4 -hydroxy- 2-isopropylhexanoyl radical (amino acid(s) N-terninal). The abbreviation AAC denotes the amino acid sequence that is linked to the C-terminus of the same central radical (amino acid(s) C-terminal).

In the description of the present invention, the term "lower" used in the definition of groups or radicals, for example lower alkyl, lower alkoxy, lower alkanoyl, etc., means that the groups or radicals so defined, unless expressly defined otherwise, contain up to and including 7 and preferably up to and including 4 carbon atoms.

The substituted a-carbon atoms of the amino acid residues of which AAN and AAC consist may have the S- or R,S-configuration. Compounds of the formula I in which these carbon atoms have the S-configuration are preferred. The a-amino acid residues of the radical AAN may be substituted N-terminally by lower alkyl, for example methyl or ethyl, in order to increase the stability of the compound of the formula I against enzymatic degradation.

0o o A bivalent a-amino acid residue of which AAN and AAC consist is, for 0 0 0 example, a residue of a natural a-emino acid having the L-configuration, O as is normal in proteins, of a homologue of such an amino acid, for o example in which the amino acid side chain is lengthened or shortened by o one or two methylene groups and/or a methyl grout has been replaced by hydrogen, of a substituted aromatic a-amino acid, for example a substituted phenylalanine or phenylglycine, in which the subst:ituent(s) may be lower alkyl, for example methyl, halogen, for example fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, for example methoxy, lower 1" alkanoyloxy, for example acetoxy, amino, lower alkylamino, for example 4 01 methylamino, di-lower alkylamino, for example dimethylamino, lower alkanoylamino, for example acetylamino or pivaloylamino, lower alkoxycarbonylamino, for example tert.-butoxycarbonylamino, arylmethoxycarbonylamino, for example benzvloxycarbonylamino, and/or nitro and occur(s) one or more times, of a benzo-fused phenylalanine or phenylglycine, such as a-naphthylalanine, or of a hydrogenated phenylalanine or phenyl- 4. 4

A

4glycine, such as cyclohexylalanine or cyclohe-ylglycine, of a five- or six-membered cyclic, benzo-fused a-amino acid, for example indoline-2carboxylic acid or 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, of a natural or homologous a-amino acid in which a carboxy group of the side chain is in esterified or amidated form, for example in the form of a lower alkyl ester group, such as methoxycarbonyl or tert.-butoxycarbonyl, or in the form of a carbamoyl group, a lower alkylcarbamoyl group, such as methylcarhamoyl, or a di-lower alkylcarbamoyl group, such as dimethylcarbamoyl, in which an amino group of the side chain is in acylated form, for example in the form of a lower alkanoylamino grout>, such as acetylamino or pivaloylamino, in the form t.f a lower alkoxycarbonylamino group, such as tert.-butoxycarbonylamino, or in the form of an arylmethoxycarbonylamino group, such as benzyloxycarbonylamino, or in which a hydroxy group of the side chain is in etherified or esterified form, for example in the form of a lower alkoxy group, such as methoxy, in the form of an aryl-lower alkoxy group, such as benzyloxy, or in the form of a lower alkanoyloxy group, such as acetoxy, or is a residue of an epimer of such an amino acid, thac is to say having the non-naturally occurring f-configuration.

Go 0 Such amino acids are, for example, glycine (H-Gly-OH), alanine 0 (H-Ala-OH), valine (H-Val-OH), norvaline (ca-aminovaleric acid), leucine 00 0 OOo (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (a-aminohexanoic acid, 0,0. H-Nle-OH), serine (H-Ser-OH), homoserine (a-amino-7-hydroxybutyric acid), 0: 00 threonine (H-Thr-OH), iethionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, ph~anylalanine (H-Phe-OH), tyrosine (H-Tyr-OH), 4-nitrophenylalanine, 4-aminophenylalanine, 4-chloro-., 3nylalanine, B-phenylserine (B-hydroxyphenylalanine), 'phenylglycine, a-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Gha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic 4. 4 acid (H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, aminomalonic 404.2 iad monoamide, glutamic acid (H-Glu-OH), glutamic acid mono-tert.-butyl ester, glutamine (H-Gln-OH), N -dimethylglutamine, histidine (H-His-OH), 4404 0 4,44 4444

YL__

arginine (H-Arg-OH), lysine (H-Lys-OH), N -tert.-butoxycarbonyl-lysine, 6-hydroxylysine, ornithine (a,6-diaminovaleric acid), N -pivaloylornithine, a,7-diaminobutyric acid or a,B-diaminopropionic acid.

The general terms and expressions used in the description of the present invention have preferably the following meanings: An etherified hydroxy group R 1 is preferably etherified by organic radicals that can be removed under physiological conditions and that, after removal, produce cleavage products that are pharmacologically harmless in the concentration concerned.

Etherified hydroxy R I is, for example, acyloxy-lower alkoxy in which acyl is the acyl group of an optionally branched lower alkanecarboxylic acid or of carbonic acid mono-esterified by optionally branched lower alkyl, for example lower alkanoyloxy-lower alkoxy, such as acetoxymethoxy, 1-acetoxyethoxy, pivaloyloxymethoxy or 1-pivaloyloxyethoxy, or lower alkoxycarbonyloxy-lower alkoxy, such as ethoxycarbonyloxymethoxy, 1-ethoxycarbonyloxyethoxy, tert.-butoxycarbonyloxymethoxy or 1-tert.- .o butoxycarbonyloxyethoxy.

Etherified hydroxy R I is also preferably lower alkoxy, for example methoxy or ethoxy, aryloxy, for example phenoxy, or aryl-lower alkoxy, So for example benzyloxy.

0 Substituted amino R 1 is, 4 ar example, an amino group that is substituted by one or optionally two organic radicals, for example unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals 0044 4 having up to and including 18, preferably up to and including 10, carbon atoms or unsubstituted or substituted, aromatic, heteroaromatic, 4 64 aromatic-aliphatic or heteroaromatic-aliphatic radicals having up to 18, Spreferably up to and including 10, carbon atoms.

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I 4 Excluded as substituted amino R 1 is the radical of an a-amino acid or its N-substituted, esterified or amidated derivatives.

0 4 A A -6- An unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radical that substitutes the amino group R' is, for example, unsubstituted or substituted alkyl having up to 10 carbon atoms, lower alkenyl or lower alkynyl havirg up to and including 7 carbon atoms, or Alcycloalkyl or cycloalkyl-lower alkyl having from 4 to 10 carbon atoms.

These radicals can be substituted by one or more of the functional groups a mentioned in connection with lower alky3 ia defined hereinafter, and by sulfo.

Preferred substituents *re hydroxy, lower alkoxy, for example methoxy, lower alkanoyloxy, for example acetoxy, substituted or unsubstituted phenoxy, for example carbamoylphenoxy or carbamoyl-hydroxy-phenoxy, carboxy, esterified carboxy, for example lower alkoxycarbonl, such as methoxyrarbonyl or tert.-butoxycarbonyl, or a physiologically cleavable esterified carboxy, for exampla 1-(lower alkanoyloxy)-lower alkoxycarbonyl, such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, 1-(lower alkoxycarbonyloxy)-lower alkoxycarbonyl, such as 1-(ethoxycarbonyloxy)-ethoxycarbonyl, or a-amino-lower alkanoyloxymethoxycarbonyl, such as a-aminoacetoxymethoxycarbonyl or oooe (S)-a-amino-1-methylbutyryloxymethoxycarbonyl, carbamoyl, substituted or 08r; unsubstituted lower alkylcarbamoyl, for example hydroxy-lower alkylcar- S bamoyl, such as 2-hydroxyethylcarbamoyl or tris-(hydroxymethyl)-methyl- 0n carbamoyl, amino, lower alkylamino, for example methylamino, di-lower o, alkylamino, for example dimethylamino, lower alkoxycarbonylamino, for 8888 example tert.-butoxycarbonylamino, guanidino, saturated five- or sixmembered heterocyclyl that is bonded via a nitrogen atom and, if desired, substituted by oxo, for e:-imple 1-piperidinyl, 4-morpholinyl or 2-oxo-1pyrrolidinyl, or sulpho.

An aromatic or aromatic-aliphatic radical in a group RI preferably has ab the same meanings as those mentioned hereinafter under aryl Ra or R or is aryl-lower alkyl Ra and is, for example, phenyl or phenyl-lower alkyl.

These radicals may be substituted in the aromatic moiety, for example by lower alkyl, for example methyl or ethyl, hydroxy, etherified hydroxy, itfor example lower alkoxy, such as methoxy or tert.butoxy, eserified I for example lower alkoxy, such as methoxy or tert.-butoxy, esterified -7hydroxy, for example lower alkanoyloxy, such as acetoxy, or halogen, for example fluorine or chlorine, carboxy, esterified carboxy, for example lower alkoxycarbonyl, such as tert.-butoxycarbonyl, carbamoyl, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, acylated amino, for example lower alkoxycarbonylamino, such as tert.-butoxyca:bonylamino, and also by nitro.

Lower alkyl in a phenyvl-lower alkyl radical may be substituted by the same substituents as may alkyl in a radical RI.

A heteroaromatic or heteroaromatic-aliphatic radical in a group R 1 preferably has the same meanings as those mentioned hereinafter under heteroaryl RandRbor heteroaryl-lowur alkyl R aand is, for example, pyridyl-lower alkyl, for example 3- or 4-pyridylmethyl, imidazolyllower alkyl, for example 2-(4-imidazolyl)-ethyl or also 2-(2-[j4imidazolyl]-ethylamino)-ethyl, or indolyl-lower alkyl, for example 3-indolylmethvl or 2-(3-indolyl)-ethyl.

Slubstituted amino R' is preferably alkvlamino, for example methyl-, 0 alkylamino, for example 2-hydroxyetbiylamino, 1-hydroxybut-2-ylamino, for example di(-hyroxyethyl)amino, lowehyraoxylower alkyl)amino, for example 2-thythytamino, lower alkanyoxylower alkylamino, for example 2-aetoxyethylamino, phnlKower alkoyamor phelanoy-hyroxmlwer 2alkoxylamino hc phenoxy-is unsubstituted or substitutedroby-lower alkyl lowern awhoch hydoxyi carby, lowed r suocbonitutor by cawraloyl, for ealey 2-henoyoxyetyamn, 2-(e 3caoyar4-hydrxpeoltya~n or by3-(myfr xml 3-carbanoyylheno-2 4hydroxypropylamino, carboxyalkylamino or amino-carboxy-alkylamino in which the carboxy radical is not in the 1-position of the alkyl radical, for example 4-carboxy-n-butylamino, 5-carboxy-n-pentylamino, '~carboxy-m-pentylanino, 6-carboxy-n-hexylamino, 7-carboxy-m-heptylamino or 8-carboxy-n-octylamimo, also dicarboxymethylamimo, lower alkoxycarbonyl- 1 11 -8alkylamino or acylamino-lower alkoxycarbonylalkylamino in which the carbonyl radical is not in the 1-position of the alkyl radical, for example 4-tert.-butoxycarboinyl-n-butylamino, methoxyr- ',--v-n-pentylamino, 7-tert.-butoxycarbonyl-n-heptylamino or 8-tertC-buto-.,ycarbonyl-n-octylamino, also di-lower alkoxycarbonyl-methylamin( or example di-methoxycarbonyl-methylamino, physiologically cleavable ea~terified carboxyalkylamino in which the ester fi.nction is not in the 1-position of the alkyl radical, for example 4-pivaloyloxymethoxycarbonyl-n-butylamino, 7-(I-ethoxycarbonyloxyethoxycarbonyl)-n-heptylamino or 7-pivaloyloxymethoxycarbonyl-n-heptylamino, carbamoylalkylamino or hydroxy-lower alky' ,arbamoylalkylamino in which the carbamoyl radical is not in the I-positi-:n of the alkyl radical, for example 4-carbamoyln-butylamino, 7-ca-:bamoyl--n-heptylamino or 4-(tris[hydroxymet'hylImethyl)-carbamoyl-n-butylamino, alao dicarbartoyl-methylamino, di-(lower alkylcarbamoyl) -me thy lamino, for example Udi-(methylcarbamoyl)-methylami-o, di-(hydcoxy-lower alkylcarbamoyl)-rniethylamino, for example di-(2- 'hydroxyethylcarbamoyl)-methylamino, or bis-(di-lower alkylcarbamoyl)methylamino, for example bis- (dime thylca rbamoyl) -me thylamino, amino-lower alkylamino, for example 2-amino ethyl amino or 4-aminobutylamino, lower alkylanino-lower alkylamino, for example 2-methylaminoethylamino, dilower alkylamino-lower alkylamino, for example 2 -dime thylaminoe thy! amino 0 0 or 3-dime thylaminopropylamino, lower alkoxycarbonylamino-lower alkyl- 0 00 0 amino, for example 2-(tert.-butoxycarbonylamino)-ethylamino, guanidinolower alkylamino, for example 2-guanidinoethylamino, saturated five- or six,-membered heterocyclyl-lower alkylamino that is bonded via a nitrogen atom, for example 2-(4-morpholinyl)-ethylamino, 3-(4-morpholinyl)-propylamino or 3-(2-oxo-1-pyrrolidinyl)-propylamino, lower alkenylamino, for example allylamino or 2- or 3-butenylamino, lower alkynylamino, for example propargylamino, cycloalkylamino, for example cyclohexylamino or decahydronaphthylamino, cycloalkyl-lo\wer alkylamino, for example cyclopropylmethyitamino or cyclohexylmethylamino, naphthylamino, phenylanmino or phenyl-lower alkylamino in which phenyl or naphthyl is unsubstitutod or mono- or poly-substituted by lower alkyl, for example methyl, phenyl, hvdroxy, lower alkoxy, for example methoxy or tert.-butoxy, lower alkanoyloxy, for example acetoxy, halogen, for example fluorine or chlorine, carboxy, lower alkoxycarbonyl, for example tert.-butoxycar- 9bonyl, carbamoyl, amino, lower alkvlamino, for exa.2-'_ methylamino, dilower alkylamino, for example dimechylamino, acylamino, for example tert.-butoxycarbonylamino and/or 1,y nitro, for example phenylamino, 2-, 3- or 4-me thylphenylamino, 4-biphenylylamino, 4-hydroxyphenylamino, 4-methoxyphenylamino, 2,4- or 2,5-dimethoxyphenylamino, 4-chiorophenylamino, 3- or 4-carboxyphenylamino, or 4-methoxy- or tert.-butoxy-carbonylphenylamino, 3- or 4-carbamoylphenylamino, 4-aminophenylam:o, 4-tert.-butoxycarbonylaminophenylamino oi. 4-nitrophenylamino, also, for example, benzylamino, 4-methylbenzylamino, 4-biphenylylm~thylamino, 4-methoxybenzylamino, 3- or 4-carboxcybenzylamino, or 4-tert.-butoxycarbonylbenzylamino, 3-or 4-carbamoylbenzylamino, 2-phenylethylamino, 3-phenylpropylamino or amino, pyridyl-lower alkylamino, for example 3- or 4-pyridylmethylamino, 3- or 4-pyridyi)-ethylamino or 3- or 4-pyridyl)propylamino, imidazolyl-lower alkylamino, for example 4-imidazolylmethylamino, 2-(4-imidazolyl)-ethylamino or 2-(2-[4-imidazolyll-ethylainino)-.

thylamino, indolyl- ower alkylamino, for example 3-indolylmethylamino or 2-(3-indolyl)-etbivlamino, or sulfo-lower allkylamino, for exanmple 2-sulfoethylamino.

Acyl R 2 has, for example, up to 25, preferably up to 19, carbon atoms and aa is especially the acyl group of a carboxylic acid, of a aemiester of carbonic acid, of an unsubstituted or N-substituted carbamic or tblqo a carbamic acid, o~f an unsubstituted or N-substituted oxalamide, tf~l phosphoric acid, of a sulfonic acid or of am unsubstituted or N-s dituted amidosulfonic acid.

Preferred acyl groups R2are, for example, alkanoyl, for example n-decanoyl, or lower alkanoyl, for example formyl, acetyl, propionyl or pivaloyl, hydroxy-lower alkanoyl, for example R-hydroxypropionyl, lower alkoxy-lower alkanoyl, for example lower alkoxyacetyl or lower alkoxy- 4propionyl, such as methoxyacetyl or [a-methoxypropionyl, phenoxy-lower 4 Salkanoyl, for example phenoxyacetyl, naphthoxy-lower alkanoyl, for 4 4 example or a-naphthoxyacetyl, lower alkanoyloxy-lower alkamoyl, for ''444 example lower alkamoyloxyacetyl or lower alkanoyloxypropiomyl, such as 4*44 Iacetoxyacetyl or ta-acetoxypropionyl, halo-lower alkanoyl, for example a-haloacetyl, such as a-chloro-, oa-bromo-, ax-iodo- or c,a,c-trichloroacetyl, or Iia4opropionyl, such as 2-chli.ro- or fR-bromo-propionyl, carboxy-lower alkancyl, for example carboxyacetyl or a-carboxypropionyl, lower alkoxycarbonyl-lower alkanoyl, for example lower alkoxycarbonylacetyl or lower alkoxycarbonyipropionyl, such as methoxycarbonylacetyl, f-methioxycarbonylpropionyl, sthoxycarbonylacetyl or (-ethoxycarbonylpropionyl, carbamoyl-lower alkanoyl, for e:xample carbamoylacetyl or 3-carbamoylpropionyl, lower alkylcarbamoyl-lower alkanoyl, for example methylcarbamoylacetyl, di-lower alkylcarbamoyl-lower alkanoyl, for example dimethylcarbamoylacetyl, oxo-lower alkanoyl, for example acetoacetyl or propionylacetyl, hydroxy-carboxy-lower alkanoyl, for example a-hydroxy-a--carboxy--acetyl or c-hydroxy-B-carboxy-propionyl, hydroxylower alkoxycarbonyl-lower alkanoyl, for example a-hydroxy-a-ethoxy- or -methoxy-carbonyl-acetyl or a-hydroxy-(-e thoxy-or -me thoxy-carbonylpropionyl, esterified hydroxy-lower alkoxycarbonyl-lower alkanoyl, for example a-acetoxy-m-methoxycarbonyl-acetyl, dihydroxy-carbo~zy-lower alkanoyl, for eximple a,a(-dihydroxy-1-carboxy-propionyl, dihydroxy-lower alkoxycarbonyl-lower alkanoyl, for example a,f3-dihydroxy-a-ethoxy- or *-retroxy-carbonyl-propionyl, esteritfied dihydroxy-lower alkoxycarbonyl-, icwer alkanoyl, for example a,f-diacetoxy-f-methoxycarbonyl-propionyl, 0 o-naphthoxy-carboxy-lower alkanoyl, for example 2-a-naphthoxy-4-carboxybutyryl, a-naphthoxy-lower alko-xYcarbonyl-lower alkanoyl, for example 0 0c-naphthoxy-ethoxycarbonyl-acetyl, 2-a-naphthoxy-3-ethoxycarbonyl- 0 propionyl, or 2-a-naphthoxy-4-tert.-butoxycarbonyl-butyryl, c-naphthoxy- 0oberizyloxycarbonyl-lower alkanoyl, for example 2-c-naphthoxy-3-benzyloxycarbonyl-propionyl, a-naphthoxy-carbamoyl-lower alkanoyl, for C~xample 2-c-raphthoxy-4-carbamoyl-butyryl, a-naphthoxy-cyano-lower alkanoyl, for example a- naphthoxy-cyano-ace tyl or 2-u-naphthoxy-4-cyano--butyryl, a'c-naphthoxy-di-lower alkylamino-lower alkanoyl, for example 2-tx- 0 0 4 naphthoxy-5-dimethylamino--pentanoyl, c-naphthoxy-oxo-lower alkanoyl, for example 2-u-naphthoxy-4-oxo-pentaqoyl, heterocyclyl-lower alkanoyl, for aexample indulylacetyl or benzofuranylacetyl, lower alkenoyl, for example 4 a acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl., lower alkynroyl, f'-r example propioloyl or 2- or 3-butynoyl, cycloalkylcarbonyl, for Sexample cyclopropyl-, cyclobutyl-, cyclopentyl-or cyclohiexyl-carbonyl, bicycloalkylcarbotiyl, for example decahydronaphthyl-2-carbonyl, en~do- or exo-norbornyl-2-carbonyl, bicyclo[2.2.2]oct-2-ylcarbonyI or bicycloli3.3.lhinon-9-ylcarbonyl, tiicycloalkylcarbonyl, for example 1- or 2-adamantylcarbonyl, cycloalkeny2-arbonyl, for example 1-cyclohexenylcarbonyl or 1, 4-cyclohexadienylcarbonyl, bicycloalkenylcarbonyl, for example 5-norbornen-2-ylcarbonyl or bicycloII2.2.2]octen-2-ylcarbonyi, cycloalkyl-lower alkanoyl, for example cyclopropylacetyl, cyclopentylacetyl, cyclohexylacetyl or 3-cyclohexyipropionyl, cycloalkyl-lower alkenoyl, for example cyclohexylacryloyl, cycloalkenyl-lower alkanoyl, for example 1-cyclohexenylacetyl or 1,4-cyclohexadienylacetyl, benzoyl unsubstituted or mono- or poly-substituted by lower alkyl, for example methyl, phenyl, hialogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, and/or by nitro, for example 4-chloro-, 4-methoxy- or 4-nLtrc-benzoyl, al~'o phenyl-, a-naphthyl- or (2-naphthyl-lower alkanoyl in which plhenyl may be unsubstituted or mono- or poly-substituted by 'lower alkyl, for example methyl, phenyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example metho~y, and/or by nitro and in which lower alkanoyl may be unsubstituted or substituted, for example, by hydroxy, lowe. alkoxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzofuranyl and/or by oxo and is optionally branched., for example phenyl- 0 ,,acetyl, a-naphthylacetyl, Ia-naphthylacetyl, lower alkyiphenylacetyl, such 4-methylphenylacetyl, lo~wer alkoxyphenylacetyl, such as 4-methoxy- 0-0 phenylacetyl, 3-phenylpropionyl, 3-(p-hydroxyphenyl)-propionyl, diphenyl- 4acetyl, di- (4-methoxyphenyl) -ace tyl, triphenylacetyl, substituted anilinopfi,niylacetyl, such as 2-(o,o-dichloroanilino)-phenylacety3 or 2-(o ,o-dichloro-N-benzylani-Lino)-phenylacetyl, 3-an- or -fQ-naphthylpropionyl, 3-phenyl- or 3-c-naphthyl-2-hydroxy-propionyl, 3-phenyl- or 3-in-napthyl-2-lower alkoxy-propionyl, such as 3-phenyl- or 3-in-naphthyl- *''2-neopentyloxy-propionyl, 3-phenyl- or 3 -e-naph thyl.-2 -a cylox y-pro piony I, 441 such as 3-phenyl-2-pivaloyloxy- or -2-acetoxy-propionyl, 3-in-naphthyl-2- 4 pivaloyloxy- or -2 -ace toxy-propionyl, 3-c-naphthyl-2-acetoacetoxy- 4 4 4 4 propiomyl, 3-a-naphthyl-2-ethylaminocarbonyloxy-propionyl or 3-in- Snaphthyl-2-(2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy)propionyl, 3-phenyl- or 3- a-naph thy1- 2- ca rboxyme thy -propionyl1, 3-phenyl- S or 3-c-naphthyl-2-lower alkoxycarbonyl-propionyl, such as 3-in-naphthyl-2ethoxycarbonyl-propionyl, 3-phenyl- or 3-i-naphthyl-2-benzyloxycarbonylnrofprred are compounds of the formula II wherein Al is -12 methyl-propionyl, 3-phenyl- or 3-mx-naphthyl-2-carbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-tert.-butylcarbamoyl-propionyl, 3-phenyl- or 3-x--naphthyl- 2-(2 2-dime thylamino ethyl) -c arbamoyl-propionyl, 3-ci-naphthyl- 2-(carboxy- or tert.-butoxycarbonyl)-methylcarbamoyl-propionyl, 3-phenylor 3-a-naphthyl-2-( 3-hydroxy-2-propyl)-carbamoyl-propionyl, 3-phenyl- or 3- a-.naph thyl-2 2, 2-dime thoxy ethyl) carbamoyl-propionyl, 3-phenyl- or 3-ct-napht'hyl-2-( 5-amino-5-carboxypentyl)-carbamoyl-propionyl, 3-phenyl-or 3-a-naphthyl-2-cyano-propionyl, 3-phenyl- or 3-a-naphthyl-2-cyanomethylpropionyl, 3-phenyl-2-pho sphono- or -phosphonomethyl-propionyl, 3-phenyl- 2 -dime thoxypho sphoryl- or -dime thoxypho sphorylme thyl-propionyl, 3-pbnyl- 2-diethoxyphosphoryl- or -die thoxypho spho rylme thyl-propionyl, 3-phenyl-2ethoxy- or -methoxy-hydroxyphosphoryl-propionyl, 3-phenyl- or 3a naph thyl-2 -ace tonyl-propionyl, 3-phenyl- or 3-c-naphthyl-2 -dime thylaminome thyl-propionyl, 2-benzyl- or 2-a-naph thylIme thy1- 4- cyano-bu tyryl1, 4-phenyl- or 4-u-naphthyl-3-carboxy-bu tyryl, 4-phenyl- or 4-a-naphthyl-3ben zyloxyc arbonyl-bu tyryl, 2 -ben zyl--4- 2-ben zo f uranyl) -4-oxo-bu tyryl, 2-benzyl- or 2-a-naphthylmethyl-4-oxo-pentanoyl, 2-benzyl- or 2a naph ~hyln.,6thyl-4 ,4-dime thyl-3-oxo-pentanoyl, 2-ben zyl- or 2-ca-no'phthyl- 2-benzyl- or dime thylamino-4-oxo-pentanoyl, 2-benzyl- or 2-a-naphthylmethyl-5, dime thyl-4-oxo-hexanoyl, c6,p-diamino--phenylacetyl, a,p-diacylaminopheny lacetyl, such as mx,p-dibenzyloxycarbonylamino-phenylacetyl or a-pivaloylamino-p--beiizyloxycarbonylamino-phenylacetyl, phenyl-lower alkenoyl, for example (-phenylacryloyl or (-phenylvinylacetyl, naphthyl- Scarbonyl, for example or B-naphthylcarbonyl or 1,8-naphthalenedicarbonyl, indenylcarbory.L, for example 2- or 3-indenylcarbonyl, indanylcarbonyl, for example -r 2-indanylcarbonyl, phenanthrenylcarbonyl, for example 9-phenanthrenylcarbonyl, unsubstituted or substituted. pyrrolylcarbonyl, for example 2- or 3-pyrrolylcarbonyl or 4- or ,*2-carbonyl, furyJlcarbonyl, for example 2-i,.'t'ylcarbonyl, thienylcarbonyl, for example 2-thienylcarbonyJ., pyridylcarbonyl, for example 3- or 4-pyridylcarbonyl, unsubstituted or substituted indolylcarbonyl, for example 3- or 5-indolylcarbonyl, 1-methyl-, 5-methyl-, 5-chloro- or 4,5--dimethyl-indolyl-2-carbonyl, 1-benzylindolyl-2- or -3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbo.nyl, cycloheptaI~blpyrroly'L- -carbonyl, unsubstituted or substituted quinolylcar- -13bonyl, for example 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2carbonyl, unsubstituted or substituted isoquinolylcarbonyl, for example 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-benzofui-anylcarbonyl, 3-chromancarbonyl, 3-thiochromancarbonyl, benz lIindolyl-2-carbonyl, fB-carbolinyl-3-carbonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinylcarbonyl, for example 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, for example 5-oxopyrrolidinyl-2-carbonyl, pipe ridinylc arbonyl, for example 3- or 4-piperidinylcarbonyl, indolinylcarbonyl, for example 2- or 3-4irdolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, for example 1,2,3,4-tetrahydroquinolyl2, or -4-carbonyl, 1,2,3,4-tetrahydroisoquinoly'lcarbonyl, for example 1,2,3,4-tetrahyd;roisoquinolyl-l-, or -4-carbonyl or I-oxo-1,2,3,4-tetrahydroisoquinoly.-3-carbonyl, lower alkoxycarbonyl, for example methoxy-, ethoxy- or tert.-lower alkoxycarbonyl, such as tert.-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2-chioro-, 2-brorno-, 2-iodo- or 2,2, 2-trichioro-ethoxycarbonyl:, aryl-lower alkoxycarbonyl, for example arylmethoxycarbonyl, in which aryl is phenyl, biphenylyl, 1- or 2-naphthyl, fluorenyl, or phenyl mono- or poly-substituted by lower alkyl, for example methyl or tert.-butyl, lower alkoxy, for example methoxy, ethoxy or tert,-butoxy, hydroxy, halogen, for example chlorine or bromine, and/o;. by nitro, for example phenyl- 2 lower alkoxycarbonyl, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4 -nitrobenzyloxycarbonyl, diphenyl-lower alkoxycarbonyl, such as %diphenylmethoxycarbonyl, di-(4-methoxyphenyl)-methoxycarbonyl or trityla oxycarbonyl, fluorenyl-lower alkoxycarbonyl, such as 9-fluorenylmethoxy- Scarbonyl, and also oxamoyl or lower alkyloxamoyl, for examp.le methyl- or ethyl-oxamoyl.

