Acyl derivatives of guanosine, inosine, xanthosine, deoxyinosine, deoxyguanosine, inosine-2',3'- (acyclic)dialcohol or their pharmaceutically acceptable salts, pharmaceutical composition, stimulating haematopoiesis, a method of treating cytopenia

 

(57) Abstract:

The invention relates to novel acyl derivatives of guanosine formula I, inosine formula II, xanthosine formula III, deoxyinosine formula IV, deoxyguanosine formula V, inosine - 2',3'-(acyclic)dialcohol formula VI or pharmaceutically acceptable salts. The values of the radicals RA, RB, RC, RD, Y, Q and Z are provided in the respective claims. Described pharmaceutical composition for stimulating hematopoiesis, containing as an active means of derivatives of guanosine or inosine or their salts. Also proposed is a method of treating cytopenia by introducing the animal an effective amount of these compounds. The invention can be used in medical practice for the prevention and therapy of disorders of haematopoiesis. 8 C. and 9 C.p. f-crystals, 68 ill., table 2.

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This application is a partially continuing application from a related Patent application U.S. serial N 487984 from 5.02.1990, which in turn is part of the ongoing application for U.S. Patent, serial N 533933 from 5.06.1990. Both applications mentioned here for details.

Region technician, including guanosine, deoxyguanosine, inosine, xanthosine, detoxication and deoxyinosine, related to these nucleoside compounds and acyl derivative of these nucleosides and related compounds and to the use of these compounds in preventive and therapeutic purposes. The present invention relates also to the appointment of these compounds alone or in combination with nonionic surfactants or other agents or without them, animals. These compounds can alter hematopoiesis in normal healthy animals and in animals with impaired or deficient haematopoiesis in the process of irradiation, chemotherapy, poisoning, disease, or similar Compounds according to the invention also improve leucocytes immune defense of the organism against infections.

Characterization of analogs of the invention

The main complication in the result of cancer chemotherapy, antiviral chemotherapy or irradiation of ionizing radiation is the destruction of bone marrow cells or suppression of their functions. In particular, chemotherapy and irradiation with ionizing radiation to destroy or destroy hematopoietic (krovetvorenie) parental cells, are mainly what eritrotsitov, monocytes, platelets, etc). Treatment of cancer patients using cyclophosphamide or 5-fluorouracil, for example, destroys the white blood cells (lymphocytes and/or granulocytes) and may lead to increased exposure of the patient to infectious diseases. Many cancer patients die from infectious diseases or other consequences of the violation of hematopoiesis as a result of chemotherapy or radiation therapy. Chemotherapy can also lead to abnormal formation of blood platelets, which occurs predisposition to bleeding. Similarly, the mustard-gas poisoning leads to disruption of hematopoiesis, increasing susceptibility to infectious diseases. Suppression of production of red blood cells can lead to anemia. The inability of surviving stem cells bone marrow to a fairly rapid prooperirovano and differentiation (resulting in no time to resume the population of cells) leads to the inability of the animal to resist pathogenic infectious organisms. Various painful conditions such as neutropenia, including idiopathic forms are also associated with the violation of the individual components of the system of hemopoiesis.

Compounds that improve gemap is a result of chemotherapy, radiation therapy, diseases or other pathological conditions associated with deficient hematopoiesis, are very much needed therapeutic and preventive agents.

There are several polypeptide hematopoietic factors (produced mainly by recombinant DNA technology). Describes the use of these hematopoietic factors, including erythropoietin (EPO), interleukins (particularly Interleukin-1, Interleukin-3 and Interleukin-6) and the factors stimulating the growth of colonies (such as a factor stimulating the growth of colonies of granulocytes, a factor stimulating the growth of colonies of granulocytes/macrophages, or a factor stimulating the growth of colonies of cells of the brain stem), to improve hemopoesis. Some substances defined by the broad term "biological response modifiers" (Mbri), can also improve some indicators of hemopoiesis, Embry-altering disorders include substances such as bacterial endotoxin, dvuhtsepochnyj RNA, agents azimexon, glucan and other yeast and bacterial polysaccharides, dextran sulfate, a polyanion deviceloop ether maleic acid (MVA), and the factors that cause necrosis of the tumor.

D. C. Bennett and A. N. Drury J. Ivalo to intensively reduce the number of leukocytes. The initial levels of leukocytes was 7700 mm3but after the appointment of guanosine number of cells dropped to 500 - 1000 mm3. 10 hours later and in the next 24 hours was observed leukocytosis (11,000 mm3).

D. G. Wright, "BLOOD, 69: 334-337 (1987) described the effects of guanosine and guanine on culture specific-human line leukemic bone marrow cells (HL-60). Transformation of immature blastogenic cells Mature in vitro caused a variety of chemicals (including retinova acid, dimethylformamide and teatterin). Incubation of cells HL-60 with guanine or garnizonom prevented them stimulated the maturation of functional neutrophils; incubation with inosine did not affect the induced maturation.

In the work of A. K. of Osita and other "BLOOD" 49:585-591 (1977) suggested that cyclic nucleotides (e.g., 3',5'-cyclo-adenosine monophosphate (CAMP) or 3',5'-cyclo-guanosin monophosphate (CGMP) may be involved in the regulation of cell proliferation. In the culture of bone marrow cells mouse CGMP gave an increase in the number of colonies formed under the stimulating influence of serum taken from mice, which was introduced endotoxin. In the absence of post-endotoxins syvorotka Belianska and others, CANCER TREAT. REP. 67:611-619 (1983) describes how the partial hydrolysis of ribosomal RNA of E. coli were given a short (approximately 40 bases) oligonucleotides, which had some lycopodiella activity in organisms rabbits, which was introduced cyclophosphamide. The authors suggested that the oligonucleotides act as primers for the replication process of DNA synthesis in bone marrow cells. They also reported that polyribonucleotide: polyguanidine-monophosphate, polyadenine-monophosphate and nucleotides copolymer of adenine and guanine did not stimulate the formation of white blood cells.

In the work So Sugahara and others, "rookhaven Symposia in Biology" 284-302 (1968) reported that hydrolyzed yeast RNA, a mixture of adenosine, cytidine, guanosine, uridine and their respective 3'-ribonucleoside-monophosphate did not increase survival after irradiation aerial doses of ionizing radiation. Compounds increased the survival of mice, only when they were introduced periodically in the course of repeated exposure to sublethal doses of gamma radiation. The authors argue that the drugs did not improve the proliferation or differentiation wygibassy cell column of the brain, but the design life of the damaged Mature cells. The hydrolysate, riboh cells (elements, forming colonies) in the spleen and in the bone marrow (the main sites of hemopoiesis) compared to irradiated control mice, untreated.

In the work of Goodman and others (U.S. Patent N 4539205, 4849411 and 4643992) described the use of derivatives aldoses-guanine having substituents, which have a stronger ability to take electrons than the hydrogen atom in the 8-position gurinovka fragment, allowing regulated immune response.

Were synthesized some acyl derivatives oxypurine nucleosides, intended for use as a protected intermediates in the synthesis of oligonucleotides or analogs of nucleosides or nucleotides. Cm. catalogue 1991 SIGMA CHEMICAL COMPANY, pp. 1702-1704.

In the work of the U. A. Fleming and T. A. MacNeil, "J. Cell PHYSIOl", 88:323-330 (1976) reported that non-ionic surfactants "Polysorbate 80" and "Saponin" increase the reactivity of bone marrow cells in culture to action sub-optimal quantities of the factors stimulating the colony. Surfactant was active only within certain concentrations, and maximum activity was observed at a concentration of 10 ng/ml, and the minimum - in is 2">

The purpose of the present invention

The main purpose of the present invention is to create a family of compounds that effectively amplify or otherwise modify haematopoiesis. The purpose of such compounds to animals before, during or after damage to the hematopoietic system to prevent or treat hematopoietic disorders.

The aim of the present invention is also to create a family of compounds to treat a wide variety of hematopoietic disorders and other pathological conditions with a low number of red blood cells.

The aim of the present invention is also to create a family of compounds that improve the body's immune defenses against infections by leukocytes.

The aim of the present invention is also to create connections that can change haematopoiesis and which may be administered orally or parenterally.

Summary of invention

These and other objectives of the invention are achieved by oxypurine nucleosides, such as guanosine, inosine, xanthosine, detoxicants, deoxyinosine and deoxyguanosine by such related oxipurinol the nucleoside compounds and also to porchetta animals including mammals, such as man. The purpose of these compounds alone or in combination helps to modify epopees animals.

Thus, the compounds of the present invention, applied separately or in combination, help to cure violations of disorders caused by radiation or chemotherapy; AIDS such as may be used in the process of chemotherapy of cancer or viral infections; they help to increase the body's immune defenses associated with leukocytes, against infections; they can be used in the treatment of other pathological conditions.

An important aspect of the present invention is the discovery that oxypurine nucleosides, such as guanosine, deoxyguanosine, inosine, xanthosine, detoxication and deoxyinosine, related nucleosides and acyl derivatives of such nucleosides and related compounds have not previously expected therapeutic properties.

The invention also includes the discovery, which is that surface-active compounds, appointed in vivo, can improve the efficiency of stimulators of hematopoiesis, including compounds according to the invention, erythropoietin, factors all cases, except as specifically stated, letters or letters with additional symbols, which are symbols of variable substituents in the chemical formulas of the compounds according to the invention, only apply the formula directly preceding this symbol.

Connections that are applicable for change of hematopoiesis, are expressed by the following formula:

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where RA= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms,

RB= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms,

Z = H, OH, =O or otherCwhere RC= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms,

L = H or orDwhere RD= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms,

M = H or orEwhere RE= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms, provided that at least one of the radicals L and M is H,

Q = H, halogen, otherFwhere RFis H or an acyl or alkyl radical with 1 to 10 carbon atoms, S is related to carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, then this nitrogen is attached by callerton a double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and preferably in Aldona fragment between positions 2' and 3' were present communication C - C.

New compositions according to the invention include the above compounds (possibly as pharmaceutically acceptable salts), in which at least one of the radicals RA, RB, RC, RDor REis not H, and in those compounds where Z represents NH2or otherCQ represents H or otherFwhere RFrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, and pharmaceutically-priemlemii media.

Guanosin, related compounds, and its acyl derivatives expressed by the General formula (I):

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where RA, RB, RCand RDhave the same or different values and each represents a hydrogen (H) or acyl radical, and Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl is th radical, containing 1 to 10 carbon atoms, =O, or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt of this compound.

Inosine, related compounds, and its acyl derivatives expressed by the General formula (II):

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where RA, RBand RDhave the same or different values and each represents H or an acyl radical, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, a =O or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms,

or pharmaceutically acceptable salt of this compound.

Xanthosine, related compounds and its acyl derivatives expressed by the General formula (III):

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where RA, RBand RDhave the same or different values, each representing H or acyl radical, and

Q = H, halogen, otherFwhere RFrepresents H or acetylenyl or alkyl radical, containing 1 to 10 carbon atoms, a =O or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt of this compound.

Detoxination, related compounds and its acyl derivatives expressed by the General formula (IV):

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where RAand RBhave the same or different values, each representing H or acyl radical, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, a =O or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, or a pharmaceutically acceptable salt of this compound.

Deoxyguanosine, related compounds and its acyl derivatives expressed by the General formula (V):

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where RA, RBand RChave the same or different values, each of which represents a hydrogen (H) or acyl radical, and

Q = H, halogen, otherFwhere RFrepresents H, acyl or alkyl radical, containing 1 to 10 carbon atoms, =O, or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms,

or pharmaceutically acceptable salt of this compound.

Detoxicants, related compounds and its acyl derivatives expressed by the General formula (VI):

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where RAand RBhave the same or different values, each representing H or acyl radical, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, a =O or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms,

or pharmaceutically acceptable salt of this compound.

Inosine 2', 3'-(acyclic)dialcohol, related compounds and its acyl derivatives expressed by the General formula (VII):

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where RA, RBand RDhave the same or different values, each representing H or acyl radical, and Z represents H, OH, =O or otherFwhere RFrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms, a =O or orHwhere RHrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms.

or pharmaceutically acceptable salt of this compound.

