Esters of amino acids, methods for their preparation, intermediates, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to the field of organic chemistry. Describes an ester of General formula (I), its N-oxide form, pharmaceutically acceptable additive salt or its stoichiometric isomeric form, where-a-b - form a bivalent radical of the formula: -N=CH (a) -,- CH=N- (b), where one hydrogen atom in the radicals (a) and (b) may be replaced1-6alkyl radical; L is an acyl part of an amino acid; D is a radical of formula (D1) or (D3), where X is N; R1is a halogen; R2is hydrogen or halogen. Also describes how to obtain the compounds of formula (I), enantiomerically pure form intermediate compound, enantiomeric mixture of intermediate products, the pharmaceutical composition having anti-fungal activity of a broad spectrum of action, and method for producing the pharmaceutical composition. The technical result obtained new compounds with useful biological properties. 7 C. and 11 C.p. f-crystals, 10 PL.

< / BR>
< / BR>

The invention relates to a new azole antifungal agents of broad-spectrum and their receipt; it is more the dark fungal infections of humans are relatively rare in countries with temperate climates, and many of the fungi that can become pathogenic, usually co-exist in the human body or are common to the environment. However, in recent decades there has been increasing evidence of cases worldwide distribution of numerous life-threatening systemic fungal infections, and they now represent the greatest threat to many at-risk patients, especially those who are already hospitalized. Most of this increase is associated with improved viability of people with low immune system and with the constant use of antimicrobials.

Moreover, the typical flora for many common fungal infections is also changed, what is the epidemiological transition, with increasing value. Patients most at risk include those who have disorders of the immune system that occur either primarily as a result of immunosuppression caused by cytotoxic drugs or HIV infection, or secondary to other debilitating diseases such as cancer, acute leukemia, invasive surgery or prolonged use of antimicrobials.

the, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis.

For the treatment and prophylaxis of systemic fungal infections in patients with weakened immune systems apply antifungal agents such as ketoconazole, Itraconazole and fluconazole. However, there is increasing concern about the sustainability of the fungi to some of these agents, especially those that have a more narrow spectrum of activity, such as fluconazole. Worse, in the medical world it is known that about 40% of people suffering from severe systemic fungal infections, can with difficulty, or not able to take medicines orally. This inability is due to the fact that these patients are in a coma or suffer from severe gastroparesis. Consequently, the use of insoluble or poorly soluble antifungal tools such as Itraconazole, which are difficult to enter intravenously, is extremely difficult in this group of patients.

Therefore, there is a need for new antifungal drugs, preferably broad-spectrum antifungal activity against which there is no resistance and which can be administered intravenously. Preferably antifungal drugs d what allows the physician to continue treatment with the same drug after as the patient will come out of the state, which requires intravenous administration of specified drugs.

In US-4267179 disclosed are heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxy-methyl-1,3-dioxolane-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles, applicable as antifungal agents. The specified patent covers Itraconazole, which is now widespread worldwide fungicide broad spectrum of action.

US-4916134 indicates 4-[4-[4-[(2,4-defloriani)-2-(1H-azolylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] triazolone with improved antimicrobial properties.

In US-4791111 disclosed derivatives[[4-[4-(4-phenyl-1-piperazinil)phenoxymethyl] -1,3-dioxolane-2-yl] -1H-imidazoles and 1H-1,2,4-triazoles, which are structurally close to some of the compounds of the present invention, which indicates that they have improved antimicrobial properties. Especially the connection, which is here Cys-4-[4-[4-[4-[[2-(2,4-defloriani)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] -methoxy] -phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazole, moreover, the specified connection is a mixture of stereoisomers of all WOSM disclosed [2R-[2, 4, 4(R*)]], [2R-[2, 4, 4(S*)]], [2S-[2, 4, 4(S*)] ] and [2S-[2, 4, 4(R*)]] stereospecific isomers of Itraconazole, which, as indicated, have a greater solubility in water than their corresponding diastereomeric mixture.

In WO 95/19983 disclosed derivatives[[4-[4-(4-phenyl-1-piperazinil)phenoxymethyl]1,3-dioxolane-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazole, structurally similar to some of the compounds of the present invention, which, as indicated, are water-soluble, antimicrobial compounds.

In WO 95/17407 disclosed tertrahydrofuran ring antifungal agents, as well as in WO 96/38443 and in WO 97/00255. In the last two publications disclosed tertrahydrofuran ring antifungal agents, which, as indicated, are soluble and/or suspendiruemye in the aquatic environment and is suitable for on/in the introduction and include group substituents, which can be easily converted in vivo in hydroxyl groups.

The present invention relates to new compounds of the formula

< / BR>
their N-oxide forms, their pharmaceutically acceptable additive salts and their stereochemical isomeric forms, And In - form a bivalent radical of the formula

-N=CH- (a);

-CH=N- (b);

-CH=CH - (),

where one hydrogen atom in the radicals (a) and (b) mo is 1-6alkyl radical;

L represents the acyl part of amino acids and, thus, -O-L is the group of ester amino acids;

D is a radical of formula (D1) or (D2)

< / BR>
< / BR>
where X is N or CH;

R1is a halogen;

R2is hydrogen or halogen;

In the definitions above and below, the term halogen represents fluorine, chlorine, bromine and iodine; C1-6alkyl characteristic for hydrocarbons with straight or branched chain, having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, and their possible branched isomers.

In the definition of L, the term "amino acid" refers, including, but not limited to

- the 20 amino acids commonly present in proteins such as glycine, alanine, valine, leucine, isoleucine, methionine, Proline, phenylalanine, tryptophan, series, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine; and

- a relatively rare amino acids that have been identified in certain types of proteins, such as, for example, 4-hydroxyproline, hydroxylysine, Desmo is or combined form, but never present in proteins, whether they are -, -, or amino acids, or they have an L - or D-configuration, such as, for example, alanine, homocysteine, homoserine, citrulline, ornithine, -aminobutyric acid, D-glutamic acid and D-alanine; and

- synthetic analogs of amino acids, such as, for example, phenylglycine, p-ferienland, tionin, norleucine and the like.

In the definition of L, the term "amino acid" also implies the inclusion of those amino acids in which the amine portion is one - or disubstituted; in such compounds L may be represented by-L'-NRXRY. Examples RXand RYinclude hydrogen, C1-6alkyl and well-known experts in this field protective group for the amine part, for example tert-butyloxycarbonyl, benzyloxycarbonyl, trifloromethyl or those protective groups which are mentioned in Chapter 7, "Protective Groups in Organic Synthesis" by T. Greene and P. Wuyts (John Wiley & Sons, Inc.1991). RXand RYcan also form together with the nitrogen atom of amine part of the amino acid ring, such as, for example, pyrolidine, piperidine, morpholine, pieperazinove or substituted pieperazinove ring, and specified substituted piperazine PR is Kilom, hydraxis1-6the alkyl, amino1-6the alkyl, mono - or di(C1-6alkyl)amino1-6the alkyl.

