Connection 2-aminocarbonyl acid, substituted 5 - arylisoxazoles-4-yl, and pharmaceutical composition based on them

 

(57) Abstract:

Describes new compounds 2-aminocarbonyl acid, substituted 5-arylisoxazoles-4-yl having the General formula I where a is a bond or a spatial group1-6alkylen, represents a-CH(NH2)-COOH or a group of formula II; E represents O, COO, O(CH2)n-COO (where n is an integer from 1 to 6) or 5-tetrazolyl; D represents O; R1represents phenyl, naphthyl, thienyl, benzothiazyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, chinoline or furyl, or phenyl, thienyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl or furyl substituted by one or two substituents selected from the group consisting of halogen, C1-6alkyl or trifluoromethyl, provided that when a represents a methylene, - group,-CH(NH2)-COOH, E represents O; D represents O, and R1is phenyl or phenyl substituted by halogen, the compound is in the form of a pure enantiomer; or a pharmaceutically acceptable salt of these compounds. New connections are strong ligands of EAA receptors. 3 S. and 7 C.p. f-crystals, 2 tab.

The invention relates to new classes is in amino acids (EAA), useful in the treatment of cerebral ischemia, Huntington's disease, seizure disorders, Parkinson's disease, Alzheimer's disease, schizophrenia, pain, depression and anxiety.

Background of the present invention

Currently, as a result of intensified study of the excitation mechanism of the Central nervous system (CNS) during the last three decades came to a common opinion that (S)-glutamate (Glu) is the major EAA neurotransmitter in the Central nervous system (Lodge D. Excitatory Amino Acids in Health and Disease. J. Wiley & Sons: Chichester, 1988; Wheal H., Thompson A. - Excitory Amino Acids and Synaptic Transmission. Academic Press: London, 1991; Meldrum B. S. Excitatory Amino Acid Antagonists. Blackwell Sci. Pubi.: Oxford, 1991; Krogs-gaard-Larsen P. , Hansen J. J. Excitory Amino Acid Receptors: Design of Agonist and Antagonist. E. Horwood: Chichester, 1992). Glu-managed neurotransmission is a large number of receptors, classified in at least 5 heterogeneous families and called NMDA, AMPA, kainic acid, and metabotropic 1-AR-4 classes of receptors (Monaghan, D. T., et al. Ann. Rev. Pharmacol. Toxicol. 1989, 29, 365-402; Watkins J. C., Krogsgaard-Larsen P. , Honore T. Trends Pharmacol. Sci. 1990, II. 25-33; Simon P. P., Excitatory Amino Acids. Thieme Med. Publ.: New York, 1992).

There is very convincing evidence to support the view that excessive excitation, portable EAA receptors ("current of the blow, the head injuries, asphyxia, subarachnoid hemorrhage, cardiac arrest and other emergencies. (Lodge D., 1988, the same reference; Meldrum B. S., 1991, the same reference). In animal models it was shown that these violations caused by different ischemic conditions can be weakened by the introduction of Glu-antagonists. So, although the relative importance of these different classes of EAA receptors in the phenomenon sustain ischemic stroke is unclear, in General consensus that in such circumstances receptor antagonists EAA are powerful therapeutic tools.

The accumulation of evidence from different directions neurochemical and pharmacological studies, suggests that violation of the mechanisms of EAA receptors, including, possibly, toxicity of excitation plays a role in Huntington's disease (Young, A. C., et al., Science, 1988, 241, 981-983), epileptic disorders (Krogsgaard-Larsen P, Hansen J. J. , 1992, ibid), Parkinson's disease (Klockgether T. Turski L. Trends Neurosci. 1989, 12, 285-286) and Alzheimer's disease (Greenamyre J. T., Maragos, W. F. Cerebrovasc. brain. Metab. Rev., 1993, 5, 61-94; Francis P. T. et al. J. Neurochem. 1993, 60, 1589-1604).

Further, the Central EAA receptors may be involved in synaptic mechanism underlying sysopen the(Eds. Krogsgaard-Larsen P., Hansen J. J. E. Hornwood: Chichester 1992, pp. 352-375) and depression (Trullas R., Skolnick P. Eur. J. Pharmacol. 1990, 185, 1-10; Trullas et al. Eur. J. Pharmacol. 1991, 203, 379-385). So, reduced function of EAA receptors (underactive EAA), as it turns out, plays a role, for example, in schizophrenia (Deutsch S. I, et al., Clin. Neuropharmacol. 1989, 12, 1-3) and some clinical symptoms found in Alzheimer's disease (Greenamyre J. T. ei al. Prog. Neuro-Psychopharniacol. & Biol. Psychit. 1988, 12, 421-430). It is possible that the toxicity excitation", as well as underactive EAA included in a complex mechanism that is associated with Alzheimer's disease (Greenamyre J. T.; 1988, ibid.; Greenamyre J. T., Maragos, W. F., 1993, ibid.).

It is therefore considered that the ligands of EAA receptors are useful for the treatment of cerebral ischemia, Huntington's disease, seizure disorders, Parkinson's disease, Alzheimer's disease, anxiety, schizophrenia, depression and pain.

Most experienced thus agonists of EAA receptors to a greater or lesser extent demonstrate expressed neurotoxicity in the simulated systems, and therefore, the clinical use of these compounds may be limited (Carlsson M, Carlsson, Trends. Neurosci., 1990, 13, 272-276; Willetts J., Balster R. L., Leander J. D., Trends Pharmacol. Sci., 1990, II, 423-428).

On the other hand, partial agonists EAA, Dios interest (Greenamyre J. t., 1988, ibid.; Christensen 1.T., et al.. Drug Des. Del. 1989, 5, 57-71; Francis P. T., et al., J. Neurochem. 1993, 60, 1589-1604). Partial agonists due to its profile of EAA antagonists can demonstrate therapeutically useful neurotoxic, and in some cases are sufficiently agonistic to prevent total blockade of neurotransmission transmitted a special EAA receptors.

It was found that ATRA representing 5-tert - botilony similar AMPA ((RS)-2-amino-3-(3-hydroxy-5 - methylisoxazol-4-yl)propionic acid) has systemic activity, while its neurotoxic effects in animals were observed (Ornstein, P. L., et al., J. Med. Chem. 1993, 36, 2046-2048; Lauridsen J., Honore So, Krogsgaard-Larsen P., J. Med. Chem., 1985, 28, 668-672).

It was found that similar to AMPA, a number of its mono - and bicyclic analogs demonstrate selective agonistic effect on AMPA receptors (Hansen J. J., Krogsgaard-Larsen P., Med. Res. Rev. 1990, 10, 55-94; Krogsgaard-Larsen P. , Hansen J. J., 1992, ibid.). One of these analogues, (RS)-2-amino-3- (3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (ARRA), in which a methyl group AMPA substituted phenyl group has a weak but characteristic agonistic profile (I. Christensen, T., et A1., 1989, ibid).

As can be seen from the above NA highly desirable for the treatment of various of the aforementioned diseases, and therefore an object of the present invention is the provision of such new drugs.

Summary of the invention

It is now established that a new class of derivatives (5 - arylisoxazoles-4-yl) substituted 2-carboxylic acid is a strong ligands of receptors EAA.

Therefore, the present invention relates to a new class of compounds (5-arylisoxazoles-4-yl)- or (5 arealization-4 - yl)substituted 2-carboxylic acids having the General formula I

< / BR>
in which A represents a bond or a spatial group selected from C1-6alkylene, C2-6Alcanena or C2-6akinlana, or cycloalkyl; choose from a group-CH(NR'r R")-COOH, where R' and R" independently of one another represent hydrogen or C1-6alkyl, or a group of formula (II)

< / BR>
in which R2, R3and R4independently chosen from the group consisting of a) hydrogen, C1-6alkyl, C2-6alkenyl, C2-6quinil, recloak(EN)yl, recloak(EN)yl-C1-6ALK(EN/in)yl, phenyl-C1-6alkyl, thienyl-C1-6alkyl, and (b) C1-6alkyl, C2-6alkenyl and C2-6quinil, in which one or more and>alkylene, C2-C6albaniles or C2-C6akinyan group; or

R4and R2connected so that they form a C1-C3alkylene, C2-C3albaniles or C2-C3akinyan group, optionally mono - or biznesmenow hydroxy, or stands, or CH2-O-CH2;

E represents O, S, COO, (CH2)n-COO -, O-(CH2)n-COO-or S-(CH2)n-COO (where n is an integer from 1 to 6, 5-tetrazolyl, 5-tetrazolyl-C1-6alkyl, 3-hydroxyisoquinoline or 3-hydroxyisobutyryl-C1-6alkyl group;

D represents O or S; and

R1represents an aryl or heteroaryl group, or an aryl or heteroaryl group, substituted by one or more substituents selected from halogen, C1-6of alkyl, C1-6alkoxy, hydroxy, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylamino or di-(C1-6alkyl)amino, cyano, nitro, trifloromethyl or triptoreline;

provided that if a is a methylene, B is a group-CH(NH2)-COOH, E is Oh, D is Oh, a R1is phenyl, or phenyl substituted by halogen, or methoxy, then the connection specified on etodo obtain new compounds of formula I.

Another aspect of the present invention relates to a pharmaceutical composition containing the new compound of the formula I together with a pharmaceutically acceptable carrier or diluent.

Another aspect of the present invention relates to the use of compounds of formula I for the treatment of cerebral ischemia, Huntington's disease, seizure disorders, Parkinson's disease, Alzheimer's disease, schizophrenia, pain, depression and anxiety.

It was found that some compounds of the present invention are selective ligands of AMPA receptors in vitro, with a binding affinity at low micromolecular concentrations, while other compounds was found to be selectively associated with NMDA receptors in vitro. Other compounds of the present invention, has been found to have affinity for receptors AMPA and NMDA receptors in vitro. Moreover, it was found that some compounds of the present invention are agonists, while the other antagonists. Thus, the compounds of the present invention are useful for the treatment of cerebral ischemia, Huntington's disease, seizure disorders, Parkinson's disease, Alzheimer's disease, shizofreniya General formula I can exist as optical isomers, and these optical isomers are also covered by the present invention.

In the General formula I, the term "C1-6alkyl" is used to denote a branched or unbranched alkyl group containing from 1 to 6 carbon atoms, including groups such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2 - propyl, etc. Similarly, the terms "C2-6alkenyl" and "C2-6quinil" denotes a branched or unbranched group containing from 2 to 6 carbon atoms, and the term "C1-6alkylen", "C2-6albaniles" and "C2-6akinyan" denotes a branched or non-branched bivalent group. The term "cycloalkyl" denotes a group having 3-7 carbon atoms.

The term "ALK(EN/in)sludge" means that the referenced group may be alkyl, alkenyl or quinil group.

The term "communication" (used for) means that B can be directly connected to position 4 isoxazolines cycle.

"Halogen" denotes fluorine, chlorine, bromine or iodine.

The term "aryl" is used to denote a carbocyclic aromatic monocyclic or fused bicyclic group or biphenylenes group, and the term "heteroaryl used for obisnuisera such groups are 5-membered aromatic heteroaryl groups (having 1 - 4 heteroatoms selected from N, O and S), such as thienyl, furyl, pirolli, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. In addition, examples are sensational, benzofuranyl, indolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyl, hinely, hintline, honokalani and cinnoline.

Some compounds of General formula I can exist as pharmaceutically acceptable salts, which are also covered by the present invention.

These salts of the compounds of General formula I are salts formed non-toxic organic salts, for example, maleic, fumaric, benzoic, ascorbic, oxalic, tartaric, lactic and malic acids or inorganic acids, e.g. hydrochloric, Hydrobromic, sulfuric, phosphoric and nitric acids; or they may be salts of inorganic bases, such as alkali metal salts, for example, salts of sodium, potassium or lithium, salts of alkaline earth metals, salts of calcium or magnesium or ammonium salts or salts of organic bases.

In the formula I is preferably A represents a bond or C1-3alkylen.

SUB>, R3and R4represent hydrogen or lower alkyl, or R4and R2connected, forming a C1-C3alkylen group. More preferably, B represents a-CH(NH2)-COOH or a group of the formula II in which each of R2, R3and R4- hydrogen.

