RU2262508C2 - New thrombin inhibitors, their preparing and applying - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

23 cl, 61 ex

Description

Field of Invention

The present invention relates to new pharmaceutically useful compounds, in particular to competitive inhibitors of trypsin-like serine proteases, especially thrombin, to their use as medicines, to pharmaceutical compositions containing them and to synthetic methods for their preparation.

BACKGROUND OF THE INVENTION

Blood coagulation is a key process that includes both homeostasis (i.e. preventing the loss of blood from damaged vessels) and thrombosis (i.e. the formation of a blood clot in a blood vessel or heart, which sometimes leads to blockage of blood vessels).

Coagulation is the result of a complex series of enzymatic reactions. One of the main stages in this series of reactions is the conversion of the proenzyme of prothrombin to the active enzyme thrombin.

Thrombin is known to play a central role in coagulation. It activates platelets, which leads to their aggregation, converts fibrinogen into fibrin monomers, which spontaneously polymerize into fibrin polymers, activates factor XIII, which, in turn, crosslinkes these polymers to form insoluble fibrin. Further, thrombin activates factor V and factor VIII, which leads to the generation of thrombin from prothrombin by the method of "positive feedback".

It can be expected, therefore, that effective thrombin inhibitors will exhibit antithrombotic activity by inhibiting platelet aggregation and the formation and crosslinking of fibrin. In addition, antithrombotic activity can be expected to be enhanced by effective inhibition of the positive feedback mechanism.

State of the art

The development of low molecular weight thrombin inhibitors has been described [Claesson, Blood Coagul. Fibrinol. (1994) 5, 411].

Known [Blombaeck et al., J. Clin. Lab.lnvest. 24, suppl.107, 59, (1969)] thrombin inhibitors based on the amino acid sequence located around the fibrinogen Aα chain cleavage site. According to the authors, of the considered amino acid sequences, the most effective inhibitor could be the Phe-Val-Arg sequence (P9-P2-P1, which is hereinafter referred to as the P3-P2-P1 sequence) [classification of substrate specificity is given in Schechten and Bergen, Biophys.Res.Commun. (1967) 27, 157; and (1968) 32, 898].

Known [US patent No. 4346078, International application WO 93/11152] thrombin inhibitors based on dipeptidyl derivatives with α, ω-aminoalkylguanidine in position P1. Similarly, structurally related dipeptidyl derivatives were reported. For example, compounds are known [International Application WO 94/29336] with, for example, aminomethylbenzamidines, cyclic aminoalkylamidines and cyclic aminoalkylguanidines at position P1; known [European Patent Application 0648780] are compounds with, for example, cyclic aminoalkylguanidines at position P1.

Known [European patent applications 0468231, 0559046 and 0641779] peptidyl derivative thrombin inhibitors also having cyclic aminoalkylguanidines (for example, either 3- or 4-aminomethyl-1-amidinopiperidine) at position P1.

Known [Application for European patent 0185390] thrombin inhibitors based on tripeptidyl derivatives with arginine aldehyde in position P1.

More recently, arginine aldehyde-based peptidyl derivatives modified in position P3 have been described, for example with hydroxy acids [International Application WO 93/18060], deamino acids [European Patent Application 0526877], O-methyl mandelic acids [European Patent Application 0542525] in position P3 .

Inhibitors of serine proteases (for example, thrombin) based on electrophilic ketones in position P1, for example, peptidyl α-ketoesters and amides [European Patent Application 0195212], fluoroalkylamide ketones [European Patent Application 0362002], α, β, δ-triceto compounds [α, β, δ-triceto compounds [] are also known. European Patent Application 0364344] and α-alkoxyketone derivatives of arginine [European Patent Application 0530167].

Known [Application for European patent 0293881] and other structurally different trypsin-like serine protease inhibitors based on arginine derivatives with C-terminal boronic acids and their isothiouronium analogues.

More recently [European Patent Applications 0669317, 0686642, 0648780 and International Applications WO 95/35309, WO 95/23609 and WO 94/29336] tripeptidyl derivative thrombin inhibitors have been disclosed.

However, there remains a need for effective trypsin-like serine protease inhibitors such as thrombin. There is a particular need for compounds that are both orally bioavailable and selective for thrombin inhibition, and not other serine proteases. Compounds that exhibit competing inhibitory activity against thrombin can be expected to be particularly useful as anticoagulants and, therefore, useful in the therapeutic treatment of thrombosis and related diseases.

SUMMARY OF THE INVENTION

The invention provides compounds of formula I

Where

p and q are independently 0, 1, 2, 3 or 4;

R ¹ represents H, 2,3-epoxypropyl, C _1-6 alkyl (the latter optionally substituted or terminated by one or more hydroxy groups), a structural fragment of formula Ia

where A ¹ represents a single bond or C _1-4 alkylene, and R ^x represents H or C _1-4 alkyl, provided that in the chain R ^x -CCA ¹ there are no more than six carbon atoms, or when p is 0 , then together with R ² represents a structural fragment of formula 1b

where R ^y represents H or C _1-3 alkyl;

R ² represents H, Si (Me) ₃ , naphthyl, indolyl, CHR ²¹ R ²² or C _1-4 alkyl (the latter optionally substituted or terminated by one or more fluoro or hydroxy groups), or C _3-8 cycloalkyl or phenyl (the last two groups are possibly substituted by one or more than C _1-4 alkyl, C _1-4 alkoxy, halogen, hydroxy, cyano, nitro, methylenedioxy, trifluoromethyl, N (H) R ²³ , C (O) OR ²⁴ groups ), or when p is 0, then together with R ¹ represents a structural fragment of formula 1b;

R ³ represents H, Si (Me) ₃ , naphthyl, indolyl, CHR ²⁵ R ²⁶ or C _1-6 alkyl (the latter optionally substituted or terminated by one or more fluoro or hydroxy groups), or C _3-8 cycloalkyl or phenyl (the last two groups are possibly substituted by one or more than C _1-4 alkyl, C _1-4 alkoxy, halogen, hydroxy, cyano, nitro, methylenedioxy, trifluoromethyl, N (H) R ²⁷ or C (O) OR ²⁸ groups );

R ²¹ , R ²² , R ²⁵ and R ^{26 are} independently cyclohexyl or phenyl;

R ²³ and R ²⁷ independently from each other represent H, C _1-4 alkyl or C (O) R ²⁹ ;

R ²⁴ , R ²⁸ and R ²⁹ independently from each other represent H or C _1-4 alkyl;

R ⁴ represents H or C _1-4 alkyl;

Y represents C _1-3 alkylene, optionally substituted with C _1-4 alkyl, hydroxyl, methylene or oxo;

n is 0, 1, 2, 3 or 4; and

C is a structural fragment of formula IVa, IVb or IVc

Where

R ⁵ represents H, halogen or C _1-4 alkyl; and

X ¹ and X ² independently represent a single bond or CH ₂ ;

with the proviso that when R ¹ , R ² and R ⁴ are all H, p is 0, Y is (CH ₂ ) ₂ , n is 1 and:

(a) R ³ is unsubstituted phenyl and:

(1) B is a structural fragment of formula IVa, and R ⁵ is H, then q is not 0 or 1; and

(2) C is a structural fragment of formula IVb, and X ¹ and X ² are both CH ₂ , then q is not 0; and

(b) R ³ is unsubstituted cyclohexyl, B is a structural fragment of formula IVa, and R ⁵ is H, then q is not 0;

or a pharmaceutically acceptable salt thereof (here referred to as “the compounds of the invention”).

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of this invention.

The compounds of the invention may also contain one or more asymmetric carbon atoms and, therefore, may exhibit optical isomerism and / or diastereoisomerism. All diastereoisomers can be resolved using conventional techniques, for example, chromatography or fractional crystallization. Para 3 stereoisomers can be isolated by resolution of a racemic or other mixture of compounds using conventional techniques, for example fractional crystallization or HPLC (high performance liquid chromatography). Alternatively, the desired optical isomers can be obtained by reacting suitable optically active starting materials under conditions which do not allow racemization or epimerization, or by derivatization, for example with homochiral acid, followed by separation of the diastereomeric esters by conventional methods (e.g., HPLC or chromatography on silica). All stereoisomers are included within the scope of this invention.

Alkyl groups with which R ¹ , R ^x , R ^y , R ² , R ³ , R ⁴ , R ⁵ , R ²³ , R ²⁴ , R ²⁷ , R ²⁸ and R ²⁹ can be represented, or with which R ² can be substituted R ³ and Y;

cycloalkyl groups with which R ² , R ³ may be represented; and alkoxy groups with which R ² and R ³ may be substituted may be linear or branched, saturated or unsaturated. Alkylene groups with which A ¹ and Y may be represented may be saturated or unsaturated.

Halogen groups with which R ⁵ can be represented and with which R ² and R ³ can be substituted include fluorine, chlorine, bromine and iodine.

The wavy lines of carbon atoms on fragments of formulas Ia, Ib, IVa, IVb, and IVc indicate the position of the bond of the fragment.

Abbreviations are listed at the end of the description of the invention.

When B is a structural fragment of formula IVa, IVc or IVb, in the latter of which X ¹ and X ^{2 are} both CH ₂ , preferred compounds of the invention include those in which n is 1.

When B is a structural fragment of formula IVb in which X ¹ is a single bond and X ² is either a single bond or CH ₂ , preferred compounds of the invention include those in which n is 2.

When B is a structural fragment of formula IVa, preferred compounds of the invention include those in which R ⁵ is H.

Preferred compounds of formula I include those in which:

R ¹ represents H, methyl, 2,3-dihydroxypropyl or (2,2-dimethyl-1,3-dioxalan-4-yl) methyl;

p is 0;

R ² represents H, optionally substituted C _1-4 alkyl, or optionally substituted phenyl; q is 0, 1 or 2;

R ³ represents C _1-6 alkyl, naphthyl, indolyl, optionally substituted cyclohexyl or optionally substituted phenyl;

Y represents CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ , CH ₂ CH (CH ₃ ) CH ₂ , CH ₂ C (= O) CH ₂ or CH ₂ C (= CH ₂ ) CH ₂ ;

R ⁴ represents N.

When R ² is C _1-4 alkyl, preferred possible substituents include a hydroxy group. Preferred attachment points for the hydroxy group include a carbon atom which is an α atom with respect to the carbon atom to which OR ¹ is attached.

More preferred compounds of the invention include those in which:

R ¹ represents H;

R ² represents H, methyl, hydroxymethyl or ethyl;

q is 0:

R ³ represents a possibly substituted phenyl or a possibly substituted cyclohexyl;

Y represents CH ₂ , (CH ₂ ) ₂ or CH ₂ C (= CH ₂ ) CH ₂ .

When R ¹ and R ^{2 are} both H, R ³ is unsubstituted phenyl or unsubstituted cyclohexyl, and q is 0 or 1, preferred compounds of the invention include those in which Y is CH ₂ or CH ₂ C (= CH ₂ ) CH ₂ .

When R ¹ is H, R ³ is unsubstituted phenyl or unsubstituted cyclohexyl, and q is 0 or 1, preferred compounds of the invention include those in which R ² is methyl, hydroxymethyl or ethyl.

When R ³ is cyclohexyl or phenyl, preferred possible substituents include hydroxy, fluoro, chloro, methyl, methoxy, amino, nitro, trifluoromethyl, methylenedioxy, ethoxy and propoxy groups. In particular, substituents include hydroxy, mono or difluoro, chloro, methyl, methoxy and methylenedioxy groups.

Particularly preferred compounds of the invention include those in which:

Y represents CH ₂ ;

B is a structural fragment of formula IVa.

The compounds of the invention in which the α-amino acid carbon of the fragment

is in S-configuration, preferred. The wavy lines at the nitrogen and carbon atoms in the above fragment indicate the bond position of the fragment.

When R ¹ and R ^{2 are} both H and p is 0, preferred compounds of the invention are those in which the α-carbon moiety

is in R configuration. The wavy line at the carbon atom of the above fragment indicates the bond position of this fragment.

Preferred compounds of the invention include:

Ch- (R, S) CH (OH) -C (O) -Aze-Pab;

Ch- (R) CH (OH) -C (O) -Aze-Pab;

Ph- (R) CH (OH) -C (O) -Aze-Pab;

Ph (3-Me) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph (3-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph- (R, S) C (Et) (OH) -C (O) -Aze-Pab;

Ph- (R, S) C (Et) (OH) -C (O) -Pro-Pab;

(Ph) ₂ C (OH) -C (O) -Aze-Pab;

Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph- (R) CH (OH) -C (O) -Aze-Pac;

Ph- (R) CH (OH) -C (O) - (R, S) Pic (cis-4-Me) -Pab;

Ph (3.4 - (- O-CH ₂ -O -)) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph (3-OMe) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph- (R, S) C (Me) (OH) -C (O) -Aze-Pab;

Ph (3,5-diMe) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph (3.4 - (- O-CH ₂ -O -)) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph (3,5-diF) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) -Aze-Pab;

Ph- (R) C (Me) (OH) -C (O) -Pro-Pab;

Ph- (S) C (Me) (OH) -C (O) -Pro-Pab;

Ph (3,4-diF) - (R, S) CH (OH) -C (O) -Pro-Pab;

Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-methylene) -Pab;

Ph (3-Cl) - (R, S) CH (OH) -C (O) -Aze-Pab;

Ph- (R, S) C (-OC (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Aze-Pab;

Ph- (R, S) C (-O-C (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Pro-Pab,

Ph- (R, S) C (CH ₂ OH) (OH) -C (O) -Aze-Pab; and

Ph- (R, S) C (CH ₂ OH) (OH) -C (O) -Pro-Pab.

Getting

The invention also provides a process for preparing compounds of formula I, in which:

(a) combine a compound of formula V

where p, q, R ¹ , R ² and R ³ are as defined above, with a compound of formula VI

where R ⁴ , Y, n and B are as defined above;

or (b) combine a compound of formula VII

where p, q, R ¹ , R ² , R ³ , R ⁴ and Y are as defined above, with a compound of formula VIII

where n and B are as defined above;

for example, in the presence of a combination system (e.g., oxalyl chloride in DMF, EDC, DCC or TBTU) of the appropriate base (e.g., pyridine, DMAP or DIPEA) and a suitable organic solvent (e.g., dichloromethane, acetonitrile or DMF).

Compounds of formula V are either commercially available, well known in the literature, or can be prepared using known techniques.

For example, compounds of formula V where R ¹ and R ^{2 are} both H, p and q are 0, and R ³ is naphthyl or phenyl optionally substituted with one or more C _1-4 alkyl, C _1-4 alkoxy , halogen, hydroxy, cyano, methylenedioxy, nitro, trifluoromethyl, N (H) R ²⁷ or C (O) R ²⁸ can be obtained by reacting an aldehyde of the formula IX

where R ^3a represents naphthyl or phenyl optionally substituted with one or more C _1-4 alkyl, C _1-4 alkoxy, halogen, hydroxy, cyano, methylenedioxy, nitro, trifluoromethyl, N (H) R ²⁷ or C (O ) OR ²⁸ , and R ²⁷ and R ²⁸ are as defined above, with:

(1) a compound of formula X

where R "represents H or (CH ₃ ) ₃ Si, for example at elevated temperature (for example, above room temperature, but below 100 ° C) in the presence of a suitable organic solvent (e.g. chloroform) and, if necessary, in the presence of a suitable catalytic systems (e.g. benzylammonium chloride) followed by hydrolysis in the presence of an appropriate base (e.g. NaOH);

(2) chloroform, for example at elevated temperature (for example, above room temperature, but below 100 ° C) in the presence of a suitable organic solvent (e.g. chloroform) and, if necessary, in the presence of a suitable catalyst system (e.g. benzylammonium chloride) followed by hydrolysis in the presence of an appropriate base (e.g., NaOH);

(3) a compound of formula XI

where M represents Mg or Li followed by oxidative cleavage (for example, ozonolysis or catalyzed by osmium or ruthenium) under conditions well known to specialists; or

(4) tris (methylthio) methane under conditions well known to those skilled in the art, followed by hydrolysis in the presence of an appropriate base.

A compound of formula V wherein R ¹ is H, R ² is CH ₂ OH, p and q are both 0, and R ³ is naphthyl or phenyl optionally substituted with one or more C _1-4 alkyl, C _{1 -4} alkoxy, halogen, hydroxy, cyano, methylenedioxy, nitro, trifluoromethyl, N (H) R ²⁷ or C (O) OR ²⁸ can be obtained by reacting a compound of formula XII

where R ^3a is as defined above with sodium hypochlorite, for example, at room temperature in the presence of a suitable solvent (e.g. water).

Compounds of formula VI and VII are either commercially available, well known in the literature, or can be prepared using known techniques. For example, compounds of formula VI can be prepared by standard peptide coupling of a compound of formula XIII

where R ⁴ and Y are as defined above with a compound of formula VIII as defined above, for example, under conditions such as those described above for the synthesis of a compound of formula I. Similarly, a compound of formula VII can also be prepared by standard peptide coupling of a compound of formula XIII as defined above with a compound of formula V as defined above, for example, under conditions such as those described above for the synthesis of a compound of formula.

Compounds of formula VIII, IX, X, XI, XII and XIII are either commercially available, well known in the literature, or can be prepared using known techniques. Substituents on the phenyl group in the compounds of formula V, VII, IX and XII can be subjected to interconversion using methods well known to those skilled in the art.

Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.

It will be apparent to those skilled in the art that in the above method, it may be necessary to protect the functional groups of the intermediates with protecting groups.

Functional groups which it is desirable to protect include hydroxy, amino, amidino, guanidino groups and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for hydroxy groups attached to an adjacent carbon atom include O, O'-isopropylidene. Suitable protecting groups for amino, amidino and guanidino groups include tert-butyloxycarbonyl or benzyloxycarbonyl. The nitrogen atoms of amidino and guanidino groups can be either mono- or dizoprotected. Suitable protecting groups for carboxylic acids include C _1-6 alkyl or benzyl esters.

The introduction and deprotection of functional groups may take place before or after the coupling reaction.

In particular, the compounds of the invention can be prepared by a process comprising a combination of N-acylated amino acids or N-protected amino acids. When using N-protected amino acids, then the acyl group can be introduced after combination, and deprotection of the nitrogen atom can then be carried out using standard methods.

Protecting groups can be removed according to methods known to those skilled in the art and as described below.

Some protected intermediates of formula I, in which the nitrogen atoms of the amidino and guanidino groups in B are protected, and which can be obtained prior to the final deprotection step to form compounds of the invention, are new.

According to a further aspect of the invention, there are provided compounds of formula XIV

where In ¹ represents a structural fragment of the formula IVg, IVd or IVe

D ¹ and D ² independently represent H or benzyloxycarbonyl, and p, q, R ¹ , R ² , R ³ , R ⁴ , Y, n, R ⁵ , X ¹ and X ² are as defined above, provided that that D ¹ and D ² do not represent both N.

The wavy lines at the carbon atom in the fragment of the formula IVg, IVd or IVe denote the bond position of the fragment.

The use of protective groups is fully described in "Protective Groups in Organic Chemistry", ed. J.W.F. McOmie, Plenum Press (1973), and in "Protective Groups in Organic Synthesis", 2nd edition, T.W. Greene and P.G.M. Wutz, Wiley-Interscience (1991).

It will also be apparent to those skilled in the art that although such protected derivatives of the compounds of Formula I may themselves not have pharmacological activity, they can be administered parenterally or orally and from then on can undergo metabolism in the body to form compounds of the invention that are pharmacologically active. Such derivatives, therefore, can be defined as "prodrugs." All prodrugs of the compounds of formula I are included within the scope of this invention.

Protected derivatives of compounds of formula I that are particularly useful as prodrugs include compounds of formula XIV.

Medical and pharmaceutical applications

The compounds of the invention are useful since they have pharmacological activity. Therefore, they are indicated as pharmaceuticals.

According to a further aspect of the invention, there is thus provided a compound of the invention for use as pharmaceuticals.

In particular, the compounds of the invention are potent thrombin inhibitors, as demonstrated, for example, in the following tests.

Thus, the compounds of the invention are expected to be useful in conditions where thrombin inhibition is required.

The compounds of the invention are thus indicated for the treatment or prevention of thrombosis and hypercoagulation in the blood and tissues of animals, including humans.

