Pharmaceutical composition containing butyrate the prodrug of lactic acid

 

(57) Abstract:

The invention relates to pharmaceutical compositions that increase fetal hemoglobin of the patient or accelerating differentiation of cells containing an effective amount of butyrate precursor drug of formula I in which a and D are independently from each other selected from the group comprising hydrogen, barbiecollector.com or C(1-4) straight or branched alkyl, S(2-4), straight or branched alkenyl or quinil, which may be independently substituted by hydroxy, alkoxy, carboxylation, alkylamides and so on, provided that a and D are not both hydrogen, R is oxygen, NH, NC(1-5) alkyl straight or branched chain or NH(2-5)of alkenyl straight or branched chain, any of which may be optionally substituted by a residue of carbocycle or heterocycle, Z is hydrogen, C(1-4) alkyl straight or branched chain, With(2-4) alkenyl or quinil straight or branched chain, carbocyclic or heterocyclic residue and so on, and each stereogenic carbon atom can be R or S configuration, and pharmaceutically acceptable adjuvant or carrier. The technical result - obtaining new parwani blood. 20 C.p. f-crystals, 4 tab., 1 Il.

The invention relates to a precursor drugs that are butyrate derived from lactic acid, pharmaceutical compositions and methods for using them either by themselves or in combination with other agents to increase the level of gamma-globin and fetal hemoglobin in patients. These compounds, compositions and methods are particularly effective in the treatment of hemoglobinopathy, including syndromes sickle cell erythrocytes and syndromes-thalassemia. In addition, this invention relates to the use of these precursors of drugs, alone or in combination with other agents for stimulating cell differentiation, which prevents the proliferation of malignant cells. These methods, in particular, useful in the treatment of cancer, particularly malignant blood diseases.

Prior

-Hemoglobinopathy are a group of transmissible by hereditary disorders biosynthesis-globin. Despite the focus on different therapeutic techniques, possible clinical treatment of these debilitating diseases are really successful.

For treatment-GE is al., "Current and Future Strategies for the Management of Hemoglobinopathies and Thalassemia", Hematology 1994, Education Program American Society of Hematology, pp. 9-20 (1994). Although chemotherapeutic agent - heromachine - stimulates fetal hemoglobin and reduces the production of sickle cell erythrocytes from patients with sickle cell anemia, its use as a monotherapy as well means potentially limited myelotoxicity and risk of carcinogenesis. Potentially long period of development Carcinogenicity is also a lack of therapy based on the use of 5-azacytidine. Erythrocyte transfusions can subject patients to the widespread impact of viral infections, as well as alloimmunization. Bone marrow transplantation are not easily accessible option for many patients. The results of therapy based on the use of erythropoietin, was not consistent for different groups of patients. Such diverse disadvantages of these therapeutic agents are contraindications to prolonged use of such funds or treatment by them.

On the basis of multilateral surveys of a large number of patients with disease characterized with less significant destruction of sickle cells and a longer survival period (O. S. Platt et al., "Pain in Sickle Cell Disease", New End. J. Med., 325, pp. 11-16 (1991); O. S. Platt et al., "Mortality ion Sickle Cell Disease," New Eng. J. Med. , 330, pp. 1639-44 (1994)). Accordingly, in seeking to avoid the disadvantages of conventional methods of therapy-hemoglobinopathy therapeutic methods have focused on ways of increasing the production of fetal hemoglobin. In a recent clinical experiments were used analogues of butyrate, including arginine butyrate and isobutyrate, to stimulate the production of fetal hemoglobin as a means of treatment (S. Perrine et al., "A Short Term Trial of Butyrate to stimulate Fetal-Globin Gene Expression in the-globin Disorders", N. Eng. J. Med., 328, pp. 81-86 (1993); S. P. Perrine et al., "Isobutyramide, an Orally Bioavailable Butyrate Analogue, Simulates Fetal Globin Gene Expression In Vitro and In Vivo", British J. Haematology, 88, pp. 551-61 (1994); A. F. Collins et al., "Oral Sodium Phenylbutyrate Therapy in Homozygous-Thalassemia: A Clinical Trial", Blood, 85, pp. 43-49 (1995).

Following the observation that butyric acid induces cellular differentiation in vitro [A. Leder and P. Leder, "Butyric Acid, a Potent Inducer of Erythroid Differentiation in Cultured Erythroleukemic Cells", Cell, 5, pp. 319-22 (1995)], it was found that this compound shows promising effects in patients with leukemia induction of cell differentiation [A. Novogrodsky et al., "Effect of Polar Organic Compounds on Leukemic Cells", Cancer, 51, pp. 9-14 (1983)]. In addition to their use in the treatment of hemoglobinopathy, it has been shown in mice that bout the first and antileykemichesky effect. [C. Chany and I. Cerutti, "Antitumor Effect of Arginine Butyrate in Conjunction with Corynebacterium Parvum and Interferon", Int. J. Cancer, 30, pp. 489-93 (1982); M. Otara et al., "Antibody - Mediated Targeting of Differentiation Inducers To Tumor Cells: Inhibition of Coionic Cancer Cell Growth in vitro and in vivo", Biochem Biophys. Res. Commun., 158; pp. 202-08 (1989)].

Although butyrate have an advantage because of their low toxicity compared with commonly used chemotherapeutics, inherent short periods of half-life in vivo is considered a potential drawback in clinical practice [A. Miller et al., "Clinical Pharmacology of Sodium Butyrate in Patients with Acute Leukemia", Eur. J. Clin. Oncol., 23, pp. 1283-87 (1987); Novogrodsky et al., Supra].

The rapid decay of these funds makes it impossible to maintain high levels in the plasma, which leads to the introduction of (their) intravenously. Another potential disadvantage of using butyrate salt is a salt overload and its physiological consequences. In view of these observations for use in differential therapy-hemoglobinopathy and leukemia have been proposed a variety of dosage forms on the basis of butyric acid. Such drug precursors include tributyrin and mono - and polyesters of n-butyric acid and monosaccharides [Z. Chen and T. Breitman, "Thibutyritics, Analogues and Current Status", Cancer Letts., 78, pp. 1-5 (1994); P. Pouillart et al. , "Pharmacokinetic Studies of N-Butyric Acid Mono - and Polyesters Derived From Monosaccharides", J. Pharm. Sci., 81, pp. 241-44 (1992)].

