Fumaric acid amides

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

 

The present invention relates to certain mono - and diamide of fumaric acid, monoethyl of monoamide fumaric acid, as well as the application of these compounds to obtain medicines containing these compounds medicines.

Dialkyl ethers fumaric acid, and monoalkyl esters of fumaric acid and their salts have long been successfully used for the treatment of psoriasis. This application is described in several patents, see, for example, the application for the European patent EP-A-0188749, patent DE-2530372, patent DE-2621214 or European patent EP-B-0312697.

It is known the use of mono - or diesters of fumaric acid for the treatment of autoimmune diseases such as polyarthritis, multiple sclerosis (see application DE 19721099.6, and application DE 19853487.6), but also for use in transplantation medicine (see application DE 19853487.6 and DE 19839566.3). From the unpublished applications DE 10101307.8 and DE 10000577.2, also known application of mono - and diesters of fumaric acid for the treatment of mediated NFkappaB diseases, the treatment of mitochondrial diseases. In all these publications, however, describes only the mono - and diesters of fumaric acid, if necessary, in the form of certain salts, i.e. compounds in which one or both of the acidic functional groups of fumaric acid tarifitsirovana using the Porta.

These esters of fumaric acid because of its volatility, respectively subliminally, however, have the disadvantage, and it is difficult to apply in the preparation of pharmaceutical products, in particular in solid form for oral administration. More specifically, for making these products the necessary protective measures, such as the use of respiratory masks, gloves, protective clothing, etc.

Moreover, the esters of fumaric acid after oral administration rezorbiruetsa in the gastrointestinal tract and nonspecific perceived by all cells of the body from the bloodstream. However, to achieve in the target cell, respectively, in the target cells, a therapeutically effective level of biologically active substances, you must enter a correspondingly high doses. These high doses, for its part, leads to the known side-effects when treatment with fumaric acid, such as symptoms of blood flow (redness) or gastrointestinal irritation (nausea, diarrhea, flatulence). Side effects, however, as described in the above prior art, can largely be reduced by the introduction of biologically active substances in the form of microtablets, however, cannot be fully avoided.

At the same time, the esters of fumaric acid is rapidly hydrolyzed in the blood samenaide products of hydrolysis alcohol and fumaric acid, accordingly, monoamine fumaric acid. To achieve therapeutically effective levels so you need to repeated, frequent introduction. However, in relation to side effects can be observed well-known effect of habituation, however, it would be desirable to further reduce the share of side effects.

The present invention is to obtain derivatives of fumaric acid and their application, which can be introduced purposefully and which are more resistant to hydrolysis and easier to handle.

The problem is solved by means of certain mono - and diamide of fumaric acid, respectively monoethers of monoamide fumaric acid, their use for the preparation of drugs for the treatment of certain diseases and containing medicines.

Diamides and monoamide fumaric acid already described in the application US-A-5242905 and US-A-5214196 firm Blank for the treatment of psoriasis. However, in these printed works only describes a specific mono - or diamide of fumaric acid. Preparation of pharmaceutical products and the use of amides in the case of a person not described. As theoretical advantages of amides of fumaric acid compared with esters of fumaric acid in these printed works call for certain amino acids from aminopropanol acid in keratinocytes to cover the deficit of metabolism in psoriasis.

The authors of the present invention it has been unexpectedly discovered that mono - and diamide of fumaric acid, and esters of monoamide fumaric acid can be mainly used for the treatment of many diseases. More specifically, the present invention relates, according to the first aspect, to the use of amides of fumaric acid of General formula (I)

R1means OR3or linked through amide bond D - or L-amino acid residue-NH-CHR4-COOH, where R3means a hydrogen atom, a linear or branched, unsubstituted or substituted (C1-C24)-alkyl group, preferably (C1-C6)-alkyl group, phenyl group, or (C6-C10)-aracelio group, and R4means a side chain of a natural or synthetic amino acids;

R2means linked through amide bond D - or L-amino acid residue-NH-CHR5-COOH, or linked through amide bond of the peptide residue from 2-100, preferably 2-30, amino acids, where R5means a side chain of a natural or synthetic amino acids,

in order to prepare medicines

(1) for the treatment of autoimmune diseases selected from the group consisting of arthritis, particularly rheumatoid arthritis, multiple sclerosis, reactions of TRANS who Lancet vs. host juvenile diabetes, tirodite Hashimoto's, graves ' disease (or graves ' disease), systemic lupus erythematosus (SLE), Sjogren syndrome, pernicious anaemia and chronic active (lupus) hepatitis;