Preferably, E represents O, COO, -O(CH2)n- COO (n = 1, 2 or 3) or tetrazolyl, a D - oxygen.

Particularly suitable groups R1are thienyl, substituted thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, imidazolyl, oxadiazolyl, substituted oxazolyl, thiadiazolyl, tetrazolyl, triazolyl, pyridyl, phenyl, biphenyl and naphthyl. A preferred group 2-thienyl, 3-thienyl, phenyl, 2-pyridyl, 4-pyridyl, 2-thienyl and phenyl, substituted by halogen or stands.

In the preferred embodiment of the present invention And represents a bond or C1-C3alkylen, represents a - CH(NH2)-COOH or a group of formula II, where each of R2, R3and R4represents a hydrogen, E and D both represent oxygen, and R1- 2-pyridyl, 4-pyridyl, thienyl, phenyl, substituted thienyl or substituted phenyl.

According to the present izobretatel B represents a-CH(NR'r R")-COOH group, where R' and R"' are defined above, removing protection from the compounds of General formula III

< / BR>
in which R1, R', A, D, and E have been defined above, R5, R7and R8- protective group, a R6is hydrogen or a protective group;

b) to obtain the compounds of formula I in which B represents-CH(NR'r R")-COOH group, where R' and R" both represent a hydrogen - removing protection from compounds of General formula IV

< / BR>
in which R1, R5And, D, and E have been defined above;

(C) to obtain the compounds of formula I in which B represents a group of formula II, the reaction attachment - elimination of compounds of General formula V with a compound of General formula VI

< / BR>
in these formulas, R1-R4The A , D and E have been defined above, a R'5represents hydrogen or a protective group;

d) to obtain the compounds of formula I in which a represents a group of formula II, where R4and R2interconnected, forming a C1-3alkylene, C2-C3albaniles or C2-C3akinyan group, optionally mono - or biznesmenow hydroxy or stands, the interaction of the compounds of formula VII

< / BR>
in which R1, R3The A , D and E have been defined above, R4and R2
(e) for obtaining the compounds of formula I in which B represents a group of formula II and one or more of R2-R4different from hydrogen - alkylation of compounds of General formula VIII

< / BR>
in which R1, R2, R3, R4The A , D and E have been defined above, with at least one of R2-R4represents hydrogen, R'5is hydrogen or a protective group.

In the method of the present invention, the preferred protective groups are R5and R'5is lower alkyl, benzyl or benzazolyl group; R6lowest alkoxycarbonyl, R7is lower alkyl and R8lowest alkylsulphonyl.

Single-stage removal of protection according to method (a) is conducted by treating compound of formula III suitable aqueous acid, it is convenient to use an aqueous solution of 48% HBr saturated solution of HBr in acetic acid or 2-12 N. aqueous solution of HCl. Removing the protection can be carried out in several stages, sequentially using aqueous acid and aqueous base; it is convenient to perform consistently in the aqueous acid, such as 1-12 N. HCl, aqueous base, such as 1-8 N. NaOH in aqueous acid, such as 1-12 N. HCl; or sequentially in a water base, so the protection from E-complete group by catalytic hydrogenation, which is convenient to carry out or before or after removing the protection from a - amino acids, using as catalyst palladium.

Source materials for the compounds of General formula III is convenient to obtain as described in the work of I. Christensen, T., et al. Drug Design and Delivery, 1989, 5, 57-71 in the work of Christensen, S. B., et al., Acta Chem. Scand., 1978, B32 27-30. Source materials for the compounds of General formula III in which E represents COO, (CH2)n-COO -, O-(CH2)n-COO -, S-(CH2)n-COO (n=1-6), 5 - tetrazolyl-C1-6alkyl group or a 3-hydroxyisoquinoline-C1-6alkyl group, it is convenient to obtain as described in the works: Krogsga-ard-Larsen P., et al. , J. Med. Chem., 1991, 34, 123-130; Madsen, U., Bio. Med. Chem. Lett., 1993, 8, 1649-1654; Madsen, U., Wong E., J. Med. Chem. 1992, 35, 107-111.

Source materials for the compounds of General formula III in which R1is a heteroaryl group that is unstable in acidic conditions, it is convenient to obtain from (3-alkoxy-4-methylisoxazol-5-yl) carboxylic acid by formation of heteroaryl in position 5 bromirovanii 4-methylisoxazole group followed by alkylation of the precursor amino acids, such as Diethylenetriamine. Alkyl, protected by a 3-hydroxyisoquinoline group may be re-secured or may not be sasia of heteroaryl in position 5 isoxazol (3-alkoxy-4 - methylisoxazol-5-yl)carboxylic acid conveniently be obtained from 3-alkoxy-4,5-dimethylisoxazole (synthesized, as described in the work of Hansen J. J., J. Chem. Soc. Perkin Trans., 1980, 1, 1826 - 1833) bromirovanii with subsequent oxidation of 5-methylisoxazole group in a corresponding compound 5-isoxazolecarboxylic acid.

In other cases, the original substance of General formula III in which R1is, for example, pyridyl group, it is convenient to obtain a modification of the method described by Tomita K., Ann. Sankyo Res. Lab., 1973, 25, 3-5. Protection of the 3-hydroxy group in the resulting 3-hydroxy-5-arylisocyanate followed by the introduction of hydroxymethylene group in position 4 isoxazolines cycle leads to intermediate compounds, which are then easily converted into the original substances of the formula III.

In case (b) single-stage removal of protection carried out by treating compound of formula IV in a suitable aqueous acid or base, it is convenient to carry in 2-8 N. aqueous hydrochloric acid. Removing protection could also be carried out sequentially in stages, using aqueous acid and aqueous base, as described above for method a). Cycle as can also be split using aqueous solution of Ba(OH)2water 10-70% sulfuric acid or by the use of enzymes, such as hydantoins. The specified splitting cycle as may be the mules IV are easily formed according to the methods described E. Ware, Chem Rev., 1950, 46, 403-470. Splitting cycle as easily be performed by analogy with the methods described by Curry K. , et A1., J. med. Chem., 1988, 31, 864-867, Farrington G. K., et al., J. Mod. Chem. , 1987, 30. 2062-2067, Grunewald, G. L., et al., J. Med. Chem., 1980, 23, 754-758, Hirol K., et al., Chem. Pharm. Bull., 1968, 16. 444-447, Stark G. R., et al, J. Biol. Chem. 1963, 238, 214-226.

The source of the substance to obtain the compounds of formula IV can be obtained by analogy with the methods described Madsen U., Eur. J. Med. Chem., 1993, 28, 791-800.

If R5represents benzyl, removing protection from E-group is easy to carry out by hydrogenation using palladium as catalyst.

Response attachment-elimination according to the method (C) is conveniently carried out in a proton organic solvent such as an alcohol, preferably in the presence of a suitable inorganic bases, such as NaOH, at room temperature. Intermediate compounds of formula VI can be obtained by methods described in the works of Cohen, S., et al., J. Amer. Chem. Soc., 1966, 88. 1533-1536, EP-A2-0496561 or W. A. Kinney et al., J. Med. Chem., 1992, 35. 4720-4726.

The intermediate compound of General formula V is easily obtained by synthesis of primary amines by Gabriel as described Sheehan J. C. et al., J. Amer. Chem. Soc. , 1950, 72, 2786-88. The source for this synthesis alkylhalogenide conveniently recip is convenient to carry out, using aqueous acid or aqueous base, preferably 0.5-8 N. HCl or 0.5-8 N. NaOH or at room temperature, or at elevated temperatures. If R'5represents benzyl, removing the protection can be carried out by hydrogenation using a catalyst of palladium.

In the method (d) interaction and the subsequent closure of the cycle and removing protection carried out as described Kinney et al., EP-A2 - 0496561.

The source of the substance to obtain the compounds of formula VII can be obtained by the interaction between, for example, 4-bromocrotonate obtained as described for the starting materials in method a), with mono-BOC-protected alkylenediamines (EP-A2-0496561).

The alkylation of compounds of General formula VIII according to method e) it is convenient to carry out in an inert organic solvent, such as a suitable alcohol, ketone or dimethylformamide, preferably in the presence of a suitable base such as sodium hydride, potassium carbonate or triethylamine, as described by W. A. Kinney, EP-A2-0496561. Educt of the formula VIII obtained according to (C).

If - ketoesters used as the source for obtaining 3-hydroxyisoquinoline, which, in turn, used to be charged methods described in Cason J., et al., J. Org. Chem., 1953, 18, 1594-1600 and Hannick, S. M., et al., J. Org. Chem., 1983, 48. 3833-3835. The corresponding source isothiazole can be obtained according to the method described in EP-A1-0336555.

Re-dissolving compounds of General formula I is conveniently carried out with the formation of salts of diastereoisomers using active acid or base, such as 1-phenylethylamine. In some cases, this re-dissolution is conveniently carried out with the formation of compounds of diastereoisomers with subsequent separation of diastereoisomers thin-layer chromatography or crystallization.

Salts of the compounds of the present invention can easily be obtained by methods well known in this area, such as the interaction of the compounds or with equivalent amounts of acid or base dissolved in water solvent (such as acetone or ethanol) with subsequent allocation of salts by evaporation and cooling or an excess of acid or base in a solvent that is not miscible with water (such as diethyl ether or chloroform) with the direct selection of the desired salt. These salts can also be obtained by the classical method of double decomposition of the corresponding salts.

Connections on the m way for example orally or parenterally, and these compounds may be in any suitable for such an introduction form, for example in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.

An effective daily dose of the compounds of General formula I or its pharmaceutically acceptable salt is from 10 μg/kg to 50 mg/kg body weight.

All values of the melting temperature was determined on the equipment Buchi SMP-20, and they are not accurate. Spectra 1H-NMR and13C-NMR were recorded on a spectrophotometer Bruker 250 MHz (250.13 MHz for the first method and 62.90 MHz for the second). As an external standard, unless otherwise specified, tetramethylsilane was used. For compounds 13A, L, 14C and 14d, mentioned in the titles, spectra1H-NMR and13C-NMR were recorded on spectrophotometer Bruker 200 MHz 200.0 MHz to1H-NMR and 50.3 MHz for13C-NMR), as an external standard, unless otherwise specified, tetramethylsilane was used.

Mass spectra were obtained on the Quattro system MS-MS VG Biotech, Fisons instruments, Manchester, GB. This system MS-MS was connected to the modular system of high performance liquid chromatography HP 1050. 20-50 μl of the sample (0.1-0.05 mg/ml) dissolved in a mixture of astrographical through the sampler at a speed of current of 30 µl/min Spectra were obtained under standard operating conditions to obtain information about the molecular weights (MH+). The background subtracted.

The enantiomeric excess enantiomeric compounds was determined by chiral high-performance liquid chromatography on a chiral crown ether column. Chromatography was performed in a 150 x 4 mm column (Daicel Crownpak CR(-) or a Crownpak CR(+) with elution at 15-40oC water perchloro acid/ methanol (100-85%/0-15%) at a rate of 0.4-1.0 ml/min was Used by one of the following devices:

1) Pump Jusco 880-PU, injector Rheodyne 7125 and detector Waters 480 UV set at 210 nm, coupled with a Merck-Hitachi D-2000 Chromato-Integratot,

2) Pump Hitachi-Merch L-6200, automatic sampler Hitachi-Merch I-40 and detector Hitachi-Merch L-4000 UV set at 210 nm, coupled with Hitachi-Merch D-2500.

The purity of the enantiomers were calculated from the peak areas.

Example 1

(RS)-2-amino-3-[3-hydroxy-5-(2-thienyl)isoxazol-4 - yl] propionic acid, 1A

A mixture of 2-bromothiophene (250.0 g, 1.53 mol) and CuCN (157.5 g, 1.76 mol) was heated in a flask under reflux in N-organic (NMP) for 90 minutes the mixture was cooled to 100oC and poured into a hot solution of NaCN in water (150 g NaCN in 2.5 l of water). The mixture was vigorously stirred for 30 min of Priya times 2 l), and then was evaporated in vacuum to 1.5 L. the Organic phase was washed with water (750 ml) and aqueous saturated NACl solution (750 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to obtain a red-purple oil. The latter was distilled under reduced pressure (1 mm Hg), resulting in a 2-thiophenecarbonitrile (105.3 g, 63%).