Such prodrugs are not, however, useful as a therapeutic agent due to factors such as short half-life, low bioavailability, lowmaxand the lack of efficacy of oral use. Other drug precursors, such as AN-9 and AN-10 [A. Nudelman et al. , "Novel Anticancer Prodrug of Butyric Acid", J. Med. Chem. , 35, pp. 687-94 (1992)], give the metabolites, which can develop in vivo formaldehyde, which leads to toxic effects on patients.

As it turned out, still commonly used methods and remedies are not safe and effective for all patients in the treatment-hemoglobinopathy. The same applies to diseases characterized by oncogenic growth, malignant or neoplastic cells, or malignant blood diseases. Accordingly, necessary alternatives have advantages and eliminates the disadvantages of existing methods and means of ensuring effective treatment of these target diseases.

The invention

The present invention solves these th acid, containing pharmaceutical compositions. These butyrate prodrugs show good bioavailability, efficacy in oral applications, acceptable "half-life" and a surprisingly high Cmax. With the introduction of the patient butyrate prodrugs in these compositions produce butyrate is more efficient than known butyrate prodrugs. This provides a higher level of butyrate in the plasma than other known butyrate predecessors.

Butyrate allocated from these butyrate predecessors, increases the synthesis of gamma-globin, increases hydration of red blood cells and stimulates cell differentiation. Increased synthesis of gamma-globin causes an increase in the formation of embryonic hemoglobin, which in turn increases the ability of red blood cells to carry oxygen and prevents the production of sickle cell erythrocytes. Increased hydration of erythrocytes also prevents the formation of sickle cell erythrocytes. The end result of this cascade of reactions is increased the period of life of erythrocytes.

This makes the pharmaceutical compositions of this invention are particularly useful in methods of treatment-hemoglo sposobnosti butyrate prodrugs of the present invention to stimulate the differentiation of cells has antiproliferative effects on cancer cells, especially malignant hematopoietic cells. Thus, the compounds and pharmaceutical compositions of this invention can be used in methods of treating cancer, in particular malignant blood diseases.

Because the patient may be prescribed a lower dose of the prodrug related to this invention, to achieve the desired concentration of butyrate in the plasma, the toxicity associated with dibutyrate part of prodrugs, less burdensome.

All these properties make it easier habitual modes of treatment often prescribed to patients suffering from-hemoglobinopathy or cancer. At the same time, they also make it easier is usually applied scheme of dosages and provide consent patients with these regimens. In addition, the methods and compositions of this invention are not accompanied by many side effects, which usually are characterized by the currently used therapeutic techniques.

A brief description of graphic materials

The drawing shows a change with time of the concentration of butyric acid due to the introduction of individual monkeys of various doses of compound IIIc.

Detailed description of the invention

Definition wide-angle is eat the term "alkyl" by itself or in combination with any other term refers to aliphatic hydrocarbon radical with a straight or branched chain, containing a specified number of carbon atoms or, if this number is not defined, preferably from 1 to 10 carbon atoms, which may have one or more unsaturated linkages. Examples of alkyl radicals include, but are not limited to: methyl, ethyl, isopropyl, butyl, pentyl etc. the Term "alkyl", as it is understood here, includes the terms "alkenyl" and "quinil", which is defined below.

The term "alkenyl" by itself or in combination refers to akinrinola the radical with a straight or branched chain, containing from 2 to 10, more preferably from 2 to 6 carbon atoms. Examples etkinlik radicals include, but are not limited to: vinyl, allyl, E-propenyl, Z-propenyl, E,E-hexadienyl, E,Z-hexadienyl, Z,Z-hexadienyl etc.

The term "quinil" by itself or in combination refers to akinrinola the radical with a straight or branched chain, containing from 2 to 10, more preferably from 2 to 6 carbon atoms. Examples of such radicals include, but are not limited to): ethinyl (acetylenyl), PROPYNYL, propargyl, butenyl, 1,4-hexadienyl, decenyl etc. "Quinil" in the sense used here also refers to radicals containing and C = C, and CC, as for example Z-Penta-2-EN-4-inyl.

The term "cycloalkyl" by itself or in combination refers to cyclic alkyl, the radical containing from 3 to 8, preferably from 3 to 6 carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to): cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "cycloalkenyl" by itself or in combination refers to cyclic alkyl, the radical containing from 4 to 8, preferably from 5 to 6 carbon atoms and one or more double bonds. Examples of such cycloalkyl radicals include, but are not limited to): cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

The term "heteroatom, independently selected from the group consisting of oxygen, nitrogen and sulfur instead of an equal number of carbon atoms. This term also refers to substituted or unsubstituted 8-11 membered bicyclic systems, which can be aromatic or non-aromatic, containing either or both rings from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and where the terms of the nitrogen or sulfur can include any oxidized form of nitrogen or sulfur and quarternizing the form of a basic nitrogen. Heterocyclic group may be linked to the compound via any atom group which forms a strong chemical bond.

Examples of non-aromatic heterocyclic radicals include, but are not limited to): 2-pyrrolyl, 3-pyrrolyl, 1,3-dioxolan, 2H-pyranyl, 4H-pyranyl, piperidyl, 1,3-dioxane, 1,4-dioxane, morpholine, 1,4-ditional, thiomorpholine, thiomorpholine, tetrahydrofuryl, piperazinil and hinokitiol.

Examples of the aromatic heterocyclic radicals include, but are not limited to): 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazoline, pyrazolidine, isoxazole, Il, 1,3,5-tritional, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo(b)furanyl, benzo(b)thiophenyl, 1H-indazole, benzimidazole, benzthiazole, purinol, 4H-hemolysins, chinoline, ethenolysis, cinnoline, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazinyl, phenoxazine and the like.

