UA78986C2 - Thioxanthine derivatives, process for their preparation (variants), their use and composition containing them - Google Patents

Abstract

There is disclosed the use of a compound of formula (Ia) or (Ib) wherein R1, R2, R3, R4, X and Y are as defined in the specification, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme myeloperoxidase (MPO) is beneficial. Certain novel compounds of formula (Ia) or (Ib) and pharmaceutically acceptable salts thereof are disclosed, together with processes for their preparation. The compounds of formulae (Ia) and (Ib) are MPO inhibitors and are thereby particularly useful in the treatment or prophylaxis of neuroinflammatory disorders. , (Ia) , (Ib)

Description

Description of the invention

The presented invention relates to the use of thioxanthin derivatives as inhibitors of the enzyme 2 myeloperoxidase (MPO). Some new thioxanthin derivatives are also disclosed, along with methods of their preparation, compositions containing them, and their use in therapy.

Myeloperoxidase (MPO) is a heme-containing enzyme found primarily in polymorphonuclear leukocytes (PMLs). MPO is one member of a diverse family of mammalian peroxidase proteins that also includes eosinophil peroxidase, thyroid peroxidase, salivary peroxidase, lactoperoxidase, 70 prostaglandin-N-synthase, and others. The developed enzyme is a dimer of identical halves. Each half of the molecule contains covalently bound heme, which exhibits unusual spectral properties corresponding to the green color of MPO. Cleavage of the disulfide bond connecting the two halves of MPO yields a half-enzyme that exhibits spectral and catalytic properties indistinguishable from those of the whole enzyme. The enzyme uses hydrogen peroxide to oxidize chloride to hypochlorous acid. Other halides and 72 pseudohalides (of the thiocyanate type) are also physiological substrates of MPO.

RMMs are particularly important for fighting infections. These cells contain MPO with a well-proven microbicidal effect. PMMs act nonspecifically by phagocytosis to engulf microorganisms, introducing them into vacuoles called phagosomes, which fuse with myeloperoxidase-containing granules to form phagolysosomes.

In phagolysosomes, the enzymatic activity of myeloperoxidase leads to the formation of hypochlorous acid, 20 a powerful bactericidal compound. Hypochlorous acid is an oxidizing agent by itself and reacts vigorously with thiols and thioethers, but it also converts amines to chloramines and chlorinates aromatic amino acids. Macrophages are large phagocytic cells, such as PMM, capable of phagocytosis of microorganisms. Macrophages can produce hydrogen peroxide and, upon activation, also produce myeloperoxidase. MPO and hydrogen peroxide can also be released outside the cells, where reaction with chloride can induce damage to nearby tissues. p 25 The relationship of myeloperoxidase activity to disease is involved in neurological diseases with a neuroinflammatory Ge) reaction, involving multiple sclerosis, Alzheimer's disease, Parkinson's disease and stroke, as well as other inflammatory diseases or conditions such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, atherosclerosis , inflammatory bowel disease, renal glomerular damage and rheumatoid arthritis. Lung cancer is also associated with high levels of MRO. ее, 30 ИМО 01/85146) discloses various compounds that are MPO inhibitors and are therefore useful in the treatment of chronic obstructive pulmonary disease (COPD). C-n-propyl-2-thioxanthin is disclosed in |Ogyd YuemeiIortepi Kezeagsi, 1999, 47, 45-53). 3-Isobutyl-b-thioxanthin was disclosed in U. Spet. Zos, 1962, 1863). 2-Thioxanthin is commercially available. at

The presented invention relates to groups of thioxanthin derivatives that unexpectedly show useful properties as inhibitors of the MPO enzyme. 3o According to the presented invention, it is proposed to use compounds of formulas (Ia) or (IB) in vy i М ' m « a chok; with s ho In me? What? 45 (iv) or (B) 7 where:

Ge | one of X and Y represents 5 and the other represents O or 5; with in! represents hydrogen or C. alkyl; 50 2 represents hydrogen or C. alkyl; the indicated alkyl, as an option, is substituted by: (ee) i) a saturated or partially unsaturated 3-7--ene ring, as an option, with one or two introduced

Ф heteroatoms independently selected from O, M and 5 and, as an option, with an introduced carbonyl group; said ring is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C-alkyloxy, and

S. valkil; the specified alkyl, as an option, is additionally substituted with hydroxy or C. alkyloxy; or her) Si. valcox; or iii) an aromatic ring selected from phenyl, furyl or thienyl; the specified aromatic ring, as a variant, except for (F) is replaced by a substituent from the group: halogen, C. valkyl or C. valkoxy; ka VZ and 27 independently represent hydrogen or C. alkyl; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of diseases 60 or conditions in which inhibition of the MPO enzyme is beneficial.

Compounds of formula (Ia) or (IB) can exist in the forms of enantiomers. Therefore, all enantiomers, diastereomers, racemates and their mixtures are included in the scope of the invention.

It should be understood that when EZ in the formulas (Ia) and (IB) represents hydrogen, the two alternative forms (Ia) and (IB) are tautomers of the same compound. All such tautomers and mixtures of tautomers are included within the scope of the present invention.

A special aspect of the invention relates to the use of a compound of formula (Ia) or (IB) or its pharmaceutically acceptable salt in the production of a medication for the treatment or prevention of neuroinflammatory disorders.

The invention also provides a method of treating or reducing the risk of diseases or conditions in which inhibition of the MPO enzyme is useful, the method involves administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of formula (Ia) or (Ir), or its pharmaceutically acceptable salt.

More specifically, there is also proposed a method of treating or reducing the risk of neuroinflammatory disorders in a person suffering from, or at risk of, the specified disease or condition, the method involves administering to the person a therapeutically effective amount of a compound of formula (Ia) or (IB), or a pharmaceutically acceptable salt thereof . 70 Another aspect of the invention relates to the formulation of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (Ia) or (IB), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in treatment or prophylaxis diseases or conditions in which inhibition of the MPO enzyme is beneficial.

Another special aspect of the invention relates to the formulation of a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (Ia) or (IB), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in treatment or prevention of neuroinflammatory disorders.

In one embodiment, it is proposed to use a compound of formula (Ia) or (IB), where at least one of X and Y represents 5, and the other represents O or 5; c' represents hydrogen or C. alkyl; 2 represents hydrogen 2o or C. valkyl; the specified alkyl is optionally substituted by a group: C3-7Cycloalkyl, C1-alkoxy, or an aromatic ring selected from phenyl, furyl or thienyl; the indicated aromatic ring, as an option, is additionally substituted with a substituent from the group: halogen, C. lalkil or Si. dalcox; KZ and KE" independently represent hydrogen or C 4 alkyl; or a pharmaceutically acceptable salt, enantiomer or racemate thereof in the manufacture of a medicament for the treatment or prevention of diseases or conditions in which inhibition of the MPO enzyme is useful. Ge!

In another embodiment, the use of a compound of formula (Ia) or (IB) is proposed, where at least one of X and Y is 5, and the other is O or 5; c represents hydrogen or C. alkyl; in? represents hydrogen or C alkyl; the specified alkyl is optionally substituted by: i) a saturated or partially unsaturated 3-7-ene ring, optionally with introduced one or two heteroatoms independently selected from O, M and 5 and, optionally, with an introduced carbonyl group ; the specified ring is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1 -alkyl, and C 1 -alkyl; the specified alkyl, as an option, is additionally substituted with hydroxy or C. . or iii) Si.lalkoxy; or iii) an aromatic ring selected from phenyl, furyl or thienyl; the indicated aromatic ring is, as an option, additionally substituted with a substituent from the group: halogen, C ylalkyl or F)

S. dalcox; BZ and E7 independently represent hydrogen or C. alkyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of diseases or conditions in which inhibition of the MPO enzyme 32 is useful. -

In one embodiment, the invention relates to the use of compounds of formulas (Ia) or (IB), where X represents 5 and Y represents 0.

In another embodiment, EZ in formula (Ia) or (IB) represents hydrogen. "

In another embodiment, in formula (Ia) or (IB) represents, as an option, substituted C..valkyl. with 70 In another embodiment of K? in formula (Ia) or (IB) represents C. alkyl, substituted with a saturated or partially unsaturated 3-7--ene ring, as a variant, with introduced one or two heteroatoms, selected :z" independently of O, M and 5 and, as an option, with an introduced carbonyl group; the specified ring is optionally substituted with one or more substituents selected from the group: halogen, hydroxy, C 1 -alkyl, and C 1 -alkyl; indicated alkyl, 45. As a variant, in addition, hydroxy or C. alkyloxy is substituted. -And in another incarnation of B? in formula (Ia) or (Iv) represents methylene, ethylene or trimethylene substituted by the group: cyclopropyl, cyclohexyl, tetrahydrofuranyl or morpholinyl. so In another embodiment of KE? in formula (Ia) or (Iv) represents C. alkyl substituted by the group: Si valkoxy. (Se) In another incarnation of KE? in formula (Ia) or (IB) represents ethylene or trimethylene substituted by the group: co 50 methoxy or ethoxy.

When X represents 5 and Y represents O, the next embodiment involves compounds of formula (Ia) or (IB) where B! 4) represents hydrogen.

When X represents 5 and Y represents O, a further embodiment involves compounds of formula (Ia) or (IV) where 7 represents hydrogen. 22 When X represents O and Y represents 5, the following embodiment involves compounds of formula (Ia) or (IV) where B" o represents C1 alkyl.

When X represents O and Y represents 5, a further embodiment involves compounds of formula (Ia) or (IV) where 7 represents C. dalkil.

In one embodiment, the invention relates to the use of compounds of formula (Ia) or (IB), where X represents 5 and Y 60 represents 0; in? represents, as a variant, substituted S..valkyl; and ET, Z and K7 each represent hydrogen.

In one embodiment, the invention relates to the use of compounds of formula (Ia) or (IB), where X represents 5 and Y represents 0; in? represents C..alkyl substituted with a saturated or partially unsaturated 3-7--ene ring, as an option, with the introduction of one or two heteroatoms independently selected from O, M and Z and, as an option, with the introduction of a carbonyl group; the specified ring, as an option, is replaced by one or more substituents selected from the group: halogen, hydroxy, C 1 -alkyl, and C -alkyl; the specified alkyl, as an option, is additionally substituted with hydroxy or C 1 -alkoxy; and B", BZ and 27 each represent hydrogen.

