DD298109A5 - INHIBITORS OF RETROVIRAL PROTEASES - Google Patents

Abstract

The present invention relates to a compound of the formula wherein A, Y, R 2, R 3, R 4, R 5, R 6, I, m, and the corresponding radicals provided with * are as defined in the description, a process for their preparation, and their use for inhibiting retroviral proteases. Formula (I)

Description

description

Inhibitors of retroviral proteases

The present invention relates to substances which inhibit the action of retroviral proteases, processes for their preparation, their use and medicaments containing them

 5

The etiological cause of "acquired immune deficiency syndrome" (AIDS) is the so-called human immunodeficiency virus (HIV) (F. Barre-Sinoussi et al., Science 220, (1983), 868- Gallo, et al., Science 224, (1984), 500-502; RC Gallo and L. Montagnier, Scient. Am., 259 (4), (1988), 40-48). HIV is a retrovirus and belongs to the group of lentiviruses (M.A. Gonda, F. Wong-Staal and R.C. Gallo,

Science, 227, (1985), 173; Sonigo, P., et al., Cell, 42, (19 * 5), 369).

The AIDS epidemic has now spread more or less over almost all states. Out of 149 countries, about 160,000 cases have been reported to the World Health Organization (WHO) so far. The WHO estimates the real number at about 500,000 cases, the number of infected persons at 5-10 million (JM Mann at the 5th International Conference on AIDS, Montreal, 4-9 June 1989, see for example C & EN, June 26, ( 1989), 7-16).

Zidovudine (AZT), the only substance approved for AIDS, has been shown to prolong patients' lives in many cases, but has serious, toxic side effects that in many cases require discontinuation of therapy. Also, the first strains of HIV were discovered, which showed a significantly lower sensitivity to AZT and thus the risk of resistance

indicate (C & EN s.o.). Other starting points; in HIV therapy are therefore urgently needed.

HIV proteins are translated analogously to proteins of other retroviruses first as long precursor polyproteins gag, pol and env (C. Dickson et al., In RNA Turmor Viruses (Editors: R. Weiss, N. Teich, H. Varrnus and J. Coffin) 2nd Ed., Pp. 513-648, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY) and then proteolytically to the structural proteins (p17 (MA), p24 (CA), p7 (NC), and p6 the enzymes (protease (PR), reverse transcriptase (RT) and Integraae (IN)), and the envelope proteins (gpl20 (SU) and gp41 (TM)) (Nomenclature: J. Leis et al., J. Virol, 62, (1988) , (1808-1809) It is believed that the cleavage of the gag and pol polyproteins is mediated by a virally encoded protease Mutations within the protease encoding region result in non-infectious virus particles (Kohl et al., Proc. Natl. Acad See, USA 85, (1988), 4686-4690).

The HIV protease consists of 99 amino acids and apparently cleaves from the pol polyprotein even by hydrolysis of the two Phe-Pro bonds in positions 68-69 and 167-168, respectively (MC Graves, JJ Lim, EP Heimer, and RA Kramer Proc. Natl. Acad., U.S.A. 85 (1988), 2449-2453, J. Hansen, S. Billich, T. Schulze, S. Sukrow and K. Moiling, EMBO J. 7 (1988), 1785-1791; EP Lillehoj et al., J. Virology 62 (1988) 3053-3058;

Schneider and S.B.H. Kent, Cell 54 (1988) 363-368).

Only a few inhibitors of HIV protease are known in the literature so far. First representative was pepstatin A with an IC ₅₀ of approximately 0.5 mmol (I. Katoh, T. Yasunaga, Y. Ikawa and Y. Yoshinaka, Nature, 329, (1987), 654-656). Meanwhile, some are more moderate to good

3 198409

Bill et al., J. Biol. Chem., 34, (1988), 17905-17098; Moore, M. et al., Biochem., Biophys. Res., Comm., 159, (1989); 420-425; AD Richards, R. Roberts, BM Dunn, MC Graves and J. Kay, FEBS Lett., 247, (1989), 113-117).

High doses of pepstatin A were able to reduce the formation of the core protein p24 in biosynthesis v.d. Helm, L. Gürtler, J. Eberle and F. Deinhardt, FEBS Lett., 247, (1989), 349-352).

A new structural class has now been found which is highly effective in inhibiting the HIV protease in the enzyme assay.

The present invention relates to compounds of the formula I.

AN R ⁵ R ⁵ * R ³ *

R ² --C - C - (Y) ₁ - (C) _m --C - R ² * (I)

R ³ R ⁶ R ⁶ * N - A *

wherein 25

Y is oxygen, sulfur, a radical of the formula II or a radical of the formula III

R ⁵ **

- C - (II) -N- (HI)

R ⁶ ** R ⁷

stands;

1 and m are independently 0 or 1;

A is a radical of the formula IV and A * is a radical of the formula IV *

D - (E) _n - (F) ₀ - (C) _p -D * - (Ε *) _η * - (F *) _o * - (G *)

(IV)

in which

E ₇ E *, F, F *, G and G * independently represent a natural or unnatural amino acid, aza-amino acid

or imino acid; η, η *, ο, ο *, ρ and p * independently of one another 0 or 1

mean; D for R ¹ or a radical of the formulas V, VI or VII

and D * is R ¹ * or a radical of the formulas V *, VI * or VII *

R ⁸ R ⁹ R ¹ -N-C-CO-

10

(V)

R ⁸ * R ⁹ * II -NC-CO-

R ¹⁰ *

R ¹¹ R ⁹ R ¹ -CH-CH-CO- (VI)

r f *

t ¹ * - CH - CH - CO - (VI *)

RV D =

R ¹ - O - CH. - CO - (VII) R ¹ * - O - CH - CO - (VII *) 25 and wherein R 1 and R ^{1 are} independently

, Hydrogen, carboxyl,

30 - (C ₁ -C ₁ Q) -alkyl, which is optionally monounsaturated or diunsaturated and which may be substituted by up to 3 identical or different radicals from the series

- Mercapto,

- hydroxy,

- (C ₁ -C ₇ ) -alkoxy,

Carbamoyl,

- (C 1 -C 3 -C) -alkanoyloxy,

- carboxy,

5 JOf469

C ^) - alkoxycarbonyl,

F, Cl, Br, I,

- Amino,

Amidino, which may optionally be substituted by one, two or three (C 1 to C 7) alkyl radicals,

Guanidino, which may optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four (C 1 -C 8) -alkyl radicals,

- (C 1 -C 4) -alkylamino,

Di- (C 1-6 CyJ-alkylamino,

- (C 1 -C 8) -alkoxycarbonylamino,

- (Cy-C ₁₅ ) -Aralkoxycarbonyl,

- (C ₇ -C ₁₅ ) -Aralkoxycarbonylamino,

Phenyl (C ₁ -C 4) alkoxy,

- 9-fluorenylmethoxycarbonylamino,

- (C ₁ -C ₆ ) alkylsulfonyl,

- (C ₁ -C ₆ ) -alkylsulfinyl,

- (C 1 -C 4) alkylthio,

Hydroxamino, hydroximino,

Sulfamoyl,

- sulfo,

- Carboxamido,

- formyl,

- Hydrazono,

- Imino,

a residue CONR ¹² R ¹³ or C0NR ¹² * R ¹³ *,

- by up to six hydroxy or

substituted by up to five (C ₁ -C ₈ ) alkanoyloxy; 30

mono-, bi- or tricyclic (C ₃ -C ₁₈ ) -cycloalkyl,

- (C ₃ -C ₁₈ ) -cycloalkyl "(C 1 -C ₆ ) -alkyl

wherein the cycloalkyl part in each case optionally by one or two identical or different radicals from the series

F, Cl, Br, I,

- carboxy,

Carbamoyl,

Carboxymethoxy,

- hydroxy,

- (C ₁ -Cy) -alkoxy,

- (C ₁ -C ₇ ) -alkyl,

- (C ₁ -Cy) -alkyloxycarbonyl,

- Amino,

(C ₁ -C ₆ ) -alkylamino (C ₁ -C ₆ ) -alkyl,

Di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl,

- Amidino,

- hydroxamino,

- Hydroximino,

- Hydrazono,

- Imino,

- Guanidino, -

- (C ₁ -C ₆ ) -alkoxycarbonylamino,

C ₁ 2) -Aryl- (C ₁ -C 3 -alkoxycarbonylamino, Cy) -alkylamino, -di (C ₁ -C 6) -alkylamino and

- Trifluoromethyl is substituted;

- (C ₆ -C ₁₄ ) -aryl,

(C ₆ -C ₁₄ ) -aryl (C ₁ -C ₆ ) -alkyl,

- (C ₆ -C ₁₄ ) -Aryloxy- (C ₁ -C ₄ ) alkyl or

- (C ₆ -C ₁₄ ) -aryl (C 3 -C ₉ ) -cycloalkyl, in which the aryl part is in each case optionally substituted by one, two or three identical or different radicals from the series - F, Cl, Br, I,

- hydroxy,

Mono-, di- or trihydroxy- (C ₁ -C ₄ ) -alkyl,

Trifluoromethyl,

- formyl,

- Carboxamido,

Mono- or di (C ₁ -C ₄ ) -alkylaminocarbonyl,

- Nitro,

- (C ₁ -Cy) -alkoxy,

- (C ^ -Cy) alkoxycarbonyl

- Amino,

-

- carboxy,

Carboxymethoxy,

- amino - (^ y)

(C ₁ -C ₆ -alkylamino (C ₁ -C ₇ ) -alkyl,

- di- (C-pCyJ alkylamino (C ₁ -C ₇₎ - alkyl, - (C ₁ -C ₇₎ -Alkoxycarbonylmethoxy,

Carbamoyl,

Sulfamoyl,

- (C ₁ -C ₇ ) alkoxysulfonyl,

(C ₁ -C ₈ -alkylsulfonyl, -sulfo (C ₁ -C ₈ ) -alkyl,

Guanidino (C ₁ -C ₈ ) alkyl and

- (C ₁ -C ₆ ) alkoxycarbonylamino is substituted;

- Het,

Het (C ₁ -C ₆ ) -alkyl,

Het (C ₃ -C ₈ ) cycloalkyl,

Het- (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C ₄ ) -alkyl,

Het (C ₃ -C ₈ ) -cycloalkoxy (C ₁ -C ₄ ) -alkyl, -Het-thio (C ₁ -C ₆ ) -alkyl,

Hetthio (C ₃ -C ₈ ) cycloalkyl,

- Het-thio (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C ₄ ) -alkyl, wherein Het is in each case the radical of a 5- to 7-membered monocyclic or 8- to 10-membered bicyclic ring system, which may be benzanellated, aromatic, partially hydrogenated or fully hydrogenated, which may contain as hetero elements one, two, three or four different radicals from the group N, 0, S, NO, SO, SO2, which may be substituted by 1 to 6 hydroxy and which is optionally defined as in (C ₆ -C ₁₄ ) -aryl under a · ^) and / or with oxo, mono-, di- or trisubstituted,

8 29 ** ⁰⁹

or a radical NR ¹² R ¹³ or NR ¹² * R ¹³ * or

a ₂ )

- a radical of formula VIII or VIII * mean.

R ^la - W (VIII) R ^la * - W * (VIII *)

wherein R ^la and R ^la * as R ¹ and R ¹ * are defined under S ₁ ) and W and W * for -CO-, -CS-, 0-C0-, -SO ₂ -, -SO-, -S-, -NHSO ₂ -, -NHCO-, -CH (OH) -, -N (OH) - or -CO-V- wherein V is a peptide of 1 to 10 amino acids;

or in which R ¹ and R ¹ *, independently of one another together with R or R ¹¹ and the atoms carrying them, form mono- or bicyclic, saturated or partially unsaturated ring systems having 5-12 ring members which, in addition to carbon, may also contain 1 sulfur atom, which may be present may be oxidized to the sulfoxide or sulfone;

a ₃ )

a glycosyl radical, preferably a glucofuranosyl or glucopyranosyl radical, which is derived from naturally occurring aldotetroses, aldopentoses, aldohexoses, ketopentoses, ketohexoses, deoxy-aldoses, aminoaldoses and oligosaccharides and their stereoisomers;

R ² and R ² *

are independently defined as R ¹ or R ¹ under a · ^ or a ₂ ) or

together with R ^ or R and the atoms carrying them mono- or bicyclic, saturated or partially unsaturated ring systems having 5 to 12 ring members, or together with R ³ or R ³ and the atoms carrying them cyclic, saturated or partially unsaturated ring systems with 3 to 12 ring links form;

298103

R ³ and R ³ *

independently of each other - hydrogen or

mean;

R ⁴ and R ⁴ *

independently of each other

- hydrogen or

- (C ₁ -Cg) -AlkYl mean; 10

R ⁵ , R ⁵ * and R ⁵ ** independently

- hydrogen,

- hydroxy, - amino or

- Carboxy, or

R, R and R ° together with the carbon atoms carrying them independently form a keto group; 20

R ⁶ , R ⁶ * and R ⁶ ** independently

- hydrogen or

- (C ₁ -C ₆ J-AIkYl mean or

in case 1 = 0, R and R may optionally form a common bond;

R ⁷

- hydrogen, - hydroxy or

means;

R ⁸ and R ⁸ *

independently of each other - hydrogen or - (C ₁ -Cg) -AIkYl mean, or

Q Q *

together with R ³ and / or R and the atoms carrying them form n-one or bicyclic, saturated or partially unsaturated ring systems having 5-12 ring members;

₁₀

R ⁹ and R ⁹ *

are independently defined as R · * · or R ^ under a ^), hydroxy or (C ^ -C _A ) alkanoyloxy or together with R or R and the atoms carrying them cyclic, saturated or partially unsaturated ring systems with 3 to 12 ring links form; or

together with R or R ^ and the atoms carrying them form a monocyclic or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members which, in addition to carbon, may also contain 1 sulfur atom, which may optionally be oxidized to the sulfoxide or sulfone; or may contain 1 nitrogen atom, which ring system may optionally be substituted by amino;

R ¹⁰ and R ¹⁰ * independently

- hydrogen or

- (C 1 -C 6) -alkyl;

R ¹¹ and R ¹¹ * independently

- hydrogen,

- hydroxy,

- (C 1 -C 4 alkanoyloxy or

- (C ₁ -C ₈ ) -alkyl;

R ¹² , R ¹² *, R ¹³ and R ¹³ * independently of one another - hydrogen,

- (C ₁ -Cq) -alkyl, which by

- Amino,

- (C ₁ -C ₄ ) -alkylamino,

Di (C ₁ -C ₄ ) alkylamino, mercapto,

- carboxy,

- hydroxy or

may be substituted

- (C ₁ -C ₄ ) alkoxycarbonyl,

"( ^c 6 ~ ^c 14)" ^Ar y ¹ '(C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) alkoxycarbonyl, which

Ί 1 ^

in the aryl moiety as described for R or R may be substituted,

- Het or

- Het- (C ₁ -C ₄ ) -alkyl, wherein Het is defined as described for R ¹ or R ¹ *, mean

or wherein R ^ and R or R ¹ ^ and R ¹ together with the nitrogen atoms carrying them form monocyclic or bicyclic, saturated, partially unsaturated or aromatic ring systems which contain, in addition to carbon, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom as further ring members may be substituted by (C ₁ -C ₄ ) -alkoxy,

in which !

in the above compounds of the formula I one or more amide groups (-CONH-) of the main chain may be replaced by -CH ₂ NR ¹⁴ -, -CH ₂ S-, -CH ₂ O-, -OCH ₂ -, -CH ₂ CH ₂ -, -CH = CH- (cis and trans), -COCH ₂ -, -CH (OH) CH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, -P (O) (UR ¹⁵ ) CH ₂ - and -P (O) (0R ¹⁵ ) NH-, or by an amide group with reverse polarity (-NHC0-);

wherein R ¹⁴ and R ¹⁵

stand independently for

- hydrogen or

- (C ₁ -C ₄ ) -alkyl;

and their physiologically acceptable salts.

The nomenclature used in this specification follows the general practice of amino acids, that is, the amino group is on the left, the carboxy group on the right of each amino acid. The same applies to azaamino acids and imino acids.

Natural or unnatural amino acids, if chiral, may be in the D or L form. Preference is given to α-amino acids. For example:

Aad, Abu, YAbu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, 3Aib, Ala, 3Ala, Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) ₂ , Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Dj en, Dpa, Dtc,. FeI, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hll, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, HyI, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Deu, Lsg, Lys, Lys, ALys, Met, Mim, Min, nArg, Never, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pie, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Lake, Sem, Ser, Thi, βThi, Thr, Thy, Thx, Tia, Tie, TyI, Trp, Trta, Tyr, VaI, NaI, Tbg, Npg, Chg, Thia (see, for example, Houben-Weyl, Methods of Organic Chemistry, Volumes XV / 1 and 2, Stuttgart, 1974):

Azaamino acids are derived from natural or unnatural amino acids, with the central unit -CHR- or CH2 "replaced by -NR- or -NH-.

Under an imino acid are generally natural or unnatural amino acids whose amino group is monosubstituted. Particular mention may be made in this connection of compounds which are substituted by (C 1 -C 8) -alkyl, which in turn is optionally substituted as described on pages 4/5. Furthermore, heterocycles from the following group come into consideration:

Pyrrolidine-2-carboxylic acid; Piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; Decahydroisoquinoline-S-carboxylic acid; Octahydroindole-2-carboxylic acid;

Decahydroquinoline-2-carboxylic acid;

Octahydrocyclopenta [b] pyrrole-2-carboxylic acid ;; 2-aza-bicyclo [2.2.2] octane-3-carboxylic acid; 2-azabicyclo [2.2.ljheptan-3-carboxylic acid;

13

J98 WS

2-azabioyl .: Io [3 .1. 0] hexane-3-carboxylic acid; 2-Λ "as? .Irr ^r 4.4] nonane-3-carboxylic acid; 2-azaspiro [4.5] decane-3-carboxylic acid; spiro [(bicyclo [2.2.1] heptane) -2,3-pyrrolidine-5 -carboxylic acid]; spiro [(bicyclo [2.2.2] octane) -2,3-pyrrolidine-5-carboxylic acid]; 2-azatricyclo [4.3.0.1] ^{/ 9} ] decane-3-carboxylic acid; decahydrocycloheptafbipyrrole-2-carboxylic acid; Decahydrocycloocta [b] pyrrole-2-carboxylic acid; octahydrocyclopenta [c] pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2,3, 33,4,5,78-hexahydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid; hydroxyproline-2-carboxylic acid, all of which may optionally be substituted:

14

298/103

ck

co '

co-

coT> α

co-;

co

co-;

co-

..N

co-;

CO-;

co-;

HO

Ck ^ ^c ° -;

Glycosyl radicals as described above are derived, in particular, from natural D or L monosaccharides occurring in microorganisms, plants, animals or humans, such as ribose (Rib), arabinose (era), xylose (XyI), lyxose. (Lyx), Allose (All), Altrose (Alt), Glucose (GIc), Mannose (Man), Gulose (GuI), Idose (Ido), Galactose (GaI), Talose (Valley), Erythrose (Ery), Threose (Thr), psicose (Psi), fructose (Fru), sorbose (Sor), tagatose (day), xylulose (Xyu), fucose (Fuc), rhamnose (Rha), olivose (Oli), oliose (Olo), mycarose (Myc), rhodosamine (RN), N-acetyl-glucosamine (GlcNAc), N-acetyl-galactosamine (GaINAc), N-acetyl-mannosamine (ManNAc) or disaccharides, such as maltose (Mal), lactose (Lac); Cellobiose (CeI), gentibiose (gene), N-acetyl-lactosamine (LacNAc), chitobiose (chit), β-galactopyranosyl- (l-3) -N-acetylgalactosamine and β-galactopyranosyl- (1-3) - or - (L-4) -N-acetyl-glucosamine, and their synthetic derivatives, such as 2-deoxy, 2-amino, 2-acetamido or 2-halo, preferably bromo- and iodo-sugars from.

The chiral centers in the compounds of formula (I) may have the R, S or O, R, S configuration.

Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom, such as e.g. Alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl and aralkyl.

Cycloalkyl also includes alkyl-substituted radicals, such as e.g. 4-methylcyclohexyl or 2,3-dimethylcyclopentyl understood.

Bicycloalkyl or tricycloalkyl is understood to mean an isocyclic aliphatic, nonaromatic radical which may optionally contain unsymmetrically distributed double bonds, and may optionally also be substituted by open-chain aliphatic side chains. The two or three rings as components of such residue are fused or spiro-linked and via a ring C atom

or a side chain C atom linked. Examples of these radicals are bornyl, norbornyl, pinanyl, norpinanyl, caranyl, norcaranyl, thujanyl, adamantyl, bicyclo (3.3.0) octyl, bicyclo (4.4.0) decyl, bicyclo (1.1 .0) butyl, spiro (3.3) heptyl substituents.

If the said cycles carry more than one substituent, they may be either in the form of ice or trans to each other.

(C ₆ -C ₁₄ ) -aryl is, for example, phenyl, naphthyl, biphenylyl or fluorenyl; preferred are phenyl and naphthyl. The same applies to radicals derived therefrom, such as, for example, aryloxy, aroyl, aralkyl and aralkoxy. Aralkyl is understood to mean an unsubstituted or substituted (C ₆ -C ₁₄ ) -aryl radical linked to (C ₁ -C ₆ ) -alkyl, for example benzyl, 1- and 2-naphthylmethyl, but aralkyl does not have the radicals mentioned would be limited.

Radicals Het as defined above are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazo.lyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl , Cinnolinyl, ß-carbolinyl, or a benzannelliertes, cyclopenta, cyclohexa or cycloheptaannelliertes derivative of these radicals.

These heterocycles can be attached to a nitrogen atom by oxides; (C ₁ -C ₇ ) -alkyl, for example methyl or ethyl; phenyl; Phenyl (C ₁ -C ₄ ) -alkyl, for example benzyl; and / or on one or more carbon atoms by (C ₁ -C ₄ ) -alkyl, for example

Methyl; phenyl; Phenyl (C ₁ -C ₄ ) -alkyl, for example benzyl; Halogen; hydroxy; (C ₁ -C ₄ ) -alkoxy, for example methoxy, phenyl (C ₁ -C ₄ ) -alkoxy, for example benzyloxy, or oxo substituted and partially or completely saturated.

Such radicals are, for example, 2- or 3-pyrrolyl; Phenylpyrrolyl, eg 4- or 5-phenyl-2-pyrrolyl; 2-furyl; 2-ThienV _; 4-imidazolyl; Methylimidazolyl, eg

1-methyl-2-, 4- or 5-imidazolyl; 1,3-thiazol-2-yl; 2-, 3- or 4-pyridyl; l-oxido-2-, 3- or 4-pyridino; 2-pyrazinyl; 2-, 4- or 5-pyrimidinyl; 2-, 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; 1-benzyl-2- or 3-indolyl; 4,5,6,7-tetrahydro-2-indolyl; Cyclohepta [b] -5-pyrrolyl; 2-, 3- or 4-quinolyl; 1-, 3- or 4-isoquinolyl; l-oxo-l ^ -dihydro-S-isoquinolyl; 2-quinoxalinyl; 2-benzofuranyl; 2-benzoxazolyl; benzothiazolyl;

Benz [e] indol-2-yl or β-carbolin-3-yl. 15

Partially hydrogenated or fully hydrogenated heterocyclic rings are, for example, dihydropyridinyl; Pyrrolidinyl, eg 2-, 3- or 4-N-methylpyrrolidinyl; piperazinyl; morpholino; thiomorpholines; tetrahydrothiophenyl; Benzodioxolanyl.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

By salts of compounds of formula (I) are meant in particular pharmaceutically acceptable or non-toxic salts.

Such salts are exemplified by compounds of formula (I) which contain acidic groups, e.g. Carboxy, formed with alkali or alkaline earth metals, e.g. Na, K, Mg and Ca, as well as physiologically compatible organic amines such as triethylamine and tris- (2-hydroxy-ethyl) -amine

 35

Compounds of formula (I) which contain basic groups, e.g. contain an amino group or a guanidino group, form with inorganic acids, e.g. Hydrochloric acid, sulfuric acid

18

or phosphoric acid and with organic carboxylic or sulphonic acids, e.g. Acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-Toluclsulfonsaure, salts. 5

Preference is given to compounds of the formula I in which the radicals and symbols with and without star are identical in each case.

Also preferred are compounds of the formula I which are symmetrical C2 ~.

Particular preference is furthermore given to compounds of the formula I in which Y is a radical of the formula II or a radical of the formula III; 1, m, A, A *, D, D *, η, η *, ο, ο *, ρ and p * are as defined above; E, E *, F, F *, G and G * independently represent a natural or unnatural α-amino acid or α-imino acid;

R ¹ and R ¹ * independently of one another represent a-jj - hydrogen; - carboxyl,

- (C - ^ - C- ^ g) -alkyl which is optionally monounsaturated and which may be substituted by up to 2 identical or different radicals from the series

- hydroxy,

- (C ₁ -C ₄ ) -alkoxy,

Carbamoyl,

- carboxy,

- (C 1 -C 4) -alkoxycarbonyl, - F,

- Amino,

- (C ₁ -Cy) -alkylamino,

Di- (C ₁ -Cy) -alkylamino,

• (C ₁ -C 6) alkoxycarbonylamino,

- benzyloxycarbonyl

19

Benzyloxycarbonylamino,

- 9-fluorenylmethoxycarbonylamino,

- (C 1 -C 4) alkylsulfonyl,

- a radical CONR ¹² R ¹³ or CONR ¹² * R ¹³ *, - by up to six hydroxy or

- is substituted by up to four (C ^ -Cg) alkanoyloxy;

- mono- or bicyclic (C ₃ -C ₁₂ ) -cycloalkyl, - (C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₆ ) -alkyl where the cycloalkyl moiety is in each case optionally substituted by one or two identical or different radicals from the series

- F,

- carboxy,

- hydroxy,

C ₄ ) -alkyloxycarbonyl, - amino,

- (C 1 -C 3) -cyclo-alkoxycarbonylamino,

- benzyloxycarbonylamino

- (C ₁ -C ₄ ) -alkylamino and

- is substituted di- (C ₁ -C ₄ ) alkylamino;

- (C ₆ -C ₁₀ ) -aryl,

- (C ₆ -C ₁₀ ) -Aryloxy- (CLC ^ -alkyl, or

- (C ₆ -C ₁₀ ) -aryl (C ₁ -C ₆ ) -alkyl, wherein the aryl moiety

in each case optionally by one, two or three identical odex-different radicals from the series

- F, Cl, Br,

Hydroxy (C ₁ -C ₄ ) alkyl, carboxamido,

- mono- or di (C ₁ -C ₄ ) -alkylaminocarbonyl

- (C ₁ -C ₄ ) -alkoxy,

- (C ₁ -C ₄ ) -alkyl,

293Ί09

-C ₄ ) alkoxycarbonyl,

- Amino,

~ (C ₁ -C ₄ ) -alkylamino,

Di- (C ₁ -C ₄ ) -alkylamino, -carboxy,

Carbamoyl,

- (C ₁ -C ₄ ) alkoxycarbonylamino is substituted;

- Het,

Het (C ₁ -C ₆ ) -alkyl,

Het- (C ₅ -C ₆ ) -cycloalkyl,

Het-thio (C ₁ -C ₄ ) -alkyl,

Hetthio (C ₅ -C ₆ ) cycloalkyl,

where Het is in each case the radical of a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring system which may be aromatic, partially hydrogenated or fully hydrogenated, containing as hetero elements one, two, three or four different radicals from the group N, O, S, NO, SO, SO may contain _9, which can be substituted with 1 to 4 hydroxy-substituted no and which optionally as defined for (C ₆ -C ₁ Q) -aryl under a · ^) and / or with oxo mono-, or di-substituted,

or a radical NR ¹² R- ¹ - ³ or NR- ^L2 * R ¹³ * or

a ₂₎ - a radical of the formula VIII or VIII * R ^la - W (VITI) R ^la * - W * '(VIII *)

where R and R how? or R are defined under a · ^) and W or W * is -Cu, -O-CO-, -SO ₂ -, -SO-, -S-, -NHCO- or -CH (OH) -, stands; 35

or R and R ^x independently of one another together with R ¹¹ or R and the atoms carrying them monocyclic, saturated or partially unsaturated Ringystsrae 5-8

21

Rinqg.liede-n form, which may contain carbon other than sulfur atom, which may be optionally oxidized to the sulfoxide or sulfone;

ag) - a glycosyl radical as defined above;

R ² and R ² *

independently of one another b.sup.-, - hydrogen, - carboxy,

- (C 1 -C 4) -alkyl, which is optionally mono- or diunsaturated and which may be substituted by up to 3 identical or different radicals from the series - hydroxy,

- (C ₁ -C ₇ ) -alkylsulfinyl _/

- (C ₁ -C ₇ ) -alkylsulfonyl, - (C 1 -C 8 -y) -alkanoyloxy,

- carboxy,

- (C 1 -C ₇ ) -alkoxycarbonyl,

- Cl, Br,

- Amino, - Amidino,

- Guanidino,

N, N'-di (benzyloxycarbonyl) guanidino,

Carbamoyl,

- (C ₇ -C 15) -Aralkoxycarbonyl, - (C ₁ -Cg) -alkoxycarbonylamino,

- (C ₇ -C ₁ 5) or -Aralkoxycarbonylamino

- 9-Fluorenylmethoxycarbonylamxno substituted;

(C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₃ ) -alkyl- (C ₆ -C ₁₄ ) -aryl,

22

- (C ₁ -C ₃ ) -alkyl, wherein the aryl part in each case optionally by one, two or three identical or different radicals from the series

F, Cl, Br, I,

- hydroxy,

- (C ₁ -C ₇ ) alkoxycarbonyl,

- Amino and

- Trifluoromethyl is substituted; or

- Het- (C ₁ -C ₆ ) -alkyl, wherein Het is the radical of a 5- or 6-membered monocyclic or 9- to 10-membered bicyclic, optionally partially or fully hydrogenated heteroaromatic, having at least 1 C-atom, 1 -4 N atoms and / or 1-2

S atoms and / or 1-2 O atoms as ring members, which is optionally mono- or disubstituted as described on pages 6/7 for the aryl part, mean; or 20

t> 2) together with R or R and the atoms carrying them pyrrolidine or piperidine, which may each still be anneliiert with cyclopentyl, cyclohexyl or phenyl, form, or together with R or R ³ and the atoms carrying them cyclic, saturated or form partially unsaturated ring systems having 3-8 ring members;

R ³ and R ³ * independently

- hydrogen,

- methyl or

- ethyl;

R ⁴ and R ⁴ * independently

- hydrogen,

- (C ₁ -C ₄ ) -alkyl;

23

R, R and R are independently defined as on page 9;

R ⁶ , R ⁶ * and R ⁶ ** independently

- hydrogen,

- (C ₁ -C ₄ JA ^ yI mean;

R ⁷ - hydrogen,

- hydroxy or

- (C ₁ -C ₄ ) -alkyl;

R ⁸ and R ⁸ * independently

- hydrogen,

- (C ₁ -C ₈ ) -alkyl or

Q Q *

together with R and R, respectively, and the atoms carrying them, pyrrolidine or piperidine, each of which may additionally be fused with cyclopentyl, cyclohexyl or phenyl;

R ⁹ and R ⁹ * are independently defined as R and R under b · ^), or (C ₁ -Cq) alkanoyloxy means or

zusanur'n with R ¹⁰ or R ¹⁰ and the atoms carrying them cyclic, saturated or partially unsaturated ring systems rait 5 to 12 ring members form; or

together with R ^ or R ^ and the atoms carrying them form a mono- or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members, which may contain, in addition to carbon, sulfur atom, which may optionally be oxidized to sulfoxide or sulfone;

R ¹⁰ and R ¹⁰ * independently of one another - hydrogen or

mean;

29 & ΊΟ3

R ¹¹ and R ¹¹ * independently

- hydrogen,

- hydroxy,

- (C ₁ -C ₄ ) alkanoyloxy or

- (C ₁ -C ₄ ) -alkyl;

R ¹² , R ¹² *, R ¹³ and R ^1? * independent of each other - hydrogen,

- (C ₁ -Cg) -AlkVl, by

- Amino,

- (C ₁ -C ₄ ) -alkylamino,

Di- (C ₁ -C ₄ ) -alkylamino, -carboxy,

- hydroxy or

- (C ₁ -C ₄ ) -alkoxy may be substituted,

- (C ₁ -C ₄ ) alkoxycarbonyl,

- (C ₆ -C ₁ Q) -ArYl, which may be substituted as described for R ^ or R *,

- (C ^ -C ₁ Q) -aryl- (C ₁ -C ₄₎ -alkoxycarbonyl,

- Het or

- Het-fC-LC ^ -alkyl, wherein Het is defined as described for R ¹ or R ¹ *, wherein

in the above compounds of formula I, one or more amide groups (-COH-) of the main chain may be replaced by a group consisting of -CH ₂ NR-, -CH ₂ O-, -OCH ₂ -, -CH ₂ CH ₂ -, -COCH ₂ -, -CH (OH) CH ₂ -, -COO- or by an amide group with reverse polarity (-NHC0-);

R ¹⁴ for

- hydrogen or

- (C ₁ -C ₄ alkyl group;

and their physiologically acceptable salts.