The term "aryl" refers to aromatic carbocyclic group, preferably with 6 carbon atoms, or an 8-14 membered aromatic polycyclic system of aromatic rings.

Examples of "aryl" groups include, but are not limited to: phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulene, fluorene and anthracene.

In the case of substitution of each carbocyclic" and "heterocyclyl" may independently contain from one to three substituents that are independently selected from the group consisting of hydroxy; halogen; C(1-6)-straight or branched alkyl, alkylamino or alkoxy; C(2-5)-straight or branched alkenyl, alkenylamine, alkynylamino, quinil, alconox or alkyloxy; nitro, NH2; thiol; alkylthio; carbocycle; carbocyclic; carbocyclization; barbiellini; heterocyclyl; geterotsiklicheskikh; heterocyclisation; Goethe is ebonyline; carbocyclic-carbylamine; geterotsiklicheskikh; sulfamido; alkylsulfonyl; alkanesulfonyl; alkylsulfonyl; arylsulfonyl. The above substituents may be attached to the carbon atom of the ring, and the heteroatom of the ring.

The term "alkoxy" means-O-C(1-6)-straight or branched alkyl radical. Examples of alkoxyalkyl are (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, fluorine-butoxy and tert-butoxy.

The term "alconox" refers to O-C(2-6)-straight or branched alkanniny radical. Examples of altnetseattle include (but are not limited to): allyloxy, E & Z-3-methyl-2-propenoic.

The term "alkyloxy" refers to O-C(2-6)straight or branched alkynylaryl radical. Examples of altnetseattle include (but are not limited to): propargyloxy and 2 butenyloxy.

The term "alkylamino" refers to C(1-6)-straight or branched alkyl-NH-radical, or C(1-6)-straight or branched alkyl-N-C(1-6) straight or branched alkyl, the radical, where alkyl radicals can be identical or different. Examples of suitable acylaminoalkyl include (but are not arylamino.

The term "alkanolamine" refers to C(2-6)-straight or branched alkenyl-NH-radical, C(2-6)-straight or branched alkenyl-N-C(1-6)-straight or branched alkyl, the radical, or C(2-6)-straight or branched alkenyl-N-C(2-6)-straight or branched Alchemilla the radical, where alkeneamine radicals may be the same or different. An example of a suitable alkenylbenzene is (but is not limited to them) allylamine.

The term "alkylamino" refers to C(3-6)-straight or branched quinil-NH-radical, C(3-6)-straight or branched quinil-NH-C(1-6)-straight or branched alkyl radical, C(3-6)-straight or branched quinil-NH-C(2-6)-straight or branched alkanniny radical or C(3-6)-straight or branched quinil-N-C(3-6)-straight or branched alkynylaryl radical, where alkyline radicals may be the same or different. An example of a suitable acylaminoalkyl is (without limitation): propargylamine and like him.

The term "amido" refers to - C(O)NH2-radical.

The term "alkylamino" denotes - C(O)NH-C(1-6)-straight or branched chain alkyl radical or-C(O)N [C(1-6)]2-straight or branched alkyl of radicals "alkylsulfanyl" refers to C(1-6)-straight or branched-chain alkyl-S(O2)NH-radical. An example of alkylsulfonic is ethanolamide. In order for the invention described here can be understood best, the following is a detailed description.

Compounds related to this invention, are the predecessors of butyrate obtained from lactic acid, which can be represented by the formula

< / BR>
in which A and D are independently selected from the group comprising hydrogen, alkoxyalkyl, barbiecollector.com or C(1-4) alkyl straight or branched chain, C(2-4)-alkenyl or quinil straight or branched chain, which may be independently substituted by hydroxy, alkoxy, carboxylation, alkylamino, arylamino, heterocyclisation, aralkylated, heterocyclisation, alkoxycarbonyl, allenxlenalee, carbonylcontaining, heterocalixarenes, carbonylcontaining, geterotsiklicheskikh, alkoxycarbonyl, amino, amido, carboxyl, Tilney, thioalkyl, tofanelli group, the aryl and the rest of the heterocycle; provided, that a and D are not simultaneously hydrogens;

R is Oh, NH, NC(1-5)alkyl straight or branched chain or NC(2-ICLA or heterocycle;

Z is hydrogen, C(1-4)alkyl straight or branched chain, C(2-4) alkenyl or quinil straight or branched chain, carbocyclic or heterocyclic, any of which may be optionally substituted 1 or 2 groups independently selected from C(1-3) alkyl, C(2-3)-alkenyl or quinil, alkoxy, alkenone, alkyloxy, amido, thioalkyl, carbocyclic or heterocyclic residue; and each stereogenic carbon atom can be R or S configuration; provided that the compound is not:< / BR>
< / BR>
In accordance with the preferred option, D - methyl and a is hydrogen in the compound of formula I, which leads to the compound of formula II

< / BR>
Preferably in formula (II) R is O, NH, N-C(1-3) alkyl; NC(2-4)-alkenyl straight or branched chain or N-benzyl; and

Z - C(1-4) straight or branched alkyl, optionally substituted by one group selected from a 5-to 10-membered carbocyclic or 5-to 10-membered heterocyclic residue.

Most preferably R is oxygen, Z is unsubstituted straight or branched alkyl, and stereochemistry metalmessage carbon atom.

According to another preferred variant of the R - oxygen in the formula I, the resulting soy or allyl; provided that a and D are not both hydrogens; and Z is C(1-3) alkyl, optionally substituted by one group selected from C(5-10)-carbocycle or heterocycle.

More preferably D is hydrogen or methyl And unsubstituted C(1-3)-alkyl, and Z is unsubstituted C(1-3) alkyl.

The preferred pharmaceutical compositions of this invention contain a compound selected from

< / BR>
< / BR>
< / BR>
A preferred prodrug is a compound IIIc.