The compounds of the invention are further indicated in the treatment of conditions in which there is an undesirable excess of thrombin without signs of hypercoagulation, for example, with neurodegenerative diseases such as Alzheimer's disease.

Specific disease conditions that should be mentioned include the treatment and / or prophylaxis of venous thrombosis and pulmonary embolism, arterial thrombosis (for example, with unstable angina pectoris, stroke due to thrombosis, and peripheral arterial thrombosis) and systemic embolism usually from the atrium with arterial fibrillation or from the left ventricle after transmural myocardial infarction.

Moreover, the compounds of the invention are expected to be useful in the prevention of reocclusion (i.e., thrombosis) after thrombolysis, percutaneous intraluminal angioplasty (PCTA), coronary artery bypass grafting, microsurgery and vascular surgery in general.

Further, indications include the treatment and prevention of disseminated intravascular coagulation caused by bacteria, multiple injuries, intoxication, or any other mechanism; treatment with anticoagulants when the blood is in contact with foreign surfaces in the body, such as vascular grafts, vascular stents, vascular catheters, mechanical and biological valve prostheses, or any other medical device; treatment with anticoagulants when the blood is in contact with medical devices outside the body, such as during cardiovascular surgery using a heart-lung apparatus or during hemodialysis.

It is known that in addition to its effect on the coagulation process, thrombin activates a large number of cells (such as neutrophils, fibroblasts, endothelial cells and smooth muscle cells). Therefore, the compounds of the invention can also be used to treat or prevent idiopathic or respiratory distress syndrome in adults, pulmonary fibrosis due to radiation or chemotherapy, septic shock, septicemia, inflammatory reactions, which include, but are not limited to, edema, acute or chronic atherosclerosis, such as coronary arterial disease, cerebral arterial disease, peripheral arterial disease, reperfusion injury, and restenosis percutaneous intraluminal angioplasty (PTCA).

Compounds of the invention that inhibit trypsin and / or thrombin may also be useful in the treatment of pancreatitis.

According to a further aspect of the invention, there is provided a method of treating conditions requiring thrombin inhibition, wherein a person suffering from or prone to such a condition is administered a therapeutically effective amount of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof.

Pharmaceuticals

The compounds of the invention should generally be administered orally, subcutaneously, buccally, rectally, transdermally, nasally, through the trachea, through the bronchi or by any other parenteral route or by inhalation, in the form of pharmaceutical preparations containing the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable unit dosage form. Depending on the disease and the patient to be treated, and the route of administration, these compositions may be administered in various doses.

The compounds of the invention can also be combined with any antithrombotic agent of any mechanism of action, such as antiplatelet agents, acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and / or synthetase inhibitors, fibrinogen receptor antagonists, prostacyclin mimetics and phosphodiesterase inhibitors.

The compounds of the invention can further be combined with thrombolytics, such as tissue plasminogen activator (natural or recombinant), streptokinase, urokinase, prourokinase, an anisolated complex of streptokinase and plasminogen activator (ASPAC), animal salivary gland plasminogen activators, and the like, in the treatment of thrombotic diseases, in particular myocardial infarction.

According to a further aspect of the invention, there is thus provided a pharmaceutical composition comprising a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are doses of about 0.001-100 mg / kg body weight when administered orally and 0.001-50 mg / kg body weight when administered parenterally.

The compounds of the invention have the advantage that they can be more effective, less toxic, can last longer, have a wider spectrum of activity, be stronger, give fewer side effects, are easier to absorb or have other beneficial pharmacological properties compared with known compounds.

Biological tests

Test a

Determination of thrombin clotting time (TT)

Human thrombin (T 6769, Sigma Chem Co) in a buffer solution, pH 7.4, 100 μl, and an inhibitor solution, 100 μl, were incubated for 1 min.

Then, pooled normal citrated human plasma, 100 μl, was added, and clot formation time was measured in an automatic device (KC 10, Amelung)

The dependence of the clotting time in seconds on the concentration of the inhibitor was built, and IC ₅₀ TT was determined by interpolation.

IC ₅₀ TT is an inhibitor concentration that doubles the thrombin clotting time for human plasma.

Test b

Determination of Partial Activated Thromboplastin Time (ARTT)

ARTT was determined in normal human citrated plasma using a PTT Automated 5 reagent manufactured by Stago. Inhibitors were added to the plasma (10 μl of the inhibitor solution per 90 μl of plasma), then the reagent and the calcium chloride solution and ART were determined in the mixture by using the KC 10 coagulation analyzer (Amelung) according to the instructions of the reagent manufacturer. The dependence of the clot formation time in seconds on the concentration of the inhibitor was built, and IC ₅₀ APTT was determined by interpolation.

IC ₅₀ APTT is defined as the concentration of inhibitor in human plasma that doubles the partial activated thromboplastin time.

Test b

Ex vivo thrombin time assay

Thrombin inhibition after oral or parenteral administration of the compounds of the invention was studied in conscious rats who had a catheter installed one or two days before the experiment to take blood samples from the carotid artery. On the day of the experiment, blood samples were taken at a fixed time after the compound was introduced into plastic tubes containing 1 part sodium citrate solution (0.13 mol / liter) and 9 parts blood. The tubes were centrifuged to obtain platelet-poor plasma. This plasma was used to determine thrombin time, as described below.

Rat citrate plasma, 100 μl, was diluted with saline, 0.9%, 100 μl, and plasma coagulation was initiated by the addition of human thrombin (T 6769, Sigma Chem Co, USA) in buffer solution, pH 7.4, 100 μl. Clot formation time was measured in an automatic device (KC 10, Amelung, Germany).

In cases where a compound of formula XIV was administered, rat plasma thrombin active inhibitor concentrations of the corresponding thrombin inhibitor of formula I were estimated using standard rat thrombin time curves of pulsed citrated plasma from rats of known concentrations of the corresponding “active” thrombin inhibitors dissolved in physiological saline.

Test g

Ex vivo determination of thrombin time in urine

Conscious rats were placed in a metabolism study chamber 24 hours after oral administration of the compounds of the invention. Thrombin time was determined by collected urine, as described below.

Pooled normal citrated human plasma (100 μl) was incubated with concentrated rat urine, or dilutions thereof in physiological saline, for 1 min. Plasma coagulation was then initiated by introducing human thrombin (T 6769, Sigma Chem Company) in a buffer solution (pH 7.4; 100 μl). Coagulation time was measured in an automatic device (KC 10, Amelung).

In cases where a compound of formula XIV was administered, the concentrations of the corresponding active thrombin inhibitors of the formula I in rat urine were evaluated using standard curves of the dependence of thrombin time in the pulsed normal citrate plasma of rats on the known concentrations of the corresponding "active" thrombin inhibitors dissolved in concentrated rat urine ( or its dilutions in saline). Multiplying the total urine production of rat urine in 24 hours by the established average concentration of the above-mentioned active inhibitor in urine, the amount of excreted active inhibitor can be calculated.

The invention is illustrated by the following examples.

Examples

General experimental techniques

Mass spectra were recorded on a Finnigan MAT TSQ 700 triplet-quadrupole mass spectrometer equipped with an electrodispersive surface (FAB-MS) and a VG Platform II mass spectrometer equipped with an electrodispersive surface (LC-MS). Measurements of ¹ H NMR and ¹³ C NMR were carried out on BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers operating at ¹ H frequencies 300.13, 399.96 and 499.82 MHz, respectively, and at ¹³ C frequencies 75.46, 100.58 and 125.69 MHz, respectively.

Example 1

Ch- (R, S) CH (OH) -C (O) -Aze-Pab × HCl

(1) Boc-Aze-OH

Di-tert-butyl dicarbonate (13.75 g; 63 mmol) was added with stirring at room temperature to a mixture of 5.777 g (57 mmol) of L-azetidine-2-carboxylic acid (H-Aze-OH) and 6.04 g ( 57 mmol) of sodium carbonate in 50 ml of water and 100 ml of THF. After 60 hours, THF was removed in vacuo, diluted with water and acidified with 2M potassium hydrogen sulfate. After extraction with methylene chloride, followed by drying (magnesium sulfate) and evaporation of the solvent, a residue is obtained, which is recrystallized from methylene chloride to obtain 10.87 g (95%) of colorless crystals.

¹ H NMR (300 MHz; CDCl ₃ ): δ 4.85-4.7 (br s, 1), 4.0-3.75 (m, 2), 2.65-2.35 (m, 2 ), 1.4 (s, 9).

(2) Boc-Aze-Pab (Z)

At room temperature, EDC (13.5 g, 70 mmol) was added to the Boc-Aze-OH mixture (10.87 g, 54 mmol; from step (1) above), H-Pab (Z) × HCl (18 , 31 g, 57 mmol; obtained according to the method described in International Application WO 94/29336) and DMAP (9.9 g; 81 mmol) in acetonitrile (270 ml). After 16 hours, the solvent was removed in vacuo and replaced with ethyl acetate. The mixture is washed with water and an aqueous solution of citric acid. The organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo to give a residue which, after crystallization from a mixture of methylene chloride, toluene, diisopropyl ether and petroleum ether, gave Boc-Aze-Pab (Z) (17.83 g),

¹ H NMR (300 MHz; CDCl ₃ ): δ 7.85-7.75 (d, 1), 7.45-7, (m, 7), 5.2 (s, 2), 4.7 ( t, 1), 4.6-4.4 (m, 2), 3.95-3.8 ("q", 1), 3.8-3.7 (q, 1), 2.5- 2.3 (m, 2); 1.4 (s, 9).

(3) H-Aze-Pab (Z)

Boc-Aze-Pab (Z) (2.44 g, 5.2 mmol; from step (2) above) was dissolved in a mixture of 10 ml of trifluoroacetic acid and 10 ml of methylene chloride. After 30 minutes, the solvent and trifluoroacetic acid were removed in vacuo and the residue was dissolved in methylene chloride. The organic phase is washed with 10% sodium carbonate and dried (potassium carbonate). The solvent was removed in vacuo to give a residue which, after crystallization from methylene chloride, gave H-Aze-Pab (Z) (1.095 g; 57%) as colorless crystals.

¹ H-NMR (300 MHz; CD ₃ OD): δ 7.85-7.75 (d, 2), 7.45-7.25 (m, 7), 5.2 (s, 2), 4 5 (s, 2), 4.3 (d, 1), 3.65 (q, 1), 3.4-3.3 (m, 1), 2.7-2.5 (m, 1 ), 2.4-2.2 (m, 1).

(4) Ch- (R, S) CH (OH) -C (O) -Aze-Pab (Z)

Receive according to the method described by Kelly and LaCour (Synth.Comm. 22, 859 (1992)), as follows. To a solution of (R, S) -hexahydromindial acid (0.30 g, 1.9 mmol), a catalytic amount of DMAP and pyridine (0.31 g, 3.9 mmol) in methylene chloride (5 ml) was added dropwise TMSCl (0 42 g, 3.9 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled to 0 ° C. and a catalytic amount of DMF (3 drops from a syringe per 2 ml) was added, followed by oxalyl chloride (0.25 g, 2.0 mmol). The reaction mixture was stirred for 1 h at 0 ° C, a mixture of H-Aze-Pab (Z) (0.67 g, 1.8 mmol; from step (3) above) and pyridine (0.50 g, 6.3 mmol), and allow the reaction mixture to warm to room temperature and stirred overnight. A 10% solution of citric acid in methanol (6 ml) was added to the reaction mixture. After 30 minutes, the reaction mixture was poured into a separatory funnel, diluted with 30 ml of ethyl acetate and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution and then with brine and dried (Na ₂ SO ₄ ). After evaporation and flash chromatography on silica gel using a mixture of methylene chloride: methanol (99: 1 to 92: 8), the subtitled compound (60 mg, 6%) was obtained as an eluent.

¹ H NMR (300 MHz; CDCl ₃ ): δ 1.0-1.9 (m, 11H), 2.4-2.7 (m, 2H), 3.80 (d, 1H), 4.05 -4.25 (m, 1H), 4.3-4.5 (m, 2H), 4.85-5.0 (m, 1H), 5.18 (s, 2H), 7.1-7 5 (m, 7H), 7.65-7.8 (m, 2H) 7.86 (bt, 1H, minor diastereomer and / or rotamer), 8.33 (bt, 1H, major diastereomer and / or rotamer )

¹³ C NMR (75 MHz; CDCl ₃ ) amidine and carbonyl carbons: δ 174.8, 170.6, 168.0 and 164.5.

(5) Ch- (R, S) CH (OH) -C (O) -Aze-Pab × HCl

Ch- (R, S) CH (OH) -C (O) -Aze-Pab (Z) (60 mg, 0.12 mmol; from step (4) above) was dissolved in ethanol (5 ml) and added 5% Pd / C and HCl (0.1 ml; conc). The mixture was hydrogenated at atmospheric pressure for 2 hours. After filtration and evaporation, the product was purified by preparative RPLC using (0.005 M NH ₄ OAc, 0.005 M HOAc): CH ₃ CN 4: 1 as eluent. After freeze-drying, HCl (aq) is added and the solution is freeze-dried. The yield of the title product was 15 mg (31%).

¹ H-NMR (300 MHz; D ₂ O) spectrum is complicated due to diastereomers and / or rotamers: δ 0.7-2.0 (m, 11H), 2.25-2.4 (m, 1H), 2, 65-2.9 (m, 1H), 3.79 (d, 1H, minor), 4.03 (d, 1H, major), 4.05-4.15 (m, 2H, minor), 4, 35-4.45 (m (bt), 2H, major), 4.5-4.6 (m, 2H), 5.20 (m, 1H, minor; the major signal is partially blocked by the HOD signal), 7.5 -7.65 (m, 2H); 7.75-7.85 (m, 2H).

¹³ C NMR (75 MHz; CDCl ₃ ) amidine and carbonyl carbons (diastereomers and / or rotamers): δ 176.3, 175.4, 173.7, 173.3, 167.2 and 167.0.

Example 2

Ch- (R) CH (OH) -C (O) -Aze-Pab × HCl

(1) Ch- (R) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 1 (4), with (R) -hexahydromindalic acid (from 0.60 g; 3.8 mmol) in 0.15 g (10%) yield.

(2) Ch- (R) CH (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ch- (R) CH (OH) -C (O) -Aze-Pab (Z) (0.12 g; 0.24 mmol; from stage (1) above). Yield: 52 mg (54%).

¹ H NMR (300 MHz; D ₂ O) spectrum complicated by rotamers: δ 0.7-2.0 (m, 11H), 2.25-2.4 (m, 1H), 2.6-2.9 (m, 1H), 3.79 (d, 1H, minor), 4.02 (d, 1H, major), 4.05-4.15 (m, 2H, minor), 4.35-4.45 (m (bt), 2H, major), 4.5-4.6 (m, 2H), 5.19 (m, 1H, minor; the major signal is partially blocked by the HOD signal), 7.5-7.65 ( m, 2H); 7.75-7.85 (m, 2H).

¹³ C NMR (75 MHz; CDCl ₃ ) amidine and carbonyl carbons (rotamers): δ 171.9, 170.2, 169.8 and 163.8.

Example 3

(Et) ₂ C (OH) -C (O) -Aze-Pab × HCl

(1) H-Aze-Pab (Z) x2HCl

The subtitled compound was prepared by reacting Boc-Aze-Pab (Z) (see Example 1 (2) above) with EtOAc saturated with HCl gas. After half an hour, the reaction mixture was evaporated to give H-Aze-Pab (Z) × 2HCl in quantitative yield.

(2) (Et) ₂ C (OH) -C (O) -Aze-Pab (Z)

A mixture of diethyl glycolic acid (0.13 g; 0.80 mmol), H-Aze-Pab (Z) × 2HCl (0.39 g; 0.88 mmol, from step (1) above), TBTU (0, 28 g, 0.88 mmol) in DMF (15 ml) are cooled in an ice bath. DIPEA (0.41 g, 3.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was poured into 500 ml of water and extracted 3 times with ethyl acetate. The combined organic phase was washed with aqueous NaHCO ₃ and water, dried (Na ₂ SO ₄ ) and evaporated. The crude product was flash chromatographed on silica gel using a mixture of methylene chloride: THF as the eluent. Yield: 30 mg (8%).

¹ H-NMR (400 MHz; CDCl ₃ ): δ 8.04 (bt, 1H), 7.77 (d, 2H), 7.40 (d, 2H), 7.35-7.2 (m, 5H), 5.17 (s, 2H), 4.90 (m, 1H), 4.46 (dd, 1H), 4.39 (dd, 1H), 4.3-4.2 (m, 2H) ), 2.66 (m, 1H), 2.44 (m, 1H), 1.8-1.5 (m, 4H), 0.9-0.75 (m, 6H).

(3) (Et) ₂ C (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from (Et) ₂ C (OH) -C (O) -Aze-Pab (Z) (30 mg; 0.063 mmol; from step (2), above). Yield: 19 mg (79%).

¹ H NMR (300 MHz; D ₂ O) spectrum complicated by rotamers: δ 7.80 (d, 2H), 7.65-7.5 (m, 2H), 5.43 (m, 1H, minor rotamer) 4.90 (m, 1H, major rotamer), 4.6-4.5 (m, 3H), 4.11 (m, 1H, rotamer), 3.70 (m, 1H, rotamer), 2, 8-2.55 (m, 1H), 2.35-2.15 (m, 1H), 1.9-1.6 (m, 4H), 1.0-0.75 (m, 6H).

¹³ C NMR (75 MHz; CDCl ₃ ) amidine and carbonyl carbons (rotamers): δ 178.3, 177.4, 175.0, 173.5 and 167.2.

Example 4

(Ph) ₂ C (OH) -C (O) -Aze-Pab × HCl

(1) (Ph) ₂ C (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from benzoic acid (0.18 g, 0.80 mmol). Yield: 0.16 g (35%).

¹ H NMR (300 MHz; D ₂ O): δ 7.93 (bt, 1H), 7.71 (d, 2H), 7.54-7.15 (m, 17H), 5.14 (s, 2H), 4.89 (m, 1H), 4.57 (m, 1H), 4.48 (dd, 1H), 4.35 (dd, 1H), 3.60 (m, 1H), 3, 44 (m, 1H); 2.44 (m, 1H); 2.23 (m, 1H).

(2) (Ph) ₂ (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from (Ph) ₂ C (OH) -C (O) -Aze-Pab (Z) (0.16 g; 0.28 mmol; from step (1) above). Yield: 90 mg (68%).

¹ H NMR (400 MHz; D ₂ O) spectrum complicated by rotamers: δ 7.65-7.55 (m, 2H), 7.4-7.1 (m, 12H), 5.13 (m, 1H minor rotamer), 4.77 (m, 1H, major rotamer), 4.43 (d, 1H), 4.40 (d, 1H), 4.12 (m, 1H, major rotamer), 4.05 -3.9 (m, 1H, plus 1H minor rotamer), 2.55 (m, 1H, minor rotamer), 2.39 (m, 1H, major rotamer), 2.08 (m, 1H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (rotamers): δ 175.7, 174.9, 174.6, 173.4 and 167.1.

Example 5

nC ₆ H ₁₃ - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

(1) nC ₆ H ₁₃ - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -2-hydroxyoctanoic acid (0.13 g; 0.80 mmol) in 0.25 g (61%) yield.

¹ H NMR (400 MHz; CDCl ₃ ): δ 8.24 (bt, 1H, one diastereomer), 7.89 (bt, 1H, one diastereomer), 7.8-7.75 (m, 2H), 7 4-7.45 (m, 2H), 7.35-7.25 (m, 5H), 5.18 (s, 2H), 4.95-4.85 (m, 1H), 4.55 -4.35 (m, 2H), 4.2-4.0 (m, 3H), 2.8-2.65 (m, 1H), 2.6-2.4 (m, 1H), 2 0-1.2 (m, 10H); 0.9-0.8 (m, 3H).

(2) n-C ₆ H ₁₃ - (R, S) CH (OH) -C (O) -Aze-Pab × HCl.

The title compound was prepared according to the method described in Example 1 (5) from nC ₆ H ₁₃ - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.14 g; 0 , 28 mmol; from (1) above) in 88 mg (78%) yield.