Acyl R 2 is also especially an acyl group of a saturated or unsaturated, aliphatic, cycloaliphatic, cycloa.'iphatic-aliphatic, aromatic, aromaticaliphatic, heteroaromatic or heteroaromatic-aliphatic carboxylic acid, 44.twith the exception of the unsubstituted or N-substituted natural amino acid methionine, which acyl group is substituted by a thio, sulfinyl or CL sulfonyl group and optionally by other groups containing hetero atoms.

14 Preferred substituents R 2 are acyl groups of the formula Ra (CH 2 CH (CH 2 C (la), n p

(CH

2 b

R

wherein R a is unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tri-cycloalkyl, cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, aryl-lower alkenyl, unsubstituted or substituted heteroaryl, heteroaryl-lower alkyl, unsubstituted or substituted hydroxy or unsubstituted or substituted amino, Rb is hydrogen, mono-, bi- or tri-cycloalkyl, unsubstituted or substituted S aryl or unsubstituted or substituted heteroaryl, m is 0, 1 or 2, n is 0, or 2, 2 is 0, 1 or 2 and is 0, 1, 2, 3 or 4.

The methine carbon atom in The partial formula la and, if m is 1, also the sulfur atom may be in the S- or R,S-configuration.

Lower alkyl Ra preferably has from 1 to 7 carbon atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert.-butyl, each of which may be substituted by one or more functional groups, for example o000 hydroxy, etherified hydroxy, for example lower alKoxy, such as methoxy or o of on ethoxy, or phenoxy, esterified hydroxy, for example lower alkanoyloxy, °0 such as acetoxy, halogen, for example chlorine or bromine, hydroxysul- *no o o fonyloxy, carboxy, esterified carboxy, for example lower alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl, amidated carboxy, for example car- 0 0 6 bamoyl or mono- or di-lower alkylcarbamoyl, such as methyl- or dimethylcarbamoyl, cyano, amino, substituted amino, for example mono-lower alkylamino, di-lower alkylamino, acylamino, or substituted amino in which the oneo amino group is part of a five-or six-membered heterocycle containing one ao r two nitrogen atoms and, if desired, an oxygen or sulfur atom, or by o o OXO• oxo.

0 0 0 00 0 0.

00 o 0

A

Substituted lower alkyl Ra is, for example, hydroxy-lower alkyl, for example 2-hydroxyethyl, lower alkoxy-lower alkyl, for example lower alkoxyethyl, such as 2-methoxyethyl, phenoxy-lower alkyl, for example 2-phenoxyethyl, lower alkanoyloxy-lower alkyl, for example lower alkanoyloxyethyl, such as 2-acetoxyethyl, halo-lower alkyl, for example haloethyl, such as 2-chloro- or 2-bromo-ethyl, hydroxysulfonyloxy-lower alkyl, for example 2-hydroxysulfonyloxyethyl, carboxy-lower alkyl, for example carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl, for example lower alkoxycarbonylmethyl or lower alkoxycarbonylethyl, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl-lower alkyl, for example carbamoylmethyl or 2-carbamoylethyl, lower alkylcarbamoyl-lower alkyl, for example methylcarbamoylmethyl, di-lower alkylcarbamoyl-lower alkyl, for example dimethvlcarbamoylmethyl, cyano-lower alkyl, for example 2-cyanoethyl, ai lower alkyl, for example 2-aminoethyl, lower alkylamino-lower alki., f-r example 2-methylaminoethyl, di-lower alkylamindlower alkyl, for example 2-dimethylaminoethyl, morpholino-lower alkyl, for example 2-morpholinoethyl, piperidino-lower alkyl, for example 2-piperidinoethyl, acylamino-lower alkyl, for example lower alkanoylamino-lower alkyl, such as 2-acetylaminoethyl, benzyloxycarbonylaminolower alkyl, such as 2-benzyloxycarbon'ylaminoethyl, lower alkoxycarbonyl- 0*0 amino-lower alkyl, such as 2-tert.-butoxycarbonylaminoethyl, or oxo-lower 0000 0,0, alkyl, for example 2-oxopropyl or 2-oxobutyl.

o00 00 0 004 Lower alkenyl Ra contains, for example, from 2 to 7, especially from 2 to 4, carbon atoms and is, for example, vinyl, allyl or 2- or 3-butenyl.

a Lower alkenyl R may be substituted by the same substituents as may lower alkyl, for example by hydroxy, etherified hydroxy, for example methoxy, esterified hydroxy, for example acetoxy, halogen, for example chlorine or bromine, carboxy, esterified carboxy, for example methoxycarbonyl or ethoxycarbonyl, or by amidated carboxy, for example carbamoyl.

Lower alkynyl Ra contains, for example, from 2 to 7, especially from 2 to 4, carbon atoms and is, for example, ethynyl, 1-propynyl or 2-propynyl.

I-.

01 4.001 i 16 ab Cycloalkyl R or R contains, for example, from 3 to 8, especially from 3 to 6, carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

a b Bicycloalkyl R or R contains, for example, from 5 to 10, especially from 6 to 9, carbon atoms and is, for example, bicyclo-hexyl, -heptyl, -octyl, -nonyl or -decyl, for example bicyclo[3.1.0]hex-l-, or -3-yl, bicyclo[4.1.0]hept-1- or -7-yl, bicyclo[2.2.1]hept-2-yl, for example endo- or exo-norbornyl, bicyclo[3.2.1]oct-2-yl, bicyclo[3.3.0]oct-3-yl or bicyclo[3.3.1]non-9-yl, also c- or B-decahydronaphthyl.

Tricycloalkyl R or R contains, for example, from 8 to 10 carbon atoms and is, for example, tricyclol5.2.1.0 2,6]dec-8-yl or adamantyl, such as 1-adamantyl.

Cycloalkyl-lower alkyl Ra contains, for example, from 4 to 10, especially from 4 to 7, carbon atoms and is, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

The cycloaliphatic or cycloaliphatic-aliphatic radicals mentioned may be a substituted by the same substituents as may lower alkyl R 0000 *040 a b S Aryl R or R contains, for example, from 6 to 14 carbn atoms and is, 0. for example, phenyl, indenyl, for example 2- or 4-indenyl, 1- or S" 2-naphthyl, anthryl, for example 1- or 2-anthryl, phenanthiryl, for example 9-phenanthryl, or acenaphthenyl, for example 1-acenaphthenyl.

Aryl Ra or Rb is substituted, for example, by lo':er alkyl, for example methyl, phenyl, hydroxy, lower alkoxy, for example methoxy, acyloxy, for example lower alkanoyloxy, such as acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, acylamino, for example tert.-butoxycarbonylamino, or halogen, for example chlorine, bromine or iodine, it being possible for the substituent to be in any position in the aryl radical, for example in the m- or Q-position of the phenyl radical, and it also being possible for the aryl n radical to be polysubstituted by the same or different substituents.

0 I 0 I-IIILI. l~ 17 Aryl-lower alkyl Ra has, for example, from 7 to 15 carbon atoms and contains, for example, an unsubstituted or substituted, optionally branched radical mentioned under lower alkyl Ra and an unsubstituted or substituted radical mentioned under aryl Ra or R b. Such an aryllower alkyl radical is, for example, benzyl, lower alkylbenzyl, such as 4-methylbenzyl, biphenylylmethyl, such as 4-biphenylylmethyl, lower alkoxybenzyl, such as 4-methoxybenzyl, 2-phenylethyl, 2-(p-hydroxyphenyl)-ethyl, diphenylmethyl, di-(4-methoxyphenyl)-methyl, trityl or aor B-naphthylmethyl.

Aryl-lower alkenyl Ra has, for example, from 8 to 16 carbon atoms and contains, for example, an unsubstituted or substituted radical mentioned under lower alkenyl Ra and an unsubstituted or substituted radical mentioned under aryl Ra or Rb. Such an aryl-lower alkenyl radical is, for example, styryl, 3-phenylallyl, 2-(a-naphthyl)-vinyl or 2-(a-naphthyl)vinyl.

a b Unsubstituted or substituted heteroaryl R or R is mono-, bi- or tricyclic and contains one or two nitrogen atoms dnd/or an oxygen or sulfur a b atom. R or R is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, n quinolyl, isoquinolyl, quinoxalinyl, B-carbolinyl or a benzo-fused or 0000 0 oP cyclopenta-, cyclohexa- or cyclobopta-fused derivative of those radicals.

0o This heterocycle may be partially saturated and, at a nitrogen atom, it 00 0 o 0 may be substituted by oxido, lower alkyl, for example methyl or ethyl, 00 0 phenyl, or phenyl-lower alkyl, for example benzyl, and/or, at one or more carbon atoms, it may be substituted by lower alkyl, for example methyl, ooUO phenyl, phenyl-lower alkyl, for example benzyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, phenyl-lower alkoxy, for example benzyloxy, or by oxo, and is, for example, 2- or S 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, o 2-furyl, 2-thienyl, 4-imidazolyl, methyl-imidazolyl, for example l-methyl-2-, or -5-imidazolyl, 1,3-thiazol-2-yl, 3-or 4-pyridyl, 00 0, 1-oxido-2-, or -4-pyridinio, 2-pyrazinyl, 4- or cJea 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, "'0"0

A

18 1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[bl- 3- or 4 -quinolyl, 4-hydroxy-2-quinolyl, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzothiazolyl, benz[e]indol-2-yl or Q-carbolin-3-yl.

Hoteroaryl-lower alkyl Ra contains, for example, an unsubstituted or substituted radical mentioned under lower alkyl Ra and an unsubstituted or substituted radical mentioned under heteroaryl Ra or Rb and is, for example, 2- or 3-pyrrolylmethyl, 3- or 4-pyridylmethyl, 3-or 4-pyridyl)-ethyl, 4-imidazolylmethyl, 2-(4-imidazolyl)-ethyl, 2- or 3indolylmethyl, 2-(3-indolyl)-ethyl or 2-quinolylmethyl.

a SHydroxy R is unsubstituted or substituted, for example, by lower alkyl or aryl and is, for example, hydroxy, methoxy, ethoxy, n-butoxy, phenoxy, 4-hydroxyphenoxy or 3, 4 -methylenedioxyphenoxy.

a Amino R is unsubstituted or substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl or is part of a five- or six-membered heterocycle containing one or two nitrogen atoms and, if desired, an oxygen or sulfur 0000 atom and is, for example, amino, methylamino, ethylamino, isopropylamino, 0000 0 0a n-butylamino, dimethylamino, diethylamino, benzylamino, acetylamino, cc 0 00 o0 pivaloylamino, methoxy-, ethoxy- or tert.-butoxy-carbonylamino, benzyl- 00 o 00 oxycarbonylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-methyl-4-pyridazinyl, 1) 00 7 0 4-morpholinyl or 4-thiomorpholinyl.

0 0000 Salts are especially the pharmaceutically acceptable non-toxic salts of compounds of the formula I.

0000 o0 Such salts are formed, for example; by compounds of the formula I having oo00 an acidic group, for example a carboxy group, and are, especially, 0 00 suitable alkali metal salts, for example sodium or potassium salts, or o00 o 0 o0 suitable alkaline earth metal salts, for example magnesium or calcium oo*oo salts, and also zinc salts or ammonium salts, and also those salts which 0 0 are formed with organic amines, such as unsubstituted or hydroxy-substi- 0000 0 0 o 32 19 tuted mono-, di- or tri-alkylamines, for example diethylamine, di-(2hydroxyethyl)-amine, triethylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine, tri-(2-hydr(:yethyl)-amine or N-methyi--D-glucamine. The compounds of the formula I having a basic group, for example an amino group, can form acid addition salts, for example with inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic or sulfo acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and with amino acids, such as, for example, the a-amino acids mentioned hereinbefore, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyeth;3nesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthal.ene-2-sulfonic acid, or with other acidic organic compounds, such as ascorbic acid. Compounds of the formula I having acidic and basic groups can also form internal salts.

For the purposes of isolation or purification it is also possible to use pharmaceutically unsuitable salts.

The compounds of the present invention exhibit gag-protease-inhibiting Seffects. In particular, they inhibit the action of the gag-protease of o* HIV-1 and HIV-2 in concentrations as low as the nanomolar range and are 4 i4 therefore suitable as agents against diseases caused by these or related retroviruses, such as, for example, against AIDS.

The ability of the compounds of the formula I to inhibit the proteolytic activity of, for example, HIV-1 protease can be demonstrated, for example, in accordance with the method described by J. Hansen et al., The EMBO Journal 7, 1785-1791 (1988). The inhibition of the action of gagprotease is measured on a substrate that is a fusion protein, expressed in E. coli, of the gag-precursor protein and MS-2. The substrate and its cleavage products are separated by polyacrylamide gel electrophoresis and rendered visible by immunoblotting with monoclonal antibodies to MS-2.

I t' 4 4 20 In a test that is even easier to use and that permits exact quantitative statements to be made, a synthetic icosapeptide that corresponds to the cleavage site of the gag precursor protein is used as the substrate for the gag protease. This substrate and its cleavage products can be measured by high pressure liquid chromatography (IHPLC). In this test, compounds of the present invention exhibit inhibitory effects in concen- -6 trations of 10 mol/l.

In another test, it is possible to demonstrate that the compounds of the present invention protect cells that are usually infected by HIV against such infection or at least retard such infection. In this test, the human T-cell leukaemia cell line MT-2 (Science 229, 563 (1985)), which is extremely sensitive to the cytopathogenic effect of HIV, is incubated with HIV only or with HIV in the presence of the compounds according to the invention and after a few days the viability of the cells so treated is evaluated. Compounds according to the invention exhibit infection- -5 inhibiting effects in concentrations of 10 5 mol/l.

Preferred compounds of the formu.a I have two or more c-amino acid residues in ,he radical AAN, or the radical AAN consists of only one a-amino acid residue and at the same time the radical R 2 is an analogue of phenylalanyl (H-Phe-) and/or they have two a-amino acid reaidues in S the radical AAC, or the radical AAC consists of only one a-amino acid S O e residue and at the same time the radical R I is an analogue of the S residue, bonded via the nitrogen, of the amino acid tyrosine (-Tyr-OH).

A radical R 2 that may be regarded as an analogue of phenylalanyl has the structural element of the formula

S

3(Ib) trrrs' 21 wherein the carbocyclic ring may also be completely or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked to C 2 or C 3 to form a preferably five- or six-membered ring, one of the carbon atoms C 2 and C 3 may have been replaced by a hetero group or atom, such as NH, O or S, the carbonyl group may be a heterocarbonyl group, such as P=O, and free valencies carry hydrogen or substituents, for example lower alkyl, lower alkylthio-lower alkyl, lower alkylsulfinyllower alkyl, lowe: alkylsulfonyl-lower alkvl, phenyl-lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, amino-lower alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, lower alkanoyl, lower alkanoyl-lower alkyl or lower alkylcarbamoyl, these substituents preferably being at C 2 A completely or partially saturated carbocyclic ring is in this connection, for example, cyclohexyl or cyclohexenyl. Five- or six-membered rings in the sense of the above paragraph are, for example, phenyl, cyclohexyl, pyrrolyl, pyranyl, dihydropyranyl or thio analogues of the mentioned heterocyclyl radicals. These definitions also apply to the radicals R' described below that are analogous to tyrosine.

Such analogues R2 are, for example, 3-phenyl- or 3-cyclohexyl-propionyl ag which may be substituted, especially in the 2-position, by substituents of the type: lower alkyl, such as methyl, ethyl or tert.-butyl, lower alkylthio-lower alkyl, such as tert.-butylthiomethyl, lower alkylsul- S finyl-lowar alkyl, such as tert.-butylsulfipylmethyl, lower alkylsula O 0 j fonyl-lower alkyl, such as tert.-butylsulfonylmethyl, phenyl-lower alkyl, such as benzyl, hydroxy, lower alkoxy, such as methoxy, phenyl-lower bOla alkoxy, such as benzyloxy, amino-lower alkyl, such as aminomethyl or 2-amino-2-propyl, lower alkylamino-lower alkyl, such as methylaminomethyl, lower alkanoylamino-lower alkyl, such as acetylaminomethyl, lower alkanoyl, such as acetyl, lower alkanoyl-lower alkyl, such as acetylmethyl, isobutyrylmethyl or pivaloylmethyl, or lower alkylcarbamoyl, such as methylcarbamoyl, or such analogues R 2 are, for example, 2-naphthylcarbonyl or hydrogenated forms thereof, auch as, for example, 2-decahydronaphthylcarbonyl, 2-(3-indolyl)-acetyl or 2-(3-benzofuranyl)-acetyl, 3-chroman- or 3-thiochroman-carbonyl, or dibenzyloxyphosphoryl.

