New ketoenamine

 

(57) Abstract:

The invention relates to new ketoenamine formula (1), where R1means phenyl, naphthyl, hinely, pyridyl, chinadoll, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, which may be unsubstituted or substituted, R2means hydrogen or alkyl, R3means alkyl, which may carry phenyl ring, X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)0-, -(CH2)n-S-(CH2)m-, -CH= CH-, -CO-CH=CH-, -(CH2)m-NHCO-(CH2)0-, -(CH2)m-CONH-(CH2)0-, -(CH2)m-NHSO2-(CH2)0-, -(CH2)m-SO2NH-(CH2)0-; R4means group OR6, NR7R8; n is a number from 0 to 2. The compounds of formula (I) possess an inhibitory activity and, therefore, are inhibitors of cysteine proteases, in particular cysteine proteases, as calpain 1 and 11 and the cathepsins B, L. 2 C.p. f-crystals, 1 PL.

The present invention relates to new chemical substances with biological activity, and more particularly to a new ketoenamine that can be used as inhibitors of Protea triketone proteolytic enzymes. Calpain are activated by high concentration of calcium, and distinguish between Kalpana I or-Kalpana, which is activated by micromolar concentrations of calcium ions, and Kalpana II or m-Kalpana, which is activated by millimolar concentrations of calcium ions (see P. Johnson, Int. J. Biochem. 1990, 22(8), pp. 811-822). Currently, there are still other isoenzymes of calpain (see K. Suzuki and others, Biol. Chem. Hoppe-Seyler, 1995, 376 (9), pp. 523-529).

There is an assumption that calpain play an important role in various physiological processes. These include the splitting of regulatory proteins, such as protein kinases, cytoskeletal proteins, such as MAP 2 and spectrin, muscle proteins, cleavage of proteins in rheumatoid arthritis, the proteins in platelet activation neuropeptide metabolism, proteins during mitosis and others, which are listed in the publications of M. Th. Barrett and others , Life Sci. 1991, 48 p. 1659-69 and K. K. Wang and others, Trends in Pharmacol. Sci., 1994, 15, PP 412-9.

In various pathophysiological processes were observed elevated levels of calpain, such as cardiac ischemia (e.g., myocardial infarction), renal ischemia or ischemia of the Central nervous system (e.g. stroke) is whether Alzheimer's disease (see the above source K. K. Wang and others). Therefore, it is assumed the Association of these diseases with a high level of calcium in the cells. Consequently dependent calcium processes excessively activated and is no longer amenable to physiological regulation. In accordance with this excessive activity of kalainov can also cause pathophysiological processes. Therefore, there are allegations that the inhibitors Kalmanovich enzymes may be useful for treating such diseases. Various studies confirm this. For example, authors such as Seung-Cial Hong and others in Stroke 1994, 25(3), pages 663-9 and R. T. Bartus and others, Neurological Res. 1995, 17, pp. 249-58 showed a neuroprotective effect of inhibitors of kalainov in acute neurodegenerative disorders or ischemia, available, for example after a stroke. After experimental brain injury inhibitors calpain improved resulting deficits in memory function and neuro-motor disorders (see K. E. Chatman and others, Proc.Natl.Acad.Sci. USA, 1996, 93 p. 3428-3433). Authors K. L. Edelstein and others, published in Proc.Natl.Acad.Sci. USA, 1995, 92 p. 7662-6, found a protective effect of inhibitors calpain damaged by hypoxia of the kidney. The authors Yoshida, Ken Ishii and others, in the publication Jap.Circ.J. 1995, were caused by ischemia or reperfusion. Due to the fact that the inhibitors calpain inhibit selection-AR-protein, it was suggested their potential use in the treatment of Alzheimer's disease (see I. Higuchi and others, Neuron, 1995, 14, PP 651-59). Secretion of interleukin-1 also inhibited by inhibitors calpain (see N. Watanabe and others , Cytokine 1994, 6(6), pp. 597-601). It was further found that the inhibitors calpain have a cytotoxic effect on tumor cells (see E. Shiba and others , 20th Meeting of the Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25-28.Sept., Int. J. Oncol. 5(Suppl.), 1994, page 381).

Other possible applications of inhibitors calpain given by the author K. K. Wang in the publication Trends in Pharmacol.Sci., 1994, 15, PP 412-8.

Inhibitors calpain have already been described in the literature. However, in most cases these are either irreversible or peptide inhibitors. Irreversible inhibitors are usually alkylating substances and have the disadvantage that they react in the body selectivity or they are unstable. For example, these inhibitors often exhibit undesirable side effects, such as toxicity, and therefore they are limited in their application or do not apply. Irreversible inhibitors are, for example, epoxides E 64 (see E. B. McGowan and others, Biochem. Wore other, Chem. Lett. 1990, pages 191-194).

Many well-known reversible inhibitors of cysteine proteases, such as calpain, are peptide aldehydes, in particular dipeptide and Tripeptide aldehydes, such as, for example, Z-Val-Phe-H (MDL 28170) (see C. Copper, Trends in Biol. Sci. 1991, 16, PP 150-3) and compounds described in European patent 520336. In physiological conditions the peptide aldehydes have often the disadvantage that they are due to their inherent reactivity unstable, can quickly metabolized, prone to non-specific reactions, which can cause toxic effects (see I. A. Franz and C. Castro, Synthesis 1983, 676-678). The use of peptide aldehydes in the treatment of diseases is thus limited or impractical.

Progress is the discovery that certain peptide derivatives of ketone are also inhibitors of cysteine-proteases and, in particular, Kalpana. So, for example, derivatives of ketone known as inhibitors of serine proteases, and ketogroup activated electron-attracting group, e.g., CF3. When the cysteine-proteases derived ketone, which ketogroup is activated by a group of CF3or similar groups, allauto effective inhibitors calpain could be found only derivatives of ketone, in which, on the one hand, being in the position of the leaving group cause irreversible inhibition and, on the other hand, carboxylic acid derivative activates ketogroup (see above authors M. P. Angelastro and others, as well as applications WO 92/11850; WO 92/12140; WO 94/00095 and WO 95/00535). However, these ketoamide and complex ketoesters still only peptide derivatives have been described as effective (see Zhao Zhao Li and others, J. Med.Chem. 1993, 36, pp. 3472-80; C. L. Harbeson etc., J. Med.Chem. 1994, 37, pp. 2918 29 and the above-mentioned publication M. P. Angelastro and others).

Next, ketoenamine have already been described in the literature. For example, complex ketoester formula PhCO-Abu-SOON2CH3described in applications WO 91/09801, WO 94/00095 and 92/11850. A similar derivative of the phenyl of the formula Ph-CONH-CH(CH2Ph)-COCOON3described by the author M. P. Angelastro and others, in J. Med. Chem. 1990, 33, pp. 11-13, however, as a weak inhibitor calpain. It is derived is described in the publication J. R. BURKHARDT, Tetrahedron Lett., 1988, page 3433-36. However, the role of the substituted benzamides so far not been studied.

The objective of the invention is the development of new ketoenamine that can be used as inhibitors calpain.