For example, if L represents the acyl part of N,N-diacylglycerol, L' represents a-C(=O)-CH2- , and-NRXRYrepresents-N(CH2CH3)2.

Many amino acids are commercially available and are listed in Novabiochem's 1997/1998 Catalog & Peptide Synthesis Handbook (Calbiochem-Novabiochem AG, Laufelfingen, Switzerland). Assume that the commercially available amino acids are also included in the term "amino acid", as used in the definition of L.

Assumes pharmaceutically acceptable salt additive, as mentioned here above, comprise therapeutically active non-toxic acid additive form salts, which are capable of forming compounds of formula (I). The latter conveniently be obtained by processing the basic form of such appropriate acids as inorganic acids, such as halogen acids, for example hydrochloric, Hydrobromic, etc.; sulfuric acid; nitric acid; phosphoric acid and so on; or organic acids, for example acetic, propionic, glycolic, 2-hydroxypropionate, 2-oxopropionate, Savelev the Wai benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form can be converted into a free basic form by treatment with alkali.

The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or aminoformic additive salts by treatment with appropriate organic and inorganic bases. Suitable basic forms salts include, for example, ammonium salts, salts of alkali and alkaline earth metals, such as lithium salts, sodium, potassium, magnesium, calcium, etc., salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propandiol, salt geranamine and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted into the free acid form by treatment with acid.

The term additive salt also comprises the hydrates and solvent additive form, which is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, and the like.

Under the maleic, L-wine and cleaners containing hydrochloride acid salt form, as well as hydrated forms.

The term "stereochemical isomeric forms" as used here previously, refers to all possible stereoisomeric forms that may exist in the compounds of formula (I), including all enantiomers, enantiomeric mixtures and diastereomer mixture. If not specifically mentioned or not indicated, the chemical designation of compounds involves the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of basic molecular structure. The same applies to the described intermediate products used to produce the final products of the formula (I).

Enantiomerically pure forms of compounds and intermediate products, as here indicated, are defined as essentially free from other enantiomeric or diastereomeric forms of the above compounds or intermediates of the same basic molecular structure.

Asymmetric centers may have the R - or S-configuration. The terms CIS and TRANS are used here in accordance with Chemical Abstracts nomenclature and refer to the position of substituents in ring number - or TRANS - configuration, discusses Deputy with the most seniority at the carbon atom in the 2-position of the dioxolane ring and Deputy with the most seniority at the carbon atom in 4-position of the dioxolane ring (and the seniority of the Deputy shall be determined in accordance with the rules of the sequence of Kan-Ingold-Prelog). When these two Deputy with the greatest seniority are on the same side of the ring, then the configuration is designated as CIS, if it is not, the configuration is designated as TRANS.

All the compounds of formula (I) contain at least 4 asymmetric center. Used here stereochemical designations denoting the stereochemical configuration of each of 4 or more asymmetric centers are also in accordance with the nomenclature of Chemical Abstracts. For example, the absolute configuration of the asymmetric carbon atoms of compound 23 as described hereafter in example C. 2, [2S-[2, 4[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-defloriani)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil] -phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methylpropyl L-phenylalanine pictured here below. Dioxolane ring in this compound has a CIS-configuration.

The same nomenclature Chemical Absracts used to describe mixtures of enantiomers. For example, the designation of the intermediate product 2i, that is, [2, 4(R*, R*)] , indicates that the intermediate product 2i is a mixture of the two enantiomers described as stereochemical [2S-[2, 4(R*, R*)]] and [2R-[2, 4(R*, R*)]] respectively.

The numbering of the atoms in the dioxolane ring in accordance with the nomenclature of Chemical Absracts given below for radicals D1 and D2

< / BR>
< / BR>
Some compounds of formula (I) and intermediates used in their production, not determined experimentally absolute stereochemical configuration. In these cases, the stereochemical isomeric form, which was allocated in the first place, it was designated as "A" and second as "B", without further specifying their actual stereochemical configuration. However, these isomeric forms "A" and "B" can clearly be characterized by, for example, optical rotation, which in the case of "a" and "b" has an enantiomeric fromhis for this well-known methods, such as, for example, diffraction of x-rays.

For example, the intermediate product 2b, described as stereochemical [2S-[2, 4[S-(R*, S*)]]] denotes the enantiomer having either [2S-[2, 4[(R*, S*)]]] or [2S-[2, 4[(S*, R*)]]] the configuration and unambiguously characterized by its optical rotation, component []D20=-17,79o(C= 49,75 mg/5 ml N,N-dimethylformamide).

Assume that the N-oxide forms of the compounds of the present invention include compounds of formula (I) in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

Used hereafter, the term "compounds of formula (I) also indicates that it includes N-oxide forms, their pharmaceutically acceptable additive salts and their stereochemical isomeric form.

In terms of the present invention-a-b - represents a suitable radical of formula (b).

D is a suitable radical of the formula D1.

X is a suitable n

R1and R2respectively are identical, preferably chlorine or fluorine. In particular, both R1and R2represent fluorine.

An interesting group of compounds of the present invention are the a amino; mono - or di(C1-6alkyl)amino; amino(C1-6alkyl); C1-6allyloxycarbonyl; benzyloxycarbonylamino; trifluromethanesulfonate; 1-pyrrolidinyl; 1-piperidinyl; 4-morpholinyl; 1-piperazinil or 1-piperazinil, substituted1-6the alkyl, hydroxys1-6the alkyl, amino1-6the alkyl or C1-6alkylamino1-6by alkyl;

R" represents hydrogen, C1-6alkyl; aryl; C1-6alkyl, substituted aryl, WITH1-6alkylthio, indolium, amino, hydroxy, mercapto, aminocarbonyl, carboxyla, guanidinium, imidazolium;

or

R' and R" together form a-CH2-CH2-CH2-NH-;

aryl is phenyl or phenyl substituted hydroxy or halogen.

A more interesting group, contains those compounds of formula (I) in which L represents the acyl part of one of the following amino acids (see diagram A in the end of the description).

or their derivatives, in which the amine portion is one - or disubstituted C1-6the alkyl or one-deputizing tert-butyloxycarbonyl.

Especially interesting acyl parts are those that come from alanine, -alanine, glycine, leucine, valine, phenylglycine, phenylalanine, and the ina, L-alanine, L-valine, 1-leucine, L-phenylglycine, L-phenylalanine, D-phenylalanine, N-((1,1-dimethylethyl)oxycarbonyl) - alanine, N-((1,1-dimethylethyl)oxycarbonyl)-glycine, N, N-diacylglycerol, N,N-diethyl-alanine, N-((1,1-dimethylethyl)oxycarbonyl)-L-alanine, N-((1,1-dimethylethyl)oxycarbonyl)-L-leucine, N-((1,1-dimethylethyl)oxycarbonyl)-L-phenylglycine, N-((1,1-dimethylethyl) oxycarbonyl)-L-valine, N-((1,1-dimethylethyl)oxycarbonyl)-L-phenylalanine, N-((1,1-dimethylethyl)oxycarbonyl)-D-phenylalanine.