In terms of efficacy and safety are desired the following classes of new derivatives of the compounds of the present invention:

(1) acyl derivatives of guanosine or related compounds of the formula:

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where RA, RBand RDhave the same or different values, which represent hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain with 6 to 22 carbon atoms,

b. amino acids selected from the group comprising glycine, L-forms of alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid with 3 to 22 carbon atoms,

d. cyclol the>and RDare hydrogen;

RCrepresents hydrogen or an acyl group derived by substitution

i. fatty acids with unbranched chain with 3 to 22 carbon atoms,

ii. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

iii. dicarboxylic acid with 3 to 22 carbon atoms,

iv. cycloalkene carboxylic acids containing 4 to 22 carbon atom,

v. nicotinic acid, or

vi. substituted or unsubstituted carboxylic acid with 7 to 22 carbon atoms, and

J = H or otherIwhere RIrepresents H or an acyl or alkyl radical containing 1 to 10 carbon atoms;

(2) acyl derivatives of inosine or related compounds of the formula:

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where RArepresents hydrogen or an acyl group derived by substitution

a. fatty acids with unbranched chain with 3 to 22 carbon atoms,

b. dicarboxylic acid with 3 to 22 carbon atoms,

c. nicotinic acid,

d. cycloalkyl carbonello group, obtained by substitution

a. fatty acids with unbranched chain with 3 to 22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid with 3 to 22 carbon atoms,

d. nicotinic acid,

e. cycloalkene carboxylic acids with 4 to 22 carbon atoms, provided that not all values of the radicals RA, RBand RDrepresent hydrogen and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGIs H or an acyl or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached kakoi carbon atoms;

(3) acyl derivatives xanthosine or related compounds of the formula:

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where RAND, RBand RDhave identical or different meanings and are hydrogen or acyl group derived by substitution

A. fatty acids with unbranched chain, 3-33 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

C. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid, or

e. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms, provided that not all of the radicals RA, RBand RDare hydrogen and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGIs H or an acyl or alkyl radical containing 1 to Tim and nitrogen becomes a simple link, and then to the nitrogen attached to any H or orHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

(4) acyl derivatives of detoxination or related compounds of the formula:

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where RAand RBhave the same or different values, each representing hydrogen or an acyl group derived by substitution

a. fatty acids with unbranched chain, 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acid with 4 to 22 carbon atoms, provided that at least one of RAand RBis not H, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical with 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is safe or alkyl radical, containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H or CRHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

(5) acyl derivatives of deoxyguanosine or related compounds of the formula:

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where RA, RBand RCcan have the same or different values, each of which is hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain, 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, L-forms of alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine, phenylalanine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. cycloalkylcarbonyl acid with 4 to 22 carbon atoms,

e. nicotinic acid

provided that not all of the radicals RA, RBand RCare hydrogen; if RCis not H, then RAand/or RB
(6) acyl derivatives desoximetasone or related compounds of the formula:

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where RAand RBhave the same or different values of hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain, 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid, or

e. cycloalkylcarbonyl acid with 4 to 22 carbon atoms, provided that at least one of RAand RBis not hydrogen, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGIs H or an acyl or alkyl radical containing 1-10 carbon atoms, O, SWAT simple connection, and then to the nitrogen attached to any H or orHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

(7) acyl derivatives of inosine (acyclic) 2',3' dialcohol or related compounds of the formula:

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where RA, RBand RChave the same or different values of hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain, 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acid with 4 to 22 carbon atoms, provided that not all of the radicals RA, RBand RDare hydrogen, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between the plastics technology: turning & >
Is H or an acyl or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H or orHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

Z represents H, OH, =O or otherCwhere RC= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms.

In all of these structures, where the Deputy in the 2 position of the purine bases (Z) or 8 position of the purine bases (O or L) is attached to the purine base is a double bond (for example, =O or =S), the neighboring double bond between carbon and nitrogen in the purine base becomes a simple relationship between carbon and nitrogen, and then the extra hydrogen atom is nitrogen this regard, carbon and nitrogen.

The present invention also includes pharmaceutically acceptable salts of the above compounds.

A brief description of the charts

Fig. 1 is a comparative chart of the weights of the spleens of mice after injection of physiological solution, guanine and guanosine, E. differences).

Fig. 2 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, guanine and guanosine as described in Example 31.

Fig. 3 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline, guanine and guanosine as described in example 31.

Fig. 4 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, tween-80", guanosine, triacetyluridine, octanophenone, laurylsarcosine and palmitoylcarnitine as described in Example 32.

Fig. 5 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, tween-80", guanosine, triacetyluridine, octanophenone, laurylsarcosine and palmitoylcarnitine as described in Example 32.

Fig. 6 is a comparative chart of the number of neutrophils in mice after introduction of physiologic saline, tween-80", guanosine, triacetyluridine, octanophenone, laurylsarcosine and palmitoylcarnitine as described in Example 32.

Fig. 7 is a chart showing the number of colonies on the femur after insertion of ciclofosfamida as described in Example 34.

Fig. 8 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, "Thelen chart the number of leukocytes in mice after introduction of physical solution, "tween-80" and palmitoylcarnitine as described in Example 35.

Fig. 10 is a comparative chart of the number of neutrophils in mice after introduction of physiologic saline, tween-80 and palmitoylcarnitine as described in Example 35.

Fig. 11 is a comparative chart of the content of lymphocytes in mice after introduction of physiologic saline, tween-80 and palmitoylcarnitine as described in Example 35.

Fig. 12 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 36. "5FU" - 5-fluorouracil.

Fig. 13 is a comparative chart of the content of lymphocytes in mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 36.

Fig. 14 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 36.

Fig. 15 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 36.

Fig. 16 is a chart of the number of platelets in mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 37.

Fig. 17 is a comparative chart Mr> Fig. 18 is a chart of the content of neutrophils in mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 37.

Fig. 19 is a chart of the number of leukocytes in mice after introduction of physiologic saline and palmitoylcarnitine as described in Example 37.

Fig. 20 is a comparative chart of the weights of the spleens of mice after introduction of "tween-80", palmitoylcarnitine and palmitoylcarnitine as described in Example 38.

Fig. 21 is a comparative chart of the number of leukocytes in mice after introduction of "tween-80", palmitoylcarnitine and palmitoylcarnitine as described in Example 38.

Fig. 22 is a comparative chart of the content of neutrophils in mice after introduction of "tween-80", palmitoylcarnitine and palmitoylcarnitine as described in Example 38.

Fig. 23 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, tween-80 and octanophenone, in various concentrations, as described in Example 39.

Fig. 24 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, tween-80 and octanophenone in various concentrations as described in Example 39.

Fig. 25 is a comparative chart stergar CLASS="ptx2">

Fig. 26 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, tween-80 and octanophenone as described in Example 40.

Fig. 27 is a graph showing the effect of physiologic saline, tween-80 and octanophenone on the value of haematopoiesis mice, which were administered cyclophosphamide as described in Example 40.

Fig. 28 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, tween-80 and octanophenone as described in Example 40.

Fig. 29 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline, tween-80 and octanophenone as described in Example 40.

Fig. 30 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, benzylguanine and palmitoylcarnitine as described in Example 41.

Fig. 31 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline, benzylguanine and palmitoylcarnitine as described in Example 41.

Fig. 32 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, benzylguanine and palmitoylcarnitine as described in Example 41.

Fig. 33 - comparative chart of colzano in Example 41.

Fig. 34 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, palmitoylation and palmitoylcarnitine as described in Example 42.

Fig. 35 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, palmitoylcarnitine and palmitoylcarnitine as described in Example 42.

Fig. 36 is a comparative chart of the number of neutrophils in mice after introduction of physiologic saline, palmitoylcarnitine and palmitoylcarnitine as described in Example 42.

Fig. 37 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, palmitoylcarnitine, palmitoylation, palmitoylcarnitine of laurylsarcosine and octanophenone as described in Example 43.

Fig. 38 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, palmitoylcarnitine, palmitoylation, palmitoylcarnitine, laurylsarcosine and octanophenone as described in Example 43.

Fig. 39 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline palmitoylcarnitine, palmitoylation, palmitoylcarnitine, laurylsarcosine and octanophenone as openwin-80", palmitoylation, polymethylphenylsiloxane, Palmitoyl-8-thioguanosine, palmitoylethanolamide, palmitoylethanolamide, palmitoylcarnitine and monopalmitate-2', 3'(acyclic) dialcohol as described in Example 44.

Fig. 41 is a comparative chart of the number of leukocytes in mice after introduction of "tween-80", palmitoylation, polymethylphenylsiloxane, Palmitoyl-8-thioguanosine, palmitoylethanolamide, palmitoylethanolamide, palmitoylcarnitine and monopalmitate 2',3'-(acyclic) dialcohol as described in Example 44.

Fig. 42 is a comparative chart of the weights of the spleens of mice after introduction of "tween-80", palmitoylation, polymethylphenylsiloxane, Palmitoyl-8-thioguanosine, palmitoylethanolamide, palmitoylethanolamide, palmitoylcarnitine and monopalmitate 2',3'-(acyclic) dialcohol as described in Example 44.

Fig. 43 is a comparative chart of the weights of the spleens of mice after introduction of "tween-80", 3'-0-palmitoylethanolamide, butyrylthiocholine, Palmitoyl-N-isobutylmethylxanthine, laurelbethany, octanoylthiophene and neutrophiles in mice after introduction of "tween-80", 3'-0-palmitoylethanolamide, butyrylthiocholine, Palmitoyl-N-isobutylmethylxanthine, laurelbethany, octanoylthiophene and palmitoylethanolamide as described in Example 45.

Fig. 45 is a comparative chart of the number of leukocytes in mice after introduction of "tween-80", 3'-0-palmitoylethanolamide, butyrylthiocholine, Palmitoyl - N-isobutylmethylxanthine, laurelbethany, octanoylthiophene and palmitoylethanolamide as described in Example 45.

Fig. 46 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline and palmitoylethanolamide in four different doses of 0.2, and 0.4, and 1.0, and 2.0 μm/mouse as described in Example 46.

Fig. 47 is a comparative chart of the number of leukocytes in mice after injection of physiological solution and palmitoylethanolamide in four doses of 0.2, and 0.4, and 1.0, and 2.0 μm/mouse as described in Example 46.

Fig. 48 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline and palmitoylethanolamide, in four different doses of 0.2, and 0.4, and 1.0, and 2.0 μm/mouse as described in Example 46.

Fig. 49 is a comparative chart of the weights of the spleens missah: 0,2, 0,4 and 1,0 and 2,0 µm/mouse as described in Example 47.

Fig. 50 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline, palmitoylethanolamide and palmitoylcarnitine in four different doses of 0.2, and 0.4, and 1.0, and 2.0 μm/mouse as described in Example 47.

Fig. 51 - comparative chart of the content of neutrophils in mice after introduction of physiologic saline, palmitoylethanolamide and palmitoylcarnitine in four different doses of 0.2, and 0.4, and 1.0, and 2.0 μm/mouse as described in Example 47.

Fig. 52 - comparative chart of the weights of the spleens of mice after introduction of physiologic saline, palmitoylethanolamide in six different doses: 0,04 0,08, 0,2, 0,4, 0,6 or 0,8 µm/mouse as described in Example 48.

Fig. 53 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline and palmitoylethanolamide in six different doses: 0,04, 0,08, 0,2, 0,4, 0,6 or 0.8 μm/mouse as described in Example 48.

Fig. 54 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline and palmitoylethanolamide in six different doses: 0,04, 0,08, 0,2, 0,4, 0,6 or 0.8 μm/mouse as described in Example 48.

Fig. 55 is a comparative chart of the number of leukocytes is. 56 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline and palmitoylethanolamide as described in Example 49.

Fig. 57 comparative chart platelet counts in mice after introduction of physiologic saline and palmitoylethanolamide as described in Example 49.

Fig. 58 is a comparative chart of the content of lymphocytes in mice after introduction of physiologic saline and palmitoylethanolamide as described in Example 49.

Fig. 59 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline, Palmitoyl-8-bromoguanosine, monopalmitate 2',2'-(acyclic) dialcohol, palmitoylcarnitine and palmitoylethanolamide as described in Example 50.

Fig. 60 - comparative chart platelet count in mice after introduction of physiologic saline, Palmitoyl-8-bromoguanosine, monopalmitate 2',3'-(acyclic)dialcohol, palmitoylcarnitine and palmitoylethanolamide as described in Example 50.

Fig. 61 is a comparative chart of the number of bone marrow cells per femur in mice after introduction of physiologic saline, Palmitoyl-8-bromoguanosine, monopalmitate 2',3'-(and the>/P>Fig. 62 comparative chart platelet counts in mice after introduction of physiologic saline and palmitoylethanolamide as described in Example 51.

Fig. 63 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline and palmitoylethanolamide as described in example 51.

Fig. 64 - comparative chart of the number of neutrophils in mice after introduction of physiologic saline and palmitoylethanolamide as described in example 51.

Fig. 65 is a comparative chart of the number of leukocytes in mice after introduction of physiologic saline and palmitoylethanolamide as described in example 51.

Fig. 66 is a comparative chart of the content of neutrophils in mice after introduction of "tween-80" in various concentrations without palmitoylcarnitine as described in example 52.

Fig. 67 is a comparative chart of the content of neutrophils in mice after introduction of physiologic saline and Palmitoyl-8-aminoguanine as described in example 53.

Fig. 68 is a comparative chart of the weights of the spleens of mice after introduction of physiologic saline and Palmitoyl-8-aminoguanine as described in example 53.

