New thrombin inhibitors, their preparing and applying

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

 

The scope of the invention

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

Background of invention

Coagulation of blood is a key process that includes both homeostasis (i.e., the prevention of blood loss from a damaged vessel), and thrombosis (formation of blood clot in a blood vessel or in the heart, which sometimes leads to the 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 proferment of prothrombin to the active enzyme thrombin.

It is known that thrombin plays a Central role in coagulation. He activates platelets, which leads to their aggregation, converts fibrinogen into fibrin monomers, which spontaneously polymerize into fibrin polymers, activates factor XIII, which, in turn, knits these polymers with the formation of insoluble fibrin. Further, thrombin activates factor V and factor VIII, which leads to the generation of thrombin from prothrombin by the method of "positive back the connection".

We can expect, therefore, that effective thrombin inhibitors will exhibit antithrombotic activity by inhibiting platelet aggregation and formation and cross-linking of fibrin. In addition, it can be expected that the antithrombotic activity can be enhanced by the effective inhibition of the positive feedback mechanism.

The level of technology

Development of a low molecular weight thrombin inhibitors 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 amino acid sequence, located around the site of cleavage of the chain Andα fibrinogen. As I thought the authors of the above amino acid sequences, the most effective inhibitor could be the sequence Phe-Val-Arg (P9-P2-P1, which is hereinafter referred to as the sequence P3-P2-P1) [classification of substrate specificity is given in Schechten and Bergen, Biophys.Res.Commun. (1967) 27, 157 and(1968) 32, 898].

Known [U.S. patent No. 4346078, international application WO 93/11152] thrombin inhibitors based on dipeptidyl derivatives with α,ω-aminoalkylation in position P1. Similarly, it was reported related structure dipeptidyl derivatives. For example, the famous [international application WO 94/29336] connection with, for example, aminomethylenemalonate, cyclic the ski aminoalkylsilane and cyclic aminoalkylindole in position P1; known [the Application for the European patent 0648780] connection with, for example, cyclic aminoalkylindole in position P1.

Known [Applications to the European patent 0468231, 0559046 and 0641779] thrombin inhibitors based on peptidyl derivatives with cyclic aminoalkylindole (e.g., either 3-or 4-aminomethyl-1-amidinopropane) in position P1.

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

Recently been described peptidyl derived on the basis of arginalized, modified in position P3, such as hydroxyacids [international application WO 93/18060], desamination [the Application for the European patent 0526877], O-methyl almond acids [an Application for a European patent 0542525] in the position P3.

Also known inhibitors of serine proteases such as thrombin) on the basis of electrophilic ketones in the position P1, for example peptidyl α-ketoesters and amides [the Application for the European patent 0195212], peralkylated ketones [the Application for the European patent 0362002], α,β,δ-trichloroethane [the Application for the European patent 0364344] α-alkoxyamine derivatives of arginine [the Application for the European patent 0530167].

Known [the Application for the European patent 0293881] other than the structure of the inhibitors Tr is pinapadala serine proteases based on the derivatives of arginine from the C-terminal baronowie acids and their isothiouronium analogues.

Recently been revealed [Applications to the European patent 0669317, 0686642, 0648780 and International application WO 95/35309, WO 95/23609 and WO 94/29336] thrombin inhibitors based on tripeptidyl derivatives.

However, there is a need for effective inhibitors of trypsin-like serine proteases, such as thrombin. There is a special need for compounds that are orally bioavailable and selective in relation to the inhibition of thrombin and other serine proteases. It can be expected that compounds that are competing inhibitory activity against thrombin, will be particularly useful as anticoagulants and, therefore, useful for therapeutic treatment of thrombosis and related diseases.

The invention

According to the proposed invention the compounds of formula I

where

p and q independently from each other 0, 1, 2, 3 or 4;

R1represents N, 2,3-epoxypropyl, C1-6alkyl (the latter possibly substituted or ends of one or more than one hydroxy-group), a structural fragment of formula Ia

where a1represents a simple bond or a C1-4alkylene, and Rxrepresents N or C1-4alkyl, provided that in the circuit Rx-C-C-A1 is not more than six carbon atoms, or when R is 0, then with R2represents a structural fragment of formula 1B

where Ryrepresents N or C1-3alkyl;

R2represents H, Si(Me)3, naphthyl, indolyl, CHR21R22or C1-4alkyl (the latter possibly substituted or ends of one or more than one fluorine - or hydroxy-group), or With3-8cycloalkyl or phenyl (the last two groups possibly substituted by one or more than one1-4alkyl, C1-4alkoxy, halogen, hydroxy, cyano, nitro, methylenedioxy, trifluoromethyl, N(H)R23C(O)OR24groups), or when p is 0, then with R1represents a structural fragment of formula 1B;

R3represents H, Si(Me)3, naphthyl, indolyl, CHR25R26or C1-6alkyl (the latter possibly substituted or ends of one or more than one fluorine - or hydroxy-group), or With3-8cycloalkyl or phenyl (the last two groups possibly substituted by one or more than one1-4alkyl, C1-4alkoxy, halogen, hydroxy, cyano, nitro, methylenedioxy, trifluoromethyl, N(H)R27or C(O)OR28groups);

R21, R22, R25and R26independently from each other represent cyclohexyl or phenyl;

23and R27independently of one another represent H, C1-4alkyl or C(O)R29;

R24, R28and R29independently of one another are N or C1-4alkyl;

R4represents N or C1-4alkyl;

Y represents a C1-3alkylen, possibly substituted C1-4by alkyl, hydroxyl, methylene or oxopropoxy;

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

Represents a structural fragment of formula IVa, IV or IVC

where

R5represents H, halogen or1-4alkyl; and

X1and X2independently represent a simple bond or CH2;

provided that when R1, R2and R4all are H, R is 0, Y is (CH2)2, n is 1 and:

(a) R3represents unsubstituted phenyl and:

(1) represents a structural fragment of formula IVa, a R5represents N, then q is not equal to 0 or 1; and

(2) represents a structural fragment of formula IV and X1and X2both are CH2then q is not equal to 0; and

(b) R3represents an unsubstituted cyclohexyl, represents a structural fragment of formula IVa, a R5represents N, then q is not equal to 0;

or its pharmaceutically acceptable salt (here, they sent the Xia as "compounds of the invention").

Compounds according to the invention can be tautomerism. All tautomeric forms and mixtures thereof are included in the scope of this invention.

Compounds according to the invention may also contain one or more than one asymmetric carbon atom and, therefore, can exhibit optical isomerism and/or diastereoisomer. All diastereoisomer can be separated using conventional techniques such as chromatography or fractional crystallization. Ranye stereoisomers may be isolated by separation of racemic or other mixture of the compounds using conventional techniques such as fractional crystallization or HPLC (liquid chromatography high resolution). Alternatively, the desired optical isomers may be obtained by the interaction of the appropriate optically active starting materials under conditions that do not allow racemization or epimerization, or by obtaining derivatives, for example with a homochiral acid followed by separation of the diastereomeric esters by traditional methods (such as HPLC or chromatography on silica). All stereoisomers are included in the scope of this invention.

Alkyl groups which may be represented by R1, Rx, Ry, R2, R3, R4, R5, R23, R24, R27, R28and R29, Lieb whom can be substituted for R 2, R3and Y;

cycloalkyl group, which can be represented by R2, R3; and alkoxygroup, which can be substituted for R2and R3may be linear or branched, saturated or unsaturated. Alkylene group, which can be represented As1and Y, can be saturated or unsaturated.

Halogen group, which may be represented by R5and which can be substituted for R2and R3include fluorine, chlorine, bromine and iodine.

Wavy line of the carbon atoms in the fragments of formulae Ia, IB, IVa, IV and IVC indicate the position of the link fragment.

Abbreviations are listed at the end of the description.

When represents a structural fragment of formula IVa, IVB or IV, the last of which X1and X2both represent CH2preferred compounds according to the invention include those in which n is 1.

When represents a structural fragment of formula IV, where X1represents a simple bond, and X2represents a simple bond or CH2preferred compounds according to the invention include those in which n is 2.

When represents a structural fragment of formula IVa, preferred compounds according to the invention include those in R 5represents N.

Preferred compounds of formula I include those in which:

R1represents H, methyl, 2,3-dihydroxypropyl or (2,2-dimethyl-1,3-dioxolan-4-yl)methyl;

p is 0;

R2represents H, possibly substituted C1-4alkyl, or substituted phenyl; q is 0, 1 or 2;

R3represents a C1-6alkyl, naphthyl, indolyl, possibly substituted cyclohexyl or possibly substituted phenyl;

Y represents CH2, (CH2)2, (CH2)3CH2CH(CH3)CH2CH2C(=O)CH2or CH2C(=CH2)CH2;

R4represents N.

When R2represents a C1-4alkyl, preferred possible substituents include hydroxy-group. The preferred attachment point of the hydroxy-group include a carbon atom, which is α-atom with respect to the carbon atom that is attached OR1.

More preferred compounds according to the invention include those in which:

R1represents N;

R2represents H, methyl, hydroxymethyl or ethyl;

q is equal to 0:

R3represents a possibly substituted phenyl or possibly substituted cyclohexyl;

Y represents CH2, (CH2 )2or CH2C(=CH2)CH2.

When R1and R2both represent N, R3represents unsubstituted phenyl or unsubstituted cyclohexyl, and q is 0 or 1, the preferred compounds according to the invention include those in which Y is CH2or CH2C(=CH2)CH2.

When R1represents H, R3represents unsubstituted phenyl or unsubstituted cyclohexyl, and q is 0 or 1, the preferred compounds according to the invention include those in which R2represents methyl, hydroxymethyl or ethyl.

When R3represents a cyclohexyl or phenyl, preferred possible substituents include hydroxy, fluorine, chlorine, methyl, methoxy, amino, nitro, trifluoromethyl, methylenedioxy, ethoxy and propoxylate. In particular, the substituents include hydroxy, mono - or debtor, chlorine, methyl, methoxy and methylenedioxy.

Particularly preferred compounds according to the invention include those in which:

Y represents CH2;

Represents a structural fragment of formula IVa.

Compounds according to the invention, in which α-amino acid carbon fragment

is S-configuration are preferred. The wavy line at atomo the nitrogen and carbon in the above fragment indicate the position of the link fragment.

When R1and R2both represent H, and p is 0, preferred compounds according to the invention are those in which α-carbon fragment

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

Preferred compounds according to 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)2C(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-CH2-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-NH2)-(R,S)CH(OH)-C(O)-Aze-Pab;

Ph(3-NH2)-(R,S)CH(OH)-C(O)-Pro-Pab;

Ph(3-NO2)-(R,S)CH(OH)-C(O)-Pro-Pab;

Ph(3,4-(-O-CH2-O-))-(R,S)CH(OH)-C(O)-Pro-Pab;

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

Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-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-F)-(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(-O-C(CH3)2-O-CH2-)-C(O)-Aze-Pab;

Ph-(R,S) (- O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab,

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

Ph-(R,S)C(CH2OH)(OH)-C(O)-Pro-Pab.

Getting

According to the invention is also a method for obtaining compounds of the formula I, in which:

(a) combining the compound of formula V

where p, q, R1, R2and R3such as defined above, with a compound of formula VI

where R4, Y, n are as defined above;

or (b) combining the compound of formula VII

where p, q, R1, R2, R3, R4and Y are such as defined above, with a compound of formula VIII

where n are as defined above;

for example in the presence of system combination (for example, oxalicacid 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).

The compounds of formula V are either commercially available, are well known from the literature or can be obtained by known methods.

For example, the compounds of formula V, where R1and R2both represent N, p and q are 0, and R3represents naphthyl or phenyl, possibly substituted by one or more1-4the alkyl, C1-4alkoxy, halogen, hydroxy, cyano, methylenedioxy is, nitro, trifluoromethyl, N(H)R27or C(O)R28can be obtained by reacting the aldehyde of formula IX

where R3Arepresents naphthyl or phenyl, possibly substituted by one or more1-4the alkyl, C1-4alkoxy, halogen, hydroxy, cyano, methylenedioxy, nitro, trifluoromethyl, N(H)R27or C(O)OR28and R27and R28such as defined above, with:

(1) the compound of the formula X

where R" represents H or (CH3)3Si, for example at elevated temperature (e.g. 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., chloride of benzylamine) followed by hydrolysis in the presence of an appropriate base (such as NaOH);

(2) chloroform, for example at elevated temperature (e.g. 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., chloride of benzylamine) followed by hydrolysis in the presence of an appropriate base (such as NaOH);

(3) a compound of formula XI

where M represents Mg or Li, followed by oxidative cleavage (e.g. by ozonolysis or catalyzed by osmium or ruthenium) under conditions well known in the art; or

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

The compound of formula V, where R1represents H, R2represents CH2HE, p and q are both equal to 0, and R3represents naphthyl or phenyl, possibly substituted by one or more1-4the alkyl, C1-4alkoxy, halogen, hydroxy, cyano, methylenedioxy, nitro, trifluoromethyl, N(H)R27or C(O)OR28can be obtained by reacting the compounds of formula XII

where R3asuch as defined above, with sodium hypochlorite, for example, at room temperature in the presence of a suitable solvent (e.g. water).

The compounds of formula VI and VII are either commercially available, are well known from the literature or can be obtained using known techniques. For example, the compounds of formula VI can be obtained by standard peptide combination of the compounds of formula XIII

where R4and Y are such as defined above, with the compound form is s VIII, as defined above, e.g., such as described above for the synthesis of compounds of formula I. Similarly, the compound of formula VII can be obtained standard peptide combination of the compounds of formula XIII as defined above, with a compound of formula V as defined above, e.g., such as described above for the synthesis of compounds of formulas.

The compounds of formula VIII, IX, X, XI, XII and XIII are either commercially available, are well known from the literature or can be obtained using known techniques. The substituents on the phenyl group in the compounds of formula V, VII, IX and XII can be subjected to vzaimoprevrascheny well-known in the art methods.

Compounds according to the invention can be isolated from their reaction mixtures using conventional techniques.

Specialist it is obvious that in the above-described method may be necessary to protect the functional groups of intermediate compounds of the protective groups.

Functional group, which is desirable to protect include hydroxy, amino, amidino, guanidinium and carboxylic acid. Suitable protective groups for hydroxyl include trialkylsilyl and diarylethylenes group (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), and tetrahydrofur the Nile. Suitable protective groups for hydroxyl groups attached to adjacent carbon atom include O,O'-isopropylidene. Suitable protective groups for amino, amidino and guanidino include tert-butyloxycarbonyl or benzyloxycarbonyl. The nitrogen atoms amidino and guanidino can be either mono-or tizamidine. Suitable protective groups for carboxylic acids include C1-6alkalemia or benzyl esters.

The introduction and removal of the protection of functional groups can take place before or after the reaction combinations.

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

The protective group can be removed according to known experts methods and as described below.

Some protected intermediate compound of the formula I, in which the nitrogen atoms amidino and guanidino in protected and which can be obtained before the final stage of removing protection from the formation of compounds according to the invention are new.

According to further aspect of the proposed invention is the compounds of formula XIV

where1represents a structural fragment of formula characterise reflexes IVG, IV or IVe

D1and D2independently represent H or benzyloxycarbonyl, and p, q, R1, R2, R3, R4, Y, n, R5X1and X2such as defined above, provided that D1and D2not represent both N.

Wavy lines at the carbon atom in the fragment of formula characterise reflexes IVG, IV or IVe indicate the position of the link fragment.

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

The specialist is also clear that, although such protected derivatives of compounds of formula I, by themselves, may not possess pharmacological activity, but they can be injected parenterally or orally, and from this time may be subject to metabolism in the body to form compounds according to the invention which are pharmacologically active. Such derivatives can therefore 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 which are particularly useful as prodrugs, including the with the compounds of formula XIV.

Medical and pharmaceutical application

Compounds according to the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.

According to further aspect of the invention, thus, the proposed compounds according to the invention for use as pharmaceuticals.

In particular, the compounds according to the invention are powerful inhibitors of thrombin, as illustrated, for example, in the following tests.

It is expected, therefore, that the compounds according to the invention will be useful in cases when you want the inhibition of thrombin.

Compounds according to the invention, therefore, is indicated for the treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues of animals, including humans.

Compounds according to the invention is further indicated for the treatment of conditions in which there is unwanted excess thrombin without signs of hypercoagulability, for example in neurodegenerative diseases such as Alzheimer's disease.

Specific painful conditions that should be mentioned include the treatment and/or prophylaxis of venous thrombosis and lung embolism, thrombosis of arteries (e.g., unstable angina, myocardial infarction, stroke as a result of thrombosis and peripheral arterial is thrombosis and systemic embolism usually from the atrium during arterial fibrillation or from the left ventricle after transmural myocardial infarction.

Moreover, it is expected that the compounds according to the invention will find application in the prevention of re-blockage (thrombosis) after thrombolyse, percutaneous intraluminal angioplasty (RSTA), coronary artery bypass operations, microsurgery and vascular surgery in General.

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

It is known that in addition to its impact on the process of coagulation thrombin activates a large number of cells (such as neutrophils, fibroblasts, endothelial cells and smooth muscle cells). Therefore, the compounds according to the invention can also be used for treatment or prophylaxis of idiopathic or respiratory distress syndrome in the tall, pulmonary fibrosis following treatment with radiation or chemotherapy, septic shock, septicemia, inflammatory responses, 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 after percutaneous intraluminal angioplasty (RTSA).

Compounds according to the invention, which ingibiruet trypsin and/or thrombin, can be also useful in the treatment of pancreatitis.

According to further aspect of the invention, a method for treatment of conditions requiring inhibition of thrombin, wherein the person suffering from such condition or are prone to this condition, introducing a therapeutically effective amount of the compounds of formula I, as defined above, or its pharmaceutically acceptability of salt.

Pharmaceutical

Compounds according to the invention should generally be administered orally, subcutaneously, transbukkalno, rectal, transdermal, nasal, through the trachea, through the bronchi or any other parenteral route or via inhalation, in the form of pharmaceutical preparations containing the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic salts of p is soedineniya organic or inorganic acid, in pharmaceutically acceptable form of the standard dose. Depending on the disease and the patient should be treated, and how the introduction of these compositions can be administered in various doses.

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

Compounds according to the invention can be further combined with thrombolytics such as tissue plasminogen activator (natural or recombinant), streptokinase, urokinase, PUK, Anatolievna complex of streptokinase and plasminogen activator (ASPAC), plasminogen activators salivary glands of animals, etc. in the treatment of thrombotic diseases, in particular myocardial infarction.

