1-(diethylamino)ethyl)-(4-triptoreline)-benzyl) aminocarbonyl lmutil)-2-(4-terbisil)thio-5,6 - trimethylenediamine-4-it or its pharmaceutically acceptable salt, method of preparation and pharmaceutical composition

 

The invention relates to new 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-triptoreline)-benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylene-pyrimidine-4-ONU formula (I):

or its pharmaceutically acceptable salts, which have the properties of inhibitors of the enzyme Lp-PLA2and can be used to treat or prevent a painful condition associated with the activity of the specified enzyme. This disease can be atherosclerosis, and diabetes, hypertension, angina, reperfusion injury, ischemia, rheumatoid arthritis, stroke, Alzheimer's disease, myocardial infarction, sepsis, acute and chronic inflammation, and psoriasis. The compounds may be used in particular for the manufacture of medicinal products, applicable for primary and secondary prevention of acute coronary attacks. The compound of formula (I) is produced by interaction of the compounds of formula (II):

with the compound of the formula (III)

in the conditions of formation of the amide. The invention also relates to pharmaceutical compositions. 3 N. and 17 C.p. f-crystals.

This izopet the changes, suitable for their production, to pharmaceutical compositions containing these compounds and to their use in therapy, in particular for the treatment of atherosclerosis.

In WO 95/00649 (SmithKline Beeccham ple) described the enzyme phospholipase A2and it is associated with the lipoprotein phospholipase a2(Lp-PLA2), its consistency, isolation and purification, isolated nucleic acid encoding this enzyme and the recombinant cell host transformed by DNA encoding the indicated enzyme. The intended therapeutic use of inhibitors of the specified enzyme is the treatment of atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion lesions, and acute and chronic inflammation. In the later publication, the same group of authors also described the specified enzyme (D. Tew et al, Arterioscler Thromb Vas Biol. 1996: 16; 591-9), where it denoted LDL-PLA2. In a later patent application (WO 95/09921, Icos Corporation) and the relevant publication in Nature (Tjoelker et al., vol. 374, 6 April 1995, 549) described the enzyme PAF-AH, which basically has the same sequence that Lp-PLA2and it is assumed that it can be used as a therapeutic protein for the regulation of pathological biostatician in the conversion of low density lipoprotein (LDL) in its oxidized form. It is known that this enzyme hydrolyzes complex sn-2 ester of oxidized phosphatidylcholine education lysophosphatidylcholine and oxidation-modified fatty acids. Both products are formed under the action of Lp-PLA2are biologically active against lysophosphatidylcholine, a component of oxidized LDL, which is known to be a strong chemoattractant for circulating monocytes. It is obvious that lysophosphatidylcholine plays a significant role in atherosclerosis, since he is responsible for the accumulation of cells loaded with a complex ester of cholesterol in the arteries. Therefore, it is assumed that the inhibition of the enzyme Lp-PLA2should lead to the termination of development of lesions associated with accumulation of macrophages by inhibiting the formation of effective absorption with added and oxidized free fatty acids), and therefore may be useful for the treatment of atherosclerosis.

In a recently published study (WOSCOPS - Packard et al., N. Engl. J. Med. 343 (2000) 1148-1155) it was shown that the level of the enzyme Lp-PLA2is an independent risk factor for coronary artery disease.

It is also assumed that the high content of effective absorption with added in oxidation-modificirovana inhibitors of Lp-PLA2can have a beneficial effect in treating this condition. Inhibitor of Lp-PLA2you may also find application in other painful conditions in which there is endothelial dysfunction, including diabetes, hypertension, angina and postischemic reperfusion lesions.

In addition, inhibitors of Lp-PLA2may also have a General application in any disorder involving activated monocytes, macrophages or lymphocytes, since all cells of these types Express Lp-PLA2. Examples of such disorders is psoriasis.

In addition, inhibitors of Lp-PLA2may also have a General application in any disorder caused by lipid oxidation in combination with the activity of Lp-PLA2in which produced two unwanted product, lysophosphatidylcholine and oxidation-modified fatty acids. Such States are above condition, namely, atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion lesions, and acute and chronic inflammation.

In patent applications WO 96/13484, WO 96/19451, WO 97/02242, WO 97/217675, WO 97/217676, WO 97/41098 and WO 97/41009 (SmithKline Beecham ple) is described, inter alia, various series 4-tional/selfinjective an irreversible alleluya inhibitors (Tew et al., Biochemistry, 37, 10087, 1998).

Was identified another class of compounds that are non-allerease inhibitors of the enzyme Lp-PLA2. So, in WO 99/24420 (SmithKline Beecham ple) describes a class pyrimidinone compounds. In international patent applications WO 00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline, Beecham ple, published later than the priority date of the present application) describes other classes pyrimidinone compounds. The authors of the present invention was discovered another class pyrimidinone compounds, which differ in the type of substitution at the 5 - and 6-position pyrimidinone ring, and which have good activity as inhibitors of the enzyme Lp-PLA2.

Accordingly, the present invention relates to the compound of formula (I):

where R3represents hydrogen, halogen, C(1-3)alkyl, C(1-3)alkoxy, hydroxys(1-3)alkyl, C(1-3)alkylthio,(1-3)alkylsulfonyl, amino-C(1-3)alkyl, mono - or di-C(1-3)alkylamino(1-3)alkyl, C(1-3)alkylcarboxylic(1-3)alkyl, C(1-3)alkoxyl(1-3)alkylcarboxylic(1-3)-alkyl, C(1-3)alkylsulfonamides(1-3)alkyl, C(1-3)alkylcarboxylic or(1-3)alkylcarboxylicaand Rbare not both hydrogen; or

Raand Rbtogether are (CH2)n, where n is 3 or 4, and taken together with the carbon atoms of the pyrimidine ring to which they are linked, form a condensed 5 - or 6-membered carbocyclic ring; or