To fully understand the essence of the present invention in General, Estulin charts, illustrating the results of experiments described in the examples.

Detailed description of the invention

The object of the present invention are oxypurine nucleosides related to these nucleoside compounds and acyl derivatives of these nucleosides and related compounds and the use of these compounds to modify disorders in animals, including humans.

A. Terminology

The term "oxipurinol basis" means here purine base with ekzoticheskim oxygen or hydroxyl group in 6-position and is hydrogen, oxygen, hydroxyl group or amino group in the 2 position.

The term "oxipurinol nukes" here describes oxipurinol base associated with Aldatu containing 5 carbon atoms, and the nitrogen in the 9 position of the base is linked to the 1' position alsadi. The term "oxipurinol the nucleoside" includes, among others, compounds such as guanosine, inosine, deoxyinosine, xanthosine, detoxication and deoxyguanosine.

The term "family connection" here means oxipurinol nuke with the Deputy, which is attached in the 7 or 8 position of the purine ring, and/or oxipurinol nucleosides used to denote derivatives oxypurine nucleosides or related compounds, in which practically non-toxic organic acyl Deputy resulting from substitution of carboxylic acid attached to one or more hydroxyl group ribosome fragment oxipurinol nucleoside via the ether bridge and/or in which such Deputy is attached to the amine substituents on the purine ring guanosine through amide linkages. Such acyl substituents derived from carboxylic acids, including compounds selected from the group of lactic acid, amino acid, fatty acid, nicotinic acid, dicarboxylic acid, para-aminobenzoic acid, orotic acid. Preferred acyl substituents are those compounds that are normally present in the animal body, or as components of food, or as intermediate metabolites.

The term "pharmaceutically acceptable salt" is used here to describe the products of accession acid residues pharmaceutically acceptable salts of the above derivatives; among such acids are sulfuric, hydrochloric or phosphoric acid.

The term "anasatasia" means that at least two of the compounds according to the invention is assigned to the overlapping each other.

The term "amino acid" means here, among other compounds, glycine, L-forms of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, cystine, methionine, tryptophan, aspartic acid, glutamic acid, arginine, lysine, histidine, ornithine, hydroxylysine, carnitine and other amino acids occurring in nature.

The term "fatty acid" means here aliphatic carboxylic acid, the content of 2-22 carbon atoms. Such fatty acids may be saturated, partially saturated or polyunsaturated.

The term "dicarboxylic acid" is used here to refer to fatty acids, the second substituent in which is a carboxylic acid.

The term "therapeutically effective amount" refers to an amount which provides a therapeutic effect in the patient's condition and at the specified receive mode or the introduction of a connection.

B. Compounds according to the invention

Compounds according to the invention is used to modify haematopoiesis, have the following formula:

< / BR>
where RA= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms,

RB= H or AC is hydrated carboxylic acid radical with 2-30 carbon atoms,

L = H or orDwhere RD= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms,

M = H or orZwhere RZ= H or acyl radical of carboxylic acid with 2 to 30 carbon atoms, provided that at least one of the radicals Z and M is H.

Q = H, halogen, otherFwhere RFrepresents H or ecially or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGrepresents H or ecially or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H or orHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, preferably between 2' and '3 position Almaznogo fragment a relationship existed C-C.

New compositions according to the invention include the above compounds in which at least one and a NH2or otherC, Then Q represents H or otherFwhere RFrepresents H or ecially or alkyl radical containing 1-10 carbon atoms, together with a pharmaceutically acceptable carrier.

In particular, the new compounds according to the invention include, among others, the following connections:

(1) acyl derivative of guanosine or related compounds of the formula:

< / BR>
where RA, RBand RDhave the same or different values, which is hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain containing 6-22 carbon atom,

b. amino acids selected from the group comprising glycine, L-forms of alanine, valine, leucine, isoleucine, tyrosine, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms, provided that not all of the radicals RA, RBand RDare H;

RCrepresents hydrogen or an acyl group derived by substitution

i. fatty acids with unbranched chain is Nina, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

iii. dicarboxylic acid having 3-22 carbon atoms,

iv. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms,

v. nicotinic acid,

vi. substituted or unsubstituted aromatic carboxylic acid containing 7-22 carbon atom,

J = H or otherIwhere RIrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

(2) an acyl derivative of inosine or related compounds of the formula:

< / BR>
where RArepresents hydrogen or an acyl group derived by substitution

a. fatty acids with unbranched chain with 3-22 carbon atoms,

b. dicarboxylic acid having 3-22 carbon atoms,

c. nicotinic acid,

d. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms, where RBand/or RDrepresents hydrogen or an acyl group derived by substitution

a. fatty acids with unbranched chain with 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, L-shape fenilalanina acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms, provided that not all of the radicals RA, RBand RDrepresent hydrogen, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H or orHwhere RHrepresents H or ecially or alkyl radical containing 1-10 carbon atoms;

(3) acyl derivatives xanthosine or related compounds of the formula

< / BR>
where RA, RBand RDhave the same or different values, which will bring with 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acid with 4 to 22 carbon atoms, provided that not all of the radicals RA, RBand RDare hydrogen, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H or orHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 ATO is>where RAand RBhave the same or different values, such as hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain with 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms, provided that at least one of the radicals RAand RBis not hydrogen, and

Q = H, halogen, otherFwhere RFrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent di or H, or orHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

(5) acyl derivatives of deoxyguanosine and related compounds of the formula:

< / BR>
where RA, RBand RCcan have the same or different values, each of which is hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain with 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, L-forms of alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine, phenylalanine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms,

e. nicotinic acid,

provided that not all of the radicals RA, RBand RCare hydrogen, and when RCis not H, RAand/or RBcan be a also acetyl,

J = H or otherIwhere RIrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms;

(6) acyl derivatives detoxicate values, what are hydrogen or an alkyl group obtained by substitution

a. fatty acids with unbranched chain with 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms,

provided that at least one of the radicals RAand RBis not hydrogen, and

Q = H, halogen, otherFwhere RFrepresents H or acyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms, O, associated with the carbon double bond, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, then this is adikal, containing 1-10 carbon atoms;

(7) acyl derivatives of inosine (acyclic) 2'3'-dialcohol or related compounds of the formula:

< / BR>
where RA, RBand RDhave the same or different values, such as hydrogen or acyl group derived by substitution

a. fatty acids with unbranched chain with 3-22 carbon atoms,

b. amino acids selected from the group comprising glycine, the L forms of phenylalanine, alanine, valine, leucine, isoleucine, tyrosine, Proline, hydroxyproline, serine, threonine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine and ornithine,

c. dicarboxylic acid having 3-22 carbon atoms,

d. nicotinic acid,

e. cycloalkylcarbonyl acids containing 4 to 22 carbon atoms,

provided that not all of the radicals RA, RBand RDare hydrogen, and

Q = H, halogen, otherFwhere RFrepresents an acyl or alkyl radical containing 1-10 carbon atoms, S, connected by a double bond with carbon, in which case the adjacent double bond between carbon and nitrogen is a simple relationship, and then to the nitrogen attached to any H, SRGwhere RGHwhere RHrepresents H or an acyl or alkyl radical containing 1-10 carbon atoms,

Z represents H, OH, =O or otherCwhere RC= H, or acyl radicals of carboxylic acids containing 2 to 30 carbon atoms.

The present invention encompasses pharmaceutically acceptable salts of the above compounds.

Preferred compounds of the present invention are imokalee esters of deoxyguanosine, deoxyinosine, guanosine, inosine, desoximetasone and xanthosine, especially those in which the acyl Deputy contains 8 or more carbon atoms. The most preferred compounds are imokalee esters of deoxyguanosine or deoxyinosine containing 12-18 carbon atoms in the acyl substituent. Compounds with a polar amino acid substituent (for example, lysine or arginine) associated with either a hydroxyl group Almaznogo fragment or ekzoticheskoy amino group of guanosine or deoxyguanosine, and, optionally, with a fatty acid, the s, containing aqueous pharmaceutical carriers.

In one of the embodiments of the invention prodrugs containing compounds according to the invention with increased solubility, is obtained by attaching a phosphate to a free hydroxyl group Almaznogo fragment of purine nucleoside.

In another embodiment of the invention the substituents, such as alkyl short circuit or substituted alkyl radical, e.g. methyl, ethyl or propyl, are attached at the 1, 3 and/or 7 position oxipurinol fragment of the above compounds.

In the following embodiment of the invention ekzoticheskaya amino group of guanosine, deoxyguanosine or related compounds may have two acyl substituent, which may be the same or different. In such cases, the acyl substituents selected from the group acyl radicals denoted by RCin the descriptions of guanosine, deoxyguanosine and related compounds.

Nonionic surfactants

It was found that a variety of nonionic surfactants, including polyoxyethylene-sorbitan-acylate, such as "tween-80" (polyoxyethylenesorbitan-mono-oleate), "twin-60" (poly the new ether) and Triton X-100"; condensates of ethylene oxide, for example, "Nonidet 40-P" (condensate of activeselectionset) increase the effectiveness of the compounds according to the invention in respect of hemopoiesis in vivo. Moreover, these surfactants themselves accelerate the recovery of hematopoiesis after disorder of the bone marrow caused by cytoreductive agents such as cyclophosphamide (see example 52). New compositions according to the invention include one or more of the above surfactants and erythropoietin, interleukin, a factor stimulating the growth of colonies, or another compound capable of stimulating hematopoiesis.

The composition of the invention

In one of the embodiments of the invention, the new pharmaceutical compositions comprise as active substance one or more oxipurinol nucleoside selected from the group comprising guanosine, inosine, xanthosine, detoxicants, deoxyinosine, deoxyguanosine related to these oxipurinol the nucleoside compounds and acyl derivatives of these oxipurinol of nucleosides and related compounds together with a pharmaceutically acceptable carrier.

In another embodiment of the invention the composition of the invention include, in addition to one or more compounds according to the image the th as IL -1, -2, -3, -4, -5, -6, -7, -8 (preferably, IL -1, -3 and -6), the factor stimulating the growth of colonies, for example, the factor stimulating the growth of colonies of granulocytes (G-CSF), factor stimulating the growth of colonies of granulocytes/macrophages (GM-CSF), erythropoietin (EPO), glucan, polyinosine-polititian or any other substance, a positive current on haematopoiesis. Compositions, depending on their purpose, are made in the form of liquids, suspensions, tablets, capsules, pills, in the form of injection solutions, solutions for local use or in the form of candles (see recipe below).

In another embodiment of the invention the composition comprises at least one compound according to the invention and the connection that protects from radiation.

In another embodiment of the invention the composition comprises at least one compound according to the invention and the anti-virus agent or anti-cancer agent or other pharmaceutical agents that reduce the number of blood cells.

The use of the compounds and compositions according to the invention for therapeutic purposes

Compounds according to the invention are used to modify, improve or assist in the process of hemopoiesis and funicle violation or suppression of bone marrow function due to chemotherapy, radiation therapy or disease; they protect the bone marrow from such violations as a result of chemotherapy, radiation therapy or diseases; they also change the number of blood cells (such as leukocytes and platelets) or their activity in the animal body. Compounds according to the invention is applicable to the treatment of people; however, the present invention is not limited to the treatment of people, it covers the treatment of all animals, which has the favorable effect of the use of the active compounds according to the invention.

A significant reduction of the adverse effects of radiation therapy in those cases where the compounds according to the invention is used together with a compound that provides protection from radiation.

Further, the implementation of the present invention also includes the destination system of the pharmaceutical compounds or compositions containing guanosine, deoxyguanosine, inosine, xanthosine, detoxicants, deoxyinosine related to these nucleoside compound or acyl derivative of such nucleosides or related compounds, or combinations of such compounds or compositions, to improve hematopoiesis in organisms of patients with a reduced content of the ü to stimulate haematopoiesis.

The specific conditions under which the use of the compounds, compositions and methods according to the invention provides advantages that include those situations where you want to improve hematopoiesis. Such conditions include treatment of animals, for example, patients-people affected by cytoreductive cancer chemotherapy, anti-virus chimiotherapie, irradiation of ionizing radiation (therapeutic purposes or in an accident), animals in need of better immune protection of the body by white blood cells, as well as animals with anemia or hypoplasia as a result of illness or accidental poisoning. The benefits of using the compounds, compositions and methods of the invention are achieved by increasing the number of leukocytes in animals with normal content of blood cells, for example, to improve the body's immune defense against infection, an increase in the number of platelets in animals with normal blood formula, for example, to increase the coagulability of the blood (e.g., before surgery), training of animals before conducting anticancer or antiviral chemotherapy (or radiation therapy), the preparation of donors for transplantation bone mongogo marrow before transplantation, treatment of bone marrow cells in cultures (for research purposes or prior to transplantation). In particular, this includes the use of these compounds in veterinary practice where you want to change the formula of blood.