According to further aspect of the invention is proposed, therefore, a pharmaceutical composition comprising a compound of formula I, as defined above, or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable daily doses of the compounds according to the invention in therapeutic lichenicolous are a dose of about 0.001 to 100 mg/kg body weight by oral administration and 0.001-50 mg/kg body weight at parenteral administration.

Compounds according to the invention have the advantage that they can be more effective, less toxic, can operate longer, to have a wider range of activity, be more strong, to give less side effects, more easily absorbed or have other useful pharmacological properties in comparison with known compounds.

Biological tests

Test And

Determination of the thrombin clotting time (TT)

Human thrombin (T 6769, Sigma Chem Co) in the buffer solution, pH 7.4, 100 μl, and the solution of inhibitor, 100 μl, were incubated for 1 minutes

Then added pulirovaniya normal citrate human plasma, 100 μl, and the measured time of formation of a clot in an automatic device (KC 10, Amelung)

Built the dependence of the clotting time in seconds from the concentration of inhibitor and by interpolating the determined IC50TT.

IC50TT represents the concentration of inhibitor, which doubles the thrombin clotting time of human plasma.

Test B

Determination of activated partial thromboplastin time (ART)

ART was determined in polerowanie normal citrate human plasma using PTT reagent Automated 5, manufactured by Stago. Inhibitors were added to the plasma (10 µl of a solution ing the inhibitors of 90 µl of plasma), then the reagent and the solution of calcium chloride, and ART were identified in the mixture by use of the coagulation analyzer CA 10 (Amelung) according to the manufacturer's instructions of the reagent. Build dependency formation of a clot in seconds from the concentration of inhibitor and by interpolating the determined IC50APTT.

IC50APTT is defined as the concentration of inhibitor in human plasma, which doubles activated partial thromboplastin time.

Test

Determination of thrombin time ex vivo

Inhibition of thrombin after oral or parenteral administration of the compounds according to the invention was studied on rats, in consciousness, which for one or two days before the experiment was installed catheter for sampling of blood from the carotid artery. On the day of the experiment, blood samples were collected at a fixed time after the introduction of the compounds into plastic tubes containing 1 part of a solution of sodium citrate (0.13 mol/liter) and 9 parts of blood. The tubes were centrifuged with getting depleted platelet plasma. This plasma was used for determination of the thrombin time, as described below.

Citrate plasma of rats, 100 μl, was diluted in a saline solution of 0.9%, 100 ál and plasma coagulation was initiated by addition of human thrombin (T 6769, Sigma Chem Co, USA) in buffer solution, pH 7.4 100 mm. The formation of the clot was measured in an automatic device (KC 10, Amelung, Germany).

In those cases, when injected with a compound of formula XIV, the concentration of the corresponding active thrombin inhibitor of formula I in the plasma of rats was estimated using standard curves thrombin time in polerowanie citrate plasma of rats from known concentrations of the respective active inhibitors of thrombin dissolved in physiological solution.

Test

Determination of thrombin time in urine ex vivo

In conscious rats were placed in a cell for the study of metabolism at 24 h after oral administration of the compounds according to the invention. Thrombin time was determined by the collected urine, as described below.

Pulirovaniya normal citrate human plasma (100 μl) were incubated with the concentrated urine of rats, or its dilutions in saline solution for 1 min. Then initiated coagulation plasma by introducing human thrombin (T 6769, Sigma Chem Company) in buffer solution (pH 7.4; 100 μl). The clotting time was measured in an automatic device (KC 10, Amelung).

In those cases, when injected with a compound of formula XIV, the appropriate concentration of active thrombin inhibitors of the formula I in the urine of rats was estimated using standard curves trombino what about the time in polerowanie normal citrate plasma of rats from known concentrations of the respective active inhibitors of thrombin, dissolved in the concentrated urine of rats (or its dilutions in physiological solution). Multiplying the total production of urine of rats for 24 h on a set average concentration above the active inhibitor in the urine, it is possible to calculate the quantity of excreted active inhibitor.

The invention is illustrated by the following examples.

Examples

General experimental procedures

Mass spectra were recorded on a Finnigan MAT TSQ 700 triplet-quadrupole mass spectrometer equipped with electroactive surface (FAB-MS), and VG Platform II mass spectrometer equipped with electroactive surface (LC-MS). Measurement1H NMR and13C NMR was performed on a BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers operating at1N frequencies 300,13, 399,96 and 499,82 MHz, respectively, and13C 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 (of 13.75 g; 63 mmol) is added under 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 h the THF removed in vacuo, dilute the mixture with water and acidified with 2M potassium hydrosulfate. After extraction with methylene chloride followed by drying (magnesium sulfate) and evaporation of the solvent receive the STATCOM, which is recrystallized from methylene chloride to obtain 10,87 g (95%) of colorless crystals.

1H NMR (300 MHz; CDCl3): δ 4,85-4,7 (br s, 1), 4,0-of 3.75 (m, 2), 2,65 to 2.35 (m, 2), and 1.4 (s, 9).

(2) Boc-Aze-Pab(Z)

At room temperature add EDC (13.5 g, 70 mmol) to a mixture of Boc-Aze-OH (10,87 g, 54 mmol; from stage (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 h the solvent is removed in vacuo and replaced with ethyl acetate. The mixture is washed with water and an aqueous solution of citric acid. The organic layer is dried (magnesium sulfate) and remove the solvent in vacuo to obtain a residue, which after crystallization from a mixture of methylene chloride, toluene, diisopropyl ether and petroleum ether to give Boc-Aze-Pab(Z) (17,83 g),

1H NMR (300 MHz; CDCl3): δ a 7.85-of 7.75 (d, 1), 7,45-7, (m, 7), and 5.2 (s, 2), 4,7 (t, 1), 4,6-4,4 (m, 2), 3.95 to 3,8 ("q", 1), and 3.8 to 3.7 (q,1), 2,5-2,3 (m, 2), and 1.4 (s, 9).

(3) H-Aze-Pab(Z)

Boc-Aze-Pab(Z) (2,44 g, 5.2 mmol; from stage (2)above) dissolved in a mixture of 10 ml triperoxonane acid and 10 ml of methylene chloride. After 30 min the solvent and triperoxonane acid is removed in vacuo and the residue is dissolved in methylene chloride. The organic phase is washed with 10%sodium carbonate and dried (potassium carbonate). Remove the solvent in vacuo to obtain a residue that pic is f crystallization from methylene chloride gives H-Aze-Pab(Z) (1,095 g; 57%) as colorless crystals.

1H-NMR (300 MHz; CD3OD): δ a 7.85-of 7.75 (d, 2), 7,45-7,25 (m, 7), and 5.2 (s, 2), and 4.5 (s, 2), 4,3 (d, 1), the 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)-hexahydroalmond acid (0,30 g, 1.9 mmol), catalytic amount of DMAP and pyridine (0.31 g, 3.9 mmol) in methylene chloride (5 ml) added dropwise TMSCl (0,42 g, 3.9 mmol). The reaction mixture was stirred at room temperature for 4 h, the Reaction mixture was cooled to 0°and add a catalytic amount of DMF (3 drops from a syringe 2 ml), and then oxalicacid (0.25 g, 2.0 mmol). The reaction mixture was stirred for 1 h at 0°add the mixture of H-Aze-Pab(Z) (of 0.67 g, 1.8 mmol; from stage (3)above) and pyridine (0.50 g, 6.3 mmol), and then allow the reaction mixture to warm to room temperature and stirred over night. To the reaction mixture are added 10%citric acid solution in methanol (6 ml). After 30 min the reaction mixture was poured into a separating funnel, diluted with 30 ml ethyl acetate and extracted the aqueous phase with ethyl acetate. The combined organic layers washed with a saturated solution of bicarbonate, and then brine and dried (Na2SO4). After evaporation and flash chromatography on silica gel used is eating a mixture of methylene chloride: methanol (99:1 to 92:8) as eluent get mentioned in the subtitle compound (60 mg, 6%).

1H NMR (300 MHz; CDCl3): δ 1,0-1,9 (m, 11H), 2,4-2,7 (m, 2H), 3,80 (d, 1H), 4,05-of 4.25 (m, 1H), a 4.3 to 4.5 (m, 2H), 4,85-5,0 (m, 1H), 5,18 (s, 2H), 7,1-7,5 (m, 7H), 7,65 one-7.8 (m, 2H) 7,86 (bt, 1H, minor diastereoisomer and/or rotamer), 8,33 (bt, 1H, major diastereoisomer and/or rotamer).

13With NMR (75 MHz; CDCl3) amidinov 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 stage (4)above) was dissolved in ethanol (5 ml) and add 5%Pd/C and HCl (0.1 ml; conc). The mixture hydrogenizing at atmospheric pressure for 2 hours After filtration and evaporation the product was then purified preparative RPLC using (M NH4OAc, 0,005M SPLA):CH3CN 4:1 as eluent. After drying freezing add HCl (aqueous) and the solution freeze dried. The yield of the product specified in the header, is 15 mg (31%).

1H-NMR (300 MHz; D2O) spectrum is complicated due to diastereomers and/or rotamers: δ 0,7-2,0 (m, 11H), 2,25-2,4 (m, 1H), 2,65 is 2.9 (m, 1H), 3,79 (d, 1H, minor), a 4.03 (d, 1H, major), 4,05-to 4.15 (m, 2H, minor), 4,35 is 4.45 (m (bt), 2H, major), 4,5-4,6 (m, 2H), 5,20 (m, 1H, minor; major signal partially obscured by HOD signal), 7.5 to the 7.65 (m, 2H), 7,75-a 7.85 (m, 2H).

13C NMR (75 MHz; CDCl3) amidinov and carbonyl carbon (diastereomers and/or rotamer): 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)C(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 1(4), with (R)-hexahydroalmond acid (0,60 g; 3.8 mmol) to yield 0.15 g (10%).

(2) Ch-(R)CH(OH)-C(O)-Aze-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ch-(R)CH(OH)-C(O)-Aze-Pab(Z) (0.12 g; 0.24 mmol; from stage (1)above). Yield: 52 mg (54%).

1H NMR (300 MHz; D2O) spectrum is 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), was 4.02 (d, 1H, major), 4,05-to 4.15 (m, 2H, minor), 4,35 is 4.45 (m (bt), 2H, major), 4,5-4,6 (m, 2H), 5,19 (m, 1H, minor; major signal partially obscured by HOD signal), 7.5 to the 7.65 (m, 2H), 7,75-a 7.85 (m, 2H).

13With NMR (75 MHz; CDCl3) amidinov and carbonyl carbon (rotamer): δ 171,9, 170,2, 169,8 and 163,8.

Example 3

(Et)2C(OH)-C(O)-Aze-Pab×HCl

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

Specified in the subtitle compound produced by the interaction of Boc-Aze-Pab(Z) (see example 1(2), above) with EtOAc, saturated with gaseous HCl. The reaction mixture after half an hour, evaporated to obtaining H-Aze-Pab(Z)×2HCl with quantitative yield.

(2) (Et)2C(OH)-C(O)-Aze-Pab(Z)

The mixture diacylglycerol acid (0,13 g; 0.80 mmol), H-Aze-Pab(Z)×2HCl (0.39 g; 0.88 mmol, from stage (1)above), TBTU (0.28 g, 0.88 mmol) in DMF (15 ml) cooled in an ice bath. Add DIPEA (0,41 g, 3.2 mmol) and stirred the reaction mixture is ri room temperature over night. 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 NaHCO3and with water, dried (Na2SO4) and evaporated. The crude product subjected to flash chromatography on silica gel using a mixture of methylene chloride : THF as eluent. Yield: 30 mg (8%).

1H-NMR (400 MHz; CDCl3): δ 8,04 (bt, 1H), to 7.77 (d, 2H), 7,40 (d, 2H), 7,35 to 7.2 (m, 5H), to 5.17 (s, 2H), 4,90 (m, 1H), 4,46 (dd, 1H), 4,39 (dd, 1H), from 4.3 to 4.2 (m, 2H), 2,66 (m, 1H), 2,44 (m, 1H), 1,8-1,5 (m, 4H), 0.9 to 0.75 in (m, 6H).

(3) (Et)2C(OH)-C(O)-Aze-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), (Et)2C(OH)-C(O)-Aze-Pab(Z) (30 mg; 0,063 mmol; from stage (2)above). Yield: 19 mg (79%).

1H NMR (300 MHz; D2O) spectrum is complicated by rotamers: δ 7,80 (d, 2H), 7,65-7,5 (m, 2H), 5,43 (m, 1H, minor rotamer), the 4.90 (m, 1H, major rotamer), 4.6 to 4.5 (m, 3H), 4,11 (m, 1H, rotamer), 3,70 (m, 1H, rotamer), 2,8-to 2.55 (m, 1H), 2,35-of 2.15 (m, 1H), 1,9-1,6 (m, 4H), from 1.0 to 0.75 (m, 6H).

13C NMR (75 MHz; CDCl3) amidinov and carbonyl carbon (rotamer): δ 178,3, 177,4, 175,0, 173.5 metric and of 167.2.

Example 4

(Ph)2C(OH)-C(O)-Aze-Pab×HCl

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

Specified in subheading connection receive according to the method described in example 3(2), petrol acid (0.18 g, 0.80 mmol). Yield: 0.16 g(35%).

1H NMR (300 MHz; D2O): δ 7,93 (bt, 1H), 7,71 (d, 2H), 7,54-to 7.15 (m, 17H), 5,14 (, 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

Specified in the header connection receive according to the method described in example 1(5), (Ph)2C(OH)-C(O)-Aze-Pab(Z) (0.16 g; 0.28 mmol; from stage (1)above). Yield: 90 mg (68%).

1H NMR (400 MHz; D2O) spectrum is complicated by rotamers: δ the 7.65 at 7.55 (m, 2H), and 7.4 to 7.1 (m, 12H), 5,13 (m, 1H, minor rotamer), of 4.77 (m, 1H, major rotamer), 4,43 (d, 1H), and 4.40 (d, 1H), 4,12 (m, 1H, major rotamer), 4,05 to-3.9 (m, 1H, plus 1H minor rotamer), to 2.55 (m, 1H, minor rotamer), 2,39 (m, 1H, major rotamer), of 2.08 (m, 1H).

13With NMR (75 MHz; D2O) amidinov and carbonyl carbon (rotamer): δ 175,7, 174,9, 174,6, 173,4 and 167,1.

Example 5

n-C6H13-(R,S)CH(OH)-C(O)-Aze-Pab×HCl

(1) n-C6H13-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-2-hydroxyoctanoic acid (0,13 g; 0.80 mmol) to yield 0.25 g (61%).

1H NMR (400 MHz; CDCl3): δ 8,24 (bt, 1H, one diastereoisomer), 7,89 (bt, 1H, one diastereoisomer), 7,8 to 7.75 (m, 2H), 7,4 was 7.45 (m, 2H), 7,35-7,25 (m, 5H), is 5.18 (s, 2H), 4.95 points-is 4.85 (m, 1H), 4,55 is 4.35 (m, 2H), from 4.2 to 4.0 (m, 3H), 2,8-to 2.65 (m, 1H), 2,6-2,4 (m, 1H), 2,0-1,2 (m, 10H), 0,9-0,8 (m, 3H).

(2) n-C6H13-(R,S)CH(OH)-C(O)-Aze-Pab×HCl.

Specified in the header connection receive according to the method described in example 1(5), n-C6H13-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.14 g; 0.28 mm is l; from (1)above) to yield 88 mg (78%).

1H NMR (400 MHz; D2O): δ, and 7.7 and 7.6 (m, 2H), 7,45 of 7.3 (m, 2H), to 5.03 (m, 1H, one diastereoisomer), 4,74 (m, 1H, one diastereoisomer partially overlapped by water signal), 4,45 is 4.35 (m, 2H), from 4.3 to 4.1 (m, 2H), of 4.0 to 3.8 (m, 1H), 2,65 at 2.45 (m, 1H), 2,3-2,1 (m, 1H), 1,6-0,9 (m, 10H), of 0.75 to 0.65 (m, 3H).

13With NMR (75 MHz; D2O) amidinov and carbonyl carbon (rotamer): δ 176,8, 176,0, 173,5, 173,3, 173,2 and of 167.2.

Example 6

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

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

Specified in subheading connection receive according to the method described in example 3(2)of (R)-almond acid (0.12 g; 0.8 mmol). The crude product (0,315 g) purified flash chromatography (Si-gel; THF:EtOAc (6:4)). Output 0,128 g (32%) of white powder, purity and 91.2% (HPLC).

1H NMR (499,803 MHz; CDCl3): δ to 8.14 (t, 1H), 7,72 (d, 2H), 7,42 (d, 2H), 7,33 (t, 4H), 7,28 (m, 3H), 7,22 (d, 2H), by 5.18 (s, 2H), 4.92 in (s, 1H), 4,79 (dd, 1H), 4,54 (broad s, 1H), 4,39 (d, 2H), 4.00 points (q, 1H), 3,53 (q, 1H), 2,48 (m, 1H), 2,24 (m, 1H), 2,19 (broad s, 1H)

13C NMR (125,688 MHz; CDCl3) (carbonyl and amidinov carbon): 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 stage (1)above) dissolved in a mixture of THF:water(2:1), added 37 mg of Pd/C (4 mol.% Pd) and hydrogenizing the resulting solution within 6 hours the Solution is filtered through filters hyflo and evaporated to dryness. To the obtained white powder add 20 ml of water, acidified at 0.42 ml of 1M HCl (2 EQ.). Floor the obtained solution was washed with 5 ml EtOAc and 10 ml of diethyl ether and twice dried by freezing. Yield: 72 mg (84%) of white powder. The purity of 91%(HPLC).

1H NMR (399,968 MHz; D2O): δ EUR 7.57 (t, 2H), was 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), to 4.38 (s, 2, major), 4,20 (dd, 1H, major), 3,98 (dd, 2H, minor), of 3.97 (m, 1H, major in), 3.75 (dd, 1H), 2,68 (s, 1H, minor), to 2.65 (m, 1H, minor), to 2.35 (m, 1H, major), 2,12 (m, 1H, major), 2,03 (m, 1H, minor).

13With NMR (111,581 MHz; D2O) (carbonyl and amidinov carbon): δ 174,5, 173,2, 172,5, 172,4.