Raand Rbtaken together with the carbon atoms of the pyrimidine ring to which they are linked, form a condensed benzo or heteroaryl ring, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different, and are selected from halogen, C(1-4)of alkyl, cyano, C(1-4)alkoxy or(1-4)alkylthio or from mono to PERFLUORO-C(1-4)of alkyl;

Rcrepresents hydrogen or C(1-3)alkyl;

R2represents aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different, and are selected from C(1-18)the alkyl (preferably, With(1-6)the alkyl), C(1-18)alkoxy (preferably With(1-6)alkoxy), C(1-18)alkylthio (preferably With(1-6)alkylthio), aryls(1-18)alkoxy (preferably arils(1-6)alkoxy), hydroxy, halogen, CN, COR6carbon>R9from mono to PERFLUORO-C(1-4)of alkyl, mono to PERFLUORO-C(1-4)alkoxyaryl and arils(1-4)of alkyl;

R3represents hydrogen, C(1-6)alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR6, COR6, carboxy, COOR6, CONR8R9, NR8R9, NR8COR9mono - or di-hydroxy (C(1-6)alkyl) amino and N-hydroxy(C(1-6)alkyl)-N-C(1-6)alkylamino, for example, 1-piperidinoethyl; or

R3is t-C(0-4)alkyl, where Het is a 5-7 membered heterocyclic ring containing N atoms and optionally O or S, linked via a ring carbon atom, and where N can be replaced by COR6, COOR6, CONR8R9or(1-6)the alkyl, optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR6, COR6, carboxy, COOR6, CONR8R9or NR8R9for example, the piperidine-4-yl, pyrrolidin-3-yl;

R4represents aryl or heteroaryl ring, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different, and are selected from C(1-18)the alkyl (preferably,(1-6)alkylthio), aryls(1-18)alkoxy (preferably arils(1-6)alkoxy), hydroxy, halogen, CN, COR6, carboxy, COOR6, NR6COR7, CONR8R9, SO2NR8R9, NR6SO2R7, NR8R9from mono to PERFLUORO-C(1-4)the alkyl and mono to PERFLUORO-C(1-4)alkoxy;

R5represents aryl or heteroaryl ring, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different, and are selected from C(1-18)-alkyl (preferably, With(1-6)the alkyl), C(1-18)alkoxy (preferably With(1-6)alkoxy), C(1-18)alkylthio (preferably With(1-6)alkylthio), aryls(1-18)alkoxy (preferably arils(1-6)alkoxy), hydroxy, halogen, CN, COR6, carboxy, COOR6, CONR8R9, NR6COR7, SO2NR8R9, NR6SO2R7, NR8R9from mono to PERFLUORO-C(1-4)the alkyl and mono to PERFLUORO-C(1-4)alkoxy;

R6and R7independently represent hydrogen or C(1-20)alkyl, for example, With(1-4)alkyl (e.g. methyl or ethyl);

R8and R9may be the same or different, and each of them is selected and the Ohm nitrogen, to which they are bound, form a 5-7-membered ring, optionally containing one or more additional heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted by one or two substituents selected from hydroxy; oxo; C(1-4)of alkyl; C(1-4)alkyls; aryl, e.g. phenyl; or aralkyl, for example, benzyl, for example, research or piperazine; or

R8and R9may be the same or different and each selected from CH2R10, chr11CO2H or salts thereof, where

R10represents COOH or its salt, COOR12, CONR6R7, CN, CH2HE or CH2OR6;

R11represents the side chain of amino acids, such as CH2HE-chain serine;

R12is(1-4)alkyl, or pharmaceutically acceptable in vitro-hydrolyzable ester group;

n is an integer from 1 to 4, preferably 1 or 3, and more preferably, 1;

X represents O or S;

Y is (CH2)p(O)qwhere p is 1, 2 or 3, and q is 0 or p is 2 or 3, and q is 1; and

Z is O or a bond.

Typical examples of Raare chlorine, bromine, methyl, ethyl, n-propyl, methoxy, hydroxymethyl, hydroxyethyl, methylthio, Matrox, methanesulfonamide (methoxyacetate)ethyl and isopropylcarbodiimide.

Typical examples of Rbare hydrogen and methyl.

Typical examples of Raand Rbforming together with the carbon atoms of the pyrimidine ring to which they are linked fused benzo or heteroaryl ring, are benzo (education chineselanguage ring), pyrido and thieno, respectively.

Preferably, Rarepresents methyl or ethyl, a, Rbrepresents hydrogen or methyl, or Raand Rbtaken together with the carbon atoms of the pyrimidine ring to which they are linked, form a condensed 5 - or 6-membered carbocyclic ring. More preferably, Raand Rbtaken together with the carbon atoms of the pyrimidine ring to which they are linked, form a condensed 5-membered carbocyclic ring.

Typical examples of Rcare hydrogen and methyl. Rcpreferably represents hydrogen.

X preferably represents S.

Y preferably represents CH2.

Z preferably represents a direct link.

Typical examples of R2in the case when R2represents an aryl group are phenyl Sa pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, hinely, benzothiazolyl, pyridazinyl and pyrazinyl.

R2preferably, represents an aryl group optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different, and are selected from C(1-6)of alkyl, C(1-6)alkoxy, C(1-6)alkylthio, hydroxy, halogen, CN, mono to PERFLUORO-C(1-4)of alkyl, mono to PERFLUORO-C(1-4)-alkoxyaryl and arils(1-4)the alkyl. More preferably, R2represents phenyl, optionally substituted with halogen, preferably 1 to 3 fluorine atoms, and most preferably, 4-fluoro-.

R2CH2X preferably represents 4-forbesii.

Typical examples of R3is hydrogen, methyl, 2-(ethylamino)ethyl, 2-(diethylamino)ethyl, 2-(ethylamino)-2-methylpropyl, 2-(tert-butylamino)ethyl, 1-piperidinoethyl, 1-ethylpiperidine-4-yl.