Cytopenia

The compounds and compositions according to the invention can be used to treat various forms of cytopenia listed below:

A. Neutropenia

Neutropenia caused by cancer or cancer chemotherapy; neutropenia in the antiviral chemotherapy; neutropenia as a result of irradiation with ionizing radiation (resulting from an accident or radiation therapy); neutropenia in the immunosuppressive chemotherapy (for example, treatment of autoimmune disorders such as rheumatoid arthritis, using cytotoxic drugs); neutropenia in patients with burns (neutropenia is common in patients suffering from severe burns); neutropenia due to virus infections (for example, pancytopenia is common in HIV-infected, it is enhanced by treatment with drugs that suppress the function of the spinal cord, such as AZT); neutropenia secondary to aplastic anemia or myelodysplastic syndrome who cancel agranulocytosis in the number of adverse actions); idiopathic neutropenia; chronic granulocytopenia; neutropenia as a result of leukemia "hairy" cells or other limfoleikozom; neutropenia caused by any other reasons; neutropenia in animals (veterinary use).

Century Thrombocytopenia

Low levels of platelets in the cancer chemotherapy; thrombocytopenia resulting antiviral chemotherapy; thrombocytopenia a result of exposure to ionizing radiation (resulting from an accident or radiation therapy); low levels of platelets in the immunosuppressive chemotherapy (for example, treatment of autoimmune disorders such as rheumatoid arthritis, using cytotoxic drugs); thrombocytopenia due to virus infections (for example, pancytopenia is common in HIV-infected, it is enhanced by treatment with drugs that suppress the function of the spinal cord, such as AZT); thrombocytopenia secondary to aplastic anemia, myelodysplastic syndrome or gipoplasticheskaya syndromes bone marrow; thrombocytopenia as a result of any other causes.

C. Lymphopenia

Low levels of lymphocytes in the cancer the e irradiation with ionizing radiation (resulting from an accident or radiation therapy); low levels of lymphocytes in the immunosuppressive chemotherapy (for example, treatment of autoimmune disorders such as rheumatoid arthritis, using cytotoxic drugs); lymphopenia caused by any other reasons.

D. Anemia

Low levels of red blood cells in the renal dialysis; low levels of red blood cells in the kidney damage; anemia due to virus infection or chemotherapy using drugs that suppress the function of the spinal cord; anemia as a result of infection or disease (e.g., malaria); anemia result in bleeding; anemia caused by any other reasons.

Treatment of complications associated with radiation

Clinical use of the active compounds according to the invention for the treatment of complications due to irradiation are shown in the following three cases: 1) when irradiated in the course of an accident, as during accidents related to nuclear energy; 2) exposure from diagnostic procedures using x-rays; 3) exposure during radiation therapy, such as radiation cancer treatment.

In the first case, according to one variant is jaczie, then the preparation is administered orally or parenterally once or several times per day in doses sufficient to increase hematopoiesis, for example, 0.01 to 3 grams per day.

In the second case, when x-ray irradiation in the course of diagnosis, according to one embodiments of the invention, the active compound is given orally before or after irradiation.

In the third case, when the radiation during cancer radiation therapy, active compounds can effectively restore marrow function after unwanted, but inevitable suppression of these functions in the course of radiation therapy.

Compounds according to the invention is prescribed before, during and/or after irradiation.

Compounds according to the invention is used to prevent or mitigate the effects of ionizing radiation together with other drugs against radiation, such as WR-2721, NAC, DDC, group probably facilitates 2-mercaptoethanol, mercaptoethylamine, dithiotreitol, glutathione, 2-mercaptoethanesulfonate acid, WR-1065, nicotinamide, 5-hydroxytryptamine, 2-beta-aminoacylation-Br-Hbr, glucan, GLP/B04, GLP/B05, OK-432, "Biostim", PSK, "Lentinan", "Sizofiran", "Regexten", "Levan", "Nanozim", MVE-3, MNR, MMZ, IL-1, IL-2, TNF timiney factor, MnC12, zinc acetate, vitamin A, beta-carotene, prostaglandins, tocopherol and methylene blue, and RAV. The purpose of these protective compounds together with the compounds according to the invention provides better protection than the appointment of compounds separately.

Treatment of complications associated with cancer chemotherapy

Patients undergoing treatment with standard anti-cancer chemicals (such as 5-fluorouracil, ftordezoksiuridin, vinylchloride, cyclophosphamide and other alkylating agents such as busulfan, hexalen or melphalan, daunorubicin, doxorubicin, methotrexate, citizenoriented, 6-mercaptopurine, 6-methylmercaptopurine, ribose, thioguanosine, podophyllotoxin, cisplatin, the combination of cytoreductive agents or cytoreductive agents plus modulators, such as leucovorin, PALA or WR-2721), it is frequently observed low number of leukocytes, in particular neutrophils. Daily oral administration (or parenteral) effective dose (for example, 0.01 to 3.0 grams) of the compounds according to the invention, such as Palmitoyl- (or other acyl derivative) of deoxyguanosine for several days mitigates or prevents the lowering of the ical preparations together with deoxyguanosine effectively increases the total number of white blood cells, including neutrophils and lymphocytes, in the following days, compared with patients who received only drugs in chemotherapy. This reduces the likelihood of infection during treatment and allows you to take higher doses of the drugs included in chemotherapy, and/or begin to undergo a second course of chemotherapy faster than the patient, not taking derivatives deoxyguanosine.

Compounds according to the invention is prescribed before, during and/or after the appointment of anti-cancer drugs.

Treatment of complications associated with antiviral chemotherapy

Treatment of patients with AIDS or related diseases, AIDS, use of azidothymidine (AZT) and other antiviral drugs, complicated by anemia, neutropenia and thrombocytopenia. The purpose of the respective doses of the compounds according to the invention, such as palmitoylcarnitine (or other acylated form guanosine) in a few days (or, depending on the course of antiviral therapy during the course of this therapy) significantly reduces neutropenia, anemia, thrombocytopenia, and other side effects of AZT and/or ddC. This reduces the risk of septic complications and allows patients predomiantly, which was treated only with antiviral drugs without compounds according to the invention.

The connection according to the invention is prescribed before, during and/or after the appointment of antiviral drugs.

Treatment of complications associated with poisoning and side effects of different medicines

Poisoning by benzene or side effects of various substances, including many prescription medications, including medications for thyroid disease, sulfonamides, phenylthiazole, phenylbutazone and aminopyrine causes agranulocytosis/neutropenia. The cytopenia is also called poisoning by benzene and mustard gas and the appropriate alkylating drugs. The purpose of the compounds according to the invention victims such as poisoning or patients receiving such drugs, promotes healing by stimulating the production of blood cells, such as neutrophils.

Treatment of cytopenias, associated with various diseases

Many diseases are associated with various forms of cytopenia. For example, leukemia hairy cell damage associated with neutropenia. Thrombocytopenic purpura and aplastic anemia associated with low platelets. The purpose of the compounds according to the image">

Treatment of complications associated with damage to the human immunodeficiency virus

Patients infected with HIV, especially AIDS patients, suffer from numerous diseases resulting from such infection, and in some cases, these diseases weaken the already affected the immune system. Many of these patients are prescribed anti-virus chemical drugs, such as AZT, which have a deleterious effect on the immune functions of the body, further reducing the resistance to all sorts of infections. The purpose of the compounds according to the invention is orally, intravenously or parenterally increases the amount of blood cells, which was reduced as a result of infection (in patients with AIDS, there is often pancytopenia). Such treatment increases the percentage of neutrophils, lymphocytes and platelets, which helps to restore immune activity. Due to the fact that increased exposure to infectious diseases is the factor which limits the dosage and intensity of chemotherapy, AIDS patients, patients with the use of compounds according to the invention reduces side effects of chemotherapy (and thus improves the condition

Some varieties of cancer associated with hematological cytopenias regardless of cytopenias result of cytoreductive chemotherapy. Leukemia hairy" cells are often associated with neutropenia. Infiltration of tumors in the bone marrow often violates haematopoiesis. The purpose of the compounds according to the invention increases the percentage of neutrophils and other cell types in patients suffering from such diseases. Some types granularities leukemias are characterized by excessive production of immature with non-differentiating precursors of granulocytes. As shown in the examples 35-51 below, the compounds according to the invention lead to increased final differentiation of the precursors of neutrophils, making these compounds can be used for the treatment of leukemias, such as leukemia granulocytes.

The use of compounds according to the invention for bone marrow

Bone marrow transplantation is used to treat patients suffering from radiation accident or radiation therapy and side effects of cytoreductive chemotherapy (anti-virus and/or anti-cancer). When bone marrow transplantation compounds according to the invention ispolzuyteskryty blood cells, such as neutrophils, lymphocytes, megakaryocytes and platelets in the peripheral blood and their precursors in the bone marrow. The purpose of the compounds according to the invention recipients of bone marrow before, after or during transplantation accelerates the recovery of hemopoiesis. In addition, incubation of bone marrow cells in culture with the use of compounds according to the invention prior to transplantation improves engraftment.

The use of the compounds according to the invention for autohemotransfusions

Autoguemotransfuzii or accumulation of certain quantities of the patient's own blood for later transfusion, for example, before elective surgery or as a precaution against unexpected situations requiring blood transfusion is an important event to avoid infection through the blood of donors such viruses as HIV or hepatitis. Compounds according to the invention can be used for recovery of blood counts after sampling the patient's blood for storage. On the contrary, these compounds can be assigned to blood collection in order to mitigate the impact of this operation.

The prophylactic use of compounds according ilen enhance or otherwise change haematopoiesis in anticipation of various difficulties.

For example, in many cases it is desirable to enhance resistance to infections, such as before surgery or contacts with a viral or bacterial infection. The purpose of the compounds according to the invention to animals with normal blood formula increases the number of leukocytes and increases resistance to infections.

There are many situations in which it is desirable to increase the clotting of blood of an animal, for example, before surgery. The purpose of the compounds according to the invention before surgery increases the number of platelets and, thus, improves blood clotting.

In cases where the damage to the bone marrow and/or system disorders, for example, anticancer or antiviral chemotherapy or radiation therapy, it is desirable to improve or enhance hematopoiesis. Prior to the appointment of an animal that should be subjected to such treatment, the compounds according to the invention accelerates the production of white blood cells and platelets and/or mitigates damage to the precursors of blood cells. Connections lead to positive changes in the system of hemopoiesis in the preventive purposes.

slichnih types, such as neutrophils, lymphocytes, megakaryocytes and platelets in the peripheral blood and increases the number of hematopoietic precursor cells in the bone marrow.

D. Purpose and preparation of medicines, including the compounds and compositions according to the invention

The compounds and compositions according to the invention is given orally, parenterally, intravenously, topically or by any other means, depending on treatment conditions.

The compounds and compositions according to the invention designated for permanent appointment or courses. The compounds and compositions according to the invention is prescribed before, during or after an event that causes damage to system disorders (e.g., irradiation or cytoreductive chemotherapy). After the specified connection event and the composition of the invention is prescribed before and/or after came the maximum decrease in the number of blood cells or bone marrow.

Compounds according to the invention are included in the matrices, with the ability to biodegradation, bioerosion or other types of gradual release connections after the introduction of their oral or subcutaneous. For intravenous and intramuscular injection of the compounds according to the invention preferably PMI pharmaceutically acceptable carriers, composed of fillers and tools that enhance the processing of the active compounds. The drugs are given as tablets, pills, capsules or suppositories. The composition is prescribed, for example, orally, rectally, vaginally or enter transbuild, they can be used in the form of a solution or injection, orally or topically. The composition can contain from about 0.01 to 99%, preferably from about 50 to 90% of the active compounds (compounds), together with the carrier(s).

For parenteral administration by injection or intravenous administration, the active compounds according to the invention are prepared as suspensions or dissolved in aqueous medium, such as sterilized water or physiologic solution. Preferably, the solution or suspension for injection include surfactants, such as polyoxyethylenesorbitan, arbitrarily, polyoxyethylenated or solvents, the type of propylene glycol or ethanol. Compounds according to the invention can be suspended or dissolved in a fat emulsion for injection for the purpose of parenteral. The solution or suspension usually contains 0.01-5% active compounds. The active compounds can be dissolved in the pharmaceutical vegetable oil for vnutripechenocnaya are sugar, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or acid phosphate of calcium, as well as such a binder, as starch paste, made of, for example, maize starch, wheat starch, rice starch or potato starch, gelatin, tragant, methylcellulose, hypromellose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone.

Auxiliary tools include substances that regulate fluidity, and lubricants, for example silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate and/or polyethylene glycol. The core tablets are covered by the relevant coverage, which, if desired, may be resistant to gastric juice. For this purpose, concentrated sugar solutions which may contain the Arabian gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lakiruyuschii solutions and suitable organic solvents or solvent mixtures. For the manufacture of coatings resistant to gastric juice, prepare solutions of suitable preparations of cellulose, such as palatial or pigments, for example, to identify compounds or doses.