A mixture of 2-thiophenecarbonitrile (25.0 g), activated zinc (22.5 g) and CuBr2(0.2 g, 0.9 mmol) in benzene (350 ml) was heated up to the melting temperature (83oC). For 60 min at 83oC was added ethyl-2-bromopropionate (62.2 g) in benzene (150 ml). The resulting mixture was heated for 2 h in a flask under reflux, and then cooled to 0oC. for 60 min was added 15% aqueous H2SO4(400 ml) at a temperature below 10oC, and the resulting mixture was stirred at 20oC for 20 h the Mixture was then filtered and the resulting phases were separated. The aqueous phase was extracted with diethyl ether (two times 500 ml), and collected together the organic phase was dried (MgSO4and boiled away in a vacuum. After column chromatography (silica gel, eluent: ethyl acetate/n - heptane/methanol 4:4:1) was obtained ethyl 2-methyl-3-(2-thienyl)-3 - oxopropionate in the form of oil (35.0 g, 72%).

The mixture of these C. Added ice (0oC) solution of NH2OH, HCl (16.6 g) and NaOH (10.0 g) in methanol/water (10: 1, 200 ml); the resulting solution was stirred for 3 h at 30oC. the Solution was kept until they reach a temperature of 5oC and then added to concentrated HCl (280 ml) for 45 min at 80oC. the resulting mixture was heated in a flask with reflux condenser for 1 h at 80oC. boiled away the methanol and added water (250 ml). The resulting solution was cooled to 5oC, and the resulting crystals were collected during the filtration process. These crystals were dissolved in CH2Cl2(500 ml). The organic phase was dried (MgSO4and boiled away in the vacuum, thus obtained 4-methyl-5-(2-thienyl)isoxazol-3-ol (12.0 g, 55%).

A suspension of 4-methyl-5-(2-thienyl)isoxazol-3-ol (12.5 g) and K2CO3(14.4 g) in acetone (250 ml) was heated up to the melting temperature. For 25 min at the temperature of melting was added ethylbromide (8.0 g) and the resulting mixture was heated in a flask under reflux for 3 hours was Added another portion of ethylbromide (8.0 g) and the resulting mixture was heated in a flask with reflux condenser within the next 3 hours After filtration and removal of solvent the residue was treated by the method of speakers prosol in the form of oil (7.3 g, 51%).

A mixture of 3-ethoxy-4-methyl-5-(2-thienyl)isoxazol (5.1 g) and N-bromosuccinimide (5.1 g) in CCl4(400 ml) was heated in a flask under reflux for 18 hours After filtration and removal of solvent received 4-methyl bromide-3-ethoxy-5-(2-thienyl)isoxazol (7.8 g, 100%).

To a mixture of Diethylenetriamine (4.6 g) and tert-butoxide potassium (2.4 g) in N-organic (NMP) (100 ml) at 22oC was added a solution of 4-methyl bromide-3-ethoxy-5-(2-thienyl)isoxazol (3.0 g) in NMP (25 ml). The resulting solution for 1 h and was stirred at 22oC, and then poured into a mixture of ice and water. The aqueous phase was extracted with diethyl ether, and collected together the organic phase was washed water saturated NaCl solution. The organic phase was dried (MgSO4) and evaporated in vacuo. The obtained residue was treated with column chromatography (silica gel, eluent: ethyl acetate/n-heptane/methanol 5:5:1), resulted in 2-acetamido-2-ethoxy-carbonyl-3- [3 - ethoxy-5- (2-thienyl)isoxazol-4-yl]propionate (3.0 g, 68%).

A mixture of 2-acetamido-2-etoxycarbonyl-3-[3-ethoxy-5-(2 - thienyl)isoxazol-4-yl]propionate (2.7 g) and 48% HBr (20 ml) was heated in a flask under reflux for 1 h the Mixture was evaporated in vacuum and the residue was dissolved in water (50 ml) and treated with charcoal. Psili in vacuum, this was mentioned in the title compound 1A (0.5 g, 30%). Melting point 237-239oC; CHN: calculated: 47.23, 3.97, 11.02; found: 47.21, 4.02, 10.92.

1H-NMR (DMSO-d6): 9.90 (b, 1H), 7.82 (dd, 1H), 7.55 (dd, 1H), 7.24 (dd, 1H), 3.70 (dd, 1H), 2.95-2.88 (m, 2H).

13C-NMR (DMSO-d6): 171.42, 171.23, 159,62, 129.27, 128.65, 128.22, 127.15, 101.89, 52.59, 24.99.

In a similar way got the connection:

(RS)-2-amino-3-[3 - hydroxy-5-(3-thienyl)isoxazol-4-yl]propionic acid, 1b, melting point 239-240oC

1H-NMR (DMSO-d6): 8.03-7.96 (m, 1H), 7.76-7.70 (m, 1H), 7.48-7.43 (m, 1H), 3.70-3.63 (m, 1H), 3.00-2.76 (m, 2H).

Using benzosulfimide group as a protective 3-hydroxyisoquinoline group similarly received:

(RS)-2-amino-3-[3-hydroxy-5-(2-naphthyl)isoxazol-4- -yl]propionic acid, hydrate 1C, melting point 235 - 237oC.

1H-NMR (DMSO-d6): 2.89-3.16 (m, 2H), 3.70-3.77 (m, 1H), 7.56-7.63 (m, 2H), 7.74 (dd, 1H), 7.92-8.09 (m, 3H), 8.22 (s, 1H).

13C-NMR (DMSO-d6): 25.10; 53.03; 103.03; 124.30; 125.90; 126.89; 126,96; 127.45; 127.79; 128.70(2C); 132.74; 133.18; 164.67; 171.41; 171.54.

MS (MH+) m/z: 299.

(RS)-2-amino-3- [3-hydroxy-5-(4-triptoreline) isoxazol-4-yl] propionic acid. 1d, the melting point 237-239oC.

1H-NMR (DMSO-d3
); 131.74; 164.13; 170.29(2C).

MS (MH+) m/z: 317.

(RS)-2-amino-3-[3-hydroxy-5-(3-benzo[b]thienyl)isoxazol-4 - yl]propionic acid, semihydrate, 1E, melting point 222-224oC.

1H-NMR (DMSO-d6): 2.75 (dd, 1H), 2.96 (dd, 1H), 3.70 (dd, 1H), 7.43-7.55 (m, 2H); 7.96-8.03 (m, 1H); 8.05-8.14 (m, 1H); 8.21 (s, 1H).

13C-NMR (DMSO-d6): 25.02: 52.96; 104.05; 123.17; 123.34; 123.67; 125.27(2C); 129.49; 136.80; 139.35; 161.49; 171.11; 171.31.

MS (MH+) m/z: 305.

The following compound was obtained in a similar manner from 2-acetamido-2-etoxycarbonyl-3-[3-ethoxy-5-(2-thienyl)isoxazol-4 - yl]propionate introduction of lithium oxide and methylation at position 5 thienyl group, followed by removal of the security using the boiling 47% aqueous HBr.

(RS)-2-amino-3-[3-hydroxy-5-(5-methyl-2-thienyl)isoxazol-4 - yl] propionic acid, hydrate 1f, melting point 242-244oC.

1H-NMR (DMSO-d6): 2.51 (s, 3H), 2.84-2.93 (m, 2H), 3.63-3.72 (m, 1H), 6.94 (dd, 1H); 7.33 (d, 1H).

13C-NMR (DMSO-d6): 14.91; 24.95; 52.62; 101.24; 126.63; 126.88; 127.23; 142.33; 159.71; 171.20; 171.31.

MS (MH+) m/z: 269.

Example 2

(RS)-2-amino-2-(3-hydroxy-5-phenylisoxazol-4-yl)acetic acid, 2a

A mixture of 3-ethoxy-4-methyl-5-phenylisoxazole (3.0 g, 15 mmol), polucen(100 ml) for 20 h was heated in a flask with reflux condenser. The resulting mixture was cooled to ambient temperature, filtered and evaporated in vacuum. The residue was dissolved in water (95 ml) and heated in a flask under reflux for 20 hours After cooling, the aqueous phase was extracted with diethyl ether (three times 100 ml). Together the organic phase was dried (Na2SO4and boiled away in the vacuum, the result was obtained 4-(3-ethoxy-5-phenylisoxazol)carbaldehyde (2.4 g, 75%).

A mixture of 4-(3-ethoxy-5-phenylisoxazol)carbaldehyde (1.9 g, 8.7 mmol), KCN (2.7 g, 40.5 mmol) and (NH4)2CO3(7.8 g, 81.1 mmol) in 50% aqueous methanol (250 ml) was heated for 6 h in a flask with reflux condenser. The methanol was boiled away in vacuum, and the aqueous phase was extracted with ethyl acetate (three times 150 ml). Together the organic phase was dried (Na2SO4), and the solvent was removed by evaporation in a vacuum. The residue was treated with column chromatography (silica gel, eluent: ethyl acetate/n-heptane/methanol 5:5:1), resulted in a 3-ethoxy-4-[5-(imidazolidin-2,4 - dione)] -5-phenylisoxazole (1.0 g, 40%).

A suspension of 3-ethoxy-4-[5-(imidazolidin-2,4-dione)]-5 - phenylisoxazole (800 mg, 2.8 mmol) in 6 BC aqueous HCl (20 ml, 120 mmol) was heated for 48 h in a flask with reflux condenser. Portret-butyl bicarbonate (930 mg, 4.3 mmol) in tetrahydrofuran (50 ml) and the resulting solution was stirred for 20 h at 20oC. the Tetrahydrofuran was boiled away in vacuo, and the pH was brought to 6.5 with 0.1 N. aqueous HCl. The aqueous phase was extracted with diethyl ether, which is then poured. the pH of the aqueous phase was brought to 2 with 0.1 N. aqueous HCl, and then this phase was extracted with diethyl ether (three times 100 ml). Together the organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in diethyl ether (40 ml) and added a saturated solution of HCl in diethyl ether. The resulting mixture was stirred for 20 h at 20oC. the Precipitate was collected with filtration and dried. The obtained crystals were dissolved in water (5 ml) and the pH was brought to 3. The precipitate was collected with filtration and dried, the result was indicated in the title compound 2A (100 mg, 15%). Melting point 228-230oC; CHN: calculated 56.40, 4.31, 11.96; found 56.20, 4.37, 11.74.

Data1H-NMR and13C-NMR for compound 2A, HCl:

1H-NMR (DMSO-d6): 7.83-7.68 (m, 2H), 7.64 - 7.40 (m, 3H), 5.12-4.95 (m, 1H), 3.90 (broad).

13C-NMR (DMSO-d6): 169.10, 168.38, 168.31, 131.39, 129.60(2C), 127.73(2C), 126.95, 99.69, 46.06.

In a manner analogous to the method of obtaining 4-isoxazolecarboxylic is epoxide acid and sodium carbonate, were obtained the following compounds:

(RS)-2-amino-2-(3-hydroxy-5-(2-thienyl)isoxazol-4 - yl)acetic acid, 2b. Melting point 191-193oC.

1H-NMR (DMSO-d6): 4.50 (s, 1H), 7.26 (dd, 1H), 7.77 (d, 1H), 7.84 (d, 1H).

13C-NMR (HCl salt) (DMSO-d6): 46.16, 98.87, 127.62, 129.15, 129.83, 131.20, 163.56, 168.45, 169.39.

MS (MH+) m/z: 241.

(RS)-2-amino-2-(3-hydroxy-5-(4-triptoreline)isoxazol - 4-yl)acetic acid, hydrate, 2C. Melting point 200-201oC.

1H-NMR (DMSO-d6): 4.46 (s, 1H), 7.92 (d, 2H), 8.11 (d, 2H).

13C-NMR (HCl salt) (DMSO-d6): 45.84, 101.16, 121.98, 126.43, 126.50, 128.76(2C), 130.75, 131.00 (q, CF3), 166.75, 168.20, 169.21.