Example 7

Ph(4-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab×HCl

(1) Ph(4-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-4-cryptomaterial acid (0,19 g; 0.88 mmol). Flash chromatography (Si-gel; CH2Cl2:THF (6:4)) gives 0,13 g (26%) of white powder.

1H NMR (300 MHz; CDCl3): δ 9,6-9,2 (b, 1H), 8,1 (bt, 1H, diastereoisomer), 7,9 (bt, 1H, diastereoisomer), 7,7-7,1 (m, 13H), 5,16 (s, 2H), 5,07 (s, 1H, diastereoisomer), to 4.98 (s, 1H, diastereoisomer), 4,80 (m, 1H), 4,5-4,2 (m, 2H), 4,1 to 3.5 (m, 2H), 2,5-2,2 (m, 2H).

13C NMR (75 MHz; CDCl3), amidinov and carbonyl carbon (diastereomers): δ 173,3, 172,4, 170,3, 168,3, 164,4.

(2) Ph(4-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab×HCl

Receive according to the method described in example 1(5), Ph(4-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (133 mg; 0.23 mmol; from stage (1)above) to obtain the specified title compound as a white crystalline is orosco. Yield 77 mg (70%).

1H NMR (300 MHz; D2O); δ 8,84 (m, 1H, diastereoisomer/rotamer), 8,73 (m, 1H, diastereoisomer/rotamer), charged 8.52 (m, 1H, diastereoisomer/rotamer), and 7.8 to 7.4 (m, 8H), 5,46, 5,44, 5,30, 5,20 (singlet, 1H, diastereomers/rotamer), 4,96 (m, 1H, diastereoisomer/rotamer, other signals of the same proton overlap signal HDO), 4,6-4,0 (m, 4H), 2,9-2,5 (m, 1H), 2,4-2,1 (m, 1H).

13With NMR (75 MHz; D2O), amidinov and carbonyl carbon (diastereomers and rotamer): 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-4-methoxymandelic acid (0.18 g; 1.0 mmol). Flash chromatography (Si-gel; EtOAc:Meon (95:5)) to give 27 mg (17%) of white powder.

The ratio of diastereomers 85:15; the signals of the major diastereoisomer:

1H NMR (400 MHz; CDCl3): δ 8,19 (m, 1H), 7,80 (d, 2H), 7,45 (d, 2H), and 7.4 to 7.2 (m, 7H), 7,13 (d, 2H, minor rotamer), of 6.90 (d, 2H, major rotamer), PC 6.82 (d, 2H, minor rotamer), to 5.21 (s, 2H), 4.9 to around 4.85 (m, 2H; his singlet on 4,89 (1H)), 4,6-4,4 (m, 2H), was 4.02 (m, 1H), 3,81 (s, 3H), 3,55 (m, 1H), 2,62 (m, 1H), 2,32 (m, 1H).

13C NMR (100 MHz; CDCl3), amidinov 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

Specified in the header connection receive according to the method described in example 1(5), Ph(4-OMe)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (27 mg; 0.05 mmol; from stage (1), given the th above). Yield 15 mg (68%) as a white powder.

The ratio of diastereomers 85:15; the signals of the major diastereoisomer:

1H NMR (400 MHz; D2O): δ, and 7.7 and 7.6 (m, 2H), 7.5 to to 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), free 5.01 (m, 1H, rotamer), was 4.76 (m, 1H, rotamer), 4,48 (s, 1H), 4,3-3,7 (m, 7H, 2 of his singlet on 3,78, of 3.77 (3H)), 2,73 (m, 1H, rotamer), the 2.46 (m, 1H, rotamer), 2,3-2,0 (m, 1H).

13C NMR (75 MHz; D2O) amidinov and carbonyl carbon (rotamer): 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-4-hydroxymandelic acid (0.34 g; 2.0 mmol). Flash chromatography (Si-gel; EtOAc/EtOH 9/1) to give 0.18 g (17%).

1H NMR (400 MHz; CDCl3): δ of 7.70 (d, 2H, minor diastereoisomer/rotamer), to 7.64 (d, 2H, major diastereoisomer/rotamer), of 7.5 to 7.0 (m, 7H), PC 6.82 (d, 2H, major diastereoisomer/rotamer), to 6.67 (d, 2H, minor diastereoisomer/rotamer), to 6.43 (d, 2H, major diastereoisomer/rotamer), 5,30, 5,26, 5,22, 5,21 (singlets, 2H, diastereoisomer/rotamer), 4,95 of 4.8 (m, 2H), 4,15-of 4.05 (m, 2H), of 4.0 to 3.7 (m, 2H), 2,7-2,5 (m, 2H).

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

Specified in subheading connection receive according to the method described in example 1(5), 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.

1H I Is P (600 MHz; D2O): 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/rotamer), 5,19 (s, 1H, diastereoisomer/rotamer), to 5.17 (s, 1H, diastereoisomer/rotamer), 5,14 (s, 1H, diastereoisomer/rotamer), free 5.01 (m, 1H, diastereoisomer/rotamer), 4,88 (m, 1H, diastereoisomer/rotamer, other signals of the proton overlap signal HDO), and 4.6 to 3.8 (m, 4H), 2,77 (m, 1H, diastereoisomer/rotamer), 2,62 (m, 1H, diastereoisomer/rotamer), 2,49 (m, 1H, diastereoisomer/rotamer), 2,3-2,1 (m, 1H).

13With NMR (75 MHz; D2O) amidinov and carbonyl carbon (diastereomers and rotamer): δ 175,9, 174,8, 174,3, 173,3, 173,2, 172,9, 167,1.

Example 10

Ph-CH2-(R)CH(OH)-C(O)-Aze-Pab×HCl

(1) Ph-CH2-(R)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2)of (R)-phenylmalonic acid (0.25 g; 1.5 mmol). Flash chromatography (Si-gel; CH2Cl2:THF (6:4)) to give 0.28 g (36%).

1H NMR (500 MHz; CDCl3): δ 8,19 (m, 1H), 7,72 (d, 2H), 7,43 (d, 2H), and 7.4 to 7.1 (m, 10H), 5,19 (s, 2H), 4,73 (m, 1H), 4,45-of 4.25 (m, 2H), 4,19 (m, 1H), 3,86 (m, 1H), 3,18 (m, 1H), from 3.0 to 2.9 (m, 2H), 2,42 (m, 1H), and 2.14 (m, 1H).

13C NMR (125 MHz; CDCl3) amidinov and carbonyl carbons: δ 174,5, 170,2, 167,9, 164,3.

(2) Ph-CH2-(R)CH(OH)-C(O)-Aze-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ph-CH2-(R)CH(OH)-C(O)-Aze-Pab(Z) (0,22 g; 0.43 mmol: stage (1)above) with the receipt of 101.5 mg (57%) of white powder is CA.

1H NMR (600 MHz; D2O): δ 7,73 (d, 2H, major rotamer), a 7.62 (d, 2H, minor rotamer), and 7.5 to 7.4 (m, 2H), and 7.4 to 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), a 4.03 (m, 1H), 3,53 (m, 1H), 3,05-2,95 (m, 2H, major rotamer), of 2.9 and 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).

13With NMR (75 MHz; D2O) amidinov and carbonyl carbon (rotamer): δ 175,9, 175,0, 173,7, 173,2, 167,1, 166,8.

Example 11

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

(1) BOC-Pic-HE

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

1H NMR (300 MHz; CDCl3): 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)

Specified in the header connection receive according to the method described in example 1(2) of Boc-Pic-OH (2,02 g, 8,8 mmol; from stage (1)above) with the release of 1.59 g (44%).

FAB-MS m/z 495(M+1)+

1H NMR (400 MHz; CDCl3): δ 7,83 (d, 2H), 7,43 (d, 2H), was 7.36-7,11 (m, 5H), of 6.52 (bs, NH), 5,20 (s, 2H), to 4.81-4.72 in (m, 1H), br4.61-4,34 (m, 2H), 4,10-3,90 (m, 1H), 2,79-of 2.64 (m, 1H), 2,36 was 2.25 (m, 1H), 1,7-1,3 (m, 14N).

(3) H-Pic-Pab(Z)×2HCl

Boc-Pic-Pab(Z) (1,59 g; 3.25 mmol; from stage (2)above) dissolved in 100 ml of EtOAc saturated with HCl. The reaction mixture is evaporated in half an hour with obtaining specified in the connection header with the amounts of the authorized access.

FAB-MS m/z 395 (M+1)+

1H NMR (300 MHz, D2O): δ of 7.82 (d, 2H), 7,63-7,41 (m, 7H), vs. 5.47 (s, 2H), 4,69-4,49 (AB-system, centered on δ 4,59, 2H), a 4.03 (dd, 1H), 3,52 (bd, 1H), 3,10 (dt, 1H), to 2.29 (dd, 1H), 2,08-to 1.61 (m, 5H).

(4) H-Pic-Pab(Z)

Specified in the title compound is obtained by dissolving the dihydrochloride of stage (3)above, in 2M NaOH followed by extraction with CH2Cl2and evaporation of the organic solvent.

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

Specified in the header connection receive according to the method described in example 3(2) of (R)-hexahydroalmond 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 with EtOAc:toluene (2:3), then EtOAc) to give 90 mg (18%).

1H NMR (300 MHz; CDCl3): δ of 7.82 (d, 2H), 7.5 to about 7.2 (m, 7H), 6,63 (t, X part of AVH system, NH), to 5.21 (s, 2H), 5,14 (d, 1H), 4,46 (AVH-system, 2H), 4.26 deaths (apparent s, 1H), 3,61 (bd, 1H), 3,52 (bd, 1H), 3,06 (dt, 1H), 2,30 (bd, 1H), 1,92-1,0 (m, 14H), of 0.95 to 0.8 (m, 1H).

13C NMR (75 MHz; CDCl3) amidinov and carbonyl carbons: δ 174,8, 170,3, 167,8 and 164,6.

(6) Ch-(R)CH(OH)-C(O)-Pic-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ch-(R)CH(OH)C(O)-Pic-Pab(Z) (59 mg; 0.11 mmol; from stage (5), above) with the yield 19 mg (40%).

FAB-MS m/z 401 (M+1)+

1H NMR (300 MHz; D2O) spectrum is complicated by rotamers: δ to $ 7.91-7,72 (m, major and minor rotamer 2H), 7,58 (d, minor rotamer, 2H), 7,53 (d, major rotamer, 2H), 5,17 (apparent bs, major rotamer, 1H), 4,66-to 4.28 (m, 3H), 3.96 points (bd, major rotamer, 1H), 3,26(bt, major rotamer, 1H), 3,05-is 2.88 (m, minor rotamer, 1H), 2,39-of 2.20 (m, 1H), 2.0 to 0.75 in (m, 16H).

13With NMR (75 MHz; MeOD) amidinov and carbonyl carbon on δ 175,86, 173,20, 168,53.

Example 12

Ch-CH2-(R)CH(OH)-C(O)-Pic-Pab×HCl

(1) Ch-CH2-(R)CH(OH)-C(O)OH

The solution phenylmalonic acid (2,75 g) and rhodium on aluminum oxide (0.75 g) in the Meon (170 ml) hydrogenizing in N2-the atmosphere at a pressure of 3 ATM for 2 days. The mixture is filtered through hyflo and evaporated to dryness to obtain the product in quantitative yield.

1H NMR (400 MHz; CDCl3): δ 4,23 (bdd, 1H), 3,24 (apparent s, HE), 1,68 (bd, 1H), 1,63 was 1.43 (m, 6H), 1,43 to 1.31 (m, 1H), 1,21-1,0 (m, 3H), of 0.95 to 0.75 (m, 157 mg (of 0.91 mmol) 2N)

(2) Ch-CH2-(R)CH(OH)-C(O)-Pic-Pab(Z)

Specified in the header connection receive according to the method described in example 1(4), H-Pic-Pab(Z)×2HCl (353 mg; 0,76 mmol; see example 11(3)) and Ch-CH2-(R)CH(OH)-COOH (157 mg, of 0.91 mmol; from stage (1)above). The product is subjected to flash chromatography (Si-gel, EtOAc:toluene (7:3)) to give 92 mg (22%).

1H NMR (300 MHz; CDCl3): δ 7,72 (d, 2H), 7,46 to 7.1 (m, 7H), 6.90 to (t, NH), by 5.18 (s, 2H), 5,07 (d, 1H), 4,45 (bd, 1H), 4,37 (d, 2H), of 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), of 1.05 to 0.75 (m, 3H)

13C NMR (75 MHz; CDCl3) amidinov and carbonyl carbons: #x003B4; 175,88, 170,43, 168,04 and 164,58.

(3) Ch-CH2-(R)CH(OH)-C(O)-Pic-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ch-CH2-(R)CH(OH)-C(O)-Pic-Pab(Z) (62 mg; 0,113 mmol; from stage (2)above) to yield 47 mg (92%).

FAB-MS m/z 415(M+1)+

1H NMR (300 MHz; D2O) spectrum is complicated by rotamers: δ a 7.85-7,71 (m, major and minor rotamer, 2H), 7,56 (d, minor rotamer, 2H), 7,50 (d, major rotamer, 2H), 5,12 (apparent bs, major rotamer, 1H), 4,68-of 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-of 0.82 (m, 17H), 0.60 and 0.40 in (m, major rotamer, 1H).

13With NMR (75 MHz; D2O) amidinov and carbonyl carbon (rotamer): 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) cooled to -40°C in argon atmosphere. Added dropwise thionyl chloride (47,1 g; 0,396 mol) and stirred the reaction mixture at -10°C for 35 minutes Added H-Aze-OH (10.0 g; 0,099 mol) and stirred the mixture at room temperature over night. Then the reaction mixture is evaporated to obtain specified in the connection header with the release of 16.1 g (100 %).

1H NMR (400 MHz; CDCl3): δ 5,12-5,24 (m, 1H), 4,08-the 4.29 (m, 2H), of 3.84 (s, 3H), 2,65-2,87 (m, 2H).

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

Specified in subheading connection receive according to FPIC is Boo, described in example 1(2), R(-)-α-methoxyphenylacetic acid (0,60 g; 3.6 mmol) and H-Aze-OMe×HCl (0.55 g, 3.6 mmol; from stage (1)above) to yield 0.32 g (34%).

1H NMR (400 MHz; CDCl3): δ 7,29-of 7.48 (m, 5H), 4,71-5,08 (m, 2H), 3,92-or 4.31 (m, 2H), 3,69-a 3.83 (m, 3H), 3,19-of 3.46 (m, 3H), 2,13-to 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 stage (2)above) in THF (10 ml) add a solution of the monohydrate of lithium hydroxide (0,071 g, 1.7 mmol) in H2O (6 ml). The reaction mixture was stirred for 3 h, and then evaporated. The residue is dissolved in N2Oh and extracted with toluene. the pH of the aqueous layer was adjusted to 3 with aqueous HCl, and then extracted with ethyl acetate (4 times). The combined organic layer is evaporated to obtain 0.28 g (92%) specified in the connection header.

1H NMR (400 MHz; CDCl3): δ 7,30-to 7.50 (m, 5H), 4,95-5,10 (m, 1H), 4,80 (s, 1H), 4,10-of 4.35 (m, 2H), 3,40 (s, 3H), 2.40 a is 2.80 (m, 2H)

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

Specified in subheading connection receive according to the method described in example 1(2), 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 stage (3)above) to yield 0.39 g (76%) as a white powder.

1H NMR (400 MHz: CDCl3): δ 08,29 (m, 1H), to 7.77 (d, 2H), 7,45 (d, 2H), and 7.4 to 7.2 (m, 10H), with 5.22 (s, 2H), is 4.93 (m, 1H), 4,69 (s, 1H), of 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

Specified in the header soy is inania get under way, described in example 1(5), from Ph-(R)CH(OMe)-C(O)-Aze-Pab(Z) (0.15 g; 0.29 mmol; from stage (4), above) with the release of 50.4 mg (41%) as a white powder.

1H NMR (400 MHz; CD3OD; α-hydrogen Aze and benzyl hydrogen of mandelate were darkened CD3HE-signal): δ 7,8-to 7.6 (m, 2H), 7,6 to 7.4 (m, 2H), and 7.4 to 7.1 (m, 5H), 4,6-4,4 (m, 2H), from 4.3 to 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)

Specified in subheading connection receive according to the method described in example 3(2), (R, S)-3-methoxymandelic acid (270 mg; 1.5 mmol) to yield 340 mg (43%); the ratio of diastereomers 1:1.

FAB-MS m/z 531 (M+1)+

1H NMR (400 MHz; CDCl3): δ 08,14 (m, 1H, diastereoisomer), 7,87 (m, 1H, diastereoisomer), to 7.0 (m, 10H), of 6.9 and 6.7 (m, 3H), 5,16 (s, 2H), 4,96 (s, 1H, diastereoisomer), 4,88 (s, 1H, diastereoisomer), 4,85 is 4.7 (m, 1H), 4,4-4,2 (m, 2H), 4,05 to-3.9 (m, 1H), 3,71 (s, 3H, diastereoisomer), 3,71 (m, 1H, diastereoisomer), 3,66 (s, 3H, diastereoisomer), to 3.58 (m, 1H, diastereoisomer), 2,5 to 2.35 (m, 1H), 2,32 (m, 1H, diastereoisomer), of 2.20 (m, 1H, diastereoisomer).

13C NMR (100 MHz; CDCl3) amidinov and carbonyl carbon (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

Specified in the header connection receive according to the method described in example 1(5), Ph(3-OMe)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (230 mg; 0.43 mmol; from stage (1)above) to yield 126 mg (67%). The ratio of diastereomers 1:1.

FAB-MS m/z 397 (M+1)+

1H NMR (400 MHz; D2O: complicated due (diastereomers/rotamers) and some impurities: δ to 7.6 and 7.1 (m, 5H), 6,9-6,6 (m, 3H), 5,2 to 4.7 (m, 1-2H), 4,4-3,7 (m, 4-5H), 3,63 (s, 3H, diastereoisomer/rotamer), 3,55 (m, 3H, diastereoisomer/rotamer), 2,5-2,3 (m, 1H), 2,2-2,0 (m, 1H).