The pharmaceutical preparations according to the invention are produced by known methods, for example by conventional mixing, granulating, the manufacture of tablets, dissolution or lyophilization. Thus, pharmaceutical preparations for oral use are obtained by combining the active compounds with solid excipients, the resulting mixture can be chopped and pelletized, and after the addition of suitable auxiliaries, if necessary, to make the core of tablets or pills.

Other pharmaceutical preparations for oral products include extrusion capsules made of gelatin, and also soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Vydavlivalsya capsules contain the active compound in granular form, which can be mixed with fillers such as lactose, binders, such as starch, and/or lubricating agents such as talc or magnesium stearate, and stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as non-volatile recrystallizes preparations for rectal application include, for example, suppositories consisting of a combination of active compounds with the main material of which is made candles. Such materials can be, for example, natural or synthetic triglycerides, paraffin waxes, polyethylene glycols or higher alkanols. In addition, can be applied gelatin capsules for rectal application, which consist of a combination of compounds according to the invention with the respective main material. Among these materials, liquid triglycerides, polyethylene glycols or paraffin.

Preparations for parenteral products include aqueous solutions of the active compounds present in water-soluble form, for example, in the form of water-soluble salts. In addition can be used suspensions or solutions of the respective active compounds in compositions for oil injection, which includes solvents such as propylene glycol or water-lipid emulsions. Among the suitable lipophilic solvents and non-volatile fatty oils, for example sesame oil, or synthetic esters of fatty acids, for example, etiloleat or triglycerides. Aqueous suspension for injection may contain substances which increase the viscosity of the suspension, such substances can be, for example, is In one of the embodiments of the invention the active compounds included in the composition of skin lotion for local purposes. In this case, suitable lipophilic solvents include non-volatile fatty oils, for example sesame oil, or coconut oil, or synthetic esters of fatty acids, for example, etiloleat or triglycerides.

E. Synthesis of compounds according to the invention

Acylated derivatives oxypurine nucleosides are synthesized by the reaction oxipurinol nucleoside or related compounds with an activated carboxylic acid. The activated carboxylic acid is carboxylic acid, which was treated with appropriate reagents so that the carbon of the carboxylic groups has become more vulnerable to destruction by the nucleophile than in the non-activated carboxylic acid. For the synthesis of compounds according to the invention can be used, for example, the following activated carboxylic acid: acid chlorides, acid anhydrides, n-hydroxysuccinimidyl or a carboxylic acid activated by BOP-DC. Carboxylic acids can join oxipurinol the nucleosides or related compounds by means of binders, such as dicyclohexylcarbodiimide (DCC).

In the preparation of acyl compounds according to the invention, when used collated the preparation of these anhydride groups blocked with protective groups, for example, tert-butyldimethylsilyl-esters or tert-BOC groups, respectively. For example, lactic acid is converted into 2-tert-butyldimethylsiloxy acid with tert-butyldimethylchlorosilane, followed by hydrolysis of the obtained similair with an aqueous alkali solution. Anhydride get through reaction of the protected acid with DCC. When using amino acids prepare derivative of N-tert-BOC (using standard methods), then using DCC converted into the anhydride. When using acids, containing multiple carboxylic groups (e.g., amber, fumana or adipic acid), the acid anhydride of the desired dicarboxylic acid react with oxipurinol a nucleoside or related compounds in pyridine or pyridine with dimethylformamide or dimethylacetamide.

Amino acids join ekzoticheskim the amino group of guanosine and deoxyguanosine and hydroxyl groups Almaznogo fragment oxypurine nucleosides or related compounds by standard methods using DCC in an appropriate solvent, in particular in a mixture of (i) methylene chloride and (ii) dimethylacetamide or dimethylformamide.

Digislide the qualification and options in different conditions, normally encountered in clinical therapy, which is obvious for specialists in this area are also covered by the present invention.

Examples

The following examples relate to methods of preparation of compounds according to the invention.

Example 1. Cooking octanophenone.

Into a flask of 100 ml put guanosin (2.0 g, 7,06 mmol) and N,N-dimethyl-4-aminopyridine (of 0.017 g, 0.14 mmol). N,N-dimethylformamide (25 ml) is added via cannula with stirring, the flask was rinsed with argon and the cannula add pyridine (14 ml). The suspension is allowed to cool for 10 minutes in an ice bath with NaCl and drop by drop add octanoate (1.6 ml, 9.2 mmol). The mixture is stirred while it is heated to 25oC. after 18 hours the mixture is poured into 300 ml of 0.1 M ice-cold sodium bicarbonate solution, getting a white solid, which is separated by vacuum filtration, washed 3 times with hot water of 100 ml, dried by air and will recrystallized from hot methanol.

Example 2. Cooking lauroylsarcosine

Into a flask of 100 ml put guanosin (2.0 g, 7,06 mmol) and N,N-dimethyl-4-aminopyridine (of 0.017 g, 0.14 mmol), N,N-dimethylformamide (25 ml) is added via cannula with stirring, the flask produite drop add laureillard (2,12 ml, 9.2 mmol). The mixture is stirred while it is heated to 25oC. After 18 hours the mixture was poured into 300 ml of ice-cold 0.1 M solution of sodium bicarbonate, getting a white solid, which was separated by vacuum filtration, washed 3 times with hot water (100 ml), dried by air and will recrystallized from hot methanol.

Example 3. Cooking palmitoylcarnitine

Into a flask of 100 ml put guanosin (2.0 g, 7,06 mmol) and N,N-dimethyl-4-aminopyridine (of 0.017 g, 0.14 mmol), N,N-dimethyl-formamide (25 ml) is added via cannula with stirring, the flask was rinsed with argon and the cannula add pyridine (14 ml). The suspension is cooled for 10 min in an ice bath with NaCl and drop by drop add palmitoylated (2.8 ml, 9.2 mmol). The mixture is stirred while it is heated to 25oC. After 18 hours the mixture was poured into 300 ml of ice-cold 0.1 M solution of sodium bicarbonate, getting a white solid, which was separated by vacuum filtration, washed 3 times with hot water (100 ml), dried by air and will recrystallized from hot 2-methoxyethanol.

Example 4. Cooking benzylguanine

Into a flask of 100 ml put guanosin (2.0 g, 7,06 mmol) and N,N-dimethyl-4-aminopyridine (0,017 g 0,14 IMO is added pyridine (16 ml). The suspension is cooled for 10 min in an ice bath with NaCl and drop add benzoyl chloride (1.2 ml, 8.5 mmol). The mixture is stirred while it is heated to 25oC. After 72 hours the mixture was poured into 300 ml of 0.1 M sodium bicarbonate solution (heated to 60oC) to give white solid, which was separated by vacuum filtration (using a medium Frit), washed 3 times with cold water 100 ml and dried with air.

Example 5. Preparation palmitoylcarnitine

Into a flask of 100 ml was placed dehydrate xanthosine (1.0 g, to 3.52 mmol) and N, N-dimethyl-4-aminopyridine (0,0086 g, 0.07 mmol). N,N-dimethylformamide (16 ml) is added via cannula with stirring, the flask was rinsed with argon and the cannula add pyridine (8 ml). The suspension is cooled for 10 min in an ice bath with NaCl and drop by drop add palmitoylated (1.6 ml, 9.2 mmol). The mixture is stirred, while it slowly warmed up to 25oC. After 18 hours the mixture is poured into 300 ml of ice-cold 0.1 M solution of sodium bicarbonate, getting a white solid, which was separated by vacuum filtration, washed 3 times with hot water of 100 ml, dried by air and will recrystallized from hot methanol.

Example 6. Preparation palmitoylethanolamide (16 ml) is added via cannula under stirring, the flask was rinsed with argon and the cannula add pyridine (8 ml). The suspension is cooled for 10 min in an ice bath with NaCl and drop by drop add palmitoylated (1.3 ml, 4.1 mmol). The mixture is stirred, while it slowly warmed up to 25oC. After 18 hours the mixture is cooled rapidly to a small piece of ice, after which the solvent is evaporated, obtaining a resin of white color. From the resin is evaporated with toluene (20 ml), which is then carefully titrated using 1:1 ethyl acetate-diethylether. Surfaced to the top substance is separated by vacuum filtration and evaporated the solvent, obtaining a syrup, which after 24 hours in a vacuum desiccator turns into a soft amorphous solid.

Example 7. Cooking palmitoylcarnitine

Into a flask of 100 ml was placed deoxyinosine (1.5 g, 5,95 mmol) and N,N-dimethyl-4-aminopyridine (0.036 g, 0,297 mmol). N,N-dimethylformamide (35 ml) is added via cannula with stirring, the flask was rinsed with argon and the cannula add pyridine (15 ml). The suspension is cooled for 10 min in an ice bath with NaCl and drop by drop add palmitoylated (2.0 ml, is 6.54 mmol). The mixture is stirred, while it slowly warmed up to 25oC. After 18 hours the mixture was poured into 300 ml of ice-cold 0.1 M solution of b is s and dried overnight in a vacuum desiccator, receiving a rating of 2.72 g (93%) of palmitoylcarnitine.

Example 8. Preparation of (5-carboxypentyl)guanosine

500 mg of guanosine in anhydrous pyridine add adipic acid (5 molar equivalents) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP C) (1.0 mol. EQ.). The mixture is stirred at room temperature for 18 hours, then under vacuum to remove the solvent. Residues added to 100 ml of ice water and adjusted the pH of the aqueous layer to 3.0, after which the extraction is carried out three times with 60 ml of ethyl acetate. The United extracts dried with anhydrous magnesium sulfate and evaporated under vacuum. The residue is subjected to chromatography on silicagel column and elute with a mixture of chloroformmethanol, after which the eluate is evaporated under vacuum.

Examples 9-11. Preparation of (5-carboxyvinyl)guanosine, (5-carboxyphenyl)guanosine and (5-carboxyphenyl)guanosine

(5-carboxyvinyl)guanosine, (5-carboxyphenyl)guanosin and (5-carboxyphenyl)guanosin prepared from guanosine, with pipelinewall acid, subernova acid and sabatinovka acid, respectively, using the method described for the preparation of (5-carboxypentyl)guanosine.

Example 12. Preparation of 3',5'-O,O-bis(5-the EQ. ) and bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP C) (2,0 mol. EQ.). The mixture is stirred at room temperature for 18 hours, then the solvent is removed under vacuum. The residue add 100 ml of ice water and the pH of the aqueous layer was adjusted to 3.0, and then extracted three times with 60 ml of ethyl acetate. The United extracts dried with anhydrous magnesium sulfate and evaporated under vacuum. The residue is subjected to chromatography on silicagel column and elute with a mixture of chloroform-ethanol, after which the eluate is evaporated under vacuum.

Examples 13-15. Preparation of 3',5'-O,O-bis-(5-carboxyvinyl)guanosine, 3', 5'-O, O-bis-(5-carboxyphenyl)guanosine 3',5'-O,O-bis-(5-carboxyphenyl)guanosine

3',5'-O,O-bis-(5-carboxyvinyl)guanosin, 3',5'-O,O - bis-(5-carboxyphenyl)guanosine and 3',5'-O,O-bis-(5-carboxyphenyl)guanosin prepared from guanosine with pipelinewall acid, subernova acid and sabatinovka acid, respectively, using the method described for the preparation of (5-carboxypentyl)guanosine.

Example 16. Preparation of (Na-FMOC-Ne-CBZ-lysyl)guanosine

500 mg of guanosine in anhydrous pyridine type Na-FMOC-Ne-CBZ-lysine (2 mol.EQ., company "Sigma") and dicyclohexylcarbodiimide (DCC) (1,0 mol.EQ.). The mixture pavlat in 100 ml of ice water and the pH of the aqueous layer was adjusted to 3.0, then extracted three times with 60 ml of ethyl acetate. The United extracts dried with anhydrous magnesium sulfate and evaporated under vacuum. The residue is subjected to chromatography on silicagel column and elute with a mixture of chloroform-ethanol, after which the eluate is evaporated under vacuum.

Example 17. Preparation of (Na-FMOC-Ne-CBZ-lysyl)-2',3'-O-isopropylideneuridine

2.0 g of 2',3'-O-isopropylideneuridine (Sigma) in anhydrous pyridine type Na-FMOC-Ne-CBZ-lysine (2 mol.EQ., company "Sigma") and dicyclohexylcarbodiimide (DCC) (1,0 mol. EQ. ). The mixture is stirred at room temperature for 18 hours, then the solvent is removed under vacuum. The residue add 100 ml of ice water and the pH of the aqueous layer was adjusted to 3.0, and then extracted three times with 60 ml of ethyl acetate. The United extracts dried with anhydrous magnesium sulfate and evaporated under vacuum. The residue is subjected to chromatography on silicagel columns and elute with a mixture of chloroform-ethanol, after which the eluate is evaporated under vacuum.