¹ H NMR (400 MHz; D ₂ O): δ 7.7-7.6 (m, 2H), 7.45-7.3 (m, 2H), 5.03 (m, 1H, one diastereomer) 4.74 (m, 1H, one diastereomer is partially blocked by a water signal), 4.45-4.35 (m, 2H), 4.3-4.1 (m, 2H), 4.0-3.8 (m, 1H), 2.65-2.45 (m, 1H), 2.3-2.1 (m, 1H), 1.6-0.9 (m, 10H), 0.75-0 65 (m, 3H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (rotamers): δ 176.8, 176.0, 173.5, 173.3, 173.2 and 167.2.

Example 6

Ph- (R) CH (OH) -C (O) -Aze-Pab

(1) Ph- (R) CH (OH) -C (O) Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R) -indamic acid (0.12 g; 0.8 mmol). The crude product (0.315 g) was purified by flash chromatography (Si gel; THF: EtOAc (6: 4)). Yield 0.128 g (32%) of white powder, purity 91.2% (HPLC).

¹ H NMR (499.803 MHz; CDCl ₃ ): δ 8.14 (t, 1H), 7.72 (d, 2H), 7.42 (d, 2H), 7.33 (t, 4H), 7, 28 (m, 3H), 7.22 (d, 2H), 5.18 (s, 2H), 4.92 (s, 1H), 4.79 (dd, 1H), 4.54 (wide s, 1H), 4.39 (d, 2H), 4.00 (q, 1H), 3.53 (q, 1H), 2.48 (m, 1H), 2.24 (m, 1H), 2, 19 (wide s, 1H)

¹³ C NMR (125.688 MHz; CDCl ₃ ) (carbonyl and amidine carbons): δ 173.1, 170.3, 168.1, 164.5.

(2) Ph- (R) CH (OH) -C (O) -Aze-Pab

Ph- (R) CH (OH) -C (O) -Aze-Pab (Z) (107 mg; 0.214 mmol; from step (1) above) was dissolved in a mixture of THF: water (2: 1), added 37 mg Pd / C (4 mol% Pd) and hydrogenate the resulting solution for 6 hours. The solution is filtered through hyflo filters and evaporated to dryness. To the resulting white powder was added 20 ml of water, acidified with 0.42 ml of 1M HCl (about 2 equiv.). The resulting solution was washed with 5 ml EtOAc and 10 ml diethyl ether and freeze dried twice. Yield: 72 mg (84%) as a white powder. Purity 91% (HPLC).

¹ H NMR (399.968 MHz; D ₂ O): δ 7.57 (t, 2H), 7.36 (d, 1H), 7.32 (s, 3), 7.27 (s, 1H), 7 25 (d, 1H), 7.19 (m, 1H), 5.17 (s, 1H, major), 5.09 (s, 1H, minor), 5.00 (dd, 1, minor), 4.38 (s, 2, major), 4.20 (dd, 1H, major), 3.98 (dd, 2H, minor), 3.97 (m, 1H, major), 3.75 (dd, 1H), 2.68 (s, 1H, minor), 2.65 (m, 1H, minor), 2.35 (m, 1H, major), 2.12 (m, 1H, major), 2.03 (m, 1H, minor).

¹³ C NMR (111.581 MHz; D ₂ O) (carbonyl and amidine carbons): δ 174.5, 173.2, 172.5, 172.4.

Example 7

Ph (4-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

(1) Ph (4-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -4-trifluoromethylmindal acid (0.19 g; 0.88 mmol). Flash chromatography (Si gel; CH2Cl ₂ : THF (6: 4)) gives 0.13 g (26%) of a white powder.

¹ H NMR (300 MHz; CDCl ₃ ): δ 9.6-9.2 (b, 1H), 8.1 (bt, 1H, diastereoisomer), 7.9 (bt, 1H, diastereomer), 7.7 -7.1 (m, 13H), 5.16 (s, 2H), 5.07 (s, 1H, diastereomer), 4.98 (s, 1H, diastereomer), 4.80 (m, 1H), 4.5-4.2 (m, 2H); 4.1-3.5 (m, 2H); 2.5-2.2 (m, 2H).

¹³ C NMR (75 MHz; CDCl ₃ ), amidine and carbonyl carbons (diastereomers): δ 173.3, 172.4, 170.3, 168.3, 164.4.

(2) Ph (4-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

Receive according to the method described in example 1 (5), from Ph (4-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (133 mg; 0.23 mmol ; from step (1) above) to give the title compound as a white crystalline powder. Yield 77 mg (70%).

¹ H NMR (300 MHz; D ₂ O); δ 8.84 (m, 1H, diastereomer / rotamer), 8.73 (m, 1H, diastereomer / rotamer), 8.52 (m, 1H, diastereomer / rotamer), 7.8-7.4 (m, 8H), 5.46, 5.44, 5.30, 5.20 (singlet, 1H, diastereomers / rotamers), 4.96 (m, 1H, diastereomer / rotamers, other signals of the same proton are blocked by the HDO signal), 4.6-4.0 (m, 4H), 2.9-2.5 (m, 1H), 2.4-2.1 (m, 1H).

¹³ C NMR (75 MHz; D ₂ O), amidine and carbonyl carbons (diastereomers and rotamers): δ 173.6, 173.3, 173.1, 173.0, 172.9, 167.0.

Example 8

Ph (4-OMe) - (R, S) CH (OH) -C (O) -Aze-P9b × HCl

(1) Ph (4-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -4-methoxymethindic acid (0.18 g; 1.0 mmol). Flash chromatography (Si gel; EtOAc: MeOH (95: 5)) gives 27 mg (17%) of a white powder.

The ratio of diastereomers is 85:15; signals of the major diastereomer:

¹ H NMR (400 MHz; CDCl ₃ ): δ 8.19 (m, 1H), 7.80 (d, 2H), 7.45 (d, 2H), 7.4-7.2 (m, 7H ), 7.13 (d, 2H, minor rotamer), 6.90 (d, 2H, major rotamer), 6.82 (d, 2H, minor rotamer), 5.21 (s, 2H), 4.9 -4.85 (m, 2H; its singlet is 4.89 (1H)), 4.6-4.4 (m, 2H), 4.02 (m, 1H), 3.81 (s, 3H) 3.55 (m, 1H); 2.62 (m, 1H); 2.32 (m, 1H).

¹³ C NMR (100 MHz; CDCl ₃ ), amidine and carbonyl carbons: δ 173.6, 170.3, 167.8, 164.6.

(2) Ph (4-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph (4-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (27 mg; 0 , 05 mmol; from step (1) above). Yield 15 mg (68%) as a white powder.

The ratio of diastereomers is 85:15; signals of the major diastereomer:

¹ H NMR (400 MHz; D ₂ O): δ 7.7-7.6 (m, 2H), 7.5-7.3 (m, 4H), 7.18 (d, 2H, rotamer), 6.97 (d, 2H, rotamer), 6.9-6.85 (m, 2H, rotamer), 5.19 (s, 1H, rotamer), 5.14 (s, 1H, rotamer), 5, 01 (m, 1H, rotamer), 4.76 (m, 1H, rotamer), 4.48 (s, 1H), 4.3-3.7 (m, 7H, 2 singlets of 3.78, 3 77 (3H)), 2.73 (m, 1H, rotamer), 2.46 (m, 1H, rotamer), 2.3-2.0 (m, 1H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (rotamers): δ 175.5, 174.1, 173.3, 173.1, 167.1, 167.0.

Example 9

Ph (4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

(1) Ph (4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -4-hydroxy-indindic acid (0.34 g; 2.0 mmol). Flash chromatography (Si gel; EtOAc / EtOH 9/1) gives 0.18 g (17%).

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.70 (d, 2H, minor diastereomer / rotamer), 7.64 (d, 2H, major diastereomer / rotamer), 7.5-7.0 (m, 7H), 6.82 (d, 2H, major diastereomer / rotamer), 6.67 (d, 2H, major diastereomer / rotamer), 6.43 (d, 2H, major diastereomer / rotamer), 5.30, 5 26, 5.22, 5.21 (singlets, 2H, diastereomer / rotamer), 4.95-4.8 (m, 2H), 4.15-4.05 (m, 2H), 4.0- 3.7 (m, 2H); 2.7-2.5 (m, 2H).

(2) Ph (4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

The subtitle compound was prepared according to the method described in Example 1 (5) from Ph (4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (94 mg; 0 , 18 mmol; from (1) above). Yield 37 mg (49%) as a white powder.

¹ H NMR (600 MHz; D ₂ O): δ 7.76, 7.72, 7.71, 7.68, 7.52, 7.47, 7.40, 7.35, 7.25, 7 , 19, 7.11, 6.97, 6.82, 6.76, 6.73, 6.71 (doublets, 8H, diastereomers / rotamers), 5.19 (s, 1H, diastereomer / rotamer), 5 , 17 (s, 1H, diastereomer / rotamer), 5.14 (s, 1H, diastereomer / rotamer), 5.01 (m, 1H, diastereomer / rotamer), 4.88 (m, 1H, diastereomer / rotamer, other signals of this proton are blocked by the HDO signal), 4.6-3.8 (m, 4H), 2.77 (m, 1H, diastereomer / rotamer), 2.62 (m, 1H, diastereomer / rotamer), 2, 49 (m, 1H, diastereomer / rotamer); 2.3-2.1 (m, 1H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (diastereomers and rotamers): δ 175.9, 174.8, 174.3, 173.3, 173.2, 172.9, 167.1.

Example 10

Ph-CH ₂ - (R) CH (OH) -C (O) -Aze-Pab × HCl

(1) Ph-CH ₂ - (R) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R) -phenyl lactic acid (0.25 g; 1.5 mmol). Flash chromatography (Si gel; CH ₂ Cl ₂ : THF (6: 4)) gives 0.28 g (36%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 8.19 (m, 1H), 7.72 (d, 2H), 7.43 (d, 2H), 7.4-7.1 (m, 10H ), 5.19 (s, 2H), 4.73 (m, 1H), 4.45-4.25 (m, 2H), 4.19 (m, 1H), 3.86 (m, 1H) 3.18 (m, 1H); 3.0-2.9 (m, 2H); 2.42 (m, 1H); 2.14 (m, 1H).

¹³ C NMR (125 MHz; CDCl ₃ ) amidine and carbonyl carbons: δ 174.5, 170.2, 167.9, 164.3.

(2) Ph-CH ₂ - (R) CH (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph-CH ₂ - (R) CH (OH) -C (O) -Aze-Pab (Z) (0.22 g; 0.43 mmol: from step (1) above) to give 101.5 mg (57%) of a white powder.

¹ H NMR (600 MHz; D ₂ O): δ 7.73 (d, 2H, major rotamer), 7.62 (d, 2H, minor rotamer), 7.5-7.4 (m, 2H), 7.4-7.2 (m, 5H), 7.10 (m, 2H, minor rotamer), 4.71 (m, 1H, major rotamer), 4.5-4.4 (m, 2H), 4.34 (m, 1H, minor rotamer), 4.14 (m, 1H), 4.03 (m, 1H), 3.53 (m, 1H), 3.05-2.95 (m, 2H , major rotamer), 2.9-2.7 (m, 2H, minor rotamer), 2.65-2.5 (m, 1H, minor rotamer), 2.5-2.3 (m, 1H, major rotamer), 2.3-2.1 (m, 1H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (rotamers): δ 175.9, 175.0, 173.7, 173.2, 167.1, 166.8.

Example 11

Ch- (R) CH (OH) -C (O) -Pic-Pab

(1) Vos-Pic-OH

Prepared according to the known method (M. Bodanszky and A. Bodanszky, "The Practise of Peptide Synthesis", Springer-Verlag) using THF instead of dioxane as a solvent.

¹ H NMR (300 MHz; CDCl ₃ ): δ 5.0-4.8 (br d, 1H), 4.0 (br s, 1H), 3.0 (br s, 1H), 2.20 ( d, 1H), 1.65 (m, 2H), 1.5-1.3 (s + m, 13H).

(2) Boc-Pic-Pab (Z)

The title compound was prepared according to the method described in Example 1 (2) from Boc-Pic-OH (2.02 g, 8.8 mmol; from step (1) above) in 1.59 g (44%) yield )

FAB-MS m / z 495 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.83 (d, 2H), 7.43 (d, 2H), 7.36-7.11 (m, 5H), 6.52 (bs, NH ), 5.20 (s, 2H), 4.81-4.72 (m, 1H), 4.61-4.34 (m, 2H), 4.10-3.90 (m, 1H), 2.79-2.64 (m, 1H); 2.36-2.25 (m, 1H); 1.7-1.3 (m, 14H).

(3) H-Pic-Pab (Z) × 2HCl

Boc-Pic-Pab (Z) (1.59 g; 3.25 mmol; from step (2) above) was dissolved in 100 ml of HCl saturated EtOAc. The reaction mixture was evaporated after half an hour to give the title compound in quantitative yield.

FAB-MS m / z 395 (M + 1) ⁺

¹ H NMR (300 MHz, D ₂ O): δ 7.82 (d, 2H), 7.63-7.41 (m, 7H), 5.47 (s, 2H), 4.69-4, 49 (AV system centered on δ 4.59, 2H), 4.03 (dd, 1H), 3.52 (bd, 1H), 3.10 (dt, 1H), 2.29 (dd, 1H ), 2.08-1.61 (m, 5H).

(4) H-Pic-Pab (Z)

The title compound was prepared by dissolving the dihydrochloride from step (3) above in 2M NaOH, followed by extraction of CH ₂ Cl ₂ and evaporation of the organic solvent.

(5) Ch- (R) CH (OH) -C (O) -Pic-Pab (Z)

The title compound was prepared according to the method described in Example 3 (2) from (R) -hexahydromindalic acid (0.152 g, 0.96 mmol) and H-Pic-Pab (Z) (0.417 g; 1.06 mmol; from stage (4) above). Flash chromatography (Si gel, first EtOAc: toluene (2: 3), then EtOAc) gives 90 mg (18%).

¹ H NMR (300 MHz; CDCl ₃ ): δ 7.82 (d, 2H), 7.5-7.2 (m, 7H), 6.63 (t, X part of the AVX system, NH), 5 21 (s, 2H), 5.14 (d, 1H), 4.46 (AVX system, 2H), 4.26 (visible s, 1H), 3.61 (bd, 1H), 3.52 (bd, 1H), 3.06 (dt, 1H), 2.30 (bd, 1H), 1.92-1.0 (m, 14H), 0.95-0.8 (m, 1H).

¹³ C NMR (75 MHz; CDCl ₃ ) amidine and carbonyl carbons: δ 174.8, 170.3, 167.8 and 164.6.

(6) Ch- (R) CH (OH) -C (O) -Pic-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ch- (R) CH- (OH) C (O) -Pic-Pab (Z) (from 59 mg; 0.11 mmol; from step (5) above) with a yield of 19 mg (40%).

FAB-MS m / z 401 (M + 1) ⁺

¹ H NMR (300 MHz; D ₂ O) spectrum complicated by rotamers: δ 7.91-7.72 (m, major and minor rotamer, 2H), 7.58 (d, minor rotamer, 2H), 7.53 (d, major rotamer, 2H), 5.17 (visible bs, major rotamer, 1H), 4.66-4.28 (m, 3H), 3.96 (bd, major rotamer, 1H), 3.26 (bt, major rotamer, 1H), 3.05-2.88 (m, minor rotamer, 1H), 2.39-2.20 (m, 1H), 2.0-0.75 (m, 16H) .

¹³ C NMR (75 MHz; MeOD) amidine and carbonyl carbons at δ 175.86, 173.20, 168.53.

Example 12

Ch-CH ₂ - (R) CH (OH) -C (O) -Pic-Pab × HCl

(1) Ch-CH ₂ - (R) CH (OH) -C (O) OH

A solution of phenyl lactic acid (2.75 g) and rhodium on alumina (0.75 g) in MeOH (170 ml) is hydrogenated in a H ₂ atmosphere at a pressure of 3 atmospheres for 2 days. The mixture was filtered through hyflo and evaporated to dryness to give the product in quantitative yield.

¹ H NMR (400 MHz; CDCl ₃ ): δ 4.23 (bdd, 1H), 3.24 (visible s, OH), 1.68 (bd, 1H), 1.63-1.43 (m, 6H), 1.43-1.31 (m, 1H), 1.21-1.0 (m, 3H), 0.95-0.75 (m, 157 mg (0.91 mmol) 2H)

(2) Ch-CH ₂ - (R) CH (OH) -C (O) -Pic-Pab (Z)

The title compound was prepared according to the method described in Example 1 (4) from H-Pic-Pab (Z) × 2HCl (353 mg; 0.76 mmol; see Example 11 (3)) and Ch-CH ₂ - ( R) CH (OH) —COOH (157 mg, 0.91 mmol; from step (1) above). The product was flash chromatographed (Si gel, EtOAc: toluene (7: 3)) to give 92 mg (22%).

¹ H NMR (300 MHz; CDCl ₃ ): δ 7.72 (d, 2H), 7.46-7.1 (m, 7H), 6.90 (t, NH), 5.18 (s, 2H ), 5.07 (d, 1H), 4.45 (bd, 1H), 4.37 (d, 2H), 3.73-3.47 (m, 2H), 3.10 (bt, 1H) 2.24 (bd, 1H), 2.15-2.0 (m, 1H), 1.90 (bd, 1H), 1.80-1.05 (m, 12H), 1.05-0 75 (m, 3H)

¹³ C NMR (75 MHz; CDCl ₃ ) amidine and carbonyl carbons: δ 175.88, 170.43, 168.04 and 164.58.

(3) Ch-CH ₂ - (R) CH (OH) -C (O) -Pic-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ch — CH ₂ - (R) CH (OH) —C (O) —Pic-Pab (Z) (62 mg; 0.113 mmol; from step (2) above) with a yield of 47 mg (92%).

FAB-MS m / z 415 (M + 1) ⁺

¹ H NMR (300 MHz; D ₂ O) spectrum complicated by rotamers: δ 7.85-7.71 (m, major and minor rotamer, 2H), 7.56 (d, minor rotamer, 2H), 7.50 (d, major rotamer, 2H), 5.12 (visible bs, major rotamer, 1H), 4.68-4.25 (m, 3H, partially hidden HDO), 3.80 (bd, major rotamer, 1H) 3.24 (bt, major rotamer, 1H), 2.89 (bt, minor rotamer, 1H), 2.25 (m, 1H), 1.92-0.82 (m, 17H), 0.60 -0.40 (m, major rotamer, 1H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (rotamers): δ 177.10, 173.88, 173.07, 167.24

Example 13

Ph- (R) CH (OMe) -C (O) -Aze-Pab × HCl

(1) H-Aze-OMe × HCl

MeOH (200 ml) was cooled to -40 ° C in argon atmosphere. Thionyl chloride (47.1 g; 0.396 mol) was added dropwise and the reaction mixture was stirred at -10 ° C for 35 minutes. H-Aze-OH (10.0 g; 0.099 mol) was added and the mixture was stirred at room temperature overnight. Then the reaction mixture was evaporated to give the title compound in 16.1 g (100%) yield.

¹ H NMR (400 MHz; CDCl ₃ ): δ 5.12-5.24 (m, 1H), 4.08-4.29 (m, 2H), 3.84 (s, 3H), 2.65 -2.87 (m, 2H).

(2) Ph- (R) CH (OMe) -C (O) -Aze-OMe

The subtitle compound was prepared according to the method described in Example 1 (2) from R (-) - α-methoxyphenylacetic acid (0.60 g; 3.6 mmol) and H-Aze-OMe × HCl (0.55 g 3.6 mmol; from step (1) above) with a yield of 0.32 g (34%).

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.29-7.48 (m, 5H), 4.71-5.08 (m, 2H), 3.92-4.31 (m, 2H) 3.69-3.83 (m, 3H); 3.19-3.46 (m, 3H); 2.13-2.65 (m, 2H).

(3) Ph- (R) CH (OMe) -C (O) -Aze-OH

To a solution of Ph- (R) CH (OMe) -C (O) -Aze-OMe (0.32 g; 1.2 mmol; from step (2) above) in THF (10 ml) is added a solution of hydroxide monohydrate lithium (0.071 g, 1.7 mmol) in H ₂ O (6 ml). The reaction mixture was stirred for 3 hours and then evaporated. The residue was dissolved in H ₂ O and extracted with toluene. The pH of the aqueous layer was adjusted to 3 with an aqueous HCl solution, and then extracted with ethyl acetate (4 times). The combined organic layer was evaporated to give 0.28 g (92%) of the title compound.