4$ i (rI t1K 1 22 A radical R 1 that may be regarded as an analogue of the residue, bonded via the nitrogen, of the amino acid tyrosine has the structural element of the formula

I

c) Y v wherein the carbocyclic ring may contain a hetero atom, such as nitrogen, and may also be completely or partially saturated and/or substituted, for example by hydroxy or by phenyl, the index v is 0 to 5, for example 0 to 3, one of the carbon atoms of the carbocyclic ring may be bonded to one of the atoms to form a preferably five- or six-membered ring and free valencies carry hydrogen or subscituents, for example lower alkyl or hydroxy-lower alkyl. Such a radical R I which may be regarded as an analogue of the residue of the amino acid tyrosine may also be lower alkylamino.

Such analogues R 1 are, for example, butylamino, cyclohexylamino, 2-deca- .oo, hydronaphthylamino, 6-hydroxy-2-tetrahydronaphthylamino or 2-tetrahydroo o naphthylamino, 6-hydroxy-2-naphthylamino or 2-naphthylamino, pyridyl- 0 methylamino, phenyl- or hydroxyphenyl-lower alkylamino, such as 2-phenyla oo Sco or hydroxyphenyl-ethylamino or 5-phenyl- or hydroxyphenyl-pentylamino, O b 0 o0 1-hydroxymethyl-2-hydroxyphenylethylamino or biphenylyl-lower alkylamino, ".0O such as 4-biphenylylmethylamino.

Preferred compounds according to the invention are compounds of the formula II i 4

I

1 I 2 Al A I a 23 wherein each of the radicals Al, A2, A3 and A4 is a bivalent a-;'mino acid residue that is bonded N-terminally to the radical to the left of it in formula II and C-terminally to the radical to the right of it, or to the radical R 1 A5 ij a single bond or a bivalent radical consisting of up to three peptide-linked a-amino acids which is bonded N-terminally to R 2 and C-terminally to A4, and the other symbols are as defined for formula I.

Preferred are compounds of the formula II wherein Al is selected from among the bivalent residues of tyrosine (Tyr), phenylalanine (Phe), naphthylalanine (Nal), tryptophan (Trp), lysine (Lys) and aspartic acid (Asp), A2 is selected from among the bivalent residues of valine (Val), isoleucine (Ile), leucine (Leu), norleucine (Nle), phenylalanine (Phe), alanine (Ala) and glycine (Gly), A3 is selected from among the bivalent residues of valine (Val), alanine (Ala), leucine (Leu), isoleucine (Ile), asparagine (Asn), glutamine (Gln), norleucine (Nle), phenylalanine (Phe), serine (Ser) and histidine (His), A'4 is selected from among the bivalent residues of phenylalanine (Phe), tyrosine (Tyr) (including tyrosine etherified by lower alkyl), tryptophan (Trp), cyclohexylalanine (Cha), leucine (Leu), naphthylalanine (Nal), histidine (His), asportic acid o (Asp) and lysine (Lys), and the other symbols are as defined for o oo formula II.

o 0 0 o Also preferred are compounds of the formula II wherein Al, A2, A3 and A4 o o have the meanings given immediately above, A5 is a single bond or a bivalent radical consisting of up to three identical or different peptide-linked a-amino acids selected from among arginine, proline, histidine, lysine, ornithine and tryptophan, R I is hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R 2 is hydrog< lower oa 0 5 alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or a radical of the formula R CH (CH) C (la), 6 n p 6 «0Sm (CHz) o a q Rb 0 0 24 wherein Ra is lower alkyl which is unsubstituted or substituted by hydroxy or by lover alkoxy, for example methyl, ethyl, isopropyl, tert.butyl, 2-hydroxyethyl or 2-methoxyethyl, phenyl, benzyl, or heteroaryl, having 1 or 2 nitrogen atoms, which is unsubstituted or substituted by oxido or by lower alkyi, for exampeia 2- or 4-imidazolyl, 1-methyl-2imidazolyl, 3- or 4-pyridyl, 1-ox-uo-2-, or -4-pyridinio or 2-pyrimidinyl, Rb is cyclohexyl )r phenyl, m is 0, 1 or 2, n is 1, p is 0 and q is 1 or 2, and salts thereof.

Among these compounds, those in .:hich A5 is a single bond or the bivalent residue Arg-Arg-Pro are preferred.

Especially preferred are compounds of the formula II wherein Al is selected from among Tyr, Phe, Trp, Nal, Lys and Asp, A2 and A3 are selected from among Val, Ile, Leu, Nle and Ala, A4 is Phe, Tyr or Nal, is a bond, RI hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is hydrogen, lowei alkanoy lower alkoxycarbonyl, or unsubstituted or lower alkoxy-substituted pl nyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, and salts thereof.

0,so Also especially preferred are compounds of the formula II wherein Al is S Tyr, A2 is selected from among Val, Ile, Nle, Leu, Phe, Ala and Gly, A3 is Val, A4 is Phe, Tyr or Nal, A5 is a bond, RI is hydroxy, lower alkoxy, lower alkylamino or amino, rind R 2 is hydrogen, lower alkanoyl, lower 00*0 400 alkoxycarbonyl, or unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alko ycarbonyl or fluorenyl-lower alkoxycarbonyl, and salts Liereof.

Also especially preferred are compounds of the formula II wherein Al is t Tyr, A2 is Val &r Leu, A3 is selected from amog Val, Leu, Ile, Nle, Ala, Asn, Gl, Phe, Ser and His, A4 is Phe, A5 is a bond, X1 is hydroxy, lower S alkoxy, lower alkylamino or amino, and R 2 is hydrogen, lower alkanoyl, s* lower lkoxycarbonyl, or unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-mwer alkoxycarbonyl or fluorenyl- 0e: lower alkoxyearbonyl, and salts thereof.

0 7 i i*l~s: -hlll1~-~-~I -^-F1 25 Also especially preferred are compounds of the formula II wherein Al is Tyr, A2 is Val or Leu, A3 is Val, A4 is selected from among Phe, Tyr, methyl-etherified Tyr, Trp, Cha, Leu, Nal and Lys, A5 is a bond, R 1 is hydroxy, lower alkoxy, lower alkylamino or amino, rand RP is hydrogen, lower alkanoyl, lower alkoxycarbonyl, or unsubstituted or lower alkoxysubstituted phonyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, and salts thereof.

Also preferred are the compounds of the formula III v YH

R

2 A3 -'R A2 -Al R

(III)

o ,oo 0 0 00 o a 00 0 a0 0 0 a 00 0 0000 0000 0 OO00 which fall within the scope of the compounds of the formula I and wherein all the symbols are as defined for formula II.

Preferred are compounds of the formula III wherein Al is selected from among the bivalent residues of tyrosine (Tyr), phenylalanine (Phe), Tryptophan (Trp), e-naphthylalanine (Nal), lysine (Lys) and aspartic acid (Asp), A2 is selected from among the bivalent residues of valine (Val), isoleucine (Ile), leucine (Leu), norleucine (Nle), phenylalanine (Phe), alanine (Ala) and glycine (Gly), A3 is selected from among the bivalent residues of valine (Val), alanine (Ala), leucine (Leu), isoleucine (Ile), asparagine (Asn), glutamine (Gln), norieucine (Nle), phenylalanine (Phe), serine (Ser) and histidine (His), and the other symbols are as defined for formula I.

Likewise preferred are compounds of the formula III wherein Al, A2, R

I

and R 2 are as defined and A3 is the bivalent residue of tyrosine (Tyr) or Sof tyrosine etherified by lower alkyl.

tt, 26 Also preferred are compounds of the formula III wherein Al, A2 and A3 are as defined immediately above, R' is hydroxy, lower alkoxy, amino or monoor di-lower alkylamino, and R 2 is a radical of the formula Ra- CH (CHz) C (la), n p 8

(CH

2 q

R

wherein R a is lower alkyl which is unsubstituted or substituted by hydroxy or by lower alkoxy, for example methyl, ethyl, isopropyl, tert.butyl, 2-hydroxyethyl or 2-methoxyethyl, phenyl, benzyl, or heteroaryl, having 1 or 2 nitrogen atoms, which is unsubstituted or substituted by oxido or by lower alkyl, for example 2- or 4-imidazolyl, l-methyl-2imidazolyl, 3- or 4-pyridyl, l-oxido-2-, or -4-pyridinio or 2-pyrimidiny., R b is cyclohexyl or phenyl, m is 0, 1 or 2, n is 1, R is 0 and g is 1 or 2.

Likewise preferred are compounds of the formula III wherein Al, A2, A3 and R 1 are as defined immediately above and R 2 is a radical having the 000o .o.u structural element Ib which may be regarded as an analogue of phenylo oo alanyl, as defined hereinbefore.

0o 0 a 00 Especially preferred are compounds of the formula III wherein Al is selected from among Tyr, Phe, Trp, Nal, Lys and Asp, A2 and A3 are Val or 000 "*00 Leu, RI is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is a radical of the formula Ia wherein R a is lower alkyl, R b is phenyl and m is 2, n is 1, p is 0 and is 1, and salts thereof.

00 I I Especially preferred are also compounds of the formula III wherein Al is STyr, A2 is selected from among Val, Ile, Leu, Nle, Phe, Ala and Gly, A3 is Val or Leu, R' is hydroxy, lower alkoxy, lower alkylamio or amino, and R 2 is a radical of the formula Ia wherein Ra is lower alkyl, Rb is phenyl and m is 2, n is 1, p is 0 and g is 1, and salts thereof.

S4 a 4 i 4 i 4 1 27 Especially preferred are also compounds of the formula III wherein Al is Tyr, A2 is Val or Leu, A3 is selected from among Val, Ala, Leu, Ile, Asn, Gln, Nle, Phe, Ser and His, R I is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is a radical of the formula Ia wherein R is lower alkyl, R b is phenyl and m is 2, n is 1, p is 0 and is 1, and salts thereof.

Especially preferred are also compounds of the formula III wherein Al is Tyr, A2 is Val, A3 is selected from among Val, Leu, Nle, Phe, Ala, Ser, Tyr and Tyr etherified by lower alkyl, R! is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is 3-phenyl- or 3-cyclohexyl-propionyl which is substituted in the 2-position by lower alkylsulfonyl-lower alkyl or by lower alkanoyl-lower alkyl, and salts thereof.

Also preferred are the compounds of the formula R2 A3 -N -A2 R (IV), which fall within the scope of the compounds of the formula I and wherein A2 and A3 are as defined under formula I, R 1 is a radical which may be 0400 orra regarded as an analogue of the residue, bonded via the nitrogen, of the amino acid tyrosine, and R 2 is a radical which may be regarded as an analogue of phenylalanyl, and salts thereof.

S The compounds of the formula IV that are preferred are those wherein A2 o 41 is selected from among the bivalent residues of valine (Val), Isoleucine (Ile), norleucine (Nle), leucine (Leu), phenylalanine (Phe), alanine 4 (Ala) and glycine (Gly), and A3 is selected from among the bivalent residues of valine (Val), alanine (Ala), leucine (Leu), asparagine (Asn), 6a a acte 'Clii t t 28 glutamine (Gln), norleucine (Nle), phenylalanine (Phe), serine (Ser) and histidine (His), especially those wherein each of A2 and A3 is Val or Leu.

Especially preferred are compounds of the formula IV wherein A2 is valine, A3 is selected from among Val, Leu, Nle, Phe, Ala, Ser, Tyr and Tyr etherified by lower alkyl, RI is lower alkylamino or a radical having the structural element of the formula Ic wherein the carbocyclic ring may be unsubstituted or substituted by hydroxy or by phenyl, the index v is 0 to 5 and free valencies carry hydrogen, and R 2 is 3-phenyl- or 3-cyclohexyl-propionyl which is substituted in the 2-position by lower alkylsulfonyl-lower alkyl or by lower alkanoyl-lower alkyl, and salts thereof.

The invention relates first and foremost to the compounds mentioned in the Examples and salts thereof.

The compounds of the formula I according to the invention and salts of such compounds having at least one salt-forming group are obtained by processes known per se, for example by 000 000 o0 a) condensing a fragment of a compound of the formula I having a terminal S carboxy group or a reactive acid derivative of that fragment with a 00 o fragment that is complementary to the compound of the formula I and has a °oo free amino group or with a reactive derivative thereof having an activated amino group to form an amide bond, functional groups present in 0000 the reactants, with the exception of the groups participating in the reaction, optionally being in protected form, or b) reducing the keto group in a compound of the formula 000.71 p 0H(CH 3 )2 0

R

2 -AAN H-C-CH- CH AAC-R CHz CsHii So* 0 0 oU 004 6 0 01 29 wherein the symbols are as defined and functional groups, with the exception of the keto group participating in the reaction, are optionally in protected form, to a hydroxy group by reaction with a suitable reducing agent, or c) reacting an aldehyde compound of the formula

R

2 AAN H H (VI), R' H C6H 11 wherein the symbols are as defined and functional groups, with the exception of the aldehyde group, are optionally in proticted form, with an organometal compound of the formula

CH(CH

3 2 M CH2 CH AAC R 1

(VII),

wherein the symbols are as defined and M is a metal radical, and hydrolysing the resulting addition product, or s. d) in a compound of the formula X YH(CH 3 2 So R2 AAN H CH H AAC R (VIII), CH2 C6H11 0 HO o wherein X is a nucleofagal leaving group, the other symbols are as 00"a defined above and functional groups are optionally in protected form, replacing the substituent X by a hydroxy group, or ,s e) in a compound of the formula 2H CH(CH3)2 f R AAN z H CH CH -AAC' CN (IX), CH2 C6H 11 1 t wherein the symbols are as defined and AAC' has the meaning of AAC without the terminal carbonyl group, and functional groups present are S optionally in protected form, converting the group AAC'-CN into a group

AAC-.

1 or '4 f) in a compound of the formula 0 CH(CH3)2

R

2 AAN N H C-H CH C AAC R CH C6sH 1 wherein the symbols are as defined and functional groups are optionally in protected form, reducing the epoxy group to a hydroxy group using a regioselective reducing agent, or g) for the preparation of a compound of the formula I wherein R 2 is a radical of the formula R a (CH 2 CH (CH2) m

(CR

2 q b

R

and m is 0 or 2, n is 1 and p is 0, adding a compound of the formula Ra-S(O) H or a salt thereof to a compound of the formula m 7" o R H yH(CH 3 2 0

-(CH

2 AAN- CH AAC R (XI), °L H C6Hjj 000 O 0 000 oo, wherein the symbols are as defined and functional groups are optionally o 0 0 0 in protected form, or h) for the preparation of a compound of the formula I wherein R 2 is a a 0o radical of the formula 0 0 m (CH2) o q q 0 R 00 "00 0 00 and p is 0, alkylating a compound of the formula 0oo00 00006o 0 0 -31 a (H H(CH3)2 Ra C AAN H- CH CH 2 CH AAC -R CHH CsH1I m

(XII),

wherein the symbols are as defined and functional groups are optionally in protected form, with a compound that introduces the radical R and, if desired, i) removing protecting groups present in a resulting compound and/or, if desired, after carrying out one of the processes a) h) mentioned above or any other process for the pr-oaration of a compound of the formula I, converting a resulting compound of the formula I having a salt-forming group into its salt or converting a resulting salt into the free compound or into a different salt and/or optionally separating resulting isomeric mixtures and/or, in a resulting compound of the formula I, reversing the configuration of a chiral carbon atom and/or converting a compound of the formula I according to the invention into a different compound of the formula I according to the invention.

The invention relates also to the compounds other than compounds of the formula I, obtainable according to any one of the processes mentioned So above (by-product), and to compounds of the formula I and salts thereof o e. that have been prepared by a process other than one of those mentioned 04 0 hereinbefore.

0500 Process a) (Production of an amide bond): -j Fragments of a compound of the formula I having a tetminal carboxy group oo that can be condensed with a fragment complementary to a compound of the formula I to form an amide bond are, for example, compounds of the formulae: R 2 OH, R 2 A5-OH, R 2 A5-A4-OH, R 2

AN-OH,

04 6 0 0 0 °H CH(CH 3 2

R

2 AAN H H CH H OH, o. CH 2 CsHi 0HHCH0

SR

2 N -H H CH A2 OH or CH2 C6HI

A

1 32 OR2 H -H(CH3)2

R

2 -AAN H CH CH AAC GH, CH C 8 Hi_ the activated esters or reactive anhydrides derived from these compounds, and also reactive cyclic amides. The reactive acid derivatives can also be formed in situ.

Activated esters are especially esters that are unsaturated at the linking carbon atom of the esterifying radical, for example of the vinyl ester type, such as vinyl esters (obtainable, for example, by transesterifying a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl esters (obtainable, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N'-disubstituted amidino esters (obtainable, for example, by treating the corresponding acid with a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide; carbodiimide method), or N,N- S disubstituted amidino esters (obtainable, for example, by treating the S corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters substituted by I ee electron-attracting substituents (obtainable, for example, by treating OaR( S the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensati'on agent, such as N,N'-dicyclohexylcarbodiimide; activated aryl ester method), cyanomethyl esters (obtainable, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thio esters, especially phenylthio esters that are unsubstituted or substituted, for example, by nitro (obtainable, for example, by treating the corresponding acid with thiophenols that are unsubstituted or substituted, for example, by nitro, inter alia with the aid of the anhydride or carbodiimide method, h i -33 activated thio ester method), or especially amino or amido esters (obtainable, for example, by treating the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound or activated derivatives thereof, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene- or -norbornane-2,3-dicarboxylic acid imide, 1-hydroxybenzotriazole or benzotriazol-1-yloxyphosphonium salts or O-benzotriazol-l-yluronium salts, or 3-hydroxy-3,4dihydro-1,2,3-benzotriazin-4-one, for example according to the anhydride or carbodiimide method; activated N-hydroxy-ester method).

Anhydrides of acids may be symmetrical or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester by way of the corresponding hydrazide and the treatment of the latter with nitrous acid; azide method), anhydrides with carbonic acid semi-esters, for example carbonic acid lower alkyl semi-esters (obtainable, for example, by treating the corresponding acid oia with chloroformic acid lower alkyl esters, or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-ethoxy- O r! 0 carbonyl-2-ethoxy-l,2-dihydroquinoline; mixed 0-alkylcarbonic acid C,0 S" anhydride method), anhydrides with dihalogenated, especially 0 eg o"a dichlorinated, phosphoric arid (obtainable. for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (for example those which can be obtained with phenyl-N-phenylphosphoramidochloridate) or with phosphorous acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an unsubstituted or substituted lower alkanecarboxylic acid halide or phenyl-lower alkanecarboxylic acid halide, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydride method) or with organic sulfonic acids (obtainable, for example, by treating a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as 34 a lower alkanesulfonic acid chloride or arylsulfonic acid chloride, for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydride method) and symmetric anhydrides (obtainable, for example, by condensing the corresponding acid in the presence of a carbodiimide or of l-diethylaminopropyne; symmetrical anhydride method).

Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazcles, for example imidazole (obtainable, for example, by treating the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazoles, for example 3,5-dimethylpyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone; pyrazolide method).

S Fragments having a free amino group that are complementary to the compound of the formula I are, for example, depending on the meaning of R

I

a primary or secondary amine, or also compounds of the formula: 0000 H H(CH 3 2 oo B H AAN H H CH 2 H AAC R 0 C oo oo C 2 C6H11 0 9H CH(CH3)2 H A4 A3 -N H CH CH 2 H AAC R,' o H CgHll -H 2 I 0000 oo 0 o 9H oH(CH3)2 0 H -A3 -N-H CH -CH- CH- C AAC R 1 CH2 CsHII H H CH(CH3)2 0 o H H CH CH2 CHC- AAC R SCHz C6H11 0 0u 0 0 o0 O The amino group that is present in a fragment complementary to a compound 0 0 of the formula I and participates in the reaction is preferably in free form, especially if the carboxy group reacting therewith is in reactive form; it can also, however, itself be derivatised, for example by reac- S tion with a phosphite, such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite. A derivative of such a complementary fragment

A

having an amino group is, for example, also a carbamic acid halide or an isocyanate, the amino group participating in the reaction being substituted by halocarbonyl, for example chlorocarbonyl, or modified in the form of an isocyanate group, it being possible in the latter case to obtain only compounds of the formula I that have a hydrogen atom at the nitrogen atom of the amide group formed by the reaction.

If the complementary fragment having an amino group is an amine mono- or di-substituted oy lower alkyl or aryl-l.wer alkyl then a corresponding urea compound also constitutes a reactive derivative. For example, on heating equimolar amounts of this urea compound and the component having a free carboxy group, corresponding compounds of the formula I are obtained. If the complementary fragment is dimethylamine, then dimethylformamide is also a reactive derivative.

Functional groups in starting materials, the reaction of which is to be avoided, especially carboxy, amino, hydroxy, mercapto and sulfo groups, .ooo can be protected by suitable protecting groups that are customarily used 0 00 o o.o in the synthesis of peptide compounds, but also of cephalosporins and penicillins. These protecting groups may already be present in the preo 0 cursors and are intended to protect the functional groups in question against undesired side-reactions, such as acylation, etherification, esterification, oxidation, solvolysis, etc.. Protecting groups may, however, also be present in the end products. Compounds of the formula I having protected functional groups can have a higher metabolic stability S than can the corresponding compounds having free functional groups.

a 00 00 0 The protection of functional groups by such protecting groups, the protecting groups themselves and the reactions by which they are removed 0 Sare described, for example, in standard works, such as in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Th. W. Greene, "Protective Groups in Organic "00. Synthesis", Wiley, New York 1981, in "The Peptides", volume 3 (edited by 0 O 0 E. Gross and J. Meienhofer), Academic Press, London and New York 1981, and in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, vol. 15/I, Georg Thieme Verlag, Stuttgart 1974.

i 36 A carboxy group is protected, for example, in the form of an ester group that is selectively cleavable under mild conditions. A carboxy group protected in esterified form is esterified especially by a lower alkyl group that is branched in the 1-positionr of the lower alkyl group or substituted by suitable substituents in the 1- or 2-position of the lower alkyl group.

A protected carboxy group esterified by a lower alkyl group that is branched in the 1-position of the lower alkyl group is, for example, tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl, or arylmethoxycarbonyl having one or two aryl radicals in which aryl is unsubstituted phenyl or phenyl mono-, di- or tri-substituted, for example, by lower alkyl, for example tert.-lower alkyl, such as tert.-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the meintioned substituents, for example 4-nitrabenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by the mentioned substituents, for example di-(4-metoxyphenyl)-methoxyc rbonyl.