Drug precursors of the formula I contain one or more asymmetric carbon atoms and therefore exist in the form of racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereoisomers. All of these isomeric forms of these compounds as well as mixtures of them, are included in the pharmaceutical compositions of the present invention.

The invention also includes prodrugs of formula I, which quarternion on any of the basic nitrogen-containing groups. The basic nitrogen can be quartersawn any agents known in this field, including, for example, halides of lower Akilov, such as methyl, ethyl, propyl and butyl chloride, bromide is for example the chlorides, the bromides and iodides of decyl, lauryl, myristyl and stearyl; halides Arakelov, including benzyl, ethoxyphenylurea. This quaternization can be obtained water - or fat-soluble or dispersible products.

Predecessors hydrolyzed in vivo to release the active ingredient. According to the present invention, the described drug precursors release (emit) butyric acid. Without being bound by any theory, we believe that the need to maintain a certain threshold concentration of butyric acid in plasma for at least a few hours a day for several days in order to start the chain of synthesis of gamma-globin and education embryonic hemoglobin or to induce the differentiation of malignant cells, which causes an anti-cancer effect. Compounds, which are characterized by the composition of the present invention, metabolize in the body in such a way that produce the highest concentration (Cmax) butyric acid in the oral administration. These compounds are also characterized by significantly longer "half-life" (t1/2) that provides effective impact the effective concentration of butyric acid in the plasma of these drugs need to enter much less than the commonly used tools. This, in turn, leads to potentially lower toxicity due to the applied dose of the prodrug, and also facilitates its introduction.

Predecessors of butyrate described in this invention can be synthesized using standard techniques of organic chemistry. Many-hydroxyacids, hydroxyether and-hydroxyamide commercially available (for example, Aldrich Catalog Handbook of Fine Chemicals, 1994-1995). In case of hydroxyamino or hydroxyamino removing the hydroxy-group can be accomplished using the activated form butyric acid such as the acid chloride; double acid anhydride; mixed anhydrides of coal, phosphine and sulfonic acids; and activated esters, such as phenyl, 4-nitrophenyl, pentafluorophenyl, hydroxybenzotriazole or N-hydroxysuccinimide.

Preferably the derivatization is carried out by means of a base, such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo(54.0)undec-7-ene, pyridine or tetramethylguanidine; or aqueous buffers or alkalis, such as sodium carbonate or sodium bicarbonate (see, for example, E. Haslam, "Recent Development in Methods for the Esterification and Protection of the Carboxyl Group", Tetrahedron, 36, pp. 2409-2433 (1980). Dehydrating and is to be used. The use of catalyst hyperchloraemia, for example, 4-dimethyl-aminopyridine, can improve the efficiency of the reaction (A. Hassner et al., "Direct Room Temperature Esterification of Carboxylic Acids", Tetrahedron Lett., 46, pp. 4475-4478 (1978)]. Additional techniques are well known in this field and can easily replace the above.

If you use-hydroxy acid, derivatization of the carboxylic acid group may be carried out first by transforming the hydroxy-group in butyryloxy group. This is followed by etherification or nidificate carboxylic acid or transformation, comprising the following stages:

1) intermediate blocking of the hydroxyl protecting group that can be removed;

2) derivateservlet carboxylic acid in the form of ester or amide;

3) removing the protective group of hydroxyl; and

4) the transformation of the hydroxy-group in butyryl, as mentioned above.

Bearing butyryl or hydroxylamine-hydroxy acid can then be converted into their corresponding esters of formula I (where R = O) activation of carboxyl, just as described above for butyric acid, followed by interaction with alcohol in the presence of a suitable base. The interaction of activated BU the result in amines of formula I (where R = NH, N-C(1-5) alkyl straight or branched chain which may be substituted carbocyclic or heterocyclic residue). A wide range of primary, secondary or tertiary alcohols and primary and secondary amines are commercially available and can easily be obtained using known methods. Thus, this process provides access to compounds of the formula I, in which R-Z can vary widely.

Some particularly useful methods for synthesizing compounds of formula I is shown in scheme 1 (see the end of the description).

In these methods, the selected-hydroxycitrate can react via hydroxyl and carboxyl groups. Interaction with a suitable solaruim agent, such as t-butyl-dimethylsilicone in the presence of imidazole in dimethylformamide yields a bis-similarvideo the compounds of formula XIa or similar silyl derivative. This compound can be converted into carboxyl-activated derivative chain the following stages:

1) partial hydrolysis of carboxylic silyl group, for example, hydrolysis using 1 molar equivalent of lithium hydroxide at about -20oC to approximately the temperature of the environment is emer, citric acid;

4) extraction with a suitable organic solvent, such as methylene chloride; and

5) carboxyl activation, as described above.

Remove hydroxyzinesee silyl group using, for example, tetrabutylammonium in tetrahydrofuran at about 0oC to about room temperature, or HF-pyridine complex in acetonitrile leads to the production of hydroxy XIV. The conversion of the compounds of formula I can then be performed as described above.

Alternative-hydroxycitrate formula X can respond by hydroxyl and carboxylate groups with alkyl substitute, such as benzyl derivative, as shown in figure 1. Other alkyl derivatives, such as allyl, 4-methoxybenzyl, 2,2,2-trichloroethyl or 2-trimethylsilylmethyl, can also be used at this stage.

Stage derivatization can be carried out by the interaction of the compounds of formula X with an excess of benzylbromide in the presence of approximately 2.2 to 3 equivalents of a strong base such as sodium hydride, potassium hydride or t-piperonyl sodium, in a suitable inert solvent such as THF or dimethylformamid is and electrophiles. In General, phasetransfer catalytic method using a base, such as K2CO3or NaOH in an inert solvent, such as toluene or acetonitrile, can be used for the alkylation. Suitable catalysts include Quaternary ammonium salts such asnBu4N+Br-and crown ethers such as dibenzo-18-crown-6.