The problem is solved prospect who was Salil, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, and aromatic and heteroaromatic ring can be substituted one, two or three radicals R5with the following value;

R2means hydrogen, C1-C6-alkyl;

R3means C1-C6-alkyl, which may carry phenyl ring;

X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)about- -(CH2)n-S-(CH2)m-, -CH= CH-, -CO-CH= CH-, -(CH2)m-NO-(CH2)o-, -(CH2)m-N-(CH2)about-, -(CH2)m-NSO2-(CH2)o-, -(CH2)m-SO2NH-(CH2)about-;

R4means group OR6, NR7R8,

R5means hydrogen, C1-C4-alkyl, -O-C1-C4-alkyl, Cl, Br, J;

R6means hydrogen or C1-C6-alkyl;

R7means hydrogen;

R8means hydrogen or C1-C6-alkyl, which may carry one or two radicals R9or may be substituted by one of the groups

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< / BR>
or

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R9means hydrogen, COOH;

R10means water is m or the two radicals R9,

n is the number 0, 1 or 2,

m is the number 0, 1, 2, 3 or 4 and

o, the number 0, 1, 2, 3, or 4

and their tautomeric and isomeric forms or their physiologically acceptable salts.

Preferred Ketobemidone formula (I) are compounds that have

R2means hydrogen, C1-C4-alkyl;

R3means-CH2-phenyl, n-butanol or n-pentanol;

R4means-NR8and

R1, X and n have the above values.

The compounds of formula I can be used as the racemate or pure enantiomeric compounds or pure diastereoisomers. If desired pure enantiomeric compounds can be obtained, for example, due to the fact that using a suitable optically active base or a suitable acid teach classical splitting of the racemate of compounds of the formula I or their intermediate products. Enantiomeric compounds can be obtained using the corresponding commercially available compounds such as optically active amino acids such as phenylalanine, tryptophan and tyrosine.

The compounds of formula I can also be available in maternal and tautomeric form, for example, those in which ketogroup formula AI acid group. In these cases, the compounds of formula I can be in the form of their physiologically acceptable salts, which are obtained by the interaction of the compounds of formula I with a suitable acid or a suitable base.

As acids for salt formation with compounds of the formula I according to the invention containing a basic group, are suitable, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonate, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid and sulfuric acid. As suitable bases are used, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, , , -Tris(hydroxymethyl)methylamine, and other amines.

Getting ketoenamine formula I according to the invention can be carried out by various methods, which are schematically shown in the following reaction schemes 1 and 2 (see the end of the description).

Esters of carboxylic acids of formula II is converted to the acid of formula III by reaction with acids or bases, such as hydrochloric acid, lithium hydroxide, sodium hydroxide, or is drofuran, at room or elevated temperature, for example at 25-100oC. the Acid of formula III is subjected to reaction in combination with a derivative-amino acids, in normal conditions, see, for example, the author of Houben Vale Methods in der organischen Chemie, 4th edition, E5, Chapter V and the author K. R. larok in Comprehensive Organic Transformations, VCH publishers Publisher, 1989, Chapter 9.

Carboxylic acid of formula III is transferred to "activated derivative of the acid of formula R1-L, where L is a leaving group such as, for example, Cl, imidazole and N-hydroxybenzotriazole, and then the interaction with the derived amino acid of the formula H2N-CHR3-COOR is converted into a derivative of formula IV. This reaction is carried out in an anhydrous inert solvent such as methylene chloride, tetrahydrofuran and dimethylformamide, at temperatures from -20 to +25oC.

Derivative of formula IV, which, as a rule, are esters, become the same as the above hydrolysis in ketocarboxylic acids of the formula V. Similar Dakine-West reaction get complicated ketoesters of formula I', and working according to the method described by Zhao Zhao Li and al in J. Med. Chem., 1993, 36, pp. 3472-80. According to this method, the carboxylic acid, such as Faure, the RA of oxalic acid in this solvent, as tetrahydrofuran, then the resulting product is subjected to interaction with such bases as methanolate sodium in ethanol at a temperature of 25-80oWith obtaining complex keeeper formula I' according to the invention. Complex ketoesters of the formula I' can be, for example, gidrolizirovanny to ketocarboxylic acids according to the invention.

The transformation in ketoenamine formula I are also produced similarly to the above method according to Zhao Zhao Li and the other Ketogroup in the compound of formula I' to protect by adding 1,2-identicial in the presence of a Lewis acid such as bactritoidea, in an inert solvent, such as methylene chloride, at room temperature, and get dition. These derivatives are subjected to interaction with amines of the formula R4-H in polar solvents, such as alcohols, at a temperature of 0-80oWith obtaining ketoenamine formula I (and, for example, R4=NR7R8).

An alternative method is presented in scheme 2. Ketocarboxylic acid III is subjected to interaction with derivative aminohydrocinnamic acid of formula VI (obtaining compounds of formula VI, see S. L. Harbeson etc. , J. Med. C is the group of amides of formula VII. These derivatives of alcohols of the formula VII can be subjected to oxidation to obtain derivatives ketocarboxylic acids of the formula I according to the invention. You can use various known oxidation reactions (see K. R. larok, Comprehensive Organic Transformations, ed. VCH Publisher, 1989, page 604 FF.), for example, the oxidation will Roll or similar will Turn oxidation. Preferably work with dimethylsulfoxide and pyridinium anhydride in a solvent such as methylene chloride or tetrahydrofuran, optionally with the addition of dimethyl sulfoxide at room temperature or at temperatures from -50 to 25o(See T. T. Tidwell, Synthesis 1990, p. 857-70) or a mixture of sodium hypochlorite and /TEMPO (S. L. Harbison and others, see above).

If the compounds of formula VII are complex-hydroxyamine (X= O-alkyl), they can be subjected to hydrolysis to obtain carboxylic acids of the formula VIII, and work the same as the above methods, but preferably with lithium hydroxide in mixtures of water with tetrahydrofuran at room temperature. Other esters or amides of formula X is produced by reacting alcohols or amines with the above combination. The derived alcohol of the formula IX .

Synthesis of esters of carboxylic acids of the formula II partially known or can be conducted using the appropriate conventional chemical methods.

Compounds in which X represents a bond, obtained by the conventional reaction of aromatic combinations, for example the reaction of a combination of Suzuki, using derivatives of boric acid and halides to palladium catalyst or the reaction of a combination of aromatic halides at the copper catalyst. Radicals with alkylamine bridges (X=-(CH2)m-) can be obtained by restoring the analogous ketones or by alkylation of organolithium compounds, such as orthogonalization, or other ORGANOMETALLIC compounds (see I. M. Dordor etc., J. Chem. Soc. Perkin Trans. I, 1984, page 1247-52).

Derivatives with ether bridges are obtained by alkylation of the corresponding alcohols or phenols halides.

The sulfoxidov and sulfones are obtained by oxidation of the corresponding thioethers.

Connection with allenbyi by alkyne and walkways receive, for example, using the Heck reaction of aromatic halides and the corresponding alkenes and alkynes (see I. Sakamoto and others, Chem.Pharm. Bull., 1986, 34, pp. 2754-59).

Amides and sulfonamides get the same as the above methods of amines and derivatives of acids.

As mentioned above, ketoenamine formula I according to the invention are inhibitors of cysteine proteases, in particular cysteine proteases, as calpain I and II and the cathepsins B, respectively L.

The inhibitory effect ketoenamine formula I was determined by means known in the literature enzymatic experiments, and as a measure of efficiency was taken as the concentration of inhibitor, which inhibited 50% of enzyme activity. Was measured the inhibitory effect of benzamide formula I on calpain I. the Results are summarized in the following table.