13C NMR (75 MHz; D2O) amidinov and carbonyl carbon (diastereomers/rotamer): 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-methylindoline acid

A mixture of 3-methylbenzaldehyde (12.0 g, 0.1 mol) and benzyltriethylammonium chloride (1.23 g; 0,005 mol) in CHCl3(16 ml) was stirred at 56°C. To the mixture is added dropwise a solution of NaOH (25 g) in H2O (25 ml). Upon completion, the reaction mixture was stirred for 1 h, the Reaction mixture was diluted with H2O (obtaining 400 ml) and extracted with diethyl ether (3×50 ml). the pH of the mixture was adjusted to 1 with N2SO4(conc.), then extracted with diethyl ether (6×50 ml). The combined organic layer is dried (MgSO4) and evaporated. The crude product (11.6 g) is recrystallized from toluene to obtain of 8.47 g (51%) specified in the connection header.

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

1H NMR (400 MHz; CD3OD): δ 7,10-7,28 (m, 4H), to 5.08 (s, 1H), 2,32 (s, 3H).

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

Specified in subheading connection receive according to the method described in p is the iMER 3(2), of (R,S)-3-methylindoline acid (0,22 g, 1.3 mmol; from stage (1)above) with the yield of 0.37 g (54%).

LC-MS m/z 515 (M+1)+

1H NMR (400 MHz; CDCl3): δ 08,11-8,21 (t, NH), 6,97-7,89 (m, 13H), 5,18-5,24 (m, 2H), a 4.83-5,00 (m, 2H), 4,37-4,58 (m, 2H), 3,50-4,11 (m, 2H), 2,39-a 2.71 (m, 2H), 2,27-of 2.38 (m, 3H).

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

A mixture of Ph(3-Me)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0,105 g; 0.20 mmol; from stage (2)above), acetic acid (0,012 g; 0.20 mmol) and Pd/C (5%, 0.14 g) in ethanol (12 ml) hydrogenizing at atmospheric pressure for 6 hours, the Reaction mixture was filtered and the filtrate is evaporated. The crude product (97 mg) was dissolved in N2O and freeze dried to obtain a sticky product. This product is dissolved in N2Oh, filtered through HPLC filter and freeze dried. The output specified in the connection header is 67 mg (76%).

LC-MS m/z 381 (M+1)+

1H NMR (400 MHz; D2O): 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-of 2.27 (m, 3H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbon (rotamer): 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-ethoxybenzene acid

(R,S)-3-hydroxymandelic acid dissolved in acetonitrile (15 ml). Add K2CO3(2,34 g, 16,94 mmol) and added dropwise to ethyliodide (of 1.03 ml, 12,71 mmol who). The reaction mixture was refluxed for 2 h and then evaporated. The residue is dissolved in N2O (25 ml) and acetone (6 ml) and the mixture is stirred at room temperature for 3 hours, the Reaction mixture is evaporated and the resulting H2O layer is extracted with ethyl acetate. the pH of the aqueous layer was adjusted to 2 aqueous solution of KHSO4and add another H2O to dissolve the salt formed. H2About the solution extracted with ethyl acetate (3 times). The combined organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue is subjected to preparative RPLC (25% acetonitrile: 75% in 0.1m HOAc) and evaporated fractions containing the product. The resulting aqueous layer extracted with ethyl acetate (3 times)and the combined organic layer was washed with H2O, dried (Na2SO4) and evaporated. The output specified in the subtitle product is 182 mg (22%).

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

1H NMR (400 MHz; CD3OD): δ 6,80-7,27 (m, 4H), to 5.08 (s, 1H), 3,99 is 4.13 (m, 2H), 1,34-of 1.40 (t, 3H).

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

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-ethoxybenzene acid (0,178 g, 0,907 mmol; from stage (1)above) with the release of 259 mg (52%).

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

1H NMR (400 MHz; CDCl3): δ 06,77-to 7.77 (m, 13H), 5,16 to 5.1 (d, 2H), 4,78-4,99 (m, 2H), 4,27-4,51 (m, 2H), 3,53-4,07 (m, 4H), 2.21 are 2,60 (m, 2H), 1,29-of 1.41 (m, 3H).

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3-OEt)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (of 0.182 g, 0.33 mmol; from stage (2)above) to yield 157 mg (100%).

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

1H NMR (400 MHz; CD3OD): δ 07,71-7,79 (m, 2H), 7,49-of 7.60 (m, 2H), 7,19-7,30 (m, 1H), 6,94-7,02 (m, 2H), for 6.81-6.90 to (m, 1H), 5,09-by 5.18 (m, 1H), 4,74-to 4.81 (m, 1H), 4,39-to 4.62 (m, 2H), 3,93 is 4.35 (m, 4H), 2,10-2,61 (m, 2H), 1.32 to 1,40 (m, 3H).

13With NMR (100,6 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbon (rotamer): 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-Allyloxymethyl acid

(R,S)-3-Hydroxymandelic acid (0,504 g, 3.0 mmol) dissolved in dry acetone (25 ml) under nitrogen atmosphere. Add allylbromide (0,907 g, 7.5 mmol) and dry To2CO3(1,037 g, 7.5 mmol) and stirred the reaction mixture under nitrogen atmosphere for 16 hours Then the reaction mixture is evaporated. The residue is dissolved in N2O (25 ml) and acetone (6 ml) and stirred the mixture for 2 h (followed by HPLC). The mixture is evaporated and the aqueous layer was extracted with ethyl acetate. the pH of the aqueous layer was adjusted to 2 with KHSO4and extracted with ethyl acetate (3 times). The combined organic layer was washed with H2Oh, dried (Na2SO 4) and evaporated to obtain specified in the subtitle of the product with the release of 0,175 g (28%).

1H NMR (500 MHz; CDCl3): 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-OCH2CH=CH2)-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-allelochemicals acid (0.167 g; 0.8 mmol; from stage (1)above) to yield 260 mg (58%).

1H NMR (500 MHz; CDCl3): δ of 8.09-8.17 and (t, NH), 6,79-7,87 (m, 13H), 5,94-between 6.08 (m, 1H), 5,20-5,44 (m, 4H), 4,86-5,02 (m, 2H), 4,32-to 4.62 (m, 4H), 3,54-to 4.15 (m, 2H), 2,30-to 2.74 (m, 2H).

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

Specified in the title compound was obtained according to the method described in example 15(3), Ph(3-OCH2CH=CH2)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.06 g; 0.1 mmol; from stage (2)above) to yield 47 mg (97%).

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

1H NMR (500 MHz; D2O): δ 6,7-7,71 (m, 8H), 4,70-a 5.25 (m, 2H), 3,78-a 4.53 (m, 6H), 2.05 is is 2.80 (m, 2H), 1.56 to about 1.75 (m, 2H), 0,82-of 0.95 (m, 3H).

Example 18

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

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

Specified in subheading connection receive according to the method described in example 16(1), (R,S)-3-hydroxymandelic acid (0,70 g; 4,16 mmol), Cs2CO3(by 5.87 g; 16,65 mmol) and Isopropylamine (1.25 ml; 12,49 mmol) to yield 62 mg (7%).

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

1H NMR (400 MHz; CD3OD): δ 06,81-7,25 (m, 4H), to 5.08(s, 1H), 4.53-in with 4.64 (m, 1H), 1,28-of 1.32 (d, 6H).

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

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-isopropoxybenzoic acid (0,063 g; 0.3 mmol; from stage (1)above) to yield 60 mg (34%).

LC-MS m/z 559 (M+1)+

1H NMR (400 MHz; CDCl3): δ 06,75-7,79 (m, 13H), 5,18-5,24 (m, 2H), 4,81-4,99 (m, 2H), or 4.31-4,58 (m, 3H), 3,97-to 4.15 (m, 1H), 3,55-of 3.77 (m, 1H), 2,24-of 2.64 (m, 2H), of 1.23 and 1.33 (m, 6H).

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3-OPr(out))-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.05 g; 0,090 mmol; from stage (2)above) to yield 41 mg (94%).

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

1H NMR (400 MHz; CD3OD): δ 06,81-7,80 (m, 8H), 5.08 to by 5.18 (m, 1H), 4,74-4,80 (m, 1H), 4.53-in with 4.64 (m, 2H), to 4.41-4,51 (m, 1H), 3,93 is 4.35 (m, 2H), 2.23 to-2,60 (m, 2H), 1,25-1,32 (m, 6N).

13With NMR (100,6 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-2-methoxymandelic acid (0.18 g; 1.0 mmol) to yield 80 mg (17%).

1H NMR (500 MHz; CDCl3): δ 08,16 is 8.22 (t, NH), for 6.81-a 7.85 (m, 13H), 5,16-5,20 (m, 2H), 4,79-4,91 (m, 1H), 4.35 the figure-4.49 (m, 2H), 3,84-was 4.02 (m, 2H), 3,63-of 3.80 (m, 3H), 3,32 of 3.56 (m, 1H), 2.21 are to 2.57 (m, 2H).

(2) Ph(2-OMe)-(R,S)CH(OH)-C(O)-Aze-Pab&x000D7; HOAc

Specified in the header connection receive according to the method described in example 15(3), Ph(2-OMe)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.08 g; 0.15 mmol; from stage (1)above) to yield 45 mg (71%).

FAB-MS m/z 397(M+1)+

1H NMR (500 MHz; D2O): δ 06,83-of 7.70 (m, 8H), 4,71 is equal to 4.97 (m, 1H), 4,34-4,51 (m, 2H), a 3.87-4,22 (m, 3H), 3,67 of 3.75 (m, 3H), 2.00 in to 2.74 (m, 2H).

3C NMR (75.5 MHz; D2O: complicated due to diastereomers/rotamers) amidinov 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×SPLA

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

Specified in subheading connection receive according to the method described in example 3(2), (R,S)is 3.5-dimethoxyindole acid (0.21 g; 1.0 mmol; obtained according to a known method (Synthesis (1974) 724)) to yield 0.31 g (62%).

1H NMR (500 MHz; CDCl3): δ 08,11-8,16 (t, NH), 7,17-7,86 (m, 9H), 6,41-of 6.49 (m, 3H), to 5.21-5,24 (d, 2H), 4,84-to 5.03 (m, 2H), 4,29-of 4.66 (m, 2H), 3,67-4,17 (m, 8H), 2,32-of 2.72 (m, 2H).

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3,5-diome)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.15 g; 0.27 mmol; from stage (1)above) to yield 120 mg (100%).

1H NMR (500 MHz; D2O): δ 07,34 to 7.75 (m, 4H), 6,44 of 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-to 2.85 (m, 2H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) AMI is new 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-4-hydroxy-3-methoxymandelic acid (0.20 g; 1,0) yield 89 mg (16%).

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

1H NMR (400 MHz; CDCl3): δ 08,07-8,15 (m, NH), 6,64-7,86 (m, 12H), 5,20 at 5.27 (m, 2H), 3,57-5,00 (m, 9H), 2,31-to 2.74 (m, 2H).

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3-OMe,4-OH)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (of 0.085 g; 0.16 mmol; from stage (1)above) to yield 57 mg (78%).

FAB-MS m/z 413 (M+1)+

1H NMR (500 MHz: D2O; complicated due to diastereomers/rotamers): δ 06,66-7,83 (m, 8H), 4.80 to a 5.25 (m, 2H), 3,88-4,59 (m, 4H), 3,68-3,88 (m, 3H), 2,10-to 2.85 (m, 2H).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

(1) Ph(2-F,5-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-2-fluoro-5-cryptomaterial acid (0.3 g; 1.2 mmol; obtained in a known manner (Org.Synth.Coll. I, 336)with 0.32 g (51%).

FAB-MS m/z 587(M+1)+

1H NMR (400 MHz; CDCl3): δ 07,15-7,87 (m, N), 5,19-and 5.30 (m, 2H), 4,87-5,00 (m, 1H), 4,36-4,60 (m, 3H), 4,05-4,20 (m, 1H), 3,60-to 3.73 (m, 1H), 2,32-of 2.72 (m, 2H).

(2) Ph(2-F,5-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

Specified in the header connection receive according to the method described in example 15(3), Ph(2-F,5-CF3)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.15 g; 0.26 mmol; from stage (1)above) to yield 110 mg (90%).

1H NMR (500 MHz; D2O): δ 07,28-7,83 (m, 7H), 5,43-the 5.65 (m, 1H), 4,82-by 5.18 (m, 1H), 3,97-4,56 (m, 4H), 2,14-to 2.85 (m, 2H).

13C NMR (75.5 MHz; D2O: complicated due to diastereomers/rotamers) amidinov and carbonyl carbon): 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-2-hydroxy-2-phenylbutanoate acid (0.18 g; 1.0 mmol) to yield 79 mg (15%).

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

1H NMR (400 MHz; CDCl3): δ 07,27-7,86 (m, 14N), with 5.22 (s, 2H), 4,82-is 4.93 (m, 1H), 4,39-of 4.57 (m, 2H), 3,84-3,98 (m, 2H), 2,02-of 2.64 (m, 4H), 0,86 with 0.93 (m, 3H).

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

Specified in the header connection receive 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 stage (1)above) to yield 62 mg (90%).

FAB-MS m/z 395(M+1)+

1H NMR (400 MHz; D2O): δ 07,27-to 7.84 (m, N)of 4.83 to 5.35 (m, 1H), 3,89-4,60 (m, 4H), 2.40 a-2,61 (m, 1H), 1,95-of 2.30 (m, 3H), 0,78-of 0.95 (m, N).

13With NMR (75,5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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)

Specified in subheading connection receive according to the method described in example 3(2), (S)-(+)-2-hydroxy-2-phenylpropionic acid (0.20 g; 1.2 mmol) to yield 0.17 g (31%).

1H NMR (500 MHz; CDCl2): δ 08,04-8,14 (t, NH), 7,17-7,80 (m, 14H), 5,20 (s, 2H), 4,76-a 4.86 (m, 1H), or 4.31-4,50 (m, 2H), 3,76-of 3.94 (m, 2H), 2,19 is 2.44 (m, 2H), 1.70 to (s, 3H).

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

Specified in the header connection receive 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 stage (1)above) to yield 48 mg (78%), the ratio of diastereomers 85:15.

1H NMR (500 MHz; D2O): δ 07,30-7,79 (m, 9H), 3,99-4,82 (m, 5H), 2,09-to 2.74 (m, 2H), 1.70 to 1.77 in (m, 3H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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 THF cooled in an ice bath. Add EDC (4.3 ml, 25 mmol) and stirred solution over night. It is evaporated, dissolved in ethyl acetate, washed with KHSO4(water, 0.3 M), Na2CO3(water, 10%), dried (MgSO4) and evaporated. Crystallization from whom thou ethyl acetate : petroleum ether gives of 3.78 g (51%) indicated in the subtitle of the connection.

1H NMR (300 MHz; CDCl2): δ 04,89 (m, 1H), 4,07 (m, 1H), 3,95 (m, 1H), 2,85 (s, 4H), to 2.67 (m, 1H), 2,45 (m, 1H), of 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 of 0.65 mmol) and triethylamine (0.2 ml, 1.4 mmol) in 10 ml THF was stirred at room temperature for 18 hours After evaporation the residue restaraunt in ethyl acetate, filtered through a plug of celite (Celite) and subjected to chromatography on silikagelevye column with a mixture of ethyl acetate : THF (2:1). Eluent is evaporated, dissolved in ethyl acetate, washed with water, dried (MgSO4) and evaporated obtaining of 0.250 g (81%) indicated in the subtitle of the connection.

1H NMR (300 MHz, CDCl3): δ 07,4 to 7.2 (m, 5H), of 5.05 (s, 2H), 4,55 (bt, 1H), 3,85 (bq, 1H), 3.72 points (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, 11N, it's by 1.36, N), 1,0-0,8 (m, 2H).

(3) H-Aze-Pac(Z)

Specified in subheading connection receive according to the method described in example 3(1)of Boc-Aze-Pac(Z) (from stage (2)above), followed by alkaline extraction.

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

Specified in subheading connection receive similarly to the method described in example 3(2), from Ph-(R)CH(OTBDMS)-C(O)OH (0,236 g; 0.89 mmol; obtained according to Hamada et al., SoC (1989) 111, 669) and H-Aze-Pac(Z) (0.25 g, of 0.53 mmol; from stage 3; pre-activated by stirring in a mixture of CH2Cl2: triperoxonane acid (1:1, 10 ml) for 30 min) to yield 160 mg (48%).

1N the Mr (500 MHz; CDCl3): δ 07,20-7,44 (m, 10H), with 5.22 (s, 1H), 5,06-5,16 (m, 2H), 4.80 to the 4.90 (m, 1H), 3,92-4,43 (m, 2H), 2,88-of 3.12 (m, 2H), 2,35-2,60 (m, 2H), 1,25-2,10 (m, 10H), 0,84-0,94 (m, N), 0,00-0,15 (m, 6N).

(5) Ph-(R)CH(OH)-C(O)-Aze-Pac×HOAc

Specified in the header connection receive 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 stage (4), above), with purification by RPLC with yield 15 mg (14%).

FAB-MS m/z 373(M+1)+

Example 26

Ph-(R)CH(OH)-C(O)-Aze-Pig×HOAc

(1) Boc-Aze-Pig(Z)

Specified in subheading connection receive similarly to the method described in example 1(2)of 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) yield 1.24 g (51%).

1H NMR (400 MHz; CDCl3): δ 07,27-the 7.43 (m, 5H), 5,12 (s, 2H), 4,60-of 4.67 (t, 1H), 4,16-4.26 deaths (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 of-1.83 (m, 3H), of 1.44 (s, 9H), 1,15-of 1.29 (m, 2H).

(2) H-Aze-Pid(Z)×2HCl

Boc-Aze-Pig(Z) (1.2 g, 2,53 mmol; from stage (1)above) in ethyl acetate saturated with HCl (75 ml) was stirred at room temperature for 1 h, the Reaction mixture is evaporated, diluted with water and extracted with toluene. The aqueous layer was then dried by freezing to produce 1,085 g (96%) specified in the connection header.

1H NMR (500 MHz; CD3OD): δ 07,32-7,46 (m, 5H), 5,28 (s, 2H), 4,99-of 5.05 (t, 1H), 4,08-4,16 (m, 1H), 3,91-3,99 (m, 3H), 3,13-of 3.25 (m, 4H), 2,79-is 2.88 (m, 1H), 2,47-to 2.57 (m, 1H), 1,82 is 1.96 (m, 3H), 1,26-of 1.40 (m, 2H).

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

Specified in subheading connection receive similarly 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 stage (3)) to yield 350 mg (46%).

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

(4) Ph-(R)CH(OH)-C(O)-Aze-Pig×HOAc

Specified in the header connection receive 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 stage (3)) to yield 81 mg (95%).