Example 3

(RS)-2-amino-5-(3-hydroxyphenylacetate-4 - yl)pentane acid hydrate. 3A

The connection specified in the title, was obtained by analogy with the method described in the work Chiristensen I. T., et al., Drug Design and Delivery, 1989, 5, 57-71, with the following modifications: 1) as the original used the ethyl benzoylbenzoate; 2) isoxazolines cycle in the intermediate 5-phenyl-4-(2-propenyl)-3 - isoxazol was obtained according to the method of Sato K., et al., Agric. Biol. Chem. , 1986, 5(7, 1831-1837; 3) amphoteric ion specified in the title compound 3A was obtained by bringing the pH of the aqueous phase to 3.5 with 0.1 N. aqueous NaOH. Temperature (m, 2H), 7.59-7.43 (m, 3H), 3.64-3.40 (m, 2H), 3.50 (broad), 3.31-3.19 (m, 1H), 1.82-1.53 (m, 4H).

13C-NMR (DMSO-d6): 170.75, 163.44, 161.65, 129.72, 129.23(2C), 128.58, 126.19(2C), 105.68, 53.93, 30.57, 25.13, 20.88.

Example 4

(RS)-2-amino-4-[5-(4-forfinal)-3-hydroxyethoxy-4 - yl]butane acid, hydrate, 4A

- ketoester, ethyl 3-oxo-3-(4-forfinal)propionate was obtained by analogy with the method described in example 1 was used 4-perbenzoate (25.0 g, 0.21 mol), ethyl 2-bromoacetate (51.7 g, 0.31 mol), activated zinc (20.3 g, 0.31 mol), CuBr2(0.2 g, 0.9 mmol) and benzene (500 ml). After column chromatography of the residue (silica gel, eluent: ethyl acetate/n-heptane/methanol 5:5:1) was obtained ethyl 3-oxo-3-(4-forfinal)propionate in the form of oil (28.0 g, 65%).

To a solution of NaH (4.4 g, 0.15 mol, 80% in mineral oil) in ethanol (500 ml) was added 3-oxo-3-(4-forfinal)propionate in the form of oil (28.0 g, 0.13 mol). The resulting solution was stirred for 1.5 h at 25oC. for 30 min at 25oC was added ethyl 3-chloropropionate (20.0 g, 0.15 mol), then the resulting mixture was heated in a flask under reflux for 20 hours, the solvent was removed by evaporation and the residue was dissolved in water (400 ml) and was extracted with ethyl acetate. Together the organic phase was dried (MgSO4) and evaporated in the ethyl 4-etoxycarbonyl-5-(4-forfinal)-5-oxopentanoate (27.5 g, 67%).

Ethyl 3-[5-(4-forfinal)-3-hydroxyethoxy-4-yl] propionate was obtained by analogy with the method described in example 1 with the following modifications: 1) as the source used ethyl 4-etoxycarbonyl-5-(4-forfinal)-5-oxopentanoate (27.5 g, 89 mmol); 2) after evaporation of methanol from a solution of methanol/water, the aqueous phase was extracted with diethyl ether. Together the organic phase was dried (MgSO4and boiled away in a vacuum. The residue was dissolved in ethanol (400 ml) and added acetylchloride (40 ml). The resulting mixture was heated for 20 h in a flask under reflux, cooled, and the solvent was removed by evaporation in a vacuum. After column chromatography of the residue (silica gel, eluent: ethyl acetate/n-heptane/methanol 2:2:1) was obtained ethyl 3-[5-(4-forfinal)-3-hydroxyethoxy-4-yl]propionate (9.3 g, 31%).

Ethyl 3-[3-ethoxy-5-(4-forfinal)isoxazol-4-yl] propionate was obtained as described in example 1 with the following modifications: 1) as the source used ethyl 3-[5-(4 - forfinal)-3-hydroxyethoxy-4-yl] propionate (5.5 g, 20 mmol), and 2) instead of two equivalents of ethylbromide was added one equivalent to it. After column chromatography of the residue (silica gel, eluent: ethyl acetate/n-heptane/methanol 10:10:1 is xazal-4-yl] propanal was obtained from ethyl 3-[3-ethoxy-5-(4-forfinal)isoxazol-4-yl] -propionate according to the method described Rich D. H., et al., J. Org. Chem., 1978, 43. 3624-3626.

3 ethoxy-5-(4-forfinal)-4-[2-[5-(imidazolidin-2,4-dione)] ethyl]isoxazol was obtained as described in example 2, using as source the corresponding aldehyde. The obtained crude product is recrystallized twice from ethanol to obtain the pure substance.

Compound 4A, indicated in the title, was obtained from as by analogy with the method described in example 2 at exit 19%. Melting point 235-237oC; CHN: calculated 55.71, 4.68, 10.00; found 54.59, 4.61, 9.97.

1H-NMR (DMSO-d6, 340 K): 7.78-7.54 (m, 2H), 7.39-7.19 (m, 2H), 5.92(b), 3.35-3.18 (m, 1H), 2.81-2.53 (m, 2H), 2.04-1.70 (m, 2H).

13C-NMR (DMSO-d6): 172.19, 170.79, 164.70 and 160.76(C-F), 162.96, 128.64, 128.50, 125.13, 116.55, 116.21, 104.52, 52.35, 31.44, 17.81.

In a similar manner there were obtained the following compounds:

(RS)-2-amino-4-[3-hydroxy-5-phenylisoxazol-4-yl] butane acid, hydrate, 4b, melting point 230-233oC.

1H-NMR (D2O): 7.59-7.48 (m, 2H), 7.47-7.32 (m, 3H), 3.61-3.50 (m, 1H), 2.57-2.41 (m, 2H), 2.08-1.90 (m, 2H).

13C-NMR (DMSO-d6): 179.12. 176.64. 161.12, 130.41, 128.79(2C), 128.13, 125.72(2C), 107.13, 53.31, 32.97, 18.62.

(RS)-2-amino-4-[3-hydroxy-5-(2-thienyl)isoxazol-4-yl]butane acid, hydrate, 4C, melting point 214-m, 1H), 2.93-2.60 (m, 2H), 2.00-1.75 (m, 2H).

13C-NMR (DMSO-d6): 172.11, 170.64, 159.47, 129.41, 128.41(2C), 126.35, 103.73, 52.42, 30.76, 17.93.

(RS)-2-amino-4-[3-hydroxy-5-(3-thienyl)isoxazol-4-yl]butane acid, 4d, melting point 212-214oC.

1H-NMR (DMSO-d6): 8.02-7.95 (m, 1H), 7.78-7.72 (m, 1H), 7.48-7.43 (m, 1H), 3.28-3.16 (m, 1H), 2.93-2.77 (m, 1H), 2.75-2.54 (m, 1H), 2.00-1.75 (m, 2H).

(RS)-2-amino-4-[3-hydroxy-5-(2-naphthyl)isoxazol-4-yl]butane acid, hydrate, 4E, melting point 209 - 211oC.

1H-NMR (DMSO-d6): 1.87-2.05 (m, 2H), 2.60-2.85 (m, 2H), 2.90-3.06 (m, 1H), 7.56-7.66 (m, 2H), 7.80 (dd, 1H), 7.93-8.16 (m, 3H), 8.26 (s, 1H).

13C-NMR (DMSO-d6): 17.92, 31.50, 52.40, 105.02, 123.21, 125.66, 125.95, 127.04, 127.44, 127.76, 128.75, 128.91, 132.82, 133.09, 163.71, 170.70, 172.30.

MS (MH+) m/z: 313.

Example 5

4-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)aminomethyl] -3 - hydroxy-5-phenylisoxazol, hemihydrate, 5A

To a mixture of phthalimide potassium (1.0 g, 5.4 mmol) in N,N-dimethylformamide (50 ml) was added 4-methyl bromide-3-ethoxy-5 - phenylisoxazol (1.4 g, 5.0 mmol) in N,N-dimethylformamide at 90oC. 4-methyl bromide-3-ethoxy-5-phenylisoxazol received by analogy with the above-described method for producing 4-methyl bromide-3-ethoxy-5-(2 - thienyl)isoxazol. Resulting mixture was stirred for 40 min at 90oC, then dobavilabi ether. Together the organic phase was washed with 0.1 N. )NaOH and water, dried (Na2SO4), and then evaporated in vacuum. The result was obtained N-[(3-ethoxy-5-phenylisoxazol-4-yl)methyl]phthalimide (1.5 g, 88%).

A suspension of N-[(3-ethoxy-5-phenylisoxazol-4-yl)methyl] phthalimide (1.3 g, 3.7 mmol) in aqueous 48% HBr (20 ml) and acetic acid (20 ml) was stirred for 6 h at 110oC. the Mixture was evaporated in vacuum and the residue dissolved in water. The resulting aqueous phase was extracted with diethyl ether, which is then removed. The aqueous phase was evaporated in vacuum and then to the residue was added acetone (5 ml). The precipitate was collected by filtration and dried, thus obtained 4-aminomethyl-5-phenyl-3-isoxazol, hydrogen bromide (700 mg, 70%).

To a solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (365 mg) obtained according to the method described by Cohen, S., et al., J. Amer. Chem. Soc., 1966, 88, 1533-1536, and hydrobromide 4-aminomethyl-5 - phenyl-3-isoxazol (700 mg, 2.6 mmol) in ethanol (75 ml) was added a solution of NaOH (210 mg, 5.2 mmol) in water (5 ml) at 22oC. the resulting mixture was stirred at 22oC for 4 h, the Solvent is boiled away, and the residue was dissolved in water (200 ml). the pH of the aqueous phase was brought to 8.5. The aqueous phase was extracted with diethyl ether, which is then removed. pH brought to 3.75, and the precipitate was collected during melting 259-261oC; CHN: calculated: 57.13, 4.12, 14.28; found 57.70, 3.85, 14.29.

1H-NMR (DMSO-d6): 7.81-7.24 (m, 5H), 4.78-4.56 (m. 2H), 3.5 (s, very broad).

13C-NMR (DMSO-d6): 183.34, 183.21, 170.14, 169.48, 169.29, 165.84, 130.58, 129.32(2C), 127.51, 126.72(2C), 102.52, 35.46.

In a similar way there were obtained the following compounds:

4-[(2-amino-N, 4-dioxo-1-cyclobutene-1-yl)aminomethyl] -3 - hydroxy-5-(2-thienyl)isoxazol, 5b. Sublimation temperature 237-239oC.

1H-NMR (DMSO-d6): 7.88 (dd, 1H), 7.67 (dd, 1H), 7.26 (dd, 1H), 4.78-4.63 (m, 2H), 3.30 (s, very broad).

13C-NMR (DMSO-d6): 183.36, 183.18, 169.97, 169.51, 168.23, 161.29, 129.80, 128.59, 128.25, 127.82, 101.41, 35.20.

4-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)aminomethyl] -3 - hydroxy-5-(3-thienyl)isoxazol, 5s. Melting point 276-278oC.

1H-NMR (DMSO-d6): 8.16-8.13 (m, 1H), 7.82-7.77 (m, 1H), 7.56-7.50 (m, 1H), 4.76-4.66 (m, 2H).

4-((2-amino-3,4-dioxo-1-cyclobutene-1-yl)aminomethyl] -3 - hydroxy-5-(4-triptoreline)isoxazol, 5d. Melting point 269-272oC.

1H-NMR (DMSO-d6): 4.72 (d, 2H), 7.93 (dd, 4H).

13C-NMR (DMSO-d6): 35.29, 104.19, 121.75, 126.12, 126.17, 127.60(2C), 130.25 (q, CF3), 131.11, 164.09, 168.21, 169.51, 170.11, 183.29(2C).

MS (MH+) m/z: 354.

Example 6

4-[2-[(2-amino-3,4-dioxo-1-cyclobutene is poxide (50 ml) was heated to 90oC. the hot reaction mixture was added dropwise 4-methyl bromide-3-ethoxy-5-(2-thienyl)isoxazol (4.9 g, 16 mmol), dissolved in dimethyl sulfoxide (50 ml). The resulting mixture was stirred for 30 min and then poured into a mixture of ice and water. The aqueous phase was extracted with CH2Cl2and the collected organic phases are washed with saturated solution of NaCl. The organic phase was dried (MgSO4and boiled away in a vacuum. The residue was treated with column chromatography (silica gel, eluent: ethyl acetate/n-heptane 1:3), got (3 ethoxy-5-(2-thienyl)isoxazolidine (2.2 g, 58%).