Due to the above activity ketoenamine formula I can be used in combating diseases associated with increased activity of enzymes of type calpain and/or cathepsin. As a result, they can be used for the treatment of neurodegenerative diseases that occur after ischemia, trauma, subarachnoid hemorrhages and hemorrhages in the brain and which include, in particular, cerebral stroke and skull trauma, and neurodegenerative diseases such as multiple infarction dementia, the th ischemia, damage to the kidneys after renal ischemia, damage of skeletal muscles, muscular dystrophies, damage caused by proliferation of smooth muscle cells, coronary artery spasm, spasm of cerebral vessels, eye cataracts or restenosis of blood stream after angioplasty. In addition, benzamide formula I can be useful when hemoterapia tumors and their metastases, and for treatment of diseases in which there is an increased level of interleukin-1, for example, inflammation and/or rheumatic diseases.

The compounds of formula I are applied in the form of pharmaceutical preparations which contain, along with the usual auxiliary substances therapeutically effective amount of compounds of formula I.

For local external use, for example as a powder, ointment or spray, the active substance may be contained in the usual concentrations. Typically, the active ingredients are contained in an amount of from 0.001 to 1 weight. %, preferably from 0.01 to 0.1 weight. %

For domestic use drugs are given in a separate doses. In a single dose given per kg of body weight from 0.1 to 100 mg of the drug can be given daily in single or multiple doses zavisimosti contain along with the active ingredient in conventional fillers and solvents. For local external use can be used pharmaceutically-technical auxiliary substances, such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated gidrirovannoe castor oil, polyacrylic acid, polyethylene glycol, polietilenglikolya, the ethoxylated fatty alcohols, paraffin oil, vaseline and lanolin. For internal use are suitable, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.

In addition, the dosage form may contain antioxidants, such as tocopherol and bottled oxyanion and bottled oxytrol, and also improves the taste of additives, stabilizers, emulsifiers and lubricants.

Contained along with active starting substances, and substances used in the manufacture of pharmaceutical preparations, are toxicologically acceptable and compatible with the respective active substance. The production of the drugs produced in the usual manner, for example by mixing the active substances with other conventional carriers and diluents.

The drugs can be given in different ways, nabrasa, such dosage forms as tablets, emulsions, solutions for infusion and injection, pastes, ointments, gels, creams, lotions, powders and sprays.

Examples

Example 1

(S)-2-(E-2-(naphthas-2-yl)-ethen-1-yl)-N-(1-(N-(3-morpholino-1-yl-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) complex ethyl ester 2-(2-(E-naphthas-2-yl)-ethen-1-yl)-benzoic acid and 29.7 g (0.13 mol) of 2-vinylnaphthalene, 25 g (0.16 mol) of a compound ethyl ester 2-bromobenzoyl acid, 22.5 ml (0.16 mol) of triethylamine, 0.54 g of palladium diacetate and 1.44 g of triphenylphosphine are heated in 200 ml of acetonitrile for 20 hours at 100oC. thereafter, the mixture was poured on water and extracted several times complex ethyl ester of acetic acid. The organic phase is concentrated under vacuum and the residue is subjected to chromatographic purification on silica gel.

Yield: 34 g (71%).

b) 2-(E-2-(naphthas-2-yl)-ethen-1-yl)-benzoic acid

34 g (112,5 mmol) of the intermediate product of stage a) is dissolved in 200 ml of tetrahydrofuran and admixed 9.5 g (168,7 mmol) of 80% potassium hydroxide dissolved in 150 ml of water. The components are heated for 10 hours under reflux. After that, the reaction mixture is acidified with concentrated hydrochloric acid and EXT under vacuum. The residue is treated with a small amount of ethyl acetate and sucked off.

Output: 23,8 g (78%).

C) (S)-O-(tert. -butyl)-N-(1-(N-(3-morpholino-1-yl-propane-1-yl)-carbarnoyl-3-phenyl-propan-1-ol-2-yl)-carbamate

To 2,95 g (10 mmol) of O-(tert.-butyl)-2-(S)-N-(1-carboxy-2-hydroxy-3-phenylpropane-1-ol-2-yl)-carbamate (see C. L. Harbeson etc., J. Med.Chem. 1994, 37, pp. 2918-29) and 1.4 g (10 mmol) of N-(3-aminopropan-1-yl)research in 50 ml of anhydrous dimethylformamide are served sequentially when -5oWith 1.6 g (10 mmol) in diethyl ether complex cyanophosphonate acid and 1.0 g (10 mmol) of triethylamine. The components are stirred for 1 hour at -5oAnd then 16 hours at room temperature. The mixture is then poured on water and extracted with ethyl acetate. The organic phase is extracted with aqueous solution of citric acid. This aqueous phase is then alkalinized diluted sodium lye and extracted with ethyl acetate. The organic phase is dried and concentrated under vacuum, thus obtain 2.3 g (55%) of product.

g) Amide 3-(S)-3-amino-2-hydroxy-3-phenyl-N-(-3-morpholine-1-yl-propane-1-yl)-butyric acid

2.1 g (5 mmol) of the intermediate product stage) is dissolved in 60 ml of methylene chloride and stirred into 60 ml triperoxonane acid. The components are stirred for 30 minues of methylene chloride and simple ether. Obtain 2.4 g of material.

d) 2-(S)-2-(E-2-(naphthas-2-yl)-ethen-1-yl)-N-(1-(N - (3-morpholino-1-yl-propane-1-yl)-carbarnoyl)-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

To 2.4 g (4 mmol) of the intermediate product stage d) and 1.1 g (4 mmol) of the intermediate product stage b) in 30 ml of anhydrous dimethylformamide at -5oWith successively added 0.65 g (4 mmol) diethyl ether complex cyanophosphonate acid and 0.8 g (8 mmol) of triethylamine. After that the reaction mixture is stirred for 1 hour at -5oAnd another 16 hours at room temperature. Then add 200 ml of water and extracted with diethyl ether complex. The aqueous phase naturalizirujut diluted sodium lye and then extracted with complex ethyl ester of acetic acid. The organic phase is dried and concentrated under vacuum. The residue is recrystallized from complex ethyl ester of acetic acid.

Yield: 0.8 g (35%).

e) 2-(S)-2-(E-2-(naphthas-2-yl)-ethen-1-yl)-N-(1-(N-(3-morpholino-1-yl-propane-1-yl)-carbarnoyl)-1-oxo-3-phenyl-propan-2-yl)-benzamide

To 0,46 g (0.8 mmol) of the intermediate product stage d) and 0.3 g (3.2 mmol) of triethylamine in 8 ml of dimethyl sulfoxide is served at room temperature of 0.38 g (2.4 mmol) of a complex of pyridine and sulfur trioxide dissolved in 4 ml of the first water and then extracted with methylene chloride. The organic phase is dried and concentrated under vacuum. The residue is treated with a simple air, you get a 0.3 g (65%) of product.

1H-NMR (Dl3): = 1,7 (2H), 2,4 (6N), AND 3.2 (1H), AND 3.5 (3H), AND 3.7 (4H), AND 5.8 (1H), AND 6.5 (1H), 7,0-8,0 (N) and 8.8 (1H) million D.

Example 2

(S)-2-(E-2-naphthas-2-yl)-ethen-1-yl)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) 2-(S)-O-(tert. -butyl)-N-(1-carbarnoyl-3-phenyl-propan-1-ol-2-yl)-carbamate

217,7 g (60 mmol) of O-(tert.-butyl)-2-(S)-N-(1-carboxy-2-hydroxy-3-phenyl-propan-1-ol-2-yl)-carbamate (see C. L. Harbeson etc., J. Med.Chem. 1994, 37, pp. 2918-29) is subjected to interaction with ethanolic ammonia under the conditions of stage C) of example 1.