Translation of suitable bis-alkyl compounds of formula XIb in the compound of formula XIIb may be carried out by saponification, for example, in aqueous methanol or dioxane using equimolar or greater amount of alkali such as sodium hydroxide, lithium or potassium at a temperature increasing from about -40oC to approximately 80oC. Or interaction with Tualatin anion, such as editionat sodium, idolreplicas, or with other reagents, chip off the ester group, will result in a protected carboxylic acid of formula XIIb (see, for example, R. C. Larock, "Comprehensive Organic Transformations", pp. 981-985, 1989 VCH. Publishers, Inc., New York, NY).

Activation and derivatization, such as those described for compounds of formula XIIa, leads to the formation of compounds of formula XIIIb. Benzyl group can then be removed in the usual way is the R coal using a hydrogen source such as hydrogen gas, ammonium formate, or catalytic transfer hydrogenation using cyclohexadiene or similar. Such methods are well known in the field of organic chemistry (see, for example, P. N. Rylander, "Catalytic Hydrogenation in Organic Synthesis", 1979, Academic Press, Inc., Orlando, FL). Recovery methods using metals, including the dissolution of the substrate in the liquid ammonium, and adding an alkali metal such as metallic sodium, is also well known to specialists.

If instead of the benzyl group is allyl, its removal can be accomplished by a transfer reactions with palladium using tetrakis-(triphenylphosphine) Pd0and allyl acceptor, such as morpholine or acetate PdIIand Bu3SnH. Methods of using these and other alcohol protective groups already described (see, for example, T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, 1991, Academic Press, Inc., Orlando, FL, pp. 14-120). The resulting compound of formula XXII can be then subjected to the reactions described above to obtain compounds of formula I.

-Hydroxyacids, hydroxyether and-hydroxyamide, if they are not commercially available, Mogul area. For example, the interaction of the ester or amide Glyoxylic acid with a suitable karbonovymi a nucleophile, such as a reagent Grignard, organoboranes or organolithium reagent, in a suitable inert solvent such as diethyl ether or tetrahydrofuran from approximately -80oC to about 0oC, results-hydroxyether or amide of formula XIV, where a is a nucleophilic group, and D is hydrogen. Similar reactions carried out on-ketoesters or Amidah, result ,-disubstituted-hydroxyethyl or Amida (see B. M. Trosk and I. Fleming, "Comprehensive Organic Syntheses, Vol. 1, p. 49-282, 1989, Pergamon Press, Oxford, England).

Many-hydroxy acid can be obtained in the usual way by the interaction of the corresponding-amino acids with diasterous agent in subnucleonic environment. For example, NaNO2can be added to a solution of amino acids in aqueous solution of sulfuric acid (R. V. Hoffman et al., Preparation of (r) - 2 - Azid Esters from 2-(p-Nitrobenzene)sulfonyl)oxy Esters and Their Use as Protected Amino Acid Equivalents for the Synthesis of Di - and Tripeptides Containing D-Amino Acid Constituents", Tetrahedron Lett., 48, pp. 3007-3020 (1992). So how many amino acids can be purchased, and received many other well-known synthetic methods, often in optically active form is 364 (1989)), this method leads to easily obtain raw materials for the compounds of formula I.

Alkalicarbonate acid and ether and amide derivatives can be converted into-hydroxy by creating an anionic group in position-carbon to obtain a carboxylated derivative, followed by reaction with an oxidizing agent such as sulfonylacetanilide that leads to obtaining the compounds of formula X or XIV (R. C. Larock, "Comprehensive Organic Transformation", p. 489, 1989, VCH Publishers, Inc., New York, NY).

Embodiments of the method described above, and other synthetic approaches known from the literature for organic chemical synthesis, are obvious to experts in the field. Other methods of temporary protection and remove it with reactive groups, and their further transformation to obtain additional compounds corresponding to the formula I, is easily fulfilled qualified in this area specialists.

In accordance with one aspect of the invention, it relates to pharmaceutical compositions containing precursor drug (prodrug) of formula I (including n-butyl ether, are excluded, in particular from compounds Yes is atii cell differentiation in a patient, and pharmaceutically acceptable carrier or adjuvant. More specifically, these compositions to treat patients-hemoglobinopathies or malignant disease. The term "malignant disease" in this here the value indicates the condition is characterized tumor, oncogenic cell growth or growth of malignant cells, or hematologic disease.

The amount effective to increase production of fetal hemoglobin or stimulation of cell differentiation in a patient will depend, of course, from the nature of the disease that should be treated, the severity of the disease, the physical condition of the patient and opinions of a treating physician. Preferably, the prodrug of formula I exist as, which could provide the concentration of butyric acid in plasma in the range from about 0.03 mm and 3.0 mm within 8 hours of its introduction. More preferably, if the drug precursor of formula I is present in an amount to provide a concentration of butyric acid in plasma in the range of approximately 0.1 mm - 1.0 mm within 6 hours of injection. The most preferred case when the drug precursor in the composition is contained in the number concentration remains within the values specified interval for at least 2 hours. Doses in the range of from about 25 mg of prodrug / kg of body weight up to 3 g prodrugs per kg of body weight, administered once or several times a day, is able to provide the desired concentration of butyric acid in the plasma. Preferably the prodrug to the patient from 1 to 4 times a day.

In the preferred embodiment, these compositions optionally contain a common tool used for the treatment of hemoglobinopathy. Known means may be present in the same or lesser amount than that which is usually applied in the treatment of hemoglobinopathy method monotherapy. The usual dose of these traditional tools are well known. Such agents include hydroxyurea, clotrimazole, isobutyramide, erythropoietin, and salts of short-chain fatty acids, such as phenylacetic acid, fenilalanina acid and valproic (Valeeva) acid. Preferably as a known means usually use hydroxyurea.

In accordance with another preferred compositions contain butyrate the prodrug of the present invention and commonly used tool used for the treatment of diseases characterized by growth of tumor, cancer or malignant is TBE, equal to or smaller than that required for the treatment of such diseases. The usual dosing of these existing tools are well known. These tools include erythropoietin or chemotherapeutic anti-cancer agents, such as hydroxyurea or 5-azacytidine. Preferably, as already known tools used hydroxyurea.