Example 18. Preparation of (Na-FMOC-Ne-CBZ-lysyl)guanosine

A solution of 1.5 g (Na-FMOC-Ne-CBZ-lysyl)-2',3'-O-isopropylideneuridine in 18 ml of 50% aqueous solution of HCO2H is left for 20 hours at room temperature. The solution is evaporated asina

Solution (Na-FMOC-Ne-CBZ-lysyl)guanosine (1.0 g) in 150 ml of dimethylformamide hydronaut for 3.5 hours at 48 psi in the presence of 0.7 g of 10% Pd/C. the Mixture is filtered and the filtrate is evaporated, and then treated with 30 ml of EtOH, and then 20 ml of H2O. the Obtained solid substance will recrystallized from MeOH-EtOAc.

Example 20. Cooking lityhuania

In the mixed solution of 800 mg (Na-FMOC-lysyl)guanosine in anhydrous pyridine added piperidine (4 mol.EQ.). The mixture is stirred for 5 hours at 0oC, then evaporated to dryness. The residue is dissolved in dimethylformamide and purified by slowly adding a solution of dimethylformamide in bystrooborachivaemy solution of EtOH-Et20, receiving sediment.

Example 21. Preparation of Palmitoyl-2'-deoxyguanosine

In a flask of 250 ml is placed 2'-deoxyguanosine (5.0 g, 17.5 mmol), triethylamine (3,13 ml of 22.4 mmol) and N,N-dimethyl-4-aminopyridine (0,046 g and 0.37 mmol). N,N-dimethylformamide (130 ml) is added via cannula under stirring and purge the flask with argon. The suspension is cooled for 10 min in an ice bath with NaCl, then drop by drop add palmitoylated (6.3 ml, of 20.6 mmol). The mixture is stirred, while it slowly warmed up to 25oC. After 72 hours the mixture peredelyvayut artelino heated to 60oC. the Obtained white solid is separated by vacuum filtration, washed with water and dried.

Example 22. Preparation of 3'-O-Palmitoyl-2'-deoxyguanosine

For preparation of this compound using the method of preparation of Palmitoyl-2'-deoxyguanosine, substituting the appropriate quantity of 5'-O-dimethoxytrityl-deoxyguanosine 2'-deoxyguanosine and freeing it from the protection of hydroxyl and 5' group as follows: dimethoxytrityl group is removed by stirring in 80% aqueous acetic acid solution at 25oC for 1 hour, the crude product is separated by filtration, within 1 hour triturated in methanol, restore the product by filtration and dried.

Example 23. Preparation of 3,5'-O,O-dipalmitoyl-2'-deoxyguanosine

This connection get as a by-product 5'-O-Palmitoyl - 2'-deoxyguanosine, prepared as described above, and is separated as follows: the crude product is suspended in toluene with silicagel, toluene is evaporated, put the obtained solid substance into a column of silica gel, covered with a thin layer of aluminum oxide, elute column with chloroform-methanol and evaporated appropriate faction.

Example 25. Preparation of lauroyl-2'-deoxyguanosine

This compound is prepared as well as Palmitoyl-2'-deoxyguanosine, replacing the corresponding amount of palmitoylated octanolwater.

Example 26. Preparation of benzoyl-2'-deoxyguanosine

This compound is prepared as well as Palmitoyl-2'-deoxyguanosine, substituting the appropriate quantity of benzoyl chloride palmitoylated and replacing on the mixture 1:1 of ice water with saturated aqueous sodium bicarbonate in the process.

Example 27. Preparation of butyryl-2'-deoxyguanosine

This compound is prepared as well as Palmitoyl-2'-deoxyguanosine, substituting the appropriate number of butyrylcholine palmitoylated and separating the connection as follows: after 72 hours the solvent is evaporated, the resulting material fray in a mixture of 1:1 diethyl ether with ethyl acetate and restore the product by filtration.

Example 28. Preparation of Palmitoyl-8-bromo-2'-deoxyguanosine

This compound is prepared as well as Palmitoyl-2'-deoxyguanosine, replacing suitable-8-mercapto-2'-deoxyguanosine

This compound is prepared as well as Palmitoyl-2'-deoxyguanosine, substituting the appropriate number of 8-mercaptoquinoline 2'-deoxyguanosine.

Example 30. Cooking palmitoylcarnitine-2',3'-(acyclic) dialcohol

This compound is prepared as well as Palmitoyl-2'-deoxyguanosine, substituting the appropriate number of guanosin-2',3'-(acyclic) dialcohol 2'-deoxyguanosine.

The following examples illustrate the advantages of the compounds according to the invention in vivo.

Example 31. Guanosine and guanine improve the recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg parenteral) was administered 30 female Balb/C mice, weighing approximately 20 g each. After 24 hours and daily for 6 days, mice were performed intraperitoneal injection of 0.4 ml or physiologic saline (control specimens), or guanine (5 mcmole/mouse/day) or guanosine (5 mcmole/mouse/day). On the 7th day, all 10 mice each of the three groups took blood and then killed by displacement of the cervical vertebrae. The spleen was removed and weighed, had a complete blood count.

The introduction of the guanidine or guanosine led to significant increased the introduction of guanine or guanosine led to a significant increase in peripheral leukocytes and neutrophils (Fig. 2 and 3). Thus, the introduction of mice guanine or guanosine after damage resulting from the introduction of cyclophosphamide definitely accelerates regeneration of myelopoiesis.

Example 32. Influence allsamsung guanosine recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg parenteral) was administered to 70 female mice Balb/C mice, weighing approximately 20 g each. After 24 hours and daily for 6 days, mice were performed intraperitoneal injection or physiologic saline (control specimens). "Tween-80" (0,2%), guanosine (5 mcmole/mouse/day in 0.2% "tween-80"), or 2.5 mcmole mouse day in one of the following acylated derivatives of guanosine 0.2% "tween-80": triacetyluridine, octanolwater, lauroylsarcosine or palmitoylcarnitine. On the 7th day after injection of cyclophosphamide all 10 animals from each of the 7 groups were drawing blood, and then the mice were omertvlenie by displacement of the cervical vertebrae. The spleen was removed and weighed, performed a full analysis of the blood.

Observed no significant differences in the weight of spleens between groups, which was introduced physiologic solution, "tween-80" or reallyreally guanosin. However, the introduction of the mice of acetylcarnosine, octanophenone, lauroylsarcosine or pall instances (Fig. 4). The introduction of each and all of these compounds significantly increased the number of leukocytes in the blood. However, with increasing chain length acyl group had an increased effect on the number of cells (the comparison was carried out within the group of medicines tested during this experiment). In this experiment, the introduction of palmitoylcarnitine had the greatest impact on the total number of leukocytes (Fig. 5); a similar relationship between chain length acyl radical and change haematopoiesis was observed in relation to the total number of neutrophils (Fig.6).

Example 33. Palmitoylcarnitine enhances survival of irradiated mice

Thirty female Balb/C mice weighing 20 grams each were irradiated with gamma radiation using cobalt-60 at the dose rate of 7.3 rad/min total dose was either 700 or 725 or 750 rad. After 24 hours and daily for 6 days, mice were performed intraperitoneal injection or physiologic saline (control specimens), or 50 mg/kg of palmitoylcarnitine. The number of surviving animals in each group were fixed in 30 days.

As shown in Table 1, all irradiated mice that were injected physiologic solution, died within the 30-day observation period, even the mouse, the(Palmitoylcarnitine was introduced only to mice, received the 2 highest doses).

Thus, the introduction of the mice of palmitoylcarnitine after irradiation significantly increases survival.

Preliminary introduction of palmitoylcarnitine before irradiation was also improved survival.

Example 34. Palmitoylcarnitine increases the number of colony forming units in the bone marrow of mice recovering after injection of cyclophosphamide

Seventy-two female Balb/C mice, weighing approximately 20 g each, were administered cyclophosphamide (275 mg/kg) via intraperitoneal injection. After 24 hours, and daily thereafter, mice were performed intraperitoneal injection of 0.4 ml or physiologic saline (control specimens), or palmitoylcarnitine (2.5 mcmole/mouse/day in 0.2% "tween-80"). 3, 5, 7 and 10-th day after injection of cyclophosphamide for 6 animals from each umertvlâl by displacement of the cervical vertebrae, and was removed from each animal left femur in sterile conditions. Then the bone marrow cells were washed from the femoral bone using environment "McCoy' 5a Modified using the measuring needle N 23. Cells from femurs of the same group were merged together, which was slightly and made calculations using hemocytometer the weave stimulated by endotoxin. Then the suspensions were sown on plates with a density of 1,2105cells/ml, except in the cells group, 3-day, for which, due to the low number of cells, the density of planting was 1,0105. Cells of each group were sown five times. After 7 days in culture at 37oC in 5% CO and humidified air) together 50 or more cells ("colony") were calculated using preprofile magnifier with a 25-fold increase.

Each time the number of colonies in terms of one thigh in mice, which was introduced palmitoylcarnitine, was much higher than the number of colonies on the thigh of mice, which were injected physiologic solution (Fig. 7 and table 2). The greatest differences between groups were observed on the 5th day.

Example 35. The dependence of the efficiency of palmitoylcarnitine recovery of hematopoiesis after injection of cyclophosphamide from start time treatment

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered to 81 female Balb/C mice weighing approximately 20 g each. After 24 hours, started treatment. Mice were performed injections of 0.4 ml intraperitoneally or physiologic saline (control specimens), "tween-80" (0,2%), or palmitoylcarnitine (5 mcmole/mouse/day in 0.2% "tween-80"). Each group nacina 1-6-th days. The group is intended for the treatment of twin-80, had injections in 1-4 days 4-6th or 1-6. Mice that are intended for the treatment palmitoylcarnitine, spent injection in 1-2nd days, 1-4, 3-5, 4-6 th or 1-6 th days. If the group of mice for the treatment of twin-80" or palmitoylcarnitine, in this day did not carry out the administration of these drugs, they did intraperitoneal injection of physiologic saline. Thus, there were 9 groups of 9 animals in each group. On the 7th day of the introduction of cyclophosphamide all animals were drawing blood and then umertvlâl them by displacement of the cervical vertebrae. The spleen was removed and weighed, performed a full analysis of the blood.

The weight of the spleens was higher compared with the control specimens in all groups treated with the exception of mice, which were injected twin-80" on 1-4 days (Fig. 8). The introduction of palmitoylcarnitine in any of the periods, including the 1st and 2nd days resulted in a significant increase in the weights of the spleens compared with the control specimens (Fig. 8). In addition, treatment with palmitoylcarnitine (in any of the specified periods) increased mass spleens of mice compared with mice that were treated only "tween-80". Treatment palmitoylcarnitine prohibited increase in the number of cells in each group of mice, which was introduced palmitoylcarnitine, compared with the control specimens (Fig. 9). Moreover, the marked increase in the number of cells in all mice, which was introduced palmitoylcarnitine (with the exception of the group, which was administered only during the 4th-6th days), compared with the number of leukocytes in mice which were injected twin-80" in any of these periods. The best scores were in mice, which was introduced palmitoylcarnitine within 1-6-th days. The number of cells in this group was also significantly higher than in all other groups of mice, which was introduced palmitoylcarnitine. The results and data on the number of neutrophils (Fig. 10): the introduction of palmitoylcarnitine for 1-6 th days gave maximum increase in the number of neutrophils. Treatment palmitoylcarnitine only for 1 or 2 days caused a significant increase in the total number of neutrophils compared with the control specimens and mice, which were injected twin-80".

The treatment of "tween-80" does not have any impact on the number of lymphocytes or in one of the specified periods of time. Only treatment palmitoylcarnitine within 1-2 and 1-6 days (in the latter case was again observed maximum values) led to uvelichenie injection of 5-fluorouracil

5-fluorouracil (5-Fu) (150 mg/kg, intraperitoneally) was administered 40 female Balb/C mice weighing approximately 20 g each. After 24 hours and daily for 8 days, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control sample) or 5'-O-palmitoylcarnitine (2.5 mcmole/mouse/day in 0.2% "tween-80"). On 6-th and 14-th day after injection of 5-fluorouracil half of the animals from each group were drawing blood, and then the mice were omertvlenie by displacement of the cervical vertebrae. The spleen was removed and weighed, had a complete blood count.

On day 7 it was observed a small but statistically significant increase in the weights of the spleens in the group, which was introduced palmitoylcarnitine (Fig. 12). Other differences between the control and test instances on day 7 was not observed. However, on day 14, it was noted that the blood of those animals, which were introduced palmitoylcarnitine, contained a significantly large number of leukocytes, lymphocytes, neutrophils and platelets, and in addition the weight of the spleens of these animals was significantly longer (Fig. 13-15).