000 a 00 00 03 4 00 0 0490 044 0 04 i O A protected carboxy group esterified by a lower alkyl group that is sub- S stituted by suitable substituents in the 1- or 2-position of the lower alkyl group is, for example, 1-lower alkoxy-lower alkoxycarbonyl, for example methoxymethoxycarbcayl, 1-metoxyethoxycarbonyl or 1-ethoxy- *0 ethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl, for example 3 methylthiomethoxycarbonyl or 1 -ethylthioethoxycarbonyl, aroylmethoxy- S carbonyl, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichlocoethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, and also 2-tri-lower alkylsilyl-lower alkoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl.

tt0 L(tt0t0 A carboxy group can also be protected in the form of an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbony group, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be

A

4-Y 37 substituted by two lower alkyl groups, for examn3 ,:Pthyl groups, and by the amino group or the carboxy group of a second molecule of the formula I. Compounds having such protect.ing group, cin be prepared, for example, with dimethylchlorosilane as the silylating agent.

A protected carboxy group is preferably tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.

An amino group can be protected, for example, in the form of an acylamino, arylmethylamino, etherified mercaptoamino or silylamino group or in the form of an azido group.

In a corresponding acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially of a lower alkanecarboxylic acid that is unsubstitut(d or substituted, for example, by halogen or aryl, or of 9000 cOO benzoic acid that is unsubstituted or substituted, for example, by oa halogen, lower alkoxy or nitro, or preferably of a carbonic acid semio ester. Such acyl groups are, for example, lower alkanoyl, such as formyl, o O0 acetyl, propionyl or pivaloyl, halo-lower alkanoyl, for example 2-haloo000 oooo acetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- oi 2,2,2cost trichloro-acetyl, benzoyl that is unsubstituted or substituted, for example, by halogen, lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxy- S carbonyl that is branched in the 1-position of the lower alkyl radical or S suitably substituted in the 1- or 2-position, for example tert.-lower o alkoxycarbonyl, such as tert.-butoxycarbonyl, arylmethoxycarbonyl having o ne or two aryl radicals which are phenyl that is unsubstituted or mono- S or poly-substituted, for example, by lower alkyl, for example tert.-lower 0o c alkyl, such as tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by nitro, for example bentyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or di-(4eooo9 o methoxyphenyl)-methoxycarbonyl, aroylmethoxycarbonyl, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2-chloroethoxycarbonyl, 2,2,Z-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 38 2-iodoethoxycarbonyl, 2-tti-lower alkylsilyl-lower alkoxycarbonyl, for example 2-trimethy1siiylethoxycarbonyl, or 2-triarylsilyl-lower alkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.

An aryimethylamino group is, for example, mono-, di- or, especially, tri-phenylmethylamino, for example benzyl-, diphenylmethyl- or tritylamino.

In an etherified mercaptoamino group, the etherified mercapto group is especially substituted arylthio, for example 4-nitrophenylthio.

A silylamino group is, for example, a tri-lower alkylsilylamino group, for example trimethylsilylamino. The silicon atom of the silylamino group can also be substituted by only two low c alkyl groups, for example methyl groups, and by the amino group or carboxy group of a second molecule of the formula I. Compounds having such protecting groups can be prepared, for example, with dimethylchlorosilane as the silylating agent.

0 Oaoo o rO Preferred amino-protecting groups are acyl radicals of carbonic acid S semi-esters, especially tert,.-butoxycarbonyl, unsubstituted or substi- Stuted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, diphenylo methoxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trio chloroethoxycarbonyl, and also trityl and fo.

A hydroxy group can be protected, for example, by a lower alkanoyl group substituted by halogen, for example chlorine, for example 2,2-dichloroacetyl, or especially by a carbonic acid semi-ester acyl radical o oi S mentioned for protected amino groups. A preferred hydroxy-protecting group is, for example, 2-chloroethoxycarbonyL, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl. A hydroxy group cin also be protected by trilower alkylsilyl, for example trimethylsilyl or, preferably, dimethyl-tert.-butylsilyl, a readily 6td removable alkyl group, such as tert.-lower alkyl, for example tert.butyl, an oxa- or a thia-aliphatic or -cycloaliphatic hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower alkylthiolower alkyl, for example methoxymethyl, 1-methoxyethyl, l-ethoxyethyl, -39 methylthiomethyl, l-methylthioethyl or l-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl having from 5 to 7 ring atoms, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, or so by 1-phenyl-lower alkyl, for example benzyl, diphenylmethyl or trityl, it being possible for the pheny.L radicals to be substituted, for example, by halogen, for example chlorine, lower alkoxy, for example methoxy, and/or by nitro.

Two adjacent hydroxy groups can be protected, for example, by a preferably substituted methylene group, for example by lower alkylidene, for example iso.ropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene.

A mercapto group, such as, for example, in cysteine, can be protected especially by S-alkylation with unsubstituted or substituted alkyl radicals, silylation, thioacetal formation, S-acylation or by the formation of asymmetric disulfide groupings. Preferred mercapto-protecting oo.. groups are, for example, benzyl that is unsubstituted or substituted in 0 .0 °s 0 the phenyl radical, for example by methoxy or nitro, such a 4-methoxyo benzyl, diphenylmethyl that is unsubstituted or substituted in the phenyl c radical, for example by methoxy, such as di-(4-methoxyphenyl)-methyl, triphenylmethyl, trimethylsilyl, benzylthiomethyl, 2-tetrahydropyranyl, acylahminomethyl, benzoyl, benzyloxycarbonyl, lo-er alkylaminocarbonyl, such as ethylaminocarbonyl, or also lower alkylthio, for example methylthio.

A sulfo group can be protected, for example, by lower alkyl, for example methyl or ethyl, or by phenyl, or it can be protected in the form of a Lulfonamide, for example in the form of an imidazolide.

The condensation for the production of the amide bond can be carried out in a manner known per se, for example as described in standard works, such as Houben-Weyl, "Methoden der organischen Chemie", 4th edition, vol. 15/11, Georg Thieme Verlag, Stuttgart 1974, "The Peptides" (edited A b 40 by E. Gross and J. Meienhofer), volumes 1 and 2, Academic Press, London and New York 1979/1980, or M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.

The condensation can be carried out in the presence of one of the customary condensation agents. Customary condensation agents are, for example, carbodiimides, for example diethyl-, dipropyl- or N-ethyl-N'- (3-dimethylaminopropyl)-carbodiimide or especially dicyclohexylcarbodiimide, also suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate and 2-tert.-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-l-ethoxycarbonyl-1,2dihydroquinoline, or activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis-(2-oxo-3-oxazolidii"vl)-phosphinic acid chloride or l-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate.

0 oO If desired, an organic base is added, for example a tri-lower alkylamine S having bulky radicals, for example ethyldiisopropylamine, or a heterol cyclic base, for example pyridine, 4-di-ethylaminopyridine or, preferably, N-methylmorpholine.

oG The condensation of acid anhydrides with amines can b. effected, for example, in the presence of inorganic carbonates, for excmple alkali i metal carbonates or hydrogen carbonates, such as sodium o" potassium S carbonate or sodium or potassium hydrogen carbonate (custonarily together Swith a sulfate).

The condensation is preferably carried out in an inert, polar, aprotic, preferably anhydrous solvent or solvent mixture, for example in a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a kecone, for example acetone, a cyclic ether, for example tetrahydrofuran, an este.. for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, optionally at A i reduced or elevated temperature, for example within a temperature range of from approximately -40 0 C to approximately +100 0 C, preferably from approximately -10 0 C to approximately +50 0 C, and optionally under an inert gas atmosphere, for example a nitrogen atmosphere.

Reactive acid derivatives can also be formed in situ. Thus, for example, N,N'-disubstituted amidino esters can be formed in situ by reacting the mixture of the fragment having a free carboxy group and the complementary fragment huving an amino group in the presence of a suitable disubstituted carbodiimide, for example dicyclohexylcarbodiimide. Amino or amido esters of such acids can also be formed in the presence of the amino component to be acylated, by reacting the mixture of the corresponding acid and amino starting materials in the presence of a disubstituted carbodiimide, for example dicyclobexylcarbodiimide, and an N-hydroxyamine or N-hydroxyamide, for example N-hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxynorbornane-2,3-dicarboxylic acid imide, optionally in the presence of a suitable base, for example 4-dimethylaminopyridine, N-methylmorpholine or ethyldiisopropylamine.

o4 I 0 0, a* The condensation of a carboxylic acid with the corresponding fragment S that is complementary to the compound of the formula I and has a free 9 4 "4 amino group can also be achieved in a manner known per se using enzymes, aooo for example as described by Jakubke et al. in Angewandte Chemie 97, 79 (1985). Suitable enzymes aia, for example, thermolysine, carboxypeptidase Y, papain, chymotrypsin, trypsin or pepsin. The reaction is preferably carried out in water or in mixtures of water with organic solvents, for example with lower alkanols, such as ethanol, dimethylformamide, dimethyl sulfoxide, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, acetone, acetonitrile or polyalcohols, for example ethylene glycol or di-, tri- or poly-ethylene glycol, but it can also be carried out with non-miscible organic solvents, for example methylene chloride or ethyl acetate, at a pH of from 5 to 8, preferably at approximately the neutral point, at temperatures of from 0°C to 50 0

C.

S The solvents and the reaction conditions are preferably so chosen that the desired compound precipitates or is extracted into the non-miscible organic phase and thus withdrawn from the reaction equilibrium. It is L I

A

42 also possible to carry out the condensation with enzymes, such as those mentioned above, immobilised on a suitable carrier, in the mentioned organic solvents in admixture with a small amount of water.

Process a) can also be carried out in automated form in a manner known per se, for example in accordance with the technique known as solid phase synthesis which was originated by R. Merrifield and is described, for example, in Angew. Chem. 97, 801-812 (1985), Naturwissenschaften 71, 252-258 (1984) or in R.A. Houghten, Proc. Natl. Acad. Sci., 82, 5131-5135 (1985).

The fragments o" the compounds of the formula I which are condensed with one another according to process a) can also be used in the form of racemates or in the form of diastereoisomeric mixtures. Diastereoisomeric mixtures that contain compounds of the formula I are formed and have to be subjected to separation of the diastereosisomers according to process i).

ono. Process b) (Reduction of a keto group): 0000 0 00 In a starting material of the formula V functional groups, with the 00 o o0 exception of the keto group to be reduced, are optionally protected by S0"0 one of the protecting groups mentioned undur process a).

For the reduction of the keto group in a compound of the formula V there are suitable those reducing agents which, under the reaction conditions of the process, reduce an isolated keto group selectively or more rapidly 0o'o than the amide groups present in compounds of the formula I.

o0 0 O O 0 0 0 There are to be mentioned, especially, suitable bor;ohydrides, such as o 0 alkali metal borohydrides, especially sodium borohydride, lithium boroo hydride or sodium cyanoborohydride, also zinc borohydride, or suitable aluminium hydrides, such as alkali metal lower alkoxyaluminium hydrides hAiving bulky radicals, for example lithium tris-tert.-butoxyaluminium Shydride.

0 0 43 The reduction can also be carried out with hydrogen in the presence of suitable heavy metal catalysts, for example Raney nickel or platinum or palladium catalysts, for example platinum on activated carbon or palladium on activated carbon, or according to the Meerwein-Ponndorf- Verley method with the aid of aluminium alkanolates, preferably aluminium 2-propanolate or ethanolate.

The reduction can be carried out preferably with stoichiometric amounts or with a reasonably proportioned excess of the reducing agent, in an inert solvent at temperatures of from -80 0 C to the boiling point of the solvent, preferably from -20 0 C to +100 0 C, if necessary under a protective gas, for example nitrogen or argon. An excess of the reducing agent is necessary especially in cases where that agent also reacts with the solvent, for example with the protons of a protic solvent.

Suitable solvents when using sodium borohydride are polar, protic solvents, for example methanol, ethanol or isopropanol, and, when using the other reduc.ng agents, the polar, aprotic solvents mentioned under oo. process for example tetrahydrofuran.

0o 0000 0 00 0° Process c) (Addition of an organometal compound): oo 0 0 0 0 00 0 o In a starting material of the formula VI functional groups, with the C"0 exception of the aldehyde group, are optionally protected by the protect- 0600 0ooo ing groups mentioned under process Functional groups present in a compound of the formula VII are also protected.

In a compound of the formula VII a metal radical -M is, for example, -Li or -MgHal, for example -MgCl, -MgBr or -MgI.

The reaction of a compound of the formula VI with a compound of the formula VII is effected in customary manner in an anhydrous, inert, aprotic solvent, for example in an ether, such as diethyl ether or tetra- I' hydrofuran, or a hydrocarbon, such as benzene or toluene, or mixtures thereof, optionally while cooling, especially after the beginning of the reaction, for example to approximately -30°C, or while heating, for 44 example to the boiling tempe-ature of the reaction mixture, optionally under an inert gas atmosphere, for example a nitrogen atmosphere. A preferred form of the process is the reaction of the aldehyde of the formula VI with an excess of the lithium compound of the formula VII.

The hydrolysis 'of the addition product is effected with solvents that yield H ions, for example water (ice-water mixture) or dilute, aqueous acids, for example dilute mineral acids, such as dilute, aqueous sulfuric acid, or dilute organic acids, for example dilute, aqueous acetic acid.

The reaction of a compound of the formula VI can also be effected with a compound of the formula VII that has been prepared in situ and that is obtained, for example, from the corresponding halide, for example Schloride, by reaction with a metallating agent, for example magnesium, lithium or tert.-butyllithiur.

Process d) (Nucleophilic substitution): o00oo0 00ooo00 e oo 0 0 0 00 00 0 Qo 00 0 00 0 00 0 46 0 0 0000 0 D 0 *00 0 0 00 00 0 0000 0 0 o In a starting material of the formula VIII functional groups are optionally protected by the protecting groups mentioned under process a).

In a compound of the formula VIII the nucleofugal leaving group X is especially hydroxy esterified by a strong inorganic or organic acid, such as a mineral acid, for example a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid, or sulfuric acid or halosulfuric acid, for example fluorosulfuric acid, or hydroxy esterified by a strong organic sulfonic acid, such as a lower alkanesulfonic acid that is unsubstituted or substituted, for example, by halogen, such as fluorine, or an aromatic sulfonic acid, for example a benzenesulfonic acid that is unsubstituted or substituted by lower alkyl, such as methyl, halogen, such as bromine, and/or by nitro, for example a methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid, or hydroxy esterified by hydrazoic acid.

A reagent that introduces a hydroxy group is, for e.xample, a hydroxidecontaining base, for example odium or potassium hydroxide.

A A

F,

'I

45 The reaction conditions are preferably so chosen that the reaction proceeds substantially as a second-order nucleophilic substitution (SN2).

The reaction with a hydroxide-containing base is preferably carried out in water to which there has optionally been added as solution aid an organic solvent, for example ethanol, tetrahydrofuran or acetone. The substitution reaction is carried out optionally at reduced or elevated temperature, for example within a temperature range of from approximately 0 C to approximately +100°C, preferably from approximately -100C to approximately +50°C, and optionally under an inert gas atmosphere, for example a nitrogen atmosphere.

Process e) (Conversion of a cyano grour 'o a group CORI): In a starting material of the formula IX functional groups are optionally protected by the protecting groups mentioned under a).

The conversion of a compound of the formula IX into a compound of the formula I can be effected, for example, by a Ritter reaction or by way of carboxylic acid enter imide salts.

0000 oooo a 00 0 00 0 00

OO

0 0 0 0 000 0 00 0000 0 00 01 0 0 00 00 0 00 00 0 0 00 000000 0 0 In the Ritter reaction, the nitriles are reacted in the presence of a strong acid, for example 85-90 sulfuric acid, or also polyphosphoric acid, hydrofluoric acid, formic acid, boron trifluoride or other Teis acids, but not aluminium chloride, with compounds that are capable of forming carbenium ions in the acidic medium, that is to say, for example, with olefins, such as propylene, or alcohols, such as benzyl alcohol, in most cases without a solvent or, for example, in glacial acetic acid.

In a variant of the Ritter reaction, a nitrile of the formula IX is reacted with an olefin and mercury(II) nitrate and the organomercury compound is subsequently reduced with sodium borohydride to an N-substituted compound of the formula I.

S000 0 6 0 Si

UL

-Li a 46 By the acid-catalysed, preferably hydrochloric acid-catalysed, addition of alcohols to the nitriles of the formula IX, there are obtained carboxylic acid ester imides which yield amides of the formula I by thermal rearrangement at temperatures above approximately For the conversion of a nitrile into a free acid, the hydrolysis is carried out with water advantageously in an inert organic solvent that is at least partially water-miscible, such as an ether (for example diethyl and diisopropyl ether, 1,2-dimethoxyethane or, especially, dioxane or tetrahydrofuran), or lower alkanols (for example methanol, ethanol, isopropyl alcohol, butyl alcohols, especially tert.-butyl alcohol), a relatively large amount of water being necessary in the last-mentioned cases in order to prevent alcoholysis. The hydrolysis can be catalysed both by strong acids, especially inorganic acids, such as sulfuric acid, or preferably hydrohalic acids, (for example hydrobromic acid or, as first choice, hydrochloric acid) and also by bases, especially inorganic bases, such as hydroxides and carbonates of the alkali metals, for example sodium and potassium hydroxide. The bases are normally used in at least stoichiometric proportions which cause carboxylic acid salts to be formed as primary products. The acid catalysts are advantageously used in the form of a dilute aqueous solution in order to obtain the best result.

If 0 o 0 0o o 0 0 00 0 V00 1 B End products of the formula I in which R I is etherified hydroxy can be "oO obtained by carrying out the solvolysis of the nitrile with the corresponding alcohol (alcoholysis) in the presence of a catalytic amount of a strong anhydrous acid, advantageously gaseous hydrochloric acid.

Normally, an excess of alcohol is used aq solvent but inert organic oo"'0 solvents, such as acyclic and cyclic ethers (especially those mentioned 0d 0 0o0o above), and/or haJogenated lower alkanes (especially chloroform and dichloromethane) can be added. If the alcoholysis is carried out under oC o strictly anhydrous conditions, the primary product (imido ester) must be 0 00 hydrolysed advantageously by the addition of water to the reaction a 0 mixture. On the other hand, if the alcoholysis is carried out in the presence of an approximately stoichiometric equivalent of water, the Sdesired ester is obtained directly.

o 47 Process f) (Reduction of the epoxide): In a starting material of the formula X functional groups are optionally protected by the protecting groups mentioned under process a).

It is possible to use those reducing agents which, under the reaction conditions of the process, reduce the epoxy group selectively or more rapidly than the amide groups present and which open the epoxide in such a manner that a sufficient, and as large as possible, proportion of the reaction products carries the newly formed hydroxy group in the position corresponding to that of the formula I. Examples of such selective reducing agents are lithium borohydride or sodium cyanoborohydride/boron trifluoride etherate. Using the last-mentioned reagent the reaction can be carried out, for example, by adding a solution of boron trifluoride etherate, BF 3

O(C

2

H

5 2 in tetrahydrofuran to 1 mole of the compound of the formula X and an excess, for example 1.4 3 moles, of sodium cyanoborohydride in tetrahydrofuran at elevated temperature, for example under reflux, in such a manner that the pH of the reaction solution is maintained close to the turning point of the indicator bromocresol green 0 which has also been added. The reduction with lithium borohydride is preferably carried out in an ether, for example tetrahydrofuran, a0 So* 1,2-dimethoxyethane or diethylene glycol dimethyl ether, at temperatures 0 eOa 1 of from room temperature to the reflux temperature.

o 0 S00o Process g) (Addition to an acrylic amide): A compound of the formula R H is either a thiol of the formula m 6 a a S* R -SH or a sulfinic acid of the formula R -SOH.

In a starting material of the formula XI, functional groups are optionally protected by the protecting groups mentioned under process a).

Functional groups present in the compound of the formula Ra-S(o) H are also optionally protected.

tlt Suitable salts of the compound of the formula Ra-S(O) H are, for m example, alkali metal salts, for example sodium or potassium salts.

IA

48 The addition of a compound of the formula Ra-S(O)m H or a suitable salt thereof to a compound of the formula XI is carried out in customary manner in an inert polar solvent, for example in a polar ether, for example tetrahydrofuran, dioxane or dimethoxyethan', a lower alkanol, for example methanol, ethanol or isopropanol, or a dipolar aprotic solvent, for example dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, N-methylpyrrolidone or acetonitrile, or optionally in mixtures of the mentioned solvents with one another or with water, at temperatures of from approximately -300° to the boiling point of the particular solvent, for example at from 0 C to +80 0 C, for example at approximately 50 0

C.

a Instead of a sulfinic acid R -SO 2 H, it is preferable to use its salts, for example the sodium or potassium salt.

A salt of a thiol of the formula Ra-SH can also be formed in situ, for example by adding a suitable base, for example an alkali metal hydroxide, such as sodium or potassium hydroxide, or an alkali metal hydride, for example sodium hydride, but only anhydrous solvents can be used in that S,0o case. It is also possible to carry out the addition reaction with a free °d thiol of the formula Ra-SH in the presence of an organic base, for I example a tertiary amine, for example triethylamine, N-methylmorpholine, o-o dimethylaniline, diaabicyclo[5.4.0]undec-7-ene or diazabicyclo[4.3.0]- Process h) (Alkylation in the acyl radical of the partial formula la): S In a starting material of the formula XII, functional groups are optionally protected by the protecting groups inentioned under proce's a).

A compound that introduces the radical R -(CHz)q- is, for example, the corresponding halide, for example chloride, bromide or iodide, or a reactive ester of the corresponding alcohol, for example a sulfonic acid ester, such as the methanesulfonic acid ester or p-toluenesulfonic acid ester.

49 For the alkylation, the compound of the formula XII is preferably converted by customary methods with a strong non-nucleophilir base into the corresponding anion, for example with the lithium or potassium salt of a sterically hindered secondary amine, for example with lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, lithium or potassium bis-(trimethylsilyl)-amide or the like. The deprotonation with the base is preferably carried out at low temperatures, for example at from -100°C to -50 0 C, in an inert polar solvent, for example in a polar ether, for example tetrahydrofuran, dioxane or dimethoxyethane, optionally mixed with a hydrocarbon, for example hexane or toluene, and/or hexamethylphosphoric acid triamide or N,N'-dimethyl-N,N'-propyleneurea. If the compound of the formula XII contains other methylene or iethine groups from which the protons are more readily removed, for example those next to the sulfinyl or sulfonyl group, then preferably two or more equivalents of the base are used in order to obtain the corresponding di-or poly-anion.

0~ G a C 0 I 0) oJ a o~ a 00o B, 0 The compound of the formula XII so deprotonated is reacted with the alkylating agent introducing the radical Rb-(CHz)q- preferably in situ at low temperatures, for example at from -78 0 C to -30°C, and with subsequent heating to room temperature or slightly elevated temperature, for example to 500C, in the same solvent or solvent mixture.