Pharmaceutically suitable salts proletarienne means of formula I (including n-butyl ether, in particular, are excluded from the compounds of the present invention) can also be used in any of the above compositions. Such salts can be obtained on the basis of a pharmaceutically suitable inorganic or organic acids and bases.

Examples of suitable acids include hydrochloric, Hydrobromic, nitric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinoyl, toluene-p-sulfonic, oxalic, acetic, citric, methansulfonate, econsultation, formic, benzoic, malonic, naphthalene-2-sulphonic and benzylmalonate acid.

Salts derived from appropriate bases include alkali metal salts (e.g. sodium) salts /P> Carriers and adjuvants included in the compositions of this invention include, for example, ion exchangers, alumina, aluminum stearate, caritin, serum proteins, such

as albumin human serum, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, a mixture of glycerides of partial replacement of saturated fatty acids of vegetable origin, water, salt electrolytes, such as preteenslut, the disubstituted nutrifaster, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose and polyethylene glycol. Adjuvant means for local use or gel bases can be selected from the group consisting of carboxymethylcellulose sodium, polyacrylates, polyoxyethylene-polyoxypropylene block polymers, polyethylene glycol and alcohols from wood tar.

In General, the pharmaceutical compositions of this invention can be prepared and administered to the patient using methods and like compositions that are applied to other pharmaceutically important tools.

Can be used any way the introduction of pharmaceutically acceptable dose, including oral, topical, intranasally, intrasynovial, intrathecal, intrasternally, intracranial, intralesionally).

The pharmaceutical compositions according to the invention can be in the form of a number of conventional forms of prolonged action. They include, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, solutions, liquid powders, solutions, suspensions, emulsions, liposomes, capsules, suppositories, solutions for injection and infusion. The preferred form depends on the intended type of introduction and forms of therapeutic applications.

For example, oral introduction of the pharmaceutical compositions of this invention can be any orally applicable dosage form (but not limited to, capsules, tablets, aqueous or non-aqueous suspensions, emulsions and oil solutions. In the case of tablets for oral use carriers that are well known include lactose and corn starch. Agents having the property of a lubricant such as magnesium stearate, are also typically added. For oral administration in the form of hard gelatin capsules used fillers include lactose and dried corn starch. Soft gelatin capsules containing oil which suspensions or emulsions of the prodrug is combined with emulsifying and suspendresume agents. If desired, can be added flavorings, sweetening and coloring tools.

Preferably the pharmaceutical compositions of the present invention are prepared for oral administration. Even more preferred emulsions for oral administration, contains in the range of from about 5 to about 40 (w./w.) the prodrug of formula I (including n-butyl ether, are particularly excluded from the group of compounds of this invention) and surfactant ionic or non-ionic nature, and the resulting composition has an HLB value in the range of 0-40. Preferred surfactants include tween-20, tween-80, Spam 20, Spam-40 and poloxamer, such as S - 108.

In accordance with another variant of the invention claimed methods of treating the sick-hemoglobinopathies. This method comprises a stage of treatment of the patient any of the above compositions. The term "treatment" in the sense in which it is used here, includes a reduction in the severity, symptoms and consequences-hemoglobinopathy. Preferably the method provides for the concentration of butyric acid in serum in the range of from about 0.03 mm to 3.0 mm in the range of about 8 hours of injection. More site to 1.0 mm for about 6 hours from the introduction. Most preferably, when the drug precursor is present in the composition in an amount to provide a concentration of butyric acid in plasma from approximately 0.1 mm to 1.0 mm within 2 hours from the time of introduction and the concentration remains at this level for at least 2 hours. These plasma levels are achieved by the introduction of prodrugs of formula I to a patient doses in an amount corresponding to the interval from approximately 25 to 3000 mg/kg body weight once or several times a day.

Preferably, the patient entered the prodrug from 1 to 4 times a day.

-Hemoglobinopathy, which can be treated this way include syndromes sickle cell red blood cells, such as sickle cell anemia; hemoglobin SC disease, hemoglobin SS disease and sickle cell-thalassemia, syndromes-thalassemia-thalassemia; other genetic mutations of the gene locus-globin, which leads to instability of hemoglobins, such as congenital anemia Heinz'a mutated-globin with abnormal affinity to oxygen and structurally changed by mutation-globin, which have thalassemias phenotype. Such zabolevaniy variant of the above method includes the additional step of treating the patient with the means which is typically used for the treatment of such-hemoglobinopathy, such as hydroxyurea. This tool can be introduced before, concurrently or after administration of the composition containing the precursor of butyrate. Of course, if treatment composition is used, which already includes such commonly used tool, this additional step can be omitted.

The number of known means entered using these methods, less than commonly used monotherapies such diseases. The usual dose of these known means are well known in the art. These tools include hydroxyurea, clotrimazole, isobutyramide, erythropoietin and salts of fatty acids with short chains, phenylalanyl acid and valhroic (velievoy) acid. Preferably as a known drug use hydroxyurea.

In accordance with another variant of the invention provides a method of treating diseases characterized by growth of tumor, cancer or malignant cells, as well as hematological diseases malignant type.

Treatment includes prevention of the progression of the disease or its renewal. To t the supports the same concentration of butyric acid in plasma, above that is highly desirable in the treatment of hemoglobinopathy.

In accordance with a preferred variant of the above method includes the additional step of treating the patient tool that is typically used for such malignant diseases. Preferably such means is hydroxyurea. This tool can be put to, at the same time and after administration of the composition containing the precursor of butyrate. Of course, if the composition is used for treatment of the disease, already contains such well-known means, this additional step may be omitted.

The number of known means entered using these methods, preferably less than commonly used monotherapies such diseases. The usual dose of these known means are well known in the art. These tools include erythropoietin or anti-cancer chemotherapeutic agents, such as hydroxyurea or 5-azacytidine. Hydroxyurea is preferable commonly used tool.