Preferably, R3is(1-3)alkyl, substituted Deputy selected from NR8R9; or R3is Het-C(0-2)alkyl, where Het is a 5-7 membered heterocyclic ring containing N, and where N may be replaced With(1-6)the alkyl. More preferably, R3is 2-(IER is about is phenyl.

Typical examples of R5are phenyl or thienyl, optionally substituted with halogen or trifluoromethyl, preferably in 4-position. R5preferably represents phenyl substituted by trifluoromethyl, preferably in 4-position.

Preferably, R4and R5taken together form a 4-(phenyl)phenyl, 2-(phenyl)pyrimidinyl or 2-(phenyl)-pyridinoline Deputy, in which distant phenyl ring may be optional substituted with halogen or trifluoromethyl, preferably in 4-position. More preferably, R4and R5taken together form a 4-(4-trichoroethylene)-phenyl fragment.

It should be noted that the compounds of formula (I) include the sub-group of compounds, which has the formula (IA):

where RaRb, Rc, n, R2, R3, R4, R5and X is defined above; and another subgroup of compounds, which has the formula (IB)

where Ra, Rb, R2, R3, R4, R5and X is defined above, in particular:

Raand Rbtaken together with the carbon atoms of the pyrimidine ring to which they are linked, form a condensed 5-membered Carbo, replaced NR8R9; or

R3is l-C(0-2)alkyl, where Het is a 5-7 membered heterocyclic ring containing N, and where N may be replaced With(1-6)by alkyl;

R4and R5form 4-(4-triptoreline)phenyl fragment.

R8and R9that may be the same or different, selected from hydrogen or C(1-6)of alkyl; and

X represents S.

Pharmaceutically acceptable in vivo hydrolyzable ester groups for R12are groups that are easily decomposed in the human body with the formation of the original acid or its salts. Pharmaceutically acceptable in vivo hydrolyzable ester groups are well known in the art, and examples of such groups used in R12are the groups described in WO 00/68208 (SmithKline, Beeccham).

It should be noted that if Rcis(1-3)alkyl, the carbon atom to which it is linked, may be a chiral center, so that it can form diastereomers. In the absence of other chiral centers, they can be enantiomers. The present invention covers all of these diastereomers and enantiomers, including mixtures thereof.

It should be noted that some with whom, who as Deputy. The following main functional groups can be used to obtain the acid additive salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts described in Berge, Bighley & Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts can be formed from inorganic and organic acids. Typical examples of such acids are maleic, fumaric, benzoic, ascorbic, Panova, amber, biotranslation, methansulfonate, ethicality, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, Takanawa, glycolic, p-aminobenzoic, glutamic, human beings need it, benzolsulfonat, p-toluensulfonate, hydrochloric, Hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acid.

It should be noted that in some cases, the compounds of the present invention may include carboxypropyl, as Deputy. Such carboxypropyl can be used to produce salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts described in Berge, Bighley & Monkhouse, J. Pharm. Sci., 19 the initial herein, the term "alkyl" and similar terms, such as "alkoxy" means all isomers with a straight or branched chain. Typical examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.

Used herein, the term "aryl", unless specified otherwise, means a mono - or bicyclic aromatic ring system containing up to 10 carbon atoms, for example phenyl or naphthyl.

Used herein, the term "heteroaryl" means mono - or bicyclic heteroaromatic ring system containing up to four, and preferably 1 or 2 heteroatoms, each of which is selected from oxygen, nitrogen and sulfur. Each ring can have from 4 to 7, and preferably 5 or 6 ring atoms. Bicyclic heteroaromatic ring system may include carbocyclic ring.

Used herein, the terms "halogen" and "halogen" means fluorine, chlorine, bromine and iodine, and the fluorescent, chloro, bromo and iodo, respectively.

Since the compounds of the present invention, and in particular, the compounds of formula (I) are intended for use in pharmaceutical composica, it is obvious that each of them receive essentially in pure form, for example, at least 50% purity, more than the weight). The crude compound of formula (I) can be used to obtain a more pure forms used in the pharmaceutical compositions. Although the purity of the intermediates of the present invention is equally important, however, it is obvious that the compounds of formula (I), preferred is essentially pure form. If possible, it is preferable that the compounds of the present invention were obtained in crystalline form.

If some compounds of the present invention can crystallize or precrystallization of organic solvents, the obtained crystalline product may contain solvent of crystallization. Such a solvate is also included in the scope of the present invention. Similarly, some compounds of the present invention may be crystallized or recrystallized from solvents containing water. In such cases, it may be formed of hydrated water. In the scope of the present invention includes a stoichiometric hydrates as well as compounds containing various amounts of water, which can be obtained in processes such as lyophilization. In addition, different conditions of crystallization can the ia includes all polymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors associated with lipoprotein phospholipase A2(Lp-PLA2and it is assumed that they can be used in therapy, and in particular, for primary and secondary prevention of acute coronary attacks, caused by, for example, arteriosclerosis, including atherosclerosis, peripheral vascular and cerebrovascular atherosclerosis. In another aspect, the present invention relates to a compound of formula I for use in therapy.

The compounds of formula (I) are inhibitors of the production of the effective absorption with added phospholipase Lp-PLA2a so they can also have a General application in any state, which include endothelial dysfunction, for example, atherosclerosis, diabetes, hypertension, stroke and reperfusion. In addition, the compounds of formula (I) may have a General application in any state associated with lipid oxidation in combination with enzymatic activity, which, for example, in addition to atherosclerosis and diabetes, there may be other conditions, such as ischemia, rheumatoid arthritis, stroke, inflammatory diseases of the brain, such as Alzheimer's disease, myocardial infarction, repeto the Lena to any disorder, which involve activated monocytes, macrophages or lymphocytes, since all cells of these types Express Lp-PLA2. Examples of such disorders is psoriasis.