In one embodiment, the invention relates to the use of compounds of formula (Ia) or (IB), where X represents 5 and Y represents OO; Ck 2 represents C 4 valkyl, which is substituted by the group: C. valkoxy; 2", BZ and B each represent hydrogen.

A special aspect of the invention concerns the use of the following compounds of formula (Ia) or (IB): 1,3-diisobutyl-8-methyl-6b-thioxanthine; 1,3-dibutyl-8-methyl-b-thioxanthine; ,3-isobutyl-1,8-dimethyl-b-thioxanthine; 70 3-(2-methylbutyl)-6b-thioxanthine; 33-isobutyl-8-methyl-b-thioxanthine;

C-isobutyl-2-thioxanthine;

C-isobutyl-2,6-dithioxanthine; 33-isobutyl-8-methyl-2-thioxanthine;

3-isobutyl-7-methyl-2-thioxanthine;

C-cyclohexylmethyl-2-thioxanthine; 3-(3-methoxypropyl)-2-thioxanthine;

C-cyclopropylmethyl-2-thioxanthine;

C-isobutyl-1-methyl-2-thioxanthine; 3-(2-tetrahydrofuryl-methyl)-2-thioxanthine; 3-(2-methoxy-ethyl)-2-thioxanthine; 3-(3-(1-morpholinyl)propyl)-2-thioxanthine; 3-(2-furyl-methyl)-2-thioxanthine; 3-(4-methoxybenzyl)-2-thioxanthine; c 3-(4-fluorobenzyl)-2-thioxanthine; at

Z-phenethyl-2-thioxanthin;. (-3-3-(2-tetrahydrofuryl-methyl)-2-thioxanthin; (-)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthin;

3-n-butyl-2-thioxanthine; (se)

C-n-propyl-2-thioxanthin;

C-isobutyl-b-thioxanthin; 09 2-thioxanthin; Ge) and their pharmaceutically acceptable salts.

Unless otherwise indicated, the term "C. alkyl" means straight or branched chain alkyl having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, 1-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl and hexyl.

The term "S. valkil" should be understood similarly.

Unless otherwise indicated, the term "C 3 -cycloalkyl" means cyclic alkyl having from 3 to 7 carbon atoms. "

Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.

Unless otherwise specified, the term "C. alkyloxy" means a linear or branched chain alkyl group having from 1 to 2 carbon atoms. Examples of such groups include methoxy, ethoxy, 1-propoxy, 2-propoxy and α-tert-butoxy. "» The term "S. dalcox" should be understood similarly.

Unless otherwise indicated, the term "halogen" means fluorine, chlorine, bromine and iodine.

Examples of a saturated or partially unsaturated 3-7-ene ring, optionally with one or two heteroatoms independently selected from O, M and Z, and optionally with an introduced carbonyl group include cyclopropyl, cyclopentyl, cyclohexyl , cyclopentanone, tetrahydrofuran, pyrrolidine, piperidine, morpholine, piperazine, pyrrolidinone and piperidinone. Specific examples include cyclopropyl, cyclohexyl, (Ce)tetrahydrofuranyl (tetrahydrofuryl), and morpholinyl. because 50 Some compounds of formula (Ia) or (IB) are new. Therefore, the next aspect of the invention relates to such new compounds of formula (Ia) or (IB) 42; KE 1 ro 4 I U- 25 XX | d--in Zh ot yut o ke e

IB - because Me) or (i) where:

X represents 5 and XU represents 0;

He represents hydrogen or S. valkyl; 65 V? represents C 4 alkyl substituted by a saturated or partially unsaturated 3-7-membered ring, as an option, with the introduction of one or two heteroatoms independently selected from O, M and Z and, as an option, with the introduction of a carbonyl group; the specified ring is optionally substituted with one or more substituents selected from the group: halogen, hydroxy, C. valukoxy, and C. valkyl; the specified alkyl, as an option, is additionally substituted with hydroxy or C. alkyloxy;

BZ and E7 independently represent hydrogen or C. alkyl; and their pharmaceutically acceptable salts.

The next aspect of the invention relates to such new compounds of formula (Ia) or (IB) 1,3-diisobutyl-8-methyl-6b-thioxanthine; 1,3-dibutyl-8-methyl-b-thioxanthine; 70 33-isobutyl-1,8-dimethyl-b-thioxanthine; 3-(2-methylbutyl)-6b-thioxanthine; 33-isobutyl-8-methyl-b-thioxanthine;

C-isobutyl-2-thioxanthine;

C-isobutyl-2,6-dithioxanthine;

3-isobutyl-8-methyl-2-thioxanthine;

3-isobutyl-7-methyl-2-thioxanthine;

C-cyclohexylmethyl-2-thioxanthine; 3-(3-methoxypropyl)-2-thioxanthine;

C-cyclopropylmethyl-2-thioxanthine;

C-isobutyl-1-methyl-2-thioxanthine; 3-(2-tetrahydrofuryl-methyl)-2-thioxanthine; 3-(2-methoxy-ethyl)-2-thioxanthine; 3-(3-(1-morpholinyl)-propyl)-2-thioxanthine; 3-(2-furyl-methyl)-2-thioxanthine; Ha 3-(4-methoxybenzyl)-2-thioxanthine; 3-(4-fluorobenzyl)-2-thioxanthine; i9)

Z-phenethyl-2-thioxanthin; (-3-3-(2-tetrahydrofuryl-methyl)-2-thioxanthin; (-)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthin; (Te)

3-n-butyl-2-thioxanthine; and their pharmaceutically acceptable salts. co

The next aspect of the invention relates to the use of new compounds of formula (Ia) or (IB) as a medicament. Gee!

According to the invention, we also proposed a method of obtaining a new compound of the formula (Ia) or (IB), or their pharmaceutically acceptable salt, enantiomer, diastereomer or racemate, which involves: (a) the reaction of the compound of the formula (Ia) or (PIB) - 2: again in M « i-n | WITH-

Z A no, shi x D s This is where

K' ;» (c) (b» aro sh- where B", B, BZ and B" are defined in the formula (Ia) or (IB), X represents O or 5, and Y represents 0;

Go! with sulfurization of the compound, such as Lawson's reagent or phosphorus pentasulfide; obtaining the corresponding compound, where XU represents 5; or ik (5) the reaction of a diamine of the formula (Ша) or (ПИБ) at 50 and in! 1 and 1) rshe MN, rya or MN, re p t di"

F) and (tiv) n) in aba de B", B, VU, X and U defined in the formula (Ia) or (IB); with formic acid or with a trialkyl orthoester; and when necessary, the transformation of the formed compound of the formula (Ia) or (IB), or another salt thereof, into its pharmaceutically acceptable salt; or the conversion of the formed compound of the formula (Ia) or (IB) into the following compound of the formula (Ia) or (IB); and when necessary, the conversion of the formed compound of the formula ( Ia) or (IB) into its optical 65 isomer.

In step (a), a compound of formula (Pa) or (PIB) and a sulfurizing agent such as Lawson's reagent or phosphorus pentasulfide are dissolved or suspended in a suitable dry organic solvent such as benzene, toluene, xylene, tetrahydrofuran, dichloromethane or dioxane , and then heated to a temperature between 302C and the boiling point of the solvent under reflux until the end of the reaction, usually within 1-30 hours. The reaction mixture is then cooled and filtered to remove insoluble solids.

The solvent is removed under reduced pressure and the crude product is purified by column chromatography or recrystallization.

In step (B), the diamine of formula (Xa) or (PV) is treated at a suitable temperature and with an excess of a suitable orthoester such as triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthobutanoate, 7/0 tripropyl orthoformate, tributyl orthoformate and triisopropyl orthoformate, optionally in the presence of a suitable solvent, such as alcohol, until the reaction is complete. The temperature is usually brought to the boiling point of the reaction mixture under reflux and the reaction time is generally from 30 minutes to overnight.

In one embodiment, the orthoester is triethyl orthoformate with ethanol as an optional solvent.

Alternatively, in step (B), the diamine of formula (Xa) or (PIB) is treated with 9895 formic acid at 7/5 a suitable temperature between ambient temperature and the boiling point of the reaction mixture under reflux. The process is continued for a suitable period of time, usually within 0.5-5 hours. After removal of the formic acid, treatment with a suitable aqueous base, for example, 10956 aqueous sodium hydroxide, then gives the compound of formula (I). Treatment with the base is carried out for a suitable time at a suitable temperature, for example, for about 10 minutes - 4 hours at a temperature between ambient temperature and 2°C boiling point of the reaction mixture under reflux.

Other ways of converting a diamine of the formula (Xa) or (IB) into a compound of the formula (Ia) or (IV) are described in the literature and are well known to specialists.

The presented invention relates to the compound of formula (Ia) or (IV) in the form of salts, in particular acid-addition salts. Suitable salts include salts formed by both organic and inorganic acids. Such acid addition salts are usually pharmaceutically acceptable, although salts of pharmaceutically unacceptable acids can be used to obtain and purify these compounds. Therefore, the best salts involve salts formed by hydrochloric, hydrobromic, sulfate, phosphate, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulfonic, and benzenesulfonic acids.

Salts of compounds of formula (Ia) or (IB) can be formed by reacting the free base or its salt, the enantiomer He)zo or the racemate with one or more equivalents of the appropriate acid. The reaction can be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble, such as water, dioxane, co-ethanol, tetrahydrofuran, or diethyl ether, or in a mixture of solvents that can be removed in vacuo or by freeze-drying. . The reaction can also be exchange, or it can be carried out on an ion exchange resin.

Compounds of formula (Ia) or (IB) and compounds of formula (Xa) or (PIB) are known in the literature or can be prepared using known methods well known to those skilled in the art. uh-

Compounds of the invention and their intermediates can be isolated from their reaction mixture, and when necessary, they are additionally purified using standard methods.

Compounds of formula (Ia) or (IB) can exist in the forms of enantiomers. Therefore, all enantiomers, diastereomers, racemates and their mixtures are included in the scope of the invention. The distinct optical isomers can be isolated by separating a racemic mixture of compounds using conventional methods such as fractional crystallization or HPLC. Alternatively, distinct optical isomers can be obtained directly using optically active and starting materials. "" Intermediates can also be in enantiomeric forms and can be used as purified enantiomers, diastereomers, racemates or mixtures.

Compounds of formula (Ia) or (IB) and their pharmaceutically acceptable salts are useful because they exhibit pharmacological activity as inhibitors of the MPO enzyme.

Compounds of formulas (Ia) and (IB) and their pharmaceutically acceptable salts are indicated for use in the treatment or prevention of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is required.