(2) for use in transplantation medicine (graft versus host);

(3) for the treatment of mitochondrial disease selected from the group consisting of Parkinson's disease, Alzheimer's disease, horii's disease, pigmentary retinopathy or mitochondrial encephalomyopathy, and

(4) to ensure mediated NFkappaB diseases selected from the group consisting of progressive systemic sclerosis, syphilis osteochondritis disease weger), Cutis marmorata (Livedo Reticularis), disease behceta, panarteritis, ulcerative colitis, vasculitis, osteoarthritis, gout, ateriosclerosis, Reiter syndrome, pulmonary granulomatosis, types of encephalitis, endotoxic shock (catechesi-toxic shock), sepsis, pneumonia, encephalomyelitis, mental anorexia, hepatitis (acute hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced hepatitis, viral hepatitis, jaundice hepatic insufficiency and cytomegalovirus hepatitis), T-lymphomatosa Rennert, mesangial jade, postangioplasty restenosis, reperfusion Sindh is Ohm, cytomegaloviral retinopathy, adenoviral diseases, such as adenoviral cold, adenoviral pharyngoconjunctival fever and the adenoviral ophthalmia, AIDS, Guillain-Barre syndrome, post herpetic neuralgia or trigeminal neuralgia after shingles, inflammatory demyelinative polyneuropathy, multiple mononeuropathy, cystic fibrosis, severe illness, ulcer of esophagus Barrett, infection with the virus of Epstein-Barr (EBV), cardiac remodeling, interstitial cystitis, diabetes mellitus type II, radiosensibility malignant tumors, frequent resistance of malignant cells to chemotherapeutic agents (resistance to many drugs in chemotherapy), ring granulomas and cancer, as breast cancer cancer of the colon, melanoma, primary hepatocellular carcinoma, adenocarcinoma, Kaposi's sarcoma, prostate cancer, leukemia such as acute myeloid leukemia, multiple myeloma (plasmacytoma), Burkitt's lymphoma and tumor of Castleman.

According to the second aspect, the present invention relates to Amida fumaric acid of the formula (I)

R1means OR3or linked through amide bond D - or L-amino acid residue-NH-CHR4/sub> -COOH, where R3means a hydrogen atom, a linear or branched, unsubstituted or substituted (C1-C24)-alkyl group, preferably (C1-C6)-alkyl group, phenyl group, or (C6-C10)-aracelio group, and R4means a side chain of a natural or synthetic amino acids;

R2means linked through amide bond D - or L-amino acid residue-NH-CHR5-COOH, or linked through amide bond of the peptide residue from 2-100, preferably 2-30, amino acids, where R5means a side chain of a natural or synthetic amino acids,

provided that

- when R3means a hydrogen atom, R2means a peptide residue selected from the group consisting of peptide hormones, growth factors, cytokines, neurotransmitters, neuropeptides, fragments of antibodies, clotting factors, and cyclosporine, their derivatives and fragments,

- when R1means-NH-CHR4-COOH, R2means a peptide residue selected from the group consisting of peptide hormones, growth factors, cytokines, neurotransmitters, neuropeptides, fragments of antibodies, cyclosporine, coagulation factors and their derivatives and fragments, or means-NH-CHR5-COOH, where R5selected from the group consisting of side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Gl, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

The term "side chain of a natural or synthetic amino acid" mean in α-carbon atoms of amino acid residues of any natural or synthetically produced amino acids. Amino acid residues R1and R2may be D - or L-configuration. Preferred natural L-configuration. Further to denote amino acids using conventional abbreviations or symbols on the three-letter code.

According to one form of the invention using compounds of formula (I)in which R1means L-amino acid residue-NH-CHR4-COOH and R2means L-amino acid residue-NH-CHR5-COOH, where R4and R5can be the same or different from each other and have the above values. More preferred R4and R5independently from each other selected from the group consisting of the side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

According to another form of the use of the compounds of formula (I)in which R1means OR3and R2means L-amino acid residue-NH-CHR5-COOH, where R5selected from the group consisting of side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

In the above the first degree preferably if R5in both forms of execution we are talking about a polar amino acid, more preferably about carrying the charge of the amino acid selected from the group consisting of asparagine, glutamine, lysine, arginine and histidine.