In accordance with another of its aspects, the present invention relates to a method for the treatment of painful conditions associated with the activity of the enzyme Lp-PLA2where the specified method comprises treating a patient in need thereof, a therapeutically effective amount of an inhibitor of this enzyme. Specified disease state may be associated with an increased accumulation of monocytes, macrophages or lymphocytes; education and effective absorption with added and oxidized free fatty acids; lipid oxidation in combination with the activity of Lp-PLA2or with endothelial dysfunction.

Compounds of the present invention can also be used for treatment of these painful conditions in combination with anti-hyperlipidemics means protivoateroskleroticheskim agent, antidiabetic agent, remedy for angina, anti-inflammatory agent or anti-hypertensive agent, or a means to reduce Lp(a). The examples above are stateliest to insulin, calcium channel antagonists and anti-inflammatory drugs, such as NSPs. Examples of agents that reduce levels of Lp(a) are aminophosphonate described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar FOR SmithKline, Beecham).

It is expected that the compounds of the present invention can be used in combination with agents that lower cholesterol levels, for example, can be introduced together with a statin. Statins are a well known class of agents that reduce the level of cholesterol in the blood (inhibitors of HMG-CoA-reductase), and such agents are atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also called S-4522, Astra Zeneca). Two agents can be taken simultaneously or at different times in accordance with the doctor's appointment.

It was found that, in General, a small number of patients (approx. 30%) with elevated cholesterol levels do not respond to treatment with a statin. Therefore, further use of the compounds of the present invention provides for the introduction of these compounds to the patient, not susceptible to treatment with a statin.

Another preferred complex therapy is the use of compounds of the present invention and any is the leading cause of death for diabetics. Of the compounds of this class, preferred for use in combination with a compound of the present invention, are activators of PPAR-gamma, for example, G1262570 (Glaxo Wellcome) and connection class glitazones, such as rosiglitazone (Avandia, SmithKline Beecham), troglitazone and pioglitazone.

The preferred indications are the primary and secondary prevention of acute coronary attacks, caused, for example, arteriosclerosis, including atherosclerosis, peripheral vascular and cerebrovascular atherosclerosis; additional therapeutic measures for the prevention of restenosis and slowing the progression of diabetic/hypertensive renal failure.

When therapeutic use of the compounds of the present invention is usually administered in a standard pharmaceutical composition. Therefore, in another aspect, the present invention relates to pharmaceutical compositions containing a compound of the formula (I) and a pharmaceutically acceptable carrier.

Suitable pharmaceutical compositions are compositions adapted for oral or parenteral administration or for administration in the form of suppositories. The compounds of formula (I), which are active in oral introduction is the ilok. The liquid composition may largely consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerin, anhydrous solvent, such as polyethylene glycol, oils or water with suspenders agent, preservative, perfume or dye. Composition in tablet form may be obtained using any suitable pharmaceutical carrier(s), typically used for solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. The composition is in the form of a capsule can be obtained using standard procedures encapsulate. So, for example, pellets containing the active ingredient, can be prepared using standard carriers and then they can be incorporated into hard gelatin capsules; alternatively, a dispersion or suspension can be obtained using any suitable pharmaceutical carrier(s), for example, aqueous gums, cellulose, silicates or oils and the dispersion or suspension is administered in soft gelatin capsules. Typical parenteral compositions consist of a process is for example, in polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, this solution can be liofilizovane, and then restored with a suitable solvent just before the introduction. A typical composition is a suppository contains a compound of the formula (I), which is active in the introduction of this method, in combination with a binder agent and/or a sizing agent such as polyethylene glycol, gelatin or cocoa butter or other low melting vegetable or synthetic waxes or fats.

The preferred composition is a unit dosage form such as tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration, preferably from 0.1 to 25 mg) of compounds of formula (I). Scheme daily intake of medicines for adult patient may include, for example, the introduction of oral doses from 1 mg to 1000 mg, preferably 1 mg to 500 mg, or an intravenous, subcutaneous or intramuscular injection, the dose is from 0.1 mg to 100 mg, and preferably from 0.1 mg to 25 mg of the compounds of formula (I), where the indicated course of treatment, for example, in the course of a week or more.

The compound of formula (I) can be obtained by interaction of the compound (II):

where X, n, Ra, Rband R2defined above, with a compound of formula (III)

where Rc, R3, R4, R5, Y and Z are defined above; an amide formation conditions.

The conditions for the formation of amide well known in the art, see, for example, Comprehensive Organic Synthesis 6, 382-399, and involve the interaction of acidic compounds of formula (II) and the amine compound of the formula (III) in an inert solvent, such as dichloromethane, at room temperature, in the presence of the agent combinations. The preferred agents of the combinations are agents designed for use in peptide chemistry, such as hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ("EDC"), preferably in the presence of an additive such as 1-hydroxybenzotriazole, or hexaphosphate O-(7-asobancaria-1-yl)-N,N,N’,N’-trimethylurea ("HATU"), preferably in the presence of diisopropylethylamine.

The compounds of formula (I) can also be obtained in other ways, for example:

(a) interactions of the compounds of formula (IV)

where n, R3, R4, R5, Rwith, Y and Z are defined above, a L1means a leaving group such as halogen, e.g. bromine, iodine or triflate (triftorbyenzola);

in the presence of a base such as a secondary or tertiary amine, for example, di-isopropylaniline, in an inert solvent, such as dichloromethane;

(b) if X represents S, the interaction of the compounds of formula (VI):

where n, Ra, Rb, Rc, R3, R4, R5, Y and Z are defined above, with a compound of formula (VII):

where R2and L1defined above,

in the presence of a base such as a secondary or tertiary amine, for example, di-isopropylaniline, in an inert solvent, such as dichloromethane; or

(C) if X is On the interaction of the compounds of formula (VIII):

where n, Ra, Rb, RcR3, R4, R5, Y and Z are defined above, and L2means a leaving group such as halogen or alkylthio, for example, methylthio, with the compound of formula (IX):

where R2defined above,

in the presence of a base such as 4-dimethylaminopyridine, in an inert solvent is placed into another compound of formula (I) by modification of a functional group methods well known in the art, for example, by transformation of compounds of formula (I), where Randis aminoalkyl, in the compound of formula (I), where Randis alkylcarboxylic, interaction with allermuir agent such as, for example, acetic anhydride.