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.30-7.50 (m, 5H), 4.95-5.10 (m, 1H), 4.80 (s, 1H), 4.10 -4.35 (m, 2H), 3.40 (s, 3H), 2.40-2.80 (m, 2H)

(4) Ph- (R) CH (OMe) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 1 (2) from H-Pab (Z) × HCl (0.36 g, 1.0 mmol) and Ph-CH (OMe) -C (O) -Aze -OH (0.25 g; 1.0 mmol; from step (3) above) with a yield of 0.39 g (76%) as a white powder.

¹ H NMR (400 MHz: CDCl ₃ ): δ 08.29 (m, 1H), 7.77 (d, 2H), 7.45 (d, 2H), 7.4-7.2 (m, 10H ), 5.22 (s, 2H), 4.93 (m, 1H), 4.69 (s, 1H), 4.44 (m, 2H), 4.15 (m, 2H), 3.35 (s, 3H), 2.69 (m, 1H), 2.42 (m, 1H)

(5) Ph- (R) CH (OMe) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph- (R) CH (OMe) -C (O) -Aze-Pab (Z) (0.15 g; 0.29 mmol; from step (4) above) with a yield of 50.4 mg (41%) as a white powder.

¹ H NMR (400 MHz; CD ₃ OD; α-hydrogen Aze and benzyl hydrogen mandelate were obscured by a CD ₃ OH signal): δ 7.8-7.6 (m, 2H), 7.6-7.4 ( m, 2H), 7.4-7.1 (m, 5H), 4.6-4.4 (m, 2H), 4.3-4.0 (m, 2H), 3.29 (s, 3), 2.7-2.5 (m, 1H), 2.4-2.1 (m, 1H).

Example 14

Ph (3-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

(1) Ph (3-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-methoxymethindic acid (270 mg; 1.5 mmol) in 340 mg (43%); the ratio of diastereomers is 1: 1.

FAB-MS m / z 531 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 08.14 (m, 1H, diastereomer), 7.87 (m, 1H, diastereomer), 7.0 (m, 10H), 6.9-6.7 (m, 3H), 5.16 (s, 2H), 4.96 (s, 1H, diastereomer), 4.88 (s, 1H, diastereomer), 4.85-4.7 (m, 1H), 4.4-4.2 (m, 2H), 4.05-3.9 (m, 1H), 3.71 (s, 3H, diastereomer), 3.71 (m, 1H, diastereomer), 3, 66 (s, 3H, diastereomer), 3.58 (m, 1H, diastereomer), 2.5-2.35 (m, 1H), 2.32 (m, 1H, diastereomer), 2.20 (m, 1H, diastereomer).

¹³ C NMR (100 MHz; CDCl ₃ ) amidine and carbonyl carbons (diastereomers): δ 173.9, 173.0, 170.5, 170.4, 168.3, 168.2, 164.5,

(2) Ph (3-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph (3-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (230 mg; 0 , 43 mmol; from step (1) above) with a yield of 126 mg (67%). The ratio of diastereomers is 1: 1.

FAB-MS m / z 397 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O: complicated due to (diastereomers / rotamers) and some impurities: δ 7.6-7.1 (m, 5H), 6.9-6.6 (m, 3H), 5 2-4.7 (m, 1-2H), 4.4-3.7 (m, 4-5H), 3.63 (s, 3H, diastereomer / rotamer), 3.55 (m, 3H, diastereomer / rotamer), 2.5-2.3 (m, 1H), 2.2-2.0 (m, 1H).

¹³ C NMR (75 MHz; D ₂ O) amidine and carbonyl carbons (diastereomers / rotamers): δ 175.8, 175.4, 174.8, 174.6, 168.5.

Example 15

Ph (3-Me) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) -3-methylmindal acid

A mixture of 3-methylbenzaldehyde (12.0 g, 0.1 mol) and benzyltriethylammonium chloride (1.23 g; 0.005 mol) in CHCl ₃ (16 ml) was stirred at 56 ° C. A solution of NaOH (25 g) in H ₂ O (25 ml) was added dropwise to the mixture. Upon completion, the reaction mixture was stirred for 1 h. The reaction mixture was diluted with H ₂ O (to give 400 ml) and extracted with diethyl ether (3 × 50 ml). The pH of the mixture was adjusted to 1 with H ₂ SO ₄ (conc.), then extracted with diethyl ether (6 × 50 ml). The combined organic layer was dried (MgSO ₄ ) and evaporated. The crude product (11.6 g) was recrystallized from toluene to give 8.47 g (51%) of the title compound.

LC-MS m / z 165 (M-1) ^- , 331 (2M-1) ^-

¹ H NMR (400 MHz; CD ₃ OD): δ 7.10-7.28 (m, 4H), 5.08 (s, 1H), 2.32 (s, 3H).

(2) Ph (3-Me) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-methylmindalic acid (0.22 g, 1.3 mmol; from step (1) above) in 0 37 g (54%).

LC-MS m / z 515 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 08.11-8.21 (t, NH), 6.97-7.89 (m, 13H), 5.18-5.24 (m, 2H) 4.83-5.00 (m, 2H); 4.37-4.58 (m, 2H); 3.50-4.11 (m, 2H); 2.39-2.71 (m, 2H), 2.27-2.38 (m, 3H).

(3) Ph (3-Me) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

Mixture of Ph (3-Me) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.105 g; 0.20 mmol; from step (2) above), acetic acid (0.012 g; 0.20 mmol) and Pd / C (5%, 0.14 g) in ethanol (12 ml) were hydrogenated at atmospheric pressure for 6 hours. The reaction mixture was filtered and the filtrate was evaporated. The crude product (97 mg) was dissolved in H ₂ O and freeze dried to give a sticky product. This product was dissolved in H ₂ O, filtered through an HPLC filter and freeze dried. The yield of the title compound was 67 mg (76%).

LC-MS m / z 381 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 06.89-7.72 (m, 8H), 4.79-5.23 (m, 2H), 3.76-4.51 (m, 4H ), 2.38-2.82 (m, 2H), 2.15-2.27 (m, 3H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons (rotamers): δ 181.21, 175.43, 174.38, 173.94, 173.23, 173, 06, 173.16, 167.00.

Example 16

Ph (3-OEt) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) -3-ethoxymethindic acid

(R, S) -3-hydroxy-indindic acid was dissolved in acetonitrile (15 ml). K ₂ CO ₃ (2.34 g, 16.94 mmol) was added and ethyl iodide (1.03 ml, 12.71 mmol) was added dropwise. The reaction mixture was refluxed for 2 hours and then evaporated. The residue was dissolved in H ₂ O (25 ml) and acetone (6 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated and the resulting H ₂ O layer was extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 2 with an aqueous KHSO ₄ solution and another H ₂ O was added to dissolve the resulting salt. The H ₂ O solution was extracted with ethyl acetate (3 times). The combined organic layer was washed with H ₂ O, dried (Na ₂ SO ₄ ) and evaporated. The residue was subjected to preparative RPLC (25% acetonitrile: 75% 0.1 M HOAc) and fractions containing the product were evaporated. The resulting aqueous layer was extracted with ethyl acetate (3 times), and the combined organic layer was washed with H ₂ O, dried (Na ₂ SO ₄ ) and evaporated. The yield of the subtitled product is 182 mg (22%).

LC-MS M / Z 195 (M-1) ^- , 391 (2M-1) ^- , 587 (3M-1) ^-

¹ H NMR (400 MHz; CD ₃ OD): δ 6.80-7.27 (m, 4H), 5.08 (s, 1H), 3.99-4.13 (m, 2H), 1, 34-1.40 (t, 3H).

(2) Ph (3-OEt) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-ethoxymethindic acid (0.178 g, 0.907 mmol; from step (1) above) in 259 mg yield (52%) )

LC-MS m / z 545 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 06.77-7.77 (m, 13H), 5.16-5.21 (d, 2H), 4.78-4.99 (m, 2H) 4.27-4.51 (m, 2H); 3.53-4.07 (m, 4H); 2.21-2.60 (m, 2H); 1.29-1.41 (m, 3H).

(3) Ph (3-OEt) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-OEt) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.182 g, 0 , 33 mmol; from step (2) above) with a yield of 157 mg (100%).

LC-MS m / z 411 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 07.71-7.79 (m, 2H), 7.49-7.60 (m, 2H), 7.19-7.30 (m, 1H ), 6.94-7.02 (m, 2H), 6.81-6.90 (m, 1H), 5.09-5.18 (m, 1H), 4.74-4.81 (m , 1H), 4.39-4.62 (m, 2H), 3.93-4.35 (m, 4H), 2.10-2.61 (m, 2H), 1.32-1.40 (m, 3H).

¹³ C NMR (100.6 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons (rotamers): δ 180.68, 174.30, 173.50, 173.07, 172.44, 172, 26.

Example 17

Ph (3-OPr (H)) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) -3-allyloxyindial acid

(R, S) -3-Hydroxymindic acid (0.504 g, 3.0 mmol) was dissolved in dry acetone (25 ml) in a nitrogen atmosphere. Allyl bromide (0.907 g, 7.5 mmol) and dry K ₂ CO ₃ (1.037 g, 7.5 mmol) are added and the reaction mixture is stirred under nitrogen for 16 hours. The reaction mixture is then evaporated. The residue was dissolved in H ₂ O (25 ml) and acetone (6 ml) and the mixture was stirred for 2 hours (then HPLC was carried out). The mixture was evaporated and the aqueous layer was extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 2 with KHSO ₄ and extracted with ethyl acetate (3 times). The combined organic layer was washed with H ₂ O, dried (Na ₂ SO ₄ ) and evaporated to give the subtitled product in 0.175 g (28%) yield.

¹ H NMR (500 MHz; CDCl ₃ ): δ 06.87-7.30 (m, 4H), 5.97-6.10 (m, 1H), 5.26-5.44 (m, 2H) 5.20 (s, 1H); 4.51-4.55 (d, 2H).

(2) Ph (3-OCH ₂ CH = CH ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -allyloxy maximal acid (0.167 g; 0.8 mmol; from step (1) above) in 260 mg yield (58%) )

¹ H NMR (500 MHz; CDCl ₃ ): δ 8.09-8.17 (t, NH), 6.79-7.87 (m, 13H), 5.94-6.08 (m, 1H) 5.20-5.44 (m, 4H), 4.86-5.02 (m, 2H), 4.32-4.62 (m, 4H), 3.54-4.15 (m, 2H), 2.30-2.74 (m, 2H).

(3) Ph (3-OPr (H)) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-OCH ₂ CH = CH ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.06 g; 0.1 mmol; from step (2) above) with a yield of 47 mg (97%).

LC-MS m / z 425 (M + 1) ⁺ , 423 (M-1) ^-

¹ H NMR (500 MHz; D ₂ O): δ 6.7-7.71 (m, 8H), 4.70-5.25 (m, 2H), 3.78-4.53 (m, 6H ), 2.05-2.80 (m, 2H), 1.56-1.75 (m, 2H), 0.82-0.95 (m, 3H).

Example 18

Ph (3-OPr (iso)) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) -3-isopropoxymindic acid

The subtitle compound was prepared according to the method described in Example 16 (1) from (R, S) -3-hydroxy-indindic acid (0.70 g; 4.16 mmol), Cs ₂ CO ₃ (5.87 g; 16 , 65 mmol) and isopropyl iodide (1.25 ml; 12.49 mmol) with a yield of 62 mg (7%).

LC-MS m / z 209 (M-1) ^-

¹ H NMR (400 MHz; CD ₃ OD): δ 06.81-7.25 (m, 4H), 5.08 (s, 1H), 4.53-4.64 (m, 1H), 1, 28-1.32 (d, 6H).

(2) Ph (3-OPr (iso)) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-isopropoxymindic acid (0.063 g; 0.3 mmol; from step (1) above) in 60 mg yield ( 34%).

LC-MS m / z 559 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 06.75-7.79 (m, 13H), 5.18-5.24 (m, 2H), 4.81-4.99 (m, 2H) 4.31-4.58 (m, 3H), 3.97-4.15 (m, 1H), 3.55-3.77 (m, 1H), 2.24-2.64 (m, 2H), 1.23-1.33 (m, 6H).

(3) Ph (3-OPr (iso)) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-OPr (iso)) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0 , 05 g; 0.090 mmol; from step (2) above) with a yield of 41 mg (94%).

LC-MS m / z 425 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 06.81-7.80 (m, 8H), 5.08-5.18 (m, 1H), 4.74-4.80 (m, 1H ), 4.53-4.64 (m, 2H), 4.41-4.51 (m, 1H), 3.93-4.35 (m, 2H), 2.23-2.60 (m , 2H); 1.25-1.32 (m, 6H).

¹³ C NMR (100.6 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.10, 173.60, 173.15, 172.48, 166.39.

Example 19

Ph (2-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) Ph (2-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -2-methoxymethindic acid (0.18 g; 1.0 mmol) in 80 mg (17%) yield.

¹ H NMR (500 MHz; CDCl ₃ ): δ 08.16-8.22 (t, NH), 6.81-7.85 (m, 13H), 5.16-5.20 (m, 2H) 4.79-4.91 (m, 1H); 4.35-4.49 (m, 2H); 3.84-4.02 (m, 2H); 3.63-3.80 (m, 3H), 3.32-3.56 (m, 1H), 2.21-2.57 (m, 2H).

(2) Ph (2-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (2-OMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.08 g ; 0.15 mmol; from step (1) above) in 45 mg (71%) yield.

FAB-MS m / z 397 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 06.83-7.70 (m, 8H), 4.71-4.97 (m, 1H), 4.34-4.51 (m, 2H ), 3.87-4.22 (m, 3H), 3.67-3.75 (m, 3H), 2.00-2.74 (m, 2H).

³ C NMR (75.5 MHz; D ₂ O: complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 179.96, 176.28, 174.97, 174.50, 173.44, 173.39, 173 29, 173.10, 167.12.

Example 20

Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,5-dimethoxymethindic acid (0.21 g; 1.0 mmol; obtained according to the known method (Synthesis (1974) 724 )) with a yield of 0.31 g (62%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 08.11-8.16 (t, NH), 7.17-7.86 (m, 9H), 6.41-6.49 (m, 3H) , 5.21-5.24 (d, 2H), 4.84-5.03 (m, 2H), 4.29-4.66 (m, 2H), 3.67-4.17 (m, 8H), 2.32-2.72 (m, 2H).

(2) Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0, 15 g; 0.27 mmol; from step (1) above) with a yield of 120 mg (100%).

¹ H NMR (500 MHz; D ₂ O): δ 07.34-7.75 (m, 4H), 6.44-6.66 (m, 3H), 4.67-5.12 (m, 1H ), 3.97-4.55 (m, 5H), 3.79 (s, 3H), 3.71-3.74 (m, 3H), 2.14-2.85 (m, 2H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.17, 174.85, 173.92, 173.53, 173.09, 172.98, 182 , 90, 166.77.

Example 21

Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -4-hydroxy-3-methoxymethindic acid (0.20 g; 1.0) in 89 mg (16%) yield.

LC-MS m / z 547 (M + 1) ⁺ , 545 (M-1) ^-

¹ H NMR (400 MHz; CDCl ₃ ): δ 08.07-8.15 (m, NH), 6.64-7.86 (m, 12H), 5.20-5.27 (m, 2H) 3.57-5.00 (m, 9H); 2.31-2.74 (m, 2H).

(2) Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) ( 0.085 g; 0.16 mmol; from step (1) above) in 57 mg (78%) yield.

FAB-MS m / z 413 (M + 1) ⁺

¹ H NMR (500 MHz: D ₂ O; complicated by diastereomers / rotamers): δ 06.66-7.83 (m, 8H), 4.80-5.25 (m, 2H), 3.88-4 59 (m, 4H); 3.68-3.88 (m, 3H); 2.10-2.85 (m, 2H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 182.01, 175.56, 174.43, 174.04, 173.20 173.05, 166, 90, 166.85.

Example 22

Ph (2-F, 5-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) Ph (2-F, 5-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -2-fluoro-5-trifluoromethylmindal acid (0.3 g; 1.2 mmol; obtained in a known manner (Org.Synth. Coll. I, 336)) with a yield of 0.32 g (51%).

FAB-MS m / z 587 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 07.15-7.87 (m, 12H), 5.19-5.30 (m, 2H), 4.87-5.00 (m, 1H) 4.36-4.60 (m, 3H); 4.05-4.20 (m, 1H); 3.60-3.73 (m, 1H); 2.32-2.72 (m, 2H).

(2) Ph (2-F, 5-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (2-F, 5-CF ₃ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.15 g; 0.26 mmol; from step (1) above) in 110 mg (90%) yield.

¹ H NMR (500 MHz; D ₂ O): δ 07.28-7.83 (m, 7H), 5.43-5.65 (m, 1H), 4.82-5.18 (m, 1H ), 3.97-4.56 (m, 4H), 2.14-2.85 (m, 2H).

¹³ C NMR (75.5 MHz; D ² O: complicated by diastereomers / rotamers) amidine and carbonyl carbons): δ 173.61, 173.33, 173.06, 172.83, 172.68, 172.62, 166.86, 164.27, 161.15, 160.92.

Example 23

Ph- (R, S) C (Et) (OH) -C (O) -Aze-Pab × HOAc

(1) Ph- (R, S) C (Et) (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -2-hydroxy-2-phenylbutanoic acid (0.18 g; 1.0 mmol) in 79 mg (15%) yield. .

LC-MS m / z 529 (M + 1) ⁺ , 527 (M-1) ^-

¹ H NMR (400 MHz; CDCl ₃ ): δ 07.27-7.86 (m, 14H), 5.22 (s, 2H), 4.82-4.93 (m, 1H), 4.39 -4.57 (m, 2H), 3.84-3.98 (m, 2H), 2.02-2.64 (m, 4H), 0.86-0.93 (m, 3H).

(2) Ph- (R, S) C (Et) (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R, S) C (Et) (OH) -C (O) -Aze-Pab (Z) (0.08 g; 0 , 15 mmol; from step (1) above) in 62 mg (90%) yield.

FAB-MS m / z 395 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 07.27-7.84 (m, 9H), 4.83-5.35 (m, 1H), 3.89-4.60 (m, 4H ), 2.40-2.61 (m, 1H), 1.95-2.30 (m, 3H), 0.78-0.95 (m, H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 0182.09, 175.79, 175.48, 174.53, 173.23, 167.05.

Example 24

Ph- (R, S) C (Me) (OH) -C (O) -Aze-Pab × HOAc

(1) Ph- (R, S) C (Me) (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (S) - (+) - 2-hydroxy-2-phenylpropionic acid (0.20 g; 1.2 mmol) in 0.17 g yield (31%).

¹ H NMR (500 MHz; CDCl ₂ ): δ 08.04-8.14 (t, NH), 7.17-7.80 (m, 14H), 5.20 (s, 2H), 4.76 -4.86 (m, 1H), 4.31-4.50 (m, 2H), 3.76-3.94 (m, 2H), 2.19-2.44 (m, 2H), 1 70 (s, 3H).

(2) Ph- (R, S) C (Me) (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R, S) C (Me) (OH) -C (O) -Aze-Pab (Z) (0.08 g; 0 , 16 mmol; from step (1) above) with a yield of 48 mg (78%), ratio of diastereomers 85:15.

¹ H NMR (500 MHz; D ₂ O): δ 07.30-7.79 (m, 9H), 3.99-4.82 (m, 5H), 2.09-2.74 (m, 2H ), 1.70-1.77 (m, 3H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons; δ 176.90, 176.34, 173.89, 173.48, 167.00.

Example 25

Ph- (R) CH (OH) -C (O) -Aze-Pac × HOAc

(1) Boc-Aze-OSu

A mixture of Boc-Aze-OH (5 g, 25 mmol) and HOSu (2.88 g, 25 mmol) in 25 ml of THF was cooled in an ice bath. EDC (4.3 ml, 25 mmol) was added and the solution was stirred overnight. It is evaporated, dissolved in ethyl acetate, washed with KHSO ₄ (aq., 0.3 M), Na ₂ CO ₃ (aq., 10%), dried (MgSO ₄ ) and evaporated. Crystallization from ethyl acetate: petroleum ether gave 3.78 g (51%) of the subtitle compound.