LC-MS m/z 374 (M+1)+

1H NMR (400 MHz CD3OD): δ 07,25-to 7.50 (m, 5H), of 5.15 (s, 1H)and 4.65-4.75 in (m, 1H), 4,25 is 4.35 (m, 1H), 3,80-4,00 (m, 3H), 2.95 and-a 3.50 (m, 4H), 2.05 is-of 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

Specified in subheading connection receive according to the method described in example 3(1)of Boc-(R,S)Hig(Z) (obtained according to a known method (international application WO 94/29336)).

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

Specified in subheading connection receive according to the method described in example 1(2)of benzyl ester of L-Proline×HCl (2 g, compared to 8.26 mmol) and Ph-(R)CH(OTBDMS)-C(O)OH (2.0 g, 7,51 mmol, obtained according to a known method (Hamada et al., SoC (1989) 111, 669)) with the release of 2.0 g (59%).

1H NMR (500 MHz; CDCl3): δ 07,22-of 7.55 (m, 10H), the 5.45 (s, 1H), further 5.15 (s, 2H), 4,45-4,55 (m, 1H), 3,70-3,82 (m, 1H), 3,05 is 3.15 (m, 1H), 1,65-of 2.15 (m, 4H), 0,85-1,05 (m, N), 0,00-0,22 (m, 6N).

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

A mixture of Ph-(R)CH(OTBDMS)-C(O)-Pro-OBn (1.9 grams, 4,19 mmol, from stage (2))and Pd/C (10%, 0.21 g) in ethanol (80 ml) hydrogenizing at atmospheric pressure for 3 hours, the Reaction mixture was filtered through celite and the filtrate evaporated. The output is 1.36 g (91%) specified in the connection header.

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

1H NMR (500 MHz; CD3CD): δ 07,20-to 7.50 (m, 5H), of 5.45 (s, 1H), 4,30-and 4.40 (m, 1H), 3,30-3,70 (m, 2H), 1,75-of 2.30 (m, 4H), of 0.85 to 1.00 (m, 9H), 0,00-0,20 (m, 6H).

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

Specified in subheading connection receive similarly to the method described in example 25(4), from Ph-(R)CH(OTBDMS)-C(O)-Pro-OH (0.36 g; 1 mmol; from stage (3)) and H-(R,S)Hig(Z)×2HCl (0.36 g, 1 mmol, from stage (1)) with exit to 0.63 g of the crude product, which is used without further purification in the next stage (17%).

LC-MS m/z 636(M+1)+

13With NMR (100,5 MHz; CDCl3) amidinov 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 stage (4)) and TFA (10 ml, 20% in CH2Cl2) was stirred at room temperature for 3 hours the pH of the reaction mixture was adjusted to 9 with water To a2CO3and then the reaction mixture was extracted with CH2Cl2. The combined organic layer is dried (Na2SO4) and evaporated. The crude product is purified flash chromatography on a column of silica gel (40 g), elwira CH2Cl2(100 ml), the mixture of CH2Cl2:EtOH (95:5) (100 ml) and the mixture of CH2 Cl2:EtOH (9:1) (300 ml). The output is 138 mg (26%) indicated in the subtitle of the connection.

LC-MS m/z 522(M+1)+

13With NMR (100,5 MHz; CDCl3) amidinov and carbonyl carbons: δ 0172,21, 171,20, 163,64, 159,11.

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

Specified in the header connection receive 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 stage (5)) yield 49 mg (80%).

LC-MS m/z 388(M+1)+

1H NMR (400 MHz; D2O; complicated due to diastereomers/rotamers): δ 07,32-7,56 (m, 5H), lower than the 5.37-5,52 (m, 1H), 4,32 with 4.64 (m, 1H), 3,57 of 3.75 (m, 2H), 3,24 of 3.56 (m, 4H), 2,89 is 3.15 (m, 2H), 1,25-2,80 (m, N).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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)

Specified in subheading connection receive similarly to the method described in example 25(4), 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)) with exit 316 mg of the crude product, which is used without further purification in the next stage.

LC-MS m/z 622(M+1)+

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

Triperoxonane acid (6 ml, 20% in CH2Cl2) add Ph-(R)CH(OTBDMS)-C(O)-Pro-Dig(Z) (0,315 g, 0,506 mmol; from stage (1)) when 0°and the mixture is stirred at room temperature is round within 2 hours the pH of the reaction mixture is adjusted to 8 with water To a2CO3and extracted with CH2Cl2. The organic layer was washed with aqueous NaCl, dried (Na2SO4) and evaporated. The crude product (250 mg) is subjected to flash chromatography on a column of silica gel, using as eluent a mixture of CH2Cl2:MeOH (9:1), to obtain 180 mg (70%) specified in the connection header.

1H NMR (400 MHz; CDCl3): δ 7,25-7,39 (m, 10H), 5,32 lower than the 5.37 (bs, 1H), 5.08 to 5,19 (m, 2H), 4,40-of 4.49 (m, 1H), 4,21 is 4.35 (m, 2H), a 3.87-a 4.03 (m, 2H), 3,71-with 3.79 (m, 2H), 3,18-of 3.32 (m, 2H), 3.00 and-3,10 (m, 1H), 2,61-by 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

Specified in the header connection receive 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 stage (2)with 112 mg (94%).

1H NMR (500 MHz; CD3OD): δ 07,27-7,44 (m, 5H), of 5.34 (s, 1H), 4,29 is 4.35 (m, 1H), 4,17-of 4.25 (m, 2H), 3.75 to 7,83 (m, 2H), 3,63-to 3.73 (m, 1H), 3.25 to to 3.34 (m, 1H), is 3.08 is 3.23 (m, 2H), 2,79-2,90 (m, 1H), 1.70 to 2,10 (m, 6H).

13C NMR (100,6 MHz; CD3OD) amidinov 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)

Specified in subheading connection receive similarly to the method described in example 1(2), (R,S)-N-Boc-Pic(CIS-4-Me)-OH (0.88 g; 4.1 mmol; obtained according to known (Shuman et al J.Org.Chem. (1990), 55, 738)method) with the release of 405 mg (19%).

FAB-MS mz 509(M+1) +

1H NMR (400 MHz; CDCl3): δ 7,25-of 7.90 (m, 9H), 5,20 (s, 2H), 4,45-4,50 (m, 2H), 4,34-and 4.40 (m, 1H), 3,15-3,70 (m, 2H), 1.70 to 2,00 (m, 4H), 1,45 (s, 9H), 1,15-1,30 (m, 1H), 0,90-of 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 stage (1)) was dissolved in CH2Cl2(5 ml), add triperoxonane acid (5 ml) and the mixture is stirred for 0.5 hours, the Reaction mixture was evaporated and the residue dissolved in CH2Cl2, washed with aqueous Na2CO3, dried (MgSO4) and evaporated. The crude product was then purified using flash chromatography on a column of silica gel, elwira mixture of CH2Cl2:Meon (95:5) and CH2Cl2:MeOH (9:1). The output is 10 mg (94%) indicated in the subtitle of the connection.

FAB-MS m/z 409(M+1)+

1H NMR (500 MHz; CD2OD): δ 07,25-a 7.85 (m, N), of 5.15 (s, 2H), 4,35 is 4.45 (m, 2H), 2,55-of 3.60 (m, 3H), 1.85 to 2.05 is (m, 1H), 1,35-of 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)

Specified in subheading connection receive similarly to the method described in example 3(2), H-(R,S)Pic(CIS-4-Me)-Pab(Z) (0,290 g; 0.71 mmol; from stage (2)and Ph-(R)CH(OTBDMS)-C(O)-OH (0,189 g, 0.71 mmol, obtained according to a known method (Hamada et al., SoC (1989) 1110, 669)with 0.40 g of the crude product, which is used without further purification in the next stage.

(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 the stage (3)) the process trifero ssnoi acid (20% in CH 2Cl2within 3 hours the Reaction mixture is evaporated and the residue purified using flash chromatography on a column of silica gel, elwira a mixture of CH2Cl2:MeOH(98:2, 95:5, 9:1). The output is 45 mg (11%) indicated in the subtitle of the connection.

(5) Ph-(R)CH(OH)-C(O)-(R or S)Pic(CIS-4-Me)-Pab×the SPLA and

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

A mixture of Ph-(R)CH(OH)-C(O)-(R,S)Pic(CIS-4-Me)-Pab(Z) (0,045 g, 0,083 mmol; from stage (4)) and Pd/C (5%, 0.06 g) in ethanol (8 ml) hydrogenizing at atmospheric pressure for 2.5 hours, the Reaction mixture was filtered and the filtrate evaporated. The crude product is subjected to preparative RPLC (0,1M NH4OAc, 30% acetonitrile), resulting diastereomers are separated. Output is 7 mg of compound 29A ratio of diastereomers >99:1 and 11 mg of compound 29B ratio of diastereomers 98:2.

Compound 29A:

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

1H NMR (500 MHz; D2O): δ 07,20-7,80 (m, 9H), the 5.65 (s, 1H), 4,65 to 5.35 (m, 1H), 4,40-4,55 (m, 2H), 3,85-4,00 (m, 1H), 3,65 of 3.75 (m, 1H), 2,65 is 3.15 (m, 2H), 2.05 is-of 2.20 (m, 1H), of 1.05 to 1.75 (m, 2H), 0.70 to about 0.90 (m, 3H)

Compound 29B:

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

1H NMR (500 MHz; D2O): δ 7,25-7,80 (m, N), 4,55-of 5.75 (m, 2H), 4,35-4,50 (m, 3H), 3.75 to of 3.85 (m, 1H), 2.70 height is 2.80 (m, 1H), 1,80-2,20 (m, 1H), 0.70 to 1.70 to (m, 6N).

Example 30

Ph-(CH2)2-(R)CH(OH)-C(O)-Aze-Pab×HCl

(1) Ph-(CH2)2-(R)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive similar is on the way described in example 3(2), H-Aze-Pab(Z)×2HCl (0,434 g; 0,988 mmol) and (R)-(-)-2-hydroxy-4-phenylalkanoic acid (rate £ 0.162 g, 0,898 mmol), TBTU (0,433 g 1,348 mmol) and N-methylmorpholine (0,363 g and 3.59 mmol) in DMF (15 ml) to yield 105 mg (22%).

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

1H NMR (500 MHz; CDCl3): δ 08,17-of 8.25 (m, NH), 7,05-7,72 (m, 14H), 5,16 with 5.22 (m, 2H), 4,71-4,88 (m, 1H), 4,32-to 4.41 (m, 2H), 3,92-Android 4.04 (m, 2H), 3,79-3,88 (m, 1H), 2,62-of 2.86 (m, 2H), 2,29-to 2.57 (m, 2H), 1,80-to 1.98 (m, 2H).

(2) Ph-(CH2)2-(R)CH(OH)-C(O)-Aze-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ph-(CH2)2-(R)CH(OH)-C(O)-Aze-Pab(Z) (0,112 g; 0,212 mmol; from stage (1)) to yield 77 mg (84%).

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

1H NMR (400 MHz; CD3OD): δ to 7.77-to 7.77 (m, 9H), 4,73-5,19 (m, 1H), 4,40-to 4.62 (m, 2H), 3,92-4,34 (m, 3H), 248-2,84 (m, 3H), 2,09 is 2.33 (m, 1H), 1,83-2,05 (m, 2H).

13With NMR (100,6 MHz, D2O: complicated due to rotamers) amidinov 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

Specified in subheading connection receive according to the method described in example 15(1), from 2-naphthaldehyde (15.6 g, 100 mmol) with access 12,37 g (61%).

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

1H NMR (500 MHz; CD3OD): δ 07,43-7,98 (m, 7H), from 5.29 to 5.35 (m, 1H).

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

Specified in subheading connection receive under the JV is soba, described in example 3(2), (R,S)-(2-naphthyl)glycolic acid (rate £ 0.162 g; 0.8 mmol; from stage (1)) with exit 266 mg (60%).

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

1H NMR (400 MHz; CDCl3): δ 7,18-to $ 7.91 (m, N), a 4.86-of 5.26 (m, 3H), 4,05-the ceiling of 5.60 (m, 3H), 3,52-of 3.78 (m, 2H), 2,24-by 2.73 (m, 2H)

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

Specified in the header connection receive according to the method described in example 15(3), 2-naphthyl-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0,266 g; 0.48 mmol; from stage (2)with 202 mg (88%),

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

1H NMR (500 MHz; CD3OD): δ 07,28-of 7.96 (m, 11N), and 5.30-of 5.40 (m, 1H), 3.95 to 4,82(m, 5H), 2,09 at 2.59 (m, 2H).

Example 32

3-Indolyl-CH2-(R,S)CH(OH)-C(O)-Aze-Pab×SPLA

(1) 3-Indolyl-CH2-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-(3-indolyl)lactic acid (0.21 g, 1.0 mmol) with access to 0.22 g (45%).

1H NMR (500 MHz; CDCl2): δ 06,57-7,80 (m, 14H), of 5.24 (s, 2H), 4,59 of 4.83 (m, 1H), 4,19-4,51 (m, 3H), 3,69-to 3.99 (m, 2H), 3,03-to 3.36 (m, 2H), 2,31-of 2.56 (m, 2H).

(2) 3-Indolyl-CH2-(R,S)CH(OH)-C(O)-Aze-Pab×SPLA

Specified in the header connection receive according to the method described in example 15(3), 3-indolyl-CH2-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.11 g; 0.20 mmol; from stage (1)) to yield 75 mg (80%)

FAB-MS m/z 420(M+1)+

1H NMR (500 MHz; D2O): δ 7,00 to 7.75 (m, N), br4.61-4,71 (m, 1H), 3,74-4,51 (m, 5H), 3.00 and of 3.28 (m, 2H), 1,95-to 2.42 (m, 2H).

13With NMR (75.5 MHz; D2O; b complicated is thanks to diastereomers/rotamers) amidinov and carbonyl carbons: δ 179,38, 176,19, 175,56, 173,06, 166,78.

Example 33

(CH3)2SN-(R)CH(OH)-C(O)-Aze-Pab×SPLA

(1) (CH3)2CH-(R)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2)of (R)-2-hydroxyisovaleric acid (0.12 g; 1.0 mmol) to yield 68 mg (16%).

1H NMR (300 MHz; CDCl3) δ 8,25-8,40 (t, NH), 7,15-of 7.90 (m, 9H), 5,20 (s, 2H), 4,85-of 4.95 (m, 1H), 4,30-4,55 (m, 2H), 4,05-of 4.25 (m, 2H), 3.75 to 3,90 (m, 1H), 1,65-of 2.75 (m, 3H), 0.70 to of 1.05 (m, 6H).

(2) (CH3)2CH-(R)CH(OH)-C(O)-Aze-Pab×SPLA

Specified in the header connection receive according to the method described in example 15(3), (CH3)2CH-(R)CH(OH)-C(O)-Aze-Pab(Z) (0,068 g; 0.15 mmol; from stage (1)) to yield 13 mg (23%).

1H NMR (300 MHz; D2O): δ 07,45-7,80 (m, 4H), 4,85-a 5.25 (m, 1H), 4,45 with 4.65 (m, 2H), 4,30-and 4.40 (m, 1H), 3,80-4,10 (m, 2H), 2,60 is 2.80 (m, 1H), measuring 2.20 to 2.35 (m, 1H), 1,90-2,05 (m, 1H), 0,70-1,00 (m, 6H).

13With NMR (75.5 MHz; D2O; complicated due to rotamers) amidinov and carbonyl carbon: 182,37, 176,34, 175,38, 173,84, 173,26, 167,16.

Example 34

(CH3)2CH-(CH2)2-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

(1) (CH3)2CH-(CH2)2-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-isoleucinol acid (0.12 g; 0.88 mmol) to yield 0.15 g (36%).

1H NMR (300 MHz; CDCl3): δ 07,15-7,80 (m, 9H), 5,20 (s, 2H), 4,85-of 4.95 (m, 1H), 4,35-4,55 (m, 2H), 3,85-4,20 (m, 3H), 2.40 a is 2.80 (m, 2H), 1,75-2,10 (m, 1H), 1,20-155 (m, 2H), 0,75-1,00 (m, 6H).

(2) (CH3)2CH-(CH2)2-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

Specified in the header connection receive according to the method described in example 15(3), (CH3)2CH-(CH2)2-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0,13 g; 0.27 mmol; from stage (1)) to yield 0.11 g (100%),

1H NMR (400 MHz; D2O): δ 7,63-of 7.69 (m, 2H), 7,37-7,46 (m, 2H), 4.72 in-5,12 (m, 1H), 4,40-to 4.46 (m, 2H), 4,17-or 4.31 (m, 2H), 3,90-was 4.02 (m, 1H), 2,50-2,69 (m, 1H), 2,11-of 2.27 (m, 1H), 1,12-1,72 (m, 3H), and 0.61-of 0.85 (m, 6H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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

Specified in subheading connection receive similarly to the method described in example 1(2)of BOC-Pro-HE (10.2 g; to 47.4 mmol) and add N-Pab(Z)×HCl (15.9 g, for 49.8 mmol) with access to 21.74 g (95,5%).

FAB-MS m/z 481 (M+1)+

1H NMR (400 MHz; CD3OD): δ 08,0 one-7.8 (m, 2H), 7.5 to 7,25 (m, 7H), to 5.17 (s, 2H), 4,6-to 4.15 (m, 3H), 3,6-to 3.35 (m, 2H), 2,3-2,1 (m, 1H), 2,1 to 1.8 (m, 3H), 1,5-1,3(two broad singlets, rotamer Boc. N).

(2) H-Pro-Pab(Z)

Specified in subheading connection receive similarly to the method described in example 3(1)of Boc-Pro-Pab(Z)×HCl (from stage (1)), followed by alkaline extraction.

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

Specified in subheading connection receive similarly to the method described in example 3(2), (R,S)-3-hydrox the almond acid (0.25 g, 1.5 mmol) and H-Pro-Pab(Z) (0,63 g; of 1.65 mmol; from stage (2)) with exit 51 mg (6%).

FAB-MS m/z 531 (M+1)+

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

Specified in the header connection receive according to the method described in example 1(5), Ph(3-OH)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0.05 g; 0,094 mmol; from stage (3)) to yield 30 mg (74%).

FAB-MS m/z 397(M+1)+

13With NMR (75.5 MHz; D2O complicated due to diastereomers/rotamers) amidinov 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)is 3.5-dimethoxyindole acid (0.08 g; 0.38 mmol; obtained according to known (Synthesis (1974), 724) method) and H-Pro-Pab(Z) (0.16 g, 0.42 mmol, see example 35(2)) to yield 61 mg (28%).