When the remainder R1means-OR3, that is used according to the invention the compound of formula (I) represents monoether monoamide fumaric acid, respectively, monoamide fumaric acid, then R3preferably selected from the group consisting of linear, branched, cyclic, saturated or unsaturated (C1-C24)-alkyl groups, preferably (C1-C6)-alkyl groups, phenyl or (C6-C10)-aranceles group, and this group is not substituted or substituted by a halogen atom (F, Cl, Br, I), hydroxyl, (C1-C4-alkoxyl, the nitro-group or cyano. Preferably R3means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2 - or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl, methoxymethyl or 2 - or 3-methoxypropyl. Most often, R3preferably means methyl or ethyl.

According to the following form of the invention, the use of compounds of formula(I), in which R1means-OR3where preferably R3means methyl or ethyl and R2means linked through amide bond of the peptide residue from 2-100, preferably 2-30 and often preferably 5-25 amino acids. In the case of peptide residue we can talk about the natural, recombinant or synthetic peptide residue.

More preferred is a peptide residue selected from the group consisting of peptide hormones, growth factors, cytokines, neurotransmitters, neuropeptides, fragments of antibodies, clotting factors, and cyclosporine, as well as their derivatives and fragments. The peptides can be isolated from natural sources, obtained by recombinant or synthesized by known methods. Preferably using synthetic peptides.

Link fragment fumaric acid with such a functional peptide has an advantage, namely through the peptide can occur targeted transfer of biologically active substances "fragment fumaric acid to target cells, interacts with the peptide part of the proposed according to the invention amides. The peptide portion can have its own impact on treatable disease, so in this case you can achieve the combined treatment. Combined treatment and/or targeted centuries is Denia, however, allow desirable, even synergistic manner to reduce the injected dose.

According to a preferred form of the invention, the peptide residue may be cyclosporiasis the remainder of the cycle which can be opened by any peptide bond to the introduction of the amide bond of fumaric acid. According to the invention, in principle, all of cyclosporine can be linked through amide bond with a fragment of fumaric acid. As cyclosporine are cyclic peptides, peptide cycle of cyclosporine, in principle, disclosed anywhere (on any amide bond) to obtain linearizing cyclosporine, suitable for the introduction of the amide bond. Preferably we are talking about Linearisation with position 1 cyclosporin A.

Used in the present description the term "peptide hormones" refers to physiologically highly active peptides exhibiting hormonal or hormone-like action of approximately up to 100 amino acids. As examples glandularia peptide hormones of the pituitary, as corticotropin, follitropin, lutropin, melanotropin, prolactin, somatotropin, thyrotropin, oxytocin and vasopressin, hormones secreted and factors inhibiting hypothalamic peptide hormones from the pancreas, stomach and intestines, as glucagon, and the municipalities, somatostatin, secretin, gastrin, cholecystokinin, peptide hormones of the thyroid gland, as calcitonin, parathyrin, and the like.

The term "growth factors" mean hormone-like peptides and proteins that promote cell division and cell differentiation, provide growth and development agencies, and are also used for healing wounds. Examples of these include colony-stimulating factors, epidermal growth factor (EGF), erythropoietin, facory growth of fibroblasts, hematopoietic growth factors, growth factors, hepatocytes, insulin and insulin-like growth factors derived from platelets growth factor (PDGF), thrombopoietin, transforming growth factors, viral factors, however, also interleukins.

Used in the present description the term "cytokine" refers to polypeptides that are secreted by the cells after binding with specific receptors can influence the function of other, often neighboring cells. Cytokines regulate primarily a complex interaction of cells of the immune system. As examples of such cytokines can be called interferons, interleukins, chemokines, or colony-stimulating factors.

Under the concept of "mediators" means the transport of substances by chemical means to cause transmission of a signal or information in inepsy nervous system. Depending on their chemical structure in the case of mediators there are amino acids like glutamic acid, derivatives of amino acids as acetylcholine, monoamines, as catecholamines, L-norepinephrine, L-adrenaline and dopamine, serotonin and peptides. Subgroup mediators are, accordingly, "neuropeptides", as bradykinin, however, the enkephalins, endorphins, etc.

Used in the present description the term "coagulation factors" refers to the proteins of the coagulation cascade. Similarly, in the case of being attached via an amide bond to fumaric acid of the peptide we can talk about the antibody fragment, and this fragment preferably also includes a recognition sequence and/or linking sequence.