Yield: 13.5 g (76%).

b) Amide 3-(S)-3-amino-2-hydroxy-3-phenylalkanoic acid

13,4 g (to 45.5 mmol) of the intermediate stage (a) is subjected to interaction similar to stage d) of example 1. Obtain 12.3 g (88%) of product.

a) 2-(S)-2-(E-2-(naphthas-2-yl)-ethen-1-yl)-N-(1-carbarnoyl-1-hydroxy-3-phenyl-prop-2-yl)-benzamide

To 1.65 g (6 mmol) of the intermediate stage b) and 0.81 g (6 mmol) of 1-hydroxybenzotriazole in 10 ml of anhydrous dimethylformamide is served when -5oWith consistently 1.26 g (6.6 mmol) of the hydrochloride of N'-(3-dimethyl-aminopropyl)-N-ethylcarbodiimide, 1.85 g (6 1 hour at -5oAnd then another 16 hours at room temperature. In the conclusion to the mixture, water is added and the precipitate is sucked off. The product yield is 1.3 g (48%).

g) (S)-2-(2-(naphthas-2-yl)-ethen-1-yl)-N-(1-carbamoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

0.45 g (1 mmol) of the intermediate stage) oxidizes similar stage f) of example 1.

Yield: 0.28 g (62%).

MS: m/e = 458(M+).

Example 3

2-(S)-2-(E-2-(3,4-acid)-ethen-1-yl)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) Complex ethyl ester 2-(E-2-(3,4-acid)-ethen-1-yl)-benzoic acid

5 g (30,5 mmol) of 3,4-dimethoxysilane subjected to interaction under the conditions of stage 1A with complex ethyl ester bramantino acid in dimethylformamide at 120oC. Obtain 7.2 g (94%) of product.

b) 2-(E-2-(3,4-acid)-ethen-1-yl)-benzoic acid

7 g (22 mmol) of the intermediate product of stage a) omelet under the conditions of stage b) of example 1 4M sodium lye.

Yield: 6.2 g (98%).

a) 2-(S)-2-(2-(3,4-acid)-ethen-1-yl)-N-(1-carbamoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

1.7 g (6 mmol) of the intermediate stage b) of example 2 are similar interaction stage) primers)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

0.45 g (1 mmol) of the intermediate stage) are oxidized under similar conditions as in stage f) of example 1. Obtain 0.28 g (62%) of product.

MS: m/e = 479 (M+).

Example 4

(S)-4-(2-naphthylamide)-methyl-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

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a) 4-(2-naphthylamide)-methyl-benzoic acid

To 10 g (66,2 mmol) 4-aminomethyl-benzoic acid in 150 ml of pyridine is added dropwise at 10o12.6 g (66,2 mmol) of acid chloride of 2-naphthoic acid, dissolved in 150 ml of tetrahydrofuran. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture is concentrated under vacuum and the resulting residue is subjected to chromatographic purification (solvent: a mixture of methylene chloride and methanol in a ratio of 10/1). Thus obtain 11.3 g (56%) of product.

b) 4-(2-naphthylamide)-methyl-N-(-3-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

1.2 g (4 mmol) of the intermediate product of stage a) is subjected to interaction similar to stage b) of example 2 with Amida 3-(S)-3-amino-2-hydroxy-3-phenylalkanoic acid stage b) of example 2 and thus obtain 1.7 g (88%) of product.

C) (S)-4-(2-naphthylamide)-methyl-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

of 0.48 g (1 m is CLASS="ptx2">

1H-NMR (D6-DMSO): = 2,9 (1H), AND 3.2 (1H), AND 4.5 (2H), AND 5.2 (1H), 7,0-8,0 (N), AND 8.2 (1H), AND 8.7 (1H) and 9.1 (2H) million D.

Example 5

(S)-2-phenyl-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) 2-phenyl-N-(-3-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

0.8 g (4 mmol) biphenyl-2-carboxylic acid and 1.2 g (4 mmol) of the intermediate stage b) of example 2 is subjected to interaction under the conditions of stage C) of example 2. Yield 1.2 g (80%).

b) (S)-2-phenyl-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

0.75 g (2 mmol) of the intermediate stage (a) is subjected to oxidation similar to stage f) of example 1. The product yield is 0.35 g (47%).

1H-NMR (D6-DMSO): = 2,8 (1H), AND 3.1 (1H), AND 5.2 (1H), 7,0-7,5 (14N), AND 7.9 (1H), AND 8.1 (1H), 8.9 (1H) million D.

Example 6

(S)-2-(naphthas-2-yl-methyl)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
(a) 4,4-dimethyl-2-(2-(naphthas-2-yl-hydroxymethyl)-phenyl)-2-oxazole

To 25 g (0.14 mol) of 4,4-dimethyl-2-phenyl-2-oxazoline and 0.1 g of triphenyl methane in 400 ml of anhydrous tetrahydrofuran is slowly added dropwise at -78oTo add 104 ml of a 1.6 M solution of utility. The resulting mixture was stirred for 1 hour. After this mixture is allowed to warm to -30oand probese 1 hour at a temperature of -20 to -30oC. After the reaction mixture is allowed to warm to room temperature and the solvent is removed under vacuum. The remainder are served in ice water, then extracted with simple ether. The organic phase is dried and concentrated under vacuum. The residue is chromatographically purified (solvent: a mixture of n-heptane acetone in the ratio 40/3). The output is 25.3 g (54%).

b) 3-naphthas-2-yl-phtalic

22 g (66 mmol) of the intermediate product of stage a) is refluxed in a mixture of 250 ml of ethanol and 100 ml of 1M hydrochloric acid for 2 hours. Then the ethanol is removed under vacuum and the precipitate is sucked off. The product yield 16.4 g (95%).

a) 2-naphthas-2-yl-benzoic acid

16 g (61,5 mmol) of the intermediate from step b) was dissolved in a mixture of 100 ml of tetrahydrofuran and 250 ml of ethanol and after the addition of 5 g of palladium on barium sulphate hydronaut. Then the mixture is filtered and the filtrate concentrated under vacuum. The residue is recrystallized in toluene and get to 13.6 g (85%) of product.

g) 2-(naphthas-2-yl)-methyl-N-(-3-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

of 1.05 g (4 mmol) of the intermediate product stage) is subjected to interaction similar to stage b) of example 2 with promezhutochni-3-phenyl-propan-2-yl)-benzamide

0.88 g (2 mmol) of the intermediate product stage g) is subjected to oxidation similar to stage f) of example 1, and obtain 0.52 g (60%) of product.

1H-NMR (D6-DMSO): = 2,8 (1H), AND 3.2 (1H), 4,1 (2N), WITH 5.3 (1H), 7,1-8,0 (17H) AND 8.1 (1H), 8.9 (1H) million D.