Particular compounds are those compounds of formula (I) in which D is the radical of the formula D1, where X is N, and R1and R2both represent fluorine; and- - - represents a radical of formula (b); a L represents the acyl part leucine, valine, phenylglycine, phenylalanine and tert-butylcarbamoyl derivatives; or L represents the acyl part of N, N-diacylglycerol.

Other particular compounds are those compounds of formula (I) in which D, whether it is a D1 or D2 has the CIS - configuration.

The preferred compounds are those compounds in which D is the radical of the formula D1, in which the substituents in the dioxolane ring have the CIS-configuration and the carbon atom number 2 dioxolanes the connections are those connections, in which 1-methylpropyl part is threo configuration, there are two chiral carbon 1-methylpropyloxy parts (both chiral carbon atom in the figure below marked with an asterisk) have the same absolute configuration, for example, they both have the R - configuration or both have the S-configuration

< / BR>
More preferred compounds are the compounds of formula (I) in their enantiomerically pure forms, in particular those compounds of formula (I), in which two chiral carbon 1-methylpropyloxy part both have the S-configuration, and D is a radical of the formula D1, in which the substituents in the dioxolane ring have the CIS-configuration and the carbon atom number 2 dioxolane ring has the S absolute configuration, which corresponds to the compounds of formula (I) in which D is the radical of the formula D1 with [2S-[2, 4[(R*, R*)]]] the configuration.

Most preferred are the compounds:

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy]phenyl]-1-piperazinil]phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl]-1-methylpropyl N,N-detillion;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl]-1-piperazinil]-phenyl]-4,5-digil)-1,3-dioxolane-4-yl] methoxy] -phenyl]-1-piperazinil]-phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl]-1-methylpropyl L-leucine;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl]-1-piperazinil]-phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl]-1-methylpropyl L-valine;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl]-1-piperazinil]-phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methylpropyl L-phenylglycine; their N-oxide forms, their pharmaceutically acceptable additive salts and their stereochemical isomeric forms, especially of their [2S-[2, 4[(R*, R*)]]] form.

Variables in the form in which they are applied in the following sequence of reactions are the same as above, unless otherwise indicated.

Compounds of the present invention can be obtained using known methods of esterification, for example, those described in "Principles of Peptide Synthesis, M. Bodanszky, Springer-Verlag Berlin Heidelberg, 1984. A special sequence of reactions described here below.

The compounds of formula (I) in General form can be obtained by O-acylation of the intermediate alcohol of formula (II) with Alliluyeva agent of formula (III), where W1is reacting removable group, such as halogen, azido, or an activated acid functions part L. This reaction can be carried out using known procedures for acylation, for example, by stirring the reactants in a reaction-inert solvent, optionally with the additional presence of a base to neutralize the acid formed during the reaction. In the opposite variant O-acylation is carried out by applying a suitable interfacing reagent, such as dicyclohexylcarbodiimide or its functional derivative

< / BR>
In this and the following preparations, the reaction products can be separated from the reaction medium and, if necessary, further purified according to conventional methodologies known to science, such as, for example, extraction, crystallization, rubbing and chromatography.

The compounds of formula (I) can also be obtained by O-alkylation of a phenol of the formula (IV) alkylating reagent of formula (V), where W2is reacting removable group, such as halogen or sulfonyloxy. This reaction can be carried out by stirring the reactants in a reaction-inert solvent, optionally with the additional presence of a suitable base to neutralize the acid, which which are above, except in specified cases

< / BR>
The intermediate products of the formula (V), where D is a radical of the formula D1, disclosed in U.S. patent 4267179.

As indicated here above, the variable L can be represented as L'-NRXRYtwo parts, that is, L'- I-N-NRXRYused in the following reaction scheme:

< / BR>
The above reaction scheme reflects the formation of compounds of formula (I) by O-acylation of the intermediate product of the formula (II) with a reagent of formula (VI), where W3is reacting removable group, such as halogen, and W1is above and is linked to the acyl part L'; and the subsequent interaction of the thus obtained intermediate of formula (VII) with an amine of formula (VIII).

The compounds of formula (I) can also be converted into each other following well-known in this field transformations. For example, the compounds of formula (I) in which L contains protected amine part, may be transformed into compounds of formula (I) where the amine portion is unsubstituted, using known in the field of methods for removing protective groups, for example, by entries batch is of the formula (I) can also be converted into the corresponding N-oxide forms, following well-known in this field means the conversion of trivalent nitrogen into its N-oxide form. This reaction N-oxidation can usually be carried out by reacting starting substances of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, such as sodium peroxide, potassium peroxide; appropriate organic peroxides may include nagkalat, such as, for example, natantia acid or halogen-substituted natantia acid, such as 3-chlormadinone acid, alcamovia nagkalat, for example peracetic acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Some of the intermediates and starting materials used in the above reaction sequences, commercially available or can be synthesized in accordance with the procedures described in the other gaining described here below.

For example, intermediates of formula (II) can be obtained by O-alkylation reagent of formula (IX) alkylating reagent of formula (V) with the following procedures, the O-alkylation described here above, to obtain compounds of formula (I)

< / BR>
Intermediates of formula (II) can be obtained by O-alkylation reagent of formula (X) alkylating reagent of formula (V) with the following procedures, the O-alkylation described here above, to obtain compounds of formula (I), and subsequent restoration of the educated thus the intermediate compounds of formula (XI). The specified recovery can be performed by stirring the intermediate of formula (XI) with regenerating reagent, such as borohydride sodium in a reaction-inert solvent such as dichloromethane, methanol or a mixture of

< / BR>
Obtaining the intermediate of formula (X) are disclosed in US-4931444.

Intermediates of formula (XI) can be obtained by N-alkylation of the intermediate compounds of formula (XII) with the following well-known in this field procedures N-alkylation using an alkylating reagent of formula (XIII), in colormania forms of the compounds and intermediates of the present invention can be obtained by applying known in the field of methods. The diastereomers can be separated using physical methods of separation, such as selective crystallization and chromatographic separation, such as liquid chromatography. Enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. In the opposite case, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. These pure stereochemical isomeric forms may also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospeakers or stereospetsifichno. If desired specific streamer, preferably to the specified connection was synthesized by stereospeakers or stereospecific methods of obtaining. In these methods is usually advantageous to use pure in respect of the enantiomers of the source materials. Stereochemical isomeric forms of the compounds of formula (I) are, obviously, for inclusion in the scope of the present invention.

As defined here above, enantiomerically pure forms of compounds of formula (I) of Obruchev formula (II), their N-oxide forms and their additive salt form is particularly applicable when obtaining enantiomerically pure compounds of formula (I). To obtain the compounds of formula (I) with the appropriate configuration is also suitable enantiomeric mixture and diastereomeric mixture of intermediate products of the formula (II). These enantiomerically pure form, as well as enantiomeric and diastereomeric mixture of intermediate products of the formula (II) are new.