Particular preference is given to compounds of the formula I in which

Y is a radical of the formula II or a radical of the formula III;

1, m, A, A *, D, D *, n, n *, o, o * are as defined above, ρ and p * are 1;

R ¹ and R ¹ * independently represent

- hydrogen,

- carboxyl,

- (C ₁ -C ₁ Q) -Alkyl,

- (C ₃ -C ₈ ) -cycloalkyl

Phenyl (C ₁ -C 6) -alkyl which may be substituted in the phenyl moiety as described on pages 19/20,

- optionally protected mono- or di-AnUnO- (C ₁ -C ₁₂ ) -alkyl or amino- (Cg-C ₁ Q) -aryl- (C ₁ -C 4) -alkyl or amino (C ₃ -C 8) -alkyl Q ₁ -cycloalkyl- (C ₁ -C ₄ ) -alkyl, such as - 2-amino-3-phenyl-propyl

- mono-, di-, tri-, tetra-, penta- or hexahydroxy- (C ₁ -C ₁ Q) -alkyl or -alkanoyl, - (C ₁ -C ₄ -j-alkoxy- (C ₁ -C ₁ Q ) -BIkYl,

- (C ₁ -C ₄ ) -alkoxycarbony1- (C ₁ -C ₁₀ ) -alkyl,

- (C ₁ -C ₁₆ ) alkylsulfonyl,

- (C 1 -C 9 alkylsulfinyl),

Mono-, di-, trihydroxy- (C ₁ -C ₈ ) -alkylsulfonyl, - mono-, di-, trihydroxy- (C ₁ -C ₈ -alkylsulfinyl)

Mono-, di-, tri- or tetra- (C ₁ -C) -alkanoyloxy- (C ₁ -C ₁₀ ) -alkyl,

26

- (C ₁ -C ₄ ) -alkanoyl,

optionally protected amino (C ₁ -C ₁₁ ) alkanoyl,

Di (C ₁ -C ₇ ) alkylamino (C ₂ -C ₁₁ ) alkanoyl,

- (C 1 -C 4) cycloalkylcarbonyl,

Amino-substituted (C ₃ -C 6) -cycloalkylcarbonyl,

- amino-substituted (CSS cgj-cycloalkylsulphonyl,

- (C ₆ -C ₁₀ ) aryl- (C ₂ -C ₁₁ ) alkanoyl,

- (C ₆ -C ₁₀ ) -Aryloxy- (C ₂ -C ₁₁ J-BIkBnOyI,

optionally substituted by amino, halogen, (C ₁ -C 7) alkyl, (C ₁ -Cy) -alkoxy or (Cj ^ -CyJ-alkoxycarbonyl-substituted benzoyl, pentenesulfonyl or (C ₆ -C ₁₀ ) -aryl (C ₁ -Cq) -alkylcarbonyi or -sufonyl,

- (C ₁ -C ₁ Q) alkoxycarbonyl,

substituted (C ₁ -C ₁₀ ) -alkoxycarbonyl, such as 2- (trimethylsilyl) -ethoxycarbonyl,

2,2,2-trichloroethoxycarbonyl or

1,1-dimethyl-2,2,2, trichloroethoxycarbonyl,

- alkoxycarbonyl, - (C ^ -C ^ ₁₎ - aryl- (C ₁ -CG ₁₎

optionally substituted amino and hydroxy substituted (C ₆ -C ₁₀ ) aryl (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₀ ) cycloalkyl (C ₁ -Cg) alkyl or (C ₁ -C ₁₀ ) -alkyl, as

2-amino-1-hydroxy-4-methylpentyl,

9-fluorenylmethoxycarbonyl, 25

- ketohexosyl,

- ketopentosyl,

- deoxyhexoketosyl,

- deoxypentoketosyl, - aldohexosyl,

- aldopentosyl,

- deoxyhexoaldosyl,

- deoxypentoaldosyl,

2-amino-2-deoxyhexosyl,

2-acetamido-2-deoxyhexosyl,

- lactosyl or

- maltosyl with the linked sugars in the pyranose

27

or furanose,

- HCt- (C ₁ -C ₆ ) -alkyl

- Het-carbonyl or -sulfonyl,

Het (C 1 -C 8) alkylcarbonyl or sulfonyl,

Het-mercapto (C ₁ -C ₆ ) -alkylcarbonyl or -sulfonyl,

where Het each for

Furyl, thienyl, benzothienyl, benzodioxolanyl, pyrrolyl, imidazolyl, isoxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl. Pyrazinyl, pyridazinyl, triazinyl, pyrrolidyl, piperidyl, piperazinyl, morpholino, thiomorpholines, tetrahydrofuryl, tetrahydropyryl, tetrahydrothienyl, indolyl, quinolyl or isoquinolyl, 15

said (even by one or zv / ei identical or different radicals from the group C ₁ -C ₄ J--alkyl, (C ₁ -C ₄ J -alkoxy, (C ₁ -C ₄₎ alkoxycarbonyl, (C ₁ - C ₄ ) alkoxycarbonylamino, hydroxy, amino, mono- or di- (C ₁ -C ₄ ) -alkylamino and oxido may be substituted;

R ² and R ² * are independent of each other

Hydrogen, carboxyl,

- (C ₁ -Cq) -alkyl, optionally substituted by up to the same or different radicals from the series

- hydroxy,

- (C ₁ -C ₄ ) -alkoxy,

- carboxy,

- (C ₁ -C ₄ ) alkoxycarbonyl

- Amino,

28

- Amidino,

, - Guanidino,

N, N'-di (benzyloxycarbonyl) guanidino,

Carbamoyl,

- (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₃ ) alkoxycarbonyl _/

- (C] ₁ -Cg) -alkoxycarbonyl-amino,

- (C ₆ -C ₁₀ ) -aryl (C ₁ -C ₃ ) alkoxycarbonylamino is substituted or

- (C ₃ -C ₁₀ ) -cycloalkyl,

(C ₃ -C ₁₀ ) -cycloalkyl- (C ₁ -C ₃ ) -alkyl,

(C ₁ -C ₄ ) -alkyl- (C ₃ -C ₁₀ ) -cycloalkyl- (C ₁ -C ₃₎ -alkyl,

- (c ₆ -c ₁₀ ) -Aryi,

- (C ₆ -C ₁₀ ) -aryl (C ₁ -C ₃ ) -alkyl, wherein the aryl part in each case optionally by one, two or three identical or different radicals from the series

- F, Cl, Br,

- hydroxy,

- (C ₁ -C ₄ ) -alkoxy,

- (C ₁ -C ₄ ) alkoxycarbonyl and

- Amino is substituted, or

- Het- (C ₁ -C ₄ ) -alkyl, wherein Het is defined as in R ¹ or R ¹ *, means

R ³ and R ³ * independently

- hydrogen or

- methyl;

R ⁴ and R ⁴ * independently

- hydrogen or

- methyl;

R ⁵ , R ⁵ * and R ⁵ ** independently

29

- hydrogen,

- hydroxy,

- Amino or

- Carboxy mean; 5

R ⁶ , R ⁶ * and R ⁶ ** independently

- hydrogen or

- methyl; 10

R ⁷

- hydrogen,

- hydroxy or

- methyl means; 15

R ⁸ and R ⁸ *

independently of each other

- hydrogen,

Methyl, ethyl or n-propyl or, together with R ³ or R ^v and the atoms carrying them, form a 1,2,3,4-tetrahydroisoquinoline or a 2-azabicyclooctane skeleton;

R ⁹ and R ⁹ *

are defined independently of each other as R ^z or. R ^ are on pages 27/28, defined or (C ^ -Cg) alkanoyloxy or together with R or R and the atoms carrying them form cyclic ring systems having 5 to 7 ring members;

11 1 "i *

or together with R or R form a thiochroman system whose sulfur atom may optionally be oxidized to the sulfone; R ¹⁰ and R ¹⁰ * independently

- hydrogen or

- methyl;

30

R ¹ · * · and R- ¹ - ¹ * are defined as described on page 24;

in which

in the above compounds of formula I, an or. several amide groups (-CONH-) of the main chain may be replaced as defined on page 24;

R ¹⁴ for

- is hydrogen or - methyl;

and their physiologically acceptable salts.

Furthermore, particular preference is given to compounds of the formula I in which

R ¹ and R ¹ *

independently of one another represent a- ^) - hydrogen, - carboxyl,

- (C 1 -C 3) -alkylsulfonyl, as

- methylsulfonyl, φ

tert-butylsulfonyl,

Isopropylsulfonyl or hexadecylsulfonyl,

- (C - ^ - Cq) mono-, di- or tri-hydroxyalkylsulfonyl, as

2-hydroxyethylsulfonyl or

2-hydroxypropylsulfonyl,

Hydroxy (C ₁ -C ₁₀ ) alkanoyl, as

2-hydroxypropionyl,

3-hydroxypropionyl,

3-hydroxybutyryl or

2-hydroxy-3-methylbutyryl,

- Mono-, di-, tri- or tetra-hydroxy- (C ₁ -C ₄ ) -alkyl, as

1,2,3-trihydroxypropyl,

₃₁ 29840S

- 1,2-dihydroxyethyl or

Hydroxymethyl,

- (C 1 -C 9) -alkanoyloxy (C 1 -C 4) -alkyl, as

- acetoxymethyl,

1,2-diacetoxyethyl,

- 1,2,3-triacetoxypropyl, "(C ₁ -C ₁₄ ) -alkanoyl, as

- n-decanoyl,

Formyl, acetyl,

- Propionyl,

- Pi "aloyl,

- isovaleryl,

- isobutyryl or - tetradecanoyl,

Amino (C ₁ -C ₁₂ ) alkanoyl, as

3-amino-3,3-dimethylpropionyl,

4-aminobutyryl,

5-aminopentanoyl, 6-aminohexanoyl,

- 12-aminododecanoyl

- N - (C ₁ -C ₄ ) alkoxycarbonylamino (C ₁ -C ₈ ) alkyl, such as

4-N-tert-butoxycarbonylaminobutyryl,

S-N-tert-butoxycarbonylaminopentanoyl, e-N-tert-butoxycarbonylaminohexanoyl,

Di- (C ₁ -Cy) -alkylamino- (C ₂ -C ₁₁ J-BkBnOyI, such as

Dimethylaminoacetyl,

- (C ₃ -Cg) -cycloalkylcarbonyl, as

Cyclopropylcarbonyl, cyclobutylcarbonyl,

Cyclopentylcarbonyl or

- cyclohexylcarbonyl,

Amino (C 3 -C 8) cycloalkylcarbonyl, as

2-aminocyclopropylcarbonyl-S-aminocyclobutylcarbonyl,

3-aminocyclopentylcarbonyl

32

- A-aminocyclohexylcarbonyl,

- Amino- (C ₃ -Cg> -cycloalkylsulfonyl, as

3-aminocyclopentylsulfonyl,

4-aminocyclohexylrulphonyl,. - phenyl,

- (C 1 -C 4) aryl- (C 2 -C ₁₁ ) alkanoyl _/ as

- 1-Napthyl acetyl,

Phenylacetyl,

Phenylpropanoyl or phenylbutanoyl,

- (C ₆ -C ₁₀ ) -Aryloxy- (C ₂ -C ₁ ) -alkanoyl, as

1-Naphthyloxycarbonyl or

Phenyloxycarbonyl,

optionally substituted by halogen, amino, (C ₁ -Cy) alkyl, (C ₁ -Cy) -alkoxy or (C ₁ -Cy) -alkoxycarbonyl-substituted benzoyl or -benzenesulfonyl, such as

4-chlorobenzoyl,

4-methylbenzoyl,

2-methoxycarbonylbenzoyl, 4-methoxybenzoyl,

Benzenesulfonyl,

4-methylphenylsulfonyl,

optionally substituted by halogen, amino, (C ₁ -Cy) alkyl, (C ₁ -Cy) alkoxy or (C ₁ -Cy) alkoxycarbonyl substituted benzylsulfonyl, benzylsulfinyl or benzylthio, such as

4-chlorobenzylsulfonyl,

Benzylsulfinyl,

4-chlorobenzylthio, - amino,

alkoxycarbonylamino

Alkanoyl, which is substituted by hydroxy, amino and optionally substituted by phenyl or cyclohexyl, such as - 2-amino-1-hydroxy-4-methylpentyl,

optionally protected amino substituted (C ₆ -C ₁₀ ) aryl or (C ₃ -C ₁₀ ) cycloalkyl (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkyl, such as

33

- 2-amino-3-phenyl-propyl or

N-tert-butoxycarbonyl-2-amino-3-phenylpropyl,

- (C 1 -C 4) -alkoxycarbonyl _/ as

- methoxycarbonyl, - ethoxycarbonyl,

- Isobutoxycarbonyl or

tert-butoxycarbonyl,

- substituted (C ^ -C ^ q) alkoxycarbonyl, as

2- (trimethylsilyl) ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,

l, l-dimethyl-2 _/ 2,2-trichloroethoxycarbonyl _/

- (C ₆ -C ₁₄ ) aryl- (C 1 -C ₆ ) alkoxycarbonyl, as

Benzyloxycarbonyl,

1-or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl,

1-deoxyhexoketo-syl or 1-deoxypentoketosyl, as

1-deoxyfructos-1-yl, 1-deoxysorbos-1-yl or

1-deoxyribulos-1-yl

- hexosyl or pentosyl, as

Mannosyl, glucosyl or galactosyl,

Xylosyl, ribosyl or arabinosyl,

6-deoxyhexosyl, as

Rhamnosyl, fucosyl or deoxyglucosyl,

- Amino sugar residues, like

2-amino-2-deoxyglucosyl,

2-acetamido-2-desoxyglucosyl,

2-amino-2-deoxygalactosyl or

2-acetamido-2-deoxygalactosyl,

- lactosyl - maltosyl

wherein the linked sugars may be in the pyranose or furanose form,

- Het how

2-pyridyl,

4-pyridyl,

- 2- (N-oxidopyridyl) or

4- (N-oxidopyridyl),

34

- Het-carbonyl or Het-sulfonyl, as

- piperidino-4-carbonyl,

- morpholino-4-carbonyl,

- pyrrolyl-2-carbonyl, - pyridyl-3-carbonyl,

Quinolyl-2-carbonyl,

4-tert-butoxycarbonylamino-1-piperidylcarbonyl,

4-amino-1-piperidylcarbonyl,

4-tert-butyloxycarbonylamino-1-piperidylsulfonyl, 4-amino-1-piperidylsulfonyl,

- Het- (C ₁ -C ₆ ) -alkyl, as

2-pyridyl (C ₁ -C ₆ ) alkyl,

3-pyridyl (C ₁ -C ₆ ) -alkyl,

4-pyridyl- (C 1 -C 9) -alkyl,

- Het- (C ₁ -C ₆ ) alkanoyl or Het- (C ₁ -C ₆ ) alkylsulfonyl, as

2-pyridyl- (C 1 -C 4) -alkanoyl,

3-pyridyl- (C 1 -C 4) -alkanoyl,

4-pyridyl (C ₁ -C ₆ ) alkanoyl,

2-pyridyl- (C 1 -C 4) alkylsulfonyl,

3-pyridyl (C ₁ -C ₆ ) alkylsulfonyl,

4-pyridyl- (C ₃ -C ₆ ) -alkylsulfonyl,

- Het-mercapto (C ₁ -C ₃ ) -alkylcarbonyl, as

2-pyridylthioacetyl,

where Het each stands for

- pyrrolyl,

- imidazolyl,

- Pyridyl,

Pyrimidyl, pyrrolidyl,

- piperidyl,

- morpholino,

- quinolyl or

- isoquinolyl,

this also by one or two identical or different radicals from the group (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ - C ^ alkoxycarbonylamino, hydroxy, amino, mono- or Di (C ₁ -C ₄ ) alkylamino may be substituted;

35

O Oil

R and R independently represent

- hydrogen,

- carboxyl,

Methyl, ethyl, isopropyl, n-propyl, n-putyl, isobutyl, sec-butyl, n-pentyl, n-hexyl,

- cyclohexyl,

Cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,

4-methylcyclohexylmethyl,

1-decahydronaphthylmethyl, 2-decahydronaphthylmethyl, - phenyl,

Benzyl,

2-phenylethyl,

1-naphthylmethyl, 2-naphthylmethyl,

2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl,

4-tert-butylbenzyl,

4-tert-butoxybenzyl

4-hydroxybenzyl,

4-methoxybenzyl,

2,4-dimethoxybenzyl,

3,4-dihydroxybenzyl,

3,4-dimethoxybenzyl,

- (benzdioxolan-5-yl) methyl,

4-chlorobenzyl, hydroxymethyl,

1-hydroxyethyl,

4-pyridyl,

4- (N-oxidopyridyl),

2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl,

2-thienylmethyl, 3-thienylmethyl,

2- (2-thienyl) ethyl, 2- (3-thienyl) ethyl,

Indole-2-ylmethyl, indol-3-ylmethyl,

- (1-methylimidazol-4-yl) methyl,

Imidazol-4-ylmethyl, imidazol-1-ylmethyl,

2-thiazolylmethyl,

3-pyrazolylmethyl,

36

- 4-pyrimidylmethyl,

2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyl,

2-furylmethyl,

2- (methylthio) ethyl _/

2- (methylsulfinyl) ethyl,

2- (methylsulfonyl) ethyl,

R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ¹⁰ and R ¹⁰ *

Mean hydrogen; 10

R ⁵ and R ⁵ * independently represent

- hydrogen

- hydroxy or - amino;

R ⁷ - hydrogen,

- hydroxy or

- methyl means; 20

R ⁸ and R ⁸ * independently of one another

- hydrogen or

together with R ⁹ or R ⁹ and the atoms carrying them form a 1,2,3,4-tetrahydroisoquinoline or 2-azabicyclooctane skeleton;

R ⁹ and R ⁹ *

are independently defined as R ² or R ² * or

- hydroxy,

Acetoxy,

tert-butoxymethyl,

3-guanidinopropyl,

Carbamoylmethyl, carbamoylethyl,

Carboxymethyl, carboxyethyl,

- mercaptomethyl,

37

- (1-mercapto-1-methyl) ethyl,

Aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl,

N, N-dimethylamino,

- Ν, Ν'-di- (benzyloxycarbonyl) -guanidino-propyl,

2-benzyloxycarbonylethyl, benzyloxycarbonylmethyl,

tert-butylsulfonylmethyl or

4-benzylcarbonylaminobutyl; 10 R and R independently

- hydrogen,

- hydroxy or

- acetoxy; 15 being

in the above compounds of this invention, one or more amide groups (-CONH-) of the main chain may be replaced by -CH ₂ NR ₁₄ - or -CH (OH) CH ₂ -; 20 R ¹⁴ for

- hydrogen or

- methyl is;

and their physiologically acceptable salts.

Very particular preference is given to compounds of the formula I

worm R and R- ^{1 are} independent of each other for

ai) - hydrogen,

- carboxyl,

(C 1 -C 3) alkylsulphonyl, such as methylsulphonyl,

tert-butylsulfonyl,

38 29g / 109

- Isopropylsulfonyl or

Hexadecylsulfonyl,

- (C ^ -Cq) mono- or Dihydroxyalkylsulfonyl, as

2-hydroxyethylsulfonyl or 2-hydroxypropylsulfonyl,

- mono-, di- or trihydroxy- (C ₁ -C ₃ ) -alkyl, such as

1,2,3-trihydroxypropyl,

- 1,2-dihydroxyethyl or

Hydroxymethyl,

- (C ₁ -Cg) alkoxycarbonyl, as

- methoxycarbonyl,

Ethoxycarbonyl,

- Isobutoxycarbonyl or

tert.-butoxycarbonyl, - (C ₁ -C ₁₄ ) -alkyl, such as

- tetradecanoyl,

- amino (C ₁ -C ₁ 2) alkanoyl, such as

12-aminododecanoyl,

(C ₁ -C ₁ Q) -Aloxy (C ₁ -C ₄ ) -alkylcarbonyl, such as - 1- or 2-naphthyloxyacetyl,

- (C ^ -C ₁ Q) -aryl- (C ₁ -C ₄₎ alkoxycarbonyl, such as

- benzyloxycarbonyl or

- 1- or 2-Naphthylmethoxycarbonyl

(C ₆ -C ₁₀ ) -aryl (C ₁ -C 4) -alkylcarbonyl, such as - 1 or 2-naphthylacetyl,

- 9-fluorenylmethoxycarbonyl,

- (C ₁ -C ₄ ) alkanoyloxy- (C ₁ -C 8) -alkyl, as described

- acetoxymethyl,

1,2-diacetoxyethyl,

1,2,3-triacetoxypropyl,

- phenyl

- optionally substituted by halogen, amino, (C ₁ -C ₄ J or methoxy substituted benzenesulfonyl, such as

Benzenesulfonyl,

4-methylphenylsulfonyl,

optionally substituted by halogen, amino, (C ₁ -C ₄ ) -alkyl,

or methoxy substituted benzylsulfonyl, -sulfinyl or -thio, such as

4-chlorobenzylsulfonyl,

Benzylsulfinyl or. 4-chlorobenzylthio,

- Het, how

- 2- or 4-pyridyl or

2- or 4- (N-oxidopyridyl),

- Het-sulfonyl like

- 4-tert-butoxycarbonylamino-1-piperidylsulfony.l or

4-amino-1-piperidylsulfonyl,

- Het- (C ₁ -C ₄ ) -alkylsulfonyl, as

2- (4-pyridyl) ethylsulfonyl,

Het (C ₁ -C ₄ ) alkanoyl, such as 2-pyridylacetyl,

3-pyridylacetyl,

4-tert-butoxycarbonylamino-1-piperidylcarbonyl,

4-amino-1-piperidylcarbonyl or

2-quinolylcarbonyl,

- Het-mercapto (C ₁ -C ₃ ) -alkylcarbonyl, as

2-pyridylthioacetyl,

where Het each stands for

- pyrrolyl, - imidazolyl,

- Pyridyl,

Pyrimidyl,

- Pyrrole idyl,

- quinolyl,

- isoquinolyl,

- piperidyl or

- morpholino,

this radical may also be substituted by one or two identical or different radicals from the group consisting of methyl, amino and (C ₁ -C ₄ ) -alkoxycarbonylamino,

40

- Amino- (C3-Cg) -cycloalkylcarbonyl, as

2-aminocyclopropylcarbonyl

3-aminocyclobutylcarbonyl,

S-aminocyclopentylcarbonyl-4-aminocyclohexylcarbonyl,

- (C 1 -C 4) -alkanoyl which is substituted by hydroxy and amino and optionally substituted by phenyl or cyclohexyl, such as 2-amino-1-hydroxy-4-methylpentyl, optionally protected amino-substituted phenyl- or cyclohexyl- (C ₁ -C 1) -alkyl, as

- 2-amino-3-phenyl-propyl or

N-tert-butoxycarbonyl-amino-S-phenyl-propyl,

- Amino,

- (C 1 -C 4) -alkoxycarbonylamino,

Benzyloxycarbonylamino,

1-deoxyhexoketo-syl or 1-deoxypentoketosyl, as

1-deoxyfructos-1-yl, 1-deoxysorbos-1-yl or 1-deoxyribulos-1-yl

- hexosyl or pentosyl, as

- mannosyl, glucosyl or galactosyl, or

Xylosyl, ribosyl or arabinosyl, the linked sugars being in the pyranose or furanose form,

R and R independently represent

- hydrogen,

Methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl,

Cyclopentylmethyl, cyclohexylmethyl,

4-methylcyclohexylmethyl,

Benzyl,

2-phenylethyl,

1-naphthylmethyl, 2-naphthylmethyl,

2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,

$ 29/109

- 2,4,6-trimethylbenzyl,

4-tert-butylbenzyl,

4-methoxybenzyl,

3,4-dihydroxybenzyl,. 2,4-dimethoxybenzyl,

3,4-dimethoxybenzyl,

3,4-methylenedioxylbenzyl,

2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl or

- 2- (4-pyridyl) ethyl, 10 R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ⁷ , R ¹⁰ and R ¹⁰ * are hydrogen;

R ⁵ and R ⁵ * are independent of each other

- hydrogen or

- hydroxy;

R ⁸ and R ⁸ * are independently defined as on page.

R ⁹ and R ⁹ *

are independently defined as R ⁹ and R ⁹ on page 36, respectively; 25 R ¹¹ and R ¹¹ * are independently defined as on page.

and their physiologically soluble salts. Furthermore, particular preference is given to compounds of the formula I in which

Y is a radical of formula III; 35 is 1 or 1;

m is 1;

A, A, D and D * are as defined above;

η, η *, ο, ο *, ρ and p * independently of one another denote O or 1; 5

E, E, F, F *, G and G independently represent an amino acid selected from VaI, Lys, LyS (Z), Phe, Chg, Ser, Asn, Gly, He, Tbg, Nva or Npg;

R ^L and R are independent of each other

- hydrogen,

- carboxyl,

Methylsulfonyl,

tert-butylsulfonyl, tert-butoxycarbonyl,

2-hydroxyethylsulfonyl,

1,2,3-trihydroxypropyl,

1,2,3-triacetoxypropyl,

Benzyloxycarbonyl,

4-methylphenylsulfonyl,

4-chlorobenzylthio,

Benzylsulfinyl,

4-chlorobenzylsulfonyl,

Hexadecylsulfonyl,

4-amino-1-piperidyl-sulfonyl,

N-tert-butoxycarbonyl-4-amino-1-piperidyl-sulfonyl,

4-amino-1-piperidylcarbonyl,

N-tert-butoxycarbonyl-4-amino-1-piperidylcarbonyl,

2-amino-3-phenylpropyl,

N-tert-butoxycarbonyl-2-amino-3-phenylpropyl,

2-amino-1-hydroxy-4-methylpentyl,

- deoxyfructos-1-yl,

- Mannofurancsyl,

4-aminocyclohexylcarbonyl, 2-quinolylcarbonyl,

1-naphthylacetyl,

43

- 1-Naphthyloxyacetvl,

1- (4-pyridyl) ethylsulfonyl,

12-aminododecanoyl,

4- (N-oxidopyridyl), 4-pyridyl,

- tetradecanoyl,

2-pyridylacetyl,

4-pyridylthioacetyl,

- phenyl,

- Amino or

- tert, -Butoxycarbonylamino mean;

ο on R and R independently

- hydrogen,

2- (4-pyridyl) ethyl,

- isopropyl,

- isobutyl,

- n-pentyl,

Benzyl,

3,4-methylenedioxybenzyl,

2,4-dimethoxybenzyl,

4-tert-butylbenzyl,

- 2-phenylethyl or

- cyclohexylmethyl; 25

R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ⁷ , R ¹⁰ and R ¹⁰ *

- mean hydrogen;

R and R independently

- hydrogen or

- hydroxy;

R ⁸ and R ⁸ * - represent hydrogen, or together with R ⁹ or R ⁹ and the atoms carrying them form a 1,2,3,4-tetrahydroquinoline-3,4-diyl system;

44

Q Q *

R ³ and R independently

- hydrogen,

- hydroxy,

Acetoxy, n-propyl,

- isopropyl,

- isobutyl,

- aminomethyl,

4-aminobutyl, hydroxymethyl,

tert-butoxymethyl,

- aminocarbonylmethyl,

2-benzyloxycarbonyl-ethyl,

4-benzyloxycarbonylamino-butyl,

N, N'-di- (benzyloxycarbonyl-guanidino-propyl).,

- cyclohexyl,

- cyclohexylmethyl,

Benzyl,

- 2-phenyl-ethyl

4-hydroxybenzyl,

4-methoxybenzyl,

4-tert-butoxybenzyl,

- 1-naphthylmethy. ¹

2-thienylmethyl,

1-imidazolylmethyl,

3-indolyl-methyl,

4-pyridylmethyl

- 4 (N-oxidopyridyl) methyl • - 2-methylthio-ethyl,

2-methylsulfonyl-ethyl

tert-butylsulfonyl-methyl or

- 2-carboxyl-ethyl;

R ¹¹ and R ¹¹ * independently

- hydrogen,

- hydroxy or

- acetoxy;

45

wherein in the above compounds one or more amide groups (-CONH-) of the main chain may be replaced by -CH ₉ NH- or -CH (OH) CH ₉ -;

and their physiologically compatible salts.

Also very preferred are compounds of formula I wherein

1 = 0; m = 1;

η + ο + ρ '= 1; D and D * are a radical of the formula VI or VI *

R ¹ and R ¹ *

(C 1 -C 3) alkylsulfonyl, which may be substituted by up to the same or different radicals from the series hydroxy,

- Amino or

- Carboxy may be substituted; mean;

R ^ "and R are independent of each other

- hydrogen,

- carboxyl,

Methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl,

- cyclohexyl,

Cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,

4-methylcyclohexylmethyl,

1-decahydronaphthylmethyl, 2-decahydronaphthylmethyl,

Phenyl, benzyl,

2-phenylethyl,

46

1-naphthylmethyl, 2-naphthylmethyl,

2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,

2,4,6-trimethylbenzyl,

- <r-tert-butylbenzyl, - 4-tert-butoxybenzyl

4-hydroxybenzyl,

4-methoxybenzyl,

2,4-dimethoxybenzyl,

3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl,

- (benzdioxolan-4-yl) methyl _/

4-chlorobenzyl,

Hydroxymethyl,

1-hydroxyethyl,

2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl,

2-thienylmethyl, 3-thienylmethyl,

2- (2-thienyl) ethyl _/ 2- (3-thienyl) ethyl,

Indol-2-ylmethyl, indol-3-ylmethyl, (l-methylimidazol-4-yl) methyl,

Imidazol-4-ylmethyl, imidazol-1-ylmethyl,

2-thiazolylmethyl,

3-pyrazolylmethyl,

4-pyrimidylmethyl,

2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyl,

2-furylmethyl,

2- (methylthio) ethyl,

- 2- (methylsulfinyl) ethyl or

- 2- (methylsulfonyl) ethyl; 30

R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ¹¹ and R ¹¹ *

- mean hydrogen;

R ⁵ and R ⁵ * are hydroxy;

R ⁹ and R ⁹ *

how R ⁹ and R ⁹ * are defined on page 44;

as well as compounds of the formula I in which

1 = 0;

m = 1; 5

η + ο + ρ = 1;

D and D * are a radical of the formula VII or VII *

R ¹ and R ¹ *

a hexosyl or pentosyl radical or a 1-deoxyhexoketosyl or 1-deoxypentoketosyl radical which is as defined above;

R ² and R ² *

- hydrogen,

- (C ₁ -C ₈ ) -alkyl,

- (C ₃ -C ₁₀ ) -cycloalkyl- (C ₁ -C 4) -alkyl or

- (C ₁ -C ₄ ) aryl- (C ₁ -C ₄ ) -alkyl, each containing up to 3 identical or different radicals from (C -) _C ₄ ) -alkyl or (C ₁ -C ₄ ) alkoxy may be substituted, mean;

R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ¹¹ and R ¹¹ * - are hydrogen;

R ⁵ and R ⁵ *

- hydroxy;

R ⁹ and R ⁹ *

as R and R are defined on page 44.

The present invention furthermore relates to a process for the preparation of compounds of the formula (I) which comprises coupling a carboxyl-terminal fragment or its reactive derivative with a corresponding fragment having a free amino group, if appropriate to protect it more functionally

48 Λ984Ό9

Groups (one) temporarily introduced protective group (s) cleaves off and the resulting compound optionally converted into its physiologically acceptable salt.

Fragments of a compound of the formula (I) having a terminal carboxyl group have e.g. the following formulas:

D - OH OH OH (VIII) D - E - OH OH (IX) D - F - OH OH (X) D - G - F - G-OH (XI) D - E - G - (XII) D - E - G - (XIII) D - F - F - (XIV) D - E - (XIVa)

The same applies to the analog, starred radicals. 20

Fragments of a compound of formula (I) having a terminal amino group have e.g. the following formulas:

H-Z-H (XV)

H-G-Z-G * -H (XVI)

H-F-Z-F * -H (XVIa)

H-E-Z-E * -H (XVIb) 30

H - F - G - Z - G * - F * - H (XVII)

H-E-G-Z- G * -E * -H (XVIIa)

H-E-F-Z-F * -E * -H (XVIIb)

H-E-F-G-Z-G * - F * - E * - H (XVIII)

49 298 * 09

where Z is a radical of the formula (XIX):

R ⁴

- NR ⁵ . R ⁵ * R ³ *

R ² --C - C - (Y) ₁ - (C) _m --C - R ² * (XIX)

R ³ R ⁶ R ⁶ * -Ν

r4 *

In the case of non-symmetrical target molecules, it is also possible to use fragments other than those of the formulas XV to XVIII, which may be protected by a terminal amino group.