1H NMR (500 MHz; CDCl3): δ 07,70-7,80 (t, NH), 7,08 is 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-of 3.80 (m, 6H), 3,35-3,55 (m, 1H), 2.95 and is 3.25 (m, 1H), 1.70 to to 2.25 (m, 4H)

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3,5-diome)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0.06 g; 0.10 mmol; from stage (1)) to yield 35 mg (72%).

1H NMR (500 MHz; D2O): δ 7.23 percent-7,80 (m, 4H), 6,41-of 6.65 (m, 3H), 5,35-of 5.45 (m, 1H), 4,35-4,60 (m, 3H), of 3.80 (s, 3H), 3,10-of 3.75 (m, 5H), 1.70 to to 2.35 (m, 4H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamer is m) amidinov 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-methoxymandelic acid (0.27 g, 1.5 mmol) and H-Pro-Pab(Z) (or 0.57 g, 1.5 mmol; see example 35(2)) to yield 158 mg (20%).

FAB-MS m/z 545(M+1)+

1H NMR (400 MHz; CDCl3): δ to 7.77-to 7.84 (m, 2H), 7,01-of 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-with 3.79 (m, 3H), 3,38 is 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

Specified in the header connection receive according to the method described in example 15(3), Ph(3-OMe)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0.06 g; 0.11 mmol; from step (1)) to yield 39 mg (75%).

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

1H NMR (400 MHz; D2O): δ for 6.81-to 7.84 (m, 8H), vs. 5.47 (s, 1H), 4,35-4,59 (m, 3H), 3,60-3,88 (m, 4H), 3,07-3,29 (m, 1H), 1,74-is 2.37 (m, 4H).

Example 38

Ph(3,4-(O-CH2-O))-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

(1) Ph(3,4-(O-CH2-O))-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3,4-methylenedioxybenzene acid (0.20 g; 1.0 mmol; obtained according to known (Synthesis (1974), 724) method) with access to 0.22 g (44%).

1H NMR (400 MHz; acetone-d6): δ 6,68-to 8.12 (m, 12H), 5,94-6,05 (m, 2H), by 5.18 (s, 2H), 3,81-5,12 (m, 6H), 2,30-of 2.54 (m, 2H).

(2) Ph(3,4-(-O-CH2-O))-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

Specified in the header connection recip which are under way, described in example 15(3), Ph(3,4-(O-CH2-O))-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0.11 g; 0.20 mmol; from stage (1)) to yield 72 mg (76%).

1H NMR (500 MHz; D2O): δ 6,64-7,80 (m, 7H), 5,91-6,01 (m, 2H), 4.80 to-5,24 (m, 2H), 3,88-of 4.57 (m, 4H), 2,11-2,84 (m, 2H).

13With NMR (75.5 MHz, D2O; complicated due to diastereomers/rotamers) amidinov 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)

Specified in subheading connection receive similarly to the method described in example 3(2), (R,S)-4-hydroxy-3-methoxymandelic acid (0.40 g; 2.0 mmol) and H-Pro-Pab(Z) (0,76 g, 2.0 mmol; see example 35(2)) to yield 132 mg(12%).

FAB-MS m/z 561 (M+1)+

1H NMR (400 MHz; CDCl3): δ 6,62-to 7.84 (m, N), 5,20-a 5.25 (m, 2H), 4,15-5,08 (m, 3H), 3,42-a-3.84 (m, 4H), 2.91 in-3,25 (m, 1H), 1,66-is 2.37 (m, 4H).

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3-OMe,4-OH)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0,048 g; 0.09 mmol; from stage (1)) to yield 23 mg (55%).

FAB-MS m/z 427(M+1)+

1H NMR (400 MHz; D2O): δ 6,72-7,83 (m, 7H), 5,42 (s, 1H), to 4.38-and 4.68 (m, 3H), 3,55-4,10 (m, 4H), 3,09 be 3.29 (m, 1H), 1,72-is 2.37 (m, 4H).

13C NMR (75.5 MHz; D2O) amidinov 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)

Specified in subheading connection receive according to FPIC is Boo, described in example 3(2), (R,S)-2-hydroxy-2-phenylbutanoate acid (0.36 g; 2.0 mmol) and H-Pro-Pab(Z) (0,76 g, 2.0 mmol; see example 35(2)) to yield 57 mg (5%).

FAB-MS m/z 543(M+1)+

1H NMR (400 MHz; CDCl3): δ 7,24-7,88 (m, 14H), 5,23 (s, 2H), of 4.44-to 4.81 (m, 3H), 2,98-of 3.25 (m, 2H), 1,49 of-2.32 (m, 6N), 0,85-0,95 (m, 3H)

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

Specified in the header connection receive according to the method described in example 15(3), from Ph-(R,S)C(Et)(OH)-C(O)-Pro-Pab(2) (to 0.055 g; 0.1 mmol; from stage (1)) to yield 34 mg (72%).

FAB-MS m/z 409(M+1)+

1H NMR (400 MHz; D2O): δ 7,33-of 7.82 (m, N), to 4.38-4,60 (m, 3H), 3,19-3,71 (m, 2H), 1,54-of 2.34 (m, 6N), 0,73-of 0.90 (m, 3H).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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)is 3.5-dimethylindoline acid

Specified in subheading connection receive according to the method described in example 15(1)of 3,5-dimethylbenzaldehyde (5.0 g; 37 mmol) to yield 2.8 g (42%).

1H NMR (400 MHz; CD3OD): 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)is 3.5-dimethylindoline acid (0.27 g; 1.5 mmol; from stage (1)) with exit 0,403 g (51%).

FAB-MS m/z 529(M+1)+

1H NMR (500 MHz; CDCl3): δ 6,85-7,88 (, N), 5,22-of 5.26 (m, 2H), 4,84-to 5.03 (m, 2H), 4,43-to 4.62 (m, 2H), 3,57 is 4.13 (m, 2H), 2,25-to 2.74 (m, 8H).

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

Specified in the header connection receive according to the method described in example 15(3), Ph(3,5-dime)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (is 0.102 g; 0,194 mmol; from stage (2)) to yield 74 mg (84%).

FAB-MS m/z 395(M+1)+

1H NMR (400 MHz; D2O): δ 6,76-of 7.82 (m, 7H), 4.80 to at 5.27 (m, 2H), a 3.87-to 4.62 (m, 4H), 2,20-2,87 (m, 8H).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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-NH2)-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

(1 )Ph(3-NO2)-(R,S)CH(OH)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-nitroindole acid (0,30 g; 1.5 mmol) with a yield of 0.40 mg (48%).

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

1H NMR (400 MHz; CDCl3): δ 7,16 is 8.22 (m, 13H), 5,18-5,23 (m, 2H), 4,85-of 5.15 (m, 2H), 4,08-4,60 (m, 3H), 3,65-3,81 (m, 1H), 2,31-a 2.71 (m, 2H).

(2) Ph(3-NH2)-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

Specified in the header connection receive according to the method described in example 15(3), Ph(3-NO2)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (is 0.102 g; 0,19 mmol; from stage (1)) with exit 0,074 g (89%).

LC-MS m/z 382(M+1)+

1H NMR (400 MHz; D2O): δ 6,58-of 7.82 (m, 8H), 4.80 to a 5.25 (m, 2H), 3,60-4,60 (m, 4H), 2,12-is 2.88 (m, 2H).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) is medinova and carbonyl carbon; δ 181,96, 175,27, 174,25, 173,84, 173,19, 173,01, 166,93.

Example 43

Ph(3-NO2)-(R,S)CH(OH)-C(O)-Aze-Pab×HOAc

To a mixture of Ph(3-NO2)-(R,S)CH(OH)-C(O)-Aze-Pab(Z) (0,100 g, 0.18 mmol, see example 42(1)) and CH2Cl2(10 ml) was added anisole (0,030 g, 0.27 mmol) and triftormetilfullerenov acid was 0.138 g of 0.92 mmol). The reaction mixture was stirred at room temperature for 10 minutes Add H2O and the pH adjusted to 9 with aqueous Na2CO3. The vacuum removes the CH2Cl2and extracted the remaining N2O-layer diethyl ether (3×5 ml) with subsequent freeze-drying. The crude product is subjected to RPLC to obtain 62 mg (60%) specified in the header product after freeze-drying.

1H NMR (400 MHz; D2O): δ 7,38-8,31 (m, 8H), a 4.83-of 5.50 (m, 2H), 4,03-of 4.57 (m, 4H), 2,17-of 2.86 (m, 2H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbons: δ 181,5, 173,84, 173,39, 173,15, 173,04, 172,96, 172,80, 166,85.

Example 44

Ph(3-NH2)-(R,S)CH(OH)-C(O)-Pro-Pab×HOAc

(1) Ph(3-NO2)-(R,S)CH(OH)-C(O)-Pro-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-nitroindole acid (0,30 g; 1.5 mmol) and H-Pro-Pab(Z)×2HCl (0.75 g, of 1.65 mmol; see example 35(2)) with the release of 0.61 g (73%).

LC-MS m/z 560(M+1)+

1H NMR (400 MHz; CDCl3): δ 7,26-8,23 (m, 13H), 5,20 is 5.28 (m, 3H), 4,33-to 4.73 (m, 3H), 3,4-3,68 (m, 1H), 2,92-3,14 (m, 1H), 1,79 is 2.33 (m, 4H).

(2) Ph(3-NH2)-(R,S)CH(OH)-C(O)-Pro-Pab×HOAc

Specified in the header connection receive according to the method described in example 15(3), Ph(3-NH2)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0.104 g g; 0,19 mmol; from step (1)) to yield 64 mg (76%).

LC-MS m/z 396(M+1)+

1H NMR (400 MHz; D2O): δ 6,74-of 7.82 (m, 8H), 5,34-of 5.40 (m, 1H), 4,55-4,58 (m, 3H), 3,09-of 3.78 (m, 2H), about 1.75 to 2.35 (m, 4H).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbons: δ 182,04, 175,38, 175,18, 173,12, 173,04, 167,07.

Example 45

Ph(3-NO2)-(R or S)CH(OH)-C(O)-Pro-Pab×HOAc

Specified in the header connection receive according to the method described in example 40(3), Ph(3-NO2)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0,117 g; 0.21 mmol; see example 44(1)). Fractions concentrated to obtain 23 mg (45%) compounds with a ratio of diastereomers more than 99:1.

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

1H NMR (500 MHz; D2O): δ 7,31-8,35 (m, 8H), 5,50-5,71 (m, 1H), 3,64-of 4.57 (m, 4H), 3,24-of 3.32 (m, 1H), 1,76-to 2.42 (m, 4H).

13C NMR (75.5 MHz; D2O; complicated due to rotamers) amidinov and carbonyl carbons: δ 175,21, 173,98, 172,58, 172,18, 167,12, 166,82.

(Earlier fractions concentrated to obtain 22 mg (43%) epimer the above compounds with a ratio of diastereomers more than 99:1).

Example 46

Ph(3,4-(-O-CH2-O-))-(R,S)CH(OH)-C(O)-Pro-Pab×HCl

(1) Ph(3,4-(-O-CH2-O-))-(R,S)CH(OH)-C(O)-Pro-Pab(Z)

The decree of the TES in the subtitle compound get under way, described in example 3(2), (R,S)-3,4-methylenedioxybenzene acid (0.20 g; 1.0 mmol; obtained according to known (Synthesis (1974), 724) method) and H-Pro-Pab(Z)×2HCl (0.35 g, of 0.91 mmol; see example 35(2)) to yield 80 mg (16%).

FAB-MS m/z 559(M+1)+

1H NMR (500 MHz; CDCl3): δ 6,69-7,89 (m, N), 5,91-6,04 (m, 2H), 4,30 is 5.28 (m, 2H), 3.00 and-3,61 (m, 6N), of 1.95 to 2.35 (m, 4H)

(2) Ph(3,4-(-O-CH2-O-))-(R,S)CH(OH)-C(O)-Pro-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ph(3,4-(-O-CH2-O-))-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0.08 g; 0.14 mmol; from stage (1)) to yield 48 mg (73%)

FAB-MS m/z 425(M+1)+

1H NMR (500 MHz; D2O): δ for 6.81-a 7.85 (m, 7H), 5,90-6,05 (m, 2H), 5,33-5,44 (m, 1H), 4,37-of 4.90 (m, 3H), 3,62-of 3.77 (m, 1H), 3,13 of 3.28 (m, 1H), 1,80-of 2.36 (m, 4H).

13With NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbons: δ 175,37, 175,09, 173,66, 173,08, 173,00, 167,03.

Example 47

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

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

Specified in subheading connection receive according to the method described in example 3(2), (R,S)is 3.5-diferendului acid (0.28 g, 1.5 mmol) and H-Pro-Pab(Z)×2HCl (0.75 g, of 1.65 mmol; see example 35(2)) with the yield of 0.42 g (51%).

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

1H NMR (400 MHz: CDCl3): δ 6,72-to 7.84 (m, 12H), with 5.22 (s, 2H), 5,08 (s, 1H), 4,34-to 4.73 (m, 3H), 3,41-of 3.60 (m, 1H), 2,96-3,19 (m, 1H), 1,80-of 2.34 (m, 4H)

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

Specified in is the head of the connection get under way, described in example 15(3), Ph(3,5-F)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0.104 g g; 0,19 mmol; from stage (1)) to yield 79 mg (88%).

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

1H NMR (400 MHz; D2O): δ 6,86-7,80 (m, 7H), of 5.50 (s, 1H), to 3.58-4,72 (m, 4H), 3,19-of 3.32 (m, 1H), 1,80-is 2.37 (m, 4H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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-CH2-(R,S)CH(OH)-CH2OH)-C(O)-Aze-Pab×HOAc

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

(R)-Almond acid (3.0 g, of 19.7 mmol) dissolved in DMF (50 ml) and added cesium carbonate (3,21 g, 9,86 mmol). The reaction mixture was stirred at room temperature overnight. The mixture is diluted with N2O (200 ml) and N2O-layer is extracted with EtOAc. After separation the organic layer was washed with aqueous HCl, dried (Na2SO4) and evaporated. The output specified in the connection header is 4.2 g (88%).

LC-MS m/z 265 (M+Na)+

1H NMR (400 MHz; CDCl3): δ 7,17-7,44 (m, 10H), 5,12-5,27 (m, 3H).

(2) Ph-(R)CH(O-CH2-CH=CH2)-C(O)OBn

A mixture of compound Ph-(R)CH(OH)-C(O)OBn (1.0 g, 4,13 mmol; from stage (1)), magnesium sulfate (0.1 g, 0.83 mmol) and silver oxide (I) (2.58 g, and 11.2 mmol) in petroleum ether (BP. 40-60°C, 25 ml) is stirred in the dark at room temperature in a nitrogen atmosphere. Added dropwise allylbromide (0.75 g, to 6.19 mmol), and then the two portions add XID silver (I) (2.58 g, of 11.2 mmol). The reaction mixture was stirred over night at room temperature. The mixture is then filtered through celite and the filtrate is evaporated to obtain to 1.143 g (98%) indicated in the subtitle of the connection.

1H NMR (500 MHz; CDCl3): δ 7,20-to 7.50 (m, 10H), of 5.89 of 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-CH2-(R,S)CH(OH)-CH2OH)-C(O)OBn

A mixture of compound Ph-(R)CH(O-CH2-CH=CH2)-C(O)OBn (0.74 g, 2,62 mmol, from stage (2)), N-methylmorpholin-N-oxide (0,425 g and 3.15 mmol) and osmium tetroxide (0.0027 g, 0.01 mmol) in a mixture of N2O:acetone (2:1, 10 ml) was stirred at room temperature for 2 days. Add sodium pyrosulphite (1.5 g, 7,89 mmol) and stirred the mixture for 1 h Then the reaction mixture was filtered through celite and the filtrate evaporated. The output specified in the subtitle compound is 0.51 g (62%).

1H NMR (400 MHz; CDCl3): δ 7,16-7,44 (m, 10H), 5,09-5,20 (m, 2H), 4,96 (s, 1H), 3,55-of 3.97 (m, 5H).

(4) Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)OBn

Ph-(R)CH(O-CH2-(R,S)CH(OH)-CH2OH)-C(O)OBn (0.51 g, of 1.61 mmol, from stage (3)) is dissolved in acetone (20 ml). Add monohydrate p-toluensulfonate acid (0,007 g, 0,0037 mmol) and the mixture is stirred at room temperature for 24 hours of Added potassium carbonate (0.09 g) and the reaction mixture was stirred at room temperature for 1 h Then the mixture is filtered through celite and the filter is evaporated at obtaining 0,559 g (97%) indicated in the subtitle of the connection.

1H NMR (400 MHz; CDCl3): δ 7,18-of 7.48 (m, 10H), 5,01-to 5.21 (m, 3H), 4,27-and 4.40 (m, 1H), was 4.02-4,11 (m, 1H), 3,76-3,90 (m, 1H) 3,49-to 3.67 (m, 2H), 1,34-of 1.41 (m, 6N).

(5) Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-OCH2-))-C(O)OH

Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)OBn (0,183 g, 0.51 mmol; from stage (4)) is dissolved in ethanol (10 ml). Add Pd/C (5%, 0.09 g) and the reaction mixture hydrogenizing at atmospheric pressure for 1 h Then the mixture is filtered through celite and the filtrate evaporated to obtain 0,137 g (100 %) specified in the subtitle of the connection.

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

1H NMR (400 MHz CD3OD): δ 7,28-of 7.48 (m, 5H), equal to 4.97 (s, 1H), 4,25 is 4.35 (m, 1H), 4,01-4.09 to (m, 1H), 3.72 points-a-3.84 (m, 1H), 3.43 points-of 3.65 (m, 2H), of 1.30 to 1.37 (m, 6N).

(6) Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), Pb-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)IT (0,165 g; of 0.62 mmol; from stage (5)) yield 0.20 g (52%).

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

1H NMR (500 MHz; CDCl3): δ 7,22-7,88 (m, 14H), with 5.22 (s, 2H), 4,87-of 4.95 (m, 2H), 3,40-of 4.54 (m, N), 2,36 was 2.76 (m, 2H), 1,22-of 1.42 (m, 6N).

(7) Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)-Aze-Pab×HOAc

Specified in the header connection receive according to the method described in example 15(3), from Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)-Aze-Pab(Z) (0.20 g; 0,325 mmol; from stage (6) with the release of 179 mg (100%).