A mixture of AlCl3(1.2 g, 9 mmol) in dry diethyl ether (50 ml) was added in drops to a mixture of LiAlH4(0.34 g, 9 mmol) in dry diethyl ether (50 ml). The reaction mixture was stirred for another 10 min at room temperature. To the stirred solution was added a mixture of [3-ethoxy-5-(2-thienyl)isoxazol] acetonitrile (2.0 g, 9 mmol) in dry diethyl ether (50 ml) and the reaction mixture was stirred for another 45 minutes Then the reaction mixture was cooled to 5oC and added water (30 ml) and 6 M H2SO4(5 ml). Using 6 M NaOH the pH of the resulting acidic solution was increased to 11. Resulting phases were separated, and the aqueous phase was extracted with diethyl ether. Abrogate (silica gel, eluent: ethyl acetate/n-heptane/methanol/triethylamine 90:10:5:5. There was obtained 4-(2-amino-ethyl)-3-ethoxy-5-(2-thienyl)isoxazol (1.7 g, 76%).

A mixture of 4-(2-amino-ethyl)-3-ethoxy-5-(2-thienyl)isoxazol (1.7 g, 7 mmol) and 47% aqueous HBr was heated in a flask under reflux for 1 h, the Reaction mixture was evaporated in vacuo and added acetone. The resulting crystals collected on the filter and dried in vacuum, there was obtained 4-(2-amino-ethyl)-3-hydroxy-5(2 - thienyl)isoxazol, hydrogen bromide (1.9 g, 94%).

To a solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (480 mg, 3.4 mmol), obtained as described previously, and the hydrobromide of 4-(2-amino-ethyl)-3-hydroxy-5(2-thienyl)isoxazol (1.0 g, 3.4 mmol) in ethanol (30 ml) was added a solution of NaOH (270 mg, 6.8 mmol) in water (5 ml) at 22oC. the resulting solution was stirred 18 h at room temperature. The reaction mixture was evaporated in vacuo, and added water and diethyl ether. The resulting phases were separated, and the aqueous phase was extracted with diethyl ether, which is then removed. The aqueous phase was acidified to pH 2.5 2M HCl and left for 18 h at 5oC. the Resulting crystals were collected by filtration and washed with water, acetone and diethyl ether. After drying the crystals under vacuum there was obtained compound 6A, shown is

1H-NMR (DMSO-d6): ] 2.77 (dd, 2H), 3.51-3.78 (m, 2H), 7.22 (dd, 2H), 7.57 (d, 1H), 7.81 (d, 1H).

13C-NMR (DMSO-d6): 24.12, 42.06, 102.06, 126.65, 127.94, 128.53, 129.00, 160.41, 168.65, 169.41, 170.05, 182.82, 183.00.

Example 7

(RS)-2-amino-3-[3-carboxymethoxy-5-(2-thienyl) isoxazol-4-yl] propionic acid, monohydrate, 7a

A suspension of 4-methyl-5-(2-thienyl)isoxazol-3-ol (10.0 g, 55 mmol), obtained as described previously, and K2CO3(19.1 g, 138 mmol) in acetone (350 ml) for 30 min was stirred at room temperature, and then heated to a temperature of melting. Within 45 min was added ethylchloride (17.6 ml, 166 mmol) in acetone (125 ml) and the resulting mixture was boiled in a flask with reflux condenser for 210 minutes Then the mixture was cooled to 5oC, filtered, and boiled away in a vacuum. The residue was dissolved in CH2Cl2(500 ml), washed with water (2 times 500 ml) and aqueous saturated NaCl solution (500 ml). The organic phase was dried (MgSO4and boiled away in a vacuum. After thin-layer chromatography (silica gel, eluent: n-heptane/ethyl acetate/methanol 20: 10: 1) and subsequent evaporation in vacuum obtained ethyl [4-methyl-5-(2-thienyl) - 3-isoxazolyl]acetate (8.7 g, 59%).

A mixture of ethyl [4-methyl-5-(2-thienyl)-3-isoxazolyl]acetate (2.5 g, 9.4 mmol) and NBS (Li, filtered and evaporated in vacuum, thus there was obtained ethyl [4-methyl bromide-5-(2-thienyl)-3-isoxazolyl]acetate (2.8 g, 88%).

A mixture of Diethylenetriamine (3.5 g, 16.2 mmol) and tert-piperonyl potassium (0.9 g, 17.0 mmol) in NMP (30 ml) was stirred for 30 min at room temperature (25oC). Added ethyl [4 - methyl bromide-5-(2-thienyl)-3-isoxazolyl]acetate (2.8 g, 8.1 mmol) in NMP (5 ml) (temperature 25-28oC), and the resulting mixture was stirred for 1 h at 28oC, and then poured into a mixture of ice and water (250 ml). The aqueous phase was extracted with diethyl ether (three times 300 ml), and collected together the organic phase washed with saturated NaCl solution (200 ml), dried (MgSO4and boiled away in a vacuum. After thin-layer chromatography (silica gel, eluent: CH2Cl2/ethyl acetate 7:1) was obtained ethyl 2-acetylamino-2-ethoxy-carbonyl-3-[3- [(etoxycarbonyl)methoxy] -5-(2-thienyl)isoxazol-4-yl] propionate (2.3 g, 59%). A suspension of ethyl 2-acetylamino-2-etoxycarbonyl-3- [3-[(etoxycarbonyl)methoxy] -5-(2 - thienyl)isoxazol-4-yl] propionate (2.0 g, 4.1 mmol) in 1 M HCl (130 ml) was boiled in a flask with reflux condenser for 24 hours the Reaction mixture is cooled, extracted with CH2Cl2(2 times 150 ml) and treated with charcoal. After evaporation in vacuumlike, received during the addition of water (1.0 g, 71%). Melting point 228-230oC. CHN: calculated 43.64, 4.27, 8.48; found 43.07, 4.17, 8.43.

1H-NMR (DMSO-d6): 2.86-3.28 (m, 2H), 3.79 (dd, 1H), 4.69 (s, 2H), 7.26 (dd, 1H), 7.69 (dd, 1H), 7.86 (dd, 1H).

13C-NMR (DMSO-d6): 23.50, 52.42, 67.39, 120.45, 127.91, 128.23, 128.48, 129.47, 161.44, 169.63, 170.14, 170.57.

MS (MH+) m/z: 313.

In a similar way, using as alkylating agent instead of ethylchloride ethyl 4-bromobutyrate, received the following connections:

(RS)-2-amino-3-[3-carboxymethoxy-5-(2-thienyl)isoxazol-4 - yl]propionic acid, 7b. Melting point 197-198oC. CHN: calculated 49.41, 4.74, 8.23. Found 49.27, 4.73, 8.30.

1H-NMR (DMSO-d6): 2.01 (qui, 2H), 2.23-2.60 (m, 2H), 2.71-3.08 (m, 2H), 3.56 (dd, 1H), 4.25 (t, 2H), 7.26 (dd, 1H), 7.70 (dd, 1H), 7.85 (dd, 1H).

13C-NMR (DMSO-d6): 24.37, 25.20, 32.44, 53.03, 69.65, 101.01, 127.92, 128.69, 128.79, 129.37, 161.15, 170.39, 170.97, 175.44.

MS (MH+) m/z: 341.

Example 8

[4-[(2-amino-3,4-dioxo-1-cyclobutene-1-yl)aminomethyl] -5-(2 - thienyl)-3-isoxazolyl]acetic acid, monohydrate, 8A

Phthalimide potassium (0.71 g, 3.8 mmol) suspended in dimethylformamide (30 ml) and was heated to 90oC. and Then for 20 min was added ethyl [4-methyl bromide-5-(2-thienyl)-3-isoxazolyl] acetate (1.2 g, 3.5 is stirred at 90oC for 40 minutes the Mixture was cooled and added CH2Cl2(200 ml) and water (200 ml). Resulting phases were separated, the organic phase was washed with saturated solution of CaCl2(twice 150 ml), dried (MgSO4) and was evaporated in vacuum. In the thin-layer chromatography (silica gel, eluent: n-heptane/ethyl acetate 2:1) was obtained ethyl [4-(N-phthalimidomethyl)-5-(2-thienyl)-3-isoxazolyl] acetate. The latter was dissolved in CH2Cl2(200 ml), washed aqueous saturated solution of CaCl2(twice 200 ml), dried (MgSO4), was evaporated in vacuum and then was led from EtOH. This has resulted in the white needle crystals (0.9 g, 64%).

Ethyl [4-(N-phthalimidomethyl)-5-(2-thienyl)-3-isoxazolyl - oxy]acetate (0.60 g, 1.5 mmol) was boiled in a flask with reflux in 1 M NaOH (60 ml) for 45 min the resulting solution was cooled, extracted with diethyl ether (three times with 60 ml) and was acidified to pH 1-2 with concentrated HCl (5 ml). The aqueous phase was extracted with CH2Cl2(three times with 80 ml) and diethyl ether (four times 80 ml). Together the organic phase was evaporated in vacuum, the result is obtained [4-[N-(2-carboxybenzoyl)methyl]-5-(2-thienyl)-3-isoxazolyl]acetic acid (0.6 g, 100%).

To a mixture of the hydrochloride [4-aminomethyl-5-(2-thienyl)-3 - isoxazolidine acetic acid (0.30 g, 1.0 mmol) and 3-amino-4 - ethoxy-3-cyclobutene-1,2-dione (0.16 g, 1.1 mmol), obtained as described above, in EtOH (50 ml) was added NaOH (0.08 g, 2.1 mmol) dissolved in water (3 ml). Then the mixture was stirred for 18 h at 22oC. the resulting suspension was evaporated in vacuo, dissolved in water and was extracted with diethyl ether (two times 150 ml). the pH of the aqueous phase (50 ml) was brought to 3 with 1 M HCl. The resulting crystals were collected by filtration and dried in vacuum. There was obtained compound 8A specified in the title (0.26 g, 69%). Melting point 222-223oC. CHN: calculated 45.78, 3.57, 11.44; found at 45.13, 3.61, 11.16.

1H-NMR (DMSO-d6): 4.75 (d, 2H), 4.86 (s, 2H), 7.30 (dd, 1H), 7.70 (d, 1H), 7,94 (d, 1H).

13C-NMR (DMSO-d6): 34.88, 66.27, 100.97, 127.45, 128.52, 128.67, 130.48, 162.42, 168.19, 168.74, 169.55, 169.95, 183.29.

MS (MH+) m/z: 350.

Example 9

(RS)-2-amino-3-[3-carboxy-5-(2-thienyl)isoxazol-4- -yl] propionic acid, hydrate, 9a

this cold solution was added 1-(2-thienyl)-1-propanol (20 ml, 0.16 mol) in EtOH (10 ml), the resulting mixture was stirred for 2 h at 0oC and then for 16 h at 22oC. the Mixture was evaporated in vacuum and the residue was dissolved in water (400 ml). The aqueous phase was acidified using 1 M HCl to pH 3-4 and extracted with CH2Cl2(three times 300 ml). Together the organic phase was dried (MgSO4) and evaporated in vacuo. After thin-layer chromatography (silica gel, eluent: n-heptane/ethyl acetate 3: 1) was obtained ethyl 2,4-dioxo-3-methyl-4-(2-thienyl)butyrate (20.5 g, 53%).

To the boiling solution of chloride of hydroxylamine (12.6 g, 0.18 mol) in EtOH (200 ml) was added ethyl 2,4-dioxo-3-methyl-4-(2 - thienyl)butyrate in EtOH (60 ml). The resulting mixture was boiled for 2 h in a flask under reflux, then cooled and evaporated in vacuum. After thin-layer chromatography (silica gel, eluent: n-heptane/ethyl acetate 4:1) was obtained ethyl [4-methyl-5-(2 - thienyl)isoxazol)-3-yl]carboxylate (13.2 g, 92%).