Example 37. Palmitoylcarnitine improves recovery of hematopoiesis after administration of 5-fluorouracil

5-fluorouracil (5-Fu) (150 mg/kg, intraperitoneally) was administered 45 female mice Balb/Drybrushing or physical solution (test instances), or palmitoylcarnitine (2.5 mcmole/mouse/day in 0.2% "tween-80"). On the 8th, 10th and 12th days after administration of 5-fluorouracil nine animals from each group were drawing blood, and then they were omertvlenie by displacement of the cervical vertebrae. The spleen was removed and weighed, performed a full analysis of the blood.

On the 8th day, the number of platelets in the blood of mice that were treated with palmitoylcarnitine, was significantly higher than the number of platelets in the control group (Fig. 16). No other statistically significant differences between groups on day 8 was not observed. On the 10th day in addition to an increased number of platelets in the group exposed to the treatment, there was also a significant increase in the weights of the spleens compared with the control group, which was introduced physiologic solution (Fig. 17). On the 12th day of the weight of the spleens of mice receiving a course of treatment, twice the weight of spleens from mice of the control group, and the number of neutrophils in the blood of mice treated three times exceeded the number of neutrophils in the blood of the control group mice (Fig. 17 and 18). In Fig. 19 presents data on the number of leukocytes.

Example 39. Palmitoylation and palmitoylcarnitine increase hemo is siteline 20 g each did 4 or 9 intraperitoneal injections (one injection per day) 0.4 ml or "tween-80" (0,2%) (reference copies) or palmitoylcarnitine (2.5 mcmole/mouse/day) or palmitoylcarnitine (2.5 mcmole/mouse/day). 24 hours after the 4th or 9th injections of 5 or 6 animals from each of the three groups were drawing blood and umertvlâl mice by displacement of the vertebrae. The spleen was removed and weighed, performed a full analysis of the blood.

On the 5th day mass spleens were significantly higher in mice that were administered palmitoylcarnitine and palmitoylation, compared with mice that were injected physiologic solution (Fig. 20). On the 10th day of the weight of the spleens, the percentage of total leukocytes and neutrophils were significantly higher in mice that were administered palmitoylation than the control group mice, which were injected twin-80" (Fig. 20-22). In mice which were introduced palmitoylcarnitine, there was also a significant increase in the number of cells in comparison with control group mice.

Example 39. The influence of different doses of octanolwater to restore hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered 45 female Balb/C mice weighing approximately 20 g each. After 24 hours and daily thereafter for 6 days, mice were injected (intraperitoneally) at 0.4 ml or piscola/mouse/day in 0.5% "tween-80". On the 7th day after injection of cyclophosphamide all 9 animals from each of the 5 groups had taken blood and killed the animals by displacement of the vertebrae. The spleen was removed and weighed, had a complete blood count.

Treatment of mice subjected to injections of cyclophosphamide, using the "tween-80" led to some increase in mass spleens on average, but the treatment octanolwater in each of these three doses resulted in a significant increase in the weights of the spleens compared with the control instances, and to a substantial increase in mass spleens compared with mice that were injected twin-80" (Fig. 23). In mice which were treated with the highest dose of octanophenone (10 mcmole), mass spleens were highest (data not shown in the diagram). Even more important is the fact that the total number of cells and the total number of neutrophils was significantly higher than in the control specimens, the increase of these parameters depended on the dose increases (Fig. 24 and 25). However, the average dose (2.5 mcmole) showed almost the same efficiency in speeding up recovery of hemopoiesis, and that the highest dose.

Example 40. Histological examination of spleens of mice that were treated octanoique Balb/C, weighing approximately 20 g each. After 24 hours and daily for 6 consecutive days, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control specimens), or "tween-80" (0,5%), or octanophenone (5.0 mcmole/mouse/day in 0.5% "tween-80"). On the 7th day after injection of cyclophosphamide all 10 mice from each group were drawing blood, and then umertvlâl animals by displacement of the cervical vertebrae. Spleens were removed, weighed and placed in 10% formalin for subsequent histological examination. Drawn blood did the clinical analysis of blood.

Treatment of mice "tween-80" led to a slight increase of the mass spleens compared with the control specimens, which were introduced physiologic solution. But the treatment catorgories gave a significant increase in the weights of the spleens compared with the control specimens, which were introduced physiologic solution, and compared with mice that were treated "tween-80" (Fig. 26). Histological examination of spleens showed that in all groups treated, tissue histology was normal, and that in the spleens of mice that were treated with catorgories, lymphopoiesis and Mylopotas was higher (i.e. there was an increase of the white pulp of the spleen and cu is Yu with mice, treated "tween-80" (Fig. 27). These observations indicate that treatment with octanolwater mice, which were administered cyclophosphamide, accelerates as mvelopes and lymphopoiesis, at least at the level of the spleen.

Treatment of mice with octanolwater has also led to an unambiguous increase in the number of peripheral white blood cells and neutrophils compared with the control specimens and mice, which were treated "tween-80" (Fig. 28 and 29).

Example 41. Benzylguanine improves recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered 48 female mice Balb/C mice, weighing approximately 20 g each. After 24 hours, and over the next 6 days, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control specimens), or benzylguanine (2.5 mcmole/mouse/day in 0.2% "tween-80"), or palmitoylcarnitine (2.5 mcmole/mouse/day in 0.2% "tween-80"). On the 7th and 10th days after injection of cyclophosphamide 8 animals from each of the three groups was drawing blood, and then umertvlâl mice by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

On day 7 the total number of leukocytes, neutrophils and weight of the spleens of both benzylguanine, and palmitoylcarnitine (Fig. 30-32, respectively). Between groups no statistically significant differences were not observed. On the 10th day, the number of platelets in both groups of mice treated with acidified by guanosine, was significantly higher than in the control group (Fig. 33).

Example 42. Palmitoylcarnitine and palmitoylation improve the recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered 36 female mice Balb/C mice, weighing approximately 20 g each. After 24 hours and daily for the next 4 or 6 days, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control specimens), or palmitoylcarnitine (2.5 mcmole/mouse), or palmitoylcarnitine (2.5 mcmole/mouse). On 5-th and 7-th day after injection of cyclophosphamide 6 of 12 animals each of the three groups was drawing blood, and then umertvlâl mice by displacement of the cervical vertebrae. The spleen was removed and weighed, clinical analysis of blood.

On the 5th day of the weight of the spleens, the total number of leukocytes and neutrophils were significantly higher in the group that was treated with palmitoylethanolamide compared with the control specimens (Fig. is she was significantly higher than the mice that were treated with palmitoylcarnitine.

On the 7th day after injection of cyclophosphamide weight of the spleens, the total number of leukocytes and neutrophils was significantly higher in both groups of mice that were treated with palmitoylation and palmitoylcarnitine, compared with the control group (Fig. 34, 35 and 36).

Example 43. Palmitoylation improves recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered 48 female mice Balb/C mice, weighing approximately 20 g each. After 24 hours, and over the next 6 days, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control specimens), or octanophenone (2.5 mcmole/mouse), or lauroylsarcosine (2.5 mcmole/mouse), or palmitoylcarnitine (2.5 mcmole/mouse), or palmitoylation (2,5 mcmole/mouse), or palmitoylcarnitine (2.5 mcmole/mouse). On the 7th day after injection of cyclophosphamide 8 mice from each of the six groups was drawing blood, and then umertvlâl animals by displacement of the cervical vertebrae. The spleen was removed and weighed, clinical analysis of blood.

The weight of the spleens, the total number of leukocytes and neutrophil count were significantly higher in each G time no statistically significant differences between these five groups were observed.

Example 44. Acyl derivatives related compounds oxypurine nucleosides improve the recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered to 96 female Balb/C mice, weighing approximately 20 g each. After 24 hours, and daily thereafter, mice were injected with 0.4 ml intraperitoneally or "tween-80" (0,2%) (test instances), or palmitoylethanolamide (2 mcmole/mouse), or palmitoylcarnitine (2 mcmole/mouse), or palmitoylation (2 mcmole/mouse), or palmitoylethanolamide (2 mcmole/mouse), or polymethylphenylsiloxane (2 mcmole/mouse), or monopalmitate 2', 3'-(acyclic)dialcohol (2 mcmole/mouse), or Palmitoyl-8-thioguanosine (2 mcmole/mouse). On 5-th and 7-th day after injection of cyclophosphamide 6 animals from each of the 8 groups were drawing blood, and then umertvlâl mice by displacement of the cervical vertebrae. The spleen was removed and weighed, clinical analysis of blood.

The total number of neutrophils was significantly higher compared with the control group at the 5 th and 7 th days in all groups of mice treated with (Fig. 40*).

*On all three charts, illustrious AHx = polymethylphenylsiloxane

8TG = Palmitoyl-8-thioguanosine

PdG = palmitoylethanolamide

AG = palmitoyltransferase

dI = palmitoylation

ACC = monopalmitate 2',3'-(acyclic) dialcohol

The number of leukocytes was significantly higher compared with the control group in all groups, except one (1-O-palmitoylation) on the 5th day and all 8 groups, treated on day 7 (Fig. 41).

On the 5th day, the weight of the spleens was significantly higher compared with the control group in the following groups:

- monopalmitate 2',3'-(acyclic)dialcohol,

- palmitoylation, palmitoylcarnitine.

The weight of the spleens was significantly increased on day 7 in all groups treated with the exception of those groups, which were treated with palmitoylethanolamide and polymethylhydrosiloxane (Fig. 42).

Example 45. Acyl derivatives of deoxyguanosine improve the recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered to 88 female Balb/C mice, weighing approximately 20 g each. After 24 hours, and daily thereafter, mice were injected with 0.4 ml intraperitoneally, or "tween-80" (0,2%) (is ámol/mouse), or Palmitoyl-N-isobutylmethylxanthine (2 ámol/mouse), or laurelbethany (2 ámol/mouse), or octanoylthiophene (2 ámol/mouse), or palmitoylethanolamide (2 ámol/mouse). On 5-th and 7-th day after injection of cyclophosphamide 6 or 7 animals from each of the 7 groups were allowed to enter the blood and

then the mice were omertvlenie by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

On the 5th day mass spleens and total number of neutrophils were significantly higher compared with the control instances, the group introduced the following connections: 3'-O-palmitoylethanolamide, Palmitoyl-N-isobutylmethylxanthine and palmitoylethanolamide (Fig. 43 and 44). 7-day weight of spleens and total number of neutrophils were significantly higher compared with the control specimens) in all groups treated.

The number of leukocytes was significantly higher at the 5-day group, which used palmitoylethanolamide. On day 7 the number of leukocytes was significantly higher compared with the control specimens in all groups exposed to treatment. (Fig. 45).

Example 46. The influence of different doses of palmitoylethanolamide n is introduced 85 female mice Balb/C, weighing approximately 20 g each. After 24 hours, and daily thereafter, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control specimens), or palmitoylethanolamide in one of four doses of 0.2, and 0.4, 1.0, or 2.0 mcmole/mouse. On 5-th and 7-th day after injection of cyclophosphamide 9 and 8 animals, respectively, from each of the 5 groups were drawing blood, and then umertvlâl mice by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

The weight of the spleens, the number of cells and the total number of necrofile significantly exceeded the indicators of the control group at the 5 th and 7 th days in all four groups, receiving treatment, except for the group that was administered the lowest dose (0,2) palmitoylcarnitine on the 5th day (Fig. 46, 47 and 48). Observed a clear dependence on the dose: the higher the dose, the greater weight of the spleens and the number of blood cells.

Example 47. Comparing the effectiveness of different doses of palmitoylethanolamide and palmitoylcarnitine to improve the recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered to 96 female Balb/C mice, weighing approximately 20 g each, after 24 hours and daily politologia in one to four doses of 0.2, of 0.4, 1.0, and 2.0 mcmole/mouse, or palmitoylethanolamide at a dose of 1.0 mcmole/mouse. On 5-th and 7-th day after injection of cyclophosphamide 8 animals from each of the 6 groups was drawing blood, and then umertvlâl mice by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

The weight of the spleens, the number of cells and the total number of neutrophils on day 5 were significantly higher compared with the control specimens) in mice that were administered the highest dose of palmitoylcarnitine (2.0 mcmole/mouse), and in mice, which was introduced palmitoylethanolamide (Fig. 49, 50 and 51). Palmitoylcarnitine at a dose of 1.0 mcmole/mouse also gave a significant increase in the total number of neutrophils on the 5th day. 7-day weight of spleens, the number of cells and the total number of neutrophils were significantly higher than those of control specimens in the groups of mice that were injected with palmitoylcarnitine at doses of 1.0 and 2.0 mcmole/mouse, and mice, which were introduced palmitoylethanolamide. There is a strong dependence on the dose: the dose of palmitoylcarnitine gives an increase in the mass of spleens and blood cells. Palmitoylethanolamide found most effective in improving these indicators than palmitoylethanolamide to improve the recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered to 112 female Balb/C mice, weighing approximately 20 g each.