¹ H NMR (300 MHz; CDCl ₂ ): δ 04.89 (m, 1H), 4.07 (m, 1H), 3.95 (m, 1H), 2.85 (s, 4H), 2, 67 (m, 1H); 2.45 (m, 1H); 1.42 (s, 9H).

(2) Boc-Aze-Pac (Z)

A mixture of H-Pac (Z) × 2HCl (0.227 g; 0.63 mmol), Boc-Aze-Osu (0.194 g, 0.65 mmol) and triethylamine (0.2 ml, 1.4 mmol) in 10 ml THF stirred at room temperature for 18 hours. After evaporation, the residue was triturated in ethyl acetate, filtered through a celite plug (Celite) and chromatographed on a silica gel column with ethyl acetate: THF (2: 1). The eluent was evaporated, dissolved in ethyl acetate, washed with water, dried (MgSO ₄ ) and evaporated to give 0.250 g (81%) of the subtitle compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 07.4-7.2 (m, 5H), 5.05 (s, 2H), 4.55 (bt, 1H), 3.85 (bq, 1H ), 3.72 (bq, 1H), 3.2-3.0 (m, 2H), 2.4-2.2 (m, 2H), 2.10 (m, 1H), 1.9- 1.7 (m, 4H), 1.5-1.3 (m, 11H, its s at 1.36, 9H), 1.0-0.8 (m, 2H).

(3) H-Aze-Pac (Z)

The subtitle compound was prepared according to the method described in Example 3 (1) from Boc-Aze-Pac (Z) (from step (2) above), followed by alkaline extraction.

(4) Ph- (R) CH (OTBDMS) -C (O) -Aze-Pac (Z)

The subtitle compound was prepared analogously to the method described in Example 3 (2) from Ph- (R) CH (OTBDMS) -C (O) OH (0.236 g; 0.89 mmol; prepared according to Hamada et al., J. Am.Chem.Soc (1989) 111, 669) and H-Aze-Pac (Z) (0.25 g, 0.53 mmol; from step 3; preactivated by stirring in a mixture of CH ₂ Cl ₂ : trifluoroacetic acid (1 : 1, 10 ml) for 30 min) with the release of 160 mg (48%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 07.20-7.44 (m, 10H), 5.22 (s, 1H), 5.06-5.16 (m, 2H), 4.80 -4.90 (m, 1H), 3.92-4.43 (m, 2H), 2.88-3.12 (m, 2H), 2.35-2.60 (m, 2H), 1 25-2.10 (m, 10H); 0.84-0.94 (m, 9H); 0.00-0.15 (m, 6H).

(5) Ph- (R) CH (OH) -C (O) -Aze-Pac × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (OTBDMS) -C (O) -Aze-Pac (Z) (0.16 g; 0.25 mmol; from step (4) above) with RPLC purification in 15 mg (14%) yield.

FAB-MS m / z 373 (M + 1) ⁺

Example 26

Ph- (R) CH (OH) -C (O) -Aze-Pig × HOAc

(1) Boc-Aze-Pig (Z)

The subtitle compound was prepared analogously to the method described in Example 1 (2) from Boc-Aze-OH (1.03 g; 5.12 mmol; see Example 1 (1)) and H-Pig (Z) × 2HCl ( 1.86 g, 5.12 mmol; obtained according to a known method (International application WO 94/29336) with a yield of 1.24 g (51%).

¹ H NMR (400 MHz; CDCl ₃ ): δ 07.27-7.43 (m, 5H), 5.12 (s, 2H), 4.60-4.67 (t, 1H), 4.16 -4.26 (d, 2H), 3.86-3.95 (m, 1H), 3.74-3.82 (m, 1H), 3.11-3.30 (m, 2H), 2 78-2.89 (m, 2H), 2.33-2.52 (bs, 2H), 1.71-1.83 (m, 3H), 1.44 (s, 9H), 1.15 -1.29 (m, 2H).

(2) H-Aze-Pid (Z) × 2HCl

Boc-Aze-Pig (Z) (1.2 g, 2.53 mmol; from step (1) above) in HCl saturated ethyl acetate (75 ml) was stirred at room temperature for 1 h. The reaction mixture was evaporated, diluted with water and extracted with toluene. The aqueous layer was freeze dried to give 1.085 g (96%) of the title compound.

¹ H NMR (500 MHz; CD ₃ OD): δ 07.32-7.46 (m, 5H), 5.28 (s, 2H), 4.99-5.05 (t, 1H), 4, 08-4.16 (m, 1H), 3.91-3.99 (m, 3H), 3.13-3.25 (m, 4H), 2.79-2.88 (m, 1H), 2.47-2.57 (m, 1H), 1.82-1.96 (m, 3H), 1.26-1.40 (m, 2H).

(3) Ph- (R) CH (OTBDMS) -C (O) -Aze-Pig (Z)

The subtitle compound was prepared analogously to the method described in Example 25 (4) from Ph- (R) CH (OTBDMS) -C (O) OH (0.401 g; 1.5 mmol) and H-Aze-Pig (Z) × 2HCl (0.672 g; 1.5 mmol; from step (3)) with a yield of 350 mg (46%).

LC-MS m / z 508 (M + 1) ⁺ , 530 (M + Na) ⁺

(4) Ph- (R) CH (OH) -C (O) -Aze-Pig × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (OTBDMS) -C (O) -Aze-Pig (Z) (0.1 g, 0.197 mmol; from step ( 3)) with a yield of 81 mg (95%).

LC-MS m / z 374 (M + 1) ⁺

¹ H NMR (400 MHz: CD ₃ OD): δ 07.25-7.50 (m, 5H), 5.15 (s, 1H), 4.65-4.75 (m, 1H), 4, 25-4.35 (m, 1H), 3.80-4.00 (m, 3H), 2.95-3.50 (m, 4H), 2.05-2.50 (m, 2H), 1.75-1.90 (m, 3H); 1.15-1.30 (m, 2H).

Example 27

Ph- (R) CH (OH) -C (O) -Pro- (R, S) Hig × HOAc

(1) H- (R, S) Hig (Z) × 2HCl

The subtitled compound was prepared according to the method described in Example 3 (1) from Boc- (R, S) Hig (Z) (obtained according to the known method (International Application WO 94/29336)).

(2) Ph- (R) CH (OTBDMS) -C (O) -Pro-OBn

The subtitle compound was prepared according to the method described in Example 1 (2) from L-Proline × HCl benzyl ester (2 g, 8.26 mmol) and Ph- (R) CH (OTBDMS) -C (O) OH ( 2.0 g, 7.51 mmol, obtained according to the known method (Hamada et al., J. Am. Chem. Soc. (1989) 111, 669)) with a yield of 2.0 g (59%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 07.22-7.55 (m, 10H), 5.45 (s, 1H), 5.15 (s, 2H), 4.45-4.55 (m, 1H), 3.70-3.82 (m, 1H), 3.05-3.15 (m, 1H), 1.65-2.15 (m, 4H), 0.85-1 05 (m, 9H); 0.00-0.22 (m, 6H).

(3) Ph- (R) CH (OTBDMS) -C (O) -Pro-OH

A mixture of Ph- (R) CH (OTBDMS) -C (O) -Pro-OBn (1.9 g, 4.19 mmol, from step (2)) and Pd / C (10%, 0.21 g) in ethanol (80 ml) was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The yield is 1.36 g (91%) of the title compound.

LC-MS m / z 362 (M-1) ^-

¹ H NMR (500 MHz; CD ₃ CD): δ 07.20-7.50 (m, 5H), 5.45 (s, 1H), 4.30-4.40 (m, 1H), 3, 30-3.70 (m, 2H), 1.75-2.30 (m, 4H), 0.85-1.00 (m, 9H), 0.00-0.20 (m, 6H).

(4) Ph- (R) CH (OTBDMS) -C (O) -Pro- (R, S) -Hig (Z)

The subtitle compound was prepared analogously to the method described in Example 25 (4) from Ph- (R) CH (OTBDMS) -C (O) -Pro-OH (0.36 g; 1 mmol; from step (3)) and H- (R, S) -Hig (Z) × 2HCl (0.36 g, 1 mmol, from step (1)) with a yield of 0.63 g of crude product, which is used without further purification in the next step (17% )

LC-MS m / z 636 (M + 1) ⁺

¹³ C NMR (100.5 MHz; CDCl ₃ ) amidine and carbonyl carbons: δ 0171.57, 171.20, 163.79, 159.22.

(5) Ph- (R) CH (OH) -C (O) -Pro- (R, S) -Hig (Z)

A mixture of Ph- (R) CH (OTBDMS) -C (O) -Pro- (R, S) -Hig (Z) (0.63 g, 1 mmol, from step (4)) and TFA (10 ml, 20 % in CH ₂ Cl ₂ ) was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 9 with aqueous K ₂ CO ₃ , and then the reaction mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by flash column chromatography on a silica gel column (40 g), eluting with CH ₂ Cl ₂ (100 ml), CH ₂ Cl ₂ : EtOH (95: 5) (100 ml) and CH ₂ Cl ₂ : EtOH ( 9: 1) (300 ml). The yield is 138 mg (26%) of the subtitled compound.

LC-MS m / z 522 (M + 1) ⁺

¹³ C NMR (100.5 MHz; CDCl ₃ ) amidine and carbonyl carbons: δ 0172.21, 171.20, 163.64, 159.11.

(6) Ph- (R) CH (OH) -C (O) -Pro- (R, S) Hig × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (OH) -C (O) -Pro- (R, S) -Hig (Z) (0.071 g; 0, 14 mmol; from step (5)) in 49 mg (80%) yield.

LC-MS m / z 388 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O; complicated by diastereomers / rotamers): δ 07.32-7.56 (m, 5H), 5.37-5.52 (m, 1H), 4.32-4 64 (m, 1H), 3.57-3.75 (m, 2H), 3.24-3.56 (m, 4H), 2.89-3.15 (m, 2H), 1.25 -2.80 (m, 9H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.92, 174.92, 173.69, 173.03.

Example 28

Ph- (R) CH (OH) -C (O) -Pro-Dig × HOAc

(1) Ph- (R) CH (OTBDMS) -C (O) -Pro-Dig (Z)

The subtitled compound was prepared analogously to the method described in Example 25 (4) from H-Dig (Z) (0.14 g; 0.507 mmol; see International Application WO 94/29336) and Ph- (R) CH (OTBDMS) -C (O) -Pro-OH (0.23 g, 0.608 mmol, see Example 27 (3)) in 316 mg of crude product, which is used without further purification in the next step.

LC-MS m / z 622 (M + 1) ⁺

(2) Ph- (R) CH (OH) -C (O) -Pro-Dig (Z)

Trifluoroacetic acid (6 ml, 20% in CH ₂ Cl ₂ ) is added to Ph- (R) CH (OTBDMS) -C (O) -Pro-Dig (Z) (0.315 g, 0.506 mmol; from step (1)) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 8 with aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. The crude product (250 mg) was flash chromatographed on a silica gel column using CH ₂ Cl ₂ : MeOH (9: 1) as an eluent to give 180 mg (70%) of the title compound.

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.25-7.39 (m, 10H), 5.32-5.37 (bs, 1H), 5.08-5.19 (m, 2H) 4.40-4.49 (m, 1H); 4.21-4.35 (m, 2H); 3.87-4.03 (m, 2H); 3.71-3.79 (m, 2H), 3.18-3.32 (m, 2H), 3.00-3.10 (m, 1H), 2.61-2.73 (m, 1H), 2.14-2.24 ( m, 1H); 1.62-2.07 (m, 8H).

(3) Ph- (R) CH (OH) -C (O) -Pro-Dig × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (OH) -C (O) -Pro-Dig (Z) (0.14 g; 0.276 mmol; from step ( 2)) with a yield of 112 mg (94%).

¹ H NMR (500 MHz; CD ₃ OD): δ 07.27-7.44 (m, 5H), 5.34 (s, 1H), 4.29-4.35 (m, 1H), 4, 17-4.25 (m, 2H), 3.75-7.83 (m, 2H), 3.63-3.73 (m, 1H), 3.25-3.34 (m, 1H), 3.08-3.23 (m, 2H), 2.79-2.90 (m, 1H), 1.70-2.10 (m, 6H).

¹³ C NMR (100.6 MHz; CD ₃ OD) amidine and carbonyl signals: δ 174.79, 173.26, 158.16.

Example 29

Ph- (R) CH (OH) -C (O) - (R or S) Pic (cis-4-Me) -Pab × HOAc and

Ph- (R) CH (OH) -C (O) - (S or R) Pic (cis-4-Me) -Pab × HOAc

(1) (R, S) -N-Boc-Pic (cis-4-Me) -Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 1 (2) from (R, S) -N-Boc-Pic (cis-4-Me) -OH (0.88 g; 4.1 mmol; prepared according to the known (Shuman et al J. Org. Chem. (1990), 55, 738) method) in 405 mg yield (19%).

FAB-MS m / z 509 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.25-7.90 (m, 9H), 5.20 (s, 2H), 4.45-4.50 (m, 2H), 4.34 -4.40 (m, 1H), 3.15-3.70 (m, 2H), 1.70-2.00 (m, 4H), 1.45 (s, 9H), 1.15-1 30 (m, 1H); 0.90-1.05 (m, 3H).

(2) H- (R, S) Pic (cis-4-Me) -Pab (Z)

(R, S) -N-Boc-Pic (cis-4-Me) -Pab (Z) (0.40 g; 0.79 mmol; from step (1)) was dissolved in CH ₂ Cl ₂ (5 ml) trifluoroacetic acid (5 ml) was added and the mixture was stirred for 0.5 h. The reaction mixture was evaporated and the residue was dissolved in CH ₂ Cl ₂ , washed with aqueous Na ₂ CO ₃ , dried (MgSO ₄ ) and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of CH ₂ Cl ₂ : MeOH (95: 5) and CH ₂ Cl ₂ : MeOH (9: 1). The yield is 10 mg (94%) of the subtitled compound.

FAB-MS m / z 409 (M + 1) ⁺

¹ H NMR (500 MHz; CD ₂ OD): δ 07.25-7.85 (m, 9H), 5.15 (s, 2H), 4.35-4.45 (m, 2H), 2, 55-3.60 (m, 3H), 1.85-2.05 (m, 1H), 1.35-1.65 (m, 2H), 0.90-1.20 (m, 5H).

(3) Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (cis-4-Me) -Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 3 (2) from H- (R, S) Pic (cis-4-Me) -Pab (Z) (0.290 g; 0.71 mmol; from step (2) )) and Ph- (R) CH (OTBDMS) -C (O) -OH (0.189 g, 0.71 mmol, obtained according to the known method (Hamada et al., J. Am. Chem. Soc. (1989) 1110, 669)) with a yield of 0.40 g of crude product, which is used without further purification in the next step.

(4) Ph- (R) CH (OH) -C (O) - (R, S) Pic (cis-4-Me) -Pab (Z)

Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (cis-4-Me) -Pab (Z) (0.40 g, crude from step (3)) is treated with trifluoroacetic acid ( 20% in CH ₂ Cl ₂ ) for 3 hours. The reaction mixture was evaporated and the residue was purified by flash chromatography on a silica gel column, eluting with a mixture of CH ₂ Cl ₂ : MeOH (98: 2, 95: 5, 9: 1) . The yield is 45 mg (11%) of the subtitled compound.

(5) Ph- (R) CH (OH) -C (O) - (R or S) Pic (cis-4-Me) -Pab × HOAc and

Ph- (R) CH (OH) -C (O) - (S or R) Pic (cis-4-Me) -Pab × HOAc

Mixture of Ph- (R) CH (OH) -C (O) - (R, S) Pic (cis-4-Me) -Pab (Z) (0.045 g, 0.083 mmol; from step (4)) and Pd / C (5%, 0.06 g) in ethanol (8 ml) was hydrogenated at atmospheric pressure for 2.5 hours. The reaction mixture was filtered and the filtrate was evaporated. The crude product is subjected to preparative RPLC (0.1 M NH ₄ OAc, 30% acetonitrile), whereby the diastereomers are separated. The yield is 7 mg of compound 29A with a ratio of diastereomers> 99: 1 and 11 mg of compound 29B with a ratio of diastereomers of 98: 2.

Compound 29A:

LC-MS m / z 409 (M + 1) ⁺ , 407 (M-1) ^-

¹ H NMR (500 MHz; D ₂ O): δ 07.20-7.80 (m, 9H), 5.65 (s, 1H), 4.65-5.35 (m, 1H), 4, 40-4.55 (m, 2H), 3.85-4.00 (m, 1H), 3.65-3.75 (m, 1H), 2.65-3.15 (m, 2H), 2.05-2.20 (m, 1H), 1.05-1.75 (m, 2H), 0.70-0.90 (m, 3H)

Compound 29B:

LC-MS m / z 409 (M + 1) ⁺ , 407 (M-1) ^-

¹ H NMR (500 MHz; D ₂ O): δ 7.25-7.80 (m, 9H), 4.55-5.75 (m, 2H), 4.35-4.50 (m, 3H ), 3.75-3.85 (m, 1H), 2.70-2.80 (m, 1H), 1.80-2.20 (m, 1H), 0.70-1.70 (m , 6H).

Example 30

Ph- (CH ₂ ) ₂ - (R) CH (OH) -C (O) -Aze-Pab × HCl

(1) Ph- (CH ₂ ) ₂ - (R) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 3 (2) from H-Aze-Pab (Z) × 2HCl (0.434 g; 0.988 mmol) and (R) - (-) - 2-hydroxy-4-phenylbased acids (0.162 g, 0.898 mmol), TBTU (0.433 g, 1.348 mmol) and N-methylmorpholine (0.363 g, 3.59 mmol) in DMF (15 ml) with a yield of 105 mg (22%).

LC-MS m / z 529 (M + 1) ⁺ , 527 (M-1) ^-

¹ H NMR (500 MHz; CDCl ₃ ): δ 08.17-8.25 (m, NH), 7.05-7.72 (m, 14H), 5.16-5.22 (m, 2H) 4.71-4.88 (m, 1H); 4.32-4.41 (m, 2H); 3.92-4.04 (m, 2H); 3.79-3.88 (m, 1H), 2.62-2.86 (m, 2H), 2.29-2.57 (m, 2H), 1.80-1.98 (m, 2H).

(2) Ph- (CH ₂ ) ₂ - (R) CH (OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph- (CH ₂ ) ₂ - (R) CH (OH) -C (O) -Aze-Pab (Z) (0.112 g; 0.212 mmol ; from step (1)) with a yield of 77 mg (84%).

LC-MS m / z 395 (M + 1) ⁺ , 393 (M-1) ^-

¹ H NMR (400 MHz; CD ₃ OD): δ 7.77-7.77 (m, 9H), 4.73-5.19 (m, 1H), 4.40-4.62 (m, 2H ), 3.92-4.34 (m, 3H), 248-2.84 (m, 3H), 2.09-2.33 (m, 1H), 1.83-2.05 (m, 2H) )

¹³ C NMR (100.6 MHz, D ₂ O: complicated by rotamers) amidine and carbonyl carbons: δ 175.66, 174.80, 172.56, 172.49, 166.14, 165.87.

Example 31

2-Naphthyl- (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) - (2-naphthyl) glycolic acid

The subtitle compound was prepared according to the method described in Example 15 (1) from 2-naphthaldehyde (15.6 g, 100 mmol) in 12.37 g (61%) yield.

LC-MS m / z 201 (M-1) ⁺ , 403 (2M-1) ^-

¹ H NMR (500 MHz; CD ₃ OD): δ 07.43-7.98 (m, 7H), 5.29-5.35 (m, 1H).

(2) 2-Naphthyl- (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) - (2-naphthyl) glycolic acid (0.162 g; 0.8 mmol; from step (1)) in 266 mg yield ( 60%).

LC-MS m / z 551 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.18-7.91 (m, 16H), 4.86-5.26 (m, 3H), 4.05-5.60 (m, 3H) 3.52-3.78 (m, 2H); 2.24-2.73 (m, 2H)

(3) 2-naphthyl- (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from 2-naphthyl- (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.266 g; 0.48 mmol ; from stage (2)) with a yield of 202 mg (88%),

LC-MS m / z 417 (M + 1) ⁺

¹ H NMR (500 MHz; CD ₃ OD): δ 07.28-7.96 (m, 11H), 5.30-5.40 (m, 1H), 3.95-4.82 (m, 5H ), 2.09-2.59 (m, 2H).