The combination of therapeutic methods based on the use of conventional means, according to this invention (either as part of their additional or synergistic effect, especially when each component exerts its action in terms of treatment or prevention of a specified disease in a different way.

For a better understanding of the invention described here below are examples. However, it should be understood that these examples are set forth for illustrative purposes only, are not intended to limit the present invention.

Example 1

The synthesis of compounds IIIa and IIIb

We synthesized the compound IIIa in the following way. Joined of 6.25 ml of methyl-(S)-lactate and 13.75 ml Et3N and then added this mixture to the methylene chloride. We cooled the mixture to 0oC in an ice bath and then slowly added to 8.2 ml butyrylcholine. This mixture was stirred overnight and then was filtered through a Buechner funnel. Sediment in the form of pellet was then washed with ether and washing was combined with the filtrate. Allocated organic layer from the filtrate, washed twice with water, once Brin and then dried over anhydrous MgSO4. The yield of the crude product was 12,48,

This material is then pererestorani in a mixture of 90% hexane/ethyl acetate and subjected to chromatography on MPLC column. Collected fractions containing the target product, and dried them perfectly is.

Compound IIIb was similarly synthesized and purified when replacing methyl-(R)-lactate, methyl-(S)-lactate.

Example 2

The synthesis of compounds S

We synthesized the compound IIIc mixing of 7.4 ml of ethyl (S)-lactate with of 13.75 ml Et3N and then added this mixture to 50 ml of methylene chloride. Cooled the mixture to 0oC in an ice bath and slowly added to 8.2 ml butyrylcholine. The mixture was stirred over night. TLC analysis of the mixture showed complete reaction. Then we added additional 0,25 mol (2.5 ml) butyrylcholine and allowed the reaction to continue for another 24 hours under stirring.

The mixture is then filtered through BONEROWSKI funnel. Sediment in the form of pellet was washed with ether and washing liquid was combined with the filtrate. Was isolated from the filtrate, the organic layer washed twice with water, once Brin and then dried over anhydrous MgSO4. The yield of the crude product 15,98, This material is then pererestorani 90% hexane/ethyl acetate and chromatographically MPLC on-column. The fractions containing the desired product were collected, dried, receiving becomes 9.97 g of pure product. NMR analysis confirmed that the product after purification is the compound IIIc.

Example 3

Oral th the availability and maintenance of concentrations of butyric acid in the plasma of rats, receiving or compound IIIa or IIIb, or IIIc oral route at doses of approximately 3 g/kg body weight. Butyrate prodrugs were prepared by simple dissolution in corn oil.

The study was performed in accordance with the techniques described in Daniel et al. , Clinica Chimica Acta, 181, pp. 255-64 (1989); Planshon et al., J. Pharm. Sci. , 82, pp. 1046-48 (1993); Pouillart et al., J. Pharm. Sci., 81, pp. 241-44 (1992). Each compound was tested at 5-6 rats (Sprague Dawley; Harlan Labs, Inc.), weighing approximately 300 g each. The corresponding values of Cmaxthese funds are given in table. 1.

These results show that the compounds of this invention are known to produce butyrate at a suitable speed and to provide significant concentration of butyrate in the plasma to be used in the treatment of hemoglobinopathy and cancer.

Example 4

Oral suitability for monkeys predecessor of butyrate from lactic acid

Compound IIIc then investigated in rhesus monkeys with anemia. A single oral dose of compound IIIc, dissolved in corn oil, was administered to monkeys. Values of Cmaxobtained for each of these doses are given in table. 2.

The residence time in the plasma concentration of butyric acid in the p 5

Studies of the efficacy of compounds IIIc in combination with hydroxyurea in rhesus monkeys, patients with anemia

The effectiveness of compounds IIIc, administered in combination with hydroxyurea, was analyzed in six anemic rhesus monkeys were divided into three groups, two in each. Each group was studied in two stages, as described below. Before and after each of the two stages of the register cells of fetal hemoglobin (F-cells), the percentage of Hemoglobin F in relation to the total Hemoglobin (% Hemoglobin F) (% HbF) and % levels Globino chain. % F cells was calculated by the method described Betke et al., Blut., 4, pp. 241-9 (1958). % HbF and % synthesis-Globino chain were determined using high performance liquid chromatography (HPLC) in accordance with the methodology described in Huisman, J. Chromatogr. 418, pp. 277 (1987) (see tab. 3 and 4).

In group I, for animal 1 counted % F cells was before stage I of 8-10%. At the end of stage I % F cells for animal 1 had increased to 25%. At the end of stage II % F cells for animal 1 had increased to 35%.

In group II for animal 2 estimated % F cells 8-10% before phase I. At the end of stage I % F cells for animal 2 increased to 15%. At the end of stage II % F cells for animal 2 had increased to 22%. Wholoesale small, but important increase % F cells without significant changes HbF and % levels Globino chain.

In all three groups was not observed noticeable differences in the content of triglycerides and ALT prior to or within two stages of this study, the effectiveness of compound IIIc.

The results demonstrated the use of butyrate of the present invention when used in conjunction with the usual means, such as hydroxyurea induction of fetal hemoglobin in hemoglobinopathy.

Despite the fact that the applicants here have described a number of embodiments of the invention, it is apparent that our basic approaches can be improved for other variants that use synthesis, processes and compositions of this invention. Therefore, you need to take into account the fact that the scope of the present invention should be determined by the asserted claims, and not by private variants of the embodiment according to the previously described examples.

Toxicity repeated oral doses of compound IIIc 28 days after injection with a two-week recovery period was evaluated in male and female rats of the Fischer 344 (daily dose of 1 and 3 g/kg comparing their one month of treatment was salivation;

no treatment-related effects on body weight and no effects on haematological or clinical chemical parameters;

- in any tissues not found any related medication histopathology;

- 2 hours after a dose 28 day average butyrate amounted to 0.23 and 0.19 mm for doses of 1 and 3 g/kg/day, respectively;

- no observed effect level (NOEL) for compounds IIIc, defined as 3 g/kg/day (18 g/m2/day) in rats after oral administration for 28 days.