Example 7

(S)-3-(2-naphthyl)-sulphonamido-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) Complex ethyl ester 3-(2-naphthylamide)-benzoic acid

To 25 g (0.15 mol) of a compound ethyl ester of 3-aminobenzoic acid and 63 ml (0.45 mol) of triethylamine in 400 ml of tetrahydrofuran is added dropwise at 0oWith 34.3 g (0.15 mol) of acid chloride of 2-naphthalenesulfonate dissolved in 250 ml of tetrahydrofuran. The resulting mixture is heated for 1 hour under reflux. The organic phase is removed under vacuum and the residue distributed between ethyl acetate and water. The ethyl acetate phase is dried and concentrated under vacuum. The yield is 55 g (100%).

b) 3-(2-naphthylamide)-benzoic acid

55 grams (0.15 mol) of the intermediate stage (a) is dissolved in 400 ml of tetrahydrofuran and stirred into 400 ml of 4M sodium lye. The resulting mixture was stirred for 1.5 hours at 60oC. the Organic solvent is removed under vacuum. the ones washed with water, dried and concentrated under vacuum. The residue is treated more with methylene chloride. Then get 37,3 g (75%) of product.

C) 3-(2-naphthyl)-sulphonamido-N(-3(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

0.55 g (1,68 mmol) of the intermediate stage (b) is subjected to interaction similar to stage b) of example 2 from the compound obtained in stage b) of example 2. The yield amounts to 0.72 g (86%).

g) (S)-3-(2-naphthyl)-sulphonamido-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

0.7 g (1.4 mmol) of the intermediate stage) oxidizes similar stage f) of example 1. The product yield 0.68 g (98%).

1H-NMR (D6-DMSO): = 2,9 (1H), AND 3.1 (1H), AND 5.2 (1H), 7,0-8,1 (17H), AND 8.2 (1H), AND 8.8 (1H) and 10.5 (1H) million D.

Example 8

(S)-3-(2-naphthyl)-sulphonamido-N-1-N-(3-(imidazol-1-yl-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) Complex ethyl ester 3-(S)-3-amino-2-hydroxy-4-phenylalkanoic acid

28 g (0.12 mol) of 3-(S)-3-amino-2-hydroxy-4-phenylalkanoic acid (see S. L. Harbeson etc., J. Med.Chem. 1994, 37, pp. 2918-29) is refluxed for 3 hours in 500 ml of 1M ethanol solution of hydrogen chloride. After that, the reaction mixture is concentrated under vacuum and Nata sodium. It releases oil. This oil is treated with ethyl acetate, dried and concentrated under vacuum.

Output: 18,

b) 3-(naphthas-2-yl)-sulfonamide-N-(2-(S)-1-etoxycarbonyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

16.5 g (of 50.4 mmol) of the intermediate product of stage b) of example 7 and 11.2 g (of 50.4 mmol) of the compound obtained in stage a), is subjected to reactions similar to stage b) of example 2. Gain of 7.8 g (30%) of product.

C) 3-(2-naphthyl)-sulphonamido-N-(2-(S)-1-carboxy-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

7,8 g (14.6 mmol) of the intermediate obtained in stage b), dissolved in 150 ml of tetrahydrofuran and mixed with 1.1 g (44 mmol) of lithium hydroxide dissolved in 20 ml of water. The reaction mixture is stirred for 1 hour at room temperature. The organic solvent is removed under vacuum and the aqueous phase is poorly oxidized by 1M hydrochloric acid. The precipitate is sucked off. The product yield is 7.2 g (98%).

g) 3-(naphthas-2-yl)-sulfonamide-N-(2-(S)-1-N-(3-(imidazol-1-yl-propane-1-yl)-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

1 g (2 mmol) of the intermediate obtained in stage C), is subjected to interaction similar to stage b) of example 2 with 3-aminopropan-1-yl-1-imidazole is l-1-oxo-3-phenylpropane-2-yl)-benzamide

0.6 g (0.98 mmol) of the intermediate stage g) oxidized analogously to stage f) of example 1, and the gain of 0.55 g (92%) of product.

Example 9

(S)-N-(1-N-(N-benzyl-piperidine-4-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-3-(naphthas-2-yl-)sulphonamido)-benzamide

< / BR>
a) N-(2-(S)-1-N-(N-benzyl-piperidine-4-yl)-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-3-(naphthas-2-yl)sulfonamide-benzamide

1 g (2 mmol) of the intermediate obtained in stage C) of example 8, 4-amino-N-benzylpiperidine subjected to reactions similar to stage b) of example 2, you get to 0.67 g (50%) of the product.

b) (S)-N-(1-N-(N-benzyl-piperidine-4-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-3-(naphthas-2-yl)-sulphonamido)-benzamide

0.65 g (1 mmol) of the intermediate stage (a) is subjected to oxidation similar to stage f) of example 1 and gain of 0.59 g (91%) of product.

Example 10

(S)-2-(E-2-(3,4-acid)-ethen-1-yl)-N-(1-N-(3-morpholino-1-yl-propane-1-yl)-carbarnoyl)-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) 2-(E-2-(3,4-acid)-ethen-1-yl)-N-(2-(S)-1-N-(3-morpholino-1-yl-propane-1-yl)-carbarnoyl)-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

1.7 g (6 mmol) of the intermediate obtained in stage b) of example 3 is subjected to interact similarly with

b) (S)-2-(E-2-(3,4-acid)-ethen-1-yl)-N-(1-N-(3-morpholino-1-yl-propane-1-yl)-carbarnoyl)-1-oxo-3-phenyl-propan-2-yl)-benzamide

0.6 g (1 mmol) of the intermediate compounds are oxidized analogously to stage f) of example 1 and obtain 0.12 g (20%) of the product.

1H-NMR (Dl3): = 1,8 (2H), 2,4-2,7 (6N), AND 3.1 (1H), 3,5 (2H), 3,6-3,8 (5H), 3,9 (6N), 5,7 (1H), AND 6.3 (1H), 6,8-7,9 (14N) and 8.5 (1H) million D.

Example 11

(S)-3-(naphtha-2-yl)-sulphonamido)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
(a) Amide 8-chinolin-N-(3-etoxycarbonyl)-sulfonic

5 g (30.3 mmol) of a compound ethyl ester of 3-aminobenzoic acid is subjected to interaction at a similar stage a) of example 7 conditions with the acid chloride 8-hinolincarbonova at 0oWith, and obtain 5.9 g (76%) of product.

b) Amide N-(3-carboxy)-8-chinolin-sulfonic acid

5.9 g of the intermediate compound obtained in stage a), amyraut similar to stage b) of example 1 and gain of 5.1 g (95%).

C) 3-(naphthas-2-yl)sulfonamide)-N-(-3-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

1 g (3 mmol) of the intermediate stage b) of example 2 is subjected to interaction with 0.95 g (3 mmol) of the compound obtained in stage b), similar to stage b) of example 2, you get a 1.3 gg (2.4 mmol) of the intermediate compound, obtained in stage C), oxidized analogously to stage f) of example 1. Yield 0.8 g (70%).

1H-NMR (D6-DMSO): = 2,9 (1H), AND 3.1 (1H), AND 5.2 (1H), 7,0-8,8 (17), 8,1 (1H) and 10.2 (1H) million D.