In the case of all these, suitable according to the invention peptides can also use fragments and/or derivatives. The term "fragment" is understood capable of amide linkages plot of the above peptides. Section preferably includes a recognition sequence for mediating binding to the cellular receptor and/or an active centre for transfer of functions of the action.

The term "derivative" refers to a peptide which is derived from the above-mentioned peptides and/or fragments by homologous substitutions, deletions or insertions of one or several is the space of a few amino acids in the peptide chain, respectively, of the peptide chain.

Proposed according to the invention amides of fumaric acid can be obtained according to the above U.S. patents firm Blank.

According to a third object, the present invention relates to a medicinal product containing defined as above, fumaric acid amide or a mixture of such amides. Generated by proposed according to the invention of application and/or by using the proposed amides of fumaric acid medicines can be in the form suitable for oral, nasal, parenteral, rectal, pulmonary, ophthalmic, or transdermal administration.

The drug is preferably intended for oral administration and is in the form of tablets, pills, capsules, granulates, solutions for drinking, liposomes, nanocapsules, microcapsules, microtablets, pills or powders, and packaged in capsules, granules, Packed in capsules microtablets, packaged in capsules pills or packaged in capsules of powder.

According to a particularly preferred form of execution, the drug is a solid oral dosage form, in an even more preferred form of execution is resistant to acid gastric juice coating. This is covered in the e may be provided, for example, in the case of tablets, pills, microtablets, pills or capsules.

Proposed according to the invention means, in principle, may contain suitable pharmaceutically acceptable carriers, excipients, additives, etc. are well known to the expert and do not need further explanation.

In most cases, it is preferable application of microtablets or pills. They have, without coating, preferably the average diameter of 300-5000 μm, more preferably 300-2000 μm.

When parenteral administration by injection, the composition is suitable for this imposing form. You can use all the usual liquid suitable for injection media.

In any case, it is preferable that the drug in a single dose contained a quantity of fumaric acid amide of the formula (I), corresponding or equivalent to the amount of 1-500 mg, preferably 10-300 mg and often preferably 10-200 mg of fumaric acid.

1. The use of amides of fumaric acid of General formula (I)

R1means OR3or linked through amide bond D - or L-amino acid residue-NH-CHR4-COOH, where R3means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, Gati is, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2 - or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl, methoxymethyl or 2-or 3-methoxypropyl, and R4means the side chain of amino acids; and

R2means linked through amide bond D - or L-amino acid residue-NH-CHR5-COOH, where R5means a side chain of natural amino acids, for the preparation of medicines

(1) for the treatment of autoimmune diseases selected from the group consisting of arthritis, multiple sclerosis, reactions, graft versus host disease, juvenile diabetes, tirodite Hashimoto's, graves ' disease (or graves ' disease), systemic lupus erythematosus (SLE), Sjogren syndrome, pernicious anaemia and chronic active (lupus) hepatitis

(2) for the treatment of reactions "host versus graft",

(3) for the treatment of mitochondrial disease selected from the group consisting of Parkinson's disease, Alzheimer's disease, horii's disease, pigmentary retinopathy or mitochondrial encephalomyopathy, and

(4) to ensure mediated NFkappaB diseases selected from the group consisting of progressive systemic sclerosis, syphilis osteochondritis disease weger), Cutis marmorata (Livedo Reticularis), disease behceta, panarteritis, ulcerative to the lita, vasculitis, osteoarthritis, gout, ateriosclerosis, Reiter syndrome, pulmonary granulomatosis, types of encephalitis, endotoxic shock (catechesi-toxic shock), sepsis, pneumonia, encephalomyelitis, mental anorexia, hepatitis (acute hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced hepatitis, viral hepatitis, jaundice, liver failure and cytomegalovirus hepatitis), T-lymphomatosa Rennert, mesangial jade, postangioplasty restenosis, reperfusion syndrome, cytomegaloviral retinopathy, adenoviral diseases, such as adenoviral cold, adenoviral pharyngoconjunctival fever and the adenoviral ophthalmia, AIDS, syndrome Guillain-Barre, herpetic neuralgia or trigeminal neuralgia after shingles, inflammatory demyelinative polyneuropathy, multiple mononeuropathy, cystic fibrosis, severe illness, ulcer of esophagus Barrett, infection with the virus of Epstein-Barr (EBV), cardiac remodeling, interstitial cystitis, diabetes mellitus type II, radiosensibility malignant tumors, frequent resistance of malignant cells to chemotherapeutic means, annular granulomas and cancer, as breast cancer, colon cancer Kish and, melanoma, primary hepatocellular carcinoma, adenocarcinoma, Kaposi's sarcoma, prostate cancer, leukemia such as acute myeloid leukemia, multiple myeloma (plasmacytoma), Burkitt's lymphoma and tumor of Castleman.