Compounds of formula (II), (IV), (VI) and (VIII) used in the above methods, can be obtained by the methods illustrated in scheme I (see the end of the description).

In scheme I, L3is(1-6)alkyl group, e.g. methyl;

R15is(1-6)alkyl group, for example, ethyl or tert-butyl and L1L2, Ra, Rb, Rc, R2, R3, R4, R5, n, X, Y, and Z are defined above.

Explanation to the scheme I:

The conditions for the formation of amide to stage (a) is well known to specialists. Preferably, the acid of formula (II) is subjected to interaction with the amine of formula (III) in an inert solvent, such as dichloromethane, at room temperature and in the presence of the agent combinations, such as hexaphosphate O-(7-asobancaria-1-yl)-N,N,N’,N’-tetramethylurea and di-isopropylaniline or hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of 1-hydroxybenzotriazole.

Usly Amin, for example, di-isopropylaniline, in an inert solvent such as dichloromethane.

Conditions for stage (C) include hydrolysis, for example using aqueous sodium hydroxide in a solvent such as dioxane, or, if R15represents tert-butyl, this stage involves dealkylation acid, such as triperoxonane acid in a solvent such as dichloromethane.

Conditions for stage (d) include the conditions for the formation of simple tiefer. The reaction is mainly carried out in the presence of a base, such as ethoxide sodium or potassium carbonate, preferably in a solvent such as ethanol, dimethylformamide or acetone, or in the presence of a secondary or tertiary amine base, such as diisopropylethylamine, in a solvent such as dichloromethane.

At stage (e) compound of formula (XVII) is subjected to interaction with thiourea in prisutstvie ethoxide sodium (preferably formed in situ from sodium and ethanol).

At stage (f) compound of formula (XVIII) is subjected to interaction with ethyl formate in the presence of a base such as sodium hydride or isopropoxide potassium.

At stage (g), the compound of formula (IV) is subjected to interaction with the compound of the formula (V) in prioritise, such as dichloromethane.

At stage (h) compound of formula (XIII) is subjected to interaction with the compound of the formula (XIV) in a solvent such as dimethylformamide with the formation of the intermediate thiourea, which is then treated with base, such as sodium methoxide.

At stage (i), the compound of formula (XVI) is subjected to interaction with the metal thiocyanate, for example, potassium thiocyanate in a solvent such as acetonitrile.

At stage (j) compound of formula (XVII) is subjected to interaction with meteorous agent such as dimethylsulfate, in the presence of a base such as potassium carbonate, followed by hydrolysis of ester intermediate in the standard way, for example, by basic hydrolysis using sodium hydroxide and obtaining the appropriate carboxylic acid, which can then be converted into acylchlorides, for example, by treatment with oxalylamino.

At stage (k) is used, a catalyst such as 4-dimethylaminopyridine, and a solvent, such as pyridine.

On stage (l) compound of formula (XIII) is subjected to interaction with the compound of the formula (XV) in a solvent such as dimethylformamide, with the formation of the intermediate thiourea, which is then treated with the basisandrepresents halogen, by treatment with N-halogenating, for example, N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride.

Compounds of formulas (II) and (IV), and in particular, compounds where Randand Rbtaken together with the carbon atoms of the pyrimidine ring to which they are linked, form a condensed five-membered carbocyclic ring, are novel and represent a further aspect of the present invention.

The present invention is illustrated with examples.

Examples

The structure and purity of the intermediates and compounds described in the examples were confirmed1H-NMR-spectroscopy and (in almost all cases) mass spectroscopy, even in cases where these data are not particularly specified.

The intermediate connection A1 - 4-(4-chlorophenyl)benzaldehyde

(a) a Mixture of 4-formylbenzeneboronic acid (2.50 g, 2 equiv.) 4-chlorobenzene (1.98 g, 1 EQ.), tetrakis(triphenylphosphine)-palladium(0) (0.50 g, of 0.05 equiv.) aqueous sodium carbonate (18 ml, 2 M solution, 2 EQ.) and dimethoxyethane (50 ml) is stirred while boiling under reflux in an argon atmosphere overnight and then cooled and diluted with ethyl acetate. The mixture is filtered, the EU is aqueous citric acid and saturated salt solution, dried and evaporated. The crude product is purified column chromatography (silica, 5% ethyl acetate in hexane); fraction of the product is evaporated to obtain white solids (1,32 g, 72%).

(b) a mixture of 4-chlorobenzophenone acid (19,4 g, 1 EQ.), 4-bromobenzaldehyde (22.9 g, 1 EQ.), the palladium(II) acetate (1.4 g of 0.05 equiv), aqueous sodium carbonate (30,3 g in 144 ml, 2 EQ.) and dimethoxyethane (500 ml) is stirred while boiling under reflux in an argon atmosphere for 2.5 h, and then evaporated to small volume and diluted with dichloromethane. Processing continues, as described in stage (a), and receive the identical product (25,2 g, 94%).1H-NMR (CDCl3): of 10.05 (1H, s), of 7.96 (2H, d), 7,73 (2H, d), EUR 7.57 (2H, d), 7,46 (2H, d), MS (AP+) for C13N359lO: found (M+1)=217; calculated 216.