Te) In particular, the connection of MRO activity with the disease is involved in neuroinflammatory diseases. Thus, compounds 5p of the present invention are particularly indicated for use in the treatment of neuroinflammatory conditions or disorders in mammals, involving humans. So conditions or disorders are well known to specialists.

F Conditions or disorders that may be specifically mentioned include multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, as well as other inflammatory diseases or conditions such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis , acute respiratory distress syndrome, sinusitis, rhinitis, psoriasis, dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory bowel disease, renal glomerular damage, liver fibrosis, sepsis, proctitis, rheumatoid arthritis and F) and inflammation associated with reperfusion injury, spinal cord injury spine and co damage/scarring/scar fusion/tissue rejection. Lung cancer has also been reported to be associated with high levels of MRO. The compounds are also expected to be useful in the treatment of pain. Prophylaxis is expected to be especially warranted for the treatment of individuals affected by the above factors, or at increased risk for a given disease or condition. Individuals at risk for developing a particular disease or condition generally include those with a family history of the disease or condition, or those who could be identified through genetic testing or screening as particularly susceptible to developing the disease or condition. 65 For the above therapeutic indications, the dosage used will of course depend on the compound used, the mode of administration and the desired treatment. However, in general, satisfactory results are obtained when the compounds are used at dosages of solid form of 1-200Omg per day.

Compounds of formulas (Ia) or (IB) and their pharmaceutically acceptable derivatives can be used by themselves or in the form of a suitable pharmaceutical composition in which the compound or derivative is admixed with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, another aspect of the invention relates to a pharmaceutical composition containing a novel compound of formula (Ia) or (IB), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be, but is not limited to, enteral (including oral, sublingual, or rectal), intranasal, inhalation, intravenous, topical, or other parenteral routes. The usual procedures for choosing and obtaining a suitable formulation of the 7/0 pharmaceutical composition are described, for example, in "Rpagtaseciisaiv - Tne Zsieepse oi ozade Rogt Oevzidpe", M.

E. Ashop, Spigepiyi I imipdziope, 1988). The pharmaceutical composition preferably comprises less than 8095 and more preferably less than 5095 of a compound of formulas (Ia) or (IB), or a pharmaceutically acceptable salt thereof.

A method of obtaining such a pharmaceutical composition, which involves mixing the ingredients, is also proposed.

The invention is illustrated, but not limited to, by the following examples:

The spectrum of "H" and "ZS" NMR is recorded on a spectrometer Vgykeg ORK at ZOOMHz or on a Magiap Opiu at 400MHz at 259. Reference signals are used: central line DMSO-4y 6 5 39.5 (3С); DMSO-yv 5 2.50 (Н) All mass spectra are recorded on a M/afegz !SM5 device (2790). Thin-layer chromatography (TLC) is carried out on Megosk TS 60 Rova aluminum sheets pre-coated with silica gel (layer thickness 0.2 mm). Silica gel MegskK 5iiisa de! 60 ( 0.063-0.200 mm) are used for column chromatography. HPLC analysis is carried out on

Supkoiek P58O HRO, dgadiepi ritr with detector Supkoiek MO 1705 OM-miv. Soitstp; U/a (eg zutteigu C18, 5μm,

Z, 9x15O0mm. Preparative liquid chromatography is carried out on a Supkoiek P58O HRO, dgadiepi riter with a detector

Supkoiek OMO 1705 OM-miv. Soitstp; U/a (egv zutteiigu C18, 5μm, 19x10 Ohm.

Source materials are obtained according to the links: p

Mepov, M.; Saute, |. Megisai, M. I!; Vagigoii, 9.; Sagsia-Kaiapeii, 9.; Bogp, 9. Eig. 9. Mea.Spet. at

Sleep Tnep; 25; 8; 1990; 653-658.

KieIPp.R. O5.; Regevop, S. A., ER 0010531. 1

Kaigi2Ku, A. K.; Ohemupiak, M., Thei. And hey. (1988), 29(15), 1755-1758.

Money map Sooi, N; Zsperegv, M. 9. R.; etegk, o. in.; Tittegptap, N., Ashg. 9). Honey. Spent (1992), 27(5), 511-517). ise)

Example 1 with 1,3-Diisobutyl-8-methyl-b-thioxanthine 1,3-Diisobutyl-8-methyl-xanthine" (0.20 g, 0.72 mmol) and Lawson's reagent (1.5 g, 3.5 mmol) are suspended in toluene (mL) and then heated at 10022 for 21 h. The reaction mixture was cooled and filtered to remove insoluble solids. The solvent was removed under reduced pressure and the crude product

Z is purified by column chromatography using silica gel and eluting with ethyl acetate/heptane (1:1) to give the title compound (9mg, 43,905 yield). "YAN NMR (DMSO-yv): 5 13.1 (in, 1H), 4.28 (a, 2H, 9-7.2Hz), 3.84 (4, 2H, 9-7.5Hz), 2 .40 (in, ZN), 2.28-2.35 (t, 1H), 2.17-2.25 (t, 1H), 0.85-0.88 (t, 12H). « 20 MS (ER) t/2 295 (M'-1).

Example 2 with 1,3-Dibutyl-8-methyl-6b-thioxanthine;" 1,3-Diisobutyl-8-methyl-xanthine" (0.20g, 0.72mmol) and Lawson's reagent (0.87g, 2.2mmol) are suspended in toluene (vml) and heated at 1202 for 30 hours. The resulting brown mixture cooled and the solvent evaporated under reduced pressure. The brown solid residue was suspended in 10905 sodium hydroxide (25 mL) -I and stirred overnight. The pH of the solution was then adjusted to pH 4 with 1095 acetic acid. The precipitate was collected by filtration and washed with water. The crude product was purified by column chromatography , using silica gel and elution with a mixture of ethyl acetate/heptane (9:1), obtaining the title compound (0.15 g, 6995 yield). ... , 1.28-1.35 (t, 4H), 0.88-0.93 (t, 6H). 13C NMR (DMSO-d5): δ 173.5, 154.2, 148.9, 143, 2, 118.9, 45.61, 43.13, 29.24, 28.37, 19.51, 19.31, 14.42, 13.60. m. MSs(ER)t/2295(M 1 ).

Example C 3-Isobutyl-1,8-dimethyl-b-thioxanthine 52 3-Isobutyl-1,8-dimethyl-xanthine" (0.150 g, b, 5 mmol, 1.0 equiv.) and Lawson's reagent (0.128 g, C3, 17 mmol,

HF) O, beq.) is dissolved in toluene (1 Oml) and the reaction mixture is heated to the boiling point under reflux for 3.5 hours. The conversion is less than 10905 by HPLC. Lawson's reagent (0.5 g) is added and the reaction mixture is heated to boiling temperature under reflux overnight. The solvent was evaporated and the brown solid residue was purified by preparative HPLC to give the title compound (78mg, 60 dor). "H NMR (DMSO-yb): δ 13.16 (in, 1H), 3.92 (d, 2H), 3.77 (in, ZN), 2.50 (in, ZN), 2.35 ( t, 1H), 0.97 (a, 6H).

Example 4 3-(2-Methylbutyl)-6-thioxanthine v5 3-(2-Methylbutyl)-xanthine2 (3g, 0.01mol) and phosphorus pentasulfide (5g, 0.025mol) in dioxane (250ml) are heated at boiling temperature under reflux refrigerator for 3 hours. Almost 150 ml of dioxane is distilled off and the solution is cooled. Water (100 ml) is added and the mixture is stirred at room temperature for 2 hours. 2N sodium hydroxide (75ml) is added, the solution is filtered and neutralized with 5N hydrochloric acid. The crude crystals were filtered off and recrystallized from ethanol to give the title compound (1.6 g,

C190).

TN NMR (DMSO-div): δ 13.53 (5, 1H), 12.32 (8, 1H), 8.11 (v, 1H), 3.85 (ad, 1H, 2) 13.1Hgu, 3) 1.1Hz), 3.78 (aa, 1H, 2) 131GHz, 3) 8.1Hz), 2.00 (t, 1H), 1.36 (t, 1H), 1.14 (t, 1H), 0.87 (i, ZN, in 7.6), 0.82 (4, ZN, in 6.6). 13C NMR (DMSO-d5): δ 175.11, 149.19, 145.73, 143.62, 118.32, 48.11, 32.93, 26.40, 16.57, 11.05.

Example 5 3-Isobutyl-8-methyl-b-thioxanthine. 3-Isobutyl-B-methyl-xanthine? (4.5g, 0.02mol) and phosphorus pentasulfide (8g, 0.04mol) in dioxane (400ml) are heated at reflux temperature for 5 hours. Almost 200 ml of dioxane is distilled off and the solution is cooled. Water (250 ml) is added and the mixture is stirred at room temperature for 2 hours. 2N sodium hydroxide (15 Oml) is added, the solution is filtered and neutralized with 5N hydrochloric acid and the solution is left overnight. The crude crystals were filtered off and washed with water, obtaining the desired product (4.3 g). A portion (2.3 g) is recrystallized from acetic acid, obtaining a pure product (1.5 3196 in total). "YAN NMR (DMSO-yv): 5 13.13 (in, 1H), 12.16 (in, 1H), 3.77 (9, 2H, 81Hz), 2.38 (in, ЗН), 2, 20 (t, 1H), 0.86 (9, ZN, 9-71). 13C NMR (DMSO-d5): δ 173.19, 154.23, 149.14, 146.11, 118.56, 49 ,29, 26.63, 19.73, 14.54.