2. The use according to claim 1, in which R1means L-amino acid residue-NH-CHR4-COOH and R2means L-amino acid residue NH-CHR5-COOH, where R4and R5can be the same or different from each other and are specified in claim 1 value.

3. The use according to claim 2, in which R4and R5independently from each other selected from the group consisting of side chains of Gly, Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Ser, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

4. The use according to claim 1, in which R1means OR3 and R2means L-amino acid residue NH-CHR5-COOH, where R5selected from the group consisting of side chains of Gly, Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Ser, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

5. The use according to claim 1, in which R3means methyl or ethyl.

6. The use according to claim 1, in which the drug is in a form suitable for oral, nasal, parenteral, rectal, pulmonary, ophthalmic, or transdermal administration.

7. The use according to claim 1, in which the drug is intended for oral what about the introduction and is in the form of tablets, pills, capsules, granulates, solutions for drinking, liposomes, nanocapsules, microcapsules, microtablets, pills or powders, as well as packaged(data) in capsules, granules, microtablets, pills or powder.

8. The use according to claim 6, in which the medicinal product is a solid oral dosage form and is resistant to gastric juice coating.

9. The use according to claim 6, in which microtablets or pill without coating have an average diameter of 300-5000 μm, preferably 300-2000 μm.

10. The use according to any one of claims 1 to 8, in which the drug in a single dose contains the amount of fumaric acid amide of the formula (I), corresponding 1-500 mg, preferably 10-300 mg of fumaric acid.

11. Amide fumaric acid of the formula (I)

R1means OR3or linked through amide bond D - or L-amino acid residue-NH-CHR4-COOH, where R3means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2 - or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl, methoxymethyl or 2 - or 3-methoxypropyl, and R4means a side chain of natural amino acids; and

R2means linked through an amide link to the ü D - or L-amino acid residue-NH-CHR 5-COOH, where R5means a side chain of a natural or synthetic amino acids, where R4and R5independently from each other selected from the group consisting of side chains of Gly, Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Ser, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hey, Hse, Hyp, Hyl, Orn, Sar and Me-Gly,

provided that if R1means-NH-CHR4-COOH, R2means the rest of cyclosporine or-NH-CHR5-COOH, where R5selected from the group consisting of the side chains of Asn, Gln, Asp, Glu, Lys, Arg, His.

12. Amide fumaric acid according to claim 11, where R1means OR3and R2means L-amino acid residue-NH-CHR5-COOH, where R5selected from the group consisting of side chains of Gly, Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Ser, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

13. Amide fumaric acid according to claim 11, where R3means methyl or ethyl.

14. The drug is intended

(1) for the treatment of autoimmune diseases selected from the group consisting of arthritis, multiple sclerosis, reactions, graft versus host disease, juvenile diabetes, tirodite Hashimoto's, graves ' disease (or graves ' disease), systemic lupus erythematosus (SLE), Sjogren syndrome, pernicious anaemia and chronic active (lupus) hepatitis

(2) for the treatment of reactions " host versus graft",

(3) for the treatment Micah ntially diseases, selected from the group consisting of Parkinson's disease, Alzheimer's disease, horii's disease, pigmentary retinopathy or mitochondrial encephalomyopathy, and

(4) to ensure mediated NFkappaB diseases selected from the group consisting of progressive systemic sclerosis, syphilis osteochondritis disease weger), Cutis marmorata (Livedo Reticularis), disease behceta, panarteritis, ulcerative colitis, vasculitis, osteoarthritis, gout, ateriosclerosis, Reiter syndrome, pulmonary granulomatosis, types of encephalitis, endotoxic shock (catechesi-toxic shock), sepsis, pneumonia, encephalomyelitis, mental anorexia, hepatitis (acute hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced hepatitis, viral hepatitis, jaundice hepatic insufficiency and cytomegalovirus hepatitis), T-lymphomatosa Rennert, mesangial jade, postangioplasty restenosis, reperfusion syndrome, cytomegaloviral retinopathy, adenoviral diseases, such as adenoviral cold, adenoviral pharyngoconjunctival fever and the adenoviral ophthalmia, AIDS, Guillain-Barre syndrome, post herpetic neuralgia or trigeminal neuralgia after shingles, inflammatory demyelinative polyneuropathy, mn is the divine of mononeuropathy, cystic fibrosis, severe illness, ulcer of esophagus Barrett, infection with the virus of Epstein-Barr (EBV), cardiac remodeling, interstitial cystitis, diabetes mellitus type II, radiosensibility malignant tumors, frequent resistance of malignant cells to chemotherapeutic means, annular granulomas and cancer, as breast cancer, cancer of the colon, melanoma, primary hepatocellular carcinoma, adenocarcinoma, Kaposi's sarcoma, prostate cancer, leukemia such as acute myeloid leukemia, multiple myeloma (plasmacytoma), Burkitt's lymphoma and tumor of Castleman,