Methods suitable for preparing an amide bond are described e.g. in Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2; Bodanszky et al., Peptide Synthesis. 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis, synthesis, biology · '(Academic Press, New York 1979). Preferably, the following methods are used:

Aktivestermethode with N-hydroxy-succinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-1, 2, 3-benzotriazine as the alcohol component, coupling with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or with n-propanephosphonic anhydride (PPA) and the mixed anhydride method with pivaloyl chloride or ethyl or isobutyl chloroformate, or coupling with phosphonium reagents, such as benzotriazol-1-yl-oxy-tris (dimethylamino-phosphonium hexafluorophosphate (BOP) or uronium reagents, such as 2- (IH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluorobarate (TBTU).

Fragments of the formula (VIII) or (VIII *), if they are below 35

a) Formula (V) or (V *) are synthesized according to the general methods for the preparation of amino acids;

so J9SJ09

b) formula (VI) or (VI *) fall, z. B. diazotization at -20 ⁰ C to 50 ⁰ C in verd. Mineral acids leads to α-bromocarboxylic acids or via the lactic acids to a-Trifiuormethansulfonyloxy carboxylic acids with an R, for example, starting from the corresponding amino acids synthesized, wherein the chiral center is maintained

and R and R * and R ^ * bearing nucleophile can be reacted, or z. B. starting from malonic esters whose alkylation mono- or disubstituted malonic ester provides, which are converted by saponification by decarboxylation in the desired derivatives.

c) Formula (VII) or (VII *) are synthesized starting from the corresponding α-amino acids, wherein the chiral center is retained. Diazotization at -2O ⁰ C to 50 ⁰ C in dilute mineral acids leads to lactic acids, which can be reacted with an R or R-carrying electrophile.

Fragments of formulas (IX), (X), (XI), (XH) and (XIII), (XIV) and (XIVa) are synthesized according to the general, well-known methods for the preparation of amino acids and peptides.

Fragments of the formula (XV) are prepared starting from optically active α-amino acids or sugars or their derivatives. For example, to prepare fragments with m = 1, 1 = 0, R ⁵ = R ⁵ * = OH and R ⁶ = R ⁶ * = H, the amino acids are converted in a known manner into N-protected amino acid aldehydes (B. Castro Synthesis 1983, 676) and reductively with suitable metals, metal salts or electrochemically to N-protected. Diaminodiols implemented. The N-protected aldehydes are for example dissolved in tetrahydrofuran and at -30 ⁰ C to 6O ⁰ C, preferably -1O ⁰ C to 30 ⁰ C, by addition of a solution of samarium (H) iodide in tetrahydrofuran in the N- protected diaminodiol compounds transferred.

Cleavage of the protecting groups provides the compounds of formula (XV). Diastereomeric mixtures are obtained with respect to the OH-carrying centers, which are separated in a manner known per se, for example by fractional crystallization and / or by chromatography.

When synthesized from sugars (derivatives) η, the chiral centers of the starting material are conserved or inverted. OH groups to be retained are suitably protected, the others are converted by conversion with e.g. a sulfonic acid chloride or Mitsunobu (Synthesis (1981), 1-28) and can be replaced by nucleophiles. The desired products are obtained here in stereochemically uniform form.

Starting e.g. of D-mannitol, the hydroxy groups of the polyol in position 3 and 4 are protected by treatment with acetone / sulfuric acid and then with aqueous acetic acid as acetonite. The conversion of the two terminal OH groups with p-toluenesulfonyl chloride / pyridine and treatment with potassium carbonate in methanol gives the 1,2R-5R, 6-diepoxy-3,4-O-isopropylidene-3R, 4R-diol (Y. Le Merrer et al., Tetrahedron Lett. 26,

(1985) 319-322). Treatment of diepoxide with cuprates in e.g. Tetrahydrofuran leads to the opening of the epoxides and introduction of substituents in positions 1 and 6. After activation of the hydroxy groups in position 2 and 5 by reaction with e.g. a sulfonic acid chloride are both replaced by conversion with an azide. Reduction of the two azide groups by e.g. Catalytic hydrogenation and cleavage of the acetonide protecting group with HCl / methanol affords the compounds of the radical (XV).

Fragments of formula (XV) with m = 1, 1 = 1 and Y = radical of formula III are obtained such that N-protected amino acid aldehydes (supra) are reacted under reductive conditions (e.g., NaBHgCN) with an appropriate amine.

52 198409

The aldehydes are incorporated in e.g. Methanol dissolved and reacted with e.g. Ammonium acetate and e.g. Sodium cyanoborohydride reacted as a reducing agent. Subsequent deprotection provides the desired building block. 5

Fragments of the formula XV where m = 0, 1 = 0, R ⁵ = 0H, R ⁶ = H are obtained such that suitable nitro compounds are deprotonated with bases such as tetramethylguanidine and added to N-protected amino acid aldehydes (see above). Reduction of the nitro group with, for example, Raney nickel and deprotection affords the compounds of formula (XV) as diastereomers, which are separated as described above.

The fragments of formulas XVI, XVIa, XVIb, XVII, XVIIa, XVIIb and XVIII are synthesized according to well-known methods for the preparation of amino acids and peptides.

In the compounds of the formula I, one or more amide groups can be replaced by -CH ₂ NR ¹⁴ -, -CH ₂ S-, -CH ₂ O-, OCH ₂ -, -CH ₂ CH ₂ -, -CH = CH- (ice and trans), -COCH ₂ -, -CH (OH) CH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, -P (O) (OR ¹⁵ ) CH ₂ -, -P ( O) (OR ¹⁵ J ₂ NH- or -NH-CO- be replaced.

Peptide analogues of this type can be prepared by known processes, which can be taken, for example, from the following references:

A. F. Spatola in "Chemistry and Biochemistry of Amino Acids Peptides and Proteins" 1983 (B. Weinstein et al., Eds.) Marcel Dekker, New York, p.267 (review article); J.S. Morley, Trends Pharm Sei. (1980) pp. 463-468 (review article);

D. Hudson et al., Int. Ζ. Pept. Prot. Res. (1979), 14, 177-185 (-CH ₉ NH-, -CH ₉ CH ₉ -);

AF Spatola et al., Life Sei. (1986), 38, 1243-1249 (-CH ₂ -S-);

M.M. Hann, J. Chem. Soc. Perkin Trans. I (1982) 307-314 (-CH = CH-, cis and trans);

JK Whitesell et al., Chirality 1, (1989) 89-91 (-CH = CH-trans) RG Almquist et al., J. Med. Chem. (1980), 23, 1392-1398 (-COCH ₂ -) ;

Jennings-White et al., Tetrahedron Lett. (1982) 23, 2533 (-COCH ₂ -);

M. Szelke et al., EP-A 45665 (1982), CA: 97: 39405 (-CH (OH) CH ₂ -);

MW Holladay et al., Tetrahedron Lett. (1983) 24, 4401-4404 (-CH (OH) CH ₂ -);

VJ Hruby, Life Sei. (1982), 31, 189-199 (-CH ₂ -S-); NE Jacobsen, PA Barlett, J. Am. Chem. Soc. (1981) 103, 654-657 (-P (O) (OR) NH-).

The preparation and postoperations required for the preparation of compounds of the formula I, such as introduction and removal of protective groups, are known from the literature and are described, for example, in TW Greene's "Protective Groups in Organic Synthesis" (John Wiley & Sons, New York, 1981). Salts of compounds of formula I having salt-forming groups are prepared in a manner known per se, for example by adding a compound of formula I having a basic group with a stoichiometric amount of a suitable acid or compounds of formula I having an acidic group with a stoichiometric amount of suitable base is reacted. Stereoisomer mixtures, in particular diastereomer mixtures, which may be obtained in the synthesis of compounds of formula I, can be separated in a conventional manner by fractional crystallization or by chromatography.

The compounds of the formula (I) according to the invention have enzyme-inhibiting properties. In particular, they inhibit the action of retroviral aspartyl proteases such as the HIV protease. Their enzyme inhibitory activity, which is in the milli-subnanomolar range, can be determined as follows.

54 298 * 09

Test principle:

Among others, the heptapeptide H-Ser-Phe-Asn-Phe-Pro-Gln-He-OH (PL Darke et al., Biophys. Res. Commun., 156 (1988) 297-303) has been used as a substrate of the HIV protease ). The HIV protease cleaves the substrate between the second Phe and Pro.

Surprisingly, it has now been found that substitution of proline by 5-oxaproline in this sequence leads to a substrate that can be cleaved much more rapidly by the HIV protease and thus allows faster analysis with less enzyme requirement.

General procedure for the testing of inhibitors of HIV proteases:

a) Preparation of the substrate solution:

2 mg of H-Ser-Phe-Asn-Phe-Opr-Gln-He-OH (H-Opr-OH = 5-oxaproline) are dissolved in 1 ml of MGTE15 buffer (possibly using ultrasound) and then via a sterile filter (0.45 μιη) filtered.

b) Preparation of the inhibitor solution:

The inhibitor is weighed 2.5 times the desired molarity per ml of solution and dissolved with DMSO (10% of the final volume). It is diluted with MGTE15 buffer to final volume and filtered through sterile filter (0.45 μιη).

c) Preparation of the protease solution:

5 μL of the HIV protease solution is diluted as needed with MGTE25 buffer.

d) Test execution:

Pipette 10 μΐ each of the substrate solution into test tubes (16x100) with screw cap. For the blind attempt

55

10 μM MGTE15 buffer containing 10% DMSO is pipetted. The remaining test tubes are mixed with 10 μl each of the inhibitor solutions. The mixture is incubated at 37 ⁰ C for 5-10 minutes and then 5 μΐ of the protease solution is added to each sample. After 2 hours of reaction at 37 ⁰ C of each Ptobe 10 or 20 μΐ abpipettie'rt (depending on the sensitivity of the HPLC Geri \ tes) filled in Mikrovials and diluted with 120 μΐ of the HPLC mobile phase.

e) Conditions for HPLC analysis:

Eluent system: 80% 0.1 M phosphoric acid pH 2.5

20% (w / w) acetonitrile

Column: Merck®IGROSORB RP18 (5 μηl) 250x4 flow: lml / min

Column temperature: 42 ⁰ C Detector parameters: 215 nm, 0.08 ON, 18.2 ⁰ C analysis time: 11 minutes Retention time of the substrate: 8.1 minutes retention time of the N-terminal tetrapeptide: 3.9 minutes

f) Required solvents:

1) MGTE15 buffer:

20 mM morpholinoethanesulfonic acid (MES) 15% (w / v) glycerol 0.1% (v / v) Triton X 100 5 mM FDTA

0.5 M NaCl 1 mM phenylmethylsulfonyl fluoride (PMSF)

2) MGTE25 buffer:

Composition similar to the MGTE15 buffer with the following deviation: 25% (w / v) glycerol, plus 1 mM dithiothreitol (DTT)

1Θ8109

Weigh MES, EDTA, NaCl, DTT and PMSF into an Erlenmeyer flask, dissolve in a little water and adjust to pH6. In a graduated flask weigh the appropriate amount of glycerol and pipetted «Triton X 100 to do so. The aqueous solution is transferred to the volumetric flask and filled up with water.

3) HPLC eluent:

It is prepared from ortho-phosphoric acid (FLUKA puriss, p.a.) A 0.1 M solution ago. With triethylamine (FLUKA puriss, p.a.), this solution is adjusted exactly to pH 2.5. The weight of the solution is determined and the appropriate amount of acetonitrile (deduction!) Weighed. Thoroughly mix and degas about 5.0 minutes with helium 5.0.

g) Evaluation:

Under the conditions chosen here, the heptapeptides separate from the N-terminal tetrapeptide formed during the enzymatic cleavage. The% content of the tetrapeptide peak in terms of sum of tetrapeptide + heptapeptide corresponds to the splitting rate. The following IC ^ Q values indicate at which inhibitor concentration the cleavage rate is halved.

Example no. ^IC 50 Example no. ^IC 50 1 10nM 18 1.2nM 5 3.6 μΜ 19 0.7nM 6 , 8.8 nM 21 220 nM 7 18 nM 25 18 μΜ 8th 30 μΜ 28 3 μΜ 10 17 nM 30 30 nM 11 0.8nM 33 20 μΜ 13 1.3 nm 39 1.3nM 14 ' 1.0 nM 40 13 nM 15 400nM 43 1.0 nM 16 0.85 nM 45 1.5 μΜ 17 0.85 nM 48 80 μΜ

Example no. ^IC 50 Example no. ^IC 50 49 1.2nM 104 24 nM 50 45 nM 105 19 nM 51 0.8nM 106 85 nM 52 3.2 nM 107 8.5 nM 53 4.0 nM 108 280 nM 54 260 nM 109 5,0nM 55 1.3nM 110 1.0 nM 58 49 nM 113 40nM 59 47 nM 115 2.2 μΜ 61 400nM 116 1.7nM 63 6.5 nM 117 19 nM 65 1.8nM 118 1.2nM 72 30 nM 119 10 μΜ 74 1.7nM 120 · 2.0 nM 75 19 nM 121 22 nM 76 0.29 nM 123 32 nM "7 9.2 nM 124 11 nM , O 1.8nM 125 0.75 nM 80 28 nM 127 46 nM 82 9 nM 131 40 μΜ 83 10nM 132 20 μΐη 84 110nM 142 140 nM 85 1.9 nM 143 2.2nM 86 2.2nM 145 95 nM 87 1.6nM 146 100nM 88 1 μΜ , 148 36 nM 89 1.8nM <? 149 360 nM 90 2.2nM 150 95 nM 91 1.3nM 151 4 nM 93 22 nM 152 1nM 94 6.5 nM 154 1nM 95 380 nM 155 10nM 97 36 nM 156 30 nM 98 1 μΜ 99 15 nM 100 400nM 101 1.4nM 102 38 nM

The target peptide was synthesized using a model 430 A peptide synthesizer from Applied Biosystems using the Fmoc method on a Fmoc-Ile-OII esterified p-benzyloxybenzyl alcohol resin from Novabiochem (loading approx. g resin) gradually built up. 1 g of the resin was used and the synthesis was carried out using a synthesis program modified for the Fmoc method.

The following amino acid derivatives are used: Fmoc-Gln-OH, Fmoc-Opr-OH, Fn -Phe-OObt, Fmoc-Asn-OH and Fmoc-Ser (tBu) -OObt. For the synthesis of Fmoc-Opr-OH, H-Opr-OtBu was prepared by the method of Vasella et al. (JCS Chem. Comm. 1981, 97-98) and reacted with Fmoc-OSu in dioxane / water (1: 1) in the presence of NaH (X.sub.1) The subsequent cleavage of the tert-butyl ester with trifluoroacetic acid gives Fmoc-Opr -OH.

In each case, 1 mmol of the amino acid derivatives with free carboxyl group together with 0.95 mmol HOObt were weighed into the cartridges of the synthesizer. The pre-activation of these amino acids was carried out directly in the cartridges by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 molar solution of diisopropylcarbodiimide in DMF. The HOObt esters of the other amino acids were dissolved in 6 ml NMP and then, like the in situ preactivated amino acids, coupled to the resin previously deblocked with 20% piperidine in DMF. After completion of the synthesis, the peptide was cleaved from the resin while removing the side-chain protecting groups with trifluoroacetic acid using thioanisole and ethanedithiol as cation scavengers. The residue obtained after removal of the trifluoroacetic acid was digested several times with ethyl acetate and centrifuged.

The remaining residue was chromatographed on an alkylated dextran gel with 10% acetic acid. The pure peptide-containing fraction was pooled and freeze-dried.

59 198ΛΟ9

Mass Spectrum (FAB): 854 (M + H ⁺ )

Amino acid analysis Asp: 0.98; Ser: 0.80; Glu: 1.00; He: 1.05;

Phe: 2,10; NH ₃ : 1.76.

The invention also relates to the use of the compounds of formula I as remedies and pharmaceutical preparations containing this compound. Preference is given to the use in primates, in particular in humans.

Pharmaceutical preparations contain an effective amount of the active ingredient of formula I together with an inorganic or organic pharmaceutically acceptable carrier. The application may be intranasal, intravenous, subcutaneous or peroral.

The dosage of the drug depends on the

Warm-blooded species, body weight, age and mode of administration.

The pharmaceutical preparations of the present invention are prepared by conventional methods of solution, mixing, granulation or coating.

For an oral application form, the active compounds with the usual additives such as

Carriers, stabilizers or inert

Diluents mixed and brought by conventional methods in suitable dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily

Solutions. As inert carriers, e.g. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. The preparation can be used both as dry or dry

Wet granules take place. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil and cod liver oil.

60

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts, if desired with the conventional substances such as solubilizers, emulsifiers or other auxiliaries in solution, suspensions or emulsions. As a solvent, e.g. in question: water, physiological saline solutions or alcohols, e.g. Ethanol, propanediol or glycerol, besides sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

Also possible is the use of injectable sustained-release preparations. As dosage forms, e.g. oily crystal suspensions, microcapsules, rods or implants, the latter being made of tissue-compatible polymers, particularly biodegradable polymers, e.g. based on polylactic acid-polyglycolic acid copolymers or Huraanalbumin,

List of abbreviations used:

Chg cyclohexylglycyl Boc tert-butyloxycarbonyl d doublet DC TLC DCC dicyclohexylcarbodiimide DCM dichloromethane DMF dimethylformamide DMAP 4-dimethylaminopyridine DMSO dimethyl sulfoxide EDAC 1- (3-Dimethylamino-propyl) -3-ethyl-1-carbodiimide hydrochloride EE ethyl acetate FAB Fast atom bombardment HOBt hydroxybenzotriazole i. Vac. in a vacuum m multiplet M Molekülarpeak

61

NEM N-Ethylmorpholxn mpg Neopentylglycyl MS Massenspetrum PPA n-propylphosphonic RT room temperature S singlet Mp. melting point t Triplett tBG tert-butylglycyl TBTU 2- (1H-benzotriazol-1-yl) -1, l, 3,3- tetramethyluronium tetrafluoroborate THF tetrahydrofuran thia 2-Thienylalanyl Z benzyloxycarbonyl

The abbreviations otherwise used for amino acids correspond to the three-letter code customary in peptide chemistry (as described, for example, in Eur. J. Biochem., 138, (1984), 9-37). Unless otherwise stated, it is always an amino acid of the L configuration.

The following examples serve to illustrate the present invention without being limited thereto.

62 29 & 1O9

example 1

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol 5

100 mg of Ν, Ν'-bis- (L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol-dihydrochloride were used together with 111 mg of N-tert-butoxycarbonyl-L- phenylalanine, 0.57 ml NEM and 60 mg HOBt dissolved in 1.5 ml OMF. After addition of 85 mg of EDAC at 0 ⁰ C. Stirring was continued for 1 h at ⁰ C, then overnight at RT. The solvent was i. Vac. The residue was removed in EE and extracted with saturated KHCO3, 10% KHSO4 solution and water. The organic phase was dried with anhydrous Na 2 SO 4 and concentrated. The residue was recrystallized from ethanol-water. The yield was 92 mg.

MS (FAB): 993 (M + H) ⁺ , 975, 893, 793

NMR (270 MHz, DMSO <D ₆ >): 0.72 (d, 5Hz, 6H); 0.75 (d, 6Hz, 6H); 1.29 (s, 18H); 1.86 (m, 2H); 2.60-2.96 (m, 8H); 3.30 (m, 2H); 4.17 (m, 2H); 4.45 (m, 2H); 4.68 (m, 2H); 7.03 (d, 9Hz, 2H); 7.05-7.30 (m, 22H); 7.53 (d, 9Hz, 2H).

Example 2

N, N ¹ -Bis (L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride

220 mg of N, N ¹ -bis (tert-butoxycarbonyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-3,4-O-isopropylidene-hexane-3R, 4R-diol were dissolved in 10 ml of an approximately 3N solution of HCl in dioxane / methanol 1/1 for 1 h at RT. The volatiles of the solution were removed i. Vac. and dried in a high vacuum. The substance was without further

Cleaning used in the next stage. Yield: 184 mg

MS (FAB): 499 (14 + H) ⁺ , 481, 463 5

Example 2a

N, N-bis (tert -butoxy: ycarbonyl-L-valyl) -2 S, 5S-diamino-1,6-diphenyl-3,4-O-isopropylidene-hexane-3R, 4R-diol

136 mg of 2S, 5S-diamino-1,6-diphenyl-3,4-O-isopropylidenhexan-3R, 4R-diol were mixed with 0.54 ml of NEM and 260 mg u- tert-butoxycarbonyl-L-valine in 2 ml dissolved dry EE. At -10 ⁰ C 0.97 ml of a 50% PPA solution in EA was added. The mixture was stirred at ⁰ ° C. for 1 h, then at RT overnight. The solution was diluted with EA, extracted with saturated NaHCO ₃ , 10% KHSO 4 solution and water. The organic phase was dried over anhydrous MgSO 4, concentrated and the residue purified by chromatography on silica gel (dichloromethane / methanol 97/3). The yield was 230 mg

MS (FAB): 739 (M + H) ⁺ , 681, 639, 569, 539 Example 2b

2S, 5S-diamino-1,6-diphenyl-3.4-0-isopropylidene-hexan-3R, 4R-diol

2.3 g of 2S, 5S-diazido-1,6-diphenyl-1,6-O-isopropylidene-hexane-3R, 4R-diol were dissolved in 50 ml of methanol and treated with about 0.2 g of palladium on carbon (10 % ig) for 2 h under atmospheric pressure. The catalyst was filtered off, after concentration of the solution, the residue was chromatographed on silica gel (dichloromethane / methanol 99/1). Yield: 1.33 g

MS (FAB): 341 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 1.29 (m, 4H); 1.37 (s, 6H); 2.71 (dd, 12Hz, 5Hz, 2H); 2.87 (m, 2H); 3.32 (m, 2H); 3.95 (s, 2H); 7,12-7,33 (m, 10H)

Example 2c

2S, 5S-diazido-1,6-diphenyl-3,4-O-isopropylidene-hexan-3R, 4R-diol

8.5 g of 2R, 5R-di- (4-nitrophenylsulfonyloxy) -1,6-diphenyl-3,4-O-isopropylidene-hexane-3S, 4S-diol were dissolved in 300 ml of DMF and treated with about 9.2 g NaN ₃ and 6.3 g of 18-crown-6 for 4 h at 5O ⁰ C heated. The solvent was predominantly i. Vac. evaporated, the residue taken up in ether and extracted with aqueous NaHCO ₃ solution. After washing with water, it was dried and concentrated. The residue was chromatographed on silica gel (toluene / n-heptane 2/5 to 2/3). The yield was 2.37 g

NMR (270 MHz, DMSO <D ₆ >): 1.48 (s, 6H); 2.92-3.12 (m, 4H); 3.74 (dd, 10Hz, 5Hz, 2H); 4.15 (s, 2H); 7.21-7.39 (m, 10H)

Example 2d

2R, 5R-di (4-nitrophenylsulfonyloxy) -1,6-diphenyl-3.4-0-isopropylidene-hexan-3S, 4S-diol

5.6 g of 2R, 5R-dihydroxy-1,6-diphenyl-3,4-O-isopropylidenehexane-3R, 4R-diol were dissolved together with 7.9 g of DMAP in 300 ml of chloroform. Was added at RT 14.5 g of p-nitrobenzenesulfonyl chloride are added and stirred for 3 h at 5O ⁰ C. It is mixed with methylene chloride and the solution was extracted with bicarbonate, KHSO ₄ - and NaCl-solution. After drying the organic phase was concentrated. Yield: 11.8 g

MS (FAB): 713 (M + H) ⁺ , 697, 510

NMR (270 MHz, DMSO <D ₆ >): 1.42 (s, 6H); 2.87 (dd, 15Hz, 9Hz, 2H); 3.11 (dd, 15Hz, 3Hz, 2H); 4.41 (s, 2H); 5.07 (dm, 9Hz, 2H); 6.95-7.11 (m, 10H); 7.73 (d, 9Hz, 4H); 8.18 (d, 9Hz, 4H) 5

Example 2e

2R, 5R-dihydroxy-1,6-diphenyl-3,4-O-isopropylidene-3R, 4R-diol

Under argon, 1.12 g of 1,2R-5R, 6-diepoxy-3,4-O-isopropylidene-3R-4R-diol (Y. Le Merrer, A. Dureault, C. Gravier, D. Languin and JC Depezay Tetrahedron Lett., (1985), 319-322) at -78 ⁰ C (to a solution of 36 mmol C ^ Hg) given 2CUL1 dry in 60 ml of ether. The cold bath was removed and allowed to warm to RT with stirring. The mixture was treated with 250 ml of EA and extracted 3 times with a mixture of 25% ammonia and ammonium chloride. The EA phase was washed with NaCl solution, dried and concentrated. The residue was purified over silica gel (dichloromethane / EA 97/3 to 90/10). The yield was 1.86 g

MS (FAB): 343 (M + H) ⁺ , 327, 285, 267 25

NMR (270 MHz, DMSO <D ₆ >): 1.39 (s, 6H); 2.58 (dd, 13Hz, 9Hz, 2H), 3.43 (dd, 13Hz, 3Hz, 2H); 3.68 (m, 2H), 3.83 (m, 2H); 5.05 (d, 6Hz, 2H); 7.14-7.32 (m, 10H)

Examples 3-5

3) N, N ¹ -bis (tert-butoxycarbonyl) -2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol

4) N, N'-bis- (tert-butoxycarbonyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol

5) N, N'-bis- (tert-butoxycarbonyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4S-diol

66

17 g of tert-butoxycarbonyl-L-phenylalaninal were dissolved in ml of dry THF and cooled under argon to 0 ⁰ C. About 20 ml: 1 1 of 0.1 molar SmI ₂ solution in THF were added and the mixture was stirred at RT for 30 min. It was acidified to pH 1-2 with 0.1 N v / aqueous HCl. Dilute with EE,

the organic phase was separated and extracted with 0.1 N HCl, 2x with Na ₂ S ₂ O ₃ solution and 2x with water. After drying over MgSO 4 was concentrated and chromatographed on silica gel (EA / petroleum ether 1/2). 10

The fraction containing the 3R, 4R isomer was recrystallized from ethanol / water.

From the fraction containing the 3S, 4S and 3R, 4S isomers, the 3S, 4S isomer could be recovered by crystallization from dichloromethane / isopropyl ether / heptane. The mother liquor was chromatographed on RP18 silica gel (acetonitrile / water 4/6) to give the 3R, 4S isomer.

Yields: 1.61 g 3R, 4R isomer

1.00 g of 3S, 4S isomer 0.71 g of 3R, 4S isomer

Rf values: silica gel, EA / hexane 1/2 0.18 3R, 4R isomer

0.41 3S, 4S isomer 0/39 3R, 4S isomer

MS (FAB): 501 (M + H) ⁺ , 401, 345, 327, 301 3R, 4R isomer 501 (M + H) ⁺ , 401, 345, 327, 301 3S, 4S isomer

501 (M + H) ⁺ , 401, 345, 327 3R, 4S isomer

IH-NMR (270 MHz, DMSO <D ₆ >):

3R, 4R-isomer

3S, 4S-isomer

3R, 4S isomer

N-H 6,16; (d; 2H)

0-H 4,43 (m, 2H)

H ³ , H ⁴ 4,12 (m, 2H)

H ² , H ⁵ 3.24 (m, 2H)

CHo 2.54-2.80 (m, 2H)

C (CH ₃ J ₃ 1.30 (s, 18H)

6.60 (d, 2H) 4.57 (d, 7Hz, 2H)

3.71 (m, 2H)

3.42 (m, 2H)

3.04 (dd, 14Hz,

4Hz, IH)

2.63 (dd, 14Hz,

9Hz, IH)

1.30 (s, 18H)

6.31 (d, 6.28 (d, IH) 4.62 (d, 4Hz, IH) 4.94 (d, 6Hz, IH) 3.91-4.12 (m, 2H) 3.27- 3.46 (m, 2H) 2.62-2.83 (m, 2H)

Ar-H

1.32 (s, 9H) 1.24 (s, 9H) 7.08-7.27 (m, 10H) 7.11-7.29 (m, 10H) 7.08-7.32 (m, 1 OH)

The assignment of the absolute stereochemistry results in

3R, 4S isomers from the double set of signals, the distinction between the 3R, 4R and the 3S, 4S isomers by comparison with synthetic reference material starting from D-mannitol (see Example 3.1). Evaluation of coupling constants after splitting off the

tert-butoxycarbonyl groups and conversion of the isomers 25 with phosgene in double 2-Oxazolidinonsysteme thus gave

consistent results.

example

Assignment of Absolute Stereo Chemistry of the Isomers of Examples 3-5

N, N'-B is (tert -butoxycarbonyl) -2S-5S-diamino-1,6-diphenylhexane-3R, 4R-diol

140 mg of 2S, 5S-diamino-1,6-diphenyl-3,4-O-isopropylidenehexane-3R, 4R-diol were dissolved in a mixture of 5 ml of 1N HCl in methanol and 5 ml of 5N HCl in dioxane and added for 4 h RT

touched. The volatiles were i. Vac. away. The residue was dried under high vacuum and the resulting 2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride (MS (FAB): 301 (M + H) ⁺ free base) was added directly in the next reaction.

45 mg of 2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol dihydrochloride were dissolved in 5 ml of dry dichloromethane and stirred together with 40 .mu.l of triethylamine and 75 mg of pyrocarbonic acid di-tert-butyl ester at RT for 3 h , Dilute with dichloromethane and extract with KHSO ₄ , NaHCO ₃ and NaCl solution. After drying over anhydrous Na 2 SO 4 was concentrated and the residue was purified over silica gel (acetonitrile / DCM 1/8).

Yield: 23 mg

MS (FAB) 501 (M + H) ⁺ , 401, 345, 327, 301

The compound was identical to the most polar isomer of Examples 3-5.

Example 6

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-1, 6-diphenyl-hexane-3S, 4S-diol

38 mg Ν, Ν ¹ -Bis (tert-butoxycarbonyl-L-valyl) -2S, 5S-diamino-l, 6-diphenyl-hexane-3S, 4S-diol were treated with 5N HCl in dioxane for 30 min. The volatiles were i. Vac. removed, the residue dried. The resulting Ν, Ν'-bis (L-valyl) -2S, 5S-diamino-1,6-diphenyl-3-hexane-3S, 4S-diol dihydrochloride was treated with 40 mg tert-butyloxycarbonylphenylalanine, 22 mg HOBt and Dissolve 51 mg of TBTU in 1 ml of dry DMF. 60 μl of ethyldiisopropylamine were added and the mixture was stirred at RT for 15 minutes. The DMF was removed by rotary evaporation, the residue was taken up in EA and extracted with KHSO ₄ , NaHCO ₃ solution and water. To

Drying over MgSO _{4 was} concentrated, the substance> recrystallized. The filtrate was filtered off, washed with ether and a yield of 30 mg of 5 was obtained

MS (FAB): 1015 (M + Na) ⁺ , 993 (M ⁺ H) ⁺ , 893, 793

NMR (270 MHz, DMSO <D ₆ >): 0.79 (m, 12H); 1.28 (s _; 18H); 1.85 (m, 2H); 2.68-2.82 (m, 4H); 2.85-3.03 (m, 4H), 3.37 (m, 2H); 4.00-4.13 (m, 4H); 4.21 (m, 2H); 4.66 (d, 7Hz, 2H); 7.03 (d, 7Hz, 2H); 7.05-7.34 (m, 20H); 7.62 (d, 7Hz, 2H); 7.68 (d, 8Hz, 2H)

Example 7

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4S-diol

Synthesis analogously to Example 6 from N, N ¹ -bis- (tert-butoxycarbonyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3R, 4S-diol

MS (FAB): 1015 (M + Na) ⁺ , 993 (M + H) ⁺ , 893, 793

NMR (270 MHz, DMSO <D ₆ >): 0.68-0.85 (m, 12H); 1.28 (s, 9H); 1.20 (s, 9H); 1.75-2.03 (m, 2H); about 2.5-3.30 (m, 8H); about 3.3-3.51 (m, 2H); 4.05-4.30 (rc, 5H); 4.43 (m, IH); 4.74 (d, 4Hz, IH); 5.-32 (d, 7Hz, IH); 6.93-7.35 (m, 22H); 7.61 (d, 8Hz, IH); 7.67 (d, 7Hz, IH); 7.85 (d, 8Hz, IH); 7.92 (d, 7Hz, IH)

Example 8

N, N ¹ -Bis (tert -butoxycarbonyl-L-valyl) -2S, 5S-diamino-1,6-Qiphenyl-hexane-3S, 4S-diol

164 mg of Ν, Ν'-bis- (tert-butoxycarbonyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol was added 1.5 h at RT to 10 ml of 5N

HCl in dioxane. The volatiles were removed i. Vac, the residue was dried. The resulting 2S, 5S-diamino- 1 ₁ 6-diphenyl-hexane-3S, 4S-diol dihydrochloride was dissolved together with 178 mg of tert-butoxycarbonyl-L-valine and 0.56 ml of NEM in 15 ml of dry DMF. At -5 ⁰ C was added thereto, 0.53 ml of a 50% solution of PPA in EE, stirred for 1 h at 0 ⁰ C and overnight at RT. The solvent was removed by rotary evaporation, the residue was taken up in EA and extracted with water, NaHCO.sub.2, KHSO.sub.4 solution and water. After drying over anhydrous ^ 2SO *, the mixture was concentrated i. Vac. on. Upon treating the residue with diethyl ether, the product crystallized out. It was recrystallized from ethanol / water. Yield: 59 mg

MS (FAB): 699 (M + H) ⁺ , 599, 499

Example 9

N, N ¹ -Bis (tert-butoxycarbonyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4S-diol

Synthesis analogously to Example 8 from N, N ¹ -bis- (tert.-butoxycarbonyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3R, 4S-diol 25

MS (FAB): 699 (M + H) ⁺ , 599, 499

Example 10

Ν, Ν'-bis- (L-lysyl-L-valyl) -2S, 5S-diamino-l, 6-diphenylhexane-3R, 4R-diol tetrahydrochloride

Synthesis analogous to Example 2 from Example 11 MS (FAB, LiI): 761 (M + Li) ⁺ , 755 (M + H) ⁺ , 737

Example 11

N, N'-bis- (Να- <tert -butoxycarbonyl> -L-lysyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-β-R ^ R-diol-dinyrochloride 5

36 mg N, N ¹ -Bis - (<Νω-benzyloxycarbonyl-Na-tert-butoxycarbonyl> L-lysyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol (Synthesis analogous to Example 1 from Νω-benzyloxycarbonyl-Na-tert-butoxycarbonyl-L-lysine and Ν, Ν'-bis (L-valyl) -2S, 5S-diamino-l, 6-diphenyl-hexane-3R, 4R-diol dihydrochloride) were hydrogenated with palladium on charcoal as a catalyst in methanol. The pH was maintained at about 3-4 with a solution of HCl in methanol. Filtration of the catalyst and concentration gave 26 mg of product.