Example 6 3-Isobutyl-2-thioxanthine a) 6-Amino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one c

Isobutylthiourea? (3.8g, 29mmol) and ethyl cyanoacetate (3.9g, 34mmol) were added to a solution of sodium ethoxide prepared from sodium (0.72g, 32mmol) and absolute ethanol (30ml). The resulting mixture is heated at about boiling temperature under reflux for 4 hours. After cooling to room temperature, the solvent is evaporated under reduced pressure. 1096 Acetic acid (45 ml) is added to the viscous syrup. The formed precipitate is collected by filtration and the solid product is washed with water. Recrystallization from (Ce) a methanol/water mixture gives the desired product (4.0 g, 70905). "IN NMR (DMSO-dyb): 5 11.8 (5, 1H), 6.99 (v, 2H), 4.85 (t, 2H), 4.61 (bg. 8, 1H), 2, 29 (t, 1H), 0.87 (a, 6H, U-6.6Hz). so

MS (ER) t/2 200 (M'n-1). (22) p) 6-Amino-1-isobutyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one so 6-Amino-1-isobutyl-2-thioxo-2,3 -dihydro-1H-pyrimidin-4-one (1.0g, 5.0mol) is suspended in 1095 acetic acid (20ml). Sodium nitrite (0.38g, 5.5mmol) was added and the resulting mixture was heated at 75°C for 1 hour. and -

The reaction mixture first turns pink and then purple. The purple mixture is cooled to room temperature. Water (20ml) was then added and the purple solid was collected by filtration and washed with water to give the title compound (1.1g, 9296 yield). This solid product is used at the next stage without further purification. 50 TN nMR (DMSO-y5) 5 13.1 (B. 8, 1H), 12.8 (r. 5, 1H), 9.1 (Bg. in, 9UN), 4.80 (r. 8, 1H), 3.78 (bBg. in, C with 1H), 2.21 (t, 1H), 0.88 (49, EN, U 6.3Hz). z» MS (ER) t/2 229 (M.-1). c) 5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one 6-Amino-1-isobutyl-5-nitroso-2-thioxo-2,3-dihydro -IN-pyrimidin-4-one. (1.1g, 4.bmmol) is suspended in 3295 aqueous ammonia (1Oml) and water (1Oml) is added. This red mixture is heated at 75920. Sodium dithionite is added. in small portions. When 1.8 g (TOmole) of dithionite is added, the color . solution changes from red to (ee) pale yellow. At the same time, all the solid product dissolves. After heating for another 5 minutes, a precipitate forms in solution c. The reaction mixture was removed from the oil bath and stirred at room temperature for 45 minutes. The pH of the solution is adjusted to neutral pH with 1095 acetic acid. The yellow precipitate was collected (ee) 50 by filtration and washed with water and dried to give the diamine (0.76 bg, 7790). This product is used without

F of further cleaning.

TN NMR (DMSO-yv): 5 11.3 (rg. 8, 1H), 6.19 (b, 2H), 4.94 (Bg. 8, 1H), 3.70 (B. 5, 1H ), 343 (v, 2H), 2.27-2.35 (t, 1H), 0.88 (a, EN, 76.1 Hz).

MS (ER) t/2 215 (M.-1). a) 3-Isobutyl-2-thioxanthin (F) 5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.22 g, 1.0 mmol) is suspended in formic acid (1.5 ml) and this solution is heated at 1002C for 1 hour. Excess formic acid is evaporated under reduced pressure. 1095 sodium hydroxide (1.5 ml) is added to the orange solid product and the resulting solution is heated at 10023 for 15 minutes. Water is added and the pH of the solution is adjusted to pH 4 with dilute acetic acid. The resulting suspension is stirred for 0.5 hours at room temperature, then the precipitate is collected by filtration and washed with water. Output: (0.21 g, 90 v). "YAN NMR (DMSO-yv): 5 13.82 (in, 1H), 12.42 (in, 1H), 8.15 (in, 1H), 4.31 (8, 2H, 9 7.6Hz) , 2.50 (t, 1H), 0.88 (a, EN, U 6.6Hz). 65 13C NMR (DMSO-d5): δ 173.81, 152.57, 149.79, 141.19, 110.68, 54.04, 26.11, 19.79.

MS (ER) t/2 225 (M.-1).

Example 7 3-Isobutyl-2,6-dithioxanthin 3-Isobutyl-2-thioxanthin (0.20g, 0.89U9mmol) and Lawson's reagent (1.1g, 2.7mmol) are suspended in toluene (vml). This mixture is heated at 1202 for 17 hours. The reaction mixture is cooled and the solvent is removed under reduced pressure, 1095 sodium hydroxide (20 ml) is added. and the mixture is stirred for 10 minutes. This solution is filtered to remove insoluble solids and the solid is washed with 1095 sodium hydroxide solution. The main filtrate is treated with diluted acetic acid to pH 4. The formed precipitate is collected by filtration and washed with water. The named compound is obtained by drying the substance (0.16 g, 7390). 70 "YAN NMR (DMSO-yv): 5 13.9 (rg. 8, 1H), 13.5 (Bg. 8, 1H), 8.27 (v, 1H), 4.32 (y, 2H, 7 7.5Hz), 2.48-2.55 (t, 1H), 0.89 (a, 6H, U 6.7Hz). 136 NMR (DMSO-d5): δ 173.3, 172.0, 144.9, 144.5, 122.8, 54.9, 26.3, 20.2.

MS (ER) t/2 241 (M.-1).

Example 8 3-Isobutyl-8-methyl-2-thioxanthine

A mixture of 5,6-diamino-1-isobutyl-2-thioxo-2,3-dihydro-AN-pyrimidin-4-one (Example 6 (c), 0.70 g, 3.2 mmol) and triethyl orthoacetate (1 Oml) is heated at 1302C for 2 hours and 40 minutes. Then the reaction mixture is cooled in an ice bath, the solid product is filtered off and washed with ethanol (4x2ml), the solid product is dried in a vacuum, obtaining the named compound (0.71g, 9596). "YAN NMR (DMSO-yv): 5 13.45 (v, 1H), 12.33 (v, 1H), 4.28 (9, 2H, 9-7.6Hz), 2.50 (t, 1H ), 2.39 (v, ZN), 0.87 (a, 6H, U 6.6Hz). 13C NMR (DMSO-d5): δ 173.47, 152.09, 151.18, 150.01, 110.62, 53.96, 26.08, 19.75, 14.41.

MS (ER) t/2 239 (M'n-1). high school

Example 9 3-Isobutyl-7-methyl-2-thioxanthine i) a). M-(6-Amino-1-isobutyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-formamide 5,6-Diamino-1-isobutyl-2-thioxo -2,3-dihydro-1H-pyrimidin-4-one (Example b (c), 0.25 g, 1.2 mmol) is dissolved in formic acid (1.5 ml) and stirred at room temperature for 0.5 hour. A pink precipitate begins to form after a few minutes. Water is added and the resulting mixture is stirred for 10 minutes.

The pink solid was collected by filtration, washed with water and dried to give the title compound CO (0.25g, 86 95). This material is used without further purification. NMR shows that the product is obtained as a mixture of two tautomers: formamide (major) and imino (secondary). "YAN NMR (DMSO-yv): 5 12.0 (Bg. 8, 1H), 8.73 (in, 1H), 8.07 (in, 1H), 6.85 (z, 2H), 4, 94 (rg. 8, 1H), 3.71 so (Bg. 8, 1H), 2.22-2.32 (t, 1H), 0.88 (a, 6H, 2 6.5Hz). Additional peaks originate from the imino isomer: 8.12 (y, 1H, h- 2711.5Gu), 7.77 (a, 1H, ,711.5Hz), 7.13 (c, 2H).

MS (ER) t/2 243 (M'-1). r) 6-Amino-1-isobutyl-5-methylamino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one "

H-(6-Amino-1-isobutyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-1H-pyrimidin-b-ol) (0.25 g, 1.0 mmol) is suspended in dry tetrahydrofuran for 70 (bml) and the borane-dimethylsulfide complex (1M in dichloromethane, 2.5ml, 2.5mMmol) are added dropwise. The reaction mixture is stirred at room temperature for 2.5 hours. A few drops of 2M hydrochloric acid are added to the resulting transparent yellow solution to remove unreacted "" borane. Water was added and the resulting aqueous solution was extracted with dichloromethane (3x15ml). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.12g, 54,905 yield). This material used without further purification. - "YAN NMR (DMSO-iv): 5 11.9 (Bg. 8, IN), 5.75 (in, 2H), 4.94 (Bg. in, 1H), 3.70 (Bg. 8, 1H), 3.43 (z, 2H), o 2.38 (c, ЗН), 2.24-2.32 (t, 1H), 0.87 (a, 6H, 76, 8 Hz).

MS (ER) t/2 229 (M.-1). and c) 3-Isobutyl-7-methyl-2-thioxanthine

Go! 20 6-Amino-1-isobutyl-5-methylamino-2-thioxo-2,3-dihydro-THN-pyrimidin-4-one. (0.11 g, 0.48 mmol) is dissolved in formic acid (Iml) and heated at 859 for 1 hour. Excess formic acid is evaporated under reduced pressure. 1095 Sodium hydroxide solution (2ml) is added and heated at 8523 for 20 minutes. Water is added and the pH is adjusted to 4 with dilute acetic acid, whereby a white solid precipitates.

The white solid was collected by filtration, washed with water and dried to give the title compound 255 (WBMg, 74 96).

HF) TN NMR (DMSO-iv): 5 12.4 (8, 1H), 8.10 (z, 1H), 4.28 (9, 2H, at 7.5 Hz), 3.89 (in, ZN ), 2.44-2.50 (t, 1H),

Ge 0.88 (4, EN, U 6.7 Hz). 13C NMR (DMSO-th): δ 174.3, 153.2, 150.1, 143.7, 111.2, 54.1, 33.6, 26.4, 201. in MS (ER) t/ 2,239 (M'n-1).

Example 10

3-Cyclohexylmethyl-2-thioxanthine; a) 6-Amino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method Kk! Example 6 (a) using 65 cyclohexylmethylthiourea" (3.92g, 22.7mmol) to give the title compound as a white solid (4.87g, 9096).

T NMR (DMSO-yv): 5 11.75 (in, MH), 6.93 (in, 2H), 5.1-4.7 (rt, 7H), 4.83 (in, 1H), 3 .55 (Bk. 1H), 1.93 (Bg, 1H), 1.75-1.30 (rgt, 5H), 1.10 (Bg, 5H).

B) 6-Amino-1-cyclohexylmethyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method from example 6 (c) from b-amino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (3.75 g, 15./mmol), obtaining C ,bOg (85965) of a purple solid product.