containing fumaric acid amide of the formula (I) according to any one of § § 11-13 in an amount corresponding 1-500 mg, preferably 10-300 mg of fumaric acid per single dose.

15. Drug for 14, characterized in that it is in a form suitable for oral, nasal, parenteral, rectal, pulmonary, ophthalmic, or transdermal administration.

16. Drug for 14, characterized in that it is intended for oral administration and is in the form of tablets, pills, capsules, granulates, solutions for drinking, liposomes, nanocapsules, microcapsules, microtablets, pills or powders, as well as packaged(data) in capsules gr is nulato, microtablets, pills or powder.

17. Drug in item 16, characterized in that it is a solid oral dosage form and is resistant to gastric juice coating.

18. Drug for 14, characterized in that microtablets or pill without coating have an average diameter of 300-5000 μm, preferably 300-2000 μm.

19. The drug according to any one of p-18, characterized in that it contains fumaric acid amide of the formula (I) in an amount corresponding 10-300 mg of fumaric acid per single dose.

Priority items:

12.01.2001 according to claims 1 to 10;

06.07.2001 in § § 11-19.



 

Same patents:

FIELD: genetic engineering, medicine.

SUBSTANCE: invention relates to isolated DNA encoding human peptide related to urocortin and peptide named as urocortin II. These peptides are relative with corticotropin-releasing factor and involves in mechanisms for initiation of hypophysis-suprarenal responses for the stress. Pharmaceutical composition comprising such peptide in combination with acceptable vehicle can be used in treatment of pathophysiological states, such as enhanced body temperature, appetite disorder, congestive cardiac insufficiency, stress, anxiety state and undesirable low levels of ACTH.

EFFECT: valuable medicinal properties of urocortin proteins.

33 cl, 27 dwg, 2 tbl, 16 ex

FIELD: molecular biology, genetic engineering, polypeptides, medicine.

SUBSTANCE: in using the double-hybrid yeast system DNA sequences encoding polypeptides (55.1 and 55.3) have been found that elicit ability for binding with intracellular domain p-55 (p-55IC) of TNF-receptor. It has been established that these polypeptides represent fragments of amino acid sequences p-55IC, respectively, from 338 to 426 and from 277 to 426 residues. As result of insertion of DNA fragments with a sequence encoding polypeptide 55.1 or 55.3 into the structure of expressing vector and transformation suitable host-cells by this vector recombinant form of indicated polypeptides have been prepared. Using this invention provides the possibility for modulating the function of intact p-55 of TNF-receptor. Invention can be used in medicine in treatment of diseases associated with transfer of TNF-signal.

EFFECT: improved preparing method and valuable properties of polypeptide.

9 cl, 17 dwg, 3 tbl, 6 ex

FIELD: biochemistry, medicine.

SUBSTANCE: invention relates to two forms of peptide isolated from annelid worm (Arenicola marina) eliciting the broad spectrum of antibacterial effect. Indicated forms differ by a single amino acid residue at position 10 wherein at position 10 arenicin-1 has Val and arenicin-2 has Ile. Invention provides expanding assortment of antibacterial agents.

EFFECT: valuable medicinal properties of peptides.