MS (FAB, LiI): 961 (M + Li) ⁺

(270 MHz, DMSO <D ₆ >): 0.75 (d, 5Hz, 6H); 0.78 (d, 5Hz,

6H); about 1.13-1.60 (m, about 12H); 1.38 (s, 18H); 1.88 (m,

2H); about 2.50-2.68 (M, 2H); 2.72-2.94 (m, 6H); 3.72 (m,

2H); 4.22 (rn, 2H); 4.37 (m, 2H); 4.41-4.55 (m, 4H); 4.72 (m, 2H); 6.76 (m, 2H); 7.05-7.23 (m, 16H); 7.66 (d, 8Hz,

2H); 8.15 (d, 9Hz, 2H) 25

Example 12

N, N ¹ -Bis (Na <tert -butoxycarbonyl-L-phenylalanyl-1-L-lysyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride 30

Synthesis analogous to Example 11.

MS (FAB): 1051 (M + H) ⁺ , 951 Example 13

Ν, Ν'-bis - <(2S- (1,1-dimethylethyl-suifonylmethyl) -3- (1-naphthyl) -propionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenylhexane-3R , 4R-diol

57 mg of N, N'-bis- (L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride, 95 mg (2S- (1,1-dimethylethylsulfonylmethyl) - 3- (1-naphthyl) -propionic acid (J.Med.Chem., 31, 1839, (1988), 41 mg of HOBt and 96 mg of TBTU were dissolved in 1 ml of dry DMF At RT, 0.11 ml of N-ethyldiisopropylamine was added added and stirred for 1 h. the solvent was removed by rotary evaporation, the residue is taken with 30 ml of EA and extracted with bisulfate, bicarbonate solution and water. After drying over W ^^ SO ^ was concentrated and purified the substance purified by chromatography on silica gel (DCM / Methanol 97/3)

 Yield: 31 mg

MS (FAB): 1153 (M + Na) ⁺ , 1131 (M + H) ⁺ , 716

NMR (270 MHz, DMSO <D ₆ >): 0.69 (d, 7Hz, 6H); 0.76 (d, 7Hz, 6H); 1.10 (s, 18H); 1.86 (m, 2H); 2.63-2.87 (m, 6H); 3.08 (m, 2H); about 3.25-3.44 (m, about 2H); 3.52-3.63 (m, 2H); 4.08 (m, 2H); 7.32 (d, 8Hz, 2H); 7.38-7.48 (m, 4H); 7.47-7.62 (m, 4H); 7.81 (m, 2H); 7.92 (m, 2H); 8,12-8,25 (m, 4H)

Example 14

N, N ¹ -Bis (L-seryl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride

Synthesis analogous to Example 16

MS (FAB, LiI): 973 (M + Li) ⁺ , 967 (M + H) ⁺ 30

Example 15

N, N'-bis- (tert-butoxycarbonyl) -L- (O-tert-butyl-seryl) -L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane 3R, 4R-diol

73

52 mg of Ν, Ν'-bis- (L-phenylalanyl-L-valyl) -2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol dihydrochloride were used together with 18. .g HOBt, 15.3 μΐ NEM and 35 mg of 0-tert-butyl-N-tert-butoxycarbonyl-L-serine dissolved in 1 ml of dry DMF and at. O ⁰ C mixed with 25.3 mg EDAC. The mixture was stirred at ⁰ ° C. for ¹ h, at RT overnight. The solvent was removed by rotary evaporation, the residue was taken up in EA and extracted with bisulfate, bicarbonate solution and water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel. The yield was 28 mg

MS (FAB): 1301 (M + Na) ⁺ , 1279 (M + H) ⁺ , 1261, 1179, 1079,

NMR (270 MHz, DMSO <D ₆ ): 0.78 (d, 7Hz, 6H), 0.81 (d, 7Hz, 6H), 1.06 (s, 18H), 1.38 (s, 18H) , 1.82 (m, 2H), 2.61-2.98 (m, 8H), about 3.15-3.45 (m, about 6H), 3.92 (m, 2H), 4.11 (dd, 8Hz, 6Hz, 2H), 4.47 (m, 2H), 4.63 (m, 4H), 6.58 (d, 8Hz _, 2H), 7.04-7.25 (m, 20H ), 7.46 (d, 9Hz, 2H), 7.77 (d, 8Hz, 2H), 7.83 (d, 8Hz, 2H).

Example 16

N, N'-bis (L-phenylalanine-L-valyl) -2S, 5S-diamino-1,6-diphenylhexane-SR 1 -R-diol dihydrochloride

100 mg of Ν, Ν'-bis (tert-butyloxycarbonyl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-l, 6-diphenyl-hexane-3R, 4R-diol (Example 1) were mixed with a Mixture of 2 ml of 5N HCl in dioxane and 1 ml of HCl in methanol for 30 min at RT. The volatiles were removed i.vac, the residue was washed with ether and the substance was dried in a high vacuum. Yield: 59 mg

MS (FAB): 793 (M + H) ⁺ , 775,

74

Example 17

N, N ¹ -Bis (L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride 5

Synthesis analogous to Example 16 MS (FAB): 793 (M + H) ⁺ , 775 Example 18

N, N'-bis- (L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4S-diol dihydrochloride Synthesis analogous to Example 16 MS (FAB): 793 (FIG. M + H) ⁺ , 775

Example 19 20

N, N'-bis- (L-seryl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3S, 4S-diol dihydrochloride

Synthesis analogous to Example 14 25

MS (FAB): 967 (M + H) ⁺

Example 20

N, N'-bis (L-seryl-L-phenylalanyl-L-valyl-2S, 5S-diamino-l, 6-diphenyl-hexfn-3R, 4S-diol-dihydrochloride Synthesis analogous to Example 14 MS ( FAB): 967 (M + H) ⁺

₇₅ 29 * 409

Example 21

Bis- (N- (L-phenylalanyl-L-valyl) -2S-amino-3-phenylpropyl) -aminotri-hydrochloride 5

Synthesis analogous to Example 16 from Example

MS (FAB): 776 (M + H) ⁺ Example 22

Bis- (N- (tert-butoxycarbony1-L-phenylalany1-L-valyl) -2S-amino-3-phenylpropyl) amine

Synthesis analogous to Example 6 from Example MS (FAB, LiI): 982 (M + Li) ⁺ , 976 (M + H) ⁺

NMR (270 MHz, DMSO <D _& >): 0.81 (m, 12H); 1.29 (s, 18H);

1.89 (m, 2H); about 2.45-2.98 (m, about 12H); 3.97 (m, 2H);

4.05-4.25 (m, 4H); 7.03 (d. 9Hz, 2H); 7.10-7.31 (m, 20H);

7.65 (d, 8Hz, 2H); 7.84 (d, 8Hz, 2H)

Example 23 25

Bis (N- (L-valyl) -2S-amino-3-phenylpropyl) amine trihydrochloride

Synthesis analogous to Example 16 from Example 30

MS (FAB): 482 (M + H) ⁺

Example 24

Bis- (N- (tert-butoxycarbonyl-L-valyl) -2S-amino-3-phenylpropyl) amine

Synthesis analogous to Example 16 from Example 25 MS (FAB): 682 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.73 (d, 6Hz, 6H); 0.77 (d, 6Hz,

6H); 1.38 (s, 18H); 1.65 (m, IH); 1.82 (m, 2H); 2.42-ca.

2.53 (m, about 4H); 2.64 (dd, 14Hz, 8Hz, 2H); 2.84 (dd, 14Hz,

6, Hz, 2H); 3.68 (m, 2H); 3.93 (m, 2H); 6.50 (d, 9Hz, 2H);

7.12-7.28 (m, 10H); 7.62 (d, 8Hz, 2H) 10

Example 25

Bis (N-tert-butoxycarbonyl-23-amino-3-phenylpropyl) -amine hydrochloride

9,6-tert-butoxycarbonyl-L-phenylalaninal were dissolved together with 30.5 NH ₄ OAc and 1.7 g of NaBH ₃ CN in 300 ml of methanol and stirred at RT for 6 h. With concentrated HCl was acidified to pH <2. The product fails. It was digested with diethyl ether and water, dried under high vacuum and gave as a yield of 3.1 g.

MS (FAB): 484 (M + H) ⁺ , 428, 372,

NMR (270 MHz, DMSO <D ₆ ): 1.33 (s, 18H), 2.55-2.90 (m, 8H), 3.82 (m, 2H), 6.75 (m, 2H), 7 , 12-7.325 (m; 10H).

Example 26

N, N'-bis (5S-amino-4S-hydroxy-7-methyloctanoyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride

Synthesis analogous to Example 16 MS (FAB): 643 (M + H) ⁺ , 625,

NMR (270 MHz, DMSO <D _& >): 0.92 (m, 12H), 1.43 (m, 4H), 1.60 (m, 4H), 1.74 (m, 2H), 2, 15 (m, 2H), 2.26 (m, 2H), 2.72 (dd, 14Hz, HHz, 2H), 2.93 (m, 2H), 3.12 (dm, 2H), 3.44 (m; 4H), 4.03 (m, 2H), about 4.85 (m, about 4H), 7.13-7.38 (m, 20H), 7.82 (m, 6H), 8.13 (d, 9Hz, 2H).

Example 26a

N, N ¹ -Bis (N-tert-butoxycarbonyl-5S-amino-7-methyl-4S- (tert -butyl-dimethyl-silyl) oxy-octanoyl) -2S, 5S-diamino-1,6-diphenyl hexane-3S, 4S-diol

88.5 mg of N, N'-bis- (tert-butyloxycarbonyl-23,5S-diamino-1,6-diphenyl-hexane-3S, 4S-dioi were treated for 30 min at RT with 2 ml of 5N HCl in dioxane The volatiles were removed in vacuo and the residue was dried under high vacuum to give the resulting 2S, 5S-diamino-1,6-diphenylhexane-3S, 5S-diol dihydrochloride with 211 mg of N-tert-butyloxycarbonyl-5S - amino-7-methyl-4S- (tert -butyldimethylsilyl) -oxy-octanoic acid, (synthesis of (5S) -5 - <(1S) -1- (N-Boc-amino) -3-methylbutyl> dihydrofuran-2 (3H) -one (AH Fray et al, J. Org. Chem. 51 (1986), 4828-4833) analogously to the preparation of 5- (t-Boc-amino) -4- <tert-butyldimethylsilyl ) Oxy> -6- (phenylmethyl) hexanoic acid (BE Evans et al., J. Org. Chem. 50, (1985), 4615-4625)), 72 mg HOBt and 28.5 μM NEM in 5 ml dissolved dry DMF. At ⁰ ° C, 101 mg EDAC was added. The solution was stirred for ¹ h at C ⁰ C, then at RT overnight. The solvent was removed by rotary evaporation, the residue was taken up in EA and extracted with KHSO ₄ , NaHCO ₃ and NaCl solutions. After drying the organic phase was concentrated and the residue purified by chromatography on silica gel (DCM / acetonitrile 5/1).

 Yield: 129 mg

MS (FAB): 1093 (M + H) ⁺ , 1071 (M + H) ⁺ , 971, 871,

NMR (270 MHz, DMSO <D ₆ >): 0.02 (s, 6H), 0.08 (s, 6H), 0.77-0.93 (m, 30H), about 1.1-1 , 4 (m, about 6H), 1.45-1.63 (m, 4H), 1.91 (m, 2H), 2.02-2.16 (m, 2H), 2.67 (d , HHz, 14Hz, 2H), 3.36 (m, 2H), 3.42-3.56 (m, 4H), 3.95 (m, 2H), 4.81 (d, 6Hz, 2H), 6.44 (d, 8Hz, 2H), 7.08-7.30 (m, 10H), 7.79 (d, 9Hz, IH).

Example 27

N, N'-bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -3S, 6S-diamino-l, 8-di- (4-pyridyl) -octane-4R, 5R-diol

Synthesis analogous to Example 6 from 3S, 6S-diamino-1,8-di-

(4-pyridyl) octane-4R, 5R-diol tetrahydrochloride 15

NMR (270 MHz, DMSO <D ₆ >): 0.85 (d, 6Hz, 12H); 1.20 (s, 18H); 1.66 (m, 2H); 1.78 (m, 2H); 2.00 (m, 2H); about 2.48 (m, 4H); 2.74 (m, 2H); 2.98 (m, 2H); about 3.31 (m, 2H); 4.08 (m, 2H); 4.19 (m, 2H); 4.30 (m, 2H); 4.68 (m, 2H); 7.01 (d, 8Hz, 2H); 7.10-7.30 (m, 14H); 7.62 (d, 8Hz, 2H); 7.74 (d, 8Hz, 2H); 8.43 (d, 4.8 Hz, 4H)

MS (FAB): 1023 (M + H) ⁺ , 923, 823 Example 27a

3S, 6S-diamino-l, 8-di- (4-pyridyl) -octane-4R, 5R-dioltetrahydrochlorid

Synthesis analogous to Example 2, 2b, 2c and 2e starting from 1,2R-5R, 6-diepoxy-3,4-0-isopropylidene-3R, 4R-diol and 4-picolyl lithium

NMR (270 MHz, DMSO <D ₆ >: 1.87-2.20 (m, 4H); 3.10 (ir., 4H); 3.29 (m, 2H); 3.84 (d, 6Hz, 2H 3,3-4,5 ('> r, ca. 4H); 8,07 (d, 7Hz, 4H); 8,18 (.'n, 6H); 8,88 (d, 7Hz , 4H)

MS FAB: 331 (M + H) ⁺

Example 28

N, N'-bis (2S- <2S-amino-3-phenyl-propyl> -amino-3-methylbutanoyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol tetrahydrochloride

Synthesis analogous to Example 16

MS (FAB): 765 (M + H) ⁺ 10

Example 29

N, N ¹ -Bis (2S- <2S-tert-butoxycarbonylamino-3-phenyl-propyl> amino-3-methyl-butanoyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S diol

50 mg of N, N ¹ -bis- (tert.-butoxycarbonyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3 S, 5-diol analogously to Example 8, the protective groups have been removed. The resulting 2S, 5S-diaminol, 6-diphenyl-hexane-3S, 5S-diol dihydrochloride was treated with 70 mg of 2S- (2S-tert-butoxycarbonylamino-3-phenyl-propyl) -amino-3-methyl-butanoic acid ( Synthesis by reductive coupling of tert-butoxycarbonyl-L-phenylalaninal and L-valine methyl ester hydrochloride with NaBH ₃ CN <RF Borch et al., J. Am. Chem. Soc., 93 (1971), 2897-2904> followed by usual methyl ester cleavage), 41 mg HOBt and 12.6 μg NEM dissolved in 5 ml L-octane DMF. At ⁰ ° C, 57 mg EDAC was added. The mixture was stirred at ⁰ ° C. for 1 h, at RT overnight. The DMF was i. Vac. removed, the residue taken up in DCM and washed with KHSO4, NaHCO ₃ and NaCl solution. After drying and concentration, the residue was triturated with diethyl ether

 Yield: 33 mg

MS (FAB): 965 (M + H) ⁺ , 865, 765

80

NMR (270 MHz, DMSO <D ₆ >): 0.74 (d, 7Hz, 6H); 0.78 (d, 6Hz, 6H); 1.33 (s, 18H); 1.63 (m, 2H); 1.94-2.16 (m, 4H); about 2.5 (m, about 4H); 2.64 (m, 2H); 2.81 (dd, 14Hz, 5Hz, 2H); 3.13 (dm, 14Hz, 2H); 3.42 (m, 2H); 3.56 (m, 2H); 4.10 (m; 2H); 4.90 (m, 2H); 6.58 (d, 9Hz, 2H); 7.05-7.30 (m, 20H); 7.85 (d, 8Hz, 2H)

Example 30

N, N ¹ -bis (L-phenylalanine-L-valyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride Synthesis analogous to Example MS (FAB): 793 (M + H) ⁺ Example 31

N, N ¹ -Bis (L-phenylalan- ¹ -L-valyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride

Synthesis analogous to Example

MS (FAB): 793 (M + H) ⁺ 25

Example 32

N, N'-bis (L-phenylalanyl-L-valyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3R, 4S-diol dihydrochloride 30

Synthesis analogous to Example MS (FAB): 793 (M + H) ⁺ Example 33

Ν, Ν ¹ -3is (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3R, 4R-diol

a 39 * 409

Synthesis analogous to Example 6

MS (FAB): 993 (M + H) ⁺ , 893, 793

NMR (270 MHz, DMSO <D _& >): 0.48 (d, 7Hz, 6H); 0.54 (d, 6Kz, 6H); 1.25 (s, 18H); 1.70 (m, 2H); 2.60 (t, 13Hz, 2H); 2.74 (dd, 14Hz, HHz, 2H); 2.96 (Jd, 13Hz, 4Hz ₄ 2H); 3.13 (dm, 14Hz, 2H); 3.39 (m, 2H); 4.02-4.25 (m, 6H); 4.88 (d, 4Hz, 2H); 7.02 (d, 9Hz, 2H); 7.07-7.33 (m, 20H); 7.60 (d, 9Hz, 2H); 8.24 (d, 9Hz, 2H);

Example 34

N, N'-bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3S, 4S-diol

Synthesis analogous to Example 6

MS (FAB): 993 (M + H) ⁺ , 893, 793 20

Example 35

N, N'-bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3R, 4S-diol 25

Synthesis analogous to Example 6

MS (FAB): 993 (M + H) ⁺ , 893, 793 Examples 36-38

36) Ν, Ν'-bis- (tert-butoxycarbonyl) -2R, 5R-diamino-l, 6-diphenyl-hexane-3R, 4R-diol

37) N, N'-bis (tert-butoxycarbonyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3S, 4S-diol

38) Ν, Ν'-bis- (tert-butoxycarbonyl) -2R, 5R-diamino-1,6-diphenyl-hexane-3R, 4S-diol

29 *** 9 ·

Synthesis analogous to Examples 3-5 from tert-butoxycarbonyl-D-phenylalaninal. The MS and NMR data correspond to those of their enantiomers from Examples 3-5.

Example 39

N, N'-bis- (L- (1-naphthyl) alanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3R, 4R-diol dihydrochloride

Synthesis analogous to Example

MS (FAB, LiI): 899 (M + Li) ⁺ , 893 (M + H) ⁺ ,

Example 40

N, N'-B i s- (tert -butoxycarbonyl-L- (1-naphthyl) alanyl-L-valyl) -2 S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 20

MS (FAB): 1093 (M + H) ⁺ ,

NMR (270 MHz, DMSO <D ₆ >): 0.76 (m, 12H); 1.23 (s, 18H); 1.89 (m, 2H); 2.60-2.87 (m, 4H); 3.12 (dd, 14Hz, 10Hz, 2H); about 3.33 (m, 2H); 3.52 (dm, 4Hz, 2H); 4.16-4.35 (m, 4H); 4.44 (in, 2H); 4.70 (s, 2H); 7.00-7.27 (m, 12H); 7.37-7.44 (m, 4H); 7.46-7.68 (m, 8H); 7.79 (m, 2H); 7.92 (d, 8Hz, 2H); 8.13 (d, 8Hz, 2H)

Example 41

N, N ¹ -is - [(2- (2-hydroxyethyl-sulfonylmethyl) -3-phenyl-propionyl) -L-valyl] -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol 35

Synthesis analogous to Example

MS (FAB): 1007 (M + H) ⁺

83

Example 42

N, N ¹ -Bis [L-phenylalanyl-L-valyl] -2S, 5S-diamino-1,6-dicyclohexyl-hexane-3R, 4R-diol dihydrochloride 5

Synthesis analogous to Example 16 MS (FAB): 805 (M + H) ⁺ , 787 Example 43

Ν, Ν'-Bis- [L-phenylalanyl-L-valyl] -2S, 5S-diamino-l, 6-dicyclohexyl-hexane-SS, 4S-diol dihydrochloride Synthesis analogous to Example 16 MS (FAB): 805 (M + H) ⁺ , 787

Example 44

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalan-1-j-valyl) -2 S, 5S-diamino-1,6-dicyclohexyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 25

MS (FAB): 1005 (M + H) ⁺ , 987 905,

Example 45

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-1, 6-dicyclohexyl-hexane-SS 4 S-diol Synthesis analogous to Example 6 MS (FAB): 1005 (M + H) ⁺ , 987, 905,

NMR (270 MHz, DMSO <D _& >): 0.86 (m, 12H); 0.99-1.67 (m, ca. 24H); 1.28 (s, 18H); 1.74 (m, 2H); 1.98 (m, 2H); 2.75 (dd,

14Hz, HHz, 2H); 2.96 (dd, 14Hz, 4Hz, 2H); 3.23 (m, 2H); 3.89 (m, 2H); 4.13-4.25 (m, 2H); 4.42 (d, 5Hz, 2H); 7.02 (d, 8Hz, 2H); 7.13-7.32 (m, 10H); 7.69-7.81 (m, 4H)

Example 46

N, N'-bis- (tert-butoxycarbonyl) -2S, 5S-diamino-1,6-dicyclohexyl-hexane-3S, 4S-diol

200 mg N, N ¹ -bis- (tert.-butoxycarbonyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3S, 4S-diol were dissolved in 25 ml of glacial acetic acid and mixed with 100 mg of platinum dioxide as a catalyst for 18 h hydrogenated at 60 ⁰ C and 120 bar. After filtering off the catalyst, the solvent was i. Vac. removed and the residue recrystallized from ethanol / water. Yield: 150 mg

MS (FAB): 535 (M + Na) ⁺ , 513 (M + H) ⁺ , 413

NMR (270 MHz, DMSO <D _& >): 0.75 (m, 2H); 0.94 (m, 2H); 1.03-1.32 (m, 10H); 1.38 (s, 18H); 1.44 (m, 2H); 1.50-1.73 (m, 8H); 1.80 (m, 2H); 3.22 (m, 2H); 3.53 (m, 2H), 4.28 (d, 6Hz, 2H); 6, -18 (d, 9Hz, 2H)

Example 47

N, N ¹ -Bis (tert-butoxycarbonyl) -2S, 5S-diamino-1,6-dicyclohexyl-hexane-3R, 4R-diol

Synthesis analogous to Example 46 MS (FAB): 513 (M + H) ⁺ , 413

NMR (270 MHz, DMSO <D ₆ >): 0.65-0.96 (m, 4H); 1.03-1.28 (m, 10H); 1.30-1.45 (m, 20H); 1.54-1.70 (m, 8H); 1.82 (m, 2H); 3.11 (m, 2H); 3.89 (m, 2H); 4.22 (m, 2H); 5.88 (d, 9Hz, 2H)

85 Example 48

N, N ¹ -Bis (tert-butoxycarbonyl) -2S, 5S-diamino-1,6-dicyclohexyl-hexane-3R, 4S-diol 5

Synthesis analogous to Example 46

MS (FAB): 513 (M + H) ⁺ , 413 Example 49

N, N'-bis (4 Z-aminocyclohexancarbonyl-L-phenylalanyl-L-valyl) -2S, 5S-diamino-l, 6-diphenyl-3 S, 5-diol dihydrochloride

Synthesis analogous to Example 16 or MS (FAB): 1043 (M + H) ⁺ , 1025

Example 50

N, N ¹ -Bis (4Z-N-tert-butoxycarbonylamino) -cyclohexanecarbony1-L-phenylalanine ¹ -L-valyl) -2S, 5S-diamino-1,6-diphenyl-3S, 5S-diol dihydrochloride

Synthesis analogous to Example 6

MS (FAB): 1243 (M + H) ⁺ , 1143, 1043

Example 51

N, N'-bis - <(2S- (1,1-dimethylethyl-sulfonylmethyl) -3- (1-naphthyl) -propionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenylhexane-3S , 4-diol

Synthesis analogous to Example MS (FAB): 1131 (14 + H) ⁺ , 716

NMR (270 MHz, DMSO <D6>): 0.77 (d, 7Hz, 6H); 0.80 (d, 7Hz,

6H); 1,12 (S, 18H); 1.87 (m, 2H); 2.75 (see 2H); 2.83 (m,

2H); 2.92-3.03 (m, 2H); 3.10-3.22 (m, 2H); about 3.27-3.49 (in,

6H); 3.54-3.67 (m, 2H); 4.02-4.15 (m, 4H); 4.66 (d, 6Hz,

2H), 7.01-7.09 (m, 2H); 7.10-7.25 (m, 8H); 7.28-7.43 (m,

4H); 7.48-7.68 (m, 6H); 7.79 (d, 8Hz, 2H); 7.88-7.95 (m 2H); 8.15-8.25 (m, 4H)

Example 52

N, N ¹ -Bis - <(2S- (1,1-dimethylethylsulfonylmethyl) -3-phenylpropionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 13

MS (FAB): 1053 (M + Na) ⁺ , 1031 (M + H) ⁺

NMR (270 MHz, DMSO <D6>): 0.72 (d, 7Hz, 6H); 0.78 (d, 7Hz, 6H); 1.14 (s, 18H); 1.85 (m, 2H); 2.62-2.94 (m, 8H); about 3.20-3.35 (m, about 4H); 3.53 (dd, 10Hz, 14Hz, 2H); 4.02-4.13 (m, 2H); 4.50 (m, 2H); 4.64 (M, 2H); 7.01-7.10 (m, 2H); 7.12-7.39 (m, 22H); 8.05 (d, 8Hz, 2H)

Example 53

N, N'-bis - <(3- (1,1-dimethylethyl-sulfonyl) -propionyl) -L-valyl> -2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 13

MS (FAB): 873 (M + Na) ⁺ , 851 (M + H) ⁺

NMR (270 MHz, DMSO <D6>): 0.69 (d, 6Hz, 6H); 0.73 (d, 6Hz, 6H); 1.33 (s, 18H); 1.84 (m, 2H); 2.54-2.59 (m, 6H); 2.67 (m, 2H); about 3.15-3.30 (m, 6H); 4.05 (dd, 7Hz, 9Hz, 2H); 4.47 (m, 2H); 4.63 (m, 2H); 7.06-7.21 (m, 10H); 7.30 (d, 9Hz, 2H); 7.94 (d, 8Hz, 2H)

87

Example 54

N, N ¹ - bite - <(2R- (1,1-dimethylethylsulfonylmethyl) -3- (2-thienyl) -propionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenylhexane-3R , 4R-diol

Synthesis analogous to Example

MS (FAB): 1065 (M + Na) ⁺ , 1049 (M + Li) ⁺

WR (270 MHz, DMSO <D6>): 0.51 (d, 7Hz, 6H); 0.56 (d, 7Hz, 6H); 1.28 (s, 18H); 1.85 (m, 2H); 2.95-3.19 (m, 8H); 3.30-3.60 (m, 8H); 3.95 (dd, 8Hz, 5.2Hz, 2H); 4.06 (m, 2H); 4.62 (d, 7Hz, 2H); 6.93 (d, 3.2Hz, 4H); 7.08-7.25 (m, 10H); 7.34 (m, 2H); 7.43 (d, 8.4Hz, 2H); 3.14 (d, 8Hz, 2H);

Example 55

N, N'-bis <L-phenyialanyl-L-valyl) -4S, 7S-diamino-2,9-dimethyldecan-5,6-diol dihydrochloride

Synthesis analogous to Example 16 from Example

MS (FAB): 725 (M + H) ⁺ 25

Example 56

N, N'-bis (tert-butoxycarbonyl-L-phenylalanine-L-valyl) -4S, 7S-diamino-2,9-dimethyl-decane-5,6-diol dihydrochloride

Synthesis analogous to Example 6 or Examples 3-5

MS (FAB): 925 (M + H) ⁺ . 826. 35

NMR (270 MHz, DMSO <D6>): 0.75-0.95 (m, 24H); 1.29 (s, 18H); 1.35-1.45 (m, 4H); 1.56 (m, 2H); 1.99 (m, 2H); 2.74 (dd,

10Hz, 13Hz, 2H); 2.95 (dd, 4Hz, 13Hz, 2H); 3.23 (m, 2H); 3.88 (m, 2H); 4.13-4.28 (m, 4H); 4.45 (d, 5Hz, 2H); 7.02 (8d, 8Hz, 2H); 7.13-7.33 (m, lOH); 7.76 (d, 8Hz, 2H); 7.80 (d, 8Hz, 2H) 5

Example 57

N, N'-bis - <(2S- (1,1-dimethylethylsulfonylmethyl) -3-phenylpropionyl) -L-valyl> -4S, 7S-diamino-2,9-dimethyl-decane-3,4-diol

Synthesis analogous to Example 13 or Examples 3-5

KS (FAB): 985 (M + Na) ⁺ , 963 (M + H) ⁺

NMR (270 MHz, DMSO <D6>): 0.78 (d, 7Hz, 6H); 0.80-0.93 (m, 18H); 1.15 (s, 18H); 1.20-1.68 (m, 6H); 1.98 (m, 2H); 2.58 (dd, 10Hz, 14Hz, 2H); 2.73 (dd, 14Hz, 3Hz, 2H); 2.98 (dd, 14Hz, 4Hz, 2H); 3.23 (m, 2H); about 3.33 (m, 2H); 3.47-3.61 (m, 2H); 3.85 (m, 2H); 4.14 (m, 2H); 4.44 (d; 5Hz, 2H); 7.15-7.33 (m, 10H); 7.69 (d, 9Hz, 2H); 8.22 (d, 9Hz, 2H)

Example 58

N, N'-bis - <(2-pyridyl) acetyl-L-valyl> -2S, 5S-diamino-l, 6-diphenyl-hexan-3R, 4R-diol

74 mg of 2S, 5S-diamino-l, 6-diphenyl-hexane-3R, 4R-diol dihydrochloride and 68 mg of 2-pyridylacetic acid hydrochloride were dissolved in 2 ml of DMF and admixed with 53 mg of HOBt, 125 mg of TBTU and 0.221 ml of diisopropylethylamine , The mixture was stirred at RT for 2 h and worked up as usual. Chromatography on silica gel (DCM / MeOH 95/5 to 90/10) gave 68 mg of product.