TN NMR: 5 13.5 (rg 5, 1H), 12.7 (rg 85, 1H), 9.1 (Bg 8, 1H), 4.84 (Bg 8, 1H), 3.82 (rg 8 , 1H), 1.80 (Bg, 1H), 1.64-1.59 (rgt, 5H), 1.07 (Brg, 5H). c) 5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound was obtained by the general method from example 6 (c) from b-amino-1-cyclohexylmethyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (3.6Og, 13.4mmol) and used without purification at the next stage. "IN NMR (DMSO-ad5): δ 6.17 (in, 2H), 5.01 (Bg, 1H), 4.0-3.0 (very broad, ЗН), 1.97 (bBg, 1H ), 1,8-1,3 (bgt, 5H) with 721.09 (bg t, 5H). a) 3-Cyclohexylmethyl-2-thioxanthine 5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2, 3-Dihydro-1H-pyrimidin-4-one, (1.44g, 5.67mmol) together with Kk!triethylorthoformate (15ml) was heated at 1462 for 2 hours and 10 minutes.The mixture was allowed to cool to ambient temperature and then cooled in an ice bath , and then heptane (5ml) was added. After filtering the suspension and washing with heptane (20ml), the resulting solid product was dried in vacuo. A suspension of the solid product (1.2g) in a hot mixture of 2-propanol (125ml), water (5ml) and tert -butyl methyl ether (25 mL) gave, after cooling and filtration, a white precipitate, which was washed with additional tert-butyl methyl ether (5 mL).The solid product was dried in vacuo to give the title compound (0.95 g, 6390).

TN NMR (DMSO-iv): δ 13.69 (z, 1H), 12.35 (v, 1H), 8.12 (v, 1H), 4.33 (0, 2H, 9-7.1 GHz) , 2.18 (t, 1H), s 1.49-1.50 (t, 5H), 1.02-1.17 (t, 5H). o 13C NMR (DMSO-iv): δ 173.65, 152.68, 149.90, 141.41, 110.96, 52.97, 35.31, 30.09, 25.88, 25.32.

MS (ER) t/2 265 (M'-1).

Example 11 Ge) 3-(3-Methoxypropyl)-2-thioxanthine a) 6-Amino-1-(3-methoxypropyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one so

Sodium methoxide (0.81 g, 21.2 mmol, 1.05 eq.) was added to a solution of 3-methoxypropylthiourea (3.00 g, F 20.2 mmol) in ethanol (1 mL). Ethyl cyanoacetate (2.18ml, 20.2mmol) in ethanol (10ml) was added and the resulting white slurry was heated to reflux for 2.5 hours. The solvent is evaporated and the remaining brown oil is treated with 2M acetic acid (15 ml). The white crystals were filtered off and washed with acetic acid to give the title compound (2.10 g, 48965). "IN NMR (DMSO-y): δ 1.77 (in, 1H), 6.95 (in, 2H), 4.86 (in, 1H), 3.39 (in, 2H), 3.24 (in, ЗН), 1.88 (t, 2Н).

B) 3-(3-Methoxypropyl)-2-thioxanthine "

Acetic acid (25 mL) was added to b-amino-1-(3-methoxypropyl)-2-thioxo-2,3-dihydro-TIN-pyrimidin-4-one (2.00 g, 9.29 mmol) and the red reaction mixture was heated to 902C. Sodium nitrite (0.71g, 10.2mmol) in water (7ml) was added, the oil bath was removed and the reaction mixture was stirred for 20 minutes. The solvents were co-evaporated with ethanol and the red solid residue (1.8 g, 7995) was used in the next step without further purification.

Platinum on charcoal (0.59) is added to a solution of crude b-amino-1-(3-methoxypropyl)-5-nitroso-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one (1.80g, 7.3 mmol) in tetrahydrofuran (8 ml) and water (20 ml) and the reaction mixture was hydrogenated at atmospheric pressure for 2 hours. o The catalyst is filtered off and the pale brown filtrate is co-evaporated with ethanol (250 ml). The resulting brown solid product (1.6 g) was used in the next step without further purification. se) 5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.6bg, 12.2mmol) is dissolved in so 50 ethanol (1Oml) and triethyl orthoformate (1Oml ) and the reaction mixture is heated at the boiling temperature under reflux for 2.5 hours. The solvents are evaporated and the resulting brown solid is purified 4; by flash chromatography (heptane/ethyl acetate, 4:1-1:1) to give the title compound (11mg, 9965).

TN NMR (DMSO-iv): 5 13.78 (in, 1H), 12.40 (in, 1H), 8.16 (in, 1H), 4.52 (5 2H, 9-7.1 GHz), 3.41 (i, 2H, 71), 3.21 (8, ЗН), 1.98 (t, 2H). 59 13C NMR (DMSO-d5): δ 173.27, 152.63, 149.30, 141.50, 110.94, 69.51, 57.82, 45.47, 26.68.

GF) Example 12 7 3-Cyclopropylmethyl-2-thioxanthines a) 6-Amino-1-cyclopropylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

To 1-cyclopropylmethyl-2-thiourea (0.60g, 4.b6mmol) in ethanol (10ml) was added sodium methoxide (0.26Hg, 604mmol) and after 5 minutes ethyl cyanoacetate (0.50ml, 4.bmmol). The resulting mixture was refluxed for 2 hours and 40 minutes, then the solvent was evaporated under reduced pressure and the resulting yellow solid was treated with 2M aqueous acetic acid (1 Oml) to give a white solid. The solid product was collected by filtration and washed with 2M aqueous acetic acid (1Oml), mixed with ethanol (1Oml), then evaporated and dried under reduced pressure to give the title compound (0.51g, 5690).

MS (ER) t/ 198 (M'n-1).

B) 3-Diclopropylmethyl-2-thioxanthine b-amino-1-cycloisopropylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.50 g, 2.5 mmol) is suspended in acetic acid (dml) and after heating at 90 °C for 15 minutes, sodium nitrite (0.19 g, 2.8 mmol) in water (ml) is added to the solution. After 15 minutes, the heating is stopped and the reaction mixture is stirred at ambient temperature for 3 hours. Ethanol (3 mL) was added and the solvents were removed under reduced pressure. The resulting oil was treated with ethanol (3 mL), obtaining, after evaporation and drying, b-amino-1-cyclopropylmethyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.61 g) as a red -brown 7/0 solid product.

The crude product (0.61g) from the previous reaction is dissolved in water (10ml) and tetrahydrofuran (30ml) and platinum on charcoal (0.30g) are added. The mixture is hydrogenated at atmospheric pressure for 4 hours, the catalyst is removed by filtration, and the solvents are removed under reduced pressure. Evaporation of the added ethanol (50 mL) gave an orange solid. The residue is dissolved in ethanol (1 ml) and triethyl orthoformate (5 ml) is added and the resulting mixture is heated at the boiling temperature under reflux overnight. Evaporation of the solvent and purification using preparative HPLC gave the desired compound (38 mg, 6.295 yield relative to b-amino-1-cyclopropylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one). "YAN NMR (DMSO-yv): 5 13.78 (in, 1H), 12.43 (in, 1H), 8.15 (z, 1H), 4.37 (a, 2H, 9-7.1Hz ), 1.50 (t, 1H), 0.52 (t, 2H), 0.45 (t, 2H). 13C NMR (DMSO-y): δ 173.52, 152.62, 149.52, 141, 48, 111.02, 51.71, 9.27, 3.50.

MS (ER) t/2 223 (M.-1).

Example 13 3-Isobutyl-1-methyl-2-thioxanthine, a) 1-Isobutyl-3-methylthiourea c

Methylamine (2M in methanol, 20.00ml, 40.2mmol) was added dropwise to isobutylisothiocyanate (2.00ml, 16.5mmol) over 15 minutes at room temperature. The reaction mixture was heated to reflux for 3.5 hours and the solvent was evaporated to give the title compound (2.37g, 9890) as a colorless oil. "IN NMR (DMSO-dy5): δ 7.40 (in, 1H), 7.29 (in, 1H), 3.15 (rg. 8, 2H), 2.80 (4, 2H), 1, 81 (t, 1H), 0.83 (a, 6H). o p) 6-Amino-1-isobutyl-3-methyl-5-nitroso-2-thioxo-1H-pyrimidin-4-one o

A solution of cyanoacetic acid (1.52g, 17.8mmol) in acetic anhydride (2.45ml, 25.9mmol) was added to 1-isobutyl-3-methylthiourea (2.37g, 16.2mmol). The reaction mixture is heated to 6°C for 1.5 hours. b

The solvent was evaporated and the red oil formed was redissolved in ethanol (bml) and 5M sodium (ee) hydroxide (1.bml, 8.1mmol) was added. The reaction mixture is heated at reflux for 2 hours, the solvent is coevaporated with ethanol, and the resulting pale brown solid is purified by flash chromatography (ethyl acetate) to give b-amino-1-isobutyl-3-methyl-2-thioxo- 1H-pyrimidin-4-one (1.0g, 2995) as a yellow solid.

Sodium nitrite (0.34g, 4.9mmol) in water (1.5bml) was added to a solution of amine (1.00g, 4.7mmol) in ethanol (7.0ml) at room temperature. 5M hydrochloric acid (1.0 mL, 4.9 mmol) was added and the resulting dark red reaction mixture was stirred at room temperature for 2 hours. Ethanol (20 mL) was added and the red crystals were filtered off and washed with diethyl ether. Drying of the crystals gives the compound named :z" (0.68g, 6096). "H NMR (DMSO-dyb): δ 12.87 (8, 1H), 9.35 (in, 1H), 4.28 (da, 2H), 3.75 (in, ЗН), 2.34 ( t, 1H), 0.90 (a, 6H). c) 3-Isobutyl-1-methyl-2-thioxanthine -I Palladium on charcoal (3.70 g) is added to a solution of b-amino-1-isobutyl-3- methyl-5-nitroso-2-thioxo-1H-pyrimidin-4-one / (6b,Og, 248mmol) in tetrahydrofuran (1200ml) and water (300ml) and the reaction mixture was hydrogenated (2.5bar) for 21 hours. The catalyst is filtered off and the tetrahydrofuran is evaporated under reduced pressure. The residue is extracted with ethyl acetate (3x200ml). 5r The organic phase is concentrated and ethanol (100ml) is added to the residue and evaporated. The brown diamine intermediate is dissolved in triethylorthoformate (50ml) and the reaction mixture is heated to

F 1402C for 40 minutes. The reaction mixture was concentrated and co-evaporation with ethanol gave a brown solid. The residue was purified by flash chromatography (heptane/ethyl acetate, 2:1-ethyl acetate) and then the solid product was washed with diethyl ether and hexane to give the title compound (16mg, 2.790). "IN NMR (DMSO-dyv): 5 13.86 (v, 1H), 8.21 (v, 1H), 4.34 (0, 2H, U 7.1Hz), 3.89 (v, ЗН) . .92, 52.83, 37.17, 25.77, 19.92. o Example 14: 3-(2-Tetrahydrofuryl-methyl)-2-thioxanthine 6o a) 6-Amino-1-(2-tetrahydrofuryl- methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one 2-Tetrahydrofuryl-methyl-thiourea (1.0 g, b.2 mmol) and ethyl cyanoacetate (0.85 g, 7.5 mmol) are added to the solution sodium ethoxide |freshly prepared from sodium (0.16g, b,Omole) and absolute ethanol (4ml)). The resulting mixture was heated at reflux for 3.5 hours. After cooling to room temperature, the solvent was evaporated under reduced under pressure and the resulting viscous syrup is redissolved in water (3 mL). This stock solution is neutralized with 2M hydrochloric acid. The precipitate formed is collected by filtration and the solid product is washed with water. The crude product (1.3 g, 90965) is used without further purification.