1 tbl, 3 dwg, 4 ex

The invention relates to the field of biotechnology and can be used in medicine

The invention relates to medicine and relates to a derivative of annexin with endogenous chelation sites and which can be used in the diagnosis of thrombosis

The invention relates to the field of biotechnology and can be used in veterinary medicine and medicine

The invention relates to medicine and relates to peptides that can be used for cell adhesion and wound healing
The invention relates to biotechnology and can be used to obtain alphafetoprotein (AFP), high-purity enriched with carbohydrates

The invention relates to medicine and the application of vascular protein-1 adhesion with aminoacylase activity

The invention relates to a method for producing long-chain N-acylated acidic amino acids (I), including stage (stage leaching) remove impurities separation of a mixture of long-chain N-acylated acidic amino acids derived from the following stages, which contains inorganic salts as impurities, and the environment, consisting mainly of water and tertiary butanol, aqueous layer and an organic layer containing long-chain N-acylated acidic amino acid, at a temperature of from 35 to 80oWith: 1) stage (stage acylation) condensation of acidic amino acids and gelegenheid long-chain fatty acids in a mixed solvent containing water and tertiary butanol, in the presence of alkali and 2) stage (stage separation by sedimentation acid) bringing the pH of the resulting reaction liquid to 1-6 mineral acid for separating a mixture of organic layer and water layer, resulting in a gain organic layer containing long-chain N-acylated acidic amino acid, three variants of long-chain N-acylated amino acids or their salts, two types of liquid and solid cosmetic compositions and two types of deterg

FIELD: medicine, oncology.

SUBSTANCE: the present innovation could be applied in complex therapy of cancer, particularly, mammary gland cancer and locally metastasizing colonic cancer. Moreover, in pre-surgical period it is necessary to sample 200 ml patient's blood to isolate autoplasma due to centrifuging, put 10 ml autoplasma and a chemopreparation into the first vial, into the second vial - the rest blood cells, autoplasma and a chemopreparation. Vials should be separately incubated for 40 min at 37° C, then comes the operation in the course of which one should intravenously introduce incubated blood with chemopreparation out of the second vial by drops. Before mobilization and removal of the tumor it is necessary to contrast tumor-abducting lymph vessels with methylene blue solution by standard technique to isolate the most proximal lymph vessel at the border of the area of removed tissues to introduce incubated autoplasma with chemopreparation out of the first vial. The innovation enables to decrease the frequency for the development of lympho- and hematogenic metastases due to complex therapy intrasurgically, at taking antilogarithms of systemic effect of intravenous autoerythrothromboleukochemotherapy and regional and systemic effects of endolymphatic autoplasmochemotherapy at low toxicity.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with complex therapy of mammary gland cancer at T1-2NO-1MO. The method includes chemo- and radiation therapy and operation procedure. Moreover, in post-surgical period, before the onset of radiation therapy course it is necessary to sample 200 ml patient's blood and due to centrifuging technique isolate autoplasma. One should place 20 ml autoplasma and chemopreparations into the first vial, into the second vial - remained blood cells and autoplasma. Vials should be separately incubated for 40 min at 37° C, then during the first day of radiation therapy before the onset of the seance one should introduce the half of autoplasma volume incubated with chemopreparations from the first vial into the ducts of operated mammary gland, as for the remained part of autoplasma incubated with chemopreparations, from the first vial it should be introduced into the site of surgical withdrawal of drainage tube. Blood incubated with chemopreparations from the second vial should be reinfused intravenously by drops. The innovation is of low toxicity and enables to carry out complex organ-saving therapy in short terms, decrease the frequency of local relapses and remote metastases, the number of radiation reactions and complications.

EFFECT: higher efficiency.

2 ex

FIELD: medicine.

SUBSTANCE: method involves introducing photosensitizer of photosense at a dose of 0.1-1.0 mg/kg of patient weight. Photodynamic therapy is applied in 48-72 h with laser radiation at wavelength of 675 nm after having introduced the photosense. Iradiation is carried out in transscleral way after having determined tumor base projection place over sclera in transillumination way. Exposure dose is equal to 80-800 mW/cm2 with cylindrical light guide set at a distance from sclera that laser radiation beam diameter overlaps tumor base diameter by 1-2 mm at its projection place on sclera.

EFFECT: enhanced effectiveness of treatment.

FIELD: medicine.

SUBSTANCE: method involves mixing patient liquor with 3 ml of 10% albumin solution, with chemopreparation and incubating. Then, the mixture is introduced via catheter into subarchnoid space. Repeated introduction is carried out 7 days later.

EFFECT: alleviated intracranial hypertension phenomena in cases of endolumbal drugs introduction; reduced risk of toxic complications.

FIELD: medicine.