If in a compound of the formula XII n is 0, then the alkylation can be carried out under considerably milder conditions, for example in one of the above-mentioned solvents or in other polar solvents, for example dimethyl sulfoxide, dimethylformamide or acetonitrile, with the alkylating agent that introduces the radical R -(CH 2 at temperatures of from -30°C to approximately room temperature and with a tertiary amine, for example triethylamine, N-methylmorpholine, diazabicyclo- [5.4.0]undec-7-ene or diazabicyclo[4.3.0]non-5-ene, or an insoluble inorganic base, for example potassium carbonate or sodium hydride, or an alcoholate, for example potassium tert.-butanolate. Also suitable is alkylation under phase transfer conditions, that is to say in a two-phase mixture comprising an aqueous base, for example sodium hydroxide soluticn, and an immiscible organic solvent, for example methylene chloride or toluene, and a phase transfer catalyst, for example an ammonium or phosphonium salt.

Process i) (Subsequent operations): The group R

I

together with the terminal carbonyl group of the radical AAC of the compounds of the formula I, forms a carboxy group, an esterified carboxy group, a carboxamide group or a substituted carboxamide group. When such groups are mentioned in connection with subsequent operations, apart from corresponding groups which may be present as substituents, for example in the amino acid residues Al, A2, A3, A4 and the C-terminal groups formed by R 1 and the carbonyl gtoup bonded directly thereto are also included.

In a resulting compound of the formula I a carboxamide group can be sdbstituted, a carboxy group present in free or ceactive form can be esterified, and an esterified carboxy group can be converted into a free carboxy group or into a carboxamide group.

ol{n o i o Substitution of a carboxamide group or another amino group is effected, for example, by alkylation.

j o Suitable agents for alkylating a carboxamide group in a compound of the j formula I are, for example, diazo compounds, for example diazomethane.

Diazomethane can be decomposed in an inert solvent and the free methylene formed in so doing reacts with the carboxamide group in the compound of S the formula I. The decomposition of diazomethane is preferably carried out by catalysis, for example in the presence of a noble metal in finely divided form, for example copper, or a noble metal salt, for example copper(I) chloride or copper(II) sulfate.

ai rit 51 Further alkylating agents are those mentioned in German Offenlegungsschrift 2 331 133, for example alkyl halides, sulfonic acid esters, Meerwein salts or 1-substituted 3-aryltriazenes, which can be reacted with a compound of the formula I having a carboxamide group under the reaction conditions mentioned in that specification.

For the esterification of a carboxy group in a compound of the formula I the free acid can be used or the free acid can be converted into one of the reactive derivatives mentioned under process a) and reacted with an alcohol, or the free acid or a reactive salt, for example the caesium salt, can be reacted with a reactive derivative of an alcohol. For S example, the caesium salt of a carboxylic acid can be reacted with the halide corresponding to the alcohol.

The esterification of a carboxy group can be effected with the alkylating agents mentioned above for the substitution of the carboxamide group and under the same reaction conditions, for example with diazomethane, alkyl halides, sulfonic acid esters, Meerwein salts, 1-substituted 3-aryltriazenes, etc..

0000oo 0 0ooo o "Qo One of the methods described under process removal of the carboxy- Go 0 o protecting groups, or, if desired, alkaline hydrolysis under the reaction o o conditions mentioned in "Organikum", 15th edition, VEB Deutscher Verlu\g 0 o oo °O der Wissenschaften, Berlin (East) 1976, can be used to convert an o esterified carboxy group in a compound of the formula I into a free carboxy group.

In a compound of the formula I an esterified carboxy group can be conoco 00o verted into an unsubstituted or substituted carboxamide group by o 0 o aminolysis with ammonia or a primary or secondary amine. The aminolysis S can be effected under the reaction conditions mentioned for such reac- 0 "0 tions in "Organikum", 15th edition, VEB Deutscher Verlag der Wissen- "0 0 °o schaften, Berlin (East), 1976.

ooQ oo 0000 000 00 a 0 1 52 In a resulting compound o'f the formula I in which the substituents have the meanings mentioned and at least one free hydroxy group is present and the other functional groups are optionally a protected form, the free hydroxy group can be etherified or esterified.

The etherification of this hydroxy group can be effected with the alkylating agents mentioned above and under l.me reaction conditions, for example with diazomethane, alkyl halides, lfonic acid esters, Meerwein salts, 1-substituted 3-aryltriazenes, etc..

The esterification of the free hydroxy group can be effected with the customary acylating agents and the customary reaction conditions indicated in "Organikum", for example with acetic anhydride.

The mentioned alkylating reactions, etherifications, esterifications etc.

can also be carried out in corresponding manner in a starting material instead of in the end product.

In a resulting compound of the formula I a thio group can be oxidised to *4o: a sulfinyl or sulfonyl group or a sulfinyl group can be oxidised to a o s sulfonyl group.

o4 0 The oxidation to the sulfonyl group can *Le tarried out with most of the oB a customary oxidising agents. It is preferable to use those oxidising agents that oxidise the thio group or the sulfinyl group selectively in the presence of other functional groups, for example the amide function and the hydroxy group, of the compound of the formula I, for example aromatic or aliphatic peroxycarboxylic acids, for example perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid, performic acid or trifluoroperacetic acid. The oxidation with peroxycarhoxylic acids is carried out in the customary solvents suitable .or S the purpose, for ex.mple chlorinated hydrocarbons, for example methylene chloride or chloroform, ethers, ethyl acetate r the like, at temperatures of from -78 0 C to room temperature, foi example at from -20°C to +10°C, preferably at approximately 0°C. The peroxycarboxylic acid can S< also be formed in situ, for example with hydrogen peroxide in acetic acid "-il CY~- -I-li'-ili i 53 or formic acid, each of which optionally contains acetic anhydride, for example with 30 or 90 hydrogen peroxide in acetic acid/acetic anhydride. Other peroxo compounds are also suitable, for example potassium peroxomonosulfate in mixtures of lower alkanol and water, for example methanol and water or ethanol and water, or in aqueous acetic acid, at temperatures of from -70 0 C to +300C, for example from -20 0 C to room temperature, also sodium metaperiodate in methanol or mixtures of methanol and water at temperatures of from 0 C to 500C, for example at approximately room temperature.

For the oxidation of the thio group to the sulfinyl group, selective oxidising agents are used in equimolar amounts or only a slight excess under controlled reaction conditions in order to prevent over-oxidation to the sulfonyl group. Suitable are, for example, sodium metaperiodate in methanol or mixtures of methanol and water at temperatures of from to room temperature, for example at approximately 00C, m-chloroperbenzoic acid in methylene chloride, chloroform or ethyl acetate at temperatures of from -78 0 C to 10 0 C, preferably at from -30°C to 0°C, also tert.-butyl hypochlorite in lower alkanols, for example methanol, or hydrogen pe uoide in acetone or acetic acid at temperatures of approximately 00C, St" or the above-mentioned potassium peroxomonosulfate at low temperatures.

nQ A0 0 0 00 In a resulting compound of the formula I having a sulfinyl group, this group can be reduced to a thio group. Selective reducing agents that leave other functional groups of the compound of the formula I, for example the amide functiun, unaltered preferred. Examples of such selective reducing agents are dichlorobo, ne, which is preferably used in tetrahydrofuran or dimethoxyethane at temperatures of from -300C to +100C, triphenylphosphine in boiling carbon tetrachloride, trichlorosilane or hexachlorodisilane, iron pentacarbonyl, also sodium hydrogen sulfite in aqueous/alcoholic solvents, for example water/methanol, water/ethanol or also water/tetrahydrofuran, at temperatures of from -100C to +5000, also sodium borohydride in the presence of cobalt(II) chloride or also hydrogen in the presence of catalytic amounts of palladium, for example palladium-on-carbon in boiling ethanol.

4 1 t Y _i i Y i :'il 54 If desired, a sulfonyl group in a resulting compound of the formula I can be reduced to a thio group, for example using diisobutylaluminium hydride in ether or tetrahydrofuran.

In a resulting compound of the formula I having a sulfonamide group, this group can be alkylated in the manner described for carboxamide groups or hydrolysed with an acid or an alkali to a sulfo group. A sulfenamide group can be oxidised to the sulfonamide with one of the reagents mentioned under the oxidation of thio groups to sulfonyl groups, for example potassium peroxomonosulfate, and immediately hydrolysed in situ.

A sulfonic acid ester group can likewise be converted into a sulfo group by an acid or a base, for example as described above for the hydrolysis of a carboxylic acid ester group.

In a resulting compound of the formula I having a sulfo group, this group can be converted in known manner into a sulfonic acid ester group or a sulfonamide group, for example by conversion into a sulfonic acid halide group and reaction with an alcohol, phenol or amine. A sulfonic acid ester group is converted with an amine into the corresponding sulfonaoide group analogously to the carboxylic acid ester group.

00 0 S In a resulting compound of the formula I in which one or more functional o iJo o groups are protected, these groups, for example carboxy, amino, hydroxy, mercapto and/or sulfo groups, can be freed in a manner known per se, S optionally in stages or simultaneously, by means of solvolysis, especially hydrolysis, optionally enzymatic hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis, or chemic.il reduction. The removal of the protecting groups is described in the standard works mentioned hereinbefore in the section "protecting groups".

For example, protected carboxy, for example tert.-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonyl, can be converted into free carboxy by treatment with a suitable acid, for example formic acid 55 or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, for example phenol or anisole. Unsubstituted or substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, that is to say by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can also be converted into free carboxy by reduction, for example by treatment with an alkali metal dithionite, for example sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal salt, such as a chromium(II) salt, for example chromium(II) chloride, customarily in the presence of a hydrogen-yielding agent that together with the metal is capable of producing nascent hydrogen, such as an acid, especially a suitable carboxylic acid, such as a lower alkanecarboxylic acid that is unsubstituted or substituted, for example, by hydroxy, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, with water preferably being added. It is also possible to convert 2-halo-lower alkoxycarbonyl (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl ooa. group) or aroylmethoxycarbonyl into free carboxy by treatment with a o reducing metal or a reducing metal salt, as described above. Aroyl- S" methoxycarbonyl can also be cleaved by treatment with a nucleophilic, 0 a preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. 2-tri-lower alkylsilyl-lower alkoxycarbonyl can also be converted into free carboxy by treatment w;',th a salt of hydrofluoric acid yielding the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, optionally in the presence of a macrocyclic poly- 0 ether ("crown ether"), or with a fluoride of an organic quaternary base, S such as tetra-lower all'ylammonium fluoride or tri-lower alkylaryl-lower 0 00 00 o o0 alkylammonium fluoride, for example tetraethylammonium fluoride or tetra- 0. a butylammonium fluoride, in the presence of an aprotic, polar solvent, "a O such as dimethyl sulfoxide or NN-dimethylacetamide. Carboxy esterified o 0o by an organic silyl group, such as tri-lower alkylsilyl, for example trmeLhylsilyl, can be freed in customary manner by solvolysis, for example by tretment with water, an alcohol or an acid, or also a o 0 r ;i; a 56 fluoride, as described above. Esterified carboxy can also be cleaved enzymatically, for example esterified arginine or lysine, such as lysine methyl ester, can be cleaved by means of trypsin.

A protected amino group is freed in a manner known per se and, depending on the nature of the protecting groups, by various methods, but preferably by solvolysis or reduction. 2-halo-lower alkoxycarbonylamino (optionally after converting a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycr..bonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such a sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino, tert.-lower alkoxycarbonylamino or 2-tri-lower alkylsilyl-lower alkoxycarbonylamino can be freed by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, unsubooo stituted or substituted benzyloxycarbonylamino can be freed, for example, o Qo by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a O suitable hydrogenation catalyst, such as a palladium catalyst, unsubsti- 000 So tuted or substituted triarylmethylamino or formylamino can be freed, for S example, by treatment with an s;cd, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water, and an amino group protected by an organic silyl group can be freed, for 'o0o example, by hydroly.sis or -inoholysis. An amino group protected by 0" 2-haloacetyl, for example 2-chloroacetyl, can be freed by treatment with o 0 So thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of thiourea, and by subsequent solvolysis, such as 0 0 alcoholysis or hydrolysis, of the resulting substitution product. An 0 o amino group protected by 2-tri-lower alkylsilyl-lower alkoxycarbonyl can aaoo also be converted into the free amino group by treatment with a salt of hydrofluoric acid yielding fluoride anions, as indicated above in 000000 0 il L -Y I 57 connection with the freeing of a correspondingly protected carboxy group.

Silyl, such as trimethylsilyl, that is bonded directly to a hetero atom, such as nitrogen, can also be removed by means of fluoride ions.

Amino protected in the form of an azido group is converted into free amino, for example, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, or also by treatment with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or alternatively in water or a mixture o* water and an organic solvent, such as an alcohol or dioxan', at approximately from 20 0 C to 30 0 or alternatively while cooling or heating.

a o t* oo 0 09 o 000 00 o00 O O u 0 00 0 o 009 0 09 0 40 9 0 9 0 G u A hydroxy or mercapto group protected by a suitable acyl group, an organic silyl group or by unsubstituted or substituted 1-phenyl-lower alkyl is freed analogously to a correspondingly protected amino group. A hydroxy or mercapto group protected by 2,2-dichloroacetyl is freed, for example, by basic hydrolysis, while a hydroxy or mercapto group protected by tert.-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid. A silyl group, for example a trimethylsilyl group or a tert.-butyldimethylsilyl group, is likewise removed by acidolysis, for example by a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. 2-halo-lower alkoxycarbonyl is removed by the abovementioned reducing agents, for example reducing metals, such as zinc, reducing metal salts, such as chromium(II) salts, or by sulfur compounds, for example sodium dithionite or, preferably, sodium sulfide and carbon disulfide.

0Q0 0 04001 0066.

0 0 58 Two hydroxy groups that are protected together by means of a preferably r-bstituted methylene group, such as by lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be freed by acid hydrolysis, for example in the presence of a mineral acid or a strong organic acid.

A sulfo group protected in the form of a sulfonic acid ester or sulfonamide is freed, for example, by acid hydrolysis, for example in the presence of a mineral acid, or preferably by basic hydrolysis, for example with alkali metal hydroxide or alkali metal carbonate, for example sodium carbonate.

Salts of compounds of the formula I having salt-forming groups can be prepared in a manner known per se. For example, salts of compounds of the formula I having acidic groups can be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, or with inorganic alkali metal or alkaline earth metal salts, for example sodium hydrogen carbonate, or with ammonia or a suitable organic amine, S preferably stoichiomitric amounts or only a small excess of the saltfSo forming agent being used. Acid addition salts of compounds of the formula S I are obtained in customary manner, for example by treatment with an acid o r a suitable anion exchange reagent. Internal salts of compounds of the 'o formula I that contain, for example, a free carboxy group and a free a amino group can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion exchangers.

Salts can be converted in customary manner into the free compounds: metal and ammonium salts, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.

Stereoisomeric mixtures, especially diastereoisomeric mixtures, can be separated into the individual isomers in a manner known per se, for example by fractional crystallisation, chromatography, etc..

i i 4 i.

59 Racemates can be split in a manner known per se, for example after converting the optical antipodes into diastereoisomers, for example by reaction with optically active acids or bases.

At individual chiral centres in a compound of the formula I, for example at the C4 atom in the central 5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoyl radical, the configuration can be deliberately reversed. For example, the configuration at the C4 atom can be reversed by second order nucleophilic substitution according to process d) after converting the hydroxy group into a nucleofugal leaving group X and reaction with a reagent that introduces a hydroxy group.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage is used as starting material and the remaining steps are carried out or in which the process is discontinued at any stage or in which a compound obtainable in accordance with the process according to the invention is produced under the process conditions and further processed in situ.

0 0 Pharmaceutical preparations: 0 (4 a The pharmacologically acceptable compounds of the present invention can Sbe used, for example, for the manufacture of pharmaceutical preparations I ow that contain an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.

i The pharmaceutical preparations according to the invention are those for enteral, such as nasal, rectal or oral, administration or for parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals), which contain an effective dose of the pharmacological active ingredient on its own or together with a significant amount of a pharmaceutically acceptable carrier. The dosage r ri I.

I

60 of the active ingredient depends on the species of warm-blooded animal, the body weight, age and individual condition, on the disease to be treated and also on the mode oi administration.

The invention releates also to a method of treating diseases caused by retroviruses, for example AIDS, which comprises administering a therapeutically effective amouIt of compounds of the formula I according to the invention. The dosages to be administered to warm-blooded animals, for example humans of approximately 70 kg body weight, are from approximately 3 mg to apprcximately 3 g, preferably from approximately 10 mg to approximately 1.5 g, for example approximately from 300 mg to 1000 mg, per person per day, divided into pceferably from 1 to 3 single doses which may, for example, be of equal size. "hildren usually receive half the adult dose.

oin o 0e o .o0 9.,a o u o 0 .4.4 9) -nr 4 o L~4 U .44 .4 OU 9 0 I Gus,', u4 0 The novel pharmaceutical preparations contain from approximately 1 to approximately 95 preferably from approximately 20 to approximately active ingredient. Pharmaceutical preparations according to the invention may, for example, be in dosage unit form, such as ampoules, phials, suppositories, drag6es, tablets or capsules.

The pharmaceutical preparations of the present invention are proluced in a manner known per se, for example by means of conventional dissolving, lyophilising, mixing, granulating or confectioning processes.

There are preferably used solutions of the active ingredient, and also suspensions, especially isotonic aqueous solutions or suspensions, it being possible, for example in the case of lyophilised preparationsi which contain the active ingredient on its own or together with a carrier, for example mannitol, to prepare these before use. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising prrcesses. The solutions or suspensions -61 mentioned may contain substances that increase the viscosity, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, pilyvinylpyrrolidone or gelatin.

Suspensions in oil contain as oily component the vegetable, synthetic or semi-synthetic oils customary for injection purposes. There may be mentioned as such especially liquid fatty acid esters that contain as acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, such as, for example, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids, such as, for example, oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid. The alcohol component of these fatty acid esters has at most 6 carbon atoms and is a mono- or polyhydric, for example mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or their isomers, but above all glycol or glycerol. There may therefore be mentioned as examples of fatty acid esters: ethyl oleate, isopropyl myristate, isot propyl palmitate, "Labrafil M 2735" (polyoxyethylene glycerol trioleate oo manufactured by Gattefoss6, Paris), "Myglyol 812" (triglyceride of o 09 oo saturated fatty acids of chain le'-gth Ca to C 12 manufactured by 0 0 0 C O, Chemische Werke Witten/Ruhr, Germany), but especially vegetable oils, 0 0 such as cotton seed oil, almond oil, olive oil, castor oil, sesame oil, 4600 o° soybean oil and, especially, groundnut oil.

The manufacture of the injection preparations is effected in customary manner under sterile conditions, as is the introduction thereof into ampoules or phials and the sealing of the containers.

Pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture and, if desired or necessary after the addition of suitable adjuncts, processing the mixture or granulate into tablets or dragee cores. They can also be incorporated into plastics carriers which release the active ingredients, or allow them to diffuse, in a controlled manner.

62 Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the abovementioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.

Drag6e cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylo aa oo cellulese phthalate. Colourings or pigments can be added to the tablets Sor dragee coatings, for exampl. for identification purposes or to indicate different doses of active ingredient.

4a0, Starting materials: Tbe present invention relates also to novel starting materials and/or intermediates and to processes for the preparation thereof. The starting materials and the reaction conditions are preferably so chosen that the compounds mentioned as being preferred are obtained.

i '4I 63 The starting materials for carrying out process a) can be prepared according to processes that are known per se, for example from the relevant amino acids by condensation in a manner analogous to that of process a) described hereinbefore. For example, a compound of the formula H N H H CHz H -CH C AAC R (XIII) CHz CsH1i can b manufactured analogously to the process described in European Patent Application EP 143 746 or EP 258 183.

Compounds of th- formula V are miaufactured, for example, by reacting a carboxylic acid of the formula

R

2 AAN H OH (XIV) CH CbH11 or a suitable functional derivative thereof, in which the symbols are as Sdefined and functional groups, with the exception of the free or modified carboxy group, are optionally in protected form, with an organometal compound of the formula VII in which M is a metal radical, for example S -Li or -MgHal, such as -MgCl, -MgBr or -Mgl, and solvolysing the addition product formed.

Suitable functional derivatives of a carbo-ylic acid of the formula XIV are, for example, the corresponding lithium salt of the carboxylic acid, a carboxylic acid halide, for example carboxylic acid chloride, an anhydride, for example the symmetrical carboxylic acid anhydride or a mixed carboxylic acid anhydride with a sterically hindered carboxylic acid, for example with pivalic acid, or a thio ester, for example 2-pyridylthio ester.

The reaction of a carboxylic acid of the formula XIV or a suitable functional derivative thereof with a compound of the formula VII is carried out in the customary manner, for example under the reaction conditions indicated in process but optionally while cooling, for 64 example at temperatures of from approximately -50°C to approximately 0°C.

In a preferred form of the process, a 2-pyridylthio ester of the carboxylic acid of the formula XIV is reacted with a bromomagnesium compound of the formula VII.

Compounds of the formula VI can be prepared according to processes that are known per se, for example by, in a compound of the formula XIV in which the symbols are as defined and functional groups are optionally in protected form, reducing the carboxy group to the aldehyde function according to methods that are known per ce, for example via the corresponding methyl or ethyl ester, via an imidazolide or via an N-methoxy- N-methylamide.

Compounds of the formula VII can be prepared, for example, by reacting a known halide, or a halide that can be prepared by methods known per se, of the formula QH(CH3)2 0 Hal CH 2 CH AAC R (XV), soi o 0 for example the chloride, with a metallating agent, for example magnesium, lithium or tert.-butyllithium.

0 0 C Compounds of the formula VIII are prepared, for example, by reacting an 0440 2 aldehyde of the formula VI with an organometal compound of the formula VII according to process c) and ezterifying the resulting hydroxy compound of the formula I, optionally after separating the isomers, with a strong organic or inorganic acid corresponding to the definition of X.

0 k Nitriles .f the formula IX are prepared, for example, by reacting a compound of the formula

SR

2 AN H -H CH- CH AAC' Hal (XVI), CH2 C6H11 0 o oo in which the symbols are as defined, with a salt of hydrocyanxic acid.

4 65 Suitable salts of hydrocyanic acid should be sufficiently soluble in the chosen inert solvent for a reaction to take place. Such salts are, for example, ammonium cyanide, alkali metal cyanides or alkaline earth metal cyanides, for example sodium or potassium cyanide, or t-ansition metal cyanides, for example copper cyanide. The transition metal cyanides are suitable owing to their lower basicity as compared with the alkali metal cyanides.

Depending on the nature of the cyanide used and the solvent, an equilibrium is established between the isomeric nitrile form and the isonitrile form. The nitrile form is formed preferentially if, for example, the reaction is effected with those metal cyanides of which the metal cations have a lower atomic weight than that of copper.

Suitable inert solvents are especially polar, aprotic solvents, for example carboxylic acid amides, for example dimethylformamide or dimethylacetamide, nitriles, for example acetonitrile or propionitrile, 0°0° or di-lower alkyl sulfoxides, for example dimethyl sulfoxide.

0oo S The reaction is effected at room temperature, a- reduced or at elevated :00 o ooo temperature, for example within a temperature range of from approximately o 00 o" -40 0 C to approximately +100°C, preferably from approximately -10 0 C to 00o approximately +50 0 C and, if desired, under an inert gas atmosphere, for example a nitrogen atmosphere.