Example 32

3-Indolyl-CH ₂ - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) 3-Indolyl-CH ₂ - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3- (3-indolyl) lactic acid (0.21 g, 1.0 mmol) in 0.22 g yield ( 45%).

¹ H NMR (500 MHz; CDCl ₂ ): δ 06.57-7.80 (m, 14H), 5.24 (s, 2H), 4.59-4.83 (m, 1H), 4.19 -4.51 (m, 3H), 3.69-3.99 (m, 2H), 3.03-3.36 (m, 2H), 2.31-2.56 (m, 2H).

(2) 3-Indolyl-CH ₂ - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from 3-indolyl-CH ₂ - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.11 g ; 0.20 mmol; from step (1)) with a yield of 75 mg (80%)

FAB-MS m / z 420 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.00-7.75 (m, 9H), 4.61-4.71 (m, 1H), 3.74-4.51 (m, 5H ), 3.00-3.28 (m, 2H), 1.95-2.42 (m, 2H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 179.38, 176.19, 175.56, 173.06, 166.78.

Example 33

(CH ₃ ) ₂ CH- (R) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (CH ₃ ) ₂ CH- (R) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R) -2-hydroxyisovalerianic acid (0.12 g; 1.0 mmol) in 68 mg (16%) yield.

¹ H NMR (300 MHz; CDCl ₃ ) δ 8.25-8.40 (t, NH), 7.15-7.90 (m, 9H), 5.20 (s, 2H), 4.85- 4.95 (m, 1H), 4.30-4.55 (m, 2H), 4.05-4.25 (m, 2H), 3.75-3.90 (m, 1H), 1, 65-2.75 (m, 3H); 0.70-1.05 (m, 6H).

(2) (CH ₃ ) ₂ CH- (R) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from (CH ₃ ) ₂ CH- (R) CH (OH) -C (O) -Aze-Pab (Z) (0.068 g; 0.15 mmol; from step (1)) with a yield of 13 mg (23%).

¹ H NMR (300 MHz; D ₂ O): δ 07.45-7.80 (m, 4H), 4.85-5.25 (m, 1H), 4.45-4.65 (m, 2H ), 4.30-4.40 (m, 1H), 3.80-4.10 (m, 2H), 2.60-2.80 (m, 1H), 2.20-2.35 (m , 1H), 1.90-2.05 (m, 1H), 0.70-1.00 (m, 6H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by rotamers) amidine and carbonyl carbons: 182.37, 176.34, 175.38, 173.84, 173.26, 167.16.

Example 34

(CH ₃ ) ₂ CH- (CH ₂ ) ₂ - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (CH ₃ ) ₂ CH- (CH ₂ ) ₂ - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -isoleucic acid (0.12 g; 0.88 mmol) in 0.15 g (36%) yield.

¹ H NMR (300 MHz; CDCl ₃ ): δ 07.15-7.80 (m, 9H), 5.20 (s, 2H), 4.85-4.95 (m, 1H), 4.35 -4.55 (m, 2H), 3.85-4.20 (m, 3H), 2.40-2.80 (m, 2H), 1.75-2.10 (m, 1H), 1 20-1.55 (m, 2H); 0.75-1.00 (m, 6H).

(2) (CH ₃ ) ₂ CH- (CH ₂ ) ₂ - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from (CH ₃ ) ₂ CH- (CH ₂ ) ₂ - (R, S) CH (OH) -C (O) -Aze-Pab (Z ) (0.13 g; 0.27 mmol; from stage (1)) with a yield of 0.11 g (100%),

¹ H NMR (400 MHz; D ₂ O): δ 7.63-7.69 (m, 2H), 7.37-7.46 (m, 2H), 4.72-5.12 (m, 1H ), 4.40-4.46 (m, 2H), 4.17-4.31 (m, 2H), 3.90-4.02 (m, 1H), 2.50-2.69 (m , 1H), 2.11-2.27 (m, 1H), 1.12-1.72 (m, 3H), 0.61-0.85 (m, 6H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 176.97, 176.80, 176.61, 176.19, 173.38, 173.28, 173 17, 173.10, 166.78, 182.02.

Example 35

Ph (3-OH) - (R, S) CH (OH) -C (O) -Pro-Pab × HCl

(1) Boc-Pro-Pab (Z) × HCl

The subtitle compound was prepared analogously to the method described in Example 1 (2) from Boc-Pro-OH (10.2 g; 47.4 mmol) and H-Pab (Z) × HCl (15.9 g, 49) was added. , 8 mmol) with a yield of 21.74 g (95.5%).

FAB-MS m / z 481 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 08.0-7.8 (m, 2H), 7.5-7.25 (m, 7H), 5.17 (s, 2H), 4, 6-4.15 (m, 3H), 3.6-3.35 (m, 2H), 2.3-2.1 (m, 1H), 2.1-1.8 (m, 3H), 1.5-1.3 (two wide singlets, rotamers Boc. 9H).

(2) H-Pro-Pab (Z)

The subtitled compound was prepared analogously to the method described in Example 3 (1) from Boc-Pro-Pab (Z) × HCl (from step (1)), followed by alkaline extraction.

(3) Ph (3-OH) - (R, S) CH (OH) -C (O) -PrO-Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 3 (2) from (R, S) -3-hydroxy-indindic acid (0.25 g, 1.5 mmol) and H-Pro-Pab (Z) (0, 63 g; 1.65 mmol; from step (2)) with a yield of 51 mg (6%).

FAB-MS m / z 531 (M + 1) ⁺

(4) Ph (3-OH) - (R, S) CH (OH) -C (O) -Pro-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph (3-OH) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.05 g ; 0.094 mmol; from step (3)) with a yield of 30 mg (74%).

FAB-MS m / z 397 (M + 1) ⁺

¹³ C NMR (75.5 MHz; D ₂ O, complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 175.36, 175.13, 172.92, 167.13.

Example 36

Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

(1) Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,5-dimethoxymethindic acid (0.08 g; 0.38 mmol; obtained according to the known (Synthesis (1974), 724 (method) and H-Pro-Pab (Z) (0.16 g, 0.42 mmol, see example 35 (2)) with a yield of 61 mg (28%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 07.70-7.80 (t, NH), 7.08-7.50 (m, 9H), 6.30-6.50 (m, 3H) 5.20 (s, 2H), 5.00-5.10 (m, 1H), 4.25-4.70 (m, 3H), 3.60-3.80 (m, 6H), 3 , 35-3.55 (m, 1H), 2.95-3.25 (m, 1H), 1.70-2.25 (m, 4H)

(2) Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3,5-diOMe) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0, 06 g; 0.10 mmol; from step (1)) with a yield of 35 mg (72%).

¹ H NMR (500 MHz; D ₂ O): δ 7.23-7.80 (m, 4H), 6.41-6.65 (m, 3H), 5.35-5.45 (m, 1H ), 4.35-4.60 (m, 3H), 3.80 (s, 3H), 3.10-3.75 (m, 5H), 1.70-2.35 (m, 4H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 175.28, 175.05, 174.03, 173.46, 172.80, 172.73, 167 , 11, 166.95.

Example 37

Ph (3-OMe) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

(1) Ph (3-OMe) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-methoxymethindic acid (0.27 g, 1.5 mmol) and H-Pro-Pab (Z) (0, 57 g, 1.5 mmol; see example 35 (2)) in 158 mg (20%) yield.

FAB-MS m / z 545 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.77-7.84 (m, 2H), 7.01-7.48 (m, 8H), 6.80-6.91 (m, 3H) 5.20-5.24 (m, 2H), 5.06-5.11 (m, 1H), 4.30-4.72 (m, 3H), 3.68-3.79 (m, 3H), 3.38-3.57 (m, 1H), 2.92-3.17 (M, 1H), 1.68-2.31 (m, 4H),

(2) Ph (3-OMe) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-OMe) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.06 g ; 0.11 mmol; from step (1)) in 39 mg (75%) yield.

LC-MS m / z 411 (M + 1) ⁺ , 409 (M-1) ^-

¹ H NMR (400 MHz; D ₂ O): δ 6.81-7.84 (m, 8H), 5.47 (s, 1H), 4.35-4.59 (m, 3H), 3, 60-3.88 (m, 4H), 3.07-3.29 (m, 1H), 1.74-2.37 (m, 4H).

Example 38

Ph (3,4- (O-CH ₂ -O)) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) Ph (3,4- (O-CH ₂ -O)) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,4-methylenedioxy maximal acid (0.20 g; 1.0 mmol; prepared according to the known (Synthesis (1974), 724 ) method) with a yield of 0.22 g (44%).

¹ H NMR (400 MHz; acetone-d ₆ ): δ 6.68-8.12 (m, 12H), 5.94-6.05 (m, 2H), 5.18 (s, 2H), 3 81-5.12 (m, 6H); 2.30-2.54 (m, 2H).

(2) Ph (3,4 - (- O-CH ₂ -O)) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3,4- (O-CH ₂ -O)) - (R, S) CH (OH) -C (O) -Aze- Pab (Z) (0.11 g; 0.20 mmol; from step (1)) in 72 mg yield (76%).

¹ H NMR (500 MHz; D ₂ O): δ 6.64-7.80 (m, 7H), 5.91-6.01 (m, 2H), 4.80-5.24 (m, 2H) ), 3.88-4.57 (m, 4H), 2.11-2.84 (m, 2H).

¹³ C NMR (75.5 MHz, D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 176.03, 175.70, 175.07, 174.82, 168.86.

Example 39

Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

(1) Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 3 (2) from (R, S) -4-hydroxy-3-methoxymethindic acid (0.40 g; 2.0 mmol) and H-Pro-Pab (Z ) (0.76 g, 2.0 mmol; see example 35 (2)) in 132 mg (12%) yield.

FAB-MS m / z 561 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 6.62-7.84 (m, 12H), 5.20-5.25 (m, 2H), 4.15-5.08 (m, 3H) 3.42-3.84 (m, 4H); 2.91-3.25 (m, 1H); 1.66-2.37 (m, 4H).

(2) Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-OMe, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) ( 0.048 g; 0.09 mmol; from step (1)) with a yield of 23 mg (55%).

FAB-MS m / z 427 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 6.72-7.83 (m, 7H), 5.42 (s, 1H), 4.38-4.68 (m, 3H), 3, 55-4.10 (m, 4H), 3.09-3.29 (m, 1H), 1.72-2.37 (m, 4H).

¹³ C NMR (75.5 MHz; D ₂ O) amidine and carbonyl carbons: δ 175.12, 173.25, 167.09.

Example 40

Ph- (R, S) C (Et) (OH) -C (O) -Pro-Pab × HOAc

(1) Ph- (R, S) C (Et) (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -2-hydroxy-2-phenylbutanoic acid (0.36 g; 2.0 mmol) and H-Pro-Pab (Z ) (0.76 g, 2.0 mmol; see example 35 (2)) with a yield of 57 mg (5%).

FAB-MS m / z 543 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.24-7.88 (m, 14H), 5.23 (s, 2H), 4.44-4.81 (m, 3H), 2.98 -3.25 (m, 2H), 1.49-2.32 (m, 6H), 0.85-0.95 (m, 3H)

(2) Ph (R, S) C (Et) (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R, S) C (Et) (OH) -C (O) -Pro-Pab (2) (0.055 g; 0.1 mmol; from step (1)) with a yield of 34 mg (72%).

FAB-MS m / z 409 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 7.33-7.82 (m, 9H), 4.38-4.60 (m, 3H), 3.19-3.71 (m, 2H ), 1.54-2.34 (m, 6H), 0.73-0.90 (m, 3H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 182.05, 176.42, 175.73, 175.59, 174.70, 174.47, 167 ,18.

Example 41

Ph (3,5-diMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) -3,5-dimethylmindal acid

The subtitle compound was prepared according to the method described in Example 15 (1) from 3,5-dimethylbenzaldehyde (5.0 g; 37 mmol) in 2.8 g (42%) yield.

¹ H NMR (400 MHz; CD ₃ OD): δ 7.05 (s, 2H), 6.94 (s, 1H), 5.04 (s, 1H), 2.28 (s, 6H).

(2) Ph (3,5-diMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,5-dimethylmindal acid (0.27 g; 1.5 mmol; from step (1)) with a yield of 0.403 g (51%).

FAB-MS m / z 529 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 6.85-7.88 (m, 12H), 5.22-5.26 (m, 2H), 4.84-5.03 (m, 2H) 4.43-4.62 (m, 2H); 3.57-4.13 (m, 2H); 2.25-2.74 (m, 8H).

(3) Ph (3,5-diMe) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3,5-diMe) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.102 g ; 0.194 mmol; from step (2)) with a yield of 74 mg (84%).

FAB-MS m / z 395 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 6.76-7.82 (m, 7H), 4.80-5.27 (m, 2H), 3.87-4.62 (m, 4H ), 2.20-2.87 (m, 8H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 182.07, 175.60, 174.49, 174.37, 173.96, 173.23, 173 09, 173.05, 172.93, 166.98, 166.90

Example 42

Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-nitromindalic acid (0.30 g; 1.5 mmol) in 0.40 mg (48%) yield.

LC-MS m / z 545 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.16-8.22 (m, 13H), 5.18-5.23 (m, 2H), 4.85-5.15 (m, 2H) 4.08-4.60 (m, 3H); 3.65-3.81 (m, 1H); 2.31-2.71 (m, 2H).

(2) Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.102 g; 0.19 mmol; from step (1)) with a yield of 0.074 g (89%).

LC-MS m / z 382 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 6.58-7.82 (m, 8H), 4.80-5.25 (m, 2H), 3.60-4.60 (m, 4H ), 2.12-2.88 (m, 2H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons; δ 181.96, 175.27, 174.25, 173.84, 173.19, 173.01, 166.93.

Example 43

Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

To a mixture of Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.100 g, 0.18 mmol, see example 42 (1)) and CH ₂ Cl ₂ (10 ml) add anisole (0.030 g, 0.27 mmol) and trifluoromethanesulfonic acid (0.138 g, 0.92 mmol). The reaction mixture was stirred at room temperature for 10 minutes. H ₂ O was added and the pH was adjusted to 9 with aqueous Na ₂ CO ₃ . CH ₂ Cl _{2 was} removed in vacuo and the remaining H ₂ O layer was extracted with diethyl ether (3 × 5 ml), followed by freeze drying. The crude product was subjected to RPLC to give 62 mg (60%) of the title product after freeze-drying.

¹ H NMR (400 MHz; D ₂ O): δ 7.38-8.31 (m, 8H), 4.83-5.50 (m, 2H), 4.03-4.57 (m, 4H ), 2.17-2.86 (m, 2H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.5, 173.84, 173.39, 173.15, 173.04, 172.96, 172 80, 166.85.

Example 44

Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

(1) Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-nitromindalic acid (0.30 g; 1.5 mmol) and H-Pro-Pab (Z) × 2HCl ( 0.75 g, 1.65 mmol; see example 35 (2)) with a yield of 0.61 g (73%).

LC-MS m / z 560 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.26-8.23 (m, 13H), 5.20-5.28 (m, 3H), 4.33-4.73 (m, 3H) 3.46-3.68 (m, 1H); 2.92-3.14 (m, 1H); 1.79-2.33 (m, 4H).

(2) Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3-NH ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.104 g; 0.19 mmol; from step (1)) in 64 mg (76%) yield.

LC-MS m / z 396 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 6.74-7.82 (m, 8H), 5.34-5.40 (m, 1H), 4.55-4.58 (m, 3H ), 3.09-3.78 (m, 2H), 1.75-2.35 (m, 4H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 182.04, 175.38, 175.18, 173.12, 173.04, 167.07.

Example 45

Ph (3-NO ₂ ) - (R or S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 40 (3) from Ph (3-NO ₂ ) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.117 g; 0.21 mmol; see example 44 (1)). Fractions were concentrated to give 23 mg (45%) of a compound with a diastereomer ratio of more than 99: 1.

LC-MS m / z 424 (M-1) ^- , 426 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.31-8.35 (m, 8H), 5.50-5.71 (m, 1H), 3.64-4.57 (m, 4H ), 3.24-3.32 (m, 1H), 1.76-2.42 (m, 4H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by rotamers) amidine and carbonyl carbons: δ 175.21, 173.98, 172.58, 172.18, 167.12, 166.82.

(Earlier fractions were concentrated to give 22 mg (43%) of the epimer of the above compound with a diastereomer ratio of more than 99: 1)

Example 46

Ph (3,4 - (- O-CH ₂ -O -)) - (R, S) CH (OH) -C (O) -Pro-Pab × HCl

(1) Ph (3,4 - (- O-CH ₂ -O -)) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,4-methylenedioxy maximal acid (0.20 g; 1.0 mmol; prepared according to the known (Synthesis (1974), 724 (method) and H-Pro-Pab (Z) × 2HCl (0.35 g, 0.91 mmol; see example 35 (2)) in 80 mg (16%) yield.

FAB-MS m / z 559 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 6.69-7.89 (m, 12H), 5.91-6.04 (m, 2H), 4.30-5.28 (m, 2H) 3.00-3.61 (m, 6H), 1.95-2.35 (m, 4H)

(2) Ph (3,4 - (- O-CH ₂ -O -)) - (R, S) CH (OH) -C (O) -Pro-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph (3,4 - (- O-CH ₂ -O -)) - (R, S) CH (OH) -C (O) - Pro-Pab (Z) (0.08 g; 0.14 mmol; from step (1)) in 48 mg (73%) yield

FAB-MS m / z 425 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 6.81-7.85 (m, 7H), 5.90-6.05 (m, 2H), 5.33-5.44 (m, 1H ), 4.37-4.90 (m, 3H), 3.62-3.77 (m, 1H), 3.13-3.28 (m, 1H), 1.80-2.36 (m , 4H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 175.37, 175.09, 173.66, 173.08, 173.00, 167.03.

Example 47

Ph (3,5-diF) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

(1) Ph (3,5-diF) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,5-difluorormindalic acid (0.28 g, 1.5 mmol) and H-Pro-Pab (Z) × 2HCl (0.75 g, 1.65 mmol; see example 35 (2)) with a yield of 0.42 g (51%).

LC-MS m / z 549 (M-1) ^- , 551 (M + 1) ⁺

¹ H NMR (400 MHz: CDCl ₃ ): δ 6.72-7.84 (m, 12H), 5.22 (s, 2H), 5.08 (s, 1H), 4.34-4.73 (m, 3H), 3.41-3.60 (m, 1H), 2.96-3.19 (m, 1H), 1.80-2.34 (m, 4H)

(2) Ph (3,5-diF) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph (3,5-diF) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.104 g ; 0.19 mmol; from step (1)) with a yield of 79 mg (88%).

LC-MS m / z 415 (M-1) ^- , 417 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 6.86-7.80 (m, 7H), 5.50 (s, 1H), 3.58-4.72 (m, 4H), 3, 19-3.32 (m, 1H); 1.80-2.37 (m, 4H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.87, 175.21, 174.98, 174.12, 172.57, 172.12, 171 97, 167.10, 165.24.

Example 48

Ph- (R) CH (O-CH ₂ - (R, S) CH (OH) -CH ₂ OH) -C (O) -Aze-Pab × HOAc

(1) Ph- (R) CH (OH) -C (O) OBn

(R) -Mindic acid (3.0 g, 19.7 mmol) was dissolved in DMF (50 ml) and cesium carbonate (3.21 g, 9.86 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with H ₂ O (200 ml) and the H ₂ O layer was extracted with EtOAc. After separation, the organic layer was washed with aqueous HCl, dried (Na ₂ SO ₄ ) and evaporated. The yield of the title compound was 4.2 g (88%).

LC-MS m / z 265 (M + Na) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.17-7.44 (m, 10H), 5.12-5.27 (m, 3H).

(2) Ph- (R) CH (O-CH ₂ -CH = CH ₂ ) -C (O) OBn

A mixture of the compound Ph- (R) CH (OH) -C (O) OBn (1.0 g, 4.13 mmol; from step (1)), magnesium sulfate (0.1 g, 0.83 mmol) and oxide silver (I) (2.58 g, 11.2 mmol) in petroleum ether (mp. 40-60 ° C, 25 ml) was stirred in the dark at room temperature in a nitrogen atmosphere. Allyl bromide (0.75 g, 6.19 mmol) was added dropwise, and then silver (I) oxide (2.58 g, 11.2 mmol) was added in two portions. The reaction mixture was stirred overnight at room temperature. The mixture was then filtered through celite and the filtrate was evaporated to give 1.143 g (98%) of the subtitled compound.