Intermediate compound A2 - N-methyl-4-(4-chlorophenyl)benzylamine

A mixture of intermediate compound A1 (3.5 g, 1 EQ.), of methylamine (32,3 ml of 2 M solution in THF, 4 EQ.) and anhydrous magnesium sulfate (4,47 g, 2 EQ.) stirred at room temperature for 16 h, and then filtered, the solid is thoroughly washed with ethyl acetate and the combined filtrates evaporated to obtain white to ice and portions add borohydride sodium (0,61 g, 1 EQ.). Then the ice bath removed and the mixture is stirred for 45 minutes at room temperature and then for 1 h at 50C. the Solvent is removed in vacuo, to the residue water is added and the product extracted with dichloromethane. After drying and evaporation of solvent to obtain white solid (of 3.56 g).1H-NMR (CDCl3): 7,51 (4H, d), 7,40 (4H, d), with 3.79 (2H, c), 2,48 (3H, s); MS (APCI+) for C14H3514CIN: computed 231, found: (M+1)=232.

The intermediate connection A3 - N-(2-diethylaminoethyl)-4-(4-chlorophenyl)benzylamine

A mixture of intermediate compound A1 (55,0 g), N,N-diethylethylenediamine (35,6 ml), molecular sieves 4A (37 g) and dichloromethane (1100 ml) is subjected to interaction at room temperature in an argon atmosphere for 16 hours, stirring occasionally. The solid is filtered off and washed with dichloromethane and then the combined filtrate is evaporated to obtain a yellow foam (72.4). The obtained intermediate Imin restore with sodium borohydride (8.7 g) in ethanol (850 ml) as described for intermediate compounds A2, obtaining specified in the title compound as a yellow oil (72,7 g).1H-NMR (CDCl3)

A solution of intermediate compound A20 (4,63 g) in dry dichloromethane (100 ml) cooled to -78In argon atmosphere, and then for 20 minutes, added dropwise DIBAL-H (26,7 ml, 1.5 M solution in toluene). Stirring is continued for 40 minutes at -78And then within 15 minutes added dropwise 2 M hydrochloric acid (52 ml). The solution slowly warmed to room temperature, and then the organic layer was separated, washed with water, dried and evaporated. After chromatography (silica, ethyl acetate/hexane, 1:1) to give the product as a white solid (3.03 g, 75%).1H-NMR (CDCl3): of 1.85 (1H, t), to 4.81 (2H, d), of 7.75 (2H, m), 7,83 (1H, DD), 8,11 (1H, d), 8,72 (1H, m); MS (APCI+) for C13H10F3NR: found (M+1)=254; calculated 253.

The intermediate connection A5 - 5-formyl-2-(4-triptoreline)pyridine

Activated manganese dioxide (3,19 g) are added to a solution of intermediate compound A4 (0.75 g) in dichloromethane (50 ml) and stirred at room temperature for 16 hours, the Solids filtered off and the filtrate is evaporated to obtain a pale yellow solid (0,57 g).1H-NMR (CDClb>F3NO: found (M+1)=252; calculated 251.

The intermediate connection A6 - Ethyl-2-(4-chlorophenyl)-4-oxopyrimidine-5-carboxylate

Ethoxide sodium (11,12 ml, 2 EQ.) in the form of a 21 wt.%/about solution in ethanol are added dropwise to a suspension of diethylethanolamine (3,03 ml, 1 EQ.) and hydrochloride 4-chlorobenzamidine (to 4.23 g, 1 EQ.) in ethanol (30 ml) and the mixture is then refluxed for 4 hours. After cooling, the solvent is removed in vacuo, and the residue triturated with ether. The solid is filtered off, and then resuspended in water and acidified to pH 2. The product is filtered, washed with water and dried; yield 2,94,1H-NMR (DMSO-d6): of 1.29 (3H, t), 4.26 deaths (2H, square), the 7.65 (2H, m), 8,18 (2H, m), 8,65 (1H, s); MC (APCI-) for C13H11IN2About3found: (M-1)=277/279; calculated 278/280.

Intermediate compound A7 - Ethyl-2-(4-chlorophenyl)-4-chloropyrimidine-5-carboxylate

Oxalicacid (0,31 ml, 2 EQ.) add to the intermediate compound A6 (0,49 g) in dichloromethane (20 ml) under ice cooling, and the mixture is then stirred for 3 hours while heating to room temperature. After evaporation of volatile components receive the product in the form of a white solid is MS (APCI+) for C13H10Cl2N2O2found (M+1)=297; calculated 296.

The intermediate connection A8 - Ethyl-2-(4-chlorophenyl)-pyrimidine-5-carboxylate

A mixture of intermediate compound A7 (6.8 g, 1 EQ.), zinc powder (1,79 g, 1.2 EQ.), acetic acid (1.57 in ml, 1.2 EQ.) and THF (100 ml) was stirred at 60C in an atmosphere of argon for 18 hours, and then add a further portion of acetic acid (1 ml) and zinc (1.0 g) and the reaction mixture stirred for further 24 hours. The solvent is removed in vacuum, the residue is dissolved in a mixture of dichloromethane and methanol, and nerastvorim zinc powder is removed by filtration. After evaporation of the solvent, the product is crystallized from ethanol, yield 2,02,1H-NMR (CDCl3): the 1.44 (3H, t), to 4.46 (2H, q), of 7.48 (2H, m), 8,48 (2H, m), of 9.30 (2H, c); MS (APCI+) for C13H11ClN2O2found: (M+1)=263; calculated 262.

The intermediate connection A9 - 5-hydroxymethyl-2-(4-triptoreline)pyrimidine

Intermediate compound A41 (0.96 g) hydronaut over 10% palladium on carbon (96 mg) in a mixture of triethylamine (2 ml) and ethanol (20 ml) for 90 minutes under a pressure of 1 atmosphere. The catalyst is removed filtrat the ammonia and aqueous sodium bicarbonate. After drying and evaporation receive specified in the header connection (0,77 g).1H-NMR (CDCl3): 4,82 (2H, s), of 7.75 (2H, m), to 8.57 (2H, m), cent to 8.85 (2H, c); MS (APCI+) for C12H9F3N2O: found: (M+1)=255; calculated 254.