Epoxides of the formula X are preparod, for example, by reacting a com- 000 J 0o a pound of the formula 0 00 00 0 Z H CHO (XVII), 0oo CHz C6Hii 0 0 a 090000 0 0 wherein Z 1 is an amino-protecting group, with a phosphoranylidene com-.

oooo pound of the formula 0000 06 0 0 66

C

R\ CH(CH3)2 R P CH CH C (XVIII),

R

wherein Rc is an unsubstituted or substituted hydrocarbon radical and Z 2 is a carboxy-protecting group, and converting a resulting compound of the formula CH(CH3)2 0 ZHN -CH CH CH H Z 2

(XIX)

6H2 C6H11 into an epoxide with an oxidising agent containing the peroxy group and, in a resulting compound, removing the protecting groups Z 1 and Z 2 and replacing them by the groups R 2 -AAN- and -AAC-R' in any desired sequence of the reaction steps.

R is preferably phenyl. The reaction of a compound of the formula XVII with a phosploranylidene compound of the formula XVIII is carried out under the reaction conditions known for Wittig reactions and described, for example, in "Organikum". The olefin of the formula XIX which is obtainable in so doing is optionally reacted in situ with the oxidising agent, for example peracetic acid or m-chloroperbenzoic acid. The removal of the protecting groups Z I and Z 2 and the introduction of the groups

R

2 -AAN- and -AAC-R L is described hereinbefore under process a).

Compounds of the formila XI are prepared, for example, by reacting an acrylic acid of the formula R b- (CH2) H COOH (XX), CH2 or a suitable functional derivative thereof, with a compound of the formula H OH CH(CH3)2 'i H AAN H- H CH C-AAC R (XXI)

CH

2 C6sH 7 67 according to process The compound of the formula XXI is also prepared according to process for example from a compound of the formula ZL-AAN-OH protected at the amino group and from a compound of the formula XIII, and by subsequent removal of the protecting group Z i Compounds of the formula XII are also obtained by condensing a compound of the formula XXI with the corresponding carboxylic acid or a suitable functional derivative thereof according to process a).

000 o 00 0 00 oQ o o o a 0 0 00 o a 00 0 S001 0 1 0 The following Examples serve to illustrate the invention the scope thereof in any way.

Temperatures are given in degrees Celsius. The Rf values on silica gel thin-layer plates in the following solvent A ethyl acetate/n-hexane B ethyl acetate/n-hexane C ethyl acetate/n-hexane D ethyl acetate/n-hexane E ethyl acetate/n-hexane F methylene chloride/methanol G methylene chloride/mtehanol H methylene chloride/methanol I methylene chloride/methanol/water J methylene chloride/ether K methylene chloride/methanol/conc. ammonia L methylene chloride/methanol/conc. ammonia M methylene chloride/methanol/water/glacial acetic acid N methylene chloride/methanol/water 0 chloroform/methanol/water/glacial a etic acid P chloroform/methanol/water/glacial acetic acid Q chloroform/methanol/water/glacial acetic acid but do not limit are determined systems: 1:1 1:2 1:4 1:6 1:9 19:1 9:1 4:1 300:10:1 4:1 40:10:1 350:50:1 150:54:10:1 14: 6:1 15G 4: 10:1 180:20:2:1 170:26:3:1

I

68 R ethyl acetate S methylene chloride/methanol/conc. ammonia 800:50:1 T methylene chloride/methanol/conc. ammonia 90:10:1 U toluene/ethyl acetate 4:1 For example, the abbreviation denotes that the Rf value has been determined in system A. The ratio of the solvents to one another is given in parts by volume.

The same abbreviations are used for the eluant systems in the flash chromatography and the medium-pressure chromatography.

The retention times (tRe t in the high-pressure liquid chromatography (HPLC) are determined over a 250 x 4.6 mm reversed phased Cis Nucleosil® p column at a flow rate of 1 ml/min. Gradient A: 0 4 100 acetonitrile in water containing 0.05 trifluoroacetic acid in 60 min.; gradient B: 10 100 acetonitrile in water containing 0.05 tri- S, fluoroacetic acid in 40 min.. For example, the abbreviation "tRet(A)" denotes that the retention time has been determined with gradient A.

0o 0 0 o0 o o The values for proton nuclear magnetic resonance spectroscopy ('H-NMR) o °o are given in ppm (parts per million) with reference to tetramethylsilane o as the internal standard. s singlet, d doublet, t triplet, q quartet, m multiplet, dd double doublet, br broad. In the fast atom bombardment mass spectrometry (FAB-MS), the values are giren for the protonated mass o 4 l S The residue referred to as -Cha-Val- denotes the bivalent radical of (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid and has the formula A i -69-

OH

4(S) 2(S) .6 Thp residue referred to as -Cha Va1- is derived from the residue -Cha cVal- by bridging NH and OH by an isopropylidene group and has the formula SThe abbreviations conventionally used in peptide chemistry are used to refer to bivalent radicals of natural a-amino acids. Tyrosine radicals referred to as Tyr(OR). Nle denotes the radical of norleucine, Cha the radical of cyclohexylalanine.

Other abbreviations.: abs. absolute (anhydrous) BBSP 2(S)-benzyl-3-tert.-butylsulfonyl-propionyl BOG tert.-butoxycarbonyl pBOP benzotriazol-1-yloxytris(dimethy.tamino)phosphonium hexafluorophosphate DCCI =dicyclohexylcarbodiimide DCL, dicyclohexylurea DMF =dimethylformamide DMSO =dimethyl sulfoxide Fmoc =9-fluorenylmethoxycarbonyl HBTU 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBH N-hydroxy-endo-norbornane-2,3-dicarboxylic acid imide HOBt 1-hydroxybenzotriazole cone. concentrated min. minute(s) b.p. boiling point m.p. melting point Tcp trichlorophenyl THF tetrahydrofuran Z benzyloxycarbonyl Example 1: Z-Arg-Arg-Pro-Phe-Val-ChaVal-Val-Tyr-OMe A mixture of 160 mg of H-Phe-Val-Cha Val-Val-Tyr-OMe, 180 mg of Z-Arg-Arg-Pro-OH.HC1, 42 mg of triethylamine hydrochloride, 62 mg of DCCI, 42 mg of HOBt and 10 ml of DMF is stirred at room temperature fdr 48 hours. The crystallised DCU is filtered off ond the filtrate is conao, centrated by evaporation. The residue is dissolve, in methanol and pre- 0 cipitated with diisopropyl ether. The crude product is then purified by o 0 0° flash chromatography on 20 g of silica gel (eluant 1M). Rf(M) 0.25; FAB-MS: 1337; t 35.2 min.

The starting materials are prepared in the following manner: ooo The starting materials are prepared in the following manner: re 0 0 4 0 04a o 0l Oa I 0 6 1 gooot 0 4 a) 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propionic acid ethyl ester: 243 g of 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propionic acid (manufacture: Helvetica Chimica Acta 57, 2131 (1974)) are placed in 600 ml of toluene and 900 ml of ethanol. The reaction mixture is cooled to 00 and 88.3 g of thionyl chloride are added dropwise within 30 minutes. The cooling is removed and the mixture is stirred for 18 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is separated by means of flash chromatography (2 kg of silica gel 40-63 pm, eluant The fractions containing the product are combined, concentrated by evaporation and dried under a high vacuum. The title compound is obtained in the form of a slightly yellowish oil.

Rf(E) 0.2; Rf(B) 0.52.

71 b) 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propanal: 116.1 g of 2(S)-benzyloxycarbonylamino-3-cyclohexyl-prpionic acid ethyl ester are placed in 2.2 litres of toluene and cooled to -650. 836 ml of diisobutylaluminium hydride are added dropwise at -650 within 30 minutes and the mixture is then stirred for 20 minutes. Then 84.2 ml of methanol are added dropwise within 10 minutes at -65' and subsequently 825 ml of aqueous potassium sodium tartrate solution without cooling. The reaction mixture is discharged onto 3 litres of potassium sodium tartrate solution/ice and extracted with 5 litres of ether. The ethereal phase is washed with 2 litres of water, then immediately poured into a solution consisting of 106 g of semicarbazide hydrochloride and 156.5 g of sodium acetate in 620 ml of water and 620 ml of ethanol. The reaction mixture is then stirred at room temperature for 1 hour and subsequently separated in a separating funnel, and the aqueous phase is extracted with 2 x 1.5 litres of ether. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The crude product is purified by 0o, means of flash chromatography (2 kg of silica gel 60, 40-63 pm, eluant o 0o*O Concentration by evaporation of the combined product-containing fracoo tions yields the semicarbazone of the title compound, Rf(G) 0.51. 130 g o of this semicarbazone are dissolved in 1 litre of THY, and 282 ml of 37 o formaldehyde solution and thei, at 100, 143 ml of 0.5N HC1 are added at thereto. The reaction mixture is stirred at room temperature for 2 hours and is filtered, and the filtrate is washed with 0.5 litre of water, litre of NaHC0 3 and 0.5 litre of water. 'he aqueous phases are extracted with 600 ml of ether. The ethereal phases are dried over magnesium sulfate and concentrated by evaporation. 100 ml of toluene are added to the residue and the whole is concentrated by evaporation to yield the title compound. The latter is further processed immediately.

c) (1(S)-benzyloxycarbonylamino-2-yclohexyl-ethyl)-oxirane: 18.9 g of sodium hydride dispersion (55 in oil) are freed of oil in a dry sulfonating flask under argon by stirring three times in 50 ml of petroleum ether and subsequently decanting off the solvent each time. After drying under a high vacuum, a grey powder is obtained which is placed in 500 ml of THF; 55.6 g of trimethylsulfoxonium iodide A i 72 are added thereto, the temperature increading to approximately 400. The grey suspension is boiled under reflux for 1 hour and then, within a period of 50 minutes at -700, a solucion of 108.6 g of 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propanal in 250 ml of THF is added. The yellow suspension is stirred at 00 for 2 hours. The yellowish turbid solution is poured onto 500 g of ice. The aqueous solution is extracted with litres of ether, and the organic phase is washed with water and, after being dried over sodium sulfate, is concentrated by evaporation.

The oily residue is separated by means of flash chromatography (2.5 kg of silica gel 60, 40-63 pm, eluant The fractions containing the product Sare combined, concentrated by evaporation and dried under a high vacuum.

The title compound (diastereoisomeric mixture, approximately 4:1) is obtained in the form of a slightly yellowish oil. R 0.71; R 0.16.

d) 3(S)-benzyloxycarbonylamino-4-cyclohexyl-l-iodo-butan-2(R,S)-ol: 42.3 g of (1(S'-benzyloxycarbonylamino-2-cyclohexyl-ethyl)-oxirane are o, taken up in 200 ml of acetonitrile and the resulting solution is cooled 0 S to 00. After the addition of 20.9 g of sodium iodide, there are added 0 03 009 a 0' dropwise at over a period of 30 minutes, 17.7 ml of trimethylchloro- S"oo silane. The mixture is stirred at 0 to 30 for 40 minutes and then poured a into 700 ml of ice-cold water. The aqueous mixture is extracted with cao ether and the organic phase is washed with 750 ml of a 5 aqueous sodium thiosulfate solution and 750 ml of saturated, aqueous sodium chloride solution. After drying over sodium sulfate and concentrating by evaporation, an oily mixture of the title compound is obtained which is further processed directly.

e) 3-benzyloxycarbonyl-4(S)-cyclohexylmethyl-2,2-dimethvl-5(R)-iodorethyl-1,3-oxazolidine: 49.3 g of the compound of Example 1 d) and 1.07 g of E-toluenesulfonic acid monohydrate are stirred in 140 ml of 2,2-dimethoxypropane and 450 ml of methylene chloride for 3 hours at room temperature. The mixture is extracted by shaking between 1 litre of ii methylene chloride and 500 ml of saturated, aqueous sodium hydrogen carbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is

I

_III1__I1I L I__LT--i -rill-l -1I I -l.illl i~ i 73 purified by means of flash chromatography (3 kg of silica gel 40-63 pm, eluant Concentration by evaporation of the purified, product-containing fractions yields the title compound in the form of a slightly yellowish oil. Rf(C) 0-55; R 0.46.

f) 2(R,S)-(3-benzyloxycarbonyl-4( )-cyclohexylmethyl-2,2-dimethyl-l,3oxazolidinyl-5(S)-methyl)-3-methyl-butyric acid methyl ester: 14.3 ml of diisopropylamine are dissolved under argon in 200 ml of absolute terrahydrofuran and cooled to 00. Then, at 0 to 65.8 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise to the mixture over a period of 20 minutes and the whole is stirred for 20 minutes. Then, at from -700 to 13.3 ml of isovaleric acid methyl ester are added dropwise and the mixture is stirred for 1.5 hours at -750. At from -600 to -750, 320 ml of hexamethylphosphoric acid triamide are added dropwise while stirring. The resulting suspension is stirred for 10 minutes and, finally, at from -700 to -750, a solution of 43.4 g of the compound of Example 1 e) in 110 ml of tetrahydrofuran is added dropwise in 5 minutes.

The reaction mixture is stirred at room temperature for 2.5 hours and finally poured onto a mixture of 1 litre of saturated, aqueous ammonium o chloride solution and 500 g of ice. The aqueous phase is extracted with 0, 2 litres of ethyl acetate, and the organic phase is washed with water and o"o dried over sodium sulfate. After concentration by evaporation, the o p dia tereoisomeric mixture of the title compound is obtained in the form 0 of a yellow oil. Rf(C) 0.36; R 0.21 (values for the less polar component).

g) 2(R,S)-(3-benzyloxycarbonyl-4(S)-cyclohexylmethyl-2,2-dimethyl-1,3oxazolidinyl-5(S)-methyl)-3-methyl-butyric acid: 1.77 ml of water are added at approximately 50 to 16.5 g of potassium tert.-butanolate in 250 ml of ether. The white suspension is stirred in an ice bath for a further 10 minutes and then 35.8 g of the compound of Example 1 f) (diastereoisomeric mixture) in 250 ml of ether are added thereto, the temperature being maintained below 100. The reaction mixture is then stirred at room temperature for 18 hours and finally poured into 500 ml of saturated, aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with 74 saturated, aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The oily crude product is separated by flash chromatography (2.5 kg of silica gel 60, 40-63 pm, eluant C).

Z-Cha-Val-OH, the less polar component of the title compound having the desired configuration of the carbon atom bonded to the isopropyl group (S-configuration), is obtained in the form of a yellow oil.

Rf(I) 0.20; Rf(J) 0.35.

h) HC1*H-Val-Tyr-OMe: 10.0 g of Z-Val-Tyr-OMe are hydrogenated under normal pressure and at room temperature in 200 ml of methanol and 24 ml of 1N HCl in the presence of 1.0 g of palladium-on-carbon (10 Pd) until saturation is reached. The reaction mixture is filtered, and the filtrate is concentrated by evaporation and dried. Rf(N) 0.64.

i) Z-Cha-cVal-Val-Tyr-OHe: A mixture of 2.06 g of HC1.H-Val-Tyr-OMe, 3,12 g of Z-Cha-cVal-OH, 1.74 g of DCCI, 1.22 g of HOBt, 0.75 g of N-methylmorpholine and 50 ml of DMF is stirred at room temperature for 16 hours. The DCU is filtered off, and the filtrate is concentrated and dried under a high vacuum. The residue is purified by means of flash SDqq chromatography (100 g of silica gel 60, eluant R 0.36.

0 S j) H-ChacVal-Val-Tyr-OMe: 3.6 g of Z-Cha-cVal-Val-Tyr-OMe are S hydrogenated under normal pressure and at room temperature in 80 ml of methanol/water 9:1 in the presence of 360 mg of palladium-on-carbon Pd) until saturation is reached. The reaction mixture is filtered, and the filtrate is diluted with 30 ml of water and stirred at room temperature for 5 hou-,. After evaporating off the solvent, the title Scompound is lyophilised from dioxane/water 9:1. Rf(H) 0.10.

k) BOC-Val-Cha-Val-Val-Tyr-OMe is obtained analogously to Example 1 i) starting from 1.45 g of H-ChacVal-Val-Tyr-OMe, 630 mg of BOC-Val-OH, 530 mg of HOBH and 660 mg of DCCI, and is purified by re-precipitation from methanol/NaHCO3 solution. Rf(G) 0.75.

1) HC1*H-Val-ChacVal-Val-:Tyr-0Me: 2.16 g of B0C-Val-Cha cVal-Val-Tyr-0He are dissolved in 20 ml of 4.3N ICi in dioxane and the whole is stirred at room temperature for 30 minutes. The reaction mixture is concentrated by evaporation, and the residue is purified by flash chromatography (60 g of silica gel 60, eluant G).

R f(G) 0.18.

m) Fmoc-Phe-Val- -Cha-Val-Val-Tyr-0Me: A mixture of 240 mg of H-ClH-Val-ChaVal-Val-Tyr-OMe, 170 mg of Fmoc-Phe-OTcp, 0.15 ml of N-ethyldiisopropylamine and 10 ml of DMF is stirred at room temperature for 20 hours. The reaction mixture is concentrated by evaporation, and the residue is precipiteted with 100 ml of diisopropyl ether. The precipitate is filtered off and thei, lyophilised from dioxane/water 9:1.

n) H-Phe-Val-Cha-Val-Val-Tyr-O~e: A solution of 305 mg of Fmoc-Phe-Val-Cha-cVal-Val-Tyr-OMe, 5 ml of piperidine and 5 ml of DMF Is stirred at room temperature for 60 minutes and then concentrated by evaporation. The residue is LOissolved in a :'aall amount of methylene 0 chloride and precipitated with diisopropy. ether. The precipitate is f0 o Eiltered off at 0' and then lyophil~sed from dioxane/water 9:1.

R f R(Hi) 0 0 006 Gro Example 2: BBSP-Val-Cha CVal-Va?.-Tyr-0He 0 Analogously to Example 1, the title compound is prepared from 760 mg of HCl.H-Val-Cha-Val--Val-Tyr-O~e (Example 1 350 mg of 2(S)-benzyl-3tert.-butylsulfonylpropionic acid (BBSP-OH), 190 mg of HOBt and 280 mg of DCCI, and is purified by flash chromatography. Rf(G) 0.50; FAB-MS: =913; te t(A) =42.1 min.

The starting material is prepared as follows: a) 2(S)-benzyl-3-tert.-butylsulfonyl-propionic acid (BBSP-OH): 142 g of 2 R,S)-benzyl-3-tert.-butylsulfonyl-propionic acid are reacted with 85.7 g of (+)-dehydroabietylanine and 27.8 ml of triethylamine in 2 litres of isopropanol. After crystallisation of the salt four times from hot isopropanol, the acid is freed again by extraiction with dilute r 7 76 sodium carbonate solution followed by acidification with dilute hydrochloric acid. Recrystallisation from ethyl acetate/hexane yields the title compound in a high degree of optical purity (over 98 ee): 20 [al. -10.9" (c 0.91 in CH 2 Cl 2 m.p. 99-101°; Rf(A) 0.16; R. 0.4.

b) 2(R,S)-benzyl-3-tert.-butylsulfonyl-propionic acid: 91.9 g of 2-benzyl-3-tert.-butylsulfonyl-propionic acid ethyl ester are boiled under reflux for 15 hours in 500 ml of 6N hydrochloric acid and 100 ml of acetic acid. Upon cooling, the title compound crystallises directly out of the reaction mixture. M.p. 147-80; Rf(B) 0.4; 1H-NMR (CDC1 3 1.35 9H), 2.97 1H), 3.05 (dd, 1H), 3.22 (dd, 1H), 3.45 2H), 7.25 5H); 8.5 (br s, 1H).

c) 2-benzyl-3-tert.-butylsulfonyl-propionic acid ethyl ester: 60 g of a-benzyla'rylic acid ethyl ester are dissolved in 600 ml of ethanol and reacted with 0.83 g cf sodium methanolate and 37 ml of tert.-butylmercaptan. The mixture is stirred at room temperature for 24 hours, diluted with 500 ml of 0.04N aqueous sulfuric acid and, while cooling with ice, 260 g of Oxone® (potassium peroxomonosulfate, 50 KHSOs, Ventron) are added thereto. The reaction mixture is stirred overnight at room tem- S perature, then filtered and concentrated. The aqueous solution is o extracted with methylene chloride, and the extracts are dried over sodium sulfate and concentrated by evaporation. M.p. 47-480; 1H-NMR (CDCl): 1.13 ppm 3H), 1.38 9H), 2.95 (dd, 1H), 3.01 (dd, 1H), 3.10 (dd, 1H), 3.42 (dd, 1H), 3.46 (dd, 1H), 4.12 2H), 7.25 oo. a-benzylacrylic acid ethyl ester: 4.0 g of KOH in 50 ml of ethanol are added at room temperature to 20 g of benzylmalonic acid diethyl ester in o oo 40 ml of ethanol, and the reaction mixture is stirred overnight at room temperature, concentrated by evaporation, 7.1 ml of water are added 0 0 thereto and the whole is acidified in an ice bath with 6.3 ml of cone.

0 S hydrochloric acid. The reaction mixture is partitioned between water and S ether, and the organic phase is dried and the ether is distilled off.

12.9 ml of pyridine, 0.61 g of piperidine and 1.78 g of paraformaldehyde o are added to the residue. The mixture is heated for 90 minutes in an oil -77 bath cooled, 220 ml of water are add IiTereto and the whole is extracted three times with 75 iml of n-hexane. The combined organic phases are washed with water, 1N HGI, water, saturated NaHC0 3 solution and brine. The title compound is obtained by distillation. 1IH-NMR (DMSO-d6): 1.2 ppm 3H), 3.6 2H), 4.1 2H), 5.6 (in, 1H), 6.15 (in, 1H-), 7.25 (in, Example BBSP-Val-Cha-cVal-Val-Tyr-OH A m~ixture of 65 mg of BESP-Val-Cha-Val-Val-Tyr-OMe (Example 2 ml of 2N NaOH- and 3 ml of dioxane is stirred at room temperature for minutes. The reaction mixture is then diluted with 2 iml of 2N HCl and lyophilised. The residue is purified by means of flash chromatography (8 g of silica gel, eluant R f(N) 0.53.

Exmle BBSP-Val-Cha-cVal-Val-Ty r-NH 2 Analogously to Example 2, the title compound is prepared from 30 mng of H-ClH-Val-Cha-Val-Val-Tyr-NH 2 15 mng of 2(S)-benzyl-3-tert.-butylsulfonyl-propionic acid (BBSP-OH), 8 mg of HO~t and 12 mg of DCCI and is purified by flash chromatography on 7 g of silica gel 60 (eluant F).

R f(G) 0.32; FAB-MS: 898: t Rt(A) 41.7 min.

The starting materials are prepared in the following~ manner: 0' a) HCl.H-Val-Cha 2 Val-Val-Tyr-NH 2 is prepared analogously 11,D~a:pl 1 1) from 360 mg of BOC-Val-Cha-Val-Val-Tyr-NH2 and 5.0 ml uf 4.3N Nd1 in dioxane. R f =0.3.

b) BCVl Cha 2 lVlTrN1 is obtained analogously to Example 1 k) from 300 mng of H-Cha-Val-Val-Tyr-NH 2 147 mg of BOC-Val-OH, 122 mng of H OBII and 268 mng of DCCI. R f(G) 0.33.

ff

A-

78 d) Z-ChaxVal-Val-Tyr-NH 2 A mixture of 772 mg of Z-Cha- x lai-Val-Tyr-OH, 590 mg of NH4iCl, 325 mng of DCCI, 217 mg of HOBt and 10 ml of DNF is adjusted to pH 5.5-6.0 with NaHCO 3 and then stirred for 16 hours. The DCU is filtered off and the filtrate is concentrated by evaporation. The residue *is purified by flash chromatography on 40 g of silica gel 6C (eluant F) R f(G) 0. e) Z-Cha2Val-Val-Tyr-OH is prepared analogously to Example S from 790 mg of Z-Cha- xVal-Val-Tyr-1e (Example 1 4 ml of 4N NaOH and 16 ml of dioxane. R f(G) =0.07.

Example 5: 3- amino- 3, 3-dimethylpropanoyl) -Tyr -Val-Cha-Val-Val- Tyr-NH 2 A solution of 12U mg of N- ter t. -butoxyca rbonylamino- 3, 3-dime thylpropanoyl) -Tyr (OMe) -Val--Cha-Val-Val-Tyr-NH 2 in 1.0 ml of 95 aqueous trifluoroacetic acid is stirred for 20 minutes. The reaction mixture is concentrateO by evaporation and the residue is purified by flash chromatography on~r 10 g of silica gel 60 (eluant R f(L) =0.06, "f 0.46; FAB-MS: 908; t Rt(A) 35.6 min.

The starting materials are prepared in the following manner: a) 3-ter t. -bu toxycarbonylamino-3, 3-dime thylpropanoyl) -Tyr (O~e) Val-Cha-Val-Val-Tyr-NH 2 is prepared analogously to Example 1 i) from mg of H-Tyr (OMe) -Va 1-Cha2 Val-Val-Tyr-NH 2, 31 mg of 3-tert.-butoxysarbonylamino-3,3-dimethylpropionic acid, 26 mg of H-OBt and 34 mg of DCCI and is purified by flash chromatography on 8 g of silica gel 60 (eluant R f(G) 0.30.

b) H-Tyr(O~e)-Val-Cha-Val-Val-Tyr-NH2 is prepared analogously to Examples 1 m) and 1 n) from 260 mg of HCl-H-Val-Cha-Val-Val-Tyr-NH 2 (Example 4 320 mg of Fmoc-Tyr(OMe)-OTcp and 0.15 ml of N-ethyldiisopropylamine.

0000 00 0 o 00 00a 0 0 00 4004 0 0000 000 Gee 0 0 A Iy- 79 c) Fmoc-Tyr(OMe)-OTcp: 0.76 g of tr~ichiorophenrol and 0.9,2 g of DCCI are added at 0' to a solution of 1.45 g of Fmoc.-Tyr(0Me)-0H in 30 ml of abs.

THF, and the reaction mixtt'.e is stirred for 1/2 hour at and then for 2 hours at room temperature. The DCU is filtered off at 00, the filtrate is concentrated by evaporation and the residue is crystallised from THF/hexane.

Example 6: Z-Arg-Arg-Pro-Tyr( .O~e)-Va1-Cha2Val-Val-Tyr-N H2 Analogously to Example 1, the title compound is prepared from 150 mg of H-Tyr(O~e)-Val-Cha-CVal-Val-Tyr-NH2, 150 mg of Z-Arg-Arg-Pro-OH-HCl, mg of t rie thy lammonium chloride, 50 mg of HOBt and 68 mg of DCCI.

R f(M) 0.24; t Rt(A) 36.3 min.

E-a pe7: N-(2 S) -benzyl-3-pivaloyl-prOpionyl) -Nle-Cha-cVal-Val- Tyr-OMe A solution of 20 mg of HCl.H-Nle--Cfna cVal--Val-Tyr-OMe, 22 mg of benzyl-3-pDivaloylpropionic acid Med. Chem. 31, 1839 (1988)), 33 mg of HBTU and 24 p 1 of triethylamine in 2 ml of DMF is stirred at room tern- 088perature for 2 hours. The mixture is completely concentrated by evapora- 0 tion, and the residue is washed with saturated sodium bicarbonate solu- 00 0..0 tion and diisopropyl ether and finally dissolved in DMF. The product is 00 precipitated with dilsopropyl ether and, after lyophilisation from 0 dioxane /tert. -bu tano 1/water, yields the title compound in the form of a 0+ diastereoisomeric mixture. FAB-MS: 891; R f(P) =0.55; HPLC: 2 dia~ce'-eoisomers in a ratio of 1.8:1, t Rt 30. 0 and 30. 4 min.

9889 8 8 8 8 9 89 8 8 9 0 48 88 4 0 8 8 8 88 808988 0 8 88 8 ~.088 8 898888 0 4 The starting material is prepared in the following manner: a) HCl.H-Nle-Cha-Val-Val-Tvr-OMe iF prepared analogous,y to Example 1 1) from 50 mg of BOC-Nle-Cha-Val-Val-Tyr-OMe and 5 ml of 4N RIi in dioxane. The product is lyophilised from dioxane. R f(P) 0.15; t Ret 19.9 min.

b) BOC-Nle-Cha-Val-Val-Tyr-OMe: A solution of 60' mg of H-Cha2Val- Val-Tyr-OMe (Example 1 28 mg of BOC-Nle-OH, 46 mg of HBTU and 35 P1 of triethylamine in 2 ml of DMF is stirred at room temperature for

A

3 ho~urs. The mixture is concentrated by evaporation, and the residue is washed with saturated sodium bicarbonate solution and diisopropyl ether and finall~y dissolved in DMF. The product is precipitated with diisopropyl ether and lyophilised from dioxang~/tert.-butanol/water. FAB-MS: 761; R f(P) 0.50; t 2 -t 27.9 min.

Example 8: BBSP-Nle-Cha cVal-Val-Tyr-O~e Analogously to Example 7, the title compound is prepared from 20 mg of HCl*H-Nle-Cha cVal-Val-Tyr-OMe (Example 7 25 mg of 2(S)-benzyl- 3-tert.-butylsulfonylpropionic acid (BBSP-OH), 33 mg of HBTUb and 24 V1l of triethylamine, is purified by flash chromatography on 10 g of silica gel (eluant P) and lyophilised from dioxane/tert.-butanol/water. FAB-HS: 927; R f(P) 0.46; tRe 28.0 min.

Example 9: BBSP-Tyr-Cba2Val-Val-Tyr-OMe A solution of 17 mg of BBSP-Tyr(OtBu)-Cha-cVal-Val-Tyr-OMe in 2 ml of aqueous trifluoroacetic acid is stirred at room temperature for 2 hours. The mixture is concentrated by evaporation and Cie residue is purified by cnromatography on 10 g of silica gel (eluant The frac- DO: tions containing the product are concentrated by evaporation, and the ooresidue is dissolved in DMF and precipitated with diisopropyl ether. The Stitle compnund is lyophilised ftom dioxane/tert.-butanol/water. FAB-HS: J~(H-iH) 977; Rf(P) 0,40; t~e 25.5 min.

The starting material is prepared in the following manner: a) BBSP-Tyr(OtBu)-Cha-Val-Val-Tyr-OMe is prepared analogously to 4 Example 7 from 20 mg of H-Tyr(OtBu)--Cha-Val--Val-Tyr-Orie, 22 mg of 2(S)-benzyl-3-tert.-butylsulfonylpropionic acid (BBSP-OI-), 30 mg of HBTU and 22 p1 of triethylamine. The crude product is purified by flash chromatography on 10 g of silica gel. (eluant P) and lyophilised from dioxane/tert.-butanol/water. R f(P) =0.55.

b) H-Tvr(OtBu)-Cha 2 Val-Val-Tyr-14e: A zolution of 70 mg of Fmoc-Tyr(0tBu)-Cha2Val-Val-Tyr-0He in 2 ml of dimethylacetamide/piperidine 30:20 is stirred at room temperature for

A

81 minutes. The mixture is concentrated by evaporation, and the residue is dissolved in DMF and precipitated with diisopropyl ether. The oily residue is washed with methylene chloride, dissolved in DMF and again precipitated with diisopropyl ether at 00, and yields the title compound in the form of an amorphous solid. R 0.30; t 22.3 min.

f Ret c c) Fmoc-Tyr(OtBu)-ChacVal-Val-Tyr-OMe is prepared analogously to Example 7 from 60 mg of H-Cha-Val-Val-Tyr-OMe, 55 mg of Fmoc-Tyr(OtBu)- OH, 46 mg of HBTU and 35 pl of triethylamine. The crude product is 1 purified by flash chromatography on 20 g of silica gel (eluant The fractions containing the product are concentrated by evaporation and the residue is precipitated from DMF/diisopropyl ether. Rf(P) 0.60; Ret 32.4 min.

Example 10: S)-benzyl-3-pivaloyl-propionyl)-Ala-Cha-Val-Val- Tyr-OMe A mixture of 185 mg of crude H-Ala-Cha-Val-Val-Tyr-010e, 17.5 mg of 2(R,S)-benzyl-3-pivaloylpropionic acid, 12.8 mg of HOBH, 15.6 mg of DCCI and 0.64 ml of DMF is stirred at room temperature for 16 hours. The reaction mixture is worked up analogously to Example 1, yielding, after oo chromatography (silica gel 60, eluant ethyl acetate) a diastereoisomeric o °o mixture of the title compound. FAB-HS: 849.7; R 0.7; S" tRet(B) 27.5 and 27.9 min.

a Ret The starting material is prepared in the following manner: a) H-Ala-ChacVal-Val-Tyr-OMe: A solution of 90 mg of BOC-Ala-ChacVali Val-Tyr-OMe in 2.3 ml of 95 aqueous trifluoroacetic acid is stirred at 0° for 1.5 hours. A small amount of water is added to the reaction mixture in an ice bath and the trifluoroacetic acid is neutralised with solid NaHC03. The residue is washed several times with ethyl acetate, and the organic phases are combined and dried over sodium sulfate. The crude title compound is obtained after concentration by evaporation. Rf(R) 0.

-82b) BOC-Ala-Cha-Val-Val-Tyr-oMe: A mixture of 109.5 mg of H-Cha-Val-Val- Tyr-:SHe (Example 1 41.6 mg of BOG-Ala-OH, 49.6 mg of DCCI, 39.8 mg of HOBH and 2 ml of DMF is stirred at room temperature for 5 hours. After cooling to 0' and filtration, the DMF is distilled off under a high vacuum at a maximum of 600. The residue is dissolved in 5 ml of methylene chloride, and the organic phase is washed with 1 ml of aqueous sodium bicarb nate solution and dried over sodium sulfate. After concentration by evaporation, the crude title compound is purified by chromatography (38 g of silica gel 60, eluant ethyl acetate). FAB-MS: 719z R f(R) 0.7.

Examp~e 11: N-(2(R,S)-benzyl-3-pivaloyl-propionyl)-Ser-Cha cVal-Val- Tyr-OMe Analogously to Example 10, a diastereoisomeric mixture of the title compound is prepared from 80 mg of H-Ser-Cha-cVal-Val-Tyr-OMe (crude product), 17.5 mg of 2(11S)-benzyl-3-pivaloyl-propionic acid, 12.8 mg of HOBH and 15.8 mg of DCCI in 0.64 ml of DMF. FAB-MS: =865; R.f 0.7; t Rt(B) 26.68 and 26.71 min.

0 a 00O The starting wiqterial is prepared in the following manner: 00 0 000 0 a) H-Ser-Cha-Val-Val-Tyr-0Me: Analogously to Example 10 the title 0 compound is prepared from 95 mg of BOC-Ser-Cha-Val-Val-Tyr-OMe in 2.3 m! of 95 trifluoroacetic acid. Rf(R) 0.

cf b) BOC-Ser-Cha-Val-Val-Tyr-OMe: Analogously to Example 10 the title compound is prepared from 109.5 mg of H-Cha2Val-Val-Tyr-OWe, 45.1 mg of o~o0 BOC-Ser-OH, 39.8 mg of HOBH and 49.6 mg of DCCI and is purified by chro- 00 0matography. FAB-MS: =735; R 0.65.

ExIape12: N-(2(R,S)-benzyl-3-pivaloyl--propionyl)-Phe-Cha--Val-Val- Tyr-OMe 048.5 mg of -Phe-Cha CVal-Val-Tyr-0Me and 20.8 mg of 2(R,S)-benzyl-3- 000* pivaloyl-propionic acid are dissolved in 2 ml of DMF, and 31.7 g of BOP and 14.6 p1 of triethylamine are added thereto. The solution is stirred I 83 at room temperature for 15 hours and then concentrated by evaporation.

The residue is digested in a small amount of diisopropyl ether. FAB-MS: 925; Rf(S) 0.5; tRet(B) 30.7 and 31.1 min.

The starting material is prepared in the following manner: a) H-Phe-Cha2Val-Val-Tyr-OMe: A solution of 83 mg of Fmoc-Phe-Cha Val-Val-Tyr-OMe, 2.4 ml of piperidine and 2.4 ml of DMF is stirred at room temperature for 90 minutes and then concentrated by evaporation. The residue is dissolved in a small amount of methylene chloride and precipitated with diisopropyl ether. The precipitate is filtered off at 00 and then lyophilised from dioxane/water 9:1. FAB-MS: 695; Rf(Q) 0.36.

b) Fmoc-Ph__-.9-.Val-Val-Tyr-OMe: A mixture of 50 mg of H-ChaSVal- Val-Tyr-OM-, 67.3 mg of Fmoc-Phe-OTcp, 17 pI of N-ethyldiisopropylamine and 1.2 ml of DMF is stirred at room temperature for 75 minutes. The reaction mixture is concentrated by evaporation, and the residue is precipitated with 5 ml of diisopropyl ether. The precipitate is filtered off S and precipitated a second time from DMF/diisopropyl ether. Rf(Q) 0.37.

O4 t Example 13: N-(2(R,S)-benzyl-3-pivaloyl-propionyl)-Leu-Cha-Val-Val- 0 Tyr-OMe o so 3F-5 mg of H-Leu-ChacVal-Val-Tyr-OMe and 16 mg of 2(R,S)-benzyl-3pivaloyl-propionic acid are dissolved in 2 ml of DMF, and 28.5 mg of BOP and 11.2 p1 of triethylamine are added thereto. After stirring at room temperature for 150 minutes, the reaction mixture is concentrated, and the residue is digested in 20 ml of diisopropyl ether. FAB-MS: 891; Rf(Q) 0.57; tRet(B) 30.1 and 30.4 min.

The starting material is prepared in the following manner: a) H-Leu-Cha-Val-Val-Tyr-OMe: A solution of 108 mg of Fmoc-Leu-Cha-Val- 9it Val-Tyr-OMe, 3.2 ml of piperidine and 3.2 ml of DMF is stirred at room temperature for 60 minutes and then concentrated by evaporation. The t a 1 I 84 residue is dissolved in a small amount of DMF and precipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at 00 and then lyophilised from dioxane/water 9:1. FAB-MS: 661; Rf(Q) 0.64.

b) Fmoc-Leu-ChacVal-Val-Tyr-OMe: A mixture of 80 mg of H-ChacVal-Val- Tyr-OMe, 101 mg of Fmoc-Leu-OTcp, 27.5 pl of N-ethyldiisopropylamine and 1.4 ml of DMF is stirred at room temperature for 90 minutes. The reaction mixture is concentrated by evaporation, and the residue is precipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyophilised from dioxane/water 9:1. Rf(Q) 0.375.

Example 14: BBSP-Leu-Cha-Val-Val-Tyr-OMe 35.5 mg of H-Leu-ChacVal-Val-Tyr-OMe and 18.4 mg of 2(S)-benzyl-3-tert.butylsulfonylpropionic acid (BBSP-OH) are dissolved in 1 ml of DMF, and 28.5 mg of BOP and 11.2 pl of triethylamine are added thereto. After stirring at room temperature for 5 hours, the reaction mixture is concentrated, and the residue is digested in diisopropyl ether. FAB-MS: 927.5; Rf(Q) 0.54; tRet(B) 28.0 min.

Co S Example 15: BBSP-Leu-Cha-Val-Val-p-biphenylylmethylamide 0 40 mg of H-Leu-Cha-Val-Val-p-biphenylylmethylamide and 18.4 mg of BBSP-OH are dissolved in 1 ml of DMF, and 28.5 mg of BOP and 11 pl of a oo triethylamine are added thereto. After stirring at room temperature for S 5 hours, the reaction mixture is concentrated, and the residue is digested in diisopropyl ether. FAB-MS: 916; R(Q) 0.58.

The starting material is prepared in the following manner: c a) H-Leu-Cha-Val-Val-p-biphenylylmethylamide: A solution of 108 mg of c Fmoc-Leu-Cha-Val-Val-E-biphenylylmethylamide, 3 ml of piperidine and 3 ml of DMF is stirred at room temperature for 60 minutes and then concentrated by evaporation. The residue is dissolved in a small amount of DMF and precipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at 00 and then lyophilised from dioxane/water 9:i. FAB-MS: 649; Rf(Q) 0.72.

A i b) Fmoc-Leu-Cha-Val-Val-p-bipheinylylmethylamide: A mixture of 100 mg of H-Cha-cVal-Val-p-biphenylylmethylamnide, 120 mg of Fmoc-L'.u-OTcp, 35 iii of N-ethyldiisopropylamine and 2 ml of DMF is stirred at room temperature for 90 minutes. The reaction mixture is concentrated by evaporation, and the residue is precipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyopliiLlised from dioxane/water 9:1.

R f(Q) =0.41.

c) H-Cha-2Va 1-Va 1-p-b iph enylylme thy lamide: 290 mg of N-(5(S)-azido-6cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl)-Val-p-biphenylylmethylamide are dissolved in 40 ml of methanol, 70 mog of palladium-on-carbon Pd) are added thereto and recluction is carried out with hydrogen.

After 2 hours at room temperature, thtv catalyst is filtered off, the solution is concentrated and the residue is precipitated. FAB-MS: 536; R f(T) 0.23.

000, 0000 0 *0 00 0 00 0 o s'o~ 0 ~0 00 0 *0000 00 0 Oct.

0 0 0 00 0 0'0 00 0 0 0~ 0.0 0 0* 0 0* 0 0 *0000 0 Os' *0 4 *00.064 0 0 d) N-(5(S)-azido-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl)Val-pbiphenylylmethylamide: 360 mg of tetrabutylammonium fluoride are added to 386 mg of N-(5(S)-azido-6-cyclohexyl-4(S)-tert.-butyldimethylsilyloxy- 2(S)-isopropyl-hexanoyl)-Val- 2 -biphenylylmethylamide in 5 ml of DHF.

After 4 hours, the solution is concentrated and the residue is taken up in approximately 100 ml of ethyl acetate and washed with sodium bicarbonate solution. After concentration of the solution, the residue is crystallised from methyJ.ane chloride /hexane. FAB-HS: 562; R f(U) 0.12.

e) N-(5(S)-azido-6-cyclohexyl-4(S)-tert.-butyldimfethylsilyloxy-2(S)isopropyl-'hexanoyl) -Val-p-biphenylylmethylamide: 376 mg of 5(s) -azido-6cyclohexyl-4 -ter t. butyldimethylsilyloxy2( S) isopropylexanoic acid Org. Chem. 54, 1178 (1989)) and 250 mg of valine-p-biphenylylmethylamide are dissolved in 10 ml of DMF, and 404 mg of BlOP and 0.16 ml of triethylamine are added thereto. After 16 hours at room temperature, the reaction mixture is concentrated, and the residue is digested with diisopropyl ether. FAB-MS: =676; R f(U) 0.45.

r i I 86 f) Valine-p-biphenylylmethylamide: 980 mg of BOC-Val-p-biphenylylmethylamide are left to stand for 30 minutes at room temperature in 10 ml of dioxane/4N HC1. The reaction mixture is then concentrated and partitioned between ethyl acetate and 1N NaOH. The organic phase is concentrated and the residue is chromatographed on silica gel. Rf(F) 0.4.

g) BOC-Val-p-biphenylylmethylamide: 3.9 g of N-tert.-butoxycarbonyl-Lvaline-N'-hydroxysuccinimide ester and 2.7 g of biphenylylmethylamine are stirred in 150 ml of methylene chloride for 1 hour at room temperature.

The mixture is filtered through silica gel and concentrated by evaporation, and the residue is crystallised from hexane. FAB-MS: 383; R 0.28.

Example 16: Gelatin solution c A sterile-filtered aqueous solution of Z-Arg-Arg-Pro-Phe-Val-Cha-Val- Val-Tyr-OMe is mixed with a sterile gelatin solution containing phenol as preservative, while heating under aseptic conditions, in such amounts that 1.0 ml of solution has the following composition: 6us 6661.

6 6" 6O 6 1.4 6 Z-Arg-Arg-Pro-Phe-Val-Cha-Val-Val-Tyr-OMe gelatin phenol distilled water up to 3 mg 150.0 mg 4.7 mg 1.0 ml o 66 00.11,6 6 as 6, The mixture is introduced into 1.0 ml vials under aseptic conditions.

Example 17: Sterile dry substance for injection mg of Z-Arg-Arg-Pro-Phe-Val-ChacVal-Val-Tyr-OMe are dissolved in 1 ml of an aqueous solution with 20 mg of mannitol. The solution is sterilefiltered and introduced under aseptic conditions into a 2 ml ampoule, deep-frozen and lyophilised. Before use, the lyophilised substance is dissolved in 1 ml of distilled water or 1 ml of physiological saline solution. The solution is administered intramuscularly or intravenously.

This formulation may also be introduced into double-chamber syringe ampoules.

-87- Example 18: Nasal spray 500 mg of finely ground pm) BBSP-Val-ChacVal-Val-Tyr-OMe are suspended in a mixture of 3.5 ml of Myglyol 812® and 0.08 g of benzyl alcohol. The suspension is introduced into a container having a metering valve. 5.0 g of Freon® 12 are introduced into the container under pressure through the valve. By shaking, the Freon® is dissolved in the Myglyol/benzyl alcohol mixture. The spray container contains approximately 100 single doses which may be administered singly.

Example 19: Lacquer-coated tablets The following constituents are processed for the preparation of 10,000 tablets each containing 100 mg of active ingredient: BBSP-Val-Cha-Val-Val-Tyr,-OMe 1000 g corn starch 680 g colloidal silica 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g o a water q.s.

0 A O S S A mixture of BBSP-Val-ChaVal-Val-Tyr-OMe, 50 g of corn starch and the Sa o colloidal silica is processed with a starch paste consisting of 250 g of "o corn starch and 2.2 kg of demineralised water to form a moist mass. This mass is forced through a sieve of 3 mm mesh size and dried for 30 minutes at 45° in a fluidised-bed drier. The dry granulate is pressed through a sieve of 1 mm mesh size, mixed with a previously sieved mixture (1 mm t' sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to form slightly convex tablets.

I. The compacts are coated in a coating vessel of 45 cm diameter by uniform spraying for 30 minutes with a solution of 20 g of shellac and 40 g of hydroxypropylmethylcellulose (low viscosity) in 110 g of methanol and 1350 g of methylene chloride; drying is effected simultaneously by Sblowing in air at 600.

88 Instead of the active ingredients mentioned in Examples 16 to 19, it is also possible to use in these Examples the same amount of a different active ingredient from the preceding Examples.

Example 20: Inhibition of isolated HIV-1 gag-:rotease il of a solution of HIV-1 gag-protease (acetone extract of a gagprotease expressed in E. coli according to J. Hansen et al., The EMBO Journal 7, 1785 (1988)) b'nd 190 pl of B-morpholinoethanesulfonic acidbuffer solution pH 6 containing 0.01 2-amino-4-nitrophenol as the internal standard are pre-incubated at 370. 10 pl of a 0.24 mM DMSO solu- S tion of the substrate H-Arg-Arg-Ser-Asn-Gln-Val-Ser-Gln-Asn-Tyr-Pro-Ile- Val-Gln-Asn-Ile-Gln-Gly-Arg-Arg-OH (icosapeptide according to J. Schneider et al., Cell 54, 363 (1988), prepared in an automated peptide synthesising apparatus with Fmoc-protected amino acid units) and pl of a DMSO solution of the compound to be investigated for its -4 -6 inhibiting action, in a concentration of 22 x 10 M or 22 x 10 M, are then added simultaneously. After one hour, 50 pl of reaction solution are removed, 5 pl of 0.3 perchloric acid are added thereto and the whole is centrifuged. The amount of unconsumed substrate and the cleavage products q in the ;upernatant solution are determined by HPLC and the percentage -4 6 o o. inhibition at 10 M and 10 M is calculated therefrom.

0 0 0 o o For the HPLC analysis there is used a 125 x 4.6 mm reversed phase C18 u 'o0 Nucleosil® 5 p column; gradient 10 acetonitrile/0.1 trifluoroacetic acid in water 25 acetonitrile/0.08 trifluoroacetic acid in water in 30 min., flow rate 1.5 ml/min.

L -4 The compounds of the preceding Examples have, at concentrations of 10 M, an inhibiting action of more than 80 and, at 10 M, an inhibiting .o action of morf than 20 as a rule more than 50 0 0 00 °a Exa ple 2i: Protection against HIV infection in a cell test O The cell line MT-2 which is used is a human T-cell leukaemia that has So been transformed with HTLV-1 and continuously produces HTLV-1, which JI renders the cells extremely sensitiva to the cytopathogenic effect of HIV 89 (Science 229, 563 (1985)). The MT-2 cells are cultivated in RPMI 1640 medium containing 12 heat-deactivated foetal calf serum (Seromed Biochrom KG, Berlin, Federal Republic of Germany), glutamine and standard antibiotics. The cells are kept at 370 in a humidified atmosphere of 5

CO

2 in air and are used for the cell test in the logarithmic growth phase.

HIV LAV-03 (AIDS Research and Reference Reagent Program, NIH, Bethesda, MD, USA) is cultured in A 3.01 cells. The titre is determined in a reverse transcriptase assay. For the batch used it is 2 x 107 IU/ml.

S 40,000 exponentially growing MT-2 cells in 50 pl of culture medium are introduced into each of th' vells in a 96 round-base titre plate. The compounds to be investigated are added in the given concentration in pl of culture medium and, immediately thereafter, HIV in 100 1l of culture mediumi is added. 100 p1 of culture medium without HIV are added to comparison samples. The titre plates are incubated for six days. The viability of the HIV-infected cells and the comparison cells is then tested in an MTT assay: the MTT assay relies on the reduction of yellowcoloured 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliu, bromide (MTT, Sigma, St. Louis, USA) by mitochondrial dehydrogenases of 000 S metabolically active cells to a blue fornazan which can be measured spectrophotometrically at 540 nm Virological Methods 20, 309 (1988)).

SThe viability of comparison cells and HIV-infected cells is also o0 determined microscopically in a haemocytometer according to the trypan blue exclusion method.

The investigated compounds 6f the preceding Examples exhibit a protective action against HIV infection at concentrations of 10' 5 mol/litre.

04 a o oo 0 04 0 0 0 0 .010 o 00 0 U 6 0 0 L i, i

Claims (9)

1. A compound of the formula R 2 -AAN-N S-AAC-RI wherein AAN is a bivalent radical, consisting of from one to five bivalent a-amino acid residues, which is bonded N-terminally to the radical R 2 and C-terminally to the group NH-, AAC is a bivalent radical, consisting of one or two bivalent a-amino acid residues, which is bonded N-terminally to the group -C=0 and C-terminafly to the radical R 1 R I is hydroxy, etherified hydroxy, amino or substituted amino with the excep- tion of an amino radical derived from an a-amino acid, and R 2 is hydrogen or an acyl radical with the exception of an unsubstituted or N-substi- tuted acyl radical of a natural amino acid, and salts of such compounds Shaving salt-forming groups, o o0 S0 0

2. A compound according to claim 1 of the formula I, which has two or m. ore a-amino acid residues in the radical AAN, or the radical AAN consists of only one 0-amino acid residue and at the same time the o, radical R 2 is an analogue of phenylalanyl (H-Phe-) and/or which has two a-amino acid residues in the radical AAC, or the radical AAC consists of only one a-amino acid residue and at the same time the radical R 1 is an analogue of the residue, bonded via the nitrogen, of the amino acid o* tyrosine (-Tyr-OH), and salts thereof. o oo 6 0 0 0 0 06 a o 0o o 0 a 0Q 0O I' 91

3. A compound according to claim 1 of the formula R 2 A5 A4 A3 H A2 Al R 1 (II) I I wherein each of the radicals Al, A2, A3 and A4 is a bivalent X-amino acid residue that is bonded N-terminally to the radical to the left of it in formula II and C-terminally to the radical to the right of it, or to the radical A5 is a single bond or a bivalent radical consisting of up to three peptide-linked a-amino acids which is bonded N-terminally to R 2 and C-terminally to A4, and R 1 and R 2 are as defined in claim 1 for formula I, and salts thereof.

4. A compounc- according to claim 3 of the formula II, wherein Al is selected from the gros:, consisting of the bivalent residues of tyrosine, phenylalanine, naphthylalanine, tryptophan, lysine and aspartic acid, A2 is seleced from the group consisting of the bivalent residues of valine, oIo isoleucine, leucine, norleucine, phenylalanine, alanine and glycine, A3 0 o is selected from the group consisting of the bivalent residues of valine, 0O 0 1o alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenyl- alanine, serine and hictidine, A4 is selected from the group consisting co, of the bivalent residues of phenylalanine, tyre:sine, tyrosine etherified °ea by lower alkyl, tryptophan, cyclohexylalanine, leucine, naphthylalanine, histidine, aspartic acid and lysine, and A5, R 1 and R 2 are as defined in claim 3, and salts thereof.

5. A compound according to claim 4 of the formula II, wherein A5 is a single bond or a bivalent radical consisting of up to three identical or different peptide-linked a-amino acids selected from the group consist- ~t it, of the bivalent residues of arginine, proline, histidine, lysine, a o 0 0 0 0 aI 92 ornithine and tryptophan, R' is hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R 2 is hydrogen, lower alkanoyl, lower alkoxy- carbonyl, aryl-lower alkoxycarbonyl or a radical of the formula Ra (CH 2 CH (CHz) (la), n p m (CH 2 b q R wherein R a is lower alkyl vhich is unsubstituted or substituted by hydroxy or by lower alkoxy, phenyl, benzyl, or heteroaryl, having, 1 or 2 nitrogen atoms, which is unsubstituted or substituted by oxido or by lower alkyl, R is cyclohexyl or phenyl, m is 0, 1 or 2, n is 1, p is 0 and q is 1 or 2, and salts thereof.

6. A compound according to claim 5 of the formula II, wherein A5 is a single bond or the bivalent residue -arginine-arginine-proline-, and salts thereof.

7. A compound according to claim 3 of the formula II, wherein Al is selected from the group consisting of the bivalent residues of tyrosine, phenylalanine, tryptophan, naphthylalanine, lysine and aspartic acid, A2 SO,, and A3 are selected from the group consisting of the bivalent residues of 0 00 o valine, isoleucine, leucine, norleucine and alanine, A4 is the bivalent residue of phenylalanine, tyrosine or naphthylalanine, A5 is a bond, R 1 o o a "n is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is hydrogen, 0000 «o0 lower alkanoyl, lower alkoxycarbonyl, ur unsubstituted or lower alkoxy- substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, and salts thereof.

8. A compound according to clai 3 of the formula II, wherein Al is the bivalent residue of tyrosine, A2 is selected from the group consisting of the bivalent residues of valine, isoleucine, norleucine, leucine, pheny- lalanine, alanine and glycine, A3 is the bivalent residue of valine, A4 is the bivalent residue of phenylalanine, tyrosine or naphthylalanine, is a bond, RI is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 t

93- is hydrogen, lower alkanoyl, lower alkoxycarbonyl, or unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxycarbonyl, and salts thereof. 9. A compound according to claim 3 of the formula II, wherein Al is the bivalent residue of tyrosine, A2 is the bivalent residue of valine or leucine, A3 is selected from the group consisting of the bivalent residues of valine, leucine, isoleucine, norleucine, alanine, asparagine, glutamine, phenylalanine, sezine and histidine, A4 is the bivalent residue of phenylalanine, A5 is a bond, R' is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is hydrogen, lower alkanoyl, lower alkoxycarbonyl, or unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxy- carbonyl, and salts thereof. A compound according to claim 3 of the formula II, wherein Al is the bivalent residue uf tyrosine, A2 is the bivalent residue of valine or leucine, A3 is the bivalent residue of valine, A4 is selected from the group consisting of the bivalent residues of phenylalanine, tyrosine, methyl-etherified tyrosine, tryptophan, cyclohexylalanine, naphthyl- alanine and lysine, A5 is a bond, R' is hydroxy, lower alkoxy, lower co0 alkylamino or amino, and R 2 is hydrogen, lower alkanoyl, lower alkoxy- 0000 0 o carbonyl, or unsubstituted or lower alkoxy-substituted phenyl-lower alkoxycarbonyl, diphenyl-lower alkoxycarbonyl or fluorenyl-lower alkoxy- carbonyl, and salts thereof. Onol 00 011 S 11. A compound according to claim 1 of the formula R 2 -A3 N A2 Al R (III) 0 0* L I 00 0 0 0000 0000 00Q000 0 0 I 94 wherein each of the radicals Al, A2 and A3 is a bivalent a-amino acid residue that is bonded N-terminally to the radical to the left of it in formula III, or to the radical R 2 and C-terminally to the radical to the right of it, or to the radical R 1 and R 1 and R 2 are as defined in claim 1 for formula I, and salts thereof. 12. A compound according to claim 11 of the formula III, wherein Al is selected from the group consisting of the bivalent residues of tyrosine, phenylalanine, tryptophan, a-naphthylalanine, lysine and aspartic acid, A2 is selected from the group consisting of the bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine, alanine and i glycine, A3 is selected from the group consisting of the bivalent residues of valine, alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, and R' and R 2 are as defined in claim 11, and salts thereof. 13. A compound according to claim 11 of the formula ITI, wherein Al is selected from the group consisting of the bivalent residues of tyrosine, phenylalanine, tryptophan, a-naphthylalanine, lysine and aspartic acid, A2 is selected from the group consisting of the bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine, alanine and o 0 glycine, A3 is the bivalent residve of tyrosine or of tyrosine etherified 0 a o O* by lower alkyl, and R 1 and R 2 are as defined in claim 11, and salts o thereof. 14. A compound according to claim 12 or 13 of the formula III, wherein R 1 is hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R 2 is a radical of the formula R- (CH) CH (CH 2 (la), m (CH) P (I b R 4 tt 41 I 1 95 wherein R a is lower alkyl which is unsubstituted or substituted by hydroxy or by lower alkoxy, phenyl, benzyl or heteroaryl, having 1 or 2 nitrogen atoms, which is unsubstituted or substituted by oxido or by lower alkyl, Rb is cyclohexyl or phenyl, m is 0, 1 or 2, n is 1, p is 0 and a is 1 or 2, and salts thereof. A compound according to claim 12 or 13 of the formula III, wherein R 1 is hydroxy, lower alkoxy, amino or mono- or di-lower alkylamino, and R 2 is a radical having the structural element of the formula 1- 3 I b) wherein the carbocyclic ring may also be completely or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked to C 2 or C 3 to form a five- or six-membered ring, one of the carbon atoms C 2 and C 3 may have been replaced by a hetero group or atom NH, O or S, the carbonyl group may be.a heterocarbonyl group P=O, and free valencies carry hydrogen or a substituent lower alkyl, lower alkylthio-lower alkyl, lower alkylsulfinyl-lower alkyl, lower alkylsulfonyl-lower alkyl, phenyl- lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, amino-lower Salkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, Slower alkanoyl, lower alkanoyl-lower alkyl or lower alkylcarbamoyl, and 4 salts thereof. 16. A compound according to claim 14 of the formula III, wherein Al is selected from the group consisting of the bivalent residues of tyrosine, phenylalanine, tryptophan, naphthylalanine, lysine and aspartic acid, A2 and A3 is the bivalent residue of valine or leucine, R' is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is a radical of the formula la wherein Ra is lower alkyl, Rb is phenyl and m is 2, n is 1, p is 0 and is 1, and salts thereof. 4 ittl U1 I- 96 17. A compound according to claim 14 of the formula III, wherein Al is the bivalent residue of tyrosine, A2 is selected from the group consist- ing of the bivalent residues of valine, isoleucine, leucine, norleucine, phenylalanine, alanine and glycine, A3 is the bivalent residue of valine or leucine, R I is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is a radical of the formula la wherein R a is lower alkyl, R b is phenyl and m is 2, n is 1, p is 0 and q is 1, and salts thereof. 18. A compound according to claim 14 of the formula III, wherein Al is the bivalent residue of tyrosine, A2 is the bivalent residue of valine or leucine, A3 is selected from the group consisting -f the bivalent residues of valine, alanine, leucine, isoleucine, asparagine, glutamine, norleucine, phenylalanine, serine and histidine, RI is hydroxy, lower alkoxy, lower alkylamino or amino, and R 2 is a radical of the formula la wherein Ra is lower alkyl, Rb is phenyl and m is 2, n is 1, p is 0 and is 1, and salts thereof. 19. A compound according to claim 15 of the formula III, wherein Al is the bivalent residue of tyrosine, A2 is the bivalent residue of vaiine, A3 is selected from the group consisting of the bivalent residues of oooo valine, leucine, norleucine, phenylalanine, alanine, serine, tyrosine and o 0 tyrosine etherified by lower alkyl, RI is hydroxy, lower alkoxy, lower 0 01 *0 alkylamino or amino, and R 2 is 3-phenyl- or 3-cyclohexyl-propionyl which S is substituted in the 2-position by lower alkylsulfonyl-lower alkyl or 0 0 by lower alkanoyl-lower alkyl, and salts thereof. 0000 00ooo00 A compound according to claim 1 of the formula Y H Y 0. A2 R 1 (IV), 000 000000 o o o0o 0 0000 ooo000000 0 0 r T 97 wherein A3 is a bivalent a-amino acid residue that is bonded N-terminally to the radical R 2 and C-terminally to the group NH-, A2 is a bivalent a-amino acid residue that is bonded N-terminally to the group -C=O and C-terminally to the radical R R 1 is lower alkylamino or a radical havi.ng the structural element of the formula (Ic) v wherein the carbocyclic ring may contain a nitrogen atom and may also be completely or partially saturated and/or substituted by hydroxy or by phenyl, the index v is 0 to 5, one of the carbon atoms of the carbocyclic ring may be bonded to one of the atoms to form a five- or six- membered ring and free valencies carry hydrogen or a substituent lower alkyl or hydroxy-lower alkyl, and R 2 is a radical having the structural element of the formula 1- 3 (Ib) oo a Oa n O nl O c0 S wherein the carbocyclic ring may also be completely or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked .o.U to C 2 or C 3 to form a five- or six-membered ring, one of the carbon atoms 0 C 2 and C 3 may have been replaced by a hetero group or atom NH, 0 or S, the carbonyl group may be a heterocarbonyl group P=O, and free valencies carry hydrogen or a substituent lower alkyl, lower alkylthio-lower alkyl, o.nu lower alkylsulfinyl-lower alkyl, lower alkylsulfonyl-lower alkyl, phenyl- 0 0 0 S lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, amino-lower a o l alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, 0o o lower alkanoyl, lower alkanoyl-lower alkyl or lower alkylcarbamoyl, and Ssalts thereof. 0000 00*000 Q A 0 0 o i ^L -i Y 11 98 21. A compound according to claim 20 of the formula IV, wherein A2 is selected from the group consisting of the bivalent residues of valine, isoleucine, norleucine, leucine, phenylalanine, alanine and glycine and A3 is selected from the group consisting of the bivalent residues of valine, alanine, leucine, asparagine, glutamine, norleucine, phenyl- alanine, serine and histidine, and salts thereof. 22. A compound according to claim 20 of the formula IV, wherein each of A2 and A3, independently of the other, is the bivalent residue of valine or leucine, and salts thereof. 23. A compound according to claim 20 of the formula IV, wherein A2 is the bivalent residue of valine, A3 is selected from the group consisting of the bivalent residues of valine, leucine, norleucine, phenylalanine, alanine, serine, tyrosine and tyrosine etherified by lower alkyl, R 1 is lower alkylamino or a radical having the structural element of the formula Ic, wherein the carbocyclic ring may be unsubstituted or substi- tuted by hydroxy or by phenyl, the index v is 0 to 5 and free valencies carry hydrogen, and R 2 is 3-phenyl-or 3-cyclohexyl-propionyl that is substituted in the 2-position by lower alkylsulfonyl-lower alkyl or by 4:44 ao., lower alkanoyl-lower alkyl, and salts thereof. 4 i4 4t. 24. The compound according to claim 11 of the formula III, wherein Al is the bivalent residue of tyrosine, each of A2 and A3 is the bivalent residue of valine, R I is methoxy and R 2 is 2(S)-benzyl-3-tert.-butylsul- fonylpropionyl. 25. A compound according to claim 1 substantially as herein described with particular reference to the examples. 26. A pharmaceutical preparation co;itLining a compound of claims 1 to 24 or a pharmaceutically acceptable salt thereof together with a pharma- S ceutically suitable carrier. r t Y W. 99 OLC< v\Q CA\a1 c3Qto 27. A pharmaceutical preparation eea-inin sub- stantially as herein described with particular reference to the examples. 28. A method of treating a subject suffering from a retroviral infection comprising administering to said subject an effective amount of a com- pound of anyone of claims 1 to 24. 29. A method of inhibiting the action of a retroviral protease in a subject comprising administering to said subject an effective amount of a compound of anyone of claims 1 to 24. A process for the preparation of a compound of the formula I mentioned in claim 1, wherein all the symbols are as defined in claim 1, and salts thereof, which comprises a) condensing a fragment of a compound of the formula I having a terminal carboxy group or a reactive acid derivative of that fragment with a fragment that is complementary to the compound of the formula I and has a free amino group or with a reactive derivative thereof having an activated amino group to form an amide bond, functional groups present in 4I« the reactants, with the exception of the groups participating in the S reaction, optionally being in protected form, or o0 b) reducing the keto group in a compound of the formula Ii 9 HH(CH 3 2 9 SR 2 AAN CH 2 CH AAC R I -CHz C 6 H 11 wherein the symbols are as defined and functional groups, with the excep- tion of the keto group participating in the reaction, are optionally in protected form, to a hydroxy group by reaction with a suitable reducing agent, or I a i rE~i 100 c) reacting an aldehyde compound of the formula R AAN H H (VI), CH2 C6sH1 wherein the symbols are as defined and functional groups, with the excep- tion of the aldehyde group, are optionally in protected form, with an organometal compound of the formula IH(CH3), 0 M CH2 CH AAC R 1 (VII), w'herein the symbols are as defined and M is a metal radical, and hydrolysing the resulting addition product, or d) in a compound of the formula Y X H(CH3)2 R AAN H- CHCH- C H 3 2 AAC R' (VIII), CHN CHIi wherein X is a nucleofugal leaving group, the other symbols are as defined above and functional groups are optionally in protected form, S replacing the substituent X by a hydroxy group, or on e) in a compound of the formula 0 yoH QH(CH 3 2 R 2 AAN H CH CH 2 CH AAC' CN (IX), -CH2 C6H 1 1 wherein the symbols are as defined and AAC' has the meaning of AAC without the terminal carbonyl group, and functional groups present are o "so optionally in protected form, converting the group AAC'-CN into a group o AAC-RI, or o u f) in a compound of the formula 2 0 OH(CH 3 2 0 R 2 AAN N H C -CH CH C AAC- R 1 C2 C6HI1 o 000 101 wherein the symbols are as defined and functional groups are optionally in protected form, reducing the epoxy group to a hydroxy group using a regioselective reducing agent, or g) for the preparation of a compound of the formula I wherein R 2 is a radical of the formula Ra (CH) CH (la), m (CH 2 I q Rb and m is 0 or 2, n is 1 and p is 0, adding a compound of the formula Ra-S(O) H or a salt thereof to a compound of the formula m b M _H H(CH 3 2 R AAN- AAC R (XI), q CHz CH2 CH1 wherein the symbols are as defined and functional groups are optionally in protected form, or h) for the preparation of a compound of the formula I wherein R 2 is a 0 0 I redical of the formula 0 Ra (CH 2 CH (CH2) (la), n p o s 6 m I m (CH 2 I b R and p is 0, alkylating a compound of the formula a H CH3)2 n Hz CsHa1 m (XII), 102 wherein the symbols a-r as defined and functional groups are optionally in protected form, with a compound that introduces the radical R -(CH 2 and, if desired, i) removing protecting groups present in a resulting compound and/or, if desired, after carrying out one of the processes a) h) mentioned above or any other process for the preparation of a compound of the formula I, converting a resulting compound of the formula I having a salt-forming group into its salt or converting a resulting salt into the free compound or into a different salt and/or optionally separating resulting isomeric mixtures and/or, in a resulting compound of the formula I, reversing the configuration of a chiral carbon acom and/or converting a compound of the formula I according to the invention into a different compound of the formula I according to the invention. 31. A process for the preparation of a compound of claim 1 substantially as herein described with particular reference to the examples. DATED the 14th day of December, 1989 CIBA-GEIGY AG By Its Patent Attorneys 0 8 't ARTHUR S. CAVE CO. o t a 4 I