A mixture of ethyl [4-methyl-5-(2-thienyl)isoxazol)-3-yl]-carboxylate (8.0 g, 34 mmol), NBS (6.6 g, 37 mmol) and dibenzoylperoxide (0.1 g, 0.4 mmol) in CCl4boiled in a flask with reflux for 6 h and then left for 14 h at 22oC. the resulting mixture was cooled, filtered and evaporated in vacuum, the result was obtained ethoxycarbonyl-5-(2 - thienyl)isoxazol-4-yl] propionate was obtained from ethyl [4 - methyl bromide-5-(2-thienyl)isoxazol-3-yl]carboxylate in analogy to method, described in example 7.

A mixture of ethyl 2-acetamido-2-etoxycarbonyl-3-[3-etoxycarbonyl - 5-(2-thienyl)isoxazol-yl] propionate (1.0 g, 2.2 mmol) and 47% aqueous HBr (50 ml) was heated to a temperature to melt and boil for 40 minutes the resulting solution was evaporated in vacuum, and then added water (20 ml). Added aqueous NaOH (0.1 M, 22 ml) and the mixture was stirred for 2 h at 22oC. the Reaction mixture was evaporated in vacuo and added water (20 ml). The resulting crystals were collected by filtration and dried in vacuum. These crystals were dissolved in 47% HBr and the resulting solution was extracted with diethyl ether, which is then discarded. The aqueous solution was evaporated in vacuum, and then added diethyl ether. The resulting reaction mixture was stirred for 16 h at 22oC, and the crystals were collected by decantation diethyl ether. The crystals were dried under vacuum and was added dropwise aqueous NaOH (0.1 M) to pH 2.5. The resulting crystals were collected during the filtration and suspended in water (15 ml). The reaction mixture was stirred for 48 h at 22oC, and the resulting crystals were collected during the filtration process. It was obtained is listed in the title compound 9a (270 mg, 43%). Melting point 227-228oC. CHN: calculated 46.07, 3.69, 9.77; found 46.15, 3.68,C-NMR (D2O, pH= 12 (NaOD); dioxane): 29.06, 57.18, 111.38, 129.00, 129.01(2C), 129.79, 162.28, 163.26, 167.76, 182.65.

MS (MH+) m/z: 283.

Example 10

(RS)-2-amino-3-[3-(5-tetrazolyl)-5-(2-thienyl)isoxazol-4 - yl]propionic acid, hydrate, 10A

To a solution of ethyl [4-methyl-5-(2-thienyl)isoxazol)-3-yl]- carboxylate (3.7 g, 15.6 mmol), obtained as described above, in tetrahydrofuran (20 ml) was added aqueous HCl (6 M, 100 ml). The reaction mixture is boiled for 6 h in a flask with reflux condenser. The cooled reaction mixture was extracted with diethyl ether (three times 100 ml), and collected together the organic phase was washed water saturated NaCl solution, dried (MgSO4) and evaporated in vacuo. To the residue was added CH2Cl2and the resulting crystals were collected during the filtration process. The filtrate was evaporated in vacuo and added a saturated aqueous solution of NaHCO3. The aqueous phase is washed CH2Cl2(two times 60 ml) and 6 M HCl was acidified to pH 1-2. The aqueous phase was extracted with diethyl ether (three times with 80 ml). Together the organic phase was dried (MgSO4) and evaporated in vacuo. Output [4-methyl-5-(2-thienyl)isoxazol-3-yl] carboxylic acid was 1.6 g (48%).

A mixture of [4-methyl-5-(2-thienyl)isoxazol-3-yl] carboxylic acid (4.0 g,Jn. The resulting solution was evaporated in vacuum. The residue was dissolved in tetrahydrofuran (50 ml) and the organic phase at 0-5oC was poured into water (25%) ammonia solution. The reaction mixture was stirred for 1 h at 22oC and was extracted with diethyl ether (four times 250 ml). Together the organic phase was washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. After that got [4-methyl-5-(2-thienyl)isoxazol-3-yl]carboxamide (3.7 g, 93%).

A mixture of [4-methyl-5- (2-thienyl)isoxazol-3-yl] carboxamide (3.4 g, 16.3 mmol) and POCl3(40 ml) was heated in a flask under reflux for 20 minutes, the Reaction mixture was evaporated in vacuum and the residue was dissolved in diethyl ether. The organic phase was poured into a mixture of ice water. The resulting phases were separated and the aqueous phase was extracted with diethyl ether (three times 100 ml). Together the organic phase was washed with water and saturated aqueous NaCl, dried (MgSO4) and was evaporated in vacuum. The result was obtained [4-methyl-5-(2-thienyl)isoxazol-3 - yl]carbonitril (2.9 g, 95%).

[4-methyl bromide-5-(2-thienyl)isoxazol-3-yl] carbonitrile was obtained from [4-methyl-5-(2-thienyl)isoxazol-3-yl] carbonitrile by analogy with the method opisannymi from [4-methyl bromide- -5-(2-thienyl)isoxazol-3-yl] carbonitrile by analogy with the method described in example 7.

A suspension of ethyl 2-acetylamino-2-etoxycarbonyl-3-[3-cyano-5- (2-thienyl)isoxazol-4-yl] propionate (2.0 g, 4.9 mmol), NaN3(0.4 g, 6.2 mmol) and triethylamine hydrochloride (0.9 g, 6.2 mmol) in dimethoxyethane (80 ml) was heated for 48 h in a flask with reflux condenser. Added NaN3(0.4 g, 6.2 mmol) and triethylamine hydrochloride (0.9 g, 6.2 mmol) and the reaction mixture was heated in a flask under reflux for another 20 h the Cooled reaction mixture was evaporated in vacuum and the residue is treated thin-layer chromatography (silica gel, eluent: ethyl acetate/acetic acid 10:1). After evaporation of the solvent was obtained ethyl 2-acetylamino - 2-etoxycarbonyl-3-[3-(5-tetrazolyl)-5-(2-thienyl)isoxazol-4 - yl]propionate (0.7 g, 32%).

A mixture of ethyl 2-acetylamino-2-etoxycarbonyl-3-[3-(5 - tetrazolyl)-5-(2-thienyl)isoxazol-4-yl] propionate (0.6 g, 1.3 mmol) and 4% aqueous HBr (20 ml) was heated in a flask under reflux for 30 minutes, the Reaction mixture was cooled and added to water (50 ml). The aqueous phase was extracted with diethyl ether (three times in 75 ml). Together the organic phase was extracted with water (50 ml). Together the aqueous phase was evaporated in vacuum. Added water (25 ml) and aqueous NaOH (0.1 M, 16 ml) and the resulting creatinine 10A (0.4 g, 90%). Melting point 209-211oC.

1H-NMR (DMSO-d6): 3.27-3.54 (m, 2H), 4.37-4.47 (m, 1H), 7.33 (dd, 1H), 7.76 (d, 1H), 7.94 (d, 1H).

13C-NMR (DMSO-d6): 24.51, 51.82, 108.03, 127.80, 127.95, 128.57, 129.71, 151.63, 155.91, 161.96, 170.40.

MS (MH+) m/z: 307.

Example 11

(RS)-2-amino-3-[3-hydroxy-5-(2-oxazolyl)isoxazol-4 - yl] propionic acid, acetate, 11a

3-hydroxy-4,5-dimethylisoxazol was obtained by the method described by R. Jacquier, et al., Bull., Soc. Chim. Fr., 1970, 2685-90 and modified Sato K., et al., Agric. Biol. Chem., 1986, 50(7). 1831-1837.

A suspension of 3-hydroxy-4,5-dimethylisoxazole (68.5 g, 0.6 mol) and K2CO3(was 125.6 g, 0.9 mmol) in acetone (1000 ml) was heated to the temperature of melting. The solution ethylbromide (99.1 g, 0.9 mol) in acetone was added to the reaction mixture dropwise. The reaction mixture was stirred for another 8 h, then cooled, filtered and evaporated in vacuum. After thin-layer chromatography (silica gel, eluent: ethyl acetate/heptane 1:3) residue has received 3 ethoxy-4,5 - dimethylisoxazol (52.7 g, 62%).

To a chilled (5oC) a mixture of 3-ethoxy-4,5-dimetrios-ash (65.6 g, 0.5 mol) in CCl4(500 ml) was added Br2(150 g, 0.9 mol). The reaction mixture for 96 h, was stirred in a dark place. Added water (200 ml), and adding sodium sulfite R is selected together the organic phase was washed with saturated aqueous NaCl solution, dried (MgSO4) and evaporated in vacuo. The residue was dissolved in a mixture of water/NMP (15:85, 700 ml) and the reaction mixture was stirred for 24 h at 100oC. was Added water and the resulting aqueous solution was extracted with diethyl ether.

Together the organic phase was washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. The residue was treated with thin layer chromatography (silica gel, eluent: ethyl acetate/n-heptane 1:2). The result was 3-ethoxy-5 - hydroxymethyl-4-methylisoxazol (26,3 g, 36%).

To a solution of 3-ethoxy-5-hydroxymethyl-4-methylisoxazole (25,0 g, 0.16 mol) in a mixture of H2SO4/H2O/acetic acid (1:2:7, 200 ml) was added a mixture of CrO3/H2O/acetic acid (1: 2: 2, 160 ml). The resulting reaction mixture was stirred for 18 h at 22oC. was Added water and the resulting aqueous phase was extracted with diethyl ether. Together the organic phase was washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. The result obtained (3-ethoxy-4-methylisoxazol-5 - yl)carboxylic acid (22.7 g, 83%).

A solution of (3-ethoxy-4-methylisoxazol-5-yl)carboxylic acid (5.0 g, 29 mmol) in CH2Cl2(250 ml), SOCl22Cl2(100 ml) and was added dropwise to a chilled (5oC) a mixture of aminoacetaldehyde (3.5 ml, 3.2 mmol) and K2CO3(6.0 g, 4.4 mmol) in CH2Cl2(100 ml). The resulting solution was stirred for 4 h at 22oC. was Added water and the resulting phases were separated. The organic phase is washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. Thus obtained 5-[N-(acetyldihydrocodeine)carboxamido] -3-ethoxy-4 - methylisoxazol (7.0 g, 93%).

A mixture of 5-[N-(acetyldihydrocodeine)carboxamido] -3-ethoxy-4-methylisoxazole (6.4 g, 25 mmol), P2O5(7.1 g, 50 mmol) and concentrated H2SO4(150 ml) was heated in a flask under reflux for 30 minutes Refrigerated (5oC) the reaction mixture was poured into a mixture of ice water and the resulting aqueous phase was extracted with diethyl ether (two times 500 ml). Together the organic phase was washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. The residue was treated with thin layer chromatography (silica gel, eluent: CH2Cl2/ethyl acetate/methanol 1:1:0.5) and received 3-hydroxy-4-methyl-5-(2-oxazolyl)isoxazol (340 mg, 8.3%).

e (0.33 ml) and tetrahydrofuran (40 ml) was added a solution of benzosulfimide (0.27 ml, 2.1 mmol) in tetrahydrofuran (40 ml). The resulting reaction mixture was stirred for 18 h at 22oC. After evaporation in vacuo of the solvent and thin-layer chromatography (silica gel, eluent: ethyl acetate/n-heptane 1:3) has received 3 benzosulfimide-4-methyl-5-(2-oxazolyl)isoxazol (520 mg, 85%).

A mixture of 3-benzosulfimide-4-methyl-5-(2-oxazolyl) isoxazol (500 mg, 1.6 mmol), NBS (300 mg, 1.7 mmol) and peroxide of Dibenzoyl (0.1 g, 0.4 mmol) in CCl4(100 ml) for 24 h was boiled in a flask with reflux condenser. The cooled reaction mixture is filtered and evaporated in vacuum. The result was 3-benzosulfimide-4-methyl bromide-5-(2 - oxazolyl)isoxazol (440 mg, 70%).

Ethyl 2-acetylamino-2-etoxycarbonyl-3- [3-benzosulfimide-5-(-2-oxazolyl)isoxazol-4-yl]propionate (120 mg, 22%) was obtained from 3-benzosulfimide-4-methyl bromide-5-(2 - oxazolyl)isoxazol (440 mg) in analogy with the method described in example 7.