Particularly preferred intermediates of formula (II) are 4-[4-[4-[4-[[2-(2,4-defloriani)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil]phenyl]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazole-3-one in his [2S-[2, 4[(R*, R*)]]] in its enantiomerically pure form and the corresponding 2,4-dichloroaniline similar.

In particular, [2S-[2, 4[(R*, R*)]]] enantiomerically pure form intermediates of formula (II) can be obtained by reaction of the corresponding enantiomerically pure form intermediate (IX), that is, [S-(R*, R*)] form represented by formula (IX-a), with the corresponding enantiomerically pure form of intermediate product (V), that is [2S-(2, 4)] form, predstavlennoi (V-a), according to the sequence of reactions as described you is X) may be conducted as described in scheme 1 (see the end of the description).

Suitable conditions stereospeakers recovery include the use of K-selectride in a suitable solvent, such as, for example, dimethylacetamide or tetrahydrofuran; the use of sodium borohydride and not necessarily in combination with l37H2Oh, ZnCl2or CaCl22H2O in a suitable solvent, such as, for example, dimethylacetamide, dimethylformamide, methanol or tetrahydrofuran. These conditions of recovery are favorable for the formation of threo form 2-hydroxy-1-methylpropyloxy part, i.e. the form in which two asymmetric carbon atoms have the same absolute configuration. Recrystallization of the mixture after stereospeakers recovery may even further improve the ratio of tree/eritro in the direction of tree form. Desired [S-(R*, R*)] form can then be allocated chromatography using chiral stationary phases, such as, for example, Chiralpak AD (amylose 3,5 dimethylphenylcarbamate) obtained from Daicel Chemical Industries, Ltd., Japan.

Alkoxyphenyl derived intermediates of formula (IX-a) can be obtained in accordance with the same sequence of the formula (IX-a) or their alkoxyphenyl analogues is depicted in scheme 2 (see at the end of the description).

Reaction of intermediate compounds of formula (XIV) with (4R-TRANS)-4,5-dimethyl-2,2-dioxide-1,3,2-diocletiana can be performed in a suitable solvent, preferably in a polar aprotic solvent such as, for example, dimethylacetamide or N,N-dimethylformamide and in the presence of a base, such as, for example, tert-butanolate potassium, potassium hydroxide or potassium hydride. Subsequently, the reaction mixture can be added acid, such as sulfuric acid, which results in that the intermediate product of formula (XV-b), in which 2-hydroxy-1-methylpropyl part has Erythro form. Then the carbon atom bearing an alcohol function specified 2-hydroxy-1-methylpropyloxy part, will epimerized, preferably with 100% inversion, thus obtaining the intermediate product (XV-a), in which 2-hydroxy-1-methylpropyl part is tree form. Both ways are easy.

The first path includes the transformation of the alcohol function in a group to delete a suitable O-LG, for example, by conversion of the hydroxyl group with an organic acid, such as, for example, carboxylic acid, for example acetic acid or 4-nitrobenzoic acid, or acid, for example the volume of carbon bearing a leaving group in the specified intermediate product (XVI), may subsequently be epimerization, preferably with 100% inversion, by the reaction of SN2-type with a suitable nucleophilic reagent, such as, for example, an alcoholate, such as benzyloxy; hydrochina salt (hydroxide), alkaline metal, for example sodium hydroxide or potassium hydroxide; an acetate such as sodium acetate. The above reaction is carried out in a suitable solvent, preferably in a polar aprotic solvent such as, for example, dimethylacetamide, N-methylpyrrolidinone, dimethylimidazolidine or sulfolan. In that case, if the reaction SN2type used alcoholate or acetate, the thus obtained intermediate product can be removed protective group using known techniques of removal of the protective groups, receiving as a result of this alcohol intermediate of formula (XV-a).

Alternative by the inversion of the stereochemistry of the carbon atom bearing an alcohol function is the application of the Mitsunobu reaction. The alcohol function of the intermediate product of formula (XV-b) is activated by using diisopropylcarbodiimide or its functional derivative, such as deethylase trementina acid, acetic acid, monochloracetic acid. Thus obtained ester in which 2-hydroxy-1-methylpropyl part transformed into tree form may subsequently be obtained using known techniques hydrolysis to produce in the result, the intermediate product of formula (XV-a).

Finally, alkoxyphenyl part of the intermediate products of the formula (XV-a) can be transformed into the phenolic part using, for example, banowati acid in acetic acid in the presence of sodium thiosulfate, obtaining thus an intermediate product of the formula (IX-a).

Suitable alternative (4R-TRANS)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxathiolanes are enantiomerically pure intermediate compounds

< / BR>
< / BR>
< / BR>
< / BR>
where LG is a removable group, such as, for example, p-toluensulfonyl.

Intermediates of formula (IX-b), where 2-hydroxy-1-methylpropyloxy part is [R-(R*, R*)] form can be obtained by applying the same sequence of reactions as depicted in scheme 2, but with substitution of (4R-TRANS)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxythiophene its enantiomer (4S-TRANS)-4,5-dimethyl-2,2-dioxide-1,3,2-diocletiana.

Interestingly, especially enantiomerically pure form intermediates of formula (IV) can be synthesized using the type of the Mitsunobu reaction in scheme 2, in which the carboxylic acid used in the reaction with active alcohol of formula (XV-b), substituted protected amino acid. The protective group of the amino acid optionally may be removed using known methods.

The compounds of formula (I), their pharmaceutically acceptable additive salts and their stereochemical isomeric forms are useful tools for combating fungi in vivo. Moreover, the profile of solubility in aqueous solutions of compounds of the formula (I) makes them suitable for intravenous administration. These compounds are detected as being active against a broad spectrum of fungi, such as Candida spp., for example Candida albicans, Candida glabrata, Candida crusei, Candida parapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., for example, Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Crytococcus neoformans; Sporothrix schenckii; Fonsecaea spp.; Epidermophyton floccosum; Microsporum canis; Trichophyton spp.; Fusarium spp.; and some skin hyphomycetes.

Chemical stability of some compounds of formula (I) were determined, as shown here below in the experimental part. Experiments show that the metabolic destruction of these compounds, to intermediates of formula (II) is organospecific and occurs with difficulty. Further, in vitro experiments show that the compounds of formula (I) possess improved internal ability to inhibit the growth of fungi, such as Candida albicans, when compared to intermediate compounds of the formula (II), antifungal activity of which is indicated in US-4791111. These in vitro experiments include the susceptibility of fungi to these compounds, as described in pharmacological example here below. Other in vitro experiments, such as determining the effects of these compounds on the synthesis of sterols, for example, Candida albicans, show their antifungal efficacy. Experiments in vivo in several models in mice, Guinea pigs and rats also show that after oral and intravenous administration of these compounds are strong anti-Christ. ruralnom receipt.

From the point of view of useful compounds of formula (I) proposed method of treating warm-blooded animals, including humans, suffering from fungal infections. The method comprises the systemic or local injection of an effective amount of the compounds of formula (I), its N-oxide form, its pharmaceutically acceptable salt additive or a possible stereoisomeric form of warm-blooded animals, including humans. Therefore, the compounds of formula (I) are available for use as a medicine, in particular offered the use of the compounds of formula (I) in the manufacture of medicaments useful for the treatment of fungal infections.