The intermediate connection a10 - 3-(4-triptoreline)-benzyl alcohol

A mixture of 4-chlorobenzotrifluoride (27,1 g, 1.5 EQ.), 3 hydroxybenzylated alcohol (12.4 g, 1 EQ.), chloride copper (I) (0.2 g, 0.02 EQ.), potassium carbonate (8,3 g, 0.6 EQ.), 8-chinoline (0.29 grams, 0.02 EQ.) and 1,3-dimethyl-2-imidazolidinone (50 ml) was stirred at 150C for 3 days in an atmosphere of argon. After cooling, the residue is poured into water and extracted with ethyl acetate. After drying and evaporation followed by chromatography (silica, dichloromethane) get mentioned in the title compound in the form of a light fluid (11.3 g).1H-NMR (CDCl3): of 1.88 (1H, t), 4,69 (2H, d), 6,97 (1H, m),? 7.04 baby mortality (3H, m), 7,17 (1H, m), of 7.36 (1H m), EUR 7.57 (2H, m); MC (APCI-) for C14H11F3O2found: (M-1)=267; calculated 268.

The intermediate connection A11 - 4-(4-triptoreline)-benzaldehyde

A mixture of 4-(trifluoromethyl)phenol (a 4.86 g, 1 EQ.), 4-forventelige (3,22 g is the group of 3 hours, and then poured into ice water. The precipitate is filtered off, washed with water, and then extracted with hot ethanol. Nerastvorimaya the solid is removed by filtration, and the filtrate is evaporated and purified by chromatography on silica.1H-NMR (CDCl3): 7,14 (4H, m), 7,66 (2H, m), of 7.90 (2H, m), becomes 9.97 (1H, s); MC (APCI+) for C14H9F3O2found: (M+1)=267; calculated 266.

Intermediate compound A12 - tert-butyl-(2-hydroxyethyl)ethylcarbamate

Di-tert-BUTYLCARBAMATE (15.5 g, 1 EQ.) added dropwise within 1 hour to a solution of 2-(ethylamino)ethanol (7.5 g, 1 EQ.) in dichloromethane (30 ml) at 0C. After stirring at room temperature for 16 hours, the solvent is evaporated, and the residue is subjected to distillation (115With, 0.6 mm RT.CT.) obtaining specified in the title compound as a colourless oil (13,42 g).1H-NMR (CDCl3): to 1.11 (3H, t), 1,47 (N, C), with 3.27 (2H, HF), to 3.38 (2H, t), of 3.75 (2H, t).

Intermediate compound A13 - tert-butyl[(2-phthalimide)ethyl]-ethylcarbamate

Diethylazodicarboxylate (12,35 g, 1 EQ.) added dropwise to a mixture of intermediate compound A12 (13,42 g, 1 EQ.) is ur in for 16 hours. The solvent is evaporated and add diethyl ether. The solution is cooled to 0With, and any insoluble products are removed by filtration. The solvent is evaporated and the residue is subjected to column chromatography (doxil silica, hexane/ethyl acetate, 9:1) to obtain the specified title compound as a colourless oil (17 g).1H-NMR (CDCl3): 1,13 (3H, m), 1,29 (N, C), 3,26 (2H, m), of 3.48 (2H, m), a-3.84 (2H, t), 7,71 (2H, m), a 7.85 (2H, m).

Intermediate compound A14 - tert-butyl-(2-amino-ethyl)-ethylcarbamate

Hydrazine monohydrate (5,2 ml, 2 EQ.) added to a solution of intermediate compound A13 (17 g, 1 EQ.) in ethanol (300 ml) and the reaction mixture was stirred at room temperature for 16 hours. The obtained solid is filtered off and the solvent is evaporated. The residue is partitioned between diethyl ether and sodium hydroxide (1 M, 150 ml), the organic phase is dried (K2CO3), and the solvent is removed, resulting in a gain specified in the title compound as a yellow oil (9,05 g).1H-NMR (CDCl3): 1,10 (3H, t), of 1.45 (9H, s) to 2.65 (2H, square), by 2.73 (2H, t), 3,23 (2H, m).

The intermediate connection A15 - 3-(4-triptorelin-4-yl)to a solution of intermediate compound A23 (5,23 g, 1 EQ.) in tetrahydrofuran (65 ml) at 0C. the Solution is allowed to warm to room temperature and continue to stir for 16 hours. The reaction is quenched by addition of water and the mixture extracted with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution, dried (MgSO4) and the solvent is evaporated to obtain the residue, which is injected into the column for chromatography (silica, dichloromethane) and get listed in the title compound as a colourless solid (or 4.31 g).1H-NMR (CDCl3): to 1.76 (2H, m) to 2.67 (2H, t), at 3.35 (2H, m), 7,32 (2H, d), to 7.64 (2H, d), 7,78 (2H, d), 7,86 (2H, d).

The intermediate connection A16 - 3-(4-triptorelin-4-yl)-Propionaldehyde

Dimethyl sulfoxide (2,36 ml, 2.4 EQ.) added dropwise to a solution of oxalicacid (1,46 ml, 1.1 EQ.) in dichloromethane (34 ml) at -55C, and the solution stirred for 2 minutes.

Then to this solution slowly at -55To add a solution of intermediate compound A15 (4,28 g, 1 EQ.) in dichloromethane (40 ml) and the resulting solution was stirred for another 10 minutes, then add triethylamine (9.7 ml, 5 EQ.). After stirring for another 5 minutes the memory is separated, dried (gSO4) and the solvent is removed, resulting in a gain specified in the header connection (3,48 g).1H-NMR (CDCl3): and 2.83 (2H, m), to 3.02 (2H, t), 7,29 (2H, d), 7,51 (2H, d), to 7.67 (4H, s), 9,85 (1H, s). MS (APCI+) for C16H13F3O: found: (M+1)=279; calculated 278.