MS (FAB): 759 (M + Na) ⁺ , 737 (M + H) ⁺

398409

NMR (270 MHz, DMSO <D6>): 0.70 (2d, 12H); 1.88 (m, 2H); 2.62 (dd, 14Hz, 5Hz, 2H); 2.77 (dd, 14Hz, 10Hz, 2H); 3.72 (m, 4H); 4.13 (dd, 6Hz, 9Hz, 2H); 4.46 (m, 2H); 7.05-7.23 (m, 1 OH); 7.28-7, ^ 0 (m, 4H); 7.48 (d, 9Hz, 2H); 7.82 (dt, 8Hz, 2Hz, 2H); 7.97 (d, 9Hz, 2H); 8.54 (m, 2H)

Example 59

N, N ¹ -Bis - <(4-pyridyl-thio) -acetyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

74 mg of 2S, 5S-diamino-l, 6-diphenyl-hexane-3R, 4R-diol dihydrochloride and 66 mg of 4-pyridylmercaptoacetic acid were dissolved in 2 ml of DMF and admixed with 53 mg HOBt, 125 mg TBTU and 0.177 ml diisopropylamine. The mixture was stirred for 2 h at RT, the solvent was removed i. Vac. and stirred the residue for 30 min between EE and NaHCO ₃ solution. The insoluble matter was filtered off and washed with EA and water. The crude product was dissolved in warm DMF, the solution filtered and stirred in EA. The precipitate was filtered off with suction and dried. Yield: 76 mg

MS (FAB): 801 (M + H) ⁺

NMR (270 MHz, DMSO <D6>): 0.68 (2d, 12H); 1.84 (m, 2H); 2.62 (dd, 14Hz, 5Hz, 2H); 2.78 (dd, 14Hz, 9Hz, 2K); 3.28 (m, 2H); 3.73 (d, 15Hz, 2H); 3.90 (d, 15Hz, 2H); 4.17 (dd, 6Hz, 9Hz, 2H); 4.43 (m, 2H); 4.70 (m, 2H); 7.05-7.20 (m, 10H); 7.30 (m, 4H); 7.58 (d, 9Hz, 2H); 8.03 (d, 9Hz, 2H); 8.34 (m, 4H)

Example 60

N, N'-bis- <L -phenylalanyl-D-valyl> -2S, 5S-diamino-l, 6-diphenylhexane-3S, 4S-diol dihydrochloride 35

Synthesis analogous to Example 16

MS (FAB): 793 (M + H) ⁺

go

Example 61

N, N'-bis- <D-phenylalanyl-L-valyl> -2S, 5S-diamino-1, 6-diphenylhexane-3S, 4S-diol dihydrochloride 5

Synthesis analogous to Example 16

MS (FAB): 793 (M + H) ⁺ Example 62

N, N ¹ - bis- <tert -butoxycarbonyl-L-phenylalkyl- ¹ -valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol

Synthesis analogous to Example 6

MS (FAB): 993 (M + H) ⁺ , 893, .793

NMR (270 MHz, DMSO <D6>): 0.42 (d, 7Hz, 6H); 0.47 (d, 7Hz, 6H); 1.26 (s, 18H); 2.58 (m, 2H); 2.73 (m, 2H); 2.98 (dd, 13Hz, 5Hz, 2H); 3.16 (m, 2H); 3.40 (m, 2H); 4.00-4.32 (m, 6H); 4.85 (d, 5Hz, 2H); 6.86 (d, 9Hz, 2H); 7.07-7.30 (m, 20H); 7.74 (d, 9Hz, 2H); 8.19 (d, 9Hz, 2H)

Example 63

N, N ¹ -Bis-tert-butoxycarbonyl-D-phenylalanyl-L-valyl-2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol

Synthesis analogous to Example 6

MS (FAB): 1015 (M + Na) ⁺ , 993 (M + H) ⁺ , 893, 793

NMR (270 MHz, DMSO <D ₆ >): 0.72, (d, 7Hz, 12Hz); 1.30 (s, 18H); 1.84 (s, 2H); 2.65-2.82 (m, 4H); 2.88-3.02 (m, 4H); 3.37 (m, 2H); 4.00-4.13 (m, 4H); 4.28 (m, 2H); 4.63 (d, 7Hz, 2H); 6.96 (d, 8Hz, 2H); 7.05-7.35 (m, 20H); 7.59 (d, 8Hz, 2H); 7.82 (d, 9Hz, 2H)

91

Example 64

N ₇ N ¹ - bis- <L-phenylalanine-1-glycyl> -2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride 5

Synthesis analogous to Example MS (FAB): 709 (14 + H) ⁺ Example 65

N, N-bis- ^l <L-phenylalanyl-L-isoleucyl> -2S, 5S-diamino-l, 6-diphenyl-hexan-3S, 4S-diol dihydrochloride Synthesis analogous to Example MS (FAB): 821 (M + H) ⁺

Example 66

N, N ¹ - bis- <L-leucyl-glycyl> -2S, 5S-di-amino-1,6-di-phenyl-hexane-3S, 4S-diol dihydrochloride

Synthesis analogous to Example 25

MS (FAB): 641 (M + H) ⁺

Example 67

N, N'-bis- <tert-butoxycarbonyl-L-phenylalanyl-glycyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol Synthesis analogous to Example 6 MS (FAB): 931 (cf. M + Na) ⁺ , 909 (M + H) ⁺ , 809,

92 jeg / 109

NMR (270 MHz, DMSO <D ₆ >): 1.38 (s, 18H); 2.58-2.78 (m, 4H); 2.92-3.09 (m, 4H); 3.43-3.62 (m, 4H); 3.78 (dd, 16Hz, 5Hz, 2H); 4.05 (m, 2H); 4.19 (m, 2H); 4.83 (d, 5Hz, 2H); 6.92 (d, 9Hz, 2H); 7.10-7.29 (m, 10H); 7.9.0 (d, 9Hz, 2H); 8.01 (m, 2H)

Example 68

N, N'-bis- <tert -butoxycarbonyl-L-phenylalanyl-L-isoleucyl> 2S, 5S-diamino-1, 6-diphenyl-hexane-3S, 4S-diol

Synthesis analogous to Example 6

MS (FAB): 1021 (M + H) ⁺ , 921, 821 15

NMR (270 MHz, DMSO <D ₆ >): 0.70-0.85 (m, 12H); 1.03 (m, 2H); 1.29 (s, 18H); 1.37 (m, 2H); 1.65 (m, 2H); 2.68-2.80 (m, 4H); 2.84-3.04 (m, 4H); 3.39 (m, 2H); 4.00-4.13 (m, 4H); 4.20 (m, 2H); 4.64 (d, 7Hz, 2H); 7.02 (d, 9Hz, 2H); 7.05-7.33 (m, 20H); 7.62-7.73 (m, 4H)

Example 69

N, N-bis ¹ <t-butoxycarbonyl-L-leucyl-glycyl> 2S, 5S diaminol, 6-diphenyl-hexane-3S, 4S-diol

Synthesis analogous to Example 6

MS (FAB): 863 (M + Na) ⁺ , 841 (M + H) ⁺ , 741, 641

NMR (270 MHz, DMSO jp ₆ ): 0.83 (d, 6Hz, 6H); 0.87 (d, 6Hz, 6H); 1.38 (s, 18H); about 1.42 (m, 4H); 1.60 (m, 2H); 2.6.2 (dd, 14Hz, 10Hz, 2H); 3.03 (dm, 14Hz, 2H); 3.44 (m, 2H); 3.52 (dd, 16Hz, 5Hz, 2H); 3.72 (dd, 16Hz, 5Hz, 2H); 3.90-4.08 (m, 4H); 4.79 (d, 5Hz, 2H); 6.93 (d, 9Hz, 2H); 7.10-7.28 (m, 10H); 7.78-7.90 (m, 4H)

93

Example 70

N, N'-bis- <L-phenylalanyl-L-seryl> -2S, 5S-diamino-1, 6-diphenylhexane-3S, 4S-diol dihydrochloride 5

Synthesis analogous to Example 16

MS (FAB): 769 (M + H) ⁺ Example 71

N, N'-bis- <5S-amino-4S-hydroxy-7-methyl-2R-propyl-octanoyl> 25,5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride 56 mg 2S , 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride and 134 mg of N-tert-butoxycarbonyl-5S-amino-7-methyl-2R-propyl-4S- (tert-butyl-dimethylsilyl) oxy) -octanoic acid were dissolved in 3 ml of DMF and admixed with 43 mg of HOBt, 101 mg of TBTU and 155 mg of diisopropylethylamine. The mixture was stirred for 4 h at RT, the solvent was removed i. Vac. and partitioned the residue between DCM and water. The organic phase was extracted with KHSO ₄ , NaHCO ₃ solution and water. After drying over anhydrous sodium sulfate, the mixture was concentrated and the residue was chromatographed on silica gel (cyclohexane / EA 3/1). As yield was obtained <(tert-butyl-dimethylsilyl-oxy.) N-tert-butoxycarbonyl. 5S- ^{amino-7-methyl-1-2R-propyl-4S-.} Octanoyl> 157 mg N, N'-bis - 2S, 5S-diamino-1,6-diphenyl-hexan-3S, 4S-diol dihydrochloride. Treatment with HCl in dioxane analogously to Example 16 gave the product.

The coupling component N-tert-butoxycarbonyl-5S-amino-7-methyl-2R-propyl-4S- (tert-butyl-dimethylsilyl-oxy) octanoic acid was prepared analogously to the description in Example 27.

The starting material (5S) -5 - <(1S) -1- (N-Boc-amino) -3-methylbutyl:> dihydrofuran-2 (3H) -one was additionally alkylated with allyl bromide and then hydrogenated (analogously to the illustration of Compound 11 in Fray et al.)

MS (FAB): 727 (M + H) ⁺

NMR (270 MHz, DMSO <D6>): 0.80-0.88 (m, 18H); 1.08-1.74 (m, 18H); about 2.55 (m, 2H); 2.72-2.88 (m, 4H); 3.02-3.18 (m, 4H); 3.48 (d, 7Hz, 2H); 3.99 (m, 2H); 7.10-7.19 (m, 2H); 7.20-7.32 (m, 10H); 7.74 (m, 6H); 8.16 (d, 9Hz, 2H)

Example 72

N, N'-bis- <L-phenylalanyl-L-cyclohexylglycyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride Synthesis analogous to Example 16 MS (FAB): 873 (M + H) ⁺ Example 73

N, N'-bis- <tert -butoxycarbonyl-L-phenylalanyl-L-cyclohexylglycyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 MS (FAB): 1073 (M + H) ⁺ , 973, 873

NMR (270 MHz, DMSO <D ₆ >): 0.82-1.66 (m, ca 22H); 1.29 (s, 18H); 2.56-2.97 (m, 8H); about 3.30 (m, 2H); 4.08-4.22 (m, 4H); 4.50 (m, 2H); 4.63 (m, 2H); 7.02 (d, 9Hz, 2H); 7.04-7.32 (m, 20H); 7.47 (d, 9Hz, 2H); 7.56 (d, 9Hz, 2H)

Example 74

N, N'-bis <L-methionyl-L-valyl> -2S, 5S-diamino-l, 6-diphenylhexane-3S, 4S-diol dihydrochloride

Synthesis analogous to Example 16 MS (FAB): 761 (M + H) ⁺

95 2S8403

Example 75

N _, N'-bis- <tert -butoxycarbonyl-L-methionyl-L-valyl> -2S _/ 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol 5

Synthesis analogous to Example 6

MS (FAB): 961 (M + H) ⁺ , 861, 761

NMR (270 MHz, DMSO <D ₆ >): 0.75 (d, 6Hz, 12H); 1.38 (s, 18H); 1.70-1.90 (m, 6H); 2.02 (s, 6H); about 2.37-2.5 (m, 4H); about 3.32 (m, 2H); 3.94-4.10 (m, 6H); 4.63 (d, 7Hz, 2H); 7.04-7.20 (m, 12H); 7.49-7.59 (m, 4H)

Example 76

N, N ^l -Bis - <(0-methyl-tyrosyl) -L-valyl> -2S, 5S-diamino-l, 6-diphenyl-hexane-3S, 4S-diol dihydrochloride

Synthesis analogous to Example 16 MS (FAB): 853 (M + H) ⁺

Example 77 25

N, N'-bis <tert.-butoxylcarbonyl- (O-methyl-tyrosyl) -L-valyl> 2S, 5S-diamino-1,6-diphenyl-hexan-3 S ₇ 4S-diol

Synthesis analogous to Example 16 30

MS (FAB): 1053 (M + H) ⁺ , 953, 853

NMR (270 MHz DMSO <D ₆ >): 0.73-0.83 (m, 12H); 1.29 (s, 12H); 1.84 (m, 2H); 2.60-3.02 (m, 8H); 3.36 (m, 2H); 3.70 (s, 6H); 3.99-4.18 (m, 6H); 4.64 (d, 6H, 2H); 6.82 (d, 9Hz, 4H); 6.93 (d, 9Hz, 2H); 7.05-7.22 (m, 14H); 7.59 (d, 9Hz, 2H); 7.65 (d, 9Hz, 2H)

96

Example 78

N, N'-bis- <L -tyrosyl-L-valyl> -2S, 5S-diamino-1, 6-diphenylhexane-3S, 4S-diol dihydrochloride 5

Synthesis analogous to Example

MS (FAB): 825 (M + H) ⁺ Example 79

N, N'-bis - <(N-tert-butoxylcarbonyl-O-tert-butyl-L-tyrosyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S- diol

Synthesis analogous to Example 6

MS (FAB): 1137 (M + H) ⁺ , 1037,

NMR (270 MHz DMSO <D ₆ >): 0.72-0.85 (m, 12H); 1.25 (s, 18H); 1.28 (s, 18H); 1.85 (m, 2H); 262-2.82 (m, 4H); 2.84-3.01 (m, 4H); 3.36 (m, 2H); 3.98-4.12 (m, 4H); 4.19 (m, 2H); 4.64 (d, 7Hz, 2H); 6.85 (d, 8Hz, 4H); 7.02 (d, 9Hz, 2H); 7.05-7.21 (m, 18H); 7.60 (d, 8Hz, 2H); 7.66 (d, 9Hz, 2H)

Example 80

ft

N, N - bis- <N -benzyloxycarbonyl-N-tert-butoxycarbonyl-L-lysyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 MS (FAB / Lil): 1229 (M + H) ⁺

Example 81

N, N'-bis- <N-benzyloxycarbonyl-N- (tert-butoxycarbonyl-L-phenylalanyl) -L-lysyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 MS (FAB): 1319 (M + H) ⁺ , 1219, 1185

NMR (270 MHz, DMSO <D6>): 1.08-1.47 (m, 30H); 2.60-2.82 (m, 6H); 2.87-3.00 (m, 6H); 3.23 (m, 2H); 4.08-4.23 (m, 4H); 4.36 (m, 2H); 4.69 (m, 2H); 4.99 (s, 4H); 6.94 (d, 9Hz, 2H); 7.04-7.40 (32H); 7.46 (i.e., 8Hz, 2U) ·. 7.69 (d, 9Hz, 2Hi

Example 82

N, N'-bis- <L-glutamyl-L-valyl> -2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride

Synthesis analogous to Example 16

MS (FAB / LiI): 763 (M + Li) ⁺ , 757 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.81 (d, 6Hz, 6H); 0.85 (d, 6Hz, 6H); 0.78-1.98 (m, 6H); 2.20-2.38 (m, 4H); 2.76 (m, 2H); 2.97 (m, 2H); about 3.35 (m, about 2H); 3.89 (m, 2H); 4.01-4.14 (m, 4H); 4.68 (d, 7Hz, 2H); 7.06-7.21 (m, 10H); 7.68 (d, 8Hz, 2H); 8.22 (m, 6H); 8.46 (d, 9Hz, 2H)

Example 83

N, N ¹ bis- (tert-butoxycarbonyl-L-glutamyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol

Synthesis of Example 84 by catalytic hydrogenation on Pd / charcoal in glacial acetic acid / water 9/1.

MS (FAB): 979 (M + Na) ⁺ , 958 (M + H) ⁺

NMR (270 MHZ, DMSO <D ₆ >): 0.70-0.82 (m, 12H); 1.38 (s, 18H); 1.62-1.93 (m, 6H); 2.17-2.29 (m, 4H); 2.74 (m, 2H); 2.95 (dm, 13Hz, 2H); about 3.35 (m, 2H); 3.90-4.09 (m, 6H); 4.12 (m, 2H); 7.00-7.20 (m, 12H); 7.48-7.62 (m, 4H)

98 pounds 38 409

Example 84

N, N'-bis - <(N-tert-butoxycarbonyl-O-benzyl-L-glutamyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol 5

Synthesis analogous to Example 6

MS (FAB): 1159 (M + Na) ⁺ , 1137 (M + H) ⁺ , 1037

NMR (270 MHz, DMSO <D ₆ >): 0.75 (d, 6Hz, 12H); 1.37 (s, 18H); 1.70-1.98 (m, 6H); 2.33-2.45 (m, 2H); 2.76 (m, 2H); 2.93 (m, 2H); about 3.3 (m, 2H); 3.94-4.08 (m, 6H); 4.60 (s, 7Hz, 2H); 5.08 (s, 4H); 7.03-7.17 (m, 12H); 7.30-7.48 (m, 10H); 7.50

(d, 8Hz, 2H); 7.58 (d, 9Hz, 2H) 15

Example 85

N, N'-bis- <glycyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride 20

Synthesis analogous to Example 16

MS (FAB): 635 (M + Na) ⁺ , 613 (M + H) ⁺ Example 86

N, N'-bis- <tert -butoxycarbonyl-glycyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6

MS (FAB): 835 (M + Na) ⁺ , 813 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.70 (d, 7Hz, 12H); 1.38 (s, 18H); 1.84 (m, 2H); 2.62 (dd, 14Hz, 4Hz, 2H); 2.87 (dd, 14Hz, 10Hz, 2H); 3.26 (m, 2H); 3.52 (d, 6Hz, 4H); 4.13 (m, 2H); 4.42 (m, 2H); 4.69 (m, 2H); 7.03 (m, 2H); 7.08-7.21 (m, 10H); 7.38 (d, 9Hz, 2H); 7.50 (d, 9Hz, 2H)

99

example

Ν, Ν ¹ -bis <L-leucyl-L-valyl> -2S, 5S-diamino-1, 6-diphenyl-hexane · 3S, 4S-diol dihydrochloride 5 Synthesis analogous to Example

MS (FAB): 747 (M + Na) ⁺ , 725 (M + H) ⁺ 10

example

Ν, Ν ¹ -bis <tert-butoxycarbonyl-L-leucyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol 15 Synthesis analogous to Example 6

MS (FAB): 947 (M + Na) ⁺ , 925 (M + H) ⁺ , 825,

NMR (270 MHz, DMSO <D ₆ >): 0.72-0.80 (m, 12H); 0.85 (d, 7Hz,

6H); 0.89 (d, 7Hz, 6H); 1.28-1.54 (m, 22H); 1.60 (m, 2H);

1.81 (m, 2H); 2.76 (dd, 13Hz, 9Hz, 2H); 2.93 (dd, 13Hz, 4Hz,

2H); about 3.33 (m, 2H); 3.92-4.09 (m, 6H); 4.60 (d, 7Hz, 2H);

7.04 (d, 8Hz, 2H); 7.05-7.20 (m, 10H); 7.48 (d, 9Hz, 4H)

example

Ν, Ν'-bis- <L- (S-dioxo) methionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride 30 Synthesis analogous to Example

MS (FAB): 847 (M + Na) ⁺ , 825 (M + H) ⁺ Example

Ν, Ν'-bis <tert.-butoxycarbonyl-L- (S-dioxo) methionyl-L-valyl> 2S, 5S-diamino-l, 6-diphenyl-hexan-3R, 4R-diol

100

238Ί03

Synthesis analogous to Example 6 MS (FAB): 1074 (M + Na) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.65-0.78 (m, 12H); 1.39 (s, 18H);

1.74-2.07 (m, 6H); 2.63 (m, 2H); 2.78 (m, 2H); 3.07 (m, 4H);

3.26 (m, 2H); 3.98-4.17 (m, 4H); 4.44 (m, 2H); 4.67 (m, 2H);

7.07-7.23 (m, 12H); 7.49 (d, 9Hz, 2H); 7.53 (d, 9Hz, 2H)

Example 91

N, N'-bis - <(2S- (1,1-dimethylethylsulfonylmethyl) -3-phenylpropionyl) -L-tert-butylglycyl> -2S, 5S-diamino-1,6-diphenylhexane-3R, 4R ~ diol 15

Synthesis analoy Example 13

MS (FAB): 1081 (M + Na) ⁺ , 1059 (M + H) ⁺

NMR (2/0 MHz, DMSO <D ₆ >): 0.83 (s, 18H); 1.12 (s, 18H); 2.39 (dd, 11Hz, 14Hz, 2H); 2.56-2.72 (m, 4H); 2.73-2.90 (m, 4H); about 3.25-3.40 (m, about 4H); 3.53 (dd, 10Hz, 14Hz, 2H); 4.20 (d, 9Hz, 2H); 4.54 (m? H); 4.62 (m, 2H); 6.98 (m, 2H); 7.07-7.36 (m, 18H); 7.47 (d, 9Hz, 2K); 7.98 (d, 9Hz _and 2H)

Example 92

N, N'-bis - <(2S- (1,1-dimethylethylsulfonylmethyl) -3-phenylpropionyl) -L-neopentylglycyl> -2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol

Synthesis analogous to Example 13

MS (FAB): 1109 (M + Na) ⁺ , 1087 (M + H) ⁺ 35

NMR (270 MHz, CDCl _3): 0.86 (s, 18H); 1.08 (dd, 8Hz, 14Hz, 2H); 1.35 (s, 18H); 1.58 (dd, 14Hz, 4Hz, 2H); 2.75-3.45 (m,

ιοί

about 8H); 3.80 (m, 2H); 4.12 (m, 2K); 5.80 (d, 8Hz, 2H); 6.27 (d, 8Hz, 2H); 7,10-7,36 (m, ca. 10H)

Example 93

N, N'-bis - <(2-S-hydroxy-3-phenylpropionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol

To 0.065 mmol Ν, Ν ¹ -Bis - <-L-valyl> -2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol hydrochloride and 33 mg S-phenyl lactic acid in 4 ml DMF were added 27 mg HOBT Add 64 mg of TBTU and then slowly 0.088 ml of diisopropylethylylamine. After 15 min at RT, the DMF was removed in vacuo, the residue taken up in EA, and extracted with KHSO 2, NaHCO 3, and water. The org. Phase was dried with MgSO 4 and concentrated, the residue triturated with ether and filtered with suction. Yield: 43 mg

MS (FAB): 795 (M + H) ⁺

NIiR (270 MHz, DMSO <D ₆ >): 0.63 (d, 7Hz, 6H); 0.67 (d, 7Hz, 6H); 1.82 (m, 2H); 2.64-2.79 (m, 4H); 2.91-3.04 (m, 4H); 3.38 (m, 2H); 3.97-4.17 (m, 6H); 4.72 (d, 6Hz, 2H); 5.77 (d, 6Hz, 2H); 7.08-7.29 (m, 20H); 7.38 (d, 9Hz, 2H); 7.85 (d, 8Hz, 2H)

Example 94

N, N'-bis - <(2S-hydroxy-4-phenylbutyryl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol

Synthesis analogous to Example 93

MS (FAB): 845 (M + Na) ⁺ , 823 (M + H) ⁺ 35

NMR (270 MHz, DMSO <D _& >): 0.73 (d, 5Hz, 6H); 0.76 (d, 5Hz, 6H); 1.76-2.00 (m, 6H); 2.55-2.78 (m, 6H); 2.98 (dm, 14Hz,

102

2H); 3.39 (m, 2H); 3.89 (m, 2H); 4.00-4.18 (m, 4H); 4.75 (d, 6Hz, 2H); 5.88 (d, 6Hz, 2H); 7.05-7.32 (m, 20H); 7.45 (d, 9Hz, 2H); 7.88 (d, 8Hz, 2H)

Example 95

N, N'-bis - <(2- (1-imidazolylmethyl) -3-phenyl-propionyl) -L-valyl-> -2S, 5S-diamino-1, 6-diphenyl-hexane-3S, 4S-diol ( from "Diastereomer 1")

35.8 mg of 2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride were treated with 90 mg of 2- (1-imidazolylmethyl) -3-phenyl-propionyl-L-valine ("diastereomer 1"). dissolved in 2 ml DMF and treated with 32 mg HOBt, 77 mg TBTU and then with 0.163 ml diisopropylethylamine at RT. The mixture was stirred for 3 h, the solvent was removed i. Vac. and partitioned the residue between EA and NaHCOg solution. The org. Phase was with half konz. NaCl solution, dried and concentrated. The residue was triturated with diethyl ether.

filtered off with suction and then chromatographed on silica gel (EA / MeOH 85/15). 57 mg of product were obtained.

MS (FAB): 923 (M + H) ⁺

The preparation of 2- (1-imidazolylmethyl) -3-phenylpropionyl-L-valine proceeded as follows: 1.53 g of benzylacrylic acid ester (J.Med.Chem., 31, 1839, (1988)) and 550 mg of imidazole were dissolved in 30 ml of EtOH dissolved and mixed under argon at RT with 40 mg NaH. After 7d, the reaction solution was poured into 50 ml of Κί ^ ΡΟ ^ solution and extracted 3x with 50 ml of methyl tert-butyl ether. The org. Phase was extracted 2x with NaHSO 2, which was aqueous; Made alkaline with K2CO3 and extracted again 2x with 50 ml of methyl tert-butyl ether. After concentration, 390 mg of ethyl 2-benzyl-3- (1-imidazolyl) propanoate are obtained. This was saponified with NaOH and using the PPA method with

103

Vinaine methyl ester coupled. The diastereomers were separated with EA / MeOH 10/1.

0.34 = diastereomer

0.18 = Diastereomer 5 Saponification with NaOH in dioxane / water resulted in the coupling components for Example 95 and

example

N, N'-bis - <(2- (1-imidazolylmethyl) -3-phenyl-propionyl) -ively 1 → 2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol (out "Diastereomer 2")

Representation see example MS (FAB): 923 (M + H) ⁺

example

N, N'-bis- <3- (4-amino-1-piperidyl-sulfonyl) -2-benzyl-propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 16

MS (FAB): 1115 (M + H) ⁺ example

N, N'-bis- <2-benzyl-3 (4-tert-butoxycarbonyl-amino-1-piperidyl-sulfonyl) -propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane 3R, 4R-diol

57 mg Ν, Ν ¹ bis <L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride and 129 mg 2-benzyl-3 (4-tert-butoxycarbonyl amino-1-piperidyl-sulfonyl) -

104

Propionic acid were dissolved in 1 ml of DMF and treated with 41 mg HOBt, 96 mg TBTU and 135 μΐ diisopropylethylamine. After min, the solvent was removed i. Vac, the residue was taken up in DCM and extracted with KHSO ₄ , KHCO ₃ and water. After drying and concentration, the viscous residue was dissolved in a little DCM / MeOH and precipitated with diethyl ether. Yield: 64 mg.

MS (FAB): 1337 (M + Na) ⁺ , 1315 (M + H) ⁺ , 1237, 1215, 1137, 1115

2-Benzyl-3 (4-tert-butoxycarbonyl-amino-1-piperidylsulfonyl) -propionic acid was synthesized in analogy to Example 1-3 according to: J. Med. Chem. 31, 1839, (1988). The intermediate of the benzylic acid ester was reacted with thioacetic acid to give 3-acetylthio-2-benzyl-propionic acid benzyl ester. Subsequent oxidation with chlorine afforded benzyl 2-benzyl-3-chlorosulfonylpropionate, which was converted to the above coupling component by coupling with 4-tert-butoxycarbonylaminopiperidine followed by hydrogenation.

Example 99

N, N'-bis- <3- (4-amino-1-piperidyl-carbonyl) -2R-benzyl-propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride

Synthesis analogous to Example 16 MS (FAB): 1043 (M + H) ⁺ Example 100

N, N'-bis- <2R-benzyl-3- (4-tert-butoxycarbonyl-amino-1-piperidyl-carbonyl) -propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl- hexane-3R, 4R-diol dihydrochloride

105

57 mg Ν, Ν ¹ -Bis <L-valyl> -2S, 5S-diamino-1 ₁ 6-diphenyl-hexane-3R, 4R-diol dihydrochloride and 129 mg 2R-benzyl-3- (4-tert. -butoxycarbonyl-amino-1-piperidyl-carbonyl) -propionic acid (synthesis by coupling 4-tert-butoxycarbonyl-amino-piperidine to 2-R-benzyl-3-carboxy-propionic acid benzyl <see reference in Example 102>) were dissolved in 1 ml of DMF dissolved and treated with 41 mg HOBt, 96 mg TBTU and then slowly added to 0.135 ml diethylisopropylamine. After 20 minutes, the solvent was i. Vac. The residue was taken up in EA and extracted with KHSO 2, NaHCO ₃ and water. The org. Phase was dried over MgSO 4 and concentrated. The residue was dissolved in a little DCM, precipitated with diethyl ether and filtered off. Yield: 64 mg

MS (FAB): 1265 (M + Na) ⁺ , 1243 (M + H) ⁺

Example 101

N, N'-bis - <(2R-benzyl-3-carboxylic) propionyl-L-valyl> 2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis from example 102 by treatment with trifluoroacetic acid 25

MS (FAB): 901 (M + Na) ⁺ , 879 (M + H) ⁺

Example 102

N, N'-bis - <(2R-benzyl-3-tert-butoxycarbonyl) -propionyl-L-valyl> -2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol

45 mg of Ν, Ν ¹ -Bis <L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride were reacted with 75 mg of 2R-benzyl-3-tert-butoxycarbonyl Propionic acid dissolved in 2 ml of DMF and 37 mg HOBt, 87 mg TBTU and 112 μΐ ethyldiisopropylamine

106

added. The mixture was stirred for 15 min at RT, the DMF i removed. Vac. The residue was taken up in EE and extracted with KHSO4, NaHCOg solution and water. The org. Phase was dried over MgSO ₄ and concentrated. The residue was triturated with diethyl ether and filtered off. Yield: 44mg

MS (FAB): 1013 (M + Na) ⁺ 991 (M + H) ⁺

NMR (270 MHz, DMSO <D _& >): 0.69 (d, 6Hz, 6H); 0.74 (d, 6Hz, 6H); 1.31 (s, 18H); 1.83 (m, 2H); 1.95 (m, 2H); 2.32-2.47 (m, 4H); 2.60-2.87 (m, 6H); 2.98 (m, 2H); 3.29 (m, 2H); 4.09 (dd, 8Hz, 7Hz, 2H); 4.46 (m, 2H); 4.64 (m, 2H); 7.02-7.31 (m, 10H); 7.38 (d, 9Hz, 2H); 7.80 (d, 8Hz, 2H)

The preparation of the carboxy-protected succinic acid derivative in enantiomerically pure form was carried out according to Evans (DAEvans et al., J. Am. Chem. Soc., 104, 1737 (1982), J. Plattner et al., J. Med. Chem., 31, 2277 (FIG. 1988)).

Example 103

N, N'-bis - <(3-amiro-2-benzyl) -propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride (from "Diastereomer 1")

Synthesis analogous to Example 16 from Example 105 MS (FAB): 843 (M + Na) ⁺ 821 (M + H) ⁺ Example 104

N, N'-bis - <(3-amino-2-benzyl) -propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride (from "Diastereomer 2 ')

107

Synthesis analogous to Example 16 from Example 106 MS (FAB): 843 (M + Na) ⁺ 821 (M + H) ⁺ . Example 105

N, N ¹ bis (2-benzyl-3-tert-butoxycarbonyl-amino) -propionyl-L-valyl-2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R- diol (from "Diastereomer 1")

37 mg of 2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride was treated with 98 mg of N, N'-bis - <(2-benzyl-3-tert-butoxycarbonyl-amino) -propionyl- L-valine coupled according to the TBTU method. After customary work-up and chromatography (DCM / methanol 98/2 to 95/5) gave 28 mg of product.

MS (FAB): 1043 (M + Na) ⁺ 1021 (M + H) ⁺ , 921, 821

The building block N, N'-bis - <(2-benzyl-3-tert-butoxycarbonylamino) -propionyl-L-valine was prepared as follows: 2.3 g of sodium were dissolved in 170 ml of EtOH and 32 ml of ethyl cyanoacetate were added. While stirring, 11.5 ml of benzyl chloride were added dropwise. The solution was at RT overnight. The NaCl was filtered off and the solvent was distilled off. The residue was dissolved in EA and extracted with K 2 O. The org. Phase was concentrated, the residue i.Vac. distilled (0.5mm / 120-125 oC). Yield: 8.1 g

The resulting benzyl cyanoacetic acid ethyl ester was dissolved in 200 ml EtOH and hydrogenated over Raney nickel. After suctioning off the catalyst and concentrating to give 8.2, oil, after chromatography on silica gel (EA to EE / MeOH 5/1) 5.5 g of 3-amino-2-benzylpropionäureethylether.

This compound was reacted with B0C2O to give 2-benzyl-3- (tert-butoxycarbony1amino) -propionic acid ethyl ester, saponified and coupled with H-VaI-OMe by the PPA method.