The present invention also provides compositions for the treatment or prevention of fungal infections comprising a therapeutically effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier or diluent.

From the point of view of their useful pharmacological properties of the compounds, which is the aim of the invention may be incorporated in various pharmaceutical forms for entry. To obtain pharmaceutical compositions of the present invention is a therapeutically effective amount specific to the m pharmaceutically acceptable carrier, which can have a wide variety of forms depending on the form of the drug to the desired injection. These pharmaceutical compositions are preferably present in unit dosage form, preferably suitable for oral, rectal, local, percutaneous or parenteral administration. For example, upon receipt of the compositions in dosage forms for oral administration may be applied by any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders connection dezintegriruetsja agents and the like in the case of powders, pills, capsules and tablets. Because of the simplicity of their administration tablets and capsules represent the most advantageous dosage form for oral administration, in which case, obviously, use solid pharmaceutical carriers. Suitable compositions for local application there may be cited all compositions usually used for local administration of drugs, such as creams, jellies, dressings, sumycine is a sterile water, at least mostly, though may include other ingredients such as cyclodextrins to achieve solubility. Can be obtained solutions for injection, for example, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Can be also obtained suspension for injection, which can be applied in a suitable liquid carriers, suspendresume agents and the like. In the compositions suitable for percutaneous administration, the carrier optionally comprises an agent that enhances the permeability and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small quantities, and these additives do not cause significant adverse effects on the skin. These supplements can expedite the introduction of the skin and/or may be useful in obtaining the desired compositions. These compositions can be administered in different ways, for example, in the form of a patch for percutaneous introduction, in the form of printed spots, in the form of ointment. For parenteral compositions, the carrier typically includes sterile water, at least mostly. Can be obtained solutions for injection, for example, where appropriate who may also be obtained suspension for injection, in the case of which can be applied in a suitable liquid carriers, suspendresume agents and the like. For parenteral compositions may include other ingredients, for example, to achieve solubility, such as cyclodextrins. Appropriate cyclodextrins are -, -, -cyclodextrins or ethers and mixed ethers, where one or more hydroxyl groups anhydroglucose units of cyclodextrin substituted C1-6the alkyl, in particular the stands, ethyl or isopropyl, e.g. randomly methylated-CD; hydraxis1-6the alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyl1-6the alkyl, in particular carboxymethyl or carboxyethyl; C1-6alkylcarboxylic, in particular acetyl. Especially noteworthy as complex-forming compounds and/or solubilization-CD, randomly methylated-CD, 2,6-dimethyl--CD, 2-hydroxyethyl--CD, 2-hydroxyethyl--, 2-hydroxypropyl--CO and (2-carboxy-methoxy)propyl--CD and in particular 2-hydroxypropyl--CD (2-HP--CD).

The term mixed ester denotes the derivative of cyclodextrin in which at least two hydroxyl groups of the cyclodextrin tarifitsirovana different g is e (m S.) is used as a measure of the average number of moles of the CNS units anhydroglucose. The average degree of substitution (D. S.) denotes the average number of substituted hydroxyl per unit anhydroglucose. M. S. and D. S. values can be determined using various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the method used can be obtained slightly different values for this cyclodextrines derived. Preferably, measured by mass spectrometry value M. S. lay in the range from 0.125 to 10 and the value of D. S. was in the range of from 0.125 to 3.

Especially advantageous to make the above pharmaceutical composition in unit dosage form for ease of administration and uniformity of dosage. Unit dosage forms used here in the description and the claims refers to physically discrete units suitable as a single unit dosage form, each unit contains a predetermined quantity of active ingredient calculated on the induction of the desired therapeutic effect, in complexa or scored tablets, or coated tablets), capsules, pills, sachets of powder, pills, solutions or suspensions for injection, the dosage in the form of a teaspoon, the dosage in the form of a tablespoon, and the like and their multiple parts.

Specialists in the treatment of warm-blooded animals suffering from diseases caused by fungi, can easily determine therapeutically effective daily dose of the results presented here tests. In General, it is expected that therapeutically effective daily dose should be between 0.05 mg/kg to 20 mg/kg body weight.

Experimental part

Next here, "DMF" means N,N-dimethylformamide, "MIK" means methylisobutylketone, "DIPE" means diisopropyl ether.

A. Obtaining an intermediate product

Example a-1

A mixture of ()-2,4-dihydro-[4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazole-3-one (0,06 mol) in DMF (500 ml) was cooled to -10oC and then stirred under a current of the N2. Was added dropwise a 1 M solution of tri-sec-butylbromide potassium in tetrahydrofuran (150 ml). The mixture was let to slowly warm to room temperature and then poured into water. The precipitate was filtered off, washed with CH3HE and crystal is th liquid chromatography] CHIRALPAC AD (eluent:ethanol). Were collected two pure fractions, which were evaporated solvents. Each of the residue triturated in CH3HE. The precipitate was filtered and dried, which gave to 7.3 g of [S-(R*, R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1a) []D20=-10,81o(C=50,43 mg/5 ml DMF).

Similarly received:

[A-(R*, S*)] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1b) []D20=-7,07o(=to 48.8 mg/5 ml DMF);

[B-(R*, S*)] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1C) []D20=+6,86o(C=49,58 mg/5 ml DMF);

[R-(R*, R*)] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1d) []D20=+10,35o(C=48,81 mg/5 ml DMF);

(R*, S*)-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil]-phenyl]-3H-1,2,4-triazole-3-one (InterMedia. cont. 1E).

Similarly received:

(R*, R*)-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil]-phenyl]-3H-1,2,4-triazole-3-one (InterMedia. cont. 1f);

[R-(R*, R*)+R-(R*, S*)]-2,4-dihydro-2-(2-guide+S-(R*, S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1h) ;

[S-(R*, R*)+R-(R*, S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1i);

[S-(R*, R*)+S-(R*, S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 1j);

Example a-2

A mixture of CIS-(2S)-4-methylbenzenesulfonate 2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-methanol (ether) (0,0134 mol), intermediate (1A) (0,0122 mol) and NaOH (0,013 mol) in DMF (200 ml) was stirred at 60oWith under a stream of nitrogen overnight. The mixture was cooled and poured into water. The precipitate was filtered and dried. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH from 94/6 to 0/100). Collected pure fractions and the solvent was evaporated. The residue is triturated in MIK. The precipitate was filtered and dried, giving 4.7 g (56%) of [2S-[2, 4[(R*, R*] ] ]-4-[4-[4-[4-[[2-(2,4-defloriani)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl]-1-piperazinil]-phenyl]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazole-3-one (InterMedia. cont. 2A) []D20=-20,14o(C=49,49 mg/5 ml DMF).

In table 1 the ENES their absolute configuration and optical rotation are also shown in table 1.