TN NMR (DMSO-iv): 5 11.9 (in, 1H), 6.79 (z, 2H), 4.91 (z, 1H), 4.62-4.65 (t, 1H), 4 ,21-4.31 (t, ЗН), 3.81-3.87 (t, 1Н), 3.63-3.68 (t, 1Н), 1.77-2.01 (t, ЗН) , 1.57-1.65 (t, 1H).

MS (ER) t/2 228 (M.-1).

B) 6-Amino-1-(2-tetrahydrofuryl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one 6-Amino-1-(2-tetrahydrofuryl-methyl- 2-thioxo-2,3-dihydro-IN-pyrimidin-4-one (1.3g, 5.bmmol) was suspended in 1095 aqueous acetic acid (25ml).Sodium nitrite (0.43g, b.2mmol) was added and the mixture heated at 75 °C for 1 70 h.The purple solid was collected by filtration, washed and dried to give the title product (1.3 g, 90905).

PN NMR: δ 13.3 (rg 5, 1H), 12.8 (rg 5, 1H), 8.93 (rg 5, 1H), 4.57 (rg 5, 1H), 4.45 (Bg 8 , 1H), 4.18-4.24 (t, 1H), 3.74-3.79 (t, 1H), 3.59-3.64 (t, 1H), 1.86-2.01 (t, 2H), 1.74-1.82 (t, 1H), 1.59-1.67 (t, 1H). c) 5,6-Diamino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one 6-Amino-1-(2-tetrahydrofuryl-methyl)-5 -nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.3g, 5.mmol) is dissolved in 3295 aqueous ammonia (15ml) and water (15ml) is added. The red solution is heated at 702C and sodium dithionite (2.2 g, 1 mmol) is added in small portions. Heating is continued for another 15 minutes, and then the yellow solution is stirred at room temperature for 1 hour. The solution is neutralized with 2M hydrochloric acid, the yellow precipitate is collected by filtration, washed with water and dried to give the title product (0.90g, 73905).

This material is used at the next stage without further purification. NMR (DMSO-yv): 5 5.96 (v, 2 H), 4.74 (rga, 1H), 4.35 (Bgv, 1H), 4.21-4.28 (t, 1H) , 3.84-3.89 (t, 1H), 3.64-3.69 (t, 1H), 3.49 (rg 8, 2H), 1.78-2.01 (t, 4H), 1.60-1.67 (1H).

MS (ER) t/2 243 (M'-1). part a) 3-(2-Tetrahydrofuryl-methyl)-2-thioxanthin cm 5,6-Diamino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one (0.25g, 1.0mmol) (o) is dissolved in formic acid (ml) and heated at 702C for 0.5 hour. After a few minutes, a pink solid product forms in the solution. The excess of formic acid is evaporated and the formed solid product is dissolved in 1095 sodium hydroxide solution (4 ml). This solution is heated at 709C for 40 minutes, then it is neutralized with 2M hydrochloric acid. The formed precipitate was collected by filtration, washed with water and dried, obtaining a pure product (0.23 g, 8790). so "YAN NMR (DMSO-yv): 5 13.8 (Bg5, 1H), 12.4 (riv, 1H), 8.16 (v, 1H), 4.53461 (t, 2H), 4.38 -4.44 (t, 1H), He»! 3.79-3.84 (t, 1H), 3.58-3.63 (t, 1H), 1.72-1.98 (t, 4H ).13C NMR (DMSO-d5): δ 173.65, 152.68, 149.90, 141.41, 110.96, 52.97, 35.31, 30.09, 25.88, 25.32 co

MS (ER) t/2 253 (M'-1). -

Example 15 3-(2-Methoxy-ethyl)-2-thioxanthine a) b-amino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one "

The title compound was prepared in the general manner of Example 14(a) but using (2-methoxy-ethyl)-thiourea (1.5g, 11mmol) to give the title compound as a white solid (2.1g, 93905). s "IN NMR (DMSO-y): 5 11.9 (in, 1H), 6.82 (in, 2H), 4.89 (in, 1H), 4.53 (Bg. 5, 2H), 3.62 (Her, 2H,.) 5.9Hz), 3.29 (in, ZN). "from MS (ER) t/2 202 (M'-1). " B) 6-Amino-1-(2-methoxy-ethyl)-5-nitroso-2-thioxo-2,3-dihydro-AN-pyrimidin-4-one 6-Amino-1-(2-methoxy-ethyl) )-2-thioxo-2,3-dihydro-THN-pyrimidin-4-one (1.0 g, 5.0 mmol) was suspended in 1095 acetic acid (20 mL). Sodium nitrite (0.38 g, 5.0 mmol) was added and the resulting mixture was heated at 759C for 1 hour. The reaction mixture first turned pink and then purple. Water (20 mL) was added and the reaction mixture was refrigerated overnight. The purple solid was collected by filtration and washed with water to give the title compound (0, 42g, 3790). The second batch of product (0.22g, 1995) is obtained by reducing the volume of the purple filtrate. The crude product is used in the next step without further purification. (ee) 20 TN NMR (DMSO-y5): 5 13.4 (riv, 71H), 12.8 (rg5, 1H), 9.06 (Bgv, 1H), 4.54 (riv, 2H), 3.60 (i, 2H, U

F 5.8 Hz), 3.24 (in, ZN). c) 5,6-Diamino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one

The named compound is obtained by the general method from example 14 (c), but using 5 b-amino-1-(2-methoxy-ethyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.42g, 1.v8mmol) to give the title compound as a yellow solid (0.28g, 68905). (F) "NMR (DMSO-yv): 5 11.9 (Bg 8, IN), 5.94 (b, 2 H), 4.58 (Bg z, 2H), 3.64 ( 2H, y 5.6 Hz), 3.47 (Bgv, ka 2H), 3.28 (in, ZN).

MS (ER) t/2 217 (M.-1). 60 a) 3-(2-Methoxy-ethyl)-2-thioxanthine 5,6-Diamino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one ( 0.27g, 1.3mmol) is suspended in formic acid (2ml) and this solution is heated at 902C for 1.5 hours.

Excess formic acid is evaporated under reduced pressure. 1095 sodium hydroxide solution (5 ml) is added to the orange solid product and the resulting solution is heated at 9092C for 2 hours. The reaction mixture is neutralized with diluted acetic acid. The resulting solution is kept in the refrigerator for several 65 days, then the orange needle-type crystals formed are collected by filtration and washed with water.

Output: (0.11 g, 40 b).

TN NMR (DMSO-yv): 5 13.8 (g. 8, 1H), 12.5 (B. 8, 1H), 8.16 (b, 1H), 4.65 (B 2H, 9 6, 4Hz), 3.73 (i, 2H, U 6.4Hz), 3.28 (v, ZN). 13C NMR (DMSO-ybv): δ 172.14, 151.06, 148.02, 139.85, 109.20, 66.04, 56.65, 44.72.

MS (ER) t/2 227 (Mt)

Example 16 3-(3-(1-Morpholinyl)-propyl)-2-thioxanthine a) 6-Amino-1-3-"(1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-1H -pyrimidin-4-one

The named compound was obtained by the general method of example 14 (a) but using 10...1-(3-(1-morpholinyl)-propyl)-2-thiourea (1.1 g, 5.mmol), obtaining the named compound as a white solid product (1.2 g, 87905).

TN NMR (DMSO-yv5): δ 11.8 (in, 1H), 7.24 (in, 2H), 4.84 (in, 1H), 4.33 (rg 8, 2H), 3.55- 3.57 (t, 4H), 2.30-2.36 (t, 6H), 1.82-1.89 (t, 2H).

MS (ER) t/2 271 (M.-1). 12 c) 5,6-Diamino-1-(3-«"1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one 6-Amino-1-(3- (1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-AN-pyrimshchin-4-one 2.mmol) is dissolved in 10905 acetic acid (1Oml). Sodium nitrite (0.16g, 2.3mmol) is added and the slurry is stirred at ambient temperature. After 2 hours, there is still a residue of starting material. Sodium nitrite (0.32g, 4.bmol) is added and the solution is stirred overnight. The precipitate is collected by filtration and washed with water. This extremely insoluble solid is recovered without analysis. The solid product is dissolved in 3295 aqueous ammonia (bml) and then water (bml) is added. The resulting red solution is heated at 7023 and sodium dithionite (0.91g, 5.2mmol) is added in small portions. The solution is then stirred at 702 for 1, 5 hours. Sodium dithionite (0.91 g, 5.2 mmol) is further added and the solution is stirred at 702C for another 2.5 hours. The neutral solution is filtered to remove the insoluble product. The filtrate is concentrated and a yellow solid is formed. kt is suspended in pure water. The solid product was collected by filtration, washed with water and dried to give the title product (o) (0.068Gg, 1196).

TN NMR: 5 12.0 (Bgv, 1H), 6.48 (z, 2H), 3.59 (t, 4H), 2.30-2.45 (t, BN), 1.88-1, 91 (t, 2H),

MS (ER) t/2 286 (M'n-1). Hezo a) 3-(3-(1-morpholinyl)-propyl)-2-thioxanthine 5,6-Diamino-1-(3-(1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro -1H-pyrimidin-4-one (0.068 g, 0.24 mmol) was dissolved in formic acid (0.4 ml) and stirred at room temperature for 1! hours The excess of formic acid is evaporated and 1095 sodium hydroxide solution (1.5 ml) is added and the yellow solution is heated at 709 for 40 minutes. The cooled solution is neutralized with 2M hydrochloric acid and kept in the refrigerator for several hours. The precipitate is collected by filtration, washed with water and dried , obtaining the named compound as a whitish solid product (0.025 g, 36905).