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.20-7.50 (m, 10H), 5.89-5.99 (m, 1H), 5.09-5.31 (m, 4H) 4.99 (s, 1H); 4.03-4.11 (m, 2H)

(3) Ph- (R) CH (O-CH ₂ - (R, S) CH (OH) -CH ₂ OH) -C (O) OBn

A mixture of the compound Ph- (R) CH (O-CH ₂ -CH = CH ₂ ) -C (O) OBn (0.74 g, 2.62 mmol, from step (2)), N-methylmorpholine-N-oxide (0.425 g, 3.15 mmol) and osmium tetrooxide (0.0027 g, 0.01 mmol) in a mixture of H ₂ O: acetone (2: 1, 10 ml) was stirred at room temperature for 2 days. Sodium pyrosulfite (1.5 g, 7.89 mmol) was added and the mixture was stirred for 1 hour. Then the reaction mixture was filtered through celite and the filtrate was evaporated. The yield of the subtitle compound is 0.51 g (62%).

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.16-7.44 (m, 10H), 5.09-5.20 (m, 2H), 4.96 (s, 1H), 3.55 -3.97 (m, 5H).

(4) Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) OBn

Ph- (R) CH (O-CH ₂ - (R, S) CH (OH) -CH ₂ OH) -C (O) OBn (0.51 g, 1.61 mmol, from step (3)) is dissolved in acetone (20 ml). P-Toluenesulfonic acid monohydrate (0.007 g, 0.0037 mmol) was added and the mixture was stirred at room temperature for 24 hours. Potassium carbonate (0.09 g) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then filtered. through celite and the filtrate was evaporated to give 0.559 g (97%) of the subtitle compound.

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.18-7.48 (m, 10H), 5.01-5.21 (m, 3H), 4.27-4.40 (m, 1H) 4.02-4.11 (m, 1H), 3.76-3.90 (m, 1H) 3.49-3.67 (m, 2H), 1.34-1.41 (m, 6H) )

(5) Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -OCH ₂ -)) - C (O) OH

Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) OBn (0.183 g, 0.51 mmol; from steps (4)) are dissolved in ethanol (10 ml). Pd / C (5%, 0.09 g) was added and the reaction mixture was hydrogenated at atmospheric pressure for 1 h. The mixture was then filtered through celite and the filtrate was evaporated to give 0.137 g (100%) of the subtitled compound.

LC-MS m / z 265 (M-1) ^-

¹ H NMR (400 MHz: CD ₃ OD): δ 7.28-7.48 (m, 5H), 4.97 (s, 1H), 4.25-4.35 (m, 1H), 4, 01-4.09 (m, 1H), 3.72-3.84 (m, 1H), 3.43-3.65 (m, 2H), 1.30-1.37 (m, 6H).

(6) Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from Pb- (R) CH (O — CH ₂ - (R, S) CH (—O — C (CH ₃ ) ₂ —O — CH ₂ -)) - C (O) OH (0.165 g; 0.62 mmol; from step (5)) with a yield of 0.20 g (52%).

LC-MS m / z 613 (M-1) ^- , 615 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.22-7.88 (m, 14H), 5.22 (s, 2H), 4.87-4.95 (m, 2H), 3.40 -4.54 (m, 9H); 2.36-2.76 (m, 2H); 1.22-1.42 (m, 6H).

(7) Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (O — CH ₂ - (R, S) CH (—OC (CH ₃ ) ₂ —O — CH ₂ -) ) -C (O) -Aze-Pab (Z) (0.20 g; 0.325 mmol; from step (6)) in 179 mg (100%) yield.

LC-MS m / z 479 (M-1) ^- , 481 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.33-7.80 (m, 9H), 4.81-5.31 (m, 2H), 3.94-4.59 (m, 6H ), 3.25-3.80 (m, 3H), 2.16-2.88 (m, 2H), 1.29-1.44 (m, 6H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.99, 173.12, 172.93, 172.18, 166.84.

(8) Ph- (R) CH (O-CH ₂ - (R, S) CH (OH) -CH ₂ OH) -C (O) -Aze-Pab × HOAc

Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) -Aze-Pab × HOAc (0.094 g, 0 , 17 mmol, from step (7) was dissolved in a mixture of HOAc: H ₂ O (4: 1, 10 ml) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was evaporated and the residue was dissolved in H ₂ O and freeze dried. The yield of the title compound was 85 mg (100%).

LC-MS m / z 439 (M-1) ^- , 441 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.32-7.78 (m, 9H), 4.81-5.28 (m, 2H), 3.28-4.56 (m, 9H ), 2.15-2.90 (m, 2H).

¹³ C NMR (100.6 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 179.14, 172.93, 172.89, 172.51, 171.96, 166.54.

Example 49

Ph- (R) CH (O-CH ₂ - (R, S) CH (OH) -CH ₂ OH) -C (O) -Pro-Pab × HOAc

(1) Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ )) - C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from Ph- (R) CH (O — CH ₂ - (R, S) CH (—O — C (CH ₃ ) ₂ —O — CH ₂ -)) - C (O) OH (0.108 g; 0.4 mmol; see example 48 (5)) and H-Pro-Pab (Z) × 2HCl (0.202 g, 0.46 mmol, see example 35 (2 )) with a yield of 0.10 g (40%).

LC-MS m / z 627 (M-1) ^- , 629 (M + 1) ⁺ , 651 (M + Na) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.23-7.87 (m, 14H), 5.03-5.27 (m, 3H), 3.34-4.64 (m, 10H) 1.71-2.39 (m, 4H); 1.23-1.41 (m, 6H).

(2) Ph- (R) CH (O-CH ₂ - (R, S) CH (-OC (CH ₃ ) ₂ -O-CH ₂ -)) - C (O) -Pro-PabxHOAc

The subtitle compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (O — CH ₂ - (R, S) CH (—O — C (CH ₃ ) ₂ —O — CH ₂ )) - C (O) -Pro-Pab (Z) (0.100 g; 0.159 mmol; from step (1)) in 85 mg yield (96%).

LC-MS m / z 493 (M-1) ^- , 495 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.30-7.82 (m, 9H), 5.22-5.38 (m, 1H), 4.32-4.62 (m, 4H ), 4.01-4.11 (m, 1H), 3.22-3.83 (m, 5H), 1.78-2.22 (m, 4H), 1.33-1.44 (m , 6H).

¹³ C NMR (100.6 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 181.47, 174.74, 173.53, 171.64, 171.50, 171.00, 170 94, 166.58.

(3) Ph- (R) CH (O-CH ₂ - (R, S) CH (OH) -CH ₂ OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared according to the method described in Example 48 (8) from Ph- (R) CH (O — CH ₂ - (R, S) CH (—O — C (CH ₃ ) ₂ —O — CH ₂ ) -C (O) -Pro-Pab × HOAc (0.038 g; 0.069 mmol; from step (2)) in 35 mg yield (98%).

LC-MS m / z 453 (M-1) ^- , 455 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.30-7.82 (m, 9H), 5.20-5.38 (m, 1H), 3.18-4.60 (m, 10H ), 1.70-2.38 (m, 4H).

¹³ C NMR (100.6 MHz; D ₂ O, complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 180.26, 174.74, 173.47, 171.80, 171.26, 166.61.

Example 50

Ph- (R or S) C (-O-C (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Aze-Pab × HOAc and

Ph- (S or R) C (-O-C (CH ₃ ) ₂ -O-CH ₂ ) -C (O) -Aze-Pab × HOAc

(1) Ph- (R, S) C (-OC (CH ₃ ) ₂ -O-CH ₂ -) - C (O) OH

The subtitle compound was prepared according to the method described in Example 48 (4) from α-hydroxytropic acid (3.5 g; 20.35 mmol; prepared according to Guthrie et al., Can.J. Chem (1991) 69, 1904 ) with a yield of 3.37 g (74%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.30-7.65 (m, 5H), 4.95 (d, 1H), 4.10 (d, 1H), 1.70 (s, 3H ), 1.50 (s, 3H).

(2) Ph- (R, S) C (-OC (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from Ph- (R, S) C (-O-C (CH ₃ ) ₂ -O-CH ₂ ) -C (O) OH (0, 25 g; 1.12 mmol; from step (1)) to give 0.30 g (53%).

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.20-7.90 (m, 14H), 5.22 (s, 2H), 3.70-5.10 (m, 7H), 2.15 -2.75 (m, 2H); 1.40-1.65 (m, 6H).

(3) Ph- (R or S) C (-OC (CH ₃ ) ₂ -O-CH ₂ ) -C (O) -Aze-Pab × HOAc and

Ph- (S or R) C (-OC (CH ₃ ) ₂ -O-CH ₂ ) -C (O) -Aze-Pab × HOAc

A mixture of Ph- (R, S) C (-OC (CH ₃ ) ₂ -O-CH ₂ ) -C (O) -Aze-Pab (Z) (0.30 g, 0.53 mmol; from step (2) )), ammonium formate (0.30 g, 4.76 mmol), formic acid (3 drops) and Pd / C (5%, 0.30 g) in methanol (10 ml) are stirred at room temperature for 30 minutes . The reaction mixture was filtered through celite and the filtrate was evaporated. The crude product (0.29 g) was subjected to preparative RPLC. Several fractions were concentrated to give 80 mg (35%) of compound 50A with a diastereomer ratio of more than 99: 1. The late fractions were concentrated to give 80 mg (35%) of compound 50B with a diastereomer ratio of more than 98: 2.

Compound 50A:

LC-MS m / z 437 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.28-7.85 (m, 9H), 3.70-4.95 (m, 7H), 2.10-2.55 (m, 2H ), 1.55 (s, 3H), 1.50 (s, 3H).

Compound 50B:

LC-MS m / z 437 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.25-7.80 (m, 9H), 3.70-5.00 (m, 7H), 2.25-2.45 (m, 2H ), 1.60 (s, 3H), 1.48 (s, 3H).

Example 51

Ph- (R or S) C (OH) (CH ₂ OH) -C (O) -Aze-Pab × HCl and

Ph- (S or R) C (OH) (CH ₂ OH) -C (O) -Aze-Pab × HCl

(1) Ph- (R or S) C (OH) (CH ₂ OH) -C (O) -Aze-Pab × HCl

Ph- (R or S) CH (-O-C (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Aze-Pab × HOAc (0.060 g; 0.12 mmol; compound 50A from example 50 ) is dissolved in acetic acid (4 ml) and H ₂ O (1 ml) is added. The mixture was stirred overnight at room temperature, and then 6 hours at 90 ° C. HCl (conc., 1 ml) was added, the mixture was stirred at room temperature for 5 minutes. Acetic acid and HCl were removed in vacuo in the presence of toluene and EtOH, the residue was dissolved in H ₂ O (4 ml) and dried by freezing. The crude product was subjected to preparative RPLC to give 9 mg (16%) of the title compound.

LC-MS m / z 395 (M-1) ^- , 397 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.20-7.85 (m, 9H), 3.90-4.70 (m, 5H), 3.30-3.70 (m, 2H ), 2.00-2.65 (m, 2H).

(2) Ph- (S or R) C (OH) (CH ₂ OH) -C (O) -Aze-Pab × HCl

The title compound was prepared according to the method described in step (1) from Ph- (S or R) CH (—O — C (CH ₃ ) ₂ —O — CH ₂ -) —C (O) -Aze-Pab × HOAc (0.060 g, 0.12 mmol; compound 50B of Example 50) in 22 mg yield (40%).

LC-MS m / z 397 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.20-7.85 (m, 9H), 3.90-4.75 (m, 6H), 3.50-3.60 (m, 1H ), 2.10-2.50 (m, 2H).

Example 52

Ph- (R or S) C (-O-C (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Pro-Pab × HOAc and

Ph- (S or R) C (-O-C (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Pro-Pab × HOAc

(1) Ph- (R, S) C (-OC (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from Ph- (R, S) C (—O — C (CH ₃ ) ₂ —O — CH ₂ -) - C (O) OH (0 25 g; 1.12 mmol; see example 50 (1)) in 0.19 g (32%) yield.

FAB-MS m / z 585 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 7.20-7.95 (m, 14H), 5.25 (s, 2H), 5.10-5.20 (m, 1H), 4.32 -4.70 (m, 3H), 3.65-3.95 (m, 2H), 3.00-3.25 (m, 1H), 1.30-2.35 (m, 10H).

(2) Ph- (R or S) C (-OC (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Pro-Pab × HOAc and

Ph- (S or R) C (-O-C (CH ₃ ) ₂ -O-CH ₂ -) - C (O) -Pro-Pab × HOAc

The title compounds were prepared according to the method described in Example 50 (3) from Ph- (R, S) C (—OC (CH ₃ ) ₂ —O — CH ₂ -) - C (O) -Pro-Pab ( Z) (0.37 g; 0.63 mmol; from step (1)). Several fractions were concentrated to give 120 mg of compound 52A with a diastereomer ratio of more than 99: 1. The late fractions were concentrated to give 120 mg of compound 52B with a diastereomer ratio of more than 98: 2.

Compound 52A:

LC-MS m / z 451 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.25-7.80 (m, 9H), 4.35-5.05 (m, 4H), 3.80-4.95 (m, 1H ), 3.60-3.65 (m, 1H), 3.00-3.10 (m, 1H), 2.10-2.20 (m, 1H), 1.75-1.90 (m , 3H); 1.55 (s, 3H); 1.45 (s, 3H).

Compound 52B:

LC-MS m / z 451 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.25-7.80 (m, 9H), 4.40-5.10 (m, 4H), 3.30-3.80 (m, 3H ), 1.75-2.20 (m, 4H), 1.50-1.55 (m, 6H)

Example 53

Ph- (R or S) C (OH) (CH ₂ OH) -C (O) -Pro-Pab × HCl and

Ph- (S or R) C (OH) (CH ₂ OH) -C (O) -Pro-Pab × HCl

(1) Ph- (R or S) C (OH) (CH ₂ OH) -C (O) -Pro-Pab × HCl

The title compound was prepared according to the method described in Example 51 (1) from Ph- (R or S) C (—O — C (CH ₃ ) ₂ —O — CH ₂ -) - C (O) -Pro- Pab × HOAc (0.060 g; 0.12 mmol; compound 52A from Example 52) in 2 mg yield (2%).

LC-MS m / z 409 (M-1) ^- , 411 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.20-7.85 (m, 9H), 4.40-4.60 (m, 3H), 4.05-4.30 (m, 1H ), 2.95-3.90 (m, 3H), 1.60-2.20 (m, 4H).

(2) Ph- (S or R) C (OH) (CH ₂ OH) -C (O) -Pro-Pab × HCl

The title compound was prepared according to the method described in Example 51 (1) from Ph- (S or R) CH (—O — C (CH ₃ ) ₂ —O — CH ₂ -) - C (O) —Pro— Pab × HOAcO (0.060 g; 0.12 mmol; compound 52B of Example 52) in 1 mg yield (1%).

LC-MS m / z 409 (M-1) ^- , 411 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.25-7.85 (m, 9H), 4.40-4.65 (m, 3H), 4.05-4.20 (m, 1H ), 3.25-3.75 (m, 3H), 1.40-2.20 (m, 4H).

Example 54

Ph- (R) C (Me) (OH) -C (O) -Pro-Pab × HCl

(1) Ph- (R) C (Me) (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R) - (-) - 2-hydroxy-2-phenylpropionic acid (0.20 g, 1.2 mmol) and H-Pro-Pab (Z) × HCl (0.50 g; 1.1 mmol; see example 35 (2)) with a yield of 0.13 g (22%),

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.18-7.87 (m, 14H), 5.25 (s, 2H), 4.35-4.61 (m, 3H), 3.03 -3.19 (m, 2H); 1.50-2.17 (m, 7H).

(2) Ph- (R) C (Me) (OH) -C (O) -Pro-Pab × HCl

The title compound was prepared analogously to the method described in Example 1 (5) from Ph- (R) C (Me) (OH) -C (O) -Pro-Pab (Z) (0.13 g; 0.25 mmol; from step (1)) with a yield of 92 mg (89%).

FAB-MS m / z 395 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.37-7.91 (m, 9H), 4.33-4.61 (m, 3H), 3.15-4.01 (m, 2H ), 1.72-2.33 (m, 7H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by rotamers) amidine and carbonyl carbons: δ 176.06, 175.49, 174.88, 166.90.

Example 55

Ph- (S) C (Me) (OH) -C (O) -Pro-Pab × HCl

(1) Ph- (S) C (Me) (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (S) - (+) - 2-hydroxy-2-phenylpropionic acid (0.20 g, 1.2 mmol) and H-Pro-Pab (Z) × 2HCl (0.50 g; 1.1 mmol; see example 35 (2)) with a yield of 0.19 g (33%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.20-7.77 (m, 14H), 5.22 (s, 2H), 4.53-4.58 (m, 1H), 4.32 -4.44 (m, 2H), 3.13-3.38 (m, 2H), 1.53-2.04 (m, 7H).

(2) Ph- (S) C (Me) (OH) -C (O) -Pro-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph- (S) C (Me) (OH) -C (O) -Pro-Pab (Z) (0.12 g; 0.23 mmol, from step (1)) with a yield of 80 mg (82%).

FAB-MS m / z 395 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 7.35-7.84 (m, 9H), 4.47-4.63 (m, 3H), 3.30-3.70 (m, 2H ), 1.60-2.29 (m, 7H).

¹³ C NMR (75.5 MHz; D ₂ O; complicated by rotamers) amidine and carbonyl carbons: δ 175.58, 175.23, 174.79, 167.07.

Example 56

Ph (3,4-diF) - (R, S) CH (OH) -C (O) -Pro-Pab × HCl

(1) Ph (3,4-diF) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3,4-difluorormindalic acid (0.20 g; 1.06 mmol) and H-Pro-Pab (Z) × 2HCl (0.53 g, 1.17 mmol; see example 35 (2)) in 445 mg (76%) yield.

LC-MS m / z 549 (M-1) ^- , 551 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 6.98-7.74 (m, 12H), 5.16-5.21 (m, 2H), 5.06-5.01 (m, 1H) 4.22-4.56 (m, 3H), 3.32-3.58 (m, 1H), 2.88-3.12 (m, 1H), 1.70-2.12 (m, 4H).

(2) Ph (3,4-diF) - (R, S) CH (OH) -C (O) -Pro-Pab × HCl

The title compound was prepared according to the method described in Example 1 (5) from Ph (3,4-diF) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.175 g ; 0.31 mmol; from step (1)) with a yield of 127 mg (88%).

LC-MS m / z 417 (M + 1) ⁺

¹ H NMR (400 MHz; CD ₃ OD): δ 7.11-7.86 (m, 7H), 5.37 (s, 1H), 4.36-5.00 (m, 1H), 3, 66-3.78 (m, 1H); 1.80-2.31 (m, 4H).

¹³ C NMR (100.6 MHz; D ₃ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 174.66, 174.40, 171.96, 171.82, 166.48.

Example 57

Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-oxo) -Pab × HOAc

(1) Boc- (R, S) Pic (4-oxo) -OCH ₃

; 1,0 г) в CH₂Cl₂ (20 мл) перемешивают при комнатной температуре в течение 4 ч. Добавляют диэтиловый эфир (60 мл), реакционную смесь фильтруют через короткую колонку с силикагелем, элюируя смесью EtOAc:гексан (1:1). Фильтрат упаривают с получением 1,0 г (92%) указанного в подзаголовке соединения.A mixture of Boc- (R, S) Pic (4-hydroxy) -OCH ₃ (1.1 g; 4.25 mmol; prepared according to Gillard et al., J. Org. Chem. (1996) 61, 2226), PCC (1.8 g, 8.5 mmol) and molecular sieves (in powder form;

; 1.0 g) in CH ₂ Cl ₂ (20 ml) was stirred at room temperature for 4 hours. Diethyl ether (60 ml) was added, the reaction mixture was filtered through a short column of silica gel, eluting with EtOAc: hexane (1: 1) . The filtrate was evaporated to give 1.0 g (92%) of the subtitled compound.