Example 12

(S)-4-(2-bromophenylacetate)-methyl-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

< / BR>
a) O-(tert.-butyl)-N-(4-etoxycarbonyl-benzyl)-carbamate

7 g (to 34.7 mmol) of a compound ethyl ester 4-aminometilbensana acid and 9.6 ml (39,4 mmol) of triethylamine are dissolved in 150 ml of a mixture of tetrahydrofuran and dimethylformamide in a ratio of 2:1 and when 0oWith mixed dropwise with a solution of 8 g (to 36.5 mmol) of anhydride tert.-butoxycarbonyl in 100 ml of tetrahydrofuran. The reaction mixture is stirred 16 hours at room temperature. After that, the mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic phase is dried and concentrated under vacuum, thus obtain 8.5 g (93%) of product.

b) O-(tert.-butyl)-N-(4-carboxybenzoyl)-carbamate

8,3 g (31,3 mmol) of the intermediate obtained in stage a), is subjected to hydrolysis similar to stage b) of example 8, you get to 7.3 g (93%) of product.

b) 4-(tert. -butylacetamide)-methyl-N-(-3-(S)-1-carbarnoyl-1-hydroxy-3-Fe is stage C) of example 2, connection stage b) of example 2. The yield of product amounted to 9.2 g (77%).

g) 4-aminomethyl-N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

9.0 g (21 mmol) of the intermediate stage) split similar to stage d) of example 1 using triperoxonane acid. Yield: 10.8 g (100%).

d) 4-(brompheniramine)-methyl-N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-benzamide

1.5 g (3.4 mmol) of the intermediate obtained in stage d), is subjected to the interaction similarly to stage a) of example 7 with the acid chloride of bromobenzonitrile at 0oWith get 1.2 g (69%) of product.

(e) (S)-4-(2-bromophenylacetate)-methyl-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

1,05 g (1.9 mmol) of the intermediate stage d) oxidized analogously to stage f) of example 1. The product yield is 0.78 g (75%).

1H-NMR (D6-DMSO): = 2,9 (1H), AND 3.2 (1H), 4.2V (2N), WITH 5.3 (1H), 7,0-8,0 (15 NM), AND 8.4 (1H) and 8.8 (1H) million D.

Example 13

(S)-N-(1-N-(3-morpholine-1-yl-3-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-2-(naphthas-2-yl-methyl)-benzamide

< / BR>
a) O-(tert. -butyl)-N-(2-(S)-1-(N-3-morpholine-1-yl-propane-1-yl)-carbarnoyl-2-hydroxy-3-phenyl-propan-2-yl)carbamate

19.2 g (65 mmol) of O-(tert.-butyl)indicate the interaction similar to stage b) of example 2 with 1-(amino-propan-1-yl)morpholine, and get 23,5 g (85%) of product.

b) Amide 3-(S)-3-amino-2-hydroxy-N-(3-morpholine-1-yl-propane-1-yl)-4-phenyl-butyric acid

23.3 g (55.3 mmol) of the intermediate obtained in stage 13A, split analogous stage f) of example 1 using triperoxonane acid. Thus obtain 28 g of a crude product, which without treatment served to the next stage.

C) N-(2-(S)-1-N-(3-morpholine-1-yl-propane-1-yl)-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-2-(naphthas-2-yl-methyl)-benzamide

of 1.57 g (6 mmol) of the intermediate stage b) of example 6 is subjected to interaction similar to stage b) of example 2 from the compound obtained in stage b). The product yield is 1.1 g (32%).

g) (S)-N-(1-N-(3-morpholine-1-yl-3-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-2-(naphthas-2-ylmethyl)-benzamide

0,57 g (1 mmol) of the intermediate stage) oxidizes similar to stage b) of example 2.

Yield: 0.14 g (25%).

1H-NMR (D6-DMSO): = 1,6 (2H), 2,2 (6N), 2,9 (1H), AND 3.2 (3H), 3,5 (4H), 4,1 (2N), WITH 5.3 (1H), 7,0-7,9 (N) and 8.9 (1H) million D.

Example 14

(S)-N-(1-N-(3-morpholine-1-yl-3-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(naphthas-2-ylamino)-methyl-benzamide

< / BR>
a) N-(2-(S)-1-N-(3-morpholine-1-yl-3-propane-1-yl)-carbarnoyl-1-hydroxy-3 is RA 4 is subjected to reactions similar to stage b) of example 2 with the connection, obtained in stage b) of example 13, with gain of 1.9 g of product.

b) (S)-(1-N-(3-morpholine-1-yl-3-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(naphthas-2-ylamino)-methyl-benzamide

1.2 g (2 mmol) of the intermediate stage (a) oxidized analogously to stage f) of example 1. The output is 0.83 g (73%).

1H-NMR (D6-DMSO): = 1,6 (2H), 2,2 (6N), AND 3.0 (1H), 3-3,2 (3H), 3,5 (4H), AND 4.6 (2H), AND 5.2 (1H), 6,9-8,0 (N), AND 8.4 (1H), AND 8.8 (1H) and 9.0 (1H) million D.

Example 15

(S)-N-(1-N-(3-morpholine-1-yl-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-2-phenyl-benzamide

< / BR>
a) N-(2-(S)-1-N-(3-morpholine-1-yl-(propane-1-yl)-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-2-phenyl-benzamide

2 g (10 mmol) biphenyl-2-carboxylic acid is subjected to interaction similar to stage b) of example 2 with the intermediate compound obtained in stage b) of example 13, you get a 1.8 g of product.

b) (S)-N-(1-N-(3-morpholine-1-yl-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-2-phenyl-benzamide

1.0 g (2 mmol) of the intermediate stage (a) oxidized analogously to stage f) of example 1. The product yield was 0.45 g (45%).

1H-NMR (D6-DMSO): = 1,7 (2H), 2,2 (6N), 2,8 (1H), AND 3.2 (3H), AND 3.6 (4H), AND 5.2 (1H), 7,0-7,8 (14N) and 8.9 (2H) million D.

Example 16

(S)-2-methyl-N-(1-N(3-morpho ethyl ester of 5-amino-2-methylbenzoic acid

of 26.5 g (127 mmol) of a compound ethyl ester of 2-methyl-5-nitrobenzoic acid hydronaut in ethanol after the addition of 1 g of 10% palladium on coal. After filtration, the filtrate concentrated under vacuum. The output is 0.1 g (89%).

b) Complex ethyl ester of 2-methyl-5-(naphthas-2-ylsulphonyl)-benzoic acid

of 12.6 g (70,4 mmol) of the intermediate stage (a) is subjected to interaction similarly to stage a) of example 7 with the acid chloride naphthalene-2-sulfonic acids at 0oC. you get to 20.1 g of the product.

C) 2-methyl-5-(naphthas-2-ylsulphonyl)-benzoic acid

20 g (54 mmol) of the intermediate stage (b) is subjected to hydrolysis similar to stage b) of example 8, you get to 15.8 g of the product.

g) 2-methyl-N-(2-(S)-1-N-(3-morpholine-1-yl-propane-1-yl)-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-5-(naphthas-2-ylsulphonyl)-benzamide

3.4 g (10 mmol) of the intermediate stage) is subjected to interaction similar to stage b) of example 2 from the compound obtained in stage b) of example 13. The product yield is 3.8,

d) (S)-2-methyl-N-(1-N(3-morpholine-1-yl-propane-1-yl)-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-5-(naphthas-2-ylsulphonyl)-benzamide

0,92 g (1.5 mmol) of the intermediate ocil is 6 (2H), 2,0 (3H), 2,3 (3H), 2,8 (1H), AND 3.2 (2H), A 3.2 TO 3.5 (3H), AND 3.6 (4H), AND 5.2 (1H), 6,9-8,1 (14N), AND 8.3 (1H), AND 8.7 (1H), 8,9 (1H) and 10.4 (1H) million D.