To a solution of ethyl 2-acetylamino-2-etoxycarbonyl-3-[3 - benzosulfimide-5-(2-oxazolyl)isoxazol-4-yl]propionate (120 mg, 0.25 mmol) in methanol (10 ml) was added NaOH (20 mg, 0.5 mmol) in methanol (10 ml). The reaction mixture was stirred for 2 h at 22oC, and the solvent is boiled away in a vacuum. To the East who were garofali CH2Cl2. Then the aqueous phase is boiled away in vacuum and added 1 M aqueous HCl (10 ml). The reaction mixture is boiled in a flask under reflux for 3 hours, the Reaction mixture was evaporated in vacuo and added ether (10 ml). The crystals obtained as a result of this, collected on the filter and dried in vacuum. The obtained crystals were dissolved in 1 M HCl, and the aqueous phase washed with diethyl ether. The aqueous phase is boiled away in vacuum and the residue dissolved in water. Then the aqueous phase is skipped through a column containing ion exchange resin [Amberlite IRA 400 (S1, 150 ml)] , using as eluent a 1 M acetic acid. After evaporation of the solvent has been specified in the title compound 11a (15 mg, 27%).

1H-NMR (D2O, dioxane): 3.26-3.36 (m, 2H), 4.11-4.21 (m, 1H), 7.40 (s, 1H), 8.04 (s,1H).

13C-NMR (D2O, dioxane): 23.41, 54.17, 105.83, 128.96, 142.16, 152.56, 171.55, 177.26, 177.74.

MS (MH+) m/z: 240.

Example 12

(RS)-2-amino-3-[3-hydroxy-5-(2-thiazolyl)isoxazol-4- -yl] propionic acid, 12A

A mixture of 5-[N-(acetylcholinesterase)carboxamido] -3- -ethoxy-4-methylisoxazole (6.5 g, 25.2 mmol), obtained as described in example 11, and P2S5(5.6 g, 25.2 mmol) in toluene was heated for 2 h in a flask with reverse holodilny the toluene/ethyl acetate 11:1), the result was 3-ethoxy-4-methyl-5-(2 - thiazolyl)isoxazol (0.5 g, 9%).

A mixture of 3-ethoxy-4-methyl-5-(2-thiazolyl)isoxazol (0.5 g, 2.4 mmol) and NBS (0.5 g, 2.6 mmol) in CCl4(50 ml) was heated for 36 h before fusion. The cooled reaction mixture is filtered and evaporated in vacuo, the obtained 4-methyl bromide-3-ethoxy-5-(2 - thiazolyl)isoxazol (0.6 g, 87%).

Ethyl 2-acetylamino-2-etoxycarbonyl-3-[3-ethoxy-5-(2-thiazolyl)isoxazol-4-yl] propionate (320 mg, 41%) was obtained from 4-methyl bromide-3-ethoxy-5-(2-thiazolyl)isoxazol (540 mg), by analogy with the method described in example 7.

A suspension of ethyl 2-acetylamino-2-etoxycarbonyl-3-[3-ethoxy-5-(2-thiazolyl)isoxazol-4-yl] propionate (245 mg, 0.6 mmol) in water 47% HBr (5 ml) was boiled in a flask with reflux condenser for 30 minutes the Reaction mixture is boiled away in vacuum and added water (30 ml). The aqueous solution was treated with charcoal, filtered and evaporated in vacuum. The residue was dissolved in water and the resulting aqueous solution skipped through a column containing ion exchange resin [Amberlite IRA 400, (Cl, 150 ml], using as eluent 2 M acetic acid. After evaporation of the solvent has been specified in the title compound 12A (66 mg, 45%).

1H-NMR (DMSO-d610% OF CF8, 51.03, 102.43, 122.64, 144.76, 154.97, 159.81, 170.31, 170.50.

MS (MH+) m/z: 256.

(RS)-2-amino-3-[3-hydroxy-5-(5-tetrazolyl)isoxazol-4 - yl] propionic acid was obtained in a similar method with the following modifications:

(3 ethoxy-4-methylisoxazol-5-yl)carboxylic acid, obtained as described above were transformed into the corresponding carboxamide known methods using SOCl2and aqueous ammonia (25%). The corresponding nitrile, (3 ethoxy-4 - methylisoxazol-5-yl)carbonitrile obtained by the dehydrogenation of amine using POCl3. Bromirovanii (3 ethoxy-4-methyl - isoxazol-5-yl)carbonitrile using NBS and the subsequent interaction with Diethylenetriamine obtained ethyl 2-acetylamino-2-etoxycarbonyl-3-(5-cyano-3-ethoxyethoxy-4- -yl)propionate. The formation of the corresponding compound 5-(5- -tetrazolyl) preferably by the interaction of ethyl 2-acetylamino-2-etoxycarbonyl-3-(5-cyano-3-ethoxyethoxy-4 - yl)propionate with NaN3and the hydrochloride of triethylamine in dimethoxyethane. Removing protection from ethyl 2-acetylamino-2-etoxycarbonyl-3-[3-ethoxy - 5-(5-tetrazolyl)isoxazol-4-yl)propionate was performed using water 47% HBr in the result obtained (RS)-2-amino-3-[3-hydroxy-5-(5-tetrazolyl)isoxazol-4- -yl] Isleta, hydrate, 13A

A solution of 5-(2-pyridyl)isoxazol-3-ol (1.14 g, 7.0 mmol) (obtained from the hydrobromide methyl 2,3-dibromo-3-(2-pyridyl) propionate using a modified method described by Tomita K., Ann. Sankyo Res. Lab., 1973, 25. 3-5) and NaOH (0.28 g, 7.0 mmol) in water (10 l) and ethanol (10 ml) was boiled away the dryness and further dried for 2 h with 0.1 mm Od. The resulting residue suspended in dry N,N-dimethylformamide (10 ml) and cooled to -10oC. was added dropwise dimethylsulfate (0.73 ml, 7.7 mmol) and the resulting mixture for 1 h and was stirred at -10oC and then for 15 h at 22oC. the resulting solution was evaporated in vacuum. To the residue was added water and the resulting mixture was extracted with methylene chloride (three times 30 ml). Together the organic phase was dried and boiled away in a vacuum. The residue was treated with thin layer chromatography (silica gel, eluent: toluene/ethyl acetate/glacial acetic acid 1:1:1), the result is obtained 3-methoxy-5-(2-pyridyl)isoxazol (0.73 g, 59%).

A solution of 3-methoxy-5-(2-pyridyl)isoxazol (1.53 g, 8.68 mmol) in dry tetrahydrofuran (40 ml) was cooled to -78oC. for 5 min, the solution was added n-utility in hexane (9.0 ml, 1.6 M, 14 mmol) and then p-formaldehyde (2.48 g, 83 mmol). Poluchenno is or vacuum, added water (25 ml) and methylene chloride (40 ml), the pH was brought to 6 with dilute HCl. The phases were separated, and the aqueous phase was extracted with methylene chloride (two times 30 ml). Together the organic phase was dried and boiled away in a vacuum. Using thin-layer chromatography (silica gel, eluent: toluene/ethyl acetate 19: 1) identified 357 mg of 4-hydroxymethyl-3-methoxy-5-(2-pyridyl)isoxazol (yield 20%).

A mixture of 4-hydroxymethyl-3-methoxy-5-(2-pyridyl)-isoxazol (357 mg, 1.73 mmol) and thionyl chloride (10 ml) was boiled in a flask with reflux for 2 h Then the reaction mixture is boiled away in a vacuum. To the residue was added an aqueous solution of acid sodium carbonate (5%, 15 ml) and the resulting mixture was extracted with methylene chloride (two times 25 ml). Together the organic phase was dried and boiled away in the vacuum, the obtained 4-chloromethyl-3-methoxy-5- (2-pyridyl)isoxazol (388 mg, 100%).

To a solution of dimethylacetamide (361 mg, 1.91 mmol) in dry N,N-dimethylformamide (4 ml) in small portions was added sodium hydride (84 mg, 60% in oil, 2.09 mmol). The resulting mixture was stirred for 45 min at 22oC. To the reaction mixture was added dropwise a solution of 4-chloromethyl-3-methoxy-5-(2 - pyridyl)isoxazol (390 mg, 1.74 mmol) in dry ATCO added water (10 ml). The aqueous reaction mixture was extracted with methylene chloride. Together the organic phase was dried and boiled away in a vacuum. In the thin-layer chromatography (silica gel, eluent: toluene/ethyl acetate 19: 1) was obtained methyl 2-acetylamino-2-methoxycarbonyl-3-[3- -methoxy-5-(2-pyridyl)isoxazol-4-yl]propionate (500 mg, 6%).

A mixture of methyl 2-acetylamino-2-methoxycarbonyl-3-[3-methoxy-5- (2-pyridyl)isoxazol-4-yl]propionate (500 mg, 1.3 mmol) and aqueous Hydrobromic acid (47%, 20 ml) was boiled in a flask with reflux for 1 h the Mixture was evaporated in vacuo and to the residue was added water (10 ml). The resulting aqueous solution was treated with charcoal and the filtrate carefully until pH 3 was added aqueous 2 N. )solution of sodium carbonate. After 24 h at 5oC collected the precipitate, washed with water and dried in vacuum. In the received connection 13A specified in the title (174 mg, 54%).

CHN: calculated at 52.07, 4.57, 16.56; found 52.03, 4.50, 16.38.

1H-NMR (200 MHz, DMSO-d6): 8.70 (d, 1H), 7.95 (m, 1H), 7.80 (d, 1H), 7.45 (m, 1H), 3.75 (m, 1H), 3.40 (dd, 1H), 3.15 (dd, 1H).

13C-NMR (200 MHz, DMSO-d6): 171.83, 171. 53, 162.88, 149.68, 147.64, 137.82, 124.41, 121.17, 104.86, 53.30, 24.24.

In a similar way received:

(RS)-2-amino-3-[3-hydroxy-5-(4-pyridyl)isoxazol-4 - yl)propehts, DMSO-d6): 8.70 (d, 2H), 7.65 (d, 2H), 3.75 (m, 1H), 3.05 (dd, 1H), 2.90 (dd, 1H).

13C-NMR (200 MHz, DMSO-d6): 172.97, 171.20, 161.73, 150.52, 135.30, 121.01, 105.39, 52.70, 24.69.

Example 14

(S)-(+)-2-amino-3-[3-hydroxy-5-phenylisoxazol-4 - yl)propionic acid, hydrate, 14a

Diastereomer salt (RS)-2-amino-3-[3-hydroxy-5 - phenylisoxazol-4-yl)propionic acid, 0.5 H2O (11.0 g, 44 mmol) (obtained as described in the work Chrictensen I. T., 1989, ibid) and (R)-(+)-1-phenylethylamine (5.1 g, 44 mmol) was besieged from ethanol (300 ml) at 0oC. the Obtained crystals were dissolved in water and the resulting mixture was acidified to pH 2.5 with 0.1 N. )hydrochloric acid. Specified in the title crystalline compound was collected during the filtration (320 mg, 6%). Melting point 251-253oC []D: +35.3o(c= 0.25, 1 N. )HCl, 20oC), ee=99.0%; CHN: calculated 58.05, 4.88, 11.29. Found 58.03, 5.22, 11.33.

(R)-(-)-2-amino-3-[3-hydroxy-5-phenylisoxazol-4-yl)Pro - peony acid, hydrate, 14b, received a similar way, using (S)-(-)-1-phenylethylamine (5.1 g, 44 mmol). The output of the connection specified in the title, amounted to 1.4 g, 26%. The water content, as defined, is 7.7%. Melting point 252-254oC; []D: -37.8o(C=1, 1 N. )HCl, 20oC) it=99.8%; CHN: calculated 54.12, 5.31, 10.52; found-3-[5-(4-forfinal)-3-hydroc - sisaxato-4-yl)propionic acid in analogy with (RS)-2-amino-3- [3-hydroxy-5-(2-thienyl)isoxazol-4-yl] propionic acid, as described in example 1:

(-)-2-amino-3-[5-(4-forfinal)-3-hydroxyethoxy-4-yl)propionic acid, 14C.

Melting point 247oC, it= 99.6%; CHN: calculated 54.12, 4.16, 10.56. Found 54.16, 4.12, 10.48.