1. Pharmaceutical composition that increase fetal hemoglobin of the patient or accelerating differentiation of cells containing an effective amount of butyrate predecessor. drugs of formula I

< / BR>
where a and D are independently from each other selected from the group comprising hydrogen, barbiecollector.com or C(1-4) straight or branched alkyl, S(2-4), straight or branched alkenyl or quinil, which may be independently substituted by hydroxy, alkoxy, carboxylation, alkylamino, arylamino, heterocyclisation, aralkylated, heterocyclisation, alkoxycarbonyl, allenxlenalee, carbonylcontaining, geterotsiklicheskikh, amino, amido, carboxyl, Tilney, thiomethyl, tofanelli group, the aryl and the rest of the heterocycle: provided that a and D are not simultaneously hydrogens;

R= O, NH, N(1-5) alkyl straight or branched chain or NH(2-5) of alkenyl straight or branched chain, any of which may be optionally substituted by a residue of carbocycle or heterocycle:

Z is hydrogen, C(1-4) alkyl straight or branched chain, With(2-4) alkenyl or quinil straight or branched chain, carbocyclic or heterocyclic residue, each of which may be optionally substituted 1 or 2 groups independently selected from C(1-3) alkyl, C(2-3) alkenyl or quinil, alkoxy, alkenone, alkyloxy, amido, thioalkyl, carbocyclic or heterocyclic residue; and each stereogenic carbon atom can be R or S configuration;

and pharmaceutically acceptable adjuvant or the media.

2. The pharmaceutical composition under item 1, in which in formula I: A is hydrogen and D is methyl.

3. The pharmaceutical composition according to p. 2, in which in formula I: R - O, NH, N-C(1-3) alkyl, NC(2-4) alkenyl straight or branched chain or N-benzyl; and Z Is C(1-4) straight or branched alkyl, optionally substituted by one g is 4. The pharmaceutical composition according to p. 3, in which in formula I: R is oxygen; Z is unsubstituted C(1-4) normal or branched alkyl; and the stereochemistry bearing the methyl carbon atom.

5. The pharmaceutical composition under item 1, in which in formula I: R - oxygen.

6. The pharmaceutical composition under item 5, in which in formula I: a and D are independently selected from hydrogen, methyl, ethyl or allyl; and Z Is C(1-3) alkyl, optionally substituted by one group selected from a 5-to 10-membered carbocyclic or 5-to 10-membered heterocyclic residue.

7. The pharmaceutical composition according to p. 6, in which in formula I: D is hydrogen or methyl; And is unsubstituted C(1-3) alkyl: and Z is unsubstituted C(1-3) alkyl.

8. The pharmaceutical composition under item 1, in which the predecessor butyracea drug selected from the group consisting of

< / BR>
(IIIa 1-methoxycarbonylethyl ether S-butyric acid)

< / BR>
(1 IIIb-methoxycarbonylethyl ether R-butyric acid)

< / BR>
(IIIc 1-ethoxycarbonylethyl ether S-butyric acid)

9. The pharmaceutical composition under item 8, in which the specified predecessor is:

< / BR>
(IIIc l-ethoxycarbonylethyl ether S-butyric acid)

10. The pharmaceutical companies which of they.

11. The pharmaceutical composition according to p. 10 for obtaining a medicinal product for the treatment of the patient-hemoglobinopathies.

12. The pharmaceutical composition according to p. 11, characterized in that it further includes the most commonly used agent for the treatment of patients-hemoglobinopathies.

13. The pharmaceutical composition according to p. 11, characterized in that it further includes hydroxyurea. used in the treatment of patients-hemoglobinopathies.

14. The pharmaceutical composition according to paragraphs.1-9 to obtain drugs stimulate cell differentiation in a patient.

15. The pharmaceutical composition according to p. 14 for obtaining a medicinal product for the treatment of patients with malignant disease.

16. The pharmaceutical composition according to p. 15, characterized in that it further includes the most commonly used agent for the treatment of patients with malignant disease.

17. The pharmaceutical composition according to p. 16, characterized in that it further includes hydroxyurea used to treat patients with malignant disease.

18. The pharmaceutical composition according to p. 12, characterized in that it is a regular article is the fact that that her predecessor drug butyracea means is S l-ethoxycarbonylethyl ether S-butyric acid.

20. The pharmaceutical composition according to p. 14, characterized in that it is above the standard agent is hydroxyurea.

21. The pharmaceutical composition according to p. 20, characterized in that it is a precursor drug butyracea means is S l-ethoxycarbonylethyl ether S-butyric acid.

Priority points:

06.10.1995 on PP.1-10, 13-14;

30.04.1996 on PP.11-12, 15-20.

 

Same patents:

The invention relates to a new process for the preparation of esters cyclopropanecarbonyl acid of the formula I

< / BR>
where R is the ester residue, split in neutral or acid medium and which WITH1-18the alkyl possibly substituted with halogen or benzyl radical, possibly substituted on the tops of the aromatic ring by one or more halogen atoms, or a radical of formula (a) -(g),

< / BR>
where R2Is h or methyl;

R3- aryl;

R4- CN, N.;

R5- fluorine, chlorine, bromine or hydrogen;

R6, R7, R8, R9is hydrogen or methyl;

S/1 symbolizes tetrahedrite

The invention relates to the production of compounds which are useful as intermediates for obtaining spirotaenia derivatives of glutarimide, especially in connection with a registered brand name candoxatril and systematic name /S/-CIS-4-/1-[2-/5-intenrational/-3-/2-methoxyethoxy/propyl] -1 - cyclopentanecarboxylic/-1 cyclohexanecarbonyl acid

The invention relates to the field of organic chemistry, namely to new chemical compound gross formula

< / BR>
where x= CF2or bond, the sum n + m + C 3 10

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The invention relates to medicine and can be used in neurosurgery and neurotraumatology and surgery to stop capillary bleeding
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