Example 17

(S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-2-methyl-5-(naphthas-2-ylsulphonyl)-benzamide

< / BR>
a) N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-2-methyl-5-(naphthas-2-alsultan-amido)-benzamide

2.7 g (8 mmol) of the intermediate stage b) of example 16 is subjected to interaction similar to stage b) of example 2 with the connection stage b) of example 2. Yield 1.5 g (46%).

b) (S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-2-methyl-5-(naphthas-2-yl-sulfonamide)-benzamide

1.0 g (2 mmol) of the intermediate stage (a) oxidized analogously to stage f) of example 1. The output is 0.65 g (65%).

1H-NMR (D6-DMSO: = 2,0 (3H), 2,8 (1H), AND 3.2 (1H), AND 5.2 (1H), 6,8-8,0 (15 NM), AND 8.2 (2H), AND 8.6 (1H) and 10.2 (1H) million D.

Example 18

(S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4(cinoxacin-2-yl-amido)-methyl-benzamide

< / BR>
a) N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-4-(cinoxacin-2-yl-amido)-methyl-benzamide

1.2 g (2.7 mmol) of the intermediate from step d) of example 12 is subjected to interaction similarly to stage a) of example 7 with the acid chloride cinoxacin-2-carboxylic acid, thus obtain 0.8 g (62%) is g (1.6 mmol) of the intermediate from step a) oxidized analogously to stage f) of example 1. Get 0,42 g (55%).

MS: m/e = 481 (M+).

Example 19

(S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(quinoline-4-yl-amido)-methyl-benzamide

< / BR>
a) N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)4-(quinoline-4-yl-amido)-methyl-benzamide

0.8 g (1.8 mmol) of the intermediate from step d) of example 12 is subjected to reactions similar to stage b) of example 2 with the quinoline-4-carboxylic acid, thus obtain 0.4 g (46%) of product.

b) (S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(quinoline-4-yl-amido)-methyl-benzamide

0.39 g (0.8 mmol) of the intermediate from step a) oxidized analogously to stage f) of example 1. The product yield is 0.27 g (70%).

1H-NMR (D6-DMSO): = 2,9 (1H), AND 3.1 (1H), 4,4 (2H), AND 5.2 (1H), 7,0-8,0 (15 NM), AND 8.8 (1H), 8,9 (1H) and 9.3 (2N) million D.

Example 20

(S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(cinoxacin-6-yl-amido)-methyl-benzamide

< / BR>
a) N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-4-(cinoxacin-6-yl-amido)-methyl-benzamide

0.8 g (1.8 mmol) of the intermediate from step d) of example 12 is subjected to interaction similar to stage b) of example 2 with cinoxacin-6-carboxylic acid, thus obtain 0.36 g (42%) of product.

b) (S)-N-(1-carbarnoyl-1-oxo-3-phenyl-disappear to Aut similar stage f) of example 1. The product yield is 0.23 g (66%).

1H-NMR (D6-DMSO): = 2,8 (1H), AND 3.2 (1H), AND 4.6 (2H), AND 5.2 (1H), A 7.0 TO 8.2 (10H), AND 8.7 (1H), AND 8.8 (1H), AND 9.0 (2H) and 9.4 (2H) million D.

Example 21

(S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(quinoline-6-yl-amido)-methyl-benzamide

< / BR>
a) N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-4-(quinoline-6-yl-amido)-methyl-benzamide

0.8 g (1.8 mmol) of the intermediate from step d) of example 12 is subjected to interaction similar to stage b) of example 2 with the quinoline-6-carboxylic acid, thus receive 0,41 g (47%) of product.

b) (S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(quinoline-6-yl-amido)-methyl-benzamide

0.4 g (0.83 mmol) of the intermediate from step a) oxidized analogously to stage f) of example 1. The product yield is about 0.34 g (85%).

1H-NMR (D6-DMSO): = 2,9 (1H), AND 3.1 (1H), 4,4 (2H), AND 5.2 (1H) and 7.0 to 9.2 (N) million D.

Example 22

(S)-N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-4-(quinoline-3-yl-amido)-methyl-benzamide

< / BR>
a) N-(2-(S)-1-carbarnoyl-1-hydroxy-3-phenyl-propan-2-yl)-4-(cinoxacin-3-yl-amido)-methyl-benzamide

1.0 g (2.3 mmol) of the intermediate from step d) of example 12 is subjected to interaction similar to stage b) of example 2 with cinoxacin-3-carboxylic acid, Atil-benzamide

0.84 g (1.7 mmol) of the intermediate from step a) oxidized analogously to stage f) of example 1.

Yield: 0.75 g (90%).

MS: m/e = 480 (M+).

Example 23

N-1-etoxycarbonyl-1-oxo-3-phenyl-propan-2-yl)-4-(naphthas-2-yl-amido)-benzamide

< / BR>
a) 3-(naphthas-2-yl-amido) benzoic acid

14.8 g (0.11 mol) of 3-aminobenzoic acid are dissolved in 300 ml of pyridine and portions mixed with 20.6 g (0.11 mol) of 2-nafolklore. The mixture is stirred for 16 hours at room temperature. After that, the mixture is concentrated under vacuum and the residue is recrystallized from ethanol. The yield amounts to 30.3 g (97%).

b) N-(1-etoxycarbonyl-3-phenyl-propan-2-yl)-4-(naphthas-2-yl-amido)-benzamide

18.0 g (61,8 mmol) of the intermediate from step a) and 14.2 g (61,8 mmol) of a compound ethyl ester of D,L-aminopropionic acid is subjected to interaction similar to stage b) of example 2. Get to 19.8 g (71%) of product.

C) N-(1-carboxy-3-phenyl-propan-2-yl)-4-(naphthas-2-yl-amido)-benzamide

19.5 g (41,8 mmol) of the intermediate from step b) hydrolyzing similar to stage b) of example 8.

Yield: 15.2 g (83%).

g) N-(1-etoxycarbonyl-1-oxo-3-phenyl-propan-2-yl)-4-(naphthas-2-yl-amido)-benzamide

To RA mmol) of pyridine in 100 ml of anhydrous tetrahydrofuran are added dropwise and 7.1 ml (63,9 mmol) of the acid chloride complex monoether oxalic acid, so the temperature rises approx. 40oC. then the mixture is refluxed for 3 hours, then stirred for further 16 hours at room temperature. Then carefully add 100 ml of water and again stirred for 30 minutes. The reaction mixture is mixed with large quantities of water and extracted with ethyl acetate. The organic phase is dried and concentrated under vacuum, thus obtain 17 g of oil. This oil is dissolved in 100 ml of absolute ethanol and added 0.24 g of tert.-butanolate potassium. Again the mixture is stirred for 18 hours at room temperature. The reaction mixture is concentrated under vacuum and the residue is subjected to chromatographic purification (solvent: a mixture of methylene chloride and ethyl acetate in a ratio of 10/1). Yield 7.5 g (54%).

1H-NMR (Dl3): = 1,3 (3H), AND 3.2 (1H), AND 3.3 (1H) AND 4.2 (2H), 5,6 (1H) and 6.9-8,4 (N) million D.

Example 24

(S)-N-(1-etoxycarbonyl-1-oxo-3-phenyl-propan-2-yl)-2-phenyl-benzamide

< / BR>
a) N-(3-(S)-1-etoxycarbonyl-1-hydroxy-3-phenyl-propan-2-yl)-2-phenyl-benzamide

Biphenyl-2-carboxylic acid is subjected to interaction similar to stage b) of example 2 with complex methyl ether 3-(S)-3-amino-2-hydroxy-4-phenylalkanoic acid.