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

1H NMR (500 MHz; D2O): δ 7,33-7,80 (m, 9H), 4,81-5,31 (m, 2H), 3,94-4,59 (m, 6H), 3.25 to of 3.80 (m, 3H), 2,16-is 2.88 (m, 2H), 1,29-of 1.44 (m, 6H).

13C NMR (75.5 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbons: δ 181,99, 173,12, 172,93, 172,18, 166,84.

(8) Ph-(R)CH(O-CH2-(R,S)CH(OH)-CH2OH)-C(O)-Aze-Pab×HOAc

Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)-Aze-Pab×HOAc (0,094 g, 0,17 mmol, from step (7) is dissolved in a mixture of SPLA:N2O (4:1, 10 ml) and the reaction mixture was stirred at room temperature for 24 h the Mixture was evaporated and the residue is dissolved in N2O and dried by freezing. The output specified in the connection header is 85 mg (100%).

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

1H NMR (500 MHz; D2O): δ 7,32 for 7.78 (m, N), 4,81 is 5.28 (m, 2H), 3,28-4,56 (m, N), 2,15-2,90 (m, 2H).

13With NMR (100,6 MHz; D2O; complicated due to diastereomers/rotamers) amidinov and carbonyl carbons: δ 179,14, 172,93, 172,89, 172,51, 171,96, 166,54.

Example 49

Ph-(R)CH(O-CH2-(R,S)CH(OH)-CH2OH)-C(O)-Pro-Pab×HOAc

(1) Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2))-C(O)-Pro-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), from Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)HE (to 0.108 g; 0.4 mmol; see example 48(5)) and H-Pro-Pab(Z)×2HCl (0,202 g, 0,46 IMO the e l e C see example 35(2)) to yield 0.10 g (40%).

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

1H NMR (500 MHz; CDCl3): δ 7.23 percent-7,87 (m, 14H), 5,03 at 5.27 (m, 3H), 3,34 with 4.64 (m, 10H), 1,71-2,39 (m, 4H), 1,23-of 1.41 (m, 6H).

(2) Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2-))-C(O)-Pro-PabxHOAc

Specified in subheading connection receive according to the method described in example 15(3), from Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2))-C(O)-Pro-Pab(Z) (0,100 g; strength of 0.159 mmol; from stage (1)) to yield 85 mg (96%).

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

1H NMR (500 MHz; D2O): δ 7,30-of 7.82 (m, 9H), 5,22 is 5.38 (m, 1H), 4,32-to 4.62 (m, 4H), 4,01-4,11 (m, 1H), 3,22-a 3.83 (m, 5H), 1,78-2,22 (m, 4H), 1,33-1,44 (m, 6H).

13C NMR (100,6 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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-CH2-(R,S)CH(OH)-CH2OH)-C(O)-Pro-Pab×HOAc

Specified in the header connection receive according to the method described in example 48(8), from Ph-(R)CH(O-CH2-(R,S)CH(-O-C(CH3)2-O-CH2)-C(O)-Pro-Pab×HOAc (0,038 g; 0,069 mmol; from stage (2)with 35 mg (98%).

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

1H NMR (500 MHz; D2O): δ 7,30-of 7.82 (m, 9H), 5,20 is 5.38 (m, 1H), 3,18-4,60 (m, 10H), 1.70 to of 2.38 (m, 4H).

13With NMR (100,6 MHz; D2O complicated due to diastereomers/rotamers) amidinov and carbonyl carbons: δ 180,26, 174,74, 173,47, 171,80, 171,26, 166,61.

the example 50

Ph-(R or S)C(-O-C(CH3)2-O-CH2-)-C(O)-Aze-Pab×the SPLA and

Ph-(S or R) (- O-C(CH3)2-O-CH2)-C(O)-Aze-Pab×SPLA

(1) Ph-(R,S)C(-O-C(CH3)2-O-CH2-)-C(O)OH

Specified in subheading connection receive according to the method described in example 48(4), α-hydroxychromone acid (3.5 g; 20,35 mmol; obtained according to Guthrie et al., Can.J.Chem (1991) 69, 1904) output 3,37 g (74%).

1H NMR (500 MHz; CDCl3): δ 7,30-the 7.65 (m, 5H), of 4.95 (d, 1H), 4,10 (d, 1H), 1,70 (s, 3H), 1,50 (s, 3H).

(2) Ph-(R,S)C(-O-C(CH3)2-O-CH2-)-C(O)-Aze-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), from Ph-(R,S) (- O-C(CH3)2-O-CH2)-C(O)HE (0.25 g; 1.12 mmol; from stage (1)) with the receipt of 0.30 g (53%).

1H NMR (400 MHz; CDCl3): δ 7,20-of 7.90 (m, 14H), with 5.22 (s, 2H), 3,70-5,10 (m, 7H), 2,15-of 2.75 (m, 2H), 1,40-of 1.65 (m, 6N).

(3) Ph-(R or S)C(-O-C(CH3)2-O-CH2)-C(O)-Aze-Pab×the SPLA and

Ph-(S or R)C(-O-C(CH3)2-O-CH2)-C(O)-Aze-Pab×SPLA

A mixture of Ph-(R,S)C(-O-C(CH3)2-O-CH2)-C(O)-Aze-Pab(Z) (0,30 g of 0.53 mmol; from stage (2)), ammonium formate (0,30 g, 4.76 mmol), formic acid (3 drops) and Pd/C (5%, of 0.30 g) in methanol (10 ml) was stirred at room temperature for 30 minutes, the Reaction mixture was filtered through celite and the filtrate evaporated. The crude product (0.29 grams) is subjected to preparative RPLC. Several fractions are concentrated floor with the rising 80 mg (35%) of compound 50A ratio of diastereomers more than 99:1. Later fractions concentrated to obtain 80 mg (35%) of compound 50B ratio of diastereomers more than 98:2.

Compound 50A:

LC-MS m/z 437(M+1)+

1H NMR (400 MHz; CD3OD): δ 7,28-a 7.85 (m, 9H), 3,70-of 4.95 (m, 7H), 2,10-to 2.55 (m, 2H), 1.55V (s, 3H), 1,50 (s, 3H).

Connection 50B:

LC-MS m/z 437(M+1)+

1H NMR (400 MHz; CD3OD): δ 7,25-7,80 (m, N), 3,70-5,00 (m, 7H), 2,25-of 2.45 (m, 2H), 1,60 (s, 3H), of 1.48 (s, 3H).

Example 51

Ph-(R or S)C(OH)(CH2OH)-C(O)-Aze-Pab×HCl and

Ph-(S or R)C(OH)(CH2OH)-C(O)-Aze-Pab×HCl

(1) Ph-(R or S)C(OH)(CH2OH)-C(O)-Aze-Pab×HCl

Ph-(R or S)CH(-O-C(CH3)2-O-CH2-)-C(O)-Aze-Pab×HOAc (to 0.060 g; 0.12 mmol; compound 50A from example 50) was dissolved in acetic acid (4 ml) and add H2O (1 ml). The mixture is stirred over night at room temperature, and then 6 h at 90°C. Add HCl (conc., 1 ml), the mixture is stirred at room temperature for 5 minutes Acetic acid and HCl is removed under vacuum in the presence of toluene and EtOH, the residue is dissolved in N2O (4 ml) and dried by freezing. The crude product is subjected to preparative RPLC to obtain 9 mg (16%) specified in the connection header.

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

1H NMR (400 MHz; CD3OD): δ 7,20-a 7.85 (m, N), 3,90-4,70 (m, 5H), 3,30-3,70 (m, 2H), 2.00 in to 2.65 (m, 2H).

(2) Ph-(S or R)C(OH)(CH2OH)-C(O)-Aze-Pab×HCl

Specified in the header of the connection get under way, is written on a stage (1), from Ph-(S or R)CH(-O-C(CH3)2-O-CH2-)-C(O)-Aze-Pab×HOAc (to 0.060 g, 0.12 mmol; compound 50B from example 50) to yield 22 mg (40%).

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

1H NMR (400 MHz; CD3OD): δ 7,20-a 7.85 (m, N), 3,90-of 4.75 (m, 6N), 3,50-3,60 (m, 1H), 2,10-of 2.50 (m, 2H).

Example 52

Ph-(R or S)C(-O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab×the SPLA and

Ph-(S or R) (- O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab×SPLA

(1) Ph-(R,S)C(-O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab(Z)

Specified in subheading connection receive according to the method described in example 3(2), from Ph-(R,S) (- O-C(CH3)2-O-CH2-)-C(O)HE (0.25 g; 1.12 mmol; see example 50(1)) with exit to 0.19 g (32%).

FAB-MS m/z 585(M+1)+

1H NMR (400 MHz; CDCl3): δ 7,20-to 7.95 (m, 14N in), 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 to 2.35 (m, 10H).

(2) Ph-(R or S)C(-O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab×the SPLA and

Ph-(S or R) (- O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab×SPLA

Listed in the connection header receive according to the method described in example 50(3), from Ph-(R,S)C(-O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab(Z) (0,37 g; 0,63 mmol; from stage (1)). Several fractions are concentrated to obtain 120 mg of compound 52A ratio of diastereomers more than 99:1. Later fractions concentrated to obtain 120 mg of the compound B ratio of diastereomers more than 98:2.

Connection 52A:

LC-MS m/z 451 (M+1)+

1H NMR (400 MHz; CD3OD): δ 7,25-7,80 (m, N), 4,35-of 5.05 (m, 4H), 3,80-of 4.95 (m, 1H), 3,60-the 3.65 (m, 1H), 3.00 and-3,10 (m, 1H), 2,10-of 2.20 (m, 1H), 1,75-1,90 (m, 3H), of 1.55 (s, 3H), 1,45 (s, 3H).

Connection B:

LC-MS m/z 451 (M+1)+

1H NMR (400 MHz; CD3OD): δ 7,25-7,80 (m, N), 4,40-5,10 (m, 4H), 3,30-of 3.80 (m, 3H), 1,75-of 2.20 (m, 4H), 1,50-1,55 (m, 6N)

Example 53

Ph-(R or S)C(OH)(CH2OH)-C(O)-Pro-Pab×HCl and

Ph-(S or R)C(OH)(CH2OH)-C(O)-Pro-Pab×HCl

(1) Ph-(R or S)C(OH)(CH2OH)-C(O)-Pro-Pab×HCl

Specified in the header connection receive according to the method described in example 51(1), from Ph-(R or S)C(-O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab×SPLA (to 0.060 g; 0.12 mmol; compound 52A of example 52) with a yield of 2 mg (2%).

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

1H NMR (400 MHz; CD3OD): δ 7,20-a 7.85 (m, 9H), 4,40-4,60 (m, 3H), 4,05-4,30 (m, 1H), 2.95 and-3,90 (m, 3H), 1.60-to of 2.20 (m, 4H).

(2) Ph-(S or R)C(OH)(CH2OH)-C(O)-Pro-Pab×HCl

Specified in the header connection receive according to the method described in example 51(1), Ph-(S or R)CH(-O-C(CH3)2-O-CH2-)-C(O)-Pro-Pab×NOAA (to 0.060 g; 0.12 mmol; compound B from example 52) exit 1 mg (1%).

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

1H NMR (400 MHz; CD3OD): δ 7,25-a 7.85 (m, 9H), 4,40 with 4.65 (m, 3H), 4,05-4,20 (m, 1H), 3,25-3,75 (m, 3H), 1,40-of 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)

Specified in subheading connection receive according to the method described in example 3(2)of (R)-(-)-2-HYDR is XI-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 the yield of 0.13 g (22%),

1H NMR (500 MHz; CDCl3): δ 7,18-7,87 (m, 14H), a 5.25 (s, 2H), 4,35-br4.61 (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

Specified in the header of the connection get similar 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 stage (1)) to yield 92 mg (89%).

FAB-MS m/z 395(M+1)+

1H NMR (500 MHz; D2O): δ 7,37-to $ 7.91 (m, 9H), 4,33-br4.61 (m, 3H), 3,15-4,01 (m, 2H), 1,72 is 2.33 (m, 7H).

13C NMR (75.5 MHz; D2O; complicated due to rotamers) amidinov 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)

Specified in subheading connection receive according to the method described in example 3(2), (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 exit to 0.19 g (33%).

1H NMR (500 MHz; CDCl3): δ 7,20-to 7.77 (m, 14H), with 5.22 (s, 2H), 4.53-in-4,58 (m, 1H), 4,32-of 4.44 (m, 2H), 3,13-to 3.38 (m, 2H), 1,53-2,04 (m, 7H).

(2) Ph(S)C(Me)(OH)-C(O)-Pro-Pab×HCl

Specified in the header connection receive according to the method described in example 1(5), Ph(S)C(Me)(OH)-C(O)-Pro-Pab(Z) (0.12 g; 0.23 mmol, from stage (1)) to yield 80 mg (82%).

FAB-MS m/z 395(M+1)+

1H NMR (500 MHz; D2O): δ 7,35-to 7.84 (m, 9H), 4,47-4,63 (m, 3H), 3,30-3,70 (m, 2H), 1.60-to to 2.29 (m, 7H).

13C NMR (75.5 MHz; D2O; complicated bliod the OC to rotamers) amidinov and carbonyl carbons: δ 175,58, 175,23, 174,79, 167,07.

Example 56

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

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

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3,4-diferendului acid (0.20 g; 1.06 mmol) and H-Pro-Pab(Z)×2HCl (0,53 g at 1.17 mmol; see example 35(2)) to yield 445 mg (76%).

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

1H NMR (400 MHz; CDCl3): δ 6,98-7,74 (m, 12H), 5,16-to 5.21 (m, 2H), 5,06-free 5.01 (m, 1H), 4,22-4,56 (m, 3H), 3,32-to 3.58 (m, 1H), 2,88-of 3.12 (m, 1H), 1.70 to a 2.12 (m, 4H).

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

Specified in the header connection receive according to the method described in example 1(5), Ph(3,4-F)-(R,S)CH(OH)-C(O)-Pro-Pab(Z) (0,175 g; 0.31 mmol; from stage (1)) to yield 127 mg (88%).

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

1H NMR (400 MHz; CD3OD): δ 7,11-7,86 (m, 7H), lower than the 5.37 (s, 1H), 4,36-5,00 (m, 1H), 3,66-of 3.78 (m, 1H), 1,80-2,31 (m, 4H).

13C NMR (100,6 MHz; D3O; complicated due to diastereomers/rotamers) amidinov 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)-OCH3

A mixture of BOC-(R,S)Pic(4-hydroxy)-och3(1.1 g; of 4.25 mmol; obtained according to Gillard et al., J.Org.Chem.(1996) 61, 2226), RCC (1.8 g, 8.5 mmol) and molecular sieves (powder form;; 1.0 g) in CH2Cl2(20 ml) was stirred at room temperature for 4 hours Add diethyl ether (60 ml), the reaction mixture is altroot through a short column with silica gel, elwira a mixture of EtOAc:hexane (1:1). The filtrate is evaporated to obtain 1.0 g (92%) indicated in the subtitle of the connection.

FAB-MS m/z 258(M+1)+

1H NMR (500 MHz; CDCl3): δ 4,75-5,20 (m, 1H), 3,55-to 4.15 (m, 5H), 2.40 a-2,90 (m, 4H), 1.30 and of 1.65 (m, N).

(2) H-(R,S)Pic(4-oxo)-OCH3

Boc-(R,S)Pic(4-oxo)-OCH3(0,48 g; of 1.87 mmol; from stage (1)) process triperoxonane acid in CH2Cl2(50%, 4 ml) at room temperature for 30 minutes, the Reaction mixture was evaporated and the residue dissolved in CH2Cl2, washed with aqueous Na2CO3, dried (K2CO3) and evaporated. The output specified in the subtitle compound is 0.23 g (78%).

1H NMR (500 MHz; CDCl3): δ 3,65-of 3.80 (m, 4H), 3,30 is 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)-OCH3

Specified in subheading connection receive similarly to the method described in example 3(2), N-(R,S)Pic(4-oxo)-och3(0,22 g; 1.4 mmol; from stage (2)and Ph-(R)CH(OTBDMS)-C(O)OH (0,372 g, 1.4 mmol, obtained according to the method described in Hamada et al., SoC.(1989) 111, 669) yield 288 mg (51%).

FAB-MS m/z 406 (M+1)+

1H NMR (500 MHz; CDCl3): δ 7,20-to 7.50 (m, 5H), 5.25 to 5,70 (m, 2H), 4,15-of 4.75 (m, 1H), 3,20-of 3.80 (m, 4H), 2.00 in 2,90 (m, 3H), 1.30 and of 1.65 (m, 1H), 0,85-1,15 (m, N), 0,10-0,35 (m, 6N).

(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)-OCH3(0.28 g, 0.69 mmol, from stage (3)) and a solution of lithium hydroxide (2M, 10 ml) in THF (10 ml) per mesilat at room temperature for 1.5 hours THF is removed in vacuo, the residue is acidified (pH 2) with KHSO4) (2M) and extracted with EtOAc. The organic layer was washed with H2Oh, dried (MgSO4) and evaporated. The output specified in the subtitle compound is 0.24 g (89%).

FAB-MS m/z 392(M+1)+

1H NMR (400 MHz; CDCl3): δ 07,20-of 7.55 (m, 5H), 5,15-of 5.75 (m, 2H), 4,10-4,30 (m, 1H), 3,20-of 3.80 (m, 1H), 2,05-3,00 (m, 4H), 1,35-of 1.55 (m, 1H), 0,90-of 1.05 (m, N), 0,10-0,25 (m, 6N).

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

Specified in subheading connection receive similarly to the method described in example 1(2), from Ph-(R)CH(OTBDMS)-C(O)-(R,S)Pic(4-oxo)-OH (0,227 g; of 0.58 mmol; from stage (4)) to yield 92 mg (24%).

FAB-MS m/z 657(M+1)+

1H NMR (500 MHz; CDCl3): δ 6,90-of 7.90 (m, 14N), 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, N), 0,00-0,25 (m, 6N).

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

Specified in subheading connection receive according to the method described in stage (2), from Ph-(R)CH(OTBDMS)-C(O)-(R,S)Pic(4-oxo)-Pab(Z) (0.09 g; 0.14 mmol, from stage (5)) yield 61 mg (82%).

FAB-MS m/z 543(M+1)+

1H NMR (500 MHz; CDCl3): δ 6,95-of 7.90 (m, 14N), 5,00-of 5.55 (m, 4H), 3.95 to 4,70 (m, 2H), 3,20-3,70 (m, 2H), 1,20 is 2.80 (m, 4H).