106

The resulting diastereomers were separated by chromatography (toluene / diisopropyl ether 1/1). Rf = O, 140 = diastereomer 1 Rf = O, 097 = diastereomer 2

Saponification with NaOH in dioxane / water resulted in the coupling components for Example 105 and 106.

Example 106

N, N ¹ -Bis - <(2R-benzyl-3-tert-butoxycarbonyl-amino) -propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol (out "Diastereomer 2")

Synthesis Analog 105 Example 15

MS (FAB): 1043 (M + Na) ⁺ , 1021 (M + H) ⁺ , 921, 821

Example 107

N, N'-bis- <0- (D-mannofuranosyl) -2S-hydroxy-3-phenyl-propionyl-valyl> -2S, 5S-diamino-1, 6-diphenyl-hexane-3R, 4R-diol

20 mg of the compound from Example 108 was stirred for 30 min at RT with methanolic hydrochloric acid. The volatiles were i. Vac. distilled off, the residue digested with diethyl ether, filtered off with suction and dried. Yield: 13 mg

NMR (270 MHz, DMSO <D ₆ >): 0.58 (d, 6Hz, 6H); 0.62 (d, 6Hz, 6H); 1.82 (m, 2H); 2.60 (dd, 4Hz, 14Hz, 2H); 2.71-2.82 (m, 4H); 2.98 (dd, 14Hz, 3Hz, 2H); about 3.25 (m, 2H); 3.30-3.49 (m, 6H); 3.58 (m, 2H); 3.67 (dd, 11Hz, 3Hz, 2H); ca 3,70-4,30 (m, ca 16H); 4.43 (m, 2H); 4.49 (d, 2Hz, 2H); 7.05-7.29 (m, 20H); 7.35 (d, 9Hz, 2H); 7.67 (d, 9Hz, 2H) 35

109

Example 107a

N, N ¹ -Bis <0- (2,3-5,6-diisopropylidene-D-mannofuranosyl) -2S-hydroxy-3-phenyl-propionyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl hexane-3R, 4R-diol

57 mg of N, N'-bis- <L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride were mixed with 10 mg of <0- (2,3-5, 6-diisopropylidene-D-mannofuranosyl) -2S-hydroxy-3-phenylpropionic acid dissolved in 1 ml of DMF and coupled by the TBTU method. Yield: 60 mg

MS (FAB): 1279 (M + H) ⁺ , 1261, 1221

NMR (270 MHz, DMSO <D ₆ >): 0.63 (d, 6Hz, 6H); 0.69 (d, 6HZ,

6H); 1.19 (s, 6H); 1.21 (s, 6H); 1.30 (s, 12H); 1.79 (m,

2H); 2.60-2.82 (m, 8H); 3.29 (m, 2H); 3.73 (dd, 8Hz, 6Hz,

2H); 3.85-3.98 (m, 4H); 4.01-4.18 (m, 4H); 4.23 (dd, 8Hz,

3Hz, 2H); 4.40 (d, 6Hz, 2H); 4.45 (m, 2H); 4.62-4.72 (m,

4H); 7.03-7.32 (m, ca 22H); 7.40 (d, 9Hz, 2H); 7.59 (d, 9Hz, 2H)

0- (2,3-5,6-diisopropylidene-D-mannofuranosyl) -2S-hydroxy-3-phenylpropionic acid was obtained by the imidate method of R.R. Schmidt from 2,3-5,6-diisopropylidene-D-mannofuranose and 2S-hydroxy-3-phenyl-propionic acid (RR Schmidt and I. Michel Angew.Chem 92,763 (1980); Angew. Chem. Int. Ed. Engl. 19, 731 (1980))

405 mg (0- (2.3 to 5.6-diisopropylidene-D-mannofuranosyltrichloracetimidat were dissolved together with 194 mg Phenylmilchsäureethylester in 15 ml of absolute CH2Cl2. It was cooled to 0 ⁰ C and sat 100 μΐ an IM BF ₃ -Etheratlösung in CH2Cl2 to. The solution was stirred for lh at 0 C ^p, ₃ solution and extracted with CH2Cl2 in 100 ml NaHCO. The org. phase was dried with Na 2 SO ^ and evaporated. After chromatography on silica gel

(Eluent: methyl tert-butyl ether / heptane (1/1)) gave 195 mg of product.

$ 29,840

110 Example 108

N, N ¹ -Bis (L-phenylalanyl-L-valyl) -3S, 6S-diamino-1,8-di- (4-pyridyl) -octane-4R, 5R-diol-tetrahydrochloride 5

Synthesis analogous to Example 16 from

MS (FAB): 823 (M + H) ⁺ Example 109

N, N'-bis <N- (ß-D-l-desoxyfructos-l-yl-L-phenylalanyl-L-valyl> 2S, 5S-diamino-1,6-diphenyl-hexan-3S, 4S-diol diacetate

69 mg Ν, Ν ¹ -Bis <L-phenylalanyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride were mixed with 79 mg D-glucose in 6 ml Suspended MeOH and 2ml pyridine and boiled for 4.5 h. The solvent was i. Vac. the residue was separated by chromatography over ®Sephadex LH20 with 10% aqueous acetic acid. Yield: 71 mg

MS (FAB): 1139 (M + Na) ⁺ , 1117 (M + H) ⁺ Example 110

Ν, Ν ¹ -Bis <D-gluconyl-L-phenylalanyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis: Treatment of the compound of Example III with ammonia-saturated methanol.

MS (FAB): 1171 (M + Na) ⁺ Example III

N, N ^l -Bis <2,3,4,5,6-penta-O-acetyl-D-gluconyl-L-phenylalanyl-L-valyl> -2 S, 5S-diamino-1,6-diphenyl-hexane 3R, 4R-diol

in

Synthesis by coupling of 2,3,4,5,6-penta-O-acetyl-D-gluconic acid (CE Braun and CD Cook, Organic Synthesis, Vol. 5, 1973, 887-889) to N, N ¹ -Bis -L-phenylalanyl-L-valyl-2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride by the TBTU method.

MS (FAB): 1569 (M + H) ⁺

example

N, N'-bis- <tert -butoxycarbonyl-L-phenylalanine-L-valyl> -1,4-diamino-butane-2R, 3R-diol

Synthesis analogous to Example 6 from 1,4-diamino-butane-2R, 3R-diol dihydrochloride

NMR (270 MHz, DMSO <D ₆ >): 0.83 (d, 6Hz, 12H); 1.31 (s, 18H);

1.93 (m, 2H); 2.73 (m, 2H); 2.91-3.07 (m, 4H); 3.28 (m, 2H);

3.42 (m, 2H); 4.18 (m, 4H); 4.57 (m, 2H); 7.02 (d, 8Hz, 2H);

7.13-7.32 (m, 10H); 7.66 (d, 8.4Hz, 2H); 8.04 (m, 2H)

MS (FAB): 835 (M + Na) ⁺ , 813 (M + H) ⁺ , 713,

Example 112a

1,4-diamino-butane-2R, 3R-diol dihydrochloride

Synthesis of (+) - 1,4-di-O-tosyl-2,3-O-isopropylidene-D-threitol analogous to Example 2, 2b and 2c 30 NMR (60 MHz, DMSO <D _& >): 2.9 (m, 4H); 3.73 (m, 2H); about 5.7-4.5 (br, about 2H); 8.1 (m, about 6H)

MS (DCI): 121 (M + H) ⁺ , 35

112

Example 113

N, N'-bis- <L-phenylalanyl-L-valyl> -l, 4-diamino-butane-2R, 3R-diol dihydrochloride 5

Synthesis analogous to Example 16 of 112

MS (FAB): 635 (M + Na) ⁺ , 613 (M + H) ⁺ Example 114

N, N'-bis <tri-benzyloxycarbonyl-L-arginyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexan-3R, 4R-diol

Synthesis analogous to Example 6

MS (FAB): 1637 (M + Na) ⁺ , 1615 (M + H) ⁺

NMR (270 MHz, DMSO <D _& >): 0.71 (d, 7Hz, 12H); 1.57 (m, 8H); 1.80 (m, 2H); 2.73 (m, 2H); 2.94 (m, 2H); 3.30 (m, 2H); 3.70-4.12 (m, 10H); 4.58 (d, 7Hz, 2H); 4.92-5.18 (m, 8H); 5.19 (s, 4H); 7.00-7.42 (m, 40H); 7.49 (d, 8Hz, 4H); 7.64 (d, 8.4Hz, 2H); 9.13 (br.s, 4H)

Example 115

N, N'-bis- tert -butyloxycarbony1-L-cyclohexylalany1-L-valyl 2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 MS (FAB): 1005 (M + H) ⁺ , 905

NMR (270 MHz, DMSO <D ₆ >): 0.67 (d, 7Hz, 6H); 0.80 (d, 7Hz, 6H); 0.80-1.84 (m, 26H); 1.42 (s, 18H); 2.13 (sept., 7Hz, 2H); 2.80 (dd, 15Hz, 9Hz, 2H); 3.35 (m, 4H); 4.03 (m, 4H); 4.30 (qd, 9Hz, 4Hz, 2H); 4.96 (d, 4Hz, 2H); 6.57 (d, PHz, 4H); 7.10-7.30 (m, 12H)

113 298 * 03

Example 116

N, N'-bis- <L -cyclohexylalanyl-L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride 5

Synthesis analogous to Example 16

MS (FAB): 805 (M + H) ⁺ , 553, 531

NMR (270 MHz, DMSO <D _& >): 0.79 (d, 7Hz .. 6H); 0.85 (d, 7Hz, 6H); 1.00-1.95 (m. 28H); 2.77 (dd, 14Hz, 7Hz, 2H); 2.93 (m, 2H); 3.37 (m, 2H); 3.89 (m, 2H); 4.09 (m, 4H); 4.70 (d, 7Hz, 2H); 7.16 (m, 10H); 7.66 (d, 8Hz, 2H); 8.17 (s, 6H); 8.47 (d, 9Hz, 2H)

Example 117

N, N ¹ -bis -benzyloxycarbonyl-L-tryptophyl-L-valyl> -2S, 5S-di-1,5-diol-1,6-diphenyl-hexane-3R, 4R-diol 20

Synthesis analogous to Example 6

MS (FAB): 1139 (M + H) ⁺ , 720

NMR (270 MHz, DMSO <D ₆ >): 0.75 (m, 12H); 1.96 (m, 2H); 2.76 (dd, 13Hz, 7Hz, 2H); 2.90-3.13 (m, 6H); 3.40 (m, 2H); 4.07 (m, 4H); 4.38 (m, 2H); 4.65 (d, 7Hz, 2H); 4.88 (d, 14Hz, 2H); 4.97 (d, 14Hz, 2H); 6.90-7.35 (m, 28H); 7.47 (d, 8Hz, 2H); 7.58 (d, 8Hz, 2H); 7.65 (d, 8Hz, 2H); 7.83 (d, 8Hz, 2H); 10.80 (s, 2H)

Example 118

N, N'-bis- <L-tryptophyl-L-valyl> -2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride

Synthesis analogous to Example 11

MS (FAB): 871 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.75 (m, 12H): 1.88 (m, 2H); 2.75 (m, 4H); 2.98 (dd, 14Hz, 2Hz, 2H); 3.13 (dd, 14Hz, 3Hz, 2H); 3.42 (m, 2H); 3.73 (m, 2H); 4.10 (m, 4H); 4.73 (d, 6Hz, 2H); 6.09-7.24 (m, 18H); 7.35 (d, 8Hz, 2H); 7.63 (d, 8Hz, 2H); 7.80 (d, 8Hz, 2H); 8.22 (s, 6H); 10.90 (s, 2H)

Example 119

N, N'-bi- H ( yloxycarbonyl-L-1,2,3,4-tetrahydro-isoquinolin-3-yl-carbonyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane 3R, 4R-diol

Synthesis analogous to Example 6

MS (FAB): 1107 (M + Na) ⁺ , 1085 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.55 (m, 12H); 1.70 (m, 2H); 2,60-

3.81 (m, 10H); 3.90 (m, 2H); 4.03 (m, 2H); 4.38-4.80 (m,

8H); 4.91-5.20 (m, 4H); 7.00-7.53 (m, 28H); 7.58 (d, 8Hz, 2H); 7.72 (d, 8Hz, 2H)

Example 120 25

N, N ¹ -Bis <L-1,2,3,4-tetrahydroisoquinolin-3-yl-carbonyl-L-valyl> -2 S, 5 S -di- diamino-1,6-diphenyl-hexane-3R, 4R diol diacetate

Synthesis analogous to Example 11 30

MS (FAB): 839 (M + Na) ⁺ , 817 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.70 (d, 7Hz, 12H); 1.86 (m, 2H); 1.92 (s, 6H); 2.64-2.89 (m, 4H); 2.92 (dd, 16Hz, 5Hz, 2H); 3.02 (dd, 13Hz, 3Hz, 2H); 3.39 (m, 2H); 3.47 (dd, 9Hz, 5Hz, 2H); 3.90 (s, 4H); 4.03 (m, 2H); 4.10 (dd, 9Hz, 5Hz, 2H); 4.74 (br.s, 2H); 7.02-7.26 (m, 18H); 7.77 (d, 9Hz, 2H); 7.85 (d, 8Hz, 2H)

115

Example 121

N, N'-bis - <{2- (benzyl-sulfinyl-methyl) -3-phenyl-propionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R ₇ 4R-diol 5

Synthesis analogous to Example 13

The synthesis of the building block (2- (benzylsulfinylmethyl) -3-phenyl-propionic acid was carried out analogously to literature: J. Med. Chem. 1 "» 31, 1839, (1988).

MS (FAB): 1089 (M + Na) ⁺ , 1067 (M + H) ⁺ , 710

NMR (270 MHz, DMSO <D ₆ >): 0.45 (m, 6H); 0.72 (m, 6H); 1.80

(m, 2H); 2.53-2.95 (m, 12H); 3.22-3.36 (m, 4H); 3.55 (m,

2H); 3.73-4.26 (m, 6H); 4.48 (m, 2H); 7.00-7.40 (m, 30H); 7.85 -8.07 (m, 4H)

Example 122

N ₇ N ¹ -bis-f. (2- (p-chlorobenzyl-thio-methyl) -3-phenyl-propionyl) L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R diol

Synthesis analogous to Example 13 25

The synthesis of the building block (2- (p-chlorobenzyl-thio-methyl) -3-phenyl-propionic acid was carried out analogously to literature: J. Med. Chem. 31, 1839, (1988).

MS (FAB): 1125 (M + Na) ⁺

NMR (270 MHz, DMSO <D _& >): 0.49 (m, 6H); 0.57 (m, 6H) - 1.80 (m, 2H); 2.10-2.33 (m, 2H); 2.38-2.60 (m, 4H); 2.62-2.83 (m, 6H); 2.95 (m, 2H); 3.28 (m, 2H); 3.65 (s, 4H); 4.03-4.17 (m, 2H); 4.45 (m, 2H); 4.54-4.67 (m, 2H); 7.00-7.50 (m, 28H); 7.64 (m, 2H); 7.88 (m, 2H)

116

Example 123

N, N'-bis - <(2- (p-chlorobenzylsulfonylmethyl) -3-phenylpropionyl) -L-valyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 13

The synthesis of the building block (2- (p-chlorobenzylsulfonylmethyl) -3-phenyl-propionic acid was carried out analogously to literature: J. Med. Chem. 31, 1839, (1988).

MS (FAB): 1191 (M + 2H + Na) ⁺ 1189 (1 - + Na ⁺ )

NMR (270 MHz, DMSO <D ₆ >): 0.52 (m, 6H); 0.74 (m, 6H); 1.83 (m, 2H); 2.42-2.95 (m, 10H); 3.28-3.54 (m, 6H); 3.90-4.70 (m, 10H); 6.98-7.47 (m, 30H); 8.03 (m, 2H)

Example 124

N, N ¹ -Bis <N-tosyl (-β-naphthyl-alanyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 25

MS (FAB): 1223 (M + Na) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.66 (m, 12H); 1.80 (m, 2H); 2.13 (s, 6H); 2.50-2.90 (m, 8H); 3.30 (m, 2H); 3.98-4.67 (m, 8H); 6,70-8,00 (m, 38H)

Example 125

N, N ¹ -Bis <N-mesyl-β-naphthyl-alanyl-L-valyl> -2S, 5S-diaminol, 6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6

117

MS (FAB): 1072 (M + Na) ⁺ , 838

NMR (270 MHz, DMSO <D ₆ >): 0.74 (m, 12H); 1.82 (s, 6H); 1.87 (m, 2H); 2.55-3.08 (m, 8H); 3.25 (m, 2H); 4.02 (m, 2H); 4.22 (m, 2H); 4.47 (m, 2H); 4.70 (m, 2H); 7.00-8.00 (m, 30H)

Example 126

N - <(2R- (1,1-dimethylethylsulfonylmethyl) -3-phenylpropionyl) -L-valyl> -N '- <(2S- (1,1-dimethylethylsulfonylmethyl) -3-phenylpropionyl) - L valyl> 2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

By-product from the synthesis of Example 52 Example 126 Rf = 0.17 (EE) Example 52 Rf = 0.35 (EE)

MS (FAB): 1053 (M + Na) ⁺

NMR (270 MHz, DMSO <D ₆ >: 0.47 (d, 7Hz, 3H); 0.48 (d, 7Hz, 3H); 0.70 (d, 7Hz, 3H); 0.75 (d, 7Hz, 3H), 1.14 (s, 9H), 1.27 (s, 9H), 1.82 (m, 2H), 2.60-3.00 (m, about 10H), 3.08 3,35 (m, ca. 3H), 3,38-3,58 (m, 3H), 3 91 (dd, 8Hz, 6Hz, IH), 4,06 (m, IH), 4,27 ( d, 5Hz, IH), 4.35-4.54 (m, 3H), 7.00-7.38 (m, 22H), 7.93 (d, 8Hz, 2H), 8.04 (d, 8Hz, 2H)

The following compounds of Examples 127-134 were obtained analogously to the syntheses according to Examples 6 and 16, respectively.

Example 127

N, N ¹ -bis <tert-butoxycarbonyl-L-valyl> -2R, 5R-diamino-1,6-diphenyl-hexane-3R, 4R-diol

MS (FAB): 699 (M + H) ⁺ , 599, 499

118

Example 128

N _, N'-bis- <tert -butoxycarbonyl-L-valyl> -2S _/ 5S-diamino-1 _/ 6-dicyclohexyl-hexane-3S, 4S-diol 5

MS (FAB / LiI): 717 (M + Li) ⁺

Example 129

N, N ¹ -bis <tert-butoxycarbonyl-L-cyclohexylglycine> -2S, 5S-diamino-l, 6-diphenyl-hexane-3R, 4R-diol MS (FAB): 801 (M + Na) ⁺ , 779 (M + H) ⁺ , Example 130

N, N ¹ -bis <tert -tactoxycarbonyl-L-asparaginyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol MS (FAB): 729 (M + H) ⁺ , Example 131

N, N'-bis <L-valyl> -2S, 5S-diamino-l, 6-dicyclohexyl-hexan-SS ^ S-diol dihydrochloride

Example 132

N, N'-bis- <N ⁶ -benzoxycarbonyl-L-lysyl> -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride

Example 133

N, N-bis ^l <glycyl> 2S, 5S diaminf - l _/ 6-diphenyl-hexane-3S _/ 4S-diol dihydrochloride

MS (FAB): 415 (M + H) ⁺ ,

119

Example 134

N, N ¹ bis- (tert-butoxycarbonyl-glycyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol 5

MS (FAB): 615 (M + H),

The following compounds of Examples 135-140 were obtained analogously to the syntheses according to Examples 23 and 24, respectively

Example 135

ilis <N- ((N-tert-butoxycarbonyl-L-lysyl) -L-leucyl) -2S-amino-3-phenyl-propyl> -amine-trihydrochloride 15

MS (FAB): 966 (M + H) ⁺

Example 136

Bis- <N- (tert-butoxycarbonyl-2S-amino-3-cyclohexyl-propyl) amine hydrochloride

MS (FAB): 496 (M + H) ⁺ Example 137

Bis- <N- (L-leucyl) -2S-amino-3-phenyl-propyl> -aminetrihydrochloride

MS (FAB): 510 (M + H) ⁺ Example 138

Bis- <N- (tert-butoxycarbonyl-L-leucyl) -2S-? .Mino- 3-phenylpropyl> -amine

MS (FAB): 710 (M + H) ⁺

120

Example 139

Bis- <2S-amino-3-phenylpropyl> -amine trihydrochloride MG (FAB): 284 (M + H) ⁺ Example 140

Bis- <N- (benzyloxycarbonyl-L-valyl) -2S-amino-3-phenyl-propyl> amine

MS (FAB): 750 (M + H) ⁺

Example 141

Bis- <N-tert-butoxycarbonyl-2S-amino-3-methyl-butyl> -amine hydrochloride

Synthesis analogous to Example 20

MS (FAB): 388 (M + H) ⁺

Example 142

N, N'-bis - <(2S- (1,1-dimethylethylsulfonylmethyl) -3- (1-naphthyl) -propionyl) -L-valyl> -3S, 6S-diamino-1,8-di ( 4-pyridyl) -octane-4R, 5R-diol

Synthesis analogous to Example 13 from 27a 30

NMR (270 MHz, DMSO <D ₆ >): 0.83 (m, 12H); 1.14 (s, 18H);

1.66 (m, 2H); 1.82 (m, 2H); 2.00 (m, 2H); 2.50-2.78 (m, 4H);

2.86 (m, 2H); 3.06-3.63 (m, 10H); 4.02 (m, 2H); 4.14 (m, 2H);

4.69 (m, 2H); 7.30-7.60 (m, 14H); 7.74 (d, 8Hz, 2H); 7.87

(m, 2H); 8.16 (m, 2H); 8.32 (d, 8Hz, 2H); 8.58 (m, 4.H)

MS (FAB): 1161 (M + H) ⁺

121

example

N, N ¹ -Bis - <(2S- (1,1-dimethylethylsulfonylmethyl) -3- (1-naphthyl) propionyl) -L-valyl> -1,4-diamino-butane-2R, 3R- Diol 5 Synthesis analogous to Example 13 from 112a

NMR (270 MHZ, DMSO <D ₆ >): 0.82 (d, 6Hz, 12H); 1.17 (s, 18H); 1.92 (m, 2H); 2.92-3.08 (m, 4H); 3.16-3.53 (m, 10H); 3.53 (dd, 12.8Hz, 8.8Hz, 2H); 4.11 (dd, 8.0Hz, 7.2Hz, 2H); 4.55 (d, 4.8Hz, 2H); 7.38-7.67 (m, 10H); 7.80 (m, 2H); 7.92 (m, 2H); 8.12 (d, 8.4Hz, 2H); 8.20 (d, 8Hz, 2H)

MS (FAB): 973 (M + Na) ⁺ ; 951 (M + H) ⁺ 15

example

N, N ¹ -Bis-tert-butoxycarbonyl-L-phenylalanyl-L-valyl-1,4-diamino-butane 20 Synthesis analogous to Example 6

NMR (270 MHz, DMSO <D ₆ >): 0.83 (d, 6Hz, 12H); 1.28 (s, 18H);

1.39 (m, 4H); 1.91 (m, 2H); 2.74 (dd, 12.8Hz, 9.6HZ, 2H);

2.89-3.16 (m, 6H); 4.08-4.23 (m, 4H); 7.02 (d, 8Hz, 2H);

7.14-7.30 (m, 10H); 7.63 (d, 8.4Hz, 2H); 7.95 (m, 2H)

MS (FAB): 781 (M + H) ⁺ , 681, JO Example

N, N'-bis <L-phenylalanyl-L-valyl> -l, 4-diamino-butane dihydrochloride

Synthesis analogous to Example 16 from MS (FAB): 581 (M + H) ⁺

122

Example 146

N, N'-bis - <(2S- (1,1-diethyl-sulfonylmethyl) -3- (1-naphthyl) -propionyl) -L-valyl> -1,4-diamino-butane 5

Synthesis analogous to Example 13

NMR (270 MHz, DMSO <D ₆ >): 0.82 (d, 6Hz, 12H); 1.19 (s, 18H);

1.32 (m, 4H); 1.89 (m, 2H); 2.98 (m, 4H); 3.32 (m, 2H);

3.42 (m, 6H); 3.54 (dd, 12.8Hz, 8Hz, 2H); 4.04 (t, J = 8Hz,

2H); 7.38 (m, 4H); 7.53 (m, 6H); 7.79 (m, 2H); 7.92 (m,

2H); 8.08 (d, 8Hz, 2H); 8.21 (m, 2H)

MS (FAB): 941 (M + Na) ⁺ , 919 (M + H), ⁺ 15

Example 147

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalanine-L-valyl) -3S, 6S-diamino-1,8-diphenyl-octane-4R, 5R-diol

Synthesis analogous to Example 6 from

3S, 6S-diamino-1,8-diphenyl-octane-4R, 5R-diol dihydrochloride (The latter compound was prepared analogously to Example 2, 2b, 2c and 2e from 1, 2R-5R, 6-diepoxy-3,4-0 -isopropylidene-3R, 4R-diol and benzyllithium)

MS ^- (FAB (LiI)): 1027 (M + Li) ⁺ , 927, 827

NMR (270 MHz, DMSO <D6>): 0.88 (m, 12H); 1.28 (s, 18H); 1.57-1.86 (m, 4H); 2.01 (m, 2H); about 2.4-2.6 (m, about 4H); 2.75 (dd, HHz, 14Hz, 2H); 2.98 (dd, 14Hz, 4Hz, 2H); about 3.32 (m, about 2H); 4.06-4.26 (m, 4H); 4.32 (dd; 6Hz, 8Hz, 2H); 4.62 (m, 2H); 7.0 (d, 8Hz, 2H); 7.10-7.32 (m, 20H); 7.62 (d, 10Hz, 2H); 7.75 (d, 8Hz, 2H);

123 Example 148

N, N ¹ -Bis (L-phenylalanyl-L-valyl) -35,6S-diamino-1,8-diphenyl-octane-4R, 5R-diol dihydrochloride 5

Synthesis analogous to Example 16 from 147

MS (FAB): 321 (M + H) +, 843 (M + Na) +, 803 Example 149

Ν, Ν'-bis (--S- (1,1-dimethylethyl-sulfonylmethyl) -3- (1-naphthyl) -propionyl-L-valyl) -3S, 6S-diamino-1,8-diphenyl- octane-4R, 5R-diol 15

Synthesis analogous to Example 13 and 147

MS (FAB (LiI)): 1165 (M + Li) +

NMR (270 MHz, DMSO <D6>): U, 92 (d, 7Hz, 12H); 1.13 (s, 18H); 1.6-1.85 (m, 4H); 2.04 (m, 2H); 2.40-2.64 (m, 4H); 2.82 (dm, 14Hz, 2H); 3.18 (m, 2H); 3.32-3.52 (m, 6H); 3.58 (m, 2H); 4.08 (m, 2H); 4.22 (t, 8Hz, 2H); 7.1-7.56 (m, 20H); 7.72 (dd, 4Hz, 2H); 7.88 (m, 2H); 8.14 (m, 2H); 8.32 (d, 8Hz, 2H)

Example 150

N, N'-bis- (tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -6S, 9S-diamino-tetradecane-7R, 8R-diol

Synthesis analogous to Example 6 from

6S, 9S-diamino-tetradecane-7R, 8R-diol dihydrochloride (The latter compound was prepared analogously to Example 2, 2b, 2c and 2e from 1, 2R-5R, 6-diepoxy-3,4-0-isopropylidene-3R, 4R -diol and n-butyllithium are shown)

124 MS (FAB (LiI)): 959 (M + Li) ⁺

NMR (270 MHz, DMSO <D6>): 0.76-0.91 (m, 18H); 1.12-1.54 (m, 16H); 1.28 (s, 18H); 1.98 (m, 2H); 2.74 (dd, 12Hz, 14Hz, 2H); 2.87 (dd, 14Hz, 4Hz, 2H); 3.22 (m, 2H); 3.98 (m, 2H); 4,14-4,32 (m, 4H); 4.46 (s, 2H); 7.0 (d, 8Hz, ΓΗ); 7.14-7.31 (d, 4Hz, 10H); 7.38 (d, 9Hz, 2H); 7.70 (d, 9Hz, 2H)

Example 151

N, N ¹ -Bis (L-phenylalanyl-L-valyl) -6S, 9S-diamino-tetradecane-7R, 8R-diol dihydrochloride

Synthesis analogous to Example 16 from 150 MS (FAB): 753 (M + H) +, 775 (M + Na) +, 735

Example 152

Ν, Ν'-bis - (<2S- (1,1-dimethylethylsulfonylmethyl) -3- (1-naphthyl) -propionyl> -L-valyl) -6S, 9S-diamino-tetradecane-7R, 8R-diol 25

Synthesis analogous to Example 13 and 150

MS (FAB (LiI)): 1097 (M + Li) ⁺

NMR (270 MHz, DMSO <D6>): 0.76 (m, 6H); 0.88 (d, 7Hz, 12H); 1.12 (s, 18H); about 1.10-1.54 (m, 16H); 2.02 (m, 2H); 2.82 (dd, 12Hz, 2Hz, 2H); 3.16 (dd, 12Hz, 16Hz, 2H); 3.24 (m, 2H); 3.36-3.52 (m, 4H); 3.58 (dd, 8Hz, 13Hz, 2H); 3.98 (m, 2H); 4.16 (t, 6Hz, 2H); 4.44 (s, 2H); 7.18 (d, 10Hz, 2H); 7.42-7.48 (m, 4H); 7.49-7.62 (m, 4H); 7.81 (m, 2H); 7.92 (m, 2H); 8.20 (d, 8HZ, 2H); 8.30 (d, 8.4Hz, 2H)

125

Example 153

Ν, Ν''-O-tert-butoxycarbonyl-L-phenylalanyl-L-valyl) -2 S, 5 S -dimaino-1,6-bis- (3,4-methylenedioxyphenyl) -hexane-3R, 4R-diol

Synthesis analogous to Example 6 from

2S ₇ 5S-diamino-1,6-bis- (3,4-methylenedioxyphenyl) -hexane-3R, 4R-diol dihydrochloride (The latter compound was prepared analogously to Example 2, 2b, 2c and 2e

1,2R-5R, 6-diepoxy-3,4-0-isopropylidene-3R, 4R-diol and 3,4-methylenedioxyphenylllithium are shown)

MS (FAB): 1103 (M + Na) +, 1081 (M + H) +

NMR (270 MHz, DMSO <D6>): 0.73 (d, 6Hz, 6H); 0.76 (d, 6HZ, 6H); 1.28 (s, 18H); 1.87 (m, 2H); 2.52-2.78 (m, 6H); 2.91 (dd, 14Hz, 4Hz, 2H); 3.26 (m, 2H); 4,11-4,22 (m, 4H); 4.35 (m, 2H); 4.66 (m, 2H); 5.84 (s, 2H); 5.86 (s, 2H); 6.63 (d, 8Hz, 2H); 6.69 (d, 8Hz, 2H); 6.75 (s, 2H); 6.99 (d, 9Hz, 2H); 7.13-7.33 (m, IGH), 7.45 (d, 9Hz, 2H); 7.59 (d, 9Hz, 2H)

Example 154 25

N, N'-bis- (L-phenylalanyl-L-valyl) -2S, 5S-diamino-1,6-bis- (3,4-methylenedioxyphenyl) hexane-3R, 4R-diol dihydrochloride

Synthesis analogous to Example 16 from 153 30

MS (FAB): 881 (M + H) +, 863

Example 155

N, N ¹ -bis ·· (<2S- (1,1-dimethylethyl-sulphonylmethyl) -3- (1-naphthyl) -p'propionyl> -L-valyl) -2S, 5S-diamino-1 ,, 6 -bis- (3,4-methylenedioxyphenyl) hexane-3R, 4R-diol

126 298403

Synthesis analogous to Example 13 and 153 MS (FAB): 1241 (M + Na) +, 1219 (M + H) ⁺

NMR (270 MHz, DMSO <D6>): 0.73 (d, 7HZ, 6H); 0.78 (d, 7Hz, 6H); 1.10 (s, 18H); 1.89 (m, 2H); 2.55-2.72 (m, 4H); 2.79 (dm 14Hz, 2H); 3.08 (dd, 14Hz, LOHZ, 2H); ca 3.22-3.43 (m, ca 6H); 3.58 (dd, 14Hz, 10Hz, 2H); 4.07 (m, 2H); 4.45 (m, 2H); 4.49 (m, 2H); 5.75 (s, 2H); 5.78 (s, 2H); 6.68 (s, 2H); 6.80 (s, 2H); 7.25 (d, 9HZ, 2H); 7.39-7.45 (m, 4H); 7.54 (m, 6H); 7.80 (m, 2H); 7.92 (m, 2H): 8.15-8.25 (m, 4H)

Example 156

N, N ¹ -Bis - (<2S- (1,1-dimethylethyl-sulfonylmethyl) -3-

(L-naphthyl) -propionyl> -L-isoleucyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3R, 4R-diol

Synthesis analogous to Example 13 20

MS (FAB): 1181 (M + Na) ⁺

NMR (270 MHz, DMSO <D6>): 0.63 (d, 7Hz, 6H); 0.73 (t, 7Hz,

6H); 0.99 (m, 2H); 1.11 (s, 18H); 1.32 (m, 2H); 1.64 (m,

2H); 2.63-2.88 (m, 6H); 3.07 (dd, 15Hz, HHz, 2H); ca

3.28-3.43 (m, ca 6H); 3.58 (dd, 14Hz, 9Hz, 2H); 4.09 (t,

8Hz, 2H); 4.48-4.62 (m, 4H); 7.03 (m, 2H); 7,12-7,31 (m,

10H); 7.43 (m, 4H); 7.54 (m, 4H); 7.81 (m, 2H); 7.92 (m, 2H); 8.15-8.25 (m, 4H)

Example 157

Ν, Ν'-bis- (N ² - <hexadecylsulfonyl> L-lysyl-L-valyl) -2 S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol 35

Synthesis analogous to Example 11 and 58

MS (FAB): 1330 (M + H) ⁺

127 Example 158

N, N ¹ -Bis (N ² - <tetradecanoyl> L-lysyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol 5

Synthesis analogous to Example 11 and

MS (FAB): 1174 (M + H) ⁺ Example 159

N, N ¹ -Bis (tert-butoxycarbonyl-L-phenylalanyl-L-asparaginyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 6 MS (FAB): 1045 (M + Na) ⁺

NMR (270MHz, DMSO <D6>): 1.27 (s, 18H); 2.20-Γ, 78 (m, 10H); 2.90 (m, 2H); 3.30 (m, 2H); 4.14 (m, 2H); 4.28 (m, 2H); 4.45 (m, 2H); 4.64 (s, 2H); 6.88 (s, 4H); 7.02-7.37 (m, 24H); 8.04 (d, 8Hz, 2H)

Example 160

N, N'-bis (L-phenylalanyl-L-asparaginyl) -2S, 5S-diaminol, 6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 16 from FIG. 30

MS (FAB): 823 (M + H) ⁺

Example 161

Ν, Ν'-bis (<2S- (1 _/ 1-dimethylethyl-5-sulfonylmethyl) -3- (1-naphthyl) -propionyl> L-asparaginyl) -2S, 5S-diamino-1,6-diphenyl-hexane 3R, 4R-diol

128

Synthesis analogous to Example MS (FAB): 1183 (M + Na) ⁺

NMR (270MHz, DMSO <D6>): 1.17 (s, 18H); 2.22 (m, 2H);

2.37-2.76 (m, 10H); 2.90 (m, 2H); 3.25 (m, 4H); 3.58 (m, 2H); 4.25 (m, 2H); 4.40 (m, 2H); 4.62 (m, 2H); 6.93-7.60 (m, 24H); 7.77 (m, 2H); 7.90 (m, 2H); 8.22 (d, 8Hz, 2H); 8.33 (d, 8Hz, 2H); 10

Example 162

Ν, Ν'-bis (<2- (1,1-dimethylethyl-sulfonyl-methyl) -3- (4-pyridyl) -propionyl> L-valyl) -2 S, 5S-diamino-1,6-diphenyl-3-hexanoate, 4R-diol dihydrochlrid

Synthesis analogous to Example 2- (l, l-dimethylethyl-sulfonylmethyl) -3- (4-pyridyl) propionic acid was used as a racemate in the coupling; the diastereomeric products were separated by chromatography.