MS: m/e = 387 (M+).

Example 25

(S)-N-(N-carboxymethyl-1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-3-(2-naphthylamide)-benzamide

< / BR>
a) O-tert.-butyl-N-(3-(S)-1-etoxycarbonyl-2-hydroxy-4-phenylpropane-2-yl)-urethane

2.3 g (7.7 mmol) of O-tert.-butyl-N-(3-(S)-1-carboxy-2-hydroxy-4-phenylpropane-2-yl)-urethane and 1.1 g (7.7 mmol) of the hydrochloride complex glycinamido ether is subjected to interaction similar to stage b) of example 2. Thus obtain 1.7 g (57%) of product.

b) Amide 3-(S)-3-amino-N-(ethoxycarbonylmethyl)-2-hydroxy-4-phenylalkanoic acid x triperoxonane acid

1.4 g (3.7 mmol) of the intermediate from step 25A dissolved in 25 ml of methylene chloride and, after adding 10 ml triperoxonane acid is stirred for 2 hours at room temperature. After that, the mixture is concentrated under vacuum, to obtain 1.5 g (100%) of product.

C) (S)-N-(1-(N-ethoxycarbonylmethyl-carbarnoyl)-1-hydroxy-3-phenyl-propan-2-yl)-3-(2-naphthyl-sulphonamido)-benzamide

The intermediate compound from stage b) of example 7 is subjected to interaction similar to stage b) of example 2 with the product of stage b). The output is 1.3,

g) (S)-N-(1-(N-carboxymethyl-carbarnoyl)-1-hydroxy-3-phenyl-propan-2-yl)-3-(2-afterscho stage C) of example 8 with lithium hydroxide. The product yield is 0.77 g (67%).

d) (S)-N-(1-(N-carboxymethyl-carbarnoyl)-1-oxo-3-phenyl-propan-2-yl)-3-(2-naphthylamide)-benzamide

0.7 g (1.2 mmol) of the intermediate from step g) is oxidized analogously to stage f) of example 1, and the gain of 0.16 g (23%) of product.

MS: m/e = 559 (M+).

Example 26

N-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-3-(2-naphthylamide)-benzamide

< / BR>
a) the Intermediate compound from stage b) of example 7 is subjected to interaction similar to stage b) of example 2 with complex ethyl ester, 3-amino-2-hydroxy-4-phenylalkanoic acid.

b) N-(N-carboxymethyl-1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-3-(2-naphthylamide)-benzamide

The intermediate compound from step (a) oxidized analogously to stage f) of example 1. You get a target product.

1H-NMR (D6-DMSO): = 2,5 (2N), AND 5.2 (1H), AND 7.1 TO 8.1 (17H), AND 8.4 (2H), AND 8.8 (1H) and 10.5 (1H) million D.

Similarly receive the following connections.

Example 27

2-(E-2-pyrid-2-yl-ethen-1-yl)-N - (1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)benzamide

MS: m/e = 399(M+).

Example 28

2-(E-2-nicotinoyl-ethen-1-yl)-N - (1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)benzamide

MS: m/e = 428(M+).

Example 30

3-(2-benzothiazyl)amido-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

MS: m/e = 472(M+).

Example 31

2-(E-2-isonicotinoyl-ethen-1-yl)-N - (1-carbarnoyl-1-oxo-3-phenyl-propane-yl)benzamide

1H-NMR (D6-DMSO): = to 3.0-3.2 (2H), with 5.3 (1H), 7,2 (1H), 7,8 AND 8.1 (14N), 8,9 (2N) and 9.0 (1H) million D.

Example 32

4-((5-trifluoromethyl-quinoline-4-yl)mercaptomethyl)-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

MS: m/e = 538(M+).

Example 33

4-(quinoline-2-yl-mercaptomethyl)-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)benzamide

1H-NMR(D6-DMSO): = 2,9-3,2 (4H), 4,0 (1H), 4,7 (2N), WITH 5.3 (1H), of 7.1-8.2 (14H) and 8.9 (1H) million D.

Example 34

4-(quinoline-2-ylmethyl)hydroxy-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

1H-NMR (D6-DMSO): = is 2.8-3.2 (4H), 4,0 (1H), AND 4.5 (2H), WITH 5.3 (1H), 7,2-8,2 (14N) and 8.8 (1H) million D.

Example 35

3-quinoline-3-yl-amido-6-methyl-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)benzamide

1H-NMR (D6-DMSO): = 2,1 (3H), AND 2.8 (2H), 4,5 (1H), 5,4 (1H), 7,1-7,3 (5H), 7,7-8,2 (6N), 8,9 (1H), AND 9.1 (1H), AND 9.4 (1H) and 10.8 (1H) million D.

Example 36

3-quinoline-5-yl-amido-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzo-tetrahydroisoquinoline-2-yl)methyl-N - (1-carbarnoyl-1-oxo-3-phenylpropane-2-yl)-benzamide

1H-NMR (D6-SO): = 2,5-3,1 (4H), 3,5-4,0 (4H), 5,1 (1H), 6,9-7,7 (15 NM), AND 7.8 (1H), AND 8.0 (1H) and 10.1 (1H) million D.

Example 38

3 pyrid-yl-N(1-carbarnoyl-1-oxo-3-phenyl-propane-yl)-Besame

MS: m/e=374(M+).

Example 39

3-naphthas-ylsulphonyl-(carbamoyl-oxo-3-phenyl-propan-2-yl)-benzamide

MS: m/e=468 (M+).

Example 40

3-(isoquinoline-5-yl)sulfonamide-(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)benzamide

1H-NMR(D6-DMSO): ' = 2,9-3,1 (2N), AND 5.5 (1H), 7,0-7,5 (5H), 7,8 AND 8.1 (10H) and 8.8 and 9.0 (4H) m d

Example 41

3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)sulfonamide-N(1-carbarnoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

MS: m/e=521 (M+).

1. Ketoenamine formula I

< / BR>
where R1means phenyl, naphthyl, hinely, pyridyl, chinadoll, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, and aromatic and heteroaromatic ring can be substituted one, two or three radicals R5with the following value;

R2means hydrogen, C1-C6-alkyl;

R3means1-C6-alkyl, which may carry phenyl ring;

X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)m-CONH-(CH2)0-, -(CH2)m-NHSO2-(CH2)0-, -(CH2)m-SO2NH-(CH2)0-;

R4means group OR6, NR7R8;

R5means hydrogen, C1-C4-alkyl, -O-C1-C4-alkyl, Cl, Br, J;

R6means hydrogen or C1-C6-alkyl;

R7means hydrogen;

R8means hydrogen or C1-C6-alkyl, which may carry one or two radicals R9or may be substituted by one of the groups

< / BR>
< / BR>
or

< / BR>
R9means hydrogen, COOH;

R10means hydrogen or C1-C6-alkyl which can be substituted phenyl ring or may be substituted by one or two radicals R9;

n is the number 0, 1 or 2;

m is the number 0, 1, 2, 3 or 4; and

o is the number 0, 1, 2, 3, or 4

and their tautomeric and isomeric forms or their physiologically acceptable salts.

2. Ketoenamine formula I under item 1, in which R2means hydrogen, C1-C4-alkyl; R3means-CH2-phenyl, n-butanol or n-pentanol; R4means-NR7R8; and R1, X and n are listed in paragraph 1.

3. Ketoenamine Faure is

 

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< / BR>
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< / BR>
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< / BR>
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