SUBSTANCE: method involves introducing water-soluble chemopreparation as a course in lymphotropic way. Riva-Rocci apparatus cuff is applied to lower part of femur and pressure of 40 mm of mercury column is created. 20 ml of chymotrypsin dissolved in 0.5% Novocain solution is subcutaneously introduced into the middle area of lateral shank surface 30 min later. Water-soluble chemopreparations are slowly subcutaneously introduced 0.5 cm below the chymotrypsin injection place in 5-7 min as single dose. The cuff is left in swollen state for 2 h. After having taken off the cuff, 50 ml of 0.5% Novocain solution is subcutaneously introduced into the place of previous water-soluble chemopreparations injection. Then the lower extremity is dressed with elastic bandage. The lymphotropic water-soluble chemopreparations introduction procedure is carried out once a day combined with standard chemotherapy course. Detralex is daily given to the patient on the background of the chemotherapy course at a dose of 2 pills twice a day combined with subcutaneous Fraxiparin injections introduced at a dose of 0.3 ml once a day.

EFFECT: avoided surgical intervention; increased antitumor effectiveness; reduced risk of recurrences, metastases and toxic complications.

5 dwg

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating metastatic hepatic disorder in patients with malignant neoplasms. The method of regional polychemotherapy (RPCT) concentrates upon catheterization of proper hepatic artery (PHA) through gastro-omental artery to fulfill intra-arterial RPCT. Moreover, additionally after PHA catheterization it is necessary to catheterize an umbilical vein (UV) due to fulfilling arterio-venous shunting. For this purpose, one should connect catheters introduced into UV and PHA, with the help of a T-joint valve appliance (TVA); before carrying out RPCT it is important to conduct hepatic arterialization due to directing the blood from PHA through UV into the liver by setting TVA valves in position being open for PHA and UV; for carrying out RPCT one should locate TVA valves in position being open for introducing chemopreparations out of the system with a dosing tank of medicinal substances into PHA to carry out the infusion of chemopreparations. Seances for alternating hepatic arterialization and RPCT should be fulfilled daily once a day during the whole course of therapy. The innovation enables to simultaneously increase the concentration of chemopreparations in metastatic hepatic foci, detoxication hepatic function and sensitivity of tumor cells to chemopreparations as a result of additional preliminary oxygenation of hepatocytes.

EFFECT: higher efficiency of therapy.

1 cl, 6 dwg, 1 ex

FIELD: medicine, prophylactic oncology, pharmacy.

SUBSTANCE: invention proposes an agent belonging to class of nonsteroid anti-inflammatory preparations, namely, associate comprising 2[(2,6-dichlorophenyl)amino]-benzene acetic acid, inosine and N-methylglucosamine. In oral administration this associate inhibits effectively origination and development of malignant and benign tumors of brain, spinal cord, kidneys, breast, esophagus, forestomach, uterus cervix and vagina induced by chemical carcinogens in laboratory animals. Invention provides preparing the preparation possessing the more expressed anti-carcinogenic activity and lesser toxic ulcerous effect.

EFFECT: improved and valuable medicinal properties of agent.

5 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves taking blood sample into sterile flask in the amount of 150 ml before and after funiculo-orchectomy. Plasma and formed elements are separated by means of centrifuging. Plasma is taken and 300 mg Bleocin and 1000 mg Cyclophosphane are dissolved in a portion of it. Platinum preparation is added to the plasma and formed elements remaining in the flask in the amount of 75-100 mg/m2. When completely dissolved, the produced solutions are incubated in thermostat at 37°C during 40 min. Endolymphatic infusion of preparations on patient autoplasma is carried out into lymphatic vessel of foot back on the side where tumor process takes place, and intravenous autohemochemotherapy with platinum preparations are sequentially carried out under hyperhydration and forced diuresis conditions.

EFFECT: concentrated purposeful action upon primary testicular carcinoma and metastases into retroperitoneal lymph nodes; reduced risk of toxic complications.

FIELD: medicine, oncology.

SUBSTANCE: in patients with prognostically unfavorable laryngeal and pharyngeal cancer therapy should be started with carrying out chemotherapy with preparations that enhance radiation action. Local hyperthermia should be conducted twice weekly at the background of radiation therapy. Moreover, during hyperthermal days a single focal dosage corresponds to 4 Gy - 2 Gyx2 at 4-h-long interval. The innovation enables to increase efficiency in treating patients with cerebral and cervical squamous cell cancer stage III-IV, improve viability values in this category of patients, decrease toxicity and improve therapeutic results at acceptable increase of topical radiation alterations and hematological toxicity.

EFFECT: higher efficiency of therapy.

1 ex

Up!