1H-NMR (200 MHz, D2O, NaOD, dioxane): 2.56 (dd, 1H), 2.82 (dd, 1H), 3.40 (dd, 1H), 7.22 (dd, 2H), 7.64 (dd, 2H).

(+)-2-amino-3-[5-(4-forfinal)-3-hydroxyethoxy-4-yl)propionic acid, 14d.

Melting point 246oC []D: +37.9o(C=0.25, 1 N. )HCl, 20oC); ee= 99.8%. CHN: calculated 54.12, 4.16, 10.56. Found 54.12, 4.06, 10.45.

1H-NMR (200 MHz, D2O, NaOD, dioxane): identical 14C.

Example 15

(-)-2-amino-3-[3-hydroxy-5-(2-thienyl)isoxazol-4-yl)propionic acid, 15A

Compound 1A (20.8 g, 81.8 mmol), obtained as described in example 1 was added to a mixture of ethanol (350 ml) and acetylchloride (35 ml) at 25oC. the reaction mixture is boiled in a flask under reflux for 3.5 hours, the Cooled solution was boiled away in vacuum, receiving the atom (RS)-2-amino-3- [3-ethoxy-5-(2-thienyl)isoxazol-4-yl)propionic acid (25.0 g, 96%).

A solution of (RS)-2-amino-3-[3-ethoxy-5-(2-thienyl)isoxazol-4 - yl)propionic acid (24.9 g, 78.1 mmol) in CH2Cl2(1200 ml) and triethanolamine (45 ml) nagivational (16.2 g, 87.9 mmol) obtained by the known methods of (S) - (+)-2-methoxy-2-phenylacetic acid in CH2Cl2(250 ml). The resulting reaction mixture was heated for another 1 h in a flask with reflux condenser. The cooled reaction mixture was evaporated in vacuum and subjected to thin-layer chromatography (silica gel, eluent: n-heptane/ethyl acetate/acetic acid 55:45:1. The result was obtained (RS)-ethyl 2-[N-(2-methoxy-2 - phenylacetamido] -3-[3-hydroxy-5-(2-thienyl)isoxazol-4 - yl]propionate (27.2 g, 81%).

To a cooled to 0oC a solution of (RS)-ethyl 2-[N-(2-methoxy - 2-phenylacetamido] -3-[3-hydroxy-5-(2-thienyl)isoxazol- -4-yl] propionate (27.2 g, 61.1 mmol) in dry tetrahydrofuran (600 ml) and triethanolamine (10 ml) for 160 min was added benzosulphochloride (12.5 g, 70.8 mmol) in dry tetrahydrofuran (300 ml). The resulting solution was stirred 18 h at 22oC. the Reaction mixture was evaporated in vacuo and added to her water and CH2Cl2. The resulting phases were separated, the organic phase was dried (MgSO4and boiled away in a vacuum. The obtained residue containing two diastereoisomer (RS)-ethyl 2-[N-(2-methoxy-2-phenylacetamido] -3-[3-benzosulfimide- -5-(2-thienyl)isoxazol-4-yl] propionate was subjected to thin-layer chromatography (silica gel, eluent: toluene/acilac the Omer 2) amounted to 9.0 g (51%).

Isomer 1 (10.4 g, 18.2 mmol) was dissolved in methanol (600 ml). Added NaOH (0.8 g, 20.0 mmol) in methanol (20 ml) and the resulting reaction mixture for 10 min was stirred at 22oC. To the reaction mixture were added water (5000 ml) and concentrated HCl pH aqueous solution was brought to 1. The aqueous phase was extracted with diethyl ether and CH2Cl2. Together the organic phase was dried and evaporated in vacuum. After thin-layer chromatography (silica gel, eluent: ethyl acetate/n-heptane/acetic acid 50:50:1) was obtained isomer 1 (RS)-ethyl 2-[N-(2-methoxy - 2-phenylacetamido]-3-[3 - hydroxy-5-(2-thienyl)isoxazol-4-yl]propionate (5.8 g, 74%).

The mixture thus obtained isomer 1 (5.8 g, 13.5 mmol) and water 47% HBr (250 ml) was boiled in a flask with reflux condenser for 1 h, the Reaction mixture is boiled away in vacuum and added water. The aqueous solution was washed CH2Cl2and processed coal. The volume of this aqueous solution was reduced to 200 ml by evaporation in a vacuum. Zwitterion isomer 1 was led from this aqueous solution by adding to pH 3 aqueous NaOH. The resulting crystals were collected during the filtration process, thus obtained (-)-2-amino-3-[3-hydroxy-5 - (2-thienyl)isoxazol-4-yl)propionic acid, 15A (1.0 g, 30%). Tempera 46.88, 3.97, at 10.89.

MS (MH+) m/z: 255.2.

Similarly when processing isomer 1 got:

(+)-2-amino-3-[3-hydroxy-5-(2-thienyl)isoxazol-4-yl)propionic acid, 15b.

Melting point 259-261oC []D: +24.4o(C=0.25, 1 N. )HCl, 20oC); ee=98.9%; CNH: calculated 47.23, 3.97, 11.02. Found 47.15, 4.05, 10.88.

MS (MH+) m/z: 255.2.

Compound 4C was processed similarly to get:

(-)-2-amino-4-[3-hydroxy-5-(2-thienyl)isoxazol-4 - yl)butane acid, 15s. Melting point 217-219oC; []D: -16.3o(C=0.25, 1 N. )HCl, 20oC); it=85.1%; and

(+)-2-amino-4-[3-hydroxy-5-(2-thienyl)isoxazol-4-yl)butane acid, 15d. Melting point 217-219oC []D: +15.6o(C=0.25, 1 N. )HCl, 20oC); ee=81.9%.

Pharmacology

Compounds of the present invention were tested by the following well-known and reliable research methods. The results of testing the binding of the receptors are shown in table 1, and results of electrophysiological studies of cortical drug rat table 2 (see end of description).

Binding of [3H]AMPA,

In this test the affinity of the drug to the AMPA receptors was determined serenityoneday method version Honore T. and Nielsen M , Neurosci. Lett., 1985, 54, 27-32, in the presence of KSCN. This means that were marked only place that has a strong affinity binding of [3H] AMPA.

Used membrane preparations obtained by the method Ransom R. W. and Stec, J. Neurochem., 1988, 51. 830-836.

Binding of [3H]RAF

In this test the affinity of the drug to the NMDA receptor was determined by measuring the ability to substitute [3H] RRA (4-(3 - phosphonopropyl)piperazine-2-carboxylic acid) of the binding sites of the vector of the NMDA receptor.

The test was carried out according to the method of Murphy D. E., et al., J. Pharm. Exp. Ther., 1987, 240. 778-784. Used membrane preparations obtained by the method described above.

The model cortical wedge

The model cortical wedge is a test in which to quantify the impact of ligand Glu receptors and assess the pharmacological profile of these ligands (for example, the properties of the agonist/antagonist) were studied thin sections of rat brain in vitro. Testing was carried out as described Harrison N. L. and Simmonds, M. A., Br. J. Pharmacol., 1985, 84, 381 - 391 modifications, Wheatley P. L., Br. J. Pharmacol., 1986, 87, 159P.

It was established in pharmacological characterization of cortical preparati selective antagonists of NMDA, and yet a number of compounds are selective antagonists of AMPA receptors and NMDA receptors. All compounds show activity in the μm range.

Results

From table 1 it is evident that some compounds of the present invention selectively replace [3H]AMPA of AMPA receptors in vitro at low micromolar concentrations. Other compounds selectively replace [3H]RAF of NMDA receptors in vitro. A number of compounds of the present invention, as has been found, replace [3H]] AMPA and [3H]RAF respectively of AMPA receptors and NMDA receptors in vitro.

In cortical preparations of some compounds of the present invention, it has been found that are agonists or partial agonists, while others are antagonists. Therefore, the present invention includes compounds with different agonistic/antagonistic profile when glutamic acid receptors, with activity at low micromolar concentrations.

Examples of formulations

Pharmaceutical formulations according to the present invention can be obtained using methods that are conventional in this field.

For example: tablets can be obtained, the shift of the mixture in a suitable tablet press machine. Examples of adjuvants or diluents include: corn starch, talc, magnesium stearate, gelatine, lactose, gums, etc. you Can also use any other adjuvants or coloring additives, flavorings, preservatives, etc. provided that they are compatible with the active ingredients.

Injectable solutions can be obtained by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, bringing the resulting solution to the desired volume, the sterilization of the solution and filling them suitable vials or containers. Can be added to any suitable additives that are useful in this area, such as toning agents, preservatives, antioxidants, etc.

Typical examples of recipes for medicines according to the present invention are listed below:

1) Tablets containing 5 mg of compound 1A:

Compound 1A - 5.0 mg

Lactose 60 mg

Corn starch 30 mg

Hydroxypropylcellulose - 2.4 mg

Microcrystalline cellulose - 19.2 mg

Croscarmellose sodium type a - 2.4 mg

Magnesium stearate - 0.84 mg

2) Tablets containing 1 mg of compound 4C:

allicesia cellulose - 14.4 mg

Croscarmellose sodium type a - 1.8 mg

Magnesium stearate - 0.63 mg

3) Syrup, containing in 1 ml:

Compound 1A - 5.0 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerol 50 mg

Methyl paraben 1 mg

Propyl-paraben - 0.1 mg

Ethanol - 0.005 ml

Flavor - 0.05 mg

Saccharin - 0.5 mg

Water Up to 1 ml

4) Solution for injection containing 1 ml:

Compound 4A - 0.5 mg

Sorbitol - 5.1 mg

Acetic acid - 0.08 mg

Water for injection To 1 IFL

1. Connection 2-aminocarbonyl acid, substituted 5-arylisoxazoles-4-yl having a General formula I

< / BR>
where a represents a bond or a spatial group1-6alkylen,

B represents-CH(NH2)-COOH or a group of formula II

< / BR>
E represents O, COO, O(CH2)n-Soo (where n is an integer from 1 to 6) or 5-tetrazolyl;

D represents O;

R1represents phenyl, naphthyl, thienyl, benzothiazyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, chinoline or furyl, or phenyl, thienyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl or furyl substituted by one or two substituents selected from propylen, In group-CH(NH2)COOH, E represents Oh, D is Oh, and R1is phenyl or phenyl substituted by halogen, the compound is in the form of a pure enantiomer, or pharmaceutically acceptable salt of these compounds.

2. Connection on p. 1, characterized in that a represents a bond or C1-C3alkylen.

3. Connection on p. 1, characterized in that a represents a-CH(NH2)-COOH or a group of formula II.

4. Connection on p. 1, where E represents Oh, soo-O-(CH2)n-Soo (n = 1,2 or 3) or 5-tetrazolyl, D represents O.

5. Connection on p. 1, wherein R1is thienyl, phenyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl or furyl substituted by one or two substituents selected from the group consisting of halogen, C1-6alkyl or trifluoromethyl.

6. Connection on p. 1, wherein R1is thienyl, oxazolyl, thiazolyl, pyridyl, phenyl, pyrazolyl, triazolyl, tetrazolyl, or furyl or naphthyl, or thienyl, or phenyl, substituted by halogen or stands.

7. Connection on p. 1, wherein R1is a 2-thienyl, 3-thienyl under item 1, wherein a represents a bond or C1-3-C3alkylen, represents a-CH(NH2)-COOH or a group of formula II, E and D both represent O, and R1represents 2-pyridyl, 4-pyridyl, thienyl or phenyl or thienyl or phenyl substituted by halogen or stands.

9. The pharmaceutical composition exhibiting the properties of ligand-receptor excitation amino acids, characterized in that it contains a compound according to any one of paragraphs.1-8 in combination with a pharmaceutically acceptable carrier or diluent.

10. Connection 2-aminocarbonyl acid, substituted 5-arylisoxazoles-4-yl, any of the PP.1-8, is used to obtain pharmaceutical compositions exhibiting the properties of ligand-receptor excitation of amino acids.

 

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< / BR>
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< / BR>
where R is

< / BR>
< / BR>
R5represents a group of the formula:

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CH3(CH2)mCH2-CH2-,< / BR>
,< / BR>
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where R9and R10independently are hydrogen or alkyl
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