TN NMR (DMSO-in): 5 13.7 (g. 8, 1H), 12.4 (in, 1H), 8.17 (in, 1H), 4.53 (5 2H, 77.5 Hz), 3.52 (t, 4H), 2.31-2.46 (t, 6H), 1.91-1.99 (t, 2H). 13C NMR (DMSO-d5): δ 173.68, 152.99, 149.82, 141.75, 111.24, 66.39, 55.70, 53.43, 46.58, 23.35.

MS (ER) t/2 296 (M'n-1). From c Example 17 "» 3-(2-Furyl-methyl)-2-thioxanthine. " a) 6-Amino-1-(-2-furyl-methyl)-2-thioxo-2,3-dihydro-IN- pyrimidine-4-one

The named compound is obtained by the general method of example 14 (a), except that the reaction time is reduced to 1.5 hours and the product is precipitated with dilute acetic acid. Using β-2-furyl-methylthiourea (1.0 g, b.4 mmol), the named product (0.95 g, 66905) is obtained. o TN NMR (DMSO-yv): 5 11.8 (rg 5, 1), 7.58-7.62 (t, 1H), 7.05 (Bg in, 2H), 6.38-6.42 (t, 1H), 6.31-6.36 (t, 1H), 5.68 (rgv, 2H), 4.85 (v, 1H). and MS (ER) t/2 224 (M.-1). (ee) 50 B) 6-Amino-1-(2-furyl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method from example 14 (p), except that the reaction mixture

Fo is first heated at 602C for 1 hour and then stirred at ambient temperature for 1 hour.

The product (0.25g, booo) is obtained as a brown solid when b-amino-1-(2-furylmethyl)-2-thioxo-2,3-dihydro-YAN-pyrimidin-4-one (0.37g, 1 ,bmmol) and 2 equivalents of sodium nitrite (0.23g, 3.3mMmol). (F. TN NMR: 5 12.1 (rg 85, 1), 7.54-7.57 (t, 1H), 7.45-7.47 (t, 1H), 6.37-6.40 (t, 1H), 6.32-6.38 (t, 1H), ko 6.30-6.32 (t, 1H), 5.62 (v, 2H), 5.48 (v, 2H) c) 5,6-Diamino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one The named compound (0.12 g, 5295) is obtained by a general method from of example 14 (c) starting from b-amino-1-(2-furyl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.25 g, 0.99 mmol ) and used without purification at the next stage.

TN NMR (DMSO-yv): 5 12.5 (rgv, 1H), 12.2 (v, 1H), 7.58-7.60 (t, 1H), 7.55-7.57 (t, 1H), 6.38-6.41 (t, 2H), 6.34-6.37 (t, 1H), 6.30 (Bg 5, 2H), 5.77 (8, 2H), 5, 63 (c, 2H). 65 MS (ER) t/2 239 (M'n-1). a) 3--2-Furyl-methyl)-2-thioxanthine

5,6-Diamino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidine (0.12 g, 0.5 mmol) in formic acid (0.5 ml) is stirred at room temperature within 0.5 hours. The excess of formic acid is evaporated and the formed solid product is dissolved in 1095 sodium hydroxide solution (Zml). This solution is heated at 709 for 0.5 hour. The reaction mixture is neutralized with 2M hydrochloric acid. The precipitate formed is collected by filtration, washed with water and dried. Yield: (0.047g, 37905). "IN NMR (DMSO-y): 5 13.9 (in, 1H), 12.5 (z, 1H), 8.18 (5, 1H), 7.55-7.57 (t, 1H), 6.36-6.39 (t, 2H), 5.69 (z, 2H). 136 NMR (DMSO-d5): δ 174.14, 152.85, 149.56, 149.33, 142.77 , 141.80, 110.93, 109.40, 44.26.

MS (ER) t/2 249 (M.-1).

Example 18 3-(4-Methoxybenzyl)-2-thioxanthine a) 6-Amino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method of example 14 (a), with the exception that the reaction is carried out for 2.5 hours at the boiling temperature under reflux, and then for 16 hours at 72 ambient temperature, and dilute acetic acid is used to precipitate the product. Starting with (4-methoxybenzyl)-thiourea (1.0 3, 5.1 mmol), the desired product is obtained. (1.2g, 92905).

T"H NMR (СО3О0): δ 7.19 (d, 2H, U 8.6Hz), 6.89 (a, 2H, y 8.6Hz), 5.72 (g 5, 2H), 5.06 (in, 1H), 3.77 (in, ЗН).

MS (ER) t/2 264 (M.-1). p) 6-Amino-1-(4-methoxybenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method of example 14 (B), but within 2.5 hours of reaction.

Using b-amino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one (1.2g, 4.7mmol) a blue-green solid product (1.2g, 8895), used in the next reaction without further purification. "IN NMR (DMSO-y): 5 11.9 (in, 1H), 7.18-7.12 (t, 2H), 6.95-6.83 (t, 2H), 5.58 (Bgv , 2H), 3.70 (c, 3H). c) 5,6-Diamino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method of example 14 (c), except that diluted acetic acid is used to neutralize the reaction mixture. The desired product (0.83g, 7390) is obtained as a yellow solid starting from b-amino-1-(4-methoxybenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one / (1.2 g, 4, mmol). "so zo "IN NMR (DMSO-dy5): 5 11.7 (bgv, 2H), 7.20-7.12 (t, 2H), 6.92, 6.85 (t, 2H), 6, 06 (in, 2H), 5.73 (rgv, 2H), 3.71 (in, ЗН).

MS (ER) ti/» 279 (M71). so a) 3--4-Methoxybenzyl)-2-thioxanthine Ge) 5,6-Diamino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0, 83g, 3.Omol) is dissolved in formic acid (3.Omol) and the resulting solution is heated at 1002 for 1 hour. Excess formic acid is removed under reduced pressure and the residue is dissolved in 1095 potassium hydroxide solution (dml) and heated at 1009 for 15 minutes. The reaction mixture is neutralized with 1095 acetic acid and the formed precipitate is collected by filtration. The precipitate is recrystallized from a mixture of ethanol dimethylformamide, and the separated crystals are dissolved in a 1M potassium hydroxide solution, precipitated by neutralization with 1095 acetic acid and collected by filtration. After drying, the named compound is obtained (0.14 g, 1690).

TN NMR (DMSO-in): δ 13.9 (Bgv, 1H), 12.5 (in, 1H), 8.15 (z, 1H), 7.36 (a, 2H, in 8.6Hz), 6.84 (4, 2H, in Z with 8.9 Hz), 5.63 (in, 2H), 3.70 (in, ZN). "from 13C NMR (DMSO-d5): δ 173.85, 158.52, 152.45, 149.36, 141.41, 129.35, 127.97, 113.58, 110.83, 55.01 , 49.63.

MS (ER) t/2 289 (M'n-1).

Example 19 - 15 3-(4-Fluorobenzyl)-2-thioxanthin a) 6-Amino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one; (ee) The named compound is obtained by the general method of example 14 (a), except that the reaction time is 16 hours, and the product is precipitated by treatment with dilute acetic acid. (4-Fluorobenzyl)-thiourea (1.0g, 5.4mmol) gave a white solid (1.2g, 8690). (ee) 20 "IN NMR (DMSO-y): 5 11.9 (bgv, 1H), 7.27-7.11 (t, 4H), 6.91 (z, 2H), 5.67 (Bgv , 2H), 4.89 (in, 1H).

F MS (ER) t/2 252 (M.-1). c) 6-Amino-1-(4-fluorobenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method of example 14 (p), with the exception of increasing the reaction time to 8

HOURS 6-Amino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.2g, 4.7mmol) provided the desired product (0.88g, 6790). iF) "IN NMR (DMSO-dy5): δ 13.1 (bgv, 1H), 12.8 (Bg in, 1H), 7.33-7.08 (t, 2H), 7.13 (Yii, 2H, U 8.7Hz), 5.62 (rgv, 2H). ko s) 5,6-Diamino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidine-4- he

The named compound is obtained by the general method from example 14 (c), except that the reaction is carried out at 759C for 1 hour, and then for 20 minutes at ambient temperature, and the reaction mixture is neutralized with diluted acetic acid.

Application of b-amino-1-(4-fluorobenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.88g,

C, mmol) gives the desired product (0.55 g, 6690). "H NMR (DMSO-dyb): δ 12.1 (bgv, 2H), 7.29-7.12 (t, 4H), 6.08 (z, 2H), 5.75 (bgv, 2H). for MS (ER) t/2 267 (M'-1). a) 3--4-Fluoro-benzyl)-2-thioxanthin

The named compound is obtained by the general method from example 18 (4), but using 5,6-diamino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-IN-pyrimidin-4-one (0.55g, 2.1 mmol), obtaining the desired product (0.24 g, 41965).

TN NMR (DMSO-in): δ 13.9 (rg 8, 1H), 12.5 (b, 1H), 8.15 (b, 1H), 7.44 (a4, 2H 8.6, 8, 6Hz), 7.12 (in 2H, in 8.9Hz), 5.68 (in, 2H).

3C NMR (DMSO-iv): δ 173.96, 160.14, 152.48, 149.28, 141.44, 132.19, 129.83 (9, 9 8.0 Hz), 115.00 (4 , at 22 Hz), 110.82, 49.49.

MS (ER) t/2 277 (M.-1).

Example 20

Z-Phenethyl-2-thioxanthin. a) 6-Amino-1-Phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method of example 14 (a) during the reaction time of 3.5 hours at the reflux temperature, and then by the reaction at ambient temperature for 16 hours.

The product is precipitated by treatment with diluted acetic acid. Phenethylthiourea (1.0g, 5.bmmol) gave a white solid (1.3g, 95 96).

TN NMR (DMSO-yv): 5 11.8 (Bgv, 1H), 7.37 (a, 2H, 9-7.1Hz), 7.31 (6 2H, LA Hz), 7.22 (B MH , 9U-7.2Gu), 7.08 (rgv, 2H), 4.88 (8, 2H), 4.52 (rgv, 1H), 3.32 (rgv, 1H), 2.92 (Yi, 2H, U 8.3Hz).

MS (ER) ti/ 248 (M71).