Table 2 lists the intermediate products are obtained analogously to example A. 2.

Example a-3

A mixture of intermediate 2A (0,01 mol) and Chloroacetic acid chloride of acid (0,0115 mol) in CH2Cl2was stirred at room temperature. Added pyridine (0,02 mol) and the mixture was stirred for 2 hours, washed with water, dried, filtered and the solvent was evaporated. The residue was led from MIK/DIPE. The precipitate was filtered and dried, which gave 6.7 g (87%) of [2S-[2, 4[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy]-phenyl]-1-piperazinil]-phenyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methylpropyl-chloracetate (InterMedia. cont. 3).

Example A. 4

a) 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] phenyl] -3H-1,2,4-triazole-3-one (0,15 mol), obtained as described in WO 94/18978, mixed in diethylacetamide (500 ml) at 60oC. was Added tert-butyl potassium (0,165 mol). The mixture was stirred at 100oWith the under current of the N2for 1 hour and then cooled to 50oC. was added dropwise (4R-TRANS)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxathion (0,165 mol). The mixture was stirred at 50-60oC for 2 hours. Was added dropwise a solution of concentrated H2SO4(20 SUP>C for 20 hours, cooled, poured into H2O (1000 ml), zaslujivali 50% NaOH and stirred. The precipitate was filtered off, washed with H2O and dried. The residue was dissolved in CH2Cl2/CH3OH. The mixture was filtered and the solvent evaporated. The residue is triturated in 2-propanol, filtered, and dried. The residue was purified on silica gel on a glass filter (eluent: CH2Cl2/CH3OH 99/1). Collected pure fractions and the solvent was evaporated. The residue is triturated in CH2Cl2(150 ml), was filtered and was dried at 110oWith that gave 0,37 g [S-(R*, S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia.cont. 5A). []D20=-5,44o(C=19,47 mg/2 ml DMF).

(b) 2, 4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinil]-phenyl]-3H-1,2,4-triazole-3-ONU (0,0925 mole), obtained as described in WO 94/18978, was added 1-methoxy-2-propanol (700 ml), water (700 ml) and NaOH (50%; 4.8 ml). The resulting mixture was heated to 45oWith and added under stirring at 45oWith TRANS-2,3-dimethyl-oxirane (0,1387 mol). The reaction mixture was stirred for 68 hours at 45oWith and for 60 hours at 60oWith, then was cooled to 20oC. Addition was added NaOH (50%; 4.8 ml)was cooled in an ice bath. The mixture was separated by filtration on a sediment (1) and the filtrate (2). The precipitate (1) was dried, pererestorani in CH2Cl2(100 ml) and was filtered. The corresponding filtrate evaporated and the residue was dried, which gave 2.2 g (R*, S*)-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] -phenyl]-3H-1,2,4-triazole-3-one (InterMedia.cont. 5b). The filtrate (2) was evaporated. The residue was stirred in CH2Cl2(150 ml) and was filtered. The corresponding filtrate was evaporated and the residue was dried, which gave 7.4 g (R*, S*)-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 5b). Two fractions of intermediate 5b were combined and further purified using activated charcoal column chromatography and recrystallization, which gave 1.5 g (total yield of 3.9%) (R*, S*)-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] -phenyl] -3H-1,2,4-triazole-3-one (InterMedia.cont. 5b).

Example A-5

A mixture of intermediate 5A (0,00327 mol), triphenylphosphine (0,00806 mole) and p-nitrobenzoic acid (0,00717 mol) in tetrahydrofuran/dimethyl 3/2 (50 ml) was heated until complete dissolution. Then was added dropwise diethylazodicarboxylate (0,00806 mol). The mixture was stirred at the; 0 ml). The mixture was poured into water (100 ml) and NaOH (1N; 90 ml) and then stirred. The precipitate was filtered and recrystallized from 2-propanol (60 ml). The mixture was stirred for 48 hours. The precipitate was filtered and dried, which gave 0,98 g (71%) [S-(R*, R*)] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil]-phenyl]-3H-1,2,4-triazole-3-one (InterMedia.cont. 5C).

Example A-6

a) N, N-dimethyl-4-pyridylamine (0,01062 mol) and intermediate 5A (0,00708 moles) suspended in CH2Cl2(50 ml). Dropwise at room temperature was added a solution of methanesulfonamide (0,01062 mol) in CH2Cl2(30 ml). The mixture was stirred at room temperature for 2 days. Re-added N,N-dimethyl-4-pyridylamine (0,00352 mol) and methanesulfonamide (0,00358 moles). The mixture was stirred overnight, washed with water (2 x 100 ml), dried, filtered through dekalim and the solvent evaporated. The residue was dissolved in MIK (150 ml). Added activated charcoal (0.5 g). The mixture was boiled, filtered warm and was stirred for 2 hours. The precipitate was filtered and dried, which gave 1.7 g (50%) [S-(R*, S*)] -2,4-dihydro-2-(2-methansulfonate-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil]phenyl]-3H-1,2,4-triazole-3-one (the product 5d (0.001 mol) was added to a solution of KOH (0.03 g) in CH3HE (7 ml) and tetrahydrofuran (3 ml). The mixture was stirred at 100oC for 4 hours, which gave [S-(R*, R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] phenyl] -3H-1,2,4-triazole-3-one (InterMedia. cont. 5C).

C. the final connection

Example-1

A mixture of N-[(1,1-dimethylmethoxy)carbonyl-L-phenylalanine (is 0.023 mol), intermediate (2A) (0,01 mol), dicyclohexylcarbodiimide (0,046 mol) and N,N-dimethyl-4-pyridylamine (0,046 mol) in CH2CL2(200 ml) was stirred at room temperature overnight. Was added water (200 ml) and the mixture was stirred for 1 hour and was extracted with CH2Cl2. The organic phase was separated, washed with water, dried, filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2CL2/CH3HE 99/1). Pure fractions were collected and the solvent evaporated, which gave 10.8 g (86,7%) [2S-[2, 4[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-defloriani)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil] phenyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methylpropyl N-[(1,1-dimethylmethoxy) (compound 22).

Example b-2

a) a Mixture of compound 22 (0,0075 mol) in triperoxonane acid (15 ml) and CH2chickpea and was extracted with CH2Cl2. The organic phase was separated, washed, dried, filtered and the solvent evaporated. The residue was purified by chromatography on a flash column of silica gel (eluent: CH2WITH2/CH3HE 96/4). Pure fractions were collected and the solvent evaporated. The residue was ground into powder in DIPE. The precipitate was filtered and dried, which gave 3.6 g of [2S-[2, 4[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil]-phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl]-1-methylpropyl L-phenylalanine (compound 23).

b) Compound 23 (0,00359 mol) was dissolved in 2-propanone (25 ml). Solution was added (Z)-2-botanically (0,00359 mol) in 2-propanone (5 ml). The mixture was stirred for 16 hours. The precipitate was filtered off, washed with 2-propanone (2.5 ml), and dried, which gave 3.12 g of [2S-[2, 4[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl]-1-piperazinil]-phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methylpropyl L-phenylalanine (Z)-2-butenedioate (1: 1) (compound 25).