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

Specified in the header connection receive 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 stage (6)) with the yield 46 mg (90%).

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

1H NMR (400 MHz; D2

Example 58

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

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

(1) BOC-(R,S)Pic(4-methylene)-och3

Methyltriphenylphosphonium bromide (2,68 g, 7.5 mmol) is dried under vacuum for 20 min and suspended in dry THF (20 ml) at 0°C. are added dropwise utility (1.6 n in hexane; 4,7 ml, 7.5 mmol) and the mixture is stirred at room temperature for 30 minutes, the Reaction mixture was cooled to -78°and add the BOC-(R,S)Pic(4-oxo)-och3(1.3 g, 5.0 mmol, see example 57(1)). The reaction mixture was stirred at -78°C for 30 min, and then 2 h at room temperature. To the reaction mixture add ammonium chloride and after the separation of the H2O-double-layer is extracted with diethyl ether. The combined organic layer is dried and evaporated to obtain the crude product, which was purified flash chromatography, elwira a mixture of EtoAc:hexane (30:70), to obtain 480 mg (37%) indicated in the subtitle of the connection.

FAB-MS m/z 256(M+1)+

1H NMR (500 MHz; CDCl3): δ 4,70-5,10 (m, 3H), 3.95 to to 4.15 (m, 1H), 3,70 (s, 3H), 2,10-3,10 (m, 5H), 1,35-to 1.60 (m, N).

(2) H-(R,S)Pic(4-methylene)-och3

BOC-(R,S)Pic(4-methylene)-och3(0,48 g, 1.88 mmol, from stage (1)) process triperoxonane acid (50% in CH2Cl2, 6 ml) at room temperature for 40 mi is. The reaction mixture is evaporated and the residue dissolved in CH2Cl2washed Na2CO3(saturated), dried (K2CO3) and evaporated. The output specified in the subtitle compounds comprise 0.27 g (95%).

1H NMR (500 MHz; CDCl3): δ 4,70-4,85 (m, 2H), 3.75 to (m, 3H), 3,35 is-3.45 (m, 1H), 3.15 and is 3.25 (m, 1H), 2,55-2,70 (m, 2H), 2,10-of 2.30 (m, 3H).

(3) Ph-(R)CH(OTBDMS)-C(O)-(R,S)Pic(4-methylene)-och3

Specified in subheading connection receive similarly 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, SOC.(1989), 111,669) and N-(R,S)Pic(4-methylene)-och3(0.21 g, 1.4 mmol; from stage (2)) with exit 0,283 g (52%).

FAB-MS m/z 404(M+1)+

1H NMR (500 MHz; CDCl3): δ 7,25-of 7.55 (m, 5H), 5,15-5,70 (m, 2H), 4,20-4,85 (m, 3H), 3,65 of 3.75 (m, 3H), 1,90-3,20 (m, 5H), 0,90-1,10 (m, N), 0,10-0,30 (m, 6N).

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

Specified in subheading connection receive according to the method described in example 57(4), from Ph-(R)CH(OTBDMS)-C(O)-(R,S)Pic(4-methylene)-och3(0.28 g; 0.69 mmol; from stage (3)) to yield 0.24 g (89%).

FAB-MS m/z 390(M+1)+

1H NMR (500 MHz; CDCl3): δ 7,15-to 7.50 (m, 5H), 5,15-5,95 (m, 2H), 3,55-5,00 (m, 3H), 1,75-of 3.25 (m, 5H), 0,85-1,05 (m, N), 0,10-0,25 (m, 6N).

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

Specified in subheading connection receive similarly to the method described in example 3(2), from Ph-(R)CH(OTBDMS)-C(O)-(R,S)Pic(4-methylene)-HE (0,235 g; 1.6 mmol; from stage(4)) and H-Pab(Z)× HCl (0,211 g, 0.66 mmol) with access 0.124 g (35%).

FAB-MS m/z 655(M+1)+

1H NMR (500 MHz; CDCl3): δ 7,10-of 7.90 (m, 14N), 5,15-5,10 (m, 4H), 4,10-of 5.05 (m, 4H), 1,75 was 3.05 (m, 6N), 0,80-1,10 (m, N), 0,00-0,25 (m, 6N).

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

Specified in subheading connection receive similarly 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 stage (5)) yield 0.06 g (91%).

LC-MS m/z 541 (M+1)+

1H NMR (500 MHz; CD3OD): δ 7,15-1,90 (m, 14N), 5,20-5,80 (m, 4H), 4,35-of 4.90 (m, 4H), 3,70-to 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×the SPLA and

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

A mixture of Ph-(R)CH(OH)-C(O)-(R,S)Pic(4-methylene)-Pab(Z) (0.035 g, 0,065 mmol, from stage (6)), ammonium acetate (0.50 g, 7.4 mmol) and imidazole (0.20 g, 3.0 mmol) in methanol (5 ml) was stirred at 60°With during the night. The reaction mixture is evaporated, and the residue is subjected to preparative RPLC. Some fraction concentrate with receiving 1.8 mg connection B. The latter fraction concentrated to obtain 7 mg of compound 58A.

Connection 58A:

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

1H NMR (400 MHz; D2O): δ 7,15-7,80 (m, 9H), 5,65-5,70 (m, 1H), 4.80 to a 5.25 (m, 1H), 4,45-4,60 (m, 2H), 3,60-4,00 (m, 2H), 1.30 and 3.30 is (m, 6H).

Connection B:

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

1H NMR (400 MHz; D2O): δ 7,30-7,80 (m, 9H), the 5.45 of 5.75 (m, 1H), 4.80 to-5,20 (m, 1H), 4,35-4,70 (m, 3H), 3.75 to 3,90 (m, 1H), 1.70 to 3,05 (m, 6H).

Example 59

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

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

Specified in subheading connection receive according to the method described in example 15(1), 3-chlorobenzaldehyde (7,03 g; 50 mmol) with a yield of 2 g (21%).

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

1H NMR (400 MHz; CD3OD): δ 7,28-7,51 (m, 4H), 5,14 (s, 1H).

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

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-harmondale acid (0,149 g; 0.8 mmol; from stage (1)) with the release of 0.30 g (70%),

1H NMR (500 MHz; CDCl3): δ 7,08-to 7.84 (m, 13H), 5,18-5,24 (m, 2H), 4,86-free 5.01 (m, 2H), was 4.02-4,56 (m, 3H), 3,57 is 3.76 (m, 1H), 2,30-of 2.72 (m, 2H).

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

Specified in the header connection receive 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 stage (2)with 55 mg (63%).

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

1H NMR (400 MHz, D2O): δ 7,10-a 7.85 (m, 8H), 4,82 lower than the 5.37 (m, 2H), 3.96 points-4,79 (m, 4H), 2,14-to 2.85 (m, 2H).

13C NMR (100,6 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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)

Specified in subheading connection receive according to the method described in example 3(2), (R,S)-3-chloro-4-hydroxymandelic acid (0.25 g; of 1.23 mmol) and H-Pro-Pab(Z)×2HCl (of 0.615 g, 1.35 mmol; see p. the emer 35(2)) to yield 382 mg (55%).

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

1H NMR (400 MHz; CD3OD): δ 6,80-a 7.85 (m, N), 5,16-a 5.25 (m, 3H), 4,35-4,51 (m, 3H), 3.45 points of 3.75 (m, 1H), 3,07-of 3.42 (m, 1H), 1,72-to 2.18 (m, 4H).

13With NMR (100,6 MHz; D2O; complicated due to diastereomers/rotamers) amidinov 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

Specified in the header of the connection get similar 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 stage (1)), 3-forexpros acid and 3.7 ml, 48 mmol) and thioanisole (1,04 ml cent to 8.85 mmol) to yield 57 mg (70%).

LC-MS m/z 431 (M+1)+

1H NMR (500 MHz; D2O): δ 6,84-7,86 (m, 7H), a 5.25-5,42 (m, 1H), 4,30-and 4.68 (m, 3H), 3,05-of 4.05 (m, 2H), 1.70 to is 2.37 (m, 4H).

Example 61

Specified in the headers of connection of premrov 1-60 tested in the above test, it was found that they all have values IC50TT less than 0.3 microns.

Reduction

aq - water

Aze - azetidin-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

SPLA - acetic acid

HOSu - N-hydroxysuccinimide

H-Dig - 1-amidino-3-aminoacylase the Dean

H-Dig(Z) - 3-amino-ethyl-1-(N-benzyloxycarbonylamino)azetidin

H-Hig - 1-amidino-3-aminomethylpyrrolidine

H-Hig(Z) - 3-amino-ethyl-1-(N-benzyloxycarbonylamino)-pyrrolidin

H-RAS - 1-amidino-4-aminoheterocycles

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

H-Pic - pipecolinate acid

H-Pig - 1-amidino-3-aminomethylpyridine

H-Pig(Z) - 3-aminomethyl-1-(N-benzyloxycarbonylamino)piperidine

H-Pab - 1-amidino-4-aminomethylbenzoic

H-Pab(Z) - 4-aminomethyl-1-(N-benzyloxycarbonylamino)benzene

RCC - pyridine chlorproma

Pro - Proline

HPLC - liquid chromatography high-resolution

Me - methyl

Ph - phenyl

RPLC - liquid chromatography high-resolution reversed-phase

Su - succinimide

TBDMS tert-butyldimethylsilyl

TBTU - [N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)Urania tetrafluoroborate

THF - tetrahydrofuran

TNR - tetrahydropyranyl

TMS - trimethylsilyl

WSCL - soluble carbodiimide

Z - benzyloxycarbonyl

Attachment n, s, i and t denote normal, ISO, secondary and tertiary. The stereochemistry of the amino acids default (S).

1. The compound of the formula I

where p and q independently are 0;

R1represents N;

R2represents N;

R3is aboufadel (this latter group is substituted by one or more 1-4the alkyl, C1-4alkoxy, halogeno, hydroxy, cyano, nitro, methylenedioxy, trifluoromethyl, N(H)R27or C(O)OR28);

R27represents H, C1-4alkyl or C(O)R29;

R28and R29independently represent N or C1-4alkyl;

R4represents N or C1-4alkyl;

Y represents a C1-3alkylen, possibly substituted C1-4by alkyl, hydroxy, methylene or oxo;

n is 1 and

Represents a structural fragment of formula IVa

where R5represents H, halogen or1-4alkyl,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R5represents H, when represents a structural fragment of formula IVa.

3. The compound according to claim 1 or 2, in which R4represents N.

4. The compound according to any one of claims 1 to 3, in which Y is CH2, (CH2)2, (CH2)3CH2CH(CH3)CH2CH2C(=O)CH2or CH2C(=CH2)CH2.

5. The compound according to claim 4, in which Y is CH2, (CH2)2or CH2C(=CH2)CH2.

6. The compound according to any one of claims 1 to 5, in which R3substituted one or more is it than one hydroxy, fluorine, chlorine, methyl, methoxy, amino, nitro, trifluoromethyl, methylenedioxy, ethoxy or propoxyphene.

7. The connection according to claim 6, in which R3substituted one or more than one hydroxy, mono - or debtor, chlorine, methyl, methoxy and methylendioxyphenyl.

8. The compound according to any one of claims 1 to 7, in which Y is CH2.

9. The compound according to any one of claims 1 to 8, in which α-amino acid carbon fragment

is in S-configuration.

10. The compound according to any one of claims 1 to 9, in which α-carbon fragment

is R-configuration.

11. Pharmaceutical composition for the inhibition of thrombin containing the compound as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. The compound as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt for use as pharmaceuticals.

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 inhibition of thrombin.

14. The compound as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt for use of the ri 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. 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 medicaments for the treatment of a condition where inhibition of thrombin.

17. Connection P16, 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 production of anticoagulant.

19. The method of treatment of a condition where inhibition of thrombin, wherein the person suffering from such condition or are prone to this condition, introducing a therapeutically effective amount of a compound as defined in any one of claims 1 to 10, or its pharmaceutically acceptable salt.

20. The method according to claim 19, where this condition is thrombosis.

21. The method according to claim 19, where this state is the hypercoagulation in the blood and tissues.

22. A method of obtaining a compound as defined in claim 1, in which

(a) combining the compound of formula V

where p, q, R1, R2and R3such as defined in claim 1,

with the compound of the formula VI,

where R4, Y, n are as defined in claim 1;

or (b) combining the compound of formula VII

where p, q, R1, R2, R3, R4and Y are such as defined in claim 1,

with the compound of the formula VIII

where n are as defined in claim 1.

23. The compound of formula XIV

where1represents a structural fragment of formula characterise reflexes IVG

D1and D2independently represent H or benzyloxycarbonyl;

p, q, R1, R2, R3, R4, Y, n and R5such as defined in claim 1, provided that D1and D2not both represent N.

Priority from 07.11.1995 installed according to claims 1-21, 22(b) and 23 except signs

R3represents phenyl, substituted by one or more cyano, nitro, methylenedioxy, trifluoromethyl, N(H)R27or C(O)OR28and

Y represents a C1-3alkylen, possibly substituted by hydroxy, methylene or oxo.

Priority from 05.12.1995 installed according to claims 1-21, 22(b) and 23 for the characteristic

R3represents phenyl substituted by trifluoromethyl.

Priority from 02.07.1996 set by article 22(a)and (1-21, 22(b) and 23 for signs

R3represents phenyl, substituted by one or more cyano, nitro, methylenedioxy, N(H)R27or C(O)OR28and

Y represents a C1-3alkylen, possibly substituted by hydroxy, methylene or oxo.



 

Same patents:

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of acetylamidiniophenylalanylcyclohexylglycilpypidinioalanin amides of formula I , wherein X anions are physiologically acceptable anions, and analogous thereof. Said compounds are effective inhibitors of fibrillation factor Xa and are useful, for example, in prevention of thrombosis. Claimed method includes coupling of 2-[2-acetylamino-3-(4-amidinophenyl)-propionylamino]-2-cyclohexylacetic acid, obtained from 2-[2-acetylamino-3-(4-cyanophenyl)acryloylamino]-2-cyclohexylacetic acid by assimetric hydration and converting of cyano group to amidine, or salt thereof with 3-(2-amino-2-carbamoylethyl)-1-methylpyridinic acid or salt thereof. Also are disclosed starting materials and intermediated used in this method, process for production the same and acetyl-(S)-4-amidiniophenylalanyl-(S)- cyclohexylglycil-(S)-(1-methyl-3-pypidinio)alanin amide in form of ditosylate.

EFFECT: simplified method; increased commercial availability of compounds with applicable anion.

14 cl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

FIELD: biotechnology, microbiology, medicine.

SUBSTANCE: method involves selection of signal sequence suitable for the effective expression of Leu-hirudine in E. coli cells by the polymerase chain reaction-screening method. Method involves construction of a protein as a precursor of hirudine based on the selected signal sequence of surface membrane protein from Serratia marcescens, oprF protein from Pseudomonas fluorescens or fumarate reductase from Shewanella putrifaciens by joining the Leu-hirudine amino acid sequence with C-end of selected signal sequence. Prepared precursor of Leu-hirudine is used in a method for preparing Leu-hirudine. Invention provides preparing Leu-hirudine by the direct secretion in E. coli cells with the high yield. Invention can be used in preparing the hirudine precursor.

EFFECT: improved preparing method.

4 cl, 1 dwg, 2 tbl, 12 ex

FIELD: medicine, hematology, cardiology, endocrinology.

SUBSTANCE: invention relates to a method for correction of disturbances at thrombocyte hemostasis in patients with metabolic syndrome. Method involves prescription of hypocaloric diet and lovastatin in the dose 20 mg before sleeping. Method provides normalization of primary hemostasis in these patients.

EFFECT: improved treatment method.

2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein A, L, Y, and k are as defined in specification. Compounds of formula I have value pharmacological activity, in particular potent antithrombosis action and are useful in treatment and prophylaxis of cardiovascular diseases such as thromboembolia. They represent also reversible inhibitors of factor X and factor VIIa (blood coagulation enzymes). Also disclosed are methods for production of compounds I, uses thereof, in particular as active ingredients in pharmaceutical compositions, as well as medicines containing the same.

EFFECT: new pharmaceutical compositions for treatment and prophylaxis of cardiovascular diseases.

10 cl, 50 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new compounds of formula

,

wherein A and B are independently CH or CR3; X is C=O or (CR4aR4b)m, (m = 1 or 2); Y is S(O)n-R2 (n = 1 or 2), S(O)n-NR2R2, or S(O)n-OR2; N1 and N2 are nitrogen atoms; Q and R1 are independently 1) optionally substituted C1-C10-alkyl; 2) optionally substituted aralkyl containing C6-C10-aryl, attached to C1-C10-alkyl; 3) optionally substituted aralkenyl containing C5-C10-aryl, attached to C1-C10-alkenyl; 4) optionally substituted C6-C10-aryl; 5) optionally substituted aryl, containing 5-10 ring atoms, selected from carbon and sulfur; each R2 and R3 are hydrogen; R4a, R4b, R5, and R6, are independently hydrogen; R2 and R3 are independently hydrogen or C1-C6-alkyl; as well as acid and base additive salts thereof. Also disclosed are method for production of claimed compounds, pharmaceutical composition inhibiting serine protease enzymes and therapeutic method based thereon.

EFFECT: new compounds and pharmaceutical composition for thrombosis preventing or abnormal thrombosis treatment.

11 cl, 7 tbl, 15 ex

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: mixture A obtained due to mixing pre-reduced acetylsalicylic acid with a carrier and glucose followed by its diluting in aqueous-alcoholic solution should be mixed with mixture B obtained due to suspending calcium gluconate, plastifying and lipophilic agents in solvent, followed by deaeration of the mixture obtained, its application onto bottom plate with subsequent drying and forming the ready-to-use medicinal form. Method enables to obtain remedy of increased stability of functional characteristics, prolonged action and increased bioavailability of acetylsalicylic acid at no side effects.

EFFECT: higher efficiency.

3 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to peroral immediate-released drug in solid form, containing low molecular thrombin inhibitor based on peptide with pH-depending solubility. Claimed drug has size particle less than 300 mum and contains combination of microcrystal cellulose and sodium glycolate starch in amount of more than 35 mass % (calculates as preparation mass).

EFFECT: drug with reduced dependence of thrombin inhibitor dissolution from pH and increased releasing rate from tablet.

17 cl, 3 ex, 3 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

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