The intermediate connection A17 - C-(4’-triptorelin-4-yl)methylamine

A solution of intermediate compound A13 (31 g, 1 EQ.) in tetrahydrofuran (300 ml) was added dropwise to a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 188 ml, 1.5 EQ.) at room temperature and under stirring. The reaction mixture is stirred for 8 hours, then add aqueous ammonium chloride (200 ml) and then water (200 ml). The resulting mixture was filtered through celite and then extracted with dichloromethane. The organic phase is dried (MgSO4), and the solvent is removed to obtain specified in the connection header (26.7 g).1H-NMR (DMSO-d6): to 3.89 (2H, c), 7,52 (2H, d), 7,73 (2H, d), of 7.82 (2H, d), 7, 98 (2H, d).

The intermediate connection A18 - N-(1-ethylpiperazin-4-yl)-(4'-triptoreline)benzylamine

A solution of intermediate compound A17 (9.3 g, 1 EQ.) and 1-ethyl-4-piperidone (5.0 ml, of 1.05 equiv.) 1 the century) at room temperature, and the mixture is stirred for 24 h the Reaction is quenched by adding sodium hydroxide (2 M, 125 ml) and extracted with diethyl ether. The organic phase is dried (MgSO4) and the solvent is evaporated to obtain the residue, which is triturated with hexane, resulting in a gain specified in the title compound in the form of not-quite-white solid (8.2 g).1H-NMR (CDCl3): of 1.06 (3H, t) to 1.48 (3H, m), a 2.01 (4H, m), of 2.38 (2H, square), to 2.55 (1H, m), of 2.92 (2H, m), 3,88 (2H, s), the 7.43 (2H, d), to 7.59 (2H, d), to 7.68 (4H, s).

Intermediate compound A120 - tert-Butyl(2-amino-2-methylpropyl " carbamate

Di-tert-BUTYLCARBAMATE (6,58 g, 1 EQ.) in tetrahydrofuran (100 ml) was added dropwise to a solution of 1,2-diamino-2-methylpropane (8,86 g, 3.3 EQ.) in tetrahydrofuran (100 ml) at 0C. Then the solution was stirred at room temperature for 16 hours. The solvent is evaporated and the residue partitioned between aqueous sodium chloride and ethyl acetate. The organic phase is dried (K2CO3), and the solvent is evaporated to obtain specified in the title compound as a colourless solid (of 5.45 g).1H-NMR (CDCl3): 1,09 (6N, (C) a 1.45 (9H, s) of 3.00 (2H, d). MS (APCI+) for C9Hylpropyl)carbamate

Intermediate compound A120 (of 5.45 g, 1 EQ.) iodoethane (2,32 ml, 1 EQ.) and potassium carbonate (4 g, 1 EQ.) in dimethylformamide (80 ml) was stirred at room temperature for 16 hours. The solvent is evaporated, and the residue partitioned between dichloromethane and water. The organic layer is dried (K2CO3), the solvent is evaporated and the residue is subjected to chromatography on a column (silica, dichloromethane/methanol, 10:1) to obtain specified in the connection header in the form of a light brown oil (to 3.89 g).1H-NMR (CDCl3): 1,05 (6N, (C) a 1.08 (3H, t), of 1.45 (9H, s) to 2.54 (2H, square), 3,03 (2H, m). MS (AS+) for C11H24N2Ozfound: (M+1)=217; calculated 216.

The intermediate connection A - Dihydrochloride N2-ethyl-2-methylpropan-1,2-diamine

Hydrogen chloride (4 M in dioxane, 70 ml) was added to a solution of intermediate compound A (to 3.89 g) in dioxane (100 ml) and the resulting suspension stirred at room temperature for 16 hours. The solvent is evaporated, and the residue is suspended in diethyl ether, after which the solid is filtered off, collect, and receive specified in the title compound in the form of bn, square), 3,19 (2H, c). MS (APCI+) for C6H16N2found: (M+1)=117; calculated 116.

The intermediate connection a - 2-(2-tert-butylaminoethyl)phthalimide

A mixture of 2-brometalia (20 g, 2 equiv.) tert-butylamine (41 ml, 1 EQ.) and potassium carbonate (10,86 g, 2 EQ.) in dimethylformamide (200 ml) heated to 50C for 48 hours the Solvent is evaporated, and the residue partitioned between dichloromethane and water. The organic phase is dried (K2CO3), and the solvent is evaporated to obtain specified in the title compound as an orange solid (18,93 g).1H-NMR (CDCl3): of 1.05 (9H, s), 2,85 (2H, t), of 3.77 (2H, t), 7,72 (2H, m), a 7.85 (2H, m).

The intermediate connection A - N-tert-butylated-1,2-diamine

A mixture of intermediate compound e (4 g, 1 EQ.) and hydrazine hydrate (1,58 ml, 2 EQ.) in ethyl alcohol denatured with methyl alcohol (100 ml) is refluxed for 16 hours. The solid is filtered off and the solution is used directly in the next stage.

The following intermediate compounds were obtained by the method described for intermediate A1: (see tab.1).

The following promisee intermediate compounds were obtained by the method described for intermediate A3 (see table.3).

The following intermediate compounds were obtained by the method described for intermediate A4 (see tab.4).

The following intermediate compounds were obtained by the method described for intermediate 5 (see tab.5).

The following intermediate compounds were obtained by the method described for intermediate compound A6 (see tbl.6).

The following intermediate compounds were obtained by the method described for intermediate compound A7 (see tab.7).

The following intermediate compounds were obtained by the method described for intermediate A16 (see tab.8).

The following intermediate compounds were obtained by the method described for intermediate connection A18 using intermediate compound A17 and appropriately substituted 1-alkyl-4-piperidone (see tab.9).

The following compounds are commercially available:

Intermediate compound B1, 2-thiouracil; intermediate connection B2, 5