B) 6-Amino-5-nitroso-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method of example 14 (p), with the exception of increasing the reaction time to 1.5 hours. 6-Amino-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.3g, 5.mmol) provided the desired product (1.3g, 92,905). re TN NMR (DMSO-iv): δ 13.5 (rg 8, 1H), 12.8 (rg 8, 1H), 9.34 (rg 5, 1H), 7.37-7.28 (t, 4H), 7.25-7.20 (t, cm 1H), 4.55 (Bg 5, 2H), 2.90 (I, 2H, at 8.4Hz). o c) 5,6-Diamino-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The named compound is obtained by the general method from example 14 (c), except that the reaction is carried out at 759 for 15 minutes, and then for 1 hour and 20 minutes at ambient temperature, and the reaction mixture is neutralized with dilute acetic acid. Using b-amino-5-nitroso-1-phenethyl-2-thioxo-2,3-dihydro-1IN-pyrimidin-4-one (1.3g, 4.bmol), the desired co-product (1.1g, 88 95). b "IN NMR (DMSO-dy5): δ 10.1 (bgv, 2H), 7.46-7.16 (t, 5H), 6.25 (v, 2H), 4.56 (rg 5, 2H ), 2.94 (i, 2H, U 8.3Hz).

MS (ER) t/2 263 (M'-1). so a) 3-Phenethyl-2-thioxanthine

The named compound is obtained by the general method from example 18 (a), except that it is neutralized with 1M hydrochloric acid. Using 5,6-diamino-1-phenethyl-2-thioxo-2,3-dihydro-TH-pyrimidin-4-one (0.55 g, 2.mmol) the desired product (0.39 g, 3490) is obtained. " "IN NMR (DMSO-dyb): δ 7.53 (in, 1H), 7.32 (d, 4H, in 4.5Hz), 7.22 (t, 1H), 4.63 (t, 2H ), 3.01 (t, 2H), 1.88 (Bgv, 2H). 13C NMR (DMSO-y5): δ 170.56, 155.20, 150.51, 146.41, 138.54, 128 .58, 128.46, 126.34, 117.49, 48.82, 32.59. in s MS (ER) t/2 273 (M.-1).

From" Example 21

Enantiomers of 3-(2-tetrahydrofuryl-methyl)-2-thioxanthin

A solution of racemic 3-(2-tetrahydrofuryl-methyl)-2-thioxanthin (Zmg/ml) is separated using chiral 42 HPLC on a Spigairak AOB-KN column (4.6x15O0mm; 5μm). The mobile phase is methanol: acetic acid: triethylamine and (100:0.1:0.1), and the flow rate is TIml/min. The injected volume is 20 μl. (o) Enantiomer 1 e.n. 93,695; MS (ER) t/2 253 (M'-1). i-o Enantiomer 2 r be o en. 97,396; MS (ER) t/» 253 (M--1).

Example 22 with 3-n-butyl-2-thioxanthine

The title compound is prepared using the procedure described in Example 6.

TN NMR (DMSO-in): δ 13.82 (8, 1H), 12.40 (b, 1H), 8.15 (b, 1), 445 (t, 2H), 1.73 (t, 2H ), 1.34 (sextet, 2H, 9U-7.5), 0.92 (i, ЗН, 9-7.5). (F, 13C NMR (DMSO-ybv): δ 173.31, 152.62, 149.30, 141.47, 110.84, 47.37, 28.61, 19.48, 13.72. ko MS (ER) t/2 225 (M.-1).

Testing in Methods of determining the inhibitory activity of MPO is disclosed in the co-filed patent application (M/O 02/0905751.

The pharmacological activity of compounds according to the invention is investigated as follows:

Assay buffer: 20 mM sodium/potassium phosphate buffer, pH 6.5, containing 10 mM taurine and 100 mM Masi.

Reagent for development: 2mM 3,3,5,5'-tetramethylbenzidine (TMB), 200μM KI, 200mM acetate buffer pH 5.4 2096 DMF. 65 To 10 μl of diluted compounds in the analysis buffer, add 400 μl of human MPO (final concentration 2.5 nM) for 10 minutes at room temperature. Then 5 µl of hydrogen peroxide (final concentration

10µM), or assay buffer alone as a control, is added over 10 minutes at room temperature.

The reaction is stopped by adding 1 µl of 0.2 µg/ml catalase (final concentration 18 ng/ml) for 5 minutes before adding 1000 µl TMB development reagent (2 mM TMB in 200 mM acetate buffer pH 5.4 containing 2096 dimethylformamide (DMF) and 2000 µM CI ). The tablets are mixed and the amount of oxidized 3,3,5,5'i-tetramethylbenzidine is then measured after about 5 minutes using absorption spectroscopy at about 6-5 Ohm. IC values are then determined using standard procedures.

When tested in the above study, the compounds of Examples 1-22 give IC 500 values of less than 10 µm, indicating that they are expected to show useful therapeutic activity. The presented results are shown 7/o In the following table: iv

An example! baby

Claims (11)

The formula of the invention p 1. Application of the compound of the formula (Ia) or (IB) (o) U (Iv) y Y re - M so zo Х re | Y-v so M x | F s EE: and - or is (c) V Y « M tu 4 - s r | i h-v;" m М x раз EE: -I where: X is 5, and Y represents 0; So Ge represents hydrogen or S. valkyl; (se) 2 represents hydrogen or C. alkyl; the indicated alkyl is optionally substituted at 20) with a saturated or partially unsaturated 3-7-ene ring, optionally with the introduction of one or two heteroatoms independently selected from O, M and 5 and optionally with the introduction of a carbonyl group ; indicated 42) ring is optionally substituted with one or more substituents selected from the group: halogen, hydroxy, C. alkyloxy and S. valkil; the specified alkyl, as an option, is additionally substituted with hydroxy or C. alkyloxy; or her) Si valkoxy; or 22ii) an aromatic ring selected from phenyl, furyl or thienyl; indicated aromatic ring, as an option, except He! it is replaced by a substituent from the group: halogen, C. valkyl or C. valkoxy; VZ represents hydrogen or C. alkyl and v represents hydrogen; de or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of diseases or conditions in which inhibition of the MPO enzyme is useful. 60 2. Use according to claim 1, in which the disease or condition is a neuroinflammatory disorder. 3. Application according to claim 1 or claim 2, in which KZ is represented by N. 4. Application according to any one of claims 1-3, in which KE? represents, as a variant, substituted S. valkil. 5. A pharmaceutical composition containing a therapeutically effective amount of a compound of formula (Ia) or (IV) according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of neuroinflammatory disorders. 6. The compound of the formula (Ia) or (IB) Ko (Iv) with y Y Pa - M M r Y M zh 2 or Ko ; (Iv) you Y in MM I reg e where: X represents 5, and ХУ represents 0; B" represents hydrogen or C. alkyl; c B? represents hydrogen or C in alkyl substituted by a saturated or partially unsaturated 3-7-membered d) ring, as an option, with the introduction of one or two heteroatoms selected independently from O, M and 5, and optionally with an introduced carbonyl group; the specified ring is optionally substituted with one or more substituents selected from the group: halogen, hydroxy, C 1-6 oxy and C 1-alkyl; the specified alkyl is optionally in addition, hydroxy or C. valkoxy is substituted; co BZ and 27 independently represent hydrogen or C. valkyl; ee) or a pharmaceutically acceptable salt thereof. 7. Compound of formula (Ia) or (IB), which is: o 1,3-diisobutyl-8-methyl-6b-thioxanthine; c 1,3-dibutyl-8-methyl-b-thioxanthine; 33-isobutyl-1,8-dimethyl-b-thioxanthine; - 3-(2-methylbutyl)-6b-thioxanthine; 33-isobutyl-8-methyl-b-thioxanthine; C-isobutyl-2-thioxanthine; "Z-isobutyl-2,6-dithioxanthine; - 33-isobutyl-8-methyl-2-thioxanthine; c 3-isobutyl-7-methyl-2-thioxanthine; c» 3-cyclohexylmethyl-2-thioxanthine; 3-(3-methoxypropyl)-2-thioxanthine; C-cyclopropylmethyl-2-thioxanthine; C-isobutyl-1-methyl-2-thioxanthine; and 3-(2-tetrahydrofuryl-methyl)-2-thioxanthine; (ee) 3-(2-methoxyethyl)-2-thioxanthine; 3-(3-(1-morpholinyl)propyl)-2-thioxanthine; ish 3-(2-furylmethyl)-2-thioxanthine; Ge | 20 3-(4-methoxybenzyl)-2-thioxanthine; 3-(4-fluorobenzyl)-2-thioxanthine; that 3-phenethyl-2-thioxanthin; (-3-3-(2-tetrahydrofurylmethyl)-2-thioxanthin; (-)-3-(2-tetrahydrofurylmethyl)-2-thioxanthin; 29 3-n-butyl-2-thioxanthin; GF) or its pharmaceutically acceptable salt . 8. Use of the compound according to claim 6 or 7 as a medicine. o 9. A pharmaceutical composition containing a compound of formula (Ia) or (IB) according to claim 6 or 7 or its pharmaceutically acceptable salt, in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 60 10. The method of obtaining the compound of the formula (Ia) or (IB), which is defined in claim 6 or 7, or its pharmaceutically acceptable salt, enantiomer, diastereomer or racemate, in which the reaction of the compound of the formula (Ia) or (IB) b5 is carried out In (pa) With you Y Pa I: M M r shli M M m EE: or with ; (IB) in! M m r i M M z | x EZ EE: where B", B, EZ and KE? are defined in claim 1; X represents O or 5; and Y represents 0; with sulfurization of the compound with a reagent such as Lawson's reagent or phosphorus pentasulfide; obtaining the corresponding compound where U represents 5; and when necessary, convert the formed compound of formula (Ia) or (IB), or another salt thereof, into its C pharmaceutically acceptable salt; o or convert the formed compound (Ia) or (IB) into the following compound of formula (Ia) or (IB); and when necessary, convert the formed compound of formula (Ia) or (IB) into its optical isomer. 11. The method of obtaining the compound of the formula (Ia) or (IB), which is defined in claim 6 or 7, or its pharmaceutically acceptable salt, enantiomer, diastereomer or racemate, |se) in which the reaction of the diamine of the formula (Ха) or (ПШБ) is carried out so Z (Sha) Ko / Ge) E" u s ke MN M | yich- r MN x | 2 « EE: Ye shi or - h , (b) . "» ri ch Y mn. М - р Го) m М Н со и я я о 50 where КЕ", В, ВУ, Х and ХУ are defined in claim 1; 4) with formic acid or trialkyl orthoester; and when necessary, convert the formed compound of formula (Ia) or ( IB), or another salt thereof, into its pharmaceutically acceptable salt; or convert the formed compound (Ia) or (IB) into the following compound of the formula (Ia) or (IB); and when necessary, convert the formed compound of the formula (Ia) or (IB) in its optical isomer. name) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 6, 10.05.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5