Example b-3

A mixture of intermediate (3) (0,0081 mol) and N,N-diethylamine (or 0.027 mol) in DMF (50 ml) was stirred at room temperature for 8 hours. The mixture gave otstraivatlsya water, was dried, filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 98/2). Pure fractions were collected and the solvent evaporated. The residue was dissolved in CH3SP (200 ml) and made acidic salt of (E)-2-botanically (1:1). The precipitate was filtered and dried, which gave 5 g (67%) of [2S-[2, 4-[(R*, R*]]]-2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1-piperazinil]phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl]-1-methylpropyl N,N-detillion (E)-2-butenedioate (compound 16).

Example b-4

[2S-[2, 4-[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-debtor-phenyl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methylpropyl-alanine (0,0028 mol) was dissolved in warm ethanol (25 ml). To the mixture was added (-)-(S)-hydroxybutyrate (0,0061 mol) and the mixture was heated until complete dissolution. The obtained clear solution was allowed to cool to room temperature and the solvent evaporated. The residue was stirred in 2-propanone, was filtered, then dried, which gave 1,53 g (53%) of [2S-[2, 4-[(R*, R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl]-4,CLASS="ptx2">

Table 3 lists the compounds of formula (I), which were obtained in accordance with one of the above examples indicated in the column "Etc. ".

Table 4 (see the end of the description).

Table 5 presents the results of elemental analysis, both experimental (column heading "exp."), and theoretical (column heading "theoretical."), for values of carbon, hydrogen and nitrogen in the compounds obtained are higher in the experimental part.

C. Physicochemical example

Example-1: solubility

The solvent was added an excess of compounds (a type of solvent specified in table 6). The mixture was shaken for 1 day at room temperature. The precipitate was filtered. Measured pH of the remaining solvent, as shown in table 6. The concentration is indicated in the column "solubility", was measured using HPLC.

Table 7 (see below).

Example-2: Chemical stability

50 mg of the test compound was placed in an open glass vessel at 40oC and a relative humidity of 75%. One week was determined by the number of remaining test compounds.

D. Pharmacological examples
used a panel of isolates of Candida and single isolates of dermatophytes Microsporum canis, Trichophyton rubrum and T. mentagrophytes; Aspergillus fumigates and Cryptococcus neoformans. The inoculum was prepared in the form of broth cultures (yeast) or as a suspension of fungal material made from crops on sloping agar (fungi). The test compound was transferred by pipette from the mother solution of DMSO in water to obtain a series of 10-fold dilution. Fungal inoculum suspended in the culture medium CYG (F. C. Odds, Journal of Clinical Microbiology, 29, (2735-2740, 1991) to approximately 50,000 colony-forming units (CFU) per ml was added to aqueous solution of the test drug.

Cultures were placed in 96-well plastic plates to micrometrology and incubated them for 2 days at 37o(Candida spp.) or for 5 days at 37o(Fungi). Growth microculture were measured for their optical density (OD) measured at a wavelength of 405 nm. OD for crops with test compounds was calculated as a percentage of control, OD for cultures without drugs. Inhibition of growth of up to 35% of control or lower was considered significant inhibition.

Minimum inhibitory concentrations (MICs; 10-6M) of the intermediate product 2 as the main metabolite and some of the compounds of formula (I) for Candida glabrata, Candida krusei, Candida parapsilosis, Candida albicanP CLASS="ptx2">

Example D-2: Disseminated Aspergillus and candids in Guinea pigs

All experiments used a special, free from pathogens (SPF) of Guinea pigs (weighing 400-500 g). The animals which were treated by intravenous infusion into the left jugular vein is injected with a catheter. Animals were injected with Aspergillus fumigatus (4,000 CFU/g of body weight) or Candida albicans (40,000 CFU/g of body weight) or via the lateral vein of the penis, or through the implanted catheter. Treatment with intravenous injection (5 mg/kg/day) was started 1 h after infection. The tested compounds were then introduced in the coming days in the form of two one-hour infusions, separated by a five-hour period, every day, a total of 19 infusions for 9.5 days. Treatment with the test compounds orally (5 mg/kg/day) was started 1 hour after infection and repeated twice a day until the 10th day after infection (19 receptions drugs). For each group of test animals (number of test animals in the group given in the column "N") recorded average life time (MST) in days, and percent survival (% vyzhe.). Animals of each group, those who died during the experiment and those that survived the experiment and were slaughtered, investigated post mortem on to the number of CFU/g in liver, positive in relation to the cultures, were calculated and presented in table 9 (after intravenous treatment) and table 10 (after oral administration) in mean log10CFU/g Column "% negative" in tables 9 and 10 reflect the total percentage negative in relation to the cultures of the internal organs after treatment. Therefore, more effective test compounds are characterized by higher values in the columns "MST", "% vyzhe." and "% negative" and lower columns ("CFU/g".

That is, the Example compositions

Example E. I: Solution for injection.

1.8 grams of methyl-1,4-hydroxybenzoate and 0.2 gram of sodium hydroxide was dissolved in about 0.5 l of boiling water for injection. After cooling to approximately the 50oSince there was added with stirring, 0.05 grams propylene glycol and 4 grams of active ingredient. The solution was cooled to room temperature and brought water for injection up to 1 l, giving a solution comprising 4 mg/ml of active ingredient. The solution was sterilized by filtration and filled them sterile containers.

1. Ester of the amino acids of the formula (I)

< / BR>
N-oxide form, pharmaceutically acceptable additive salt or its stoichiometric isomeration in the radicals (a) and (b) may be substituted C1-6alkyl radical;

L represents the acyl part of an amino acid;

D is a radical of the formula

(D1)

< / BR>
or (D2)

< / BR>
where X is N;

R1is a halogen;

R2is hydrogen or halogen.

2. Connection on p. 1, in which L represents a radical of formula (a)

< / BR>
where R' represents amino, mono - or di(C1-6alkyl)amino, mono - or di(C1-6alkyl)amino1-6alkyl, amino(C1-C6)alkyl or C1-6allyloxycarbonyl;

R" represents hydrogen, C1-6alkyl; aryl, C1-6alkyl, substituted aryl or amino;

aryl is phenyl or phenyl substituted proxy or halogen.

3. Connection on p. 2, in which L represents the acyl part of one of the following amino acids of formulas (see graphic part to p. 3)

or their derivatives, in which the amine portion is mono - or disubstituted by C1-6the alkyl or one-deputizing tert-butyloxycarbonyl.

4. The compound according to any one of paragraphs. 1-3, in which the substituents in the dioxolane ring have the CIS-configuration.

5. The compound according to any one of paragraphs. 1-4, in which D represents the Wallpaper fluorine, X is N-a-b - represents a radical of formula (b).

7. The compound according to any one of paragraphs. 1-4, in which both chiral carbon 1-methylpropyloxy parts have S-configuration, a D is a radical of the formula D1, where the substituents on the dioxolane ring have the CIS-configuration and the carbon atom number 2 dioxolane ring has an S-configuration.