FAB-MS m / z 258 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 4.75-5.20 (m, 1H), 3.55-4.15 (m, 5H), 2.40-2.90 (m, 4H) 1.30-1.65 (m, 9H).

(2) H- (R, S) Pic (4-oxo) -OCH ₃

Boc- (R, S) Pic (4-oxo) -OCH ₃ (0.48 g; 1.87 mmol; from step (1)) is treated with trifluoroacetic acid in CH ₂ Cl ₂ (50%, 4 ml) at room temperature for 30 minutes The reaction mixture was evaporated and the residue was dissolved in CH ₂ Cl ₂ , washed with aqueous Na ₂ CO ₃ , dried (K ₂ CO ₃ ) and evaporated. The yield of the subtitle compound is 0.23 g (78%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 3.65-3.80 (m, 4H), 3.30-3.40 (m, 1H), 2.90-3.00 (m, 1H) 2.30-2.70 (m, 4H).

(3) Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-oxo) -OCH ₃

The subtitle compound was prepared analogously to the method described in example 3 (2) from H- (R, S) Pic (4-oxo) -OCH ₃ (0.22 g; 1.4 mmol; from step (2)) and Ph- (R) CH (OTBDMS) -C (O) OH (0.372 g, 1.4 mmol) was prepared according to the method described in Hamada et al., J. Am. Chem. Soc. (1989) 111, 669 ) with a yield of 288 mg (51%).

FAB-MS m / z 406 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.20-7.50 (m, 5H), 5.25-5.70 (m, 2H), 4.15-4.75 (m, 1H) 3.20-3.80 (m, 4H), 2.00-2.90 (m, 3H), 1.30-1.65 (m, 1H), 0.85-1.15 (m, 9H), 0.10-0.35 (m, 6H).

(4) Ph- (R) CH (OTBDMS) C (O) - (R, S) Pic (4-oxo) -OH

A mixture of Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-oxo) -OCH ₃ (0.28 g, 0.69 mmol, from step (3)) and a hydroxide solution lithium (2M, 10 ml) in THF (10 ml) was stirred at room temperature for 1.5 hours. THF was removed in vacuo, the residue was acidified (pH 2) with KHSO ₄ ) (2M) and extracted with EtOAc. The organic layer was washed with H ₂ O, dried (MgSO ₄ ) and evaporated. The yield of the subtitle compound was 0.24 g (89%).

FAB-MS m / z 392 (M + 1) ⁺

¹ H NMR (400 MHz; CDCl ₃ ): δ 07.20-7.55 (m, 5H), 5.15-5.75 (m, 2H), 4.10-4.30 (m, 1H) 3.20-3.80 (m, 1H), 2.05-3.00 (m, 4H), 1.35-1.55 (m, 1H), 0.90-1.05 (m, 9H), 0.10-0.25 (m, 6H).

(5) Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-oxo) -Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 1 (2) from Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-oxo) -OH (0.227 g; 0 , 58 mmol; from step (4)) with a yield of 92 mg (24%).

FAB-MS m / z 657 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 6.90-7.90 (m, 14H), 5.10-5.80 (m, 4H), 3.60-4.70 (m, 3H) 2.10-3.20 (m, 4H), 1.40-1.70 (m, 1H), 0.80-1.10 (m, 9H), 0.00-0.25 (m, 6H).

(6) Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-oxo) -Pab (Z)

The subtitle compound was prepared according to the method described in step (2) from Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic- (4-oxo) -Pab (Z) (0 , 09 g; 0.14 mmol, from step (5)) with a yield of 61 mg (82%).

FAB-MS m / z 543 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 6.95-7.90 (m, 14H), 5.00-5.55 (m, 4H), 3.95-4.70 (m, 2H) 3.20-3.70 (m, 2H); 1.20-2.80 (m, 4H).

(7) Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-oxo) -Pab × OAc

The title compound was prepared according to the method described in Example 15 (3) from Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-oxo) -Pab (Z) (0.061 g; 0.11 mmol; from step (6)) with a yield of 46 mg (90%).

LC-MS m / z 407 (M-1) ^- , 409 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 07.20-7.85 (m, 9H), 5.00-5.80 (m, 2H), 4.35-4.55 (m, 2H ), 3.40-4.05 (m, 2H), 1.80-3.10 (m, 4H).

Example 58

Ph- (R) CH (OH) -C (O) - (R or S) Pic (4-methylene) -Pab × HOAc and

Ph- (R) CH (OH) -C (O) - (S or R) Pic (4-methylene) -Pab × HOAc

(1) Boc- (R, S) Pic (4-methylene) -OCH ₃

Methyl triphenylphosphonium bromide (2.68 g, 7.5 mmol) is dried under vacuum for 20 minutes and suspended with dry THF (20 ml) at 0 ° C. Butyl lithium (1.6 N in hexane; 4.7 ml, 7.5 mmol) was added dropwise and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -78 ° C and Boc- (R, S) Pic (4-oxo) -OCH ₃ (1.3 g, 5.0 mmol) was added, see Example 57 (1)). The reaction mixture was stirred at -78 ° C for 30 minutes and then at room temperature for 2 hours. Ammonium chloride was added to the reaction mixture, and after separation of the H ₂ O layer, it was extracted twice with diethyl ether. The combined organic layer was dried and evaporated to give a crude product, which was purified by flash chromatography, eluting with EtoAc: hexane (30:70), to give 480 mg (37%) of the subtitled compound.

FAB-MS m / z 256 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 4.70-5.10 (m, 3H), 3.95-4.15 (m, 1H), 3.70 (s, 3H), 2.10 -3.10 (m, 5H); 1.35-1.60 (m, 9H).

(2) H- (R, S) Pic (4-methylene) -OCH ₃

Boc- (R, S) Pic (4-methylene) -OCH ₃ (0.48 g, 1.88 mmol, from step (1)) is treated with trifluoroacetic acid (50% in CH ₂ Cl ₂ , 6 ml) at room temperature for 40 minutes The reaction mixture was evaporated and the residue was dissolved in CH ₂ Cl ₂ , washed with Na ₂ CO ₃ (saturated), dried (K ₂ CO ₃ ) and evaporated. The yield of the subtitle compound is 0.27 g (95%).

¹ H NMR (500 MHz; CDCl ₃ ): δ 4.70-4.85 (m, 2H), 3.75 (m, 3H), 3.35-3.45 (m, 1H), 3.15 -3.25 (m, 1H); 2.55-2.70 (m, 2H); 2.10-2.30 (m, 3H).

(3) Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-methylene) -OCH ₃

The subtitle compound was prepared analogously to the method described in Example 3 (2) from Ph- (R) CH (OTBDMS) -C (O) OH (0.37 g; 1.4 mmol), obtained according to the method described in Hamada et al, J. Am. Chem. Soc. (1989), 111.669) and H- (R, S) Pic (4-methylene) -OCH ₃ (0.21 g, 1.4 mmol; from step (2) ) with a yield of 0.283 g (52%).

FAB-MS m / z 404 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.25-7.55 (m, 5H), 5.15-5.70 (m, 2H), 4.20-4.85 (m, 3H) 3.65-3.75 (m, 3H), 1.90-3.20 (m, 5H), 0.90-1.10 (m, 9H), 0.10-0.30 (m, 6H).

(4) Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-methylene) -OH

The subtitle compound was prepared according to the method described in Example 57 (4) from Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-methylene) -OCH ₃ (0.28 g; 0.69 mmol; from step (3)) with a yield of 0.24 g (89%).

FAB-MS m / z 390 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.15-7.50 (m, 5H), 5.15-5.95 (m, 2H), 3.55-5.00 (m, 3H) 1.75-3.25 (m, 5H); 0.85-1.05 (m, 9H); 0.10-0.25 (m, 6H).

(5) Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-Methylene) -Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 3 (2) from Ph- (R) CH (OTBDMS) -C (O) - (R, S) Pic (4-methylene) -OH (0.235 g; 1 6 mmol; from step (4)) and H-Pab (Z) × HCl (0.211 g, 0.66 mmol) in 0.124 g (35%) yield.

FAB-MS m / z 655 (M + 1) ⁺

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.10-7.90 (m, 14H), 5.15-5.10 (m, 4H), 4.10-5.05 (m, 4H) 1.75-3.05 (m, 6H); 0.80-1.10 (m, 9H); 0.00-0.25 (m, 6H).

(6) Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-methylene) -Pab (Z)

The subtitle compound was prepared analogously to the method described in Example 57 (6) from Ph- (R) CH (OTBDMS) -C (O) - 1 (R, S) Pic (4-methylene) -Pab (Z) 0 (0.08 g; 0.12 mmol; from step (5)) with a yield of 0.06 g (91%).

LC-MS m / z 541 (M + 1) ⁺

¹ H NMR (500 MHz; CD ₃ OD): δ 7.15-1.90 (m, 14H), 5.20-5.80 (m, 4H), 4.35-4.90 (m, 4H ), 3.70-4.15 (m, 1H), 3.20-3.40 (m, 1H), 1.10-2.90 (m, 4H).

(7) Ph- (R) CH (OH) -C (O) - (R or S) Pic (4-methylene) -Pab × HOAc and

Ph- (R) CH (OH) -C (O) - (S or R) Pic (4-methylene) -Pab × HOAc

Mixture of Ph- (R) CH (OH) -C (O) - (R, S) Pic (4-methylene) -Pab (Z) (0.035 g, 0.065 mmol, from step (6)), ammonium acetate (0 , 50 g, 7.4 mmol) and imidazole (0.20 g, 3.0 mmol) in methanol (5 ml) were stirred at 60 ° C. overnight. The reaction mixture was evaporated and the residue was subjected to preparative RPLC. Some fractions were concentrated to obtain 1.8 mg of compound 58B. The last fractions were concentrated to give 7 mg of compound 58A.

Compound 58A:

LC-MS m / z 405 (M-1) ^- , 407 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 7.15-7.80 (m, 9H), 5.65-5.70 (m, 1H), 4.80-5.25 (m, 1H ), 4.45-4.60 (m, 2H), 3.60-4.00 (m, 2H), 1.30-3.30 (m, 6H).

Compound 58B:

LC-MS m / z 407 (M + 1) ⁺

¹ H NMR (400 MHz; D ₂ O): δ 7.30-7.80 (m, 9H), 5.45-5.75 (m, 1H), 4.80-5.20 (m, 1H ), 4.35-4.70 (m, 3H), 3.75-3.90 (m, 1H), 1.70-3.05 (m, 6H).

Example 59

Ph (3-Cl) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

(1) (R, S) -3-chloro-mandelic acid

The subtitle compound was prepared according to the method described in Example 15 (1) from 3-chlorobenzaldehyde (7.03 g; 50 mmol) in 2 g (21%) yield.

LC-MS m / z 185 (M-1) ^- , 370 (2M-1) ^-

¹ H NMR (400 MHz; CD ₃ OD): δ 7.28-7.51 (m, 4H), 5.14 (s, 1H).

(2) Ph (3-Cl) - (R, S) CH (OH) -C (O) -Aze-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2) from (R, S) -3-chloro-mandelic acid (0.149 g; 0.8 mmol; from step (1)) in a yield of 0.30 g (70 %)

¹ H NMR (500 MHz; CDCl ₃ ): δ 7.08-7.84 (m, 13H), 5.18-5.24 (m, 2H), 4.86-5.01 (m, 2H) 4.02-4.56 (m, 3H); 3.57-3.76 (m, 1H); 2.30-2.72 (m, 2H).

(3) Ph (3-Cl) - (R, S) CH (OH) -C (O) -Aze-Pab × HOAc

The title compound was prepared according to the method described in Example 43 from Ph (3-Cl) - (R, S) CH (OH) -C (O) -Aze-Pab (Z) (0.10 g; 0, 19 mmol; from step (2)) with a yield of 55 mg (63%).

LC-MS m / z 399 (M-1) ^- , 401 (M + 1) ⁺

¹ H NMR (400 MHz, D ₂ O): δ 7.10-7.85 (m, 8H), 4.82-5.37 (m, 2H), 3.96-4.79 (m, 4H ), 2.14-2.85 (m, 2H).

¹³ C NMR (100.6 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 174.00, 173.17, 172.83, 172.61, 166.59.

Example 60

Ph (3-Cl, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

(1) Ph (3-Cl, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab (Z)

The subtitle compound was prepared according to the method described in Example 3 (2), from (R, S) -3-chloro-4-hydroxy-mindic acid (0.25 g; 1.23 mmol) and H-Pro-Pab (Z ) × 2HCl (0.615 g, 1.35 mmol; see example 35 (2)) in 382 mg (55%) yield.

LC-MS m / z 564 (M-1) ^-

¹ H NMR (400 MHz; CD ₃ OD): δ 6.80-7.85 (m, 12H), 5.16-5.25 (m, 3H), 4.35-4.51 (m, 3H ), 3.45-3.75 (m, 1H), 3.07-3.42 (m, 1H), 1.72-2.18 (m, 4H).

¹³ C NMR (100.6 MHz; D ₂ O; complicated by diastereomers / rotamers) amidine and carbonyl carbons: δ 174.62, 174.27, 173.02, 172.88, 170.41, 165.04.

(2) Ph (3-Cl, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab × HOAc

The title compound was prepared analogously to the method described in Example 43 from Ph (3-Cl, 4-OH) - (R, S) CH (OH) -C (O) -Pro-Pab (Z) (0.10 g; 0.177 mmol; from step (1)), 3-fluoroacetic acid (3.7 ml, 48 mmol) and thioanisole (1.04 ml, 8.85 mmol) in 57 mg (70%) yield.

LC-MS m / z 431 (M + 1) ⁺

¹ H NMR (500 MHz; D ₂ O): δ 6.84-7.86 (m, 7H), 5.25-5.42 (m, 1H), 4.30-4.68 (m, 3H ), 3.05-4.05 (m, 2H), 1.70-2.37 (m, 4H).

Example 61

The title compounds of Examples 1-60 were tested in the above Test A, and it was found that they all had IC ₅₀ TT values of less than 0.3 μM.

Abbreviations

aq - water

Aze - azetidine-2-carboxylic acid

Boc - tert-butyloxycarbonyl

Bn - benzyl

Bu-butyl

Ch - cyclohexyl

DCC - Dicyclohexylcarbodiimide

DIPEA - Diisopropylethylamine

DMAP - N, N-dimethylaminopyridine

DMF - dimethylformamide

DC -1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Et - ethyl

EtOH - Ethanol

HCl - hydrochloric acid

HOAc - acetic acid

HOSu - N-hydroxysuccinimide

H-Dig - 1-amidino-3-aminoethylazetidine

H-Dig (Z) - 3-aminoethyl-1- (N-benzyloxycarbonylamidino) azetidine

H-Hig - 1-amidino-3-aminoethylpyrrolidine

H-Hig (Z) - 3-aminoethyl-1- (N-benzyloxycarbonylamidino) pyrrolidine

N-Ras - 1 -amidino-4-aminomethylcyclohexane

H-Pac (Z) - 4-aminomethyl-1- (N-benzyloxycarbonylamidino) cyclohexane

H-Pic - Pipecolic Acid

H-Pig - 1-amidino-3-aminomethylpiperidine

H-Pig (Z) - 3-aminomethyl-1- (N-benzyloxycarbonylamidino) piperidine

H-Pab - 1-amidino-4-aminomethylbenzene

H-Pab (Z) - 4-aminomethyl-1- (N-benzyloxycarbonylamidino) benzene

RCC - Pyridine Chlorochromate

Pro - Proline

HPLC - High Resolution Liquid Chromatography

Me - methyl

Ph - phenyl

RPLC - reverse phase high performance liquid chromatography

Su - Succinimide

TBDMS - tert-butyldimethylsilyl

TBTU - [N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate

THF - tetrahydrofuran

THR - tetrahydropyranyl

TMS - Trimethylsilyl

WSCL - Water Soluble Carbodiimide

Z - benzyloxycarbonyl

The prefixes n, s, i and t mean: normal, iso, secondary and tertiary. The default stereochemistry of amino acids (S).

Claims (23)

1. The compound of formula I

where p and q are independently 0; R ¹ represents H; R ² represents H; R ³ is phenyl (this last group is substituted by one or more than one C _1-4 alkyl, C _1-4 alkoxy, halo, hydroxy, cyano, nitro, methylenedioxy, trifluoromethyl, N (H) R ²⁷ or C (O) OR ²⁸ ); R ²⁷ represents H, C _1-4 alkyl or C (O) R ²⁹ ; R ²⁸ and R ²⁹ independently represent H or C _1-4 alkyl; R ⁴ represents H or C _1-4 alkyl; Y represents C _1-3 alkylene, optionally substituted with C _1-4 alkyl, hydroxy, methylene or oxo; n is 1 and B is a structural fragment of formula IVa

where R ⁵ represents H, halogen or C _1-4 alkyl, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, in which R ⁵ represents H when B is a structural fragment of formula IVa. 3. The compound according to claim 1 or 2, in which R ⁴ represents N. 4. The compound according to any one of claims 1 to 3, in which Y represents CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ , CH ₂ CH (CH ₃ ) CH ₂ , CH ₂ C (= O) CH ₂ or CH ₂ C (= CH ₂ ) CH ₂ . 5. The compound according to claim 4, in which Y represents CH ₂ , (CH ₂ ) ₂ or CH ₂ C (= CH ₂ ) CH ₂ . 6. The compound according to any one of claims 1 to 5, in which R ^{3 is} substituted by one or more hydroxy, fluoro, chloro, methyl, methoxy, amino, nitro, trifluoromethyl, methylenedioxy, ethoxy or propoxy. 7. The compound according to claim 6, in which R ^{3 is} substituted by one or more hydroxy, mono - or difluoro, chloro, methyl, methoxy and methylenedioxy groups. 8. The compound according to any one of claims 1 to 7, in which Y represents CH ₂ . 9. The compound according to any one of claims 1 to 8, in which the α-amino acid carbon of the fragment

is in S configuration. 10. The compound according to any one of claims 1 to 9, in which the α-carbon fragment

is in R configuration. 11. A pharmaceutical composition for inhibiting thrombin containing a compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 12. The compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. 13. The compound, as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt for use in the treatment of a condition where thrombin inhibition is required. 14. The compound, as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt for use in the treatment of thrombosis. 15. The compound, as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt for use as an anticoagulant. 16. A compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, as an active ingredient in the manufacture of a medicament for the treatment of a condition where thrombin inhibition is required. 17. The compound according to clause 16, where this condition is thrombosis. 18. The compound, as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt as an active ingredient in the manufacture of an anticoagulant. 19. A method of treating a condition where thrombin inhibition is required in which a person suffering from or prone to such a condition is administered a therapeutically effective amount of a compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. 20. The method according to claim 19, where this condition is thrombosis. 21. The method according to claim 19, where this condition is hypercoagulation in the blood and tissues. 22. A method of producing a compound as defined in claim 1, wherein (a) combine a compound of formula V

where p, q, R ¹ , R ² and R ³ are as defined in claim 1, with a compound of formula VI,

where R ⁴ , Y, n and B are as defined in claim 1; or (b) combine a compound of formula VII

where p, q, R ¹ , R ² , R ³ , R ⁴ and Y are as defined in claim 1, with the compound of formula VIII

where n and B are as defined in claim 1. 23. The compound of formula XIV

where In ¹ represents a structural fragment of the formula IV

D ¹ and D ² independently represent H or benzyloxycarbonyl; p, q, R ¹ , R ² , R ³ , R ⁴ , Y, n, and R ⁵ are as defined in claim 1, provided that D ¹ and D ^{2 are} not both N. Priority from 11/7/1995 is established according to claims 1-21, 22 (b) and 23, with the exception of signs R ³ represents phenyl substituted with one or more than one cyano, nitro, methylenedioxy, trifluoromethyl, N (H) R ²⁷ or C (O) OR ²⁸ and Y represents C _1-3 alkylene, optionally substituted with hydroxy, methylene or oxo. The priority from 12/05/1995 is established according to claims 1-21, 22 (b) and 23 for the attribute R ³ represents phenyl substituted with trifluoromethyl. The priority of 07/02/1996 is established according to paragraph 22 (a) and 1-21, 22 (b) and 23 for signs R ³ represents phenyl substituted with one or more than one cyano, nitro, methylenedioxy, N (H) R ²⁷ or C (O) OR ²⁸ and Y represents C _1-3 alkylene, optionally substituted with hydroxy, methylene or oxo.