Rf values: eluent ethyl acetate / methanol / glacial acetic acid 60/40/1

a) Rf = 0.50

b) Rf = 0.44

c) Rf = 0.33

MS (FAB): 30

a) Isomer 1: 1055 (M + Na) ⁺ 1033 (M + H) ⁺

b) Isomer 2: 1055 (M + Na) ⁺ 1033 (M + H) ⁺

c) isomer 3: 1055 (M + Na) ⁺

NMR (270 MHz, DMSO <D6>):

129

a) isomer 1: 0.68 (d, 7Hz, 6H); 0.74 (d, 7Hz, 6H); 1.19 (s, .18H); 1.83 (m, 2H); 2.53-2.94 (m, 10H); about 3.2-3.45 (m, about 10ΗΪ 3.53 (dd, 14Hz, 9Hz, 2H); 4.06 (dd, 9hz, 7Hz, 2H); 4.52 (m, 2H); 7.05 (d) m, 2H); 7,10-7,25 (m, 8H), 7,28, d, 6Hz, 4H), 7,53 (d, 9Hz, 2H); 8.19 (d, 9Hz, 2H); 8.46 (d, 6Hz, 4H)

b) isomer 2: 0.38, 0.44, 0.65, 0.73 (4d, 7Hz each, 3H each); 1.18 1.28 (2s, 9H each); 1.70-1.88 (m, 2H); 2.54-3.05 (m, ca.11H); 3.15-3.60 (m, ca. 10K); 3.97 (dd, 8Hz, 6Hz, IH); 4.03 (dd, 9Hz, 7Hz, IH); 4.36-4.52 (m, 2H); ca. 4.4-5, C (IH); 7.00-7.30 (m, 14H); 7,41, 7,58, 8,18, 8,27 (4d, each 9Hz, each IH); 8,43, 8,46 (2d, each 6Hz, each IH)

c) isomer 3: 0.34 (d, 7Hz, 6H), 0.40 (d, 7Hz, 6H); 1.31 (ε, 18H); 1.73 (m, 2H); 2.60-3.07 (m, 12H); 3.26 (s, 2H); 3.38-3.58 (m, 4H); 3.81 (dd, 8Hz, 6Hz, 2H); 4.42 (m, 2K); about 4.3-5.3 (2K); 7.03-7.30 (m, 14K); 7.43 (d, 9Hz, 2H);

8.28 (d, 9Hz, 2H); 8.43 (d, 6Hz, 4H) 20

Example 163

N, N'-bis (<2- (1,1-dimethylethyl-sulfonylmethyl) -3- (N-oxido-4-pyridyl) -propionyl> L-valyl) -2S, 5S-diamino-1,6- diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 162.

2- (1,1-Dimethyl ethylsulfonylmethyl) -3- (N-oxido-4-pyridyl) propionic acid is obtained from the precursor 2- (1,1-dimethylethylthio-methyl) -3- (4 -pyridyl) -propionic acid by oxidation with three instead of two equivalents of oo, as in Example 162.

MS (FAB): 1065 (Μ + Η) ⁺

130

Example 164

Ν, Ν'-bis (<bis (1,1-dimethylethylthio-methyl) -acetyl> L-valyl) -2 S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol 5

Synthesis analogous to Example 13. The synthesis of bis (1,1-dimethylethyl-thio-methyl) -acetic acid was carried out from bis (hydroxymethyl) -malonsäurediethylester by reaction with hydrogen bromide and subsequent substitution of the obtained ß, ß'-dibromoisobutyric with Kai ium tert-butyl sulfide.

MS (FAB): 990 (M + H) ⁺

NMR (270 MHz, CDC13): 0.59 (d, 7Hz, 6H); 0.85 (d, 7Hz, 6H); 1.29 (s, 18H); 1.33 (s, 18H); 2.16 (m, 2H); 2.42 (m, 2H); 2.70-3.02 (m, 14H); 3.48 (br.s, 2H); 4.13 (m, 2H); 4.28 (m, 2H); 5.33 (d, 8Hz, 2H); 6.47 (d, 8Hz, 2H); 7,20-7,28 (m,

10H) 20

Example 165

N, N'-bis (<bis (1,1-dimethylethyl-sulfonylmethyl) -acetyl> L-valyl) -2 S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol 25

Synthesis analogous to Example 164 and 13

MS (FAB): 1118 (M + H) ⁺ Example 166

N, N ¹ -bis - (<1-naphthyl> -acetyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 58 MS (FAB): 834 (M + H) ⁺

131

example

N, N ¹ -bis - (<1-naphthyloxy> -acetyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol 5 Synthesis analogous to Example

MS (FAB): 866 (M + H) ⁺ example

N, N'-bis- (<2S- (1,1-dimethylethyl-sulfonylmethyl) -3- (1-naphthyl-propionyl> L-valyl) -2S, 5S-diamino-1,6-bis- (4- tert-butylphenyl) -hexan-3R, 4R-diol

Synthesis analogous to Example 6 from 2S, 5S-diamino-1,6-bis (4-tert-butylphenyl) hexane-3R, 4R-diol dihydrochloride (The latter compound was prepared analogously to Example 2, 2b, 2c and 2e of FIG , 2R-SR ₇ O-di-epoxy-S 1 -O-isopropylidene-3R, 4R-diol and 4-tert-butylphenyllithium are shown)

MS (FAB): 1265 (M + H) ⁺

NMR (270 MHz, DM0 <D6>): 0.67 (d, 7Hz, 6H); 0.76 (d, 7Hz, 6H); 1.09 (s, 18H); 1.11 (s, 18H); 1.87 (m, 2H); 2.60-2.85 (m, 6H); 3.08 (dd, 14Hz, 12Hz, 2H); 3.25-3.50 (m, 8H); 3.60 (dd, 14Hz, 9Hz, 2K); 4.06 (m, 2H); 4.52 (m, 2H); 7.10-7.22 (m, 8H); 7.27 (d, 9Hz, 2H); 7.34-7.62 (m, 8H); 7.80 (m, 2H); 7.92 (m, 2H); 8.22 (d, 8Hz, 4H) 30

example

N, N ¹ -Bis - (<2S- (1,1-dimethylethyl-sulfonylmethyl) -3- (1-naphthyl) -propionyl> L-valyl) -2S, 5S-diamino-1,6-bis (2 , 4-dimethoxyphenyl) hexane-3R, 4R-diol

i3ia

Example 179

ν ', Ν' bis- (di- (1-naphthylmethyl) -acetyl-L-valyl) -2 S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol 5

Synthesis analogous Example

MS (FAB): 1165 (M + Na) ⁺ , 1143 (M + H) ⁺

NMR (270 MHz, DMSO <D ₆ >): 0.36 (d, 7Hz, 6H); 0.42 (d, 7Hz, 6H); 1.62 (m, 2H); 2.57-2.80 (m, 4H); 2.90-3.42 (m, approx. 12H); 3.96 (t, 8Hi :, 2H); 4.38 (m, 2H); 4.63 (m, 2H); 6.98-7.54 (m, 30H); 7.67-7.96 (m, 12H)

Example 180

Ν, Ν'-bis [12- (tert-butoxycarbonylamino) -dodecanoyl-L-valyl] 2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous Example

MS (FAB): 1115 (M + Na) ⁺ , 1093 (M + H) ⁺ , J93

NMR (270 MHz, DMSO <D _ß>: 0.68 (d, 7Hz, 6H), 0.72 (d, 7Hz, 6K

1.10-1.54 (m, 54H); 1.82 (m, 2H); 2.08 (m, 4H); 2.55-2.82

(m, 4H); 2.88 (m, 4H); 3.25 (m, 2H); 4.04 (m, 2H); 4.42 (m,

2H); 4.67 (m, 2H); 6.73 (m, 2H); 7.05-7.22 (m, 5H); 7:32

(d, 9Hz, 2H); 7.58 (d, 9Hz, 2H)

Example 181

Ν, Ν ¹ -Bis [benzyloxycarbonyl-Lv * vl] -25,4-diaryl-l, 5-diphenyl-pentanes-3-ol

Synthesis analogous to Example 6 fron Example MS (FAB): 759 (M + Na ⁺ ) 737 (M + H) ⁺

131b

Example 182

N, N -Bis [L-3- (2-naphthyl) alanyl-L-valyl] -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol dihydrochloride 5

Synthesis analogous to Example 16

MS (FAB: 89 3 (M + H) ⁺ Example 183

Ν, Ν'-bis - ([bis (1,1-dimethylethyl-sulfinylmethyl) acetyl] -L-valyl) -2S, 5S-diamino-l, 6-diphenyl-hexane-3R, 4R-diol

Synthesis from Example 164 by oxidation with m-chloroperbenzoic acid

MS (FAB): 1055 (M + H) ⁺

Additional data: Example 166

NMR (270 MHz, DMSO <D _g >: 0.68 (d, 6Hz, 6H); 0.71 (d, 6Hz, 6H); 1.88 (m, 2H); 2.26 (dd, 14Hz, 4Hz, 2H); 2.76 (dd , 14Hz, 10Hz, 2H); 3.29 (m, 2H); 3.84 (d, 16Hz, 2H); 4.05 (d, 16Hz, 2H); 4.12 (dd, 8Hz, 6Hz, 2H); 4.45 (m, 2H) ; 4.7 (m, 2H); 7.1-7.22 (m, 10H); 7.40-7.56 (m, 10H); 7.81 (dd, 8Kz, 2Hz, 2H); 7.87-7.96 (m, 4H); 8.08 (m, 2H)

Example 167

NMR (270 MHz, DMSO <Dg>): 0.69 (d, 7Hz, 6H); 0.7 3 (d, 7Hz, 6H); 1.93 (m, 2H); 2.64 (dd, 14Hz, 4Hz, 2H); 2.80 (dd, 14H3, 10Hz, 2H); 3.30 (m, 2H); 4.24 (dd, 9H2, 6Hz, 2H); 4.50 (m, 2H); 4.68 (d, 15Hz, 2H); 4.77 (d, 15Hz, 2H); 4.79 (m, 2H); 6.92 (d, 8Hz, 2H); 7.02-7.24 (m, 10H); 7.42 (t, 3Hz, 2H); 7.48-7.6 (m, 6H); 7.68 (d, 10Hz, 2H); 7.75 (d, 8Hz, 2H); 7.90 (m, 2H); 8.24 (m, 2H)

Example 168

NMR (270 MHz, DMSO <Dg>): 0.67 (d, 7Hz, 2H); 0.76 (d, 7Hz,

2H); 1.09 (s, 18H); 1.88 (m, 2H); 2.50 (see 18H); 2.59-2.86

(m, 6H); 3.09 (dd, 14Hz, 12Hz, 2H); 3.23-3.50 (m, 8H); 3.59 (dd, 14Hz, 8Hz, 2H); 4.05 (t, 8Hz, 2H); 4.52 (m, 2H);

7.08-7.22 (m, 8H); 7.28 (d, 9Hz, 2H); 7.33-7.46 (m, 4H);

7.46-7.62 (m, 4H); 7.80 (m, 2H); 7.92 (m, 2H); 8.23 (d, 8Hz, 4H) 10

Example 169

NMR (270 MHz, DMSO <Dg>): 0.72 (d, 6Hz, 6H); 0.77 (d, 6Hz,

6H); 1.09 (m, 18H); 1.90 (m, 2H); 2.54 (m, 2H); 2.7-2.9 (ir.

4H); 3.02 (m, 2H); 3.25-3.4 (m, about 6H); 3.47 (s, 6H);

3.52-3.65 (m, 2H); 3.74 (s, 6H); 4.02 (m, 2H); 4:43 to 4:58

(m, 4H); 6.28 (dd, 8Hz, 2Hz, 2H); 6.38 (d, 2Hz, 2H); 7.1

(d, 8Hz, 4H); 7.40-7.45 (m, 4H); 7.45-7.62 (m, 4H); 7.8 (::.,

2H); 7.91 (m, 2H)

Example 171

NMR (270 MHz, DMSO <Dg>): 0.68 (d, 7Hz, 6H); 0.72 (d, 7Hz, 6H); 1.15-1.36 (m, 28H); 1.36-1.60 (r,., 8H); 1.83 (m, 2H); 2.09 (m, 4H); 2.55-2.83 (m, 2H); 3.27 (m, 2H); 4.05 (dd, 7Hz, 8Hz, 2H); 4.42 (m, 2H); 4.68 (m, 2H); 7.05-7.22 (m, 5H); 7.36 (d, 9Hz, 2H); 7.59 (d, 9Hz, 2H); 7.78 (m, 6H)

132 292409

Synthesis analogous to Example 6 from

2S, 5S-Diamino-1,6-bis- (2,4-dimethoxyphenyl) -hexane-3R, 4R-diol dihydrochloride (The latter compound was analogous to Example 2, 2b, 2c and 2e

1, 2R-5R, 6-diepoxy-3,4-O-isopropylidene-3R, 4R-diol and 2,4-dimethoxyphenyllithium) MS (FAB): 1250 (M + H) ⁺ Example 170

N _, N'-bis (2 <4-pyridyl> ethylsulfonyl-L-valyl) -2S _/ 5S · diamino-1,6-diphenyl-hexane-3R, 4R-diol Synthesis analogous to Example 58 MS (FAB): 836 (M + H) ⁺

Example 171

Ν, Ν'-bis (12-amino-dodecanoyl-L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexan-3R, 4R-diol

Synthesis analogous to Example 58 25

MS (FAB): 892 (M + H) ⁺

Example 172

N, N ¹ -Bis - (<2-quinolylcarbonyl> -L-valyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 58 MS (FAB): 831 (M + Na) ⁺ , 809 (M + H) ⁺

133 3.SSA03

NMR (270 MHz, DMSO <D6>): 0.80 (d, 7Hz, 6H); 0.84 (d, 7Hz, 6H); 2.65 (dd, 14Hz, 4Hz, 2H); 2.83 (dd, 14Hz, 10Hz, 2H); 3.34 (m, 2H); 4.43 (dd, 6Hz, 9Hz, 2H); 4.55 (m, "2H); 4.80 (m, 2H); 6.86 (m, 2H); 7.07 (t, 8Hz, 4H); 7.22 (d, 8Hz, 4H); 7.74 (m, 2H), 7.89 (m, 4H), 7.89 (m, 4H), 8.12 (d, 8Hz, 2H), 8.19 (m, 4H), 8.57 (d, 9Hz, 2H); 8.61 (d, 9Hz, 2H)

Example 173

N, N ¹ -Bis - (<2-quinolylcarbonyl> -L-asparaginyl) -2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

Synthesis analogous to Example 58 15

MS (FAB): 861 (M + Na) ⁺

NMR (270 MHz, DMSO <D6>): 2.33-2.78 (m, 8H); 3.30 (m, 2H); 4.33 (m, 2H); 4.70 (m, 4H); 4.70 (m, 4H); 6.80-8.22 (m, 26H); 8.59 (d, 8Hz, 2H), 8.92 (d, 8Hz, 2H)

Example 174

N, N'-bis- (tert-butoxycarbonyl) -2S, 4-diamino-1,5-diphenylpentan-3-ol

2.3 g of tert-butoxycarbonyl-L-phenylalanal were dissolved in 10 ml of ethanol. After addition (at 0 ^° C.) of 0.05 ml of tetramethylguanidine and a solution of 2.42 g of 2-nitro-1-phenylethane in 2 ml of ethanol, the mixture was allowed to warm to RT and stirred overnight. The solution was concentrated and the remaining light oil (4.8 g) was used directly.

4.7 g of the oil obtained above was dissolved in 70 ml of ethanol. After addition of 0.1 ml of glacial acetic acid and 1 g

134

Raney nickel, the solution was shaken for 16 h at 50 ⁰ C and 25 atm of hydrogen in the glass insert in an autoclave. The catalyst was filtered off, the eluate evaporated to an oil. The residue was dissolved in water / in HCL and extracted 4x with ethyl acetate. The ethyl acetate extract was concentrated and used directly (2.6 g). 2.57 g of the amino compound obtained obon were dissolved in 25 ml of dioxane at RT. After addition of 0.86 ml of triethylamine and 1.7 g of di-tert-butyl dicarbonate, the mixture was stirred for a further 30 min. The solution was concentrated, the residue was combined with ice water, ethyl acetate and KHSO ₄ solution until pH 2. The ethyl acetate phase was washed with aqueous NaCl solution, dried over anhydrous ^ 2SO ₄ and concentrated. This gave 3.3 g of an oil. This was further purified by chromatography on silica gel (C 1 -C 4 / methanol / glacial acetic acid 100/3 / 0.3). This gave 2.2 g of product as a mixture of diastereomers.

MS (FAB): 471 (M + H) ⁺ , 371, 315 20

Example 175

N, N ¹ -Bis (tert-butoxycarbonyl) -1,3-diaminopropane MS (FAB): 495 (M + Na) ⁺ ; 473 (M + H) ⁺

NMR (270 MHz, CDCl 3): 0.97 (d, 6Hz, 12H); 1.45 (8, 18H); 1.70 (t, 6Hz, 2H); 2.03 (m; 2H); 3.08 (m, 2H); 3.58 (m, 2H); 3.88 (dd, 2H); 5.09 (d, 2H); 7.21 (s, 2H) 30

Example 176

N, N ¹ -bis (tert-butoxycarbonyl) -1,3-diaminopropane-2-oil MS (FAB / LiCl): 495 (M + Li) ⁺ ;

135 238 Aod

NMR (270 MHz, CDCl _3): 0.97 (dd, 12H); 1.45 (s, 18H); 2.04 (m, 2H); 3.20 (m, 2H); 3.61 (m, 2H); 3.90 (dd, 2H), 3.95 (m, IH); 5.16 (dd, 2H); 7.18 (s, IH); 7.49 (s, IH)

Example 177

N, N'-bis (tert-butoxycarbonyl) -1,3-diaminoacetone

MS (FAB / LiCl): 493 (M + Li) ⁺ 10

NMR (270 MHz, CDCl 3): 0.98 (dd, 12H); 1.45 (s, 18H); 2.09 (m, 2H); 3.94 (dd, 2H); 4.10 (s, 2H); 4.18 (s, 2H); 5.20. (d, 2H); 7.50 (s, 2H)

Example 178

N, N ¹ -Bis (tert-butoxycarbonyl) -1,4-diaminobutan-2-one

MS (FAB): 523 (M + Na) ⁺ ; 501 (M + H) ⁺ 20

NMR (270 MHz, CDCl 3): 0.95 (m, 12H); 1.43 (d, 18H); 2.09 (m, 2H); 2.69 (m, 2H); 3.45 (m, IH); 3.86 (m, IH); 3.90 (m, IH); 3.99 (m, IH); 4.18 (m, IH); 5.23 (d, 2H); (d, 2H);

6.91 (s, IH); 7,17 (s, IH) 25

Examples 175-178 were prepared analogously to Example 174 (introduction of the Boc protecting group).

Claims (13)