8. Connection on p. 1, characterized in that it is a

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] -phenyl] -4,5-dihydro-5-oxo-1H-1,2, 4-triazole-1-yl] -1-methyl-propyl N, N-detillion;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil] -phenyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methyl-propyl L-phenylalanine;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil] -phenyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methyl-propyl L-leucine;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] -phenyl] -1-piperazinil] -phenyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl] -1-methyl-propyl L-valine;

2-[4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] the mu its pharmaceutically acceptable additive salt and its stereochemical isomeric form.

9. Enantiomerically pure form intermediate compounds of formula (II)

< / BR>
its N-oxide or salt additive, where D and-A-In-as specified in paragraph 1.

10. The intermediate compound of formula (II), under item 9, in which the intermediate product is [2S-[2, 4[(R*, R*)] ] ] -4-[4-[4-[4-[[2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazole-3-one or [2S-[2, 4[(R*, R*)] ] ] -4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazole-3-one.

11. The enantiomeric mixture of intermediate products of the formula (II)

< / BR>
their N-oxides or their additive salts, where D and-A-In-as defined in paragraph 1.

12. Enantiomeric mixture according to p. 11, characterized in that it is a

[2, 4[(R*, R*)] ] -4-[4-[4-[4-[[2-[2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazole-3-one.

13. The compound according to any one of paragraphs. 1-8, suitable for the preparation of a pharmaceutical to the second composition, possessing antifungal activity of a wide range of actions, including pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of paragraphs. 1-8.

15. The pharmaceutical composition according to p. 14, used for intravenous injection.

16. A method of obtaining a composition as specified in paras. 14 and 15, characterized in that the pharmaceutically acceptable carrier is thoroughly mixed with a therapeutically effective amount of a compound, as claimed in any of paragraphs. 1-8.

17. A method of obtaining a connection on p. 1, characterized in that conduct On-acylation of the intermediate alcohol of formula (II)

< / BR>
where D and-As-such, as defined in paragraph 1,

using Alliluyeva reagent of formula (III)

W1-L, (III),

where W1is removed by reactive group associated with the acyl part of L, and L is as defined in paragraph 1, is carried out by mixing the reactants in a reaction-inert solvent, optionally adding to the mixture of base to neutralize the acid formed during the reaction;

and, if desired, converting compounds of formula (I) into each other with p) into a therapeutically active non-toxic acid additive salt by treatment with acid, or conversely, converting the acid additive salt form into the free base by treatment with alkali; and, if desired, to obtain stoichiometric isomeric forms or N-oxide forms.

18. A method of obtaining a connection on p. 1, characterized in that the compound of formula (II)

< / BR>
put O-acylation using a reagent of formula (VI)

W1-L'-W3, (VI)

with the subsequent interaction of the thus obtained intermediate of formula (VII)

< / BR>
with an amine of formula (VIII)

< / BR>
where W3is removed by reactive group; D and-As-such, as defined in paragraph 1, and NRxRyis an optional one - or disubstituted amino group of amino acids, as defined with respect to L in paragraph 1, and L' is identical to L, as indicated in paragraph 1, excluding optional one - or disubstituted by an amino group;

and, if desired, converting compounds of formula (I) into each other by means known in the field of transformations; and further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic acid additive salt by treatment with acid, or conversely, converting the acid-additive with the Eski isomeric forms or N-oxide forms.

Priority points:

11.02.1997 - PP. 1-9 and 14-19;

15.10.1997 - PP. 10-13.

 

Same patents:

The invention relates to new substituted pyrazolylborate General formula (I) in which R1-R6have the meanings given in the description of the invention

The invention relates to piperazine derivatives of the formula I, in which R1denotes a substituted radicals CN or Hal indole-3-ilen residue, R2denotes unsubstituted 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl

The invention relates to novel azole compounds having antifungal activity, their preparation and application

The invention relates to 1,4-disubstituted the piperazines of General formula I, the method of production thereof, containing compositions and their use for the clinical treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, causing neurogenic pain or inflammation
The invention relates to an improved process for the preparation of doxazosin, which is known antihypertensive agent used in hypertension and prostate cancer

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to pharmaceutical industry and relates to a suppository having antifungal activity

The invention relates to novel azole compounds having antifungal activity, their preparation and application

The invention relates to the field of medicine and is suitable for the treatment of fungal diseases, as well as for the prevention and treatment of fungal complications of antibiotic therapy
The invention relates to medicine, specifically to pharmacology and dermatology

The invention relates to pharmacology and medicine, in particular to the preparation of solid dosage forms of the drug rapamycin, which includes a core and a sugar coating

The invention relates to a composition and antifungal activity containing at least one cyclopentane-β-amino acid and/or its derivative of the General formula IB, in which R1and R2together denote a residue of the formula =CH2, R6and Y means hydrogen, and optionally at least one alpha-amino acid and/or its derivative of the General formula Ia, in which R3means a linear or branched alkyl, C1-C8, R4and R5mean hydrogen, X is hydroxyl, and alpha-amino acid and/or derivative and cyclopentane-β-amino acid and/or its derivative are in a molar ratio of 1:1 to 1:5; the dipeptide of the General formula A, where R1-R6above, X and Y mean the part of the covalent bond of the alpha-amino acid and cyclopentane-β-amino acids; and farmatsevticheskii composition with antifungal activity, containing as active substance at least one dipeptide of the formula And in an effective amount and a non-toxic pharmaceutically inert carrier

The invention relates to medicine and can be used in the treatment of this form may be accompanied shape rubromycosis feet and hands, caused by the pathogenic fungus Trichophyton rubrum

The invention relates to new derivatives phenylalkylamines acid, having superior activity in lowering blood sugar levels in the blood, and their pharmacologically acceptable salts or pharmaceutically acceptable esters, compositions comprising the specified connection as the active ingredient for the treatment or prevention of hyperglycemia; their use as a medicinal product for treatment or prevention of hyperglycemia; or the treatment or prevention of hyperglycemia, in which a warm-blooded animal is administered a pharmacologically effective amount of the compounds

The invention relates to veterinary Virology and biotechnology, in particular the production of kits for the detection of antibodies to the virus, egg drop syndrome -76 (EDS ' 76) chicken enzyme linked immunosorbent assay

The invention relates to the use of fluorinated derivatives of carbamino acid, namely polyfluoroankyl-N-arylcarbamates General formula

< / BR>
where R and R' = H, o-, m-or p-alkyl (C1-C3, CF3CH3S, Cl, NO2, NHCOOCHR"R"';

R" = H, CF3;

R"' = CF3, (CF2)nH, where n = 2-6, or-CF2NO2except 2.2-debtor-2-nitroethyl-N-phenylcarbamate, 2.2.2-triptorelin-N-p-nitrophenylacetate,

possessing antimicrobial activity

The invention relates to the field of pharmacology and medicine and relates to a combined anti-TB drug
Up!