After 24 hours, and daily thereafter, mice were injected with 0.4 ml intraperitoneally or physiologic saline (control group) or palmitoylethanolamide in one of six different doses: 0,04, 0,08, 0,2, 0,4, 0,6 or 0.8 mcmole/mouse. On 5-th and 7-th day after injection of cyclophosphamide 8 animals from each of the 7 groups were drawing blood, and then the mice were omertvlenie by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

On the 5th day mass spleens significantly more than the weight of the spleens of the control group in all groups of mice that were administered palmitoylethanolamide in doses of 0.2 mcmole/mouse and above, and on the 7th day this picture was observed in all groups of mice, except for the group that was administered palmitoylethanolamide dose of only 0.04 mcmole/mouse (Fig. 52).

On the 5th day, the number of leukocytes was significantly higher compared with the control group, all groups of mice that were administered palmitoylethanolamide in doses of 0.4 mcmole/mouse and above (Fig. 53). On the 7th day of statistically-significant differences were observed in the groups in which Ino was higher than in the control group, all mice which was introduced palmitoylethanolamide all 6 doses (Fig. 54).

Observed a clear dependence on the dose: the higher the dose, the greater the mass of the spleen and above the number of blood cells.

Example 49. Palmitoylethanolamide improves recovery in the number of neutrophils, platelets and lymphocytes in rats, which were injected cyclophosphamide

Cyclophosphamide (CP) (40 mg/kg, intraperitoneally) introduced 16 male F344 rats weighing approximately 200 g each. After 24 hours, and daily thereafter, rats were injected with 0.5 ml intraperitoneally or physiologic saline (control group) or palmitoylethanolamide at a dose of 10 mcmole/rat. On the 5th, 7th and 10th days after injection of cyclophosphamide in all 8 animals from each group took blood and did a CBC. On the 10th day, all rats killed, spleens were removed and weighed.

All the days of analyses number of cells and the total number of neutrophils in rats, which was introduced palmitoylethanolamide, significantly higher than the control group (Fig. 55 and 56). On the 10th day there was a considerable increase in the number of platelets and lymphocytes in rats, which was introduced palmitoylethanolamide (Fig. 57 and 58). MA

Results in rats confirm the above results of the tests on mice and suggest that the acylated derivatives of purine nucleosides effectively improve the recovery of hematopoiesis after disturbance caused by chemical drugs. An important result of this experiment is the existence of persistent elevated levels of leukocytes after stopping treatment palmitoylethanolamide.

Example 50. Acyl derivatives of compounds related oxipurinol the nucleosides, enhance hematopoiesis in normal mice

Normal female Balb/C mice weighing approximately 20 g each were daily injected at 0.4 ml intraperitoneally or physiologic solution (control group) or palmitoylcarnitine (2.6 mcmole/mouse), or palmitoylethanolamide (2.6 mcmole/mouse), or monopalmitate 2',3'-(acyclic)dialcohol (2.6 mcmole/mouse) or Palmitoyl-8-bromoguanosine (2.6 mcmole/mouse) for 4 days. On the 5th day all 3 animals from each of the 5 groups were drawing blood, and then umertvlâl them by displacement of the vertebrae. The spleen was removed and weighed, clinical blood analysis. Each mouse took bone marrow from the femur and bone marrow smears provide - 61) used the following abbreviations:

P8BG = Palmitoyl-8-bromoguanosine

PG-CIl = monopalmitate 2',3'-(acyclic)dialcohol

PG = palmitoylcarnitine

PdG = palmitoylethanolamide

Mass spleens significantly more than the weight of the spleens of the control group of mice who were treated with the following compounds: palmitoylcarnitine 2',3'-(acyclic)dialcohols, palmitoylethanolamide and palmitoylcarnitine (Fig. 59).

The number of platelets was significantly higher in all groups treated, with the exception of the group, which was introduced palmitoylcarnitine 2',3'-(acyclic)dialcohol (Fig. 60).

The number of plasmic order has been revealed (obligatory precursors of neutrophils) was significantly higher than the control group of mice that were administered monopalmitate 2',3'-(acyclic)dialcohol, palmitoylethanolamide, Palmitoyl-8-bromoguanosine (Fig. 61).

These results suggest that the effectiveness of some of these compounds in a positive change of hemopoiesis in healthy animals. They are clear about the effectiveness of these compounds at the level of the bone marrow.

Example 51. Pre-treatment of mice with Palmasol approximately 20 g each were injected with 0.4 ml intraperitoneally or physical solution (control group) or palmitoylethanolamide (1 µmol/mouse) daily for three days. On the fourth day all 28 animals were injected with 5-fluorouracil (5-FU) (150 mg/kg, intraperitoneally). On the 5th, 8th and 11th days after administration of 5-fluorouracil 4 (5-day) or 5 (on the 8th and 11th days) the animals from both groups were drawing blood, and then umertvlâl them by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

On day 5 there was a significant increase in the number of platelets in the group who received treatment compared with the control group. On the 8th day mass spleens, the number of platelets and the total number of neutrophils in mice held a preliminary treatment palmitoylethanolamide, significantly higher than in the control group. On the 11th day of the animals, held preliminary treatment palmitoylethanolamide, mass spleens, the number of leukocytes, platelets, total number of neutrophils and the number of lymphocytes were significantly higher than these values in the control group (Fig. 62, 63, 64 and 65).

These results show that pre-treatment of animals with palmitoylethanolamide significantly softens the impact of 5-Faroese after injection of cyclophosphamide and increases the efficiency of octanolwater

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered 45 female Balb/C mice weighing approximately 20 g each. After 24 hours and daily thereafter for 6 days to mice, which were divided into seven groups were injected with 0.4 ml intraperitoneally or physiologic saline (control group) or "tween-80" in three concentrations of 0.02%, 0.2% and 1%), or octanophenone (50 mg/kg/dose) in three different concentrations of tween-80" (0,02%, 0.2% and 1%). On the 7th day after injection of cyclophosphamide all 9 animals from each of the 5 groups were drawing blood, and then umertvlâl their displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

Seven days after administration of cyclophosphamide, the number of neutrophils in all groups treated was higher than in the control group of mice that after injection of cyclophosphamide was injected with physiologic saline, and differed significantly (compared with the control group) in mice, which were treated only with 0.1% "tween-80", and in mice, which were treated with octanolwater 0.02% and 0.2% "tween-80" (Fig. 66). The number of neutrophils in animals that were administered 50 mg/kg of octanolwater 0.2%"tween-80", was significantly higher than in animals that were administered octanolwater in the same dose, but in 0.02% "tween-80"e enhanced recovery of the number of blood cells in mice which was administered cyclophosphamide.

Example 53. The Palmitoyl-8-aminoguanine improves recovery of hematopoiesis after injection of cyclophosphamide

Cyclophosphamide (CP) (275 mg/kg, intraperitoneally) was administered 28 Balb/C mice weighing approximately 20 g each. After 24 hours, and during the next 4 days the mice were injected with 0.4 ml intraperitoneally or physiologic saline (control group) or Palmitoyl-8-aminoguanine (25 mg/kg/day in 0.2% "tween-80"). On 5-th and 7-th day after injection of cyclophosphamide 7 animals from each group were drawing blood, and then they were omertvlenie by displacement of the vertebrae. The spleen was removed and weighed, clinical analysis of blood.

On the 5th and 7th days the number of neutrophils and the weight of the spleens from mice that were treated with Palmitoyl-8-aminoguanine, were significantly greater than in the control group (Fig. 67 - 68).

The above examples illustrate the present invention but do not limit its scope. In the framework of the present invention can be numerous variations and modifications without going beyond the basic provisions.

Characterising data for a number of compounds in the scope of the claimed invention:

1. 3',5'-O-dihexadecyl-N2-palmito ciganin, so pl. 40 - 41oC, more solid;

3. N2-Palmitoyl-3', 5'-O-Dilauroyl deoxyguanosine, so pl. 37 - 38oC, white viscous solid;

4. N2-Palmitoyl-3', 5'-O-diphenadione deoxyguanosine, so pl. 36 - 37oC, white solid;

5. N2,3'-O-dipalmitoyl-5'-O-tetradecanoylphorbol deoxyguanosine, so pl. 42 - 44oC, white scaly crystals;

6. N2-stearoyl-3', 5'-O-dipalmitoyl deoxyguanosine, so pl. 42 - 43oC, white powder;

7. N2, 3'-O-dipalmitoyl-5'-myristoyl deoxyguanosine, so pl. 35 - 37oC, white powder;

8. N2, 3', 5'-O-trimyristin deoxyguanosine, so pl. 74 - 75oC white crystalline solid;

9. N2, 3', 5'-O-creeptacular deoxyguanosine, so pl. 53oC white crystalline solid;

10. N2,3',4'-O-dipalmitoyl deoxyguanosine, so pl. 83 - 84oC; so pl. polymorphic form 48 - 51oC.

1. Acyl derivatives of guanosine formula

< / BR>
where RA, RB, RDhave identical or different meanings and represent hydrogen or acyl group derived dicarboxylic acids with 10 to 18 carbon atoms;

RCrepresents hydrogen or dicarboxylic acid 10 - 18 carbon atoms, or unsubstituted carboxylic acid with 7 carbon atoms;

Y represents H,

or pharmaceutically acceptable salts of these compounds.

2. Acyl derivatives of inosine formula

< / BR>
where RA, RB, RDhave identical or different meanings and represent hydrogen or acyl group derived fatty acids with unbranched chain with 3 to 22 carbon atoms;

Q = H

or their pharmaceutically acceptable salts.

3. Acyl derivatives xanthosine formula

< / BR>
where RA, RB, RDhave identical or different meanings and represent hydrogen or acyl group derived fatty acids with unbranched chain with 3 to 22 carbon atoms;

Q = H

or their pharmaceutically acceptable salts.

4. Acyl derivatives of deoxyinosine formula

< / BR>
where RAand RBhave identical or different meanings and represent hydrogen or acyl group derived from fatty acids with unbranched chain with 3 to 22 carbon atoms;

Q = H

or their pharmaceutically acceptable salts.

5. Acyl derivatives of deoxyguanosine formula

< / BR>

Y represents H,

or pharmaceutically acceptable salts of these compounds.

6. Acyl derivatives of inosine 2',3'-(acyclic)dialcohol formula

< / BR>
where RA, RB, RDhave identical or different meanings and represent hydrogen or acyl group derived from fatty acids with unbranched chain with 3 to 22 carbon atoms;

Q - H;

Z represents H, = O,

or their pharmaceutically acceptable salts.

7. Pharmaceutical composition for stimulating hematopoiesis, comprising the active agent and a carrier, wherein the active means it contains compounds on PP.1 and 2, or their pharmaceutically acceptable salts.

8. The pharmaceutical composition according to p. 7, characterized in that it further comprises a radioprotector.

9. The pharmaceutical composition according to p. 7, characterized in that it further contains a nonionic surfactant.

10. A method of treating cytopenia by introducing animal of the active substance, characterized in that the LM cytopenia is a consequence of ionizing radiation.

12. The method according to p. 10, wherein the cytopenia is a consequence of the introduction of pharmaceutical drugs that reduce the number of blood cells.

13. The method according to p. 10, wherein the cytopenia is a consequence of the introduction of anti-tumor agents.

14. The method according to p. 10, wherein the cytopenia is a consequence of the introduction of anti-virus agents.

15. The method according to p. 10, wherein the cytopenia is a consequence of AIDS.

16. The method according to p. 10, wherein the cytopenia is a consequence of cancer.

17. The method according to p. 10, wherein the cytopenia is a consequence of the destruction of bone marrow.

 

Same patents:

The invention relates to O6substituted derivatives of guanine, method of their production and to their use for the treatment of tumor cells

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d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition" target="_blank">

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula I:

< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>
or their salts

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula

(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts

The invention relates to a method for producing derivatives of S-adenosylmethionine (HIMSELF), General formula

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where R is benzene, p-toluensulfonyl or linear aliphatic acyl radical containing 2-6 carbon atoms; R1H or benzoyl or linear aliphatic acyl containing 2 to 6 carbon atoms; R and R1same or different when R1has a value other than hydrogen; n is 1-5; And is the equivalent of the acid with PKandless than 2.5

The invention relates to certain substituted purine to arabinoside and acceptable from the physiological standpoint derivatives, in particular esters and their use for the treatment of certain DNA-viral diseases

The invention relates to medicine, in particular to the production of medical biological preparations, and relates to oral formulations of recombinant human erythropoietin, which is used for the treatment of various forms of anemia

The invention relates to veterinary medicine, relates to a method of increasing the resistance of newborn calves and can be used to increase the integrity of the calves

The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to a method of obtaining pectic polysaccharides from vegetable raw materials

The invention relates to the field of experimental medicine and concerns the stimulation of immunological resistance in tuberculosis infection

The invention relates to medicine
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