136 claims 1. A process for the preparation of a compound of the formula I R ⁴ AN R ⁵ R ⁵ * R ³ * R ² --C - C - (Y) ₁ - (C) _m --C - R ² * (I) R ³ R ⁶ R ⁶ * N-A * R ⁴ * wherein 10 Y is oxygen, sulfur, a radical of the formula II or a radical of the formula III R ⁵ ** - C - (II) - N - (HI) R ⁶ ** R ⁷ stands; 1 and m are independently 0 or 1; A is a radical of the formula IV and A * is a radical of the formula IV * D - (E) _n - (F) _O - (G) _p - (IV) D * - (E *) _n * - (F *) _o * - (G *) _p * - (IV *) in which E, E *, F, F *, G and G * independently represent a natural or unnatural amino acid, aza-amino acid or imino acid; η, η *, ο, ο *, ρ and p * independently of one another 0 or mean; D is R ¹ or a radical of the formulas V, VI or VII and D * is R ¹ * or a radical of the formulas V *, VI * or VII * 137 R ⁸ R ⁹ R ⁸ * R ⁹ * R ¹ - N - C - CO - (V) R ¹ * - N - C - CO - (V *) R ¹ ^ R ¹⁰ * K ¹¹ P. ⁹ R ¹¹ * R ⁹ * R ¹ - CH - CH - CO - (VI) R ¹ * - CH - CH - CO - (VI *) R ⁹ R ⁹ * R ¹ - O - CH - CO - (VII) R ¹ * - O - CH - CO - (VII *) 10 and wherein R ¹ and R ¹ * independently represent - hydrogen,
- carboxyl, - (C ₁ -C ₁ Q) -alkyl which is optionally mono- or diunsaturated and which may be substituted by up to 3 identical or different radicals from the series - mercapto,
- hydroxy, Carbamoyl, - (C 1 -C 8) -alkanoyloxy, - carboxy, - (C ₁ -C ₇ ) alkoxycarbonyl, - F, Cl. Br, I, - Amino, - Amidino, which may optionally be substituted by one, two or three (C - ^ - CgJ-alkyl radicals, - guanidino, optionally substituted by one or two Benzyloxycarbonylreste or by one, two, three or four (C ^ -CgJ-alkyl radicals can be, - (C ₁ -C ₇ ) -alkylamino, Di- (C ₁ -C ₇ ) -alkylamino, - (C 1 -C 4) -alkoxycarbonylamino, - (C ₇ -C ₁ ) -alkoxycarbonyl, - (C ₇ -C ₁₅ ) -Aralkoxycarbony! Amino, 138 29 * 403 Phenyl (C ₁ -C ^) - alkoxy, 9-fluorenylmethoxycarbonylamino, (C ₁ -C ₆₎ alkylsulfonyl, (C ₁ -C ₆₎ alkylsulfinyl, - hydroxamino, - Hydro :: imino, Sulfamoyl, - sulfo, - Carboxamido, - formyl, - Hydrazono, - Imino, - a radical CONR ¹² R ¹³ or CONR ¹² * R ¹³ *, - by up to six hydroxy or - is substituted by up to five (C ₁ -Cg) alkanoyloxy; - mono-, bi or tricyclic - (C ₃ -C ₁₈ ) -cycloalkyl- (C ^ CgJ wherein the cycloalkyl part in each case optionally by one or two identical or different radicals from the series F, Cl, Br, I, Carboxy, carbamoyl, Carboxymethoxy, - hydroxy, - (C ₁ -C ₇ ) -alkyl, - (C ₁ -Cy) -alkyloxycarbonyl, - Amino, (C ₁ -C ₆ ) -alkylrmino (C ₁ -C ₆ ) -alkyl, - di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl - Amidino, - hydroxamino, - Hydroximino, - Hydrazono, ₁₃₉ imino, Guanidino, (C 1 -C 8) alkoxynesulfonyl, - (C ₁ -C ₆ ) alkoxycarbonylamino _/ - (Cg-C ₁ 2) -aryl (C 1 -C ₄ ) -alkoxycarbonylamino, - (C ₁ -C ₇ ) -alkylamino, - di- (C ₁ -Cy) -alkylamino and - Trifluoromethyl is substituted; - (C ₆ -C ₁₄ ) -aryl (C ₁ -C ₆ ) -alkyl _/ - (C ₆ -C ₁₄ J-ArylOXy- (C ₁ -C ₆ J-BIkYl or - (C ₆ -C ₁₄ ) -aryl (C ₃ -C ₈ ) -cycloalkyl, wherein the aryl part in each case optionally by one, two or three identical or different radicals from the series F, Cl, Br, I, - hydroxy, - mono-, di- or trihydroxy- (C ₁ -C ₄ ) -alkyl, - trifluoromethyl, - formyl, - Carboxamido, Mono- or di (C ₁ -C ₄ ) -alkylaminocarbonyl, - Nitro, - (C ₁ -C ₇ ) -alkoxy, - (C ₁ -C ₇ ) alkoxycarbonyl, - Amino, - (C 1 -C 8) -J-alkylamino, Di- (C ₁ -C ₇ -alkylamino, - carboxy, Carboxymethoxy, Amino (C ₁ -C ₇ ) alkyl, - (C ₁ -C ₇₎ alkylamino (C ₁ -C ₇ J-alkyl, - di (C ₁ -C ₇₎ alkylamino (C ₁ -C ₇₎ alkyl - (C ₁ -C ₇ ) -alkoxycarbonylmethoxy, Carbamoyl, 140
Sulfamoyl, "(C" _{1 "} -C" _{8 "} ) alkylsulfonyl, -SuIfO- (C ₁ -C ₈ ) -alkyl, Guanidino- (C ₁ -C ₈ J-BIkyl and - (C ₁ -Cg) alkoxycarbonylamino
is substituted; - Het, Het (C ₁ -C ₆ ) -alkyl, - Het- (C ₃ -C ₈ ) -cycloalkyl Het- (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C ₄ ) -alkyl, Het (C ₃ -C ₈ ) -cycloalkoxy (C ₁ -C ₄ ) -alkyl, Het-thio (C 1 -C 17) alkyl, Hetthio (C ₃ -C ₈ ) cycloalkyl, - Het-thio (C ₃ -C ₈ ) -cycloalkyl (C ₁ -C ₄ ) -alkyl, wherein Het is in each case the radical of a 5- to 7-membered monocyclic or 8- to 10-membered bicyclic ring system which may be benzanellated, aromatic, partially hydrogenated or fully hydrogenated, which may contain as hetero elements one, two, three or four different radicals from the group N, 0, S, NO, SO, SO ₂ , which is 1 to 6 hydroxy may be substituted and optionally as in (C ₆ -C ₁₄ ) -aryl defined under a- ^) and / or with oxo, mono-, di- or tisubstituiert, or a radical NR ¹² R ¹³ or NR ¹² * R ¹³ * or '30 a ₂ ) - a radical of formula VIII or VIII * mean R ^la - W (VIII) R ^la * - W * (VIII *) wherein R ^la and R ^la * as R ¹ and R ¹ * are defined under Sl ₁ ) and W and W * for -CO-, -CS-, 0-C0-, -SO ₂ -, -SO-, -S-, -NHSO ₂ -, -NHCO-, -CH (OH) -, -N (OH) - or -CO-V- wherein V is a peptide of 1 to 10 amino acids; 141 or in which R ¹ and R ^1, independently of one another together with R ¹¹ or RH and the atoms carrying them, form mono- or bicyclic, saturated or partially unsaturated ring systems having 5-12 ring members which, in addition to carbon, may also contain 1 sulfur atom which may be added to Sulfoxide or sulfone can be oxidized; a ₃ ) • a glycosyl radical, preferably a glucofuranosyl or glucopyranosyl radical, which is derived from naturally occurring aldotetroses, aldopentoses, aldohexoses, ketopentoses, ketohexoses, deoxyaldoses, aminoaldoses and oligosaccharides and their stereoisomers; R ² and R ² * are independently defined as R * or R ^ under a ^) or ^ 2) or together with R baw. R and the tragenden.Atomen mono- or bicyclic, saturated or partially unsaturated ring systems with 5 to 12 ring members form, or together with R or R and the atoms carrying them cyclic, saturated or partially unsaturated ring systems having 3 to 12 ring members ; R ³ and R ³ * independently - hydrogen or - (C ₁ -C ₃ ) -alkyl; R ⁴ and R ⁴ * independently - hydrogen or mean; R ⁵ , R ⁵ * and R ⁵ ** independently - hydrogen, - hydroxy, 142 - Amino or - Carboxy, or R ⁶ , R ⁶ and R ^6, together with the carbon atoms carrying them, each independently form a keto group; R ⁶ , R ⁶ * and R ⁶ **
independently of each other - hydrogen or - (C ₁ -Cg) -AlkVl mean or in the case of 1 = 0, R ⁶ and R ⁶ * may optionally form a common bond; R ⁷
- hydrogen, - hydroxy or - (C ₁ -C ₆ ) -alkyl; R ⁸ and R ⁸ *
independent of each other - hydrogen or - (C ₁ -Cg) -Al ^ yI mean, or Q Q * together with R or R and the atoms carrying them form mono- or bicyclic, saturated or partially unsaturated ring systems having 5-12 ring members; R ⁹ and R ⁹ * are independently defined as R and R under a · ^), hydroxy or (C ₁ -C ^) - alkanoyloxy or together with R or R and the atoms carrying them cyclic, saturated or partially unsaturated ring systems with 3 bis 12 ring members form; or
together with R ¹¹ or R * ¹ * and the atoms carrying them form a monocyclic or bicyclic, saturated or partially unsaturated ring system with 5-12 ring members, which, in addition to carbon, may also contain 1 sulfur atom, 143 which may optionally be oxidized to the sulfoxide or sulfone; or may contain 1 nitrogen atom, which ring system may optionally be substituted by amino; , R ¹⁰ and R ¹⁰ * independently of each other - hydrogen or - (C 1 -C 4) alkyl; 10 'R ¹¹ and R ¹¹ * independently of each other - hydrogen, - hydroxy, - (C ₁ -C 4) alkanoyloxy or - (C ₁ -C ₈ ) -alkyl; R ¹² , R ¹² *, R ¹³ and R ¹³ * independently - hydrogen, - (C 1 to C 6) alkyl, which is substituted by - Amino, - (C ₁ -C ₄ ) -alkylamino, Di- (C ₁ -C ₄ ) -alkylamino, - Mercapto,
- carboxy, - hydroxy or - (C ₁ -C ₄ ) -alkoxy may be substituted, - (C ₃ -C ₇ ) -cycloalkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl (C ₁ -C ₄ ) -alkoxycarbonyl which may be substituted in the aryl part as described for R and R, - Het or - Het- (C ₁ -C ₄ ) -alkyl, wherein Het is defined as described for R ¹ or R ¹ *, mean or wherein R ¹² and R ¹³ and R ¹² * and R ¹³ * together with the carrying them Nitrogen atoms monocyclic or 144 form bicyclic, saturated, partially unsaturated or aromatic ring systems which contain, in addition to carbon, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom as further ring members and may be substituted by in which in the above compounds of the formula I one or more amide groups (-CONH-) of the main chain may be replaced by -CH ₂ NR ¹⁴ -, -CH ₂ S-, -CH ₂ O-, -OCH ₂ -, -CH ₂ CH ₂ -, -CH = CH- (cis and trans), -COCH ₂ -, -CH (OH) CH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, - (O) (OR ¹⁵ ) CH ₂ - and -P (O) (0R ¹⁵ ) NH-, or by a reverse polarity (-NHCO-) amine group; wherein R ¹⁴ and R ¹⁵ stand independently for - hydrogen or - (C ₁ -C ₄ ) -alkyl; and their physiologically tolerated salts, characterized in that one couples a fragment with terminal carboxyl group or its reactive derivative with a corresponding fragment having a free amino group, optionally to protect further functional groups (a) temporarily introduced protecting group (s) cleaves and dij thus obtained compound optionally converted into their physiologically acceptable salt. 2. A process for the preparation of a compound of formula I according to claim 1, characterized in that the radicals and symbols with and without star are identical. 3. A process for the preparation of a compound of the formula I according to claims 1 to 2, characterized in that the compound C _{2 is} -symmetric. 145 298409 4. A process for the preparation of a compound of formula I according to claims 1 to 3, characterized in that Y is a radical of formula II or a radical of formula III; 1, m, Λ, A *, D, D *, η, η *, ο, ο *, ρ and p * are as defined in claim 1; E, E *, F, F *, G and G * independently represent a natural or unnatural α-amino acid or o-imino acid;
10 R ¹ and R ¹ * stand independently for a- ^) - hydrogen;
- carboxyl, - (C ₁ -C ₁₆ ) -alkyl which is optionally monounsaturated and which may be substituted by up to 2 identical or different radicals from the series - hydroxy, - (C ₁ -C ₄ ) -alkoxy, Carbamoyl, - carboxy, - (C ₁ -C 4) -alkoxycarbonyl,
- F, - Amino, - (C ₁ -C ₇ ) -alkylamino, Di- (C 1 -C 6 -alkylamino, - (Cj ^ -Cgi-alkoxycarbonylamino,
- benzyloxycarbonyl Benzyloxycarbonylamino, - 9-fluorenylmethoxycarbonylamino, - (C ₁ -C ₄ ) -alkylsulfonyl, - a radical CONR ¹² R ¹³ or CONR ¹² * R ¹³ *, - by up to six hydroxy or substituted by up to four (C 1 to C 6) alkanoyloxy; ₁₄₆ 298409 mono- or bicyclic (C ₃ -C ₁₂ ) -cycloalkyl- (C ₁ -C ₆ ) -alkyl wherein the cycloalkyl part in each case optionally by one or two identical or different radicals from the series - F, - carboxy, - hydroxy, - (C ₁ -C ₄ ) -alkyl, - (C ₁ -C ₄ ) -alkyloxycarbonyl, - Amino, - (C ₁ -C ₆ ) alkoxycarbonylamino, Benzyloxycarbonylamino (C ₁ -C ₄ ) alkylamino and - substituted di- (C ₁ -C ₄ ) -alkylamino - (C ₆ -C ₁₀ ) -aryl. - (C ₆ -C ₁₀ ) -Aryloxy- (C 1 -C 7) alkyl or - (C ₆ -C _lo) aryl (Cj ^ -CgJ-alkyl wherein the aryl moiety being optionally substituted by one, two or three identical or different radicals from the series F, Cl, Br, - hydroxy, Hydroxy (C ₁ -C ₄ ) alkyl, - Carboxamido, Mono- or di (C ₁ -C ₄ ) -alkylaminocarbonyl, (C ₁ -C ₄ ) -alkoxy, - (C ₁ -C ₄ -alkyl), - (C ₁ -C ₄ ) alkoxycarbonyl, - Amino, - (C ₁ -C ₄ ) -alkylamino, Di- (C ₁ -C ₄ ) -alkylamino, -carboxy, Carbamoyl, - (C ₁ -C ₄ ) alkoxycarbonylamino is substituted; 147 - Het, Het (C ₁ -C ₆ ) -alkyl, Het- (C ₅ -C ₆ ) -cycloalkyl, Het-thxo- (C ₁ -C ₄ ) -alkyl, , Het-thio (Cg-CgJ-cycloalkyl, where Het is in each case the radical of a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring system which may be aromatic, partially hydrogenated or fully hydrogenated, containing as hetero elements one, two, three or four different radicals from the group N, O, S, NO, SO, SO ₂ may contain, which may be substituted with 1 to 4 hydroxy and which optionally as in (C ₆ rC ₁₀ ) -aryl defined under a ₁ ) and / or with oxo mono-, or di-substituted, or a radical NR ¹² R ¹³ or NR ¹² * R ¹³ * or a ₂ ) - a radical of the formula VIII or VIII * mean R ^la - W (VIII) R ^la * - W * (VIII *) in which R ^1a and R ^1a * as R ¹ and R ¹ * are defined under a · ^ and W and W * for -CO-, -O-CO-, -SO ₂ -, -SO-, -S- , -NHCO- or -CH (OH) -; or in which R ¹ and R ¹ * independently of one another together with R ¹¹ or R ¹¹ * and the atoms carrying them form monocyclic, saturated or partially unsaturated ring systems having 5-8 ring members which, in addition to carbon, may also contain 1 sulfur atom, which may be added to Sulfoxide or sulfone can be oxidized; a ₃ ) - a glycosyl radical as defined in claim 1; 148 298409 R ² and R ² * independently of one another b ±) - hydrogen, - carboxy, - (C ^ -C ^ q) alkyl, which is optionally mono- or diunsaturated and which may be substituted by up to 3 identical or different radicals from the series - hydroxy, - (C ₁ -C ₇ ) -alkoxy, - (Ci-C - ^ - alkylthio, - (C ₁ -C ₇ ) -alkylsulfinyl, - (C ₁ -C ₇ ) -alkyl sulfonyl, - carboxy, - (C ₁ -C ₇ ) alkoxycarbonyl, - Cl, Er, - Amino, - Amidines, - Guanidino, - N, N ¹ -di (benzyloxycarbonyl) -guanidino, Carbamoyl, - (C ₇ -C ₁₅ ) -Aralkoxycarbonyl, - (C ₁ -C ₅ ) alkoxycarbonylamino, - (C ₇ -C ₁₅ ) -Aralkoxycarbonylamino or - 9-Fluorenylmethoxycarbonylamino is substituted; - (C ₃ -C ₁ 2) cycloalkyl, - (C ₃ -C ₁₂ ) -cycloalkyl- - (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₃ ) -alkyl, wherein the aryl moiety in each case optionally by one, two or three identical or different radicals from the series F, Cl, Br, I, - hydroxy, - (C ₁ -C ₇ ) -alkoxy, 149 - (C 1 -Cy) alkoxycarbonyl, - Amino and - Tr is luormethyl substituted; ode ,. - Het- (C ₁ -Ck) -alkyl, wherein Het is the radical of a 5- or 6-membered monocyclic or 9- to 10-membered bicyclic, optionally partially or fully hydrogenated heteroaromatic, having at least 1 C-atom, 1- 4 N atoms and / or 1-2 S atoms and / or 1-2 O atoms as Rin ^ members, which is optionally mono- or disubstituted as described in claim 1 for the aryl part, mean; or b2) together with R or R and the atoms carrying them pyrrolidine or piperidine, which may each still be fused with cyclopentyl, cyclohexyl or phenyl form, or together with R "or R ³ * and the atoms carrying them cyclic, saturated or partially unsaturated ring systems form ir.it 3-8 ring members; R ³ and R ³ * independently - hydrogen, - methyl or - ethyl; R ⁴ and R ⁴ * independently of one another - hydrogen, mean; R ⁵ , R ⁵ * and R ⁵ * are independently defined as in claim 1; 35 R ⁶ , R ⁶ * and R ⁶ ** independently 298409 150 * - hydrogen, - (C ₁ -C ₄ ) -alkyl; R ⁷ - hydrogen, - hydroxy or means; R ⁸ and R ⁸ *
independently of each other - hydrogen, - (C ₁ -CQ) -alkyl or together with R or R ⁹ and the atoms carrying them, pyrrolidine or piperidine, each of which may additionally be fused with cyclopentyl, cyclohexyl or phenyl; R ⁹ and R ⁹ * are independently defined as R and R ^ under b- ^), or (C ₁ -Cq) alkanoyloxy means or together with R ^ or R ^ and the atoms carrying them form cyclic, saturated or partially unsaturated ring systems with 5 to 12 ring members; or together with R ¹¹ or R ¹¹ * and the atoms carrying them form a mono- or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members, which may contain, in addition to carbon, 1 sulfur atom, which may optionally be oxidized to the sulfoxide or sulfone ; R ¹⁰ and R ¹⁰ * independently of each other - hydrogen or - (C ₁ -C ₄ ) -alkyl; 298409 R ¹¹ and R ¹¹ *
independently of each other - hydrogen, - hydroxy, - (C 1 -C ₄ ) alkanoyloxy or Alkyl; R ¹² , R ¹² *, R ¹³ and R ¹³ *
independently of each other
- hydrogen, - (C ₁ -C 4) - AIkYl, by - Amino, - (C ₁ -C ₄ ) -alkylamino, Di- (C ₁ -C ₄ ) -alkylamino,
- carboxy, - hydroxy or - (C ₁ -C ₄ ) -alkoxy may be substituted, - (C ₁ -C ₄ ) alkoxycarbonyl, - (C ₆ -C ₁₀ ) -aryl which may be substituted as described for R ¹ or R ¹ , - (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₄ ) alkoxy-carbonyl, - Het or Het (C ₁ -C ₄ ) -alkyl, wherein Het is defined as described for R ¹ or R ¹ *, in which in the above compounds of the formula I, one or more amide groups (-CONH-) of the main chain may be replaced by a group consisting of -CH ₂ NR-, -CH ₂ O-, -OCH ₂ -, -CH ₂ CH ₂ -, -COCH ₂ -, -CH (OH) CH ₂ -, -COO- or by an amide group of opposite polarity (-NHCO-); R ¹⁴ for
- hydrogen or stands; and their physiologically acceptable salts. 152 5. A process for preparing a compound of formula I according to claims 1 to 4, characterized in that Y is a radical of formula II or a radical of formula III;
1, m, A, A *, D, D *, n, n *, o, o * as defined in claim 1 are,
ρ and p * are 1; R ¹ and R ¹ *
stand independently for - hydrogen, - carboxyl, - (C ₃ -C ₈ ) -cycloalkyl - (Cg-CgJ-cycloalkyl- Phenyl (C ₁ -C ₈ ) -alkyl, which may be substituted in the phenyl part as in claim 4, - optionally protected mono- or di-amino (C ₁ -C ₄ ) -alkyl or amino (C ₆ -C ₁₀ ) -aryl (C ₁ -C ₄ ) -alkyl or amino (C ₃ -C ₁₀ ) -cycloalkyl (C ₁ -C ₄ ) - alkyl, - mono-, di-, tri-, tetra-, penta- or hexahydroxy- or alkanoyl, (C ₁ -C 4) -alkoxycarbonyl (C ₁ -C ₁₀ ) -alkyl, - (C 1 -C 4) -alkylsulfonyl, - (C 1 -C 6) -alkylsulfinyl, Mono-, di-, trihydroxy- (C 1 -C 4 -alkylsulfonyl, Mono-, di-, trihydroxy- (C ₁ -C ₈ ) -alkylsulfinyl, Mono-, di-, tri- or tetra- (C ₁ -C ₈ ) alkanoyloxy - (C ₁ -C ₁₄ ) alkanoyl, - optionally protected amino (C ₁ -C ₁₁ ) alkanoyl Di (C ₁ -C 7) alkylamino (C ₂ -C ₁₁ ) alkanoyl, (C ₁ -C 6) cycloalkylcarbonyl, Amino-substituted (C 3 -C 9 -cycloalkylcarbonyl, Amino-substituted (C 1 -C 9 -cycloalkylsulfonyl, 153 "(C ₆ -C ₁₀ ) -aryl" (C ₆ -C ₁₀ ) -aryloxy optionally substituted by amino, halogen, (C ₁ -C ₇ ) -alkyl, (C ₁ -C 4) -alkoxy or (C ₁ -C ₆ -cyclo-alkoxycarbonyl-substituted benzoyl, benzenesulfonyl or (C ₆ -C ₁₀ ) -aryl (C ₁ -C 4) -alkylcarbonyl or -sufonyl, - (C ₁ -C ₁₀ ) -tractoloxycarbonyl, - substituted (C 1 -C 4) -alkoxycarbonyl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkoxycarbonyl, - substituted by optionally protected amino and hydroxy (C ₆ -C ₁₀₎ -aryl- (C ₁ -C ₈₎ alkyl, ^(C3-C ₁₀₎ cycloalkyl (C - ^ - CGJ-alkyl or (C ₁ -C ₁₀ ) -alkyl, 9-fluorenylmethoxycarbonyl, 15 - ketohexosyl, - ketopentosyl, - deoxyhexoketosyl, - deoxypentoketosyl, - aldohexosyl, - aldopentosyl, - deoxyhexoaldosyl, - deoxypentoaldosyl, 2-amino-2-deoxyhexosyl, 2-acetamido-2-deoxyhexosyl, - lactosyl or Maltosyl wherein the linked sugars may be in pyranose or furanose, - Het (C ₁ -C ₆ ) -alkyl - Het-carbonyl or -sulfonyl, Het (C ₁ -C ₆ ) alkylcarbonyl or sulfonyl, Het-mercapto (C ₁ -C ₆ ) -alkylcarbonyl or -sulfonyl, where Het each for 35 154 Furyl, thienyl, benzothienyl, benzodioxolanyl, pyrrolyl, imidazolyi, isoxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolidyl, piperidyl, piperazinyl, morpholino, thiomorpholino, tetrahydrofuryl, tetrahydropyryl, tetrahydrothienyl, indolyl, quinolyl or isoquinolyl, this also by one or two identical or different radicals from the group (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) Alkoxycarbonyl amino, hydroxy, amino, mono- or di- (C ₁ -C ₄ ) -alkylamino and oxido may be substituted; R ² and R ² * are independent of each other - hydrogen, - carboxyl, - (C 1 -C 3 -C 6) -alkyl which may be substituted by up to the same or different radicals from the series - hydroxy, - (C ₁ -C ₄ ) -alkoxy, - (C ₁ -C ₄ ) -alkylsulfinyl, - (C ₁ -C ₄ ) -alkylsulfonyl, - (C ₁ -C ₄ ) -alkanoyloxy, - carboxy, - (C ₁ -C ₄ ) alkoxycarbonyl, - Amino, - Amidino, - Guanidino, N, N'-di (benzyloxycarbonyl) guanidino, Carbamoyl, - (C ₆ -C ₁₀ ) aryl- (C ₁ -C 3) alkoxycarbonyl, - (C 1 -C 3 -C) -alkoxycarbonylamino, - (C ₆ -C ₁₀ ) -aryl (C ₁ -C ₃ ) alkoxycarbonylamino is substituted or 155 (C ₃ -C ₁₀ ) -cycloalkyl- (C ₁ -C ₃ ) -alkyl, - (C ₁ -C ₄₎ alkyl- (C ₃ -C ₁₀₎ -cycloalkyl- (C ₁ -C ₃₎ alkyl _/ "(C ₆ -C ₁₀₎ -aryl, - (C ₆ -C ₁₀ ) -aryl (C ₁ -C ₃ ) -alkyl, wherein the aryl part in each case optionally by one, two or three identical or different radicals from the series - F, Cl, Br, - hydroxy, - (C ₁ -C ₄ -alkoxy-J, - (C ₁ -C ₄₎ -alkyl, - (C ₁ -C ₄ ) alkoxycarbonyl and - Amino is substituted, or - Het- (C ₁ -C ₄ ) -alkyl, wherein Het is as defined for R ¹ or R ¹ *, means; R ³ and R ³ * independently of each other - hydrogen or - methyl; 20 R ⁴ and R ⁴ * independently of each other - hydrogen or - methyl; 25 R ⁵ , R ⁵ * and R ⁵ ** independently - hydrogen, - hydroxy,
- Amino or - Carboxy mean; R ⁶ , R ⁶ * and R ⁶ ** independently of one another - hydrogen or - methyl; 156 298 * 09 R ⁷ - hydrogen, - hydroxy or - methyl means; 5 R ⁸ and R ⁸ * independently of each other - hydrogen, Methyl, ethyl or n-propyl or, together with R 'or R and the atoms carrying them, form a 1,2,3,4-tetrahydroisoquinoline or a 2-azabicyclooctane skeleton; R ⁹ and R ⁹ *
are independently defined as R ^ or R ^ in claim 4, or (C ^ -Cq) alkanoyloxy or form together with R and R and the atoms carrying them cyclic ring systems with 5 to 7 ring members; or together with R or R 1 form a thiochroman system whose sulfur atom may optionally be oxidized to the sulfone; R ¹⁰ and R ¹⁰ * independently - hydrogen or - methyl; R ¹¹ and R ¹¹ * are as defined in claim 4; in which in the above compounds of formula I, one or more amide groups (-CONH-) of the main chain may be replaced as defined in claim 4; 157 29 ** 09 R ¹⁴ for - hydrogen or - methyl is; , and their physiologically acceptable salts. 6. A process for the preparation of a compound of formula I according to claims 1 to 5, characterized in that R ¹ and R ¹ * stand independently for a-jj - hydrogen, - carboxyl, - (C ₁ -C ₁₆ ) alkylsulfonyl, - (C ₁ -C ₈ ) -alkylsulfinyl, - (C ₁ -Cg) -MOnO-, di- or tri-hydroxyalkylsulfonyl, Hydroxy (C ₁ -C ₁₀ ) alkanoyl, Mono-, di-, tri- or tetra-hydroxy- (C ₁ -C ₄ ) -alkyl, - (C ₁ -C ₆ -alkanoyloxy- (C ₁ -C ₁₀ ) -alkyl, 1,2-diacetoxyethyl, 1,2,3-triacetoxypropyl, - (C ₁ -C ₁₄ ) alkanoyl, Amino (C ₁ -C ₁₂ ) alkanoyl 1, N- (C 1 -C 3) -alkoxycarbonylamino (C 1 -C 3) alkyl, Di (C ₁ -C ₇ ) alkylamino (C ₂ -C ₁₁ ) alkanoyl, - (C 3 -C 9 -cycloalkylcarbonyl, Amino (C 3 -C 6) -cycloalkylcarbonyl, - Amino- (C3-Cg) -cycloalkylsulfonyl, - phenyl - (C ₆ -C ₁₀ ) aryl- (C ₂ -C _n ) alkanoyl, - (C ₆ -C ₁₀ ) -Aryloxy- (C ₂ -C _{1: L} ) -alkanoyl, - optionally substituted by halogen, amino, (C ₁ -C ₇ ) alkyl, (C ₁ -C ^) - AIkOXy or (C ^ C ^ alkoxycarbonyl substituted benzoyl or - benzenesulfonyl - optionally substituted by halogen, amino, (C ₁ -C ^) - alkyl, (C ₁ -C ₇ -alkoxy-J or (C ₁ -C ₇₎ alkoxycarbonyl substituted benzylsulfonyl, benzylsulfinyl or benzylthio, - Amino, - (C 1 -C 4) -alkoxycarbonylamino, - (C ₁ -C ₁ 2) -alkanoyl _/ which is substituted by hydroxy, amino and optionally by phenyl or cyclohexyl, optionally protected amino-substituted (C ₆ -C ₁₀ ) -aryl or (C ₃ -C ₁₀ ) -cycloalkyl- (C ₁ -C ₄ ) -alkyl or (C ₁ -Cg) -alkyl, - (C ₁ -C ₁ Q) alkoxycarbonyl, substituted (C 1 -C 3) -cyclo-Q 1 -alkoxycarbonyl, - 9-fluorenylmethoxycarbonyl, 1-deoxyhexoketosyl or 1-deoxypentoketosyl, Hexosyl or pentosyl, 6-deoxyhexosyl, - Amino sugar residues, - lactosyl
- Kaltosyl wherein the linked sugars may be in the pyranose or furanose form, -.Het, Het carbonyl or het sulfonyl, Het (C ₁ -C ₆ ) -alkyl, Het (C ₁ -C ₆ ) alkanoyl, - Ht- (C ₁ -C ₆ ) alkylsulfonyl or - Het-mercapto (C ₁ -Cg) alkylcarbonyl, wherein Het in each case represents - pyrrolyl, - imidazolyl, - Pyridyl, Pyrimidyl,
- Pyrrole idyl, - piperidyl, 159 - morpholino, - quinolyl or - isoquinolyl, this one also by one or two same. or different radicals from the group (C · ^ -C ^) - alkyl, (C ₁ -C ₄₎ alkoxycarbonyl, (C ₁ -C ₄₎ alkoxycarbonylamino, hydroxy, amino, mono- or di- (C- ^ -C ^ alkylamino may be substituted; O ic R '' and R independently represent - hydrogen, - carboxyl, Methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, - cyclohexyl, Cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 4-methylcyclohexylmethyl, 1-decahydronaphthylmethyl, 2-decahydronaphthylmethyl, - phenyl,
Benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 4-tert-butylbenzyl, 4-tert-butoxybenzyl 4-hydroxybenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, - (benzdioxolan-5-yl) methyl, 4-chlorobenzyl, Hydroxymethyl, 1-hydroxyethyl, 4-pyridyl, 4- (N-oxidopyridyl), 160 298 Ί09 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyi, 2- (4-pyridyl) ethyl, 2-thienylmethyl, 3-thienylmethyl, 2- (2-thienyl) ethyl, 2- (3-thienyl) ethyl, -indol-2-yl-methyl, indol-3-yl-methyl, - (1-methylimidazol-4-yl) methyl, Imidazol-4-ylmethyl, imidazol-1-ylmethyl, 2-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidylmethyl, 2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyi, 2-furylmethyl, 2- (methylthio) ethyl, 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ¹⁰ and R ¹⁰ * are hydrogen; R ⁵ and R ⁵ * stand independently for - hydrogen - hydroxy or - amino;
25 R ⁷ - hydrogen, - hydroxy or - methyl means; R ⁸ and R ⁸ * mean independently of each other - hydrogen or together with R or R ^ and the atoms carrying them form a 1,2,3,4-tetrahydroisoquinoline or 2-azabicyclooctane skeleton; 161 298 * 0 $ R ⁹ and R ⁹ * independently of each other as R ² or R ² * are defined or - hydroxy,
Acetoxy, tert-butoxymethyl, 3-guanidinopropyl, Carbamoylmethyl, carbamoylethyl, Carboxymethyl, carboxyethyl, mercaptomethyl, - (1-mercapto-1-methyl) ethyl, Aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, N, N-dimethylamino, - N, N ¹ -di (benzyloxycarbonyl) -guanidino-propyl, - 2-Benzyloxycarhonylethyl, benzyloxycarbonylmethyl tert-butylsulfonylmethyl or 4-benzylcarbonylaminobutyl; 20 R and R independently - hydrogen, - hydroxy or - acetoxy; 25 in which in the above compounds of this invention, one or more amide groups (-CONH-) of the main chain may be replaced by -CH ₂ NR ₁₄ - or -CH (OH) CH ₂ -; R ¹⁴ for ' - hydrogen or - methyl is; and their physiologically acceptable salts. 35 I ₆₂ 7. A method for Hei division of a compound of formula I according to claims 1 to 6, characterized in that R ¹ and R ¹ *
stand independently for a ^) - hydrogen, - carboxyl, - (C ₁ -C ₁₆ ) alkylsulfonyl, - (C ₁ -Cg) -MOnO- or dihydroxyalkylsulfonyl, Mono-, di- or trihydroxy- (C ₁ -C 3) -alkyl, - (C 1 -C 3 -C) -alkoxycarbonyl, - (C ₁ -C ₁₄ ) -mayanoyl, - amino (C ₁ -C ₁ 2) alkanoyl (C ₁ -C ₄ ) 1-aryl- (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₆ -C ₁₀ -aryl (C 1 -C 4) -alkylcarbonyl, - 9-fluorenylmethoxycarbonyl, (C ₁ -C ₆ ) -alkanoyloxy (C ₁ -C ₆ ) -alkyl, 1,2-diacetoxyethyl, 1,2,3-triacetoxypropyl, - phenyl optionally benzenesulfonyl substituted by halogen, amino, (C ₁ -C ₄ ) -alkyl, or methoxy, benzylsulfonyl, -sulfinyl or -thio optionally substituted by halo, amino, (C ₁ -C 4) -alkyl, or methoxy, Het or Het sulphonyl, Het (C ₁ -C ₄ ) alkanoyl, Het-mercapto (C ₁ -C ₃ ) alkylcarbonyl, 30 where Het each stands for - pyrrolyl, - imidazolyl, - Pyridyl,
Pyrimidyl, - Pyrrole idyl, - quinolyl, 163 J98409 - isoquinolyl, - piperidyl or - morpholino, this remainder also being replaced by one or two. identical or different radicals from the group methyl, amino and (C 1 -C 4) -alkoxycarbonylamino may be substituted, Amino (C 3 -C 4) -cycloalkylcarbonyl, - (C 1 -C 8) -alkanoyl which is substituted by hydroxy and amino and optionally by phenyl or cyclohexyl, optionally protected amino-substituted phenyl or cyclohexyl (C 1 -C 8) -alkyl, - Amino, - (C ₁ -C _i j) alkoxycarbonylamino, Benzyloxycarbonylamino, 1-deoxyhexoketosyl or 1-deoxypentoketosyl, Hexosyl or pentosyl, wherein the linked sugars may be in the pyranose or furanose form, R and R ^ independently represent - hydrogen, Methyl, ethyl, isopropyl, n-propyl, η-butyl, isobutyl, sec-butyl, pentyl, hexyl,
'Cyclopentylmethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, Benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 4-tert-butylbenzyl,
4-methoxybenzyl, 3,4-dihydroxybenzyl, 2,4-dimethoxybenzyl, 164 298103 - 3,4-dimethoxybenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, - 3,4-methylenedioxybenzyl or - 2- (4-pyridyl) ethyl, 5 R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ⁷ , R ¹ O and R ¹⁰ * are hydrogen; R ⁵ and R ⁵ * are independent of each other - hydrogen or - hydroxy; R ° and R ° are independently defined as in claim; R ⁹ and R ⁹ * are independently defined as R and R, respectively; 20 R and R are independently defined as claim, and their physiologically acceptable salts. 8. A process for the preparation of a compound of formula I according to claims 1 to 7, characterized in that Y is a radical of formula III; 10 or 1; m is 1; A, A, D and D * are as defined in claim 1; 35 η, η *, ο, ο *, ρ and p * are independently 0 or meaning; 165 E, E, F, F *, G and G independently represent an amino acid selected from VaI, Lys, Lys (2), Phe, Chg, Ser, Asn, Gly, He, Tbg, Nva or Npg; R ¹ and R ^{1 are} independent of each other - hydrogen, - carboxyl, Methylsulfonyl, tert-butylsulfonyl, tert-butoxycarbonyl, 2-hydroxyethylsulfonyl, 1,2,3-trihydroxypropyl, 1,2,3-triacetoxypropyl, Benzyloxycarbonyl, 4-methylphenylsulfonyl, 4-chlorobenzylthio, Benzylsulfinyl, 4-chlorobenzylsulfonyl, Hexadecylsulfonyl, 4-amino-1-piperidyl-sulfonyl, N-tert-butoxycarbonyl-4-amino-1-piperidyl-sulfonyl, 4-amino-1-piperidylcarbonyl, N-tert-butoxycarbonyl-4-amino-1-piperidylcarbonyl, 2-amino-3-phenylpropyl, N-tert-butoxycarbonyl-2-amino-3-phenylpropyl, 2-amino-1-hydroxy-4-methyl-pentyl, - deoxyfructos-1-yl, - mannofuranosyl, 4-aminocyclohexylcarbonyl, 2-pyridylacetyl, 4-pyridylthioacetyl, 2-quinolylcarbonyl, 1-naphthylacetyl, 1-naphthyloxyacetyl, , l- (4-pyridyl) ethylsulfonyl, 12-aminododecanoyl, 4- (N-oxidopyridyl), 166 4-pyridyl, - tetradecanoyl, - phenyl, - Amino or tert-butoxycarbonylamino; R ² and r ^{2 are} independent of each other - hydrogen, 2- (4-pyridyl) ethyl, isopropyl, Isobutyl, n-pentyl, Benzyl, 3,4-methylenedioxybenzyl, 2,4-dimethoxybenzyl, - 4-tert-butylbenzyl, • - 2-phenylethyl or - cyclohexylmethyl; R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ⁷ , R ¹⁰ and R ¹⁰ * - mean hydrogen; R ⁵ and R ^ independently of one another - hydrogen or - hydroxy; R ⁸ and R ⁸ * Q Q * Hydrogen or together with R or R 'and the atoms carrying them form a 1,2,3,4-tetrahydroquinoline-3,4-diyl system; R and R independently Hydrogen, hydroxy, Acetoxy, - n-propyl, I ₆₇ Z 984 - isopropyl, - isobutyl, - aminomethyl, 4-aminobutyl,. Hydroxymethyl, tert-butoxymethyl, - aminocarbonylmethyl, 2-benzyloxycarbonyl-ethyl, 4-benzyloxycarbonylamino-butyl, N, N'-di- (benzyloxycarbonyl) -guanidino-propyl, - cyclohexyl, - cyclohexylmethyl, Benzyl, 2-phenylethyl-4-hydroxybenzyl 4-methoxybenzyl, 4-tert-butoxybenzyl, - 1-naphthylmethyl, 2-thienylmethyl, - 1 ~ imidazolylmethyl, 3-indolyl-methyl, 4-pyridylmethyl - 4- (N-Oxiaopyridyl) methyl 2-methylthio-ethyl, 2-methylsulfonyl-ethyl tert-butylsulfonyl-methyl or - 2-carboxyl-ethyl; R ^ and R are independent of each other - hydrogen, - hydroxy or - acetoxy; wherein in the above compounds one or more amide groups (-CONH-) of the main chain may be replaced by -CH ₂ NH- or -CH (OH) CH ₂ -; and their physiologically acceptable salts. 168 9. A process for the preparation of a compound of formula I according to claims 1 to 8, characterized in that 1 = 0; m = 1; η + ο + ρ = 1; D and D * are a radical of the formula VI or VI * R ¹ and R ¹ * - (C ^ -C ^ alkylsulfonyl, ^{which may} be substituted by up to the same or different radicals from the series - hydroxy, - amino or - Carboxy may be substituted; mean; R and R ^ are independently hydrogen, - carboxyl, Methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, - cyclohexyl, Cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 4-methylcyclohexylmethyl, 1-decahydronaphthylmethyl, 2-decahydronaphthylmethyl, - phenyl, Benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 4-tert-butylbenzyl, 4-tert-butoxybenzyl 4-hydroxybenzyl, 4-methoxybenzyl, 169 298409 2,4-dimethoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (Benzdioxolan-4-yl) methyl, 4-chlorobenzyl, Hydroxymethyl, 1-hydroxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 2-thienylmethyl, 3-thienylmethyl, 2- (2-thienyl) ethyl, 2- (3-thienyl) ethyl, Indole-2-ylmethyl, indol-3-ylmethyl, - (1-methyl-imidazol-4-yl-methyl, Imidazol-4-ylmethyl, imidazol-1-ylmethyl, 2-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidylmethyl, 2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyl, 2-furylmethyl, 2- (methylthio) ethyl, - 2- (methylsulfinyl) ethyl or - 2- (methylsulfonyl) ethyl; R ³ , R ³ *, R ⁴ , R ⁴ *, R ⁶ , R ⁶ *, R ¹¹ and R ¹¹ * - are hydrogen; R ⁵ and R ⁵ * - hydroxy; R ⁹ and R ⁹ * as defined in claim 8; and their physiologically acceptable salts. 10. A process for the preparation of a pharmaceutical agent, comprising a compound of formula I according to claims 1 to 8, characterized in that this 170 29 * 4 * 3 and optionally one or more carriers in a suitable dosage form brings. 11. Use of a compound of formula I according to claims 1 to 9 as a remedy. 12. Use of a compound of the formula I according to claims 1 to 9 for the inhibition of retroviral proteases. 13. Use of a compound of the formula I according to claims 1 to 9 in the treatment of the acquired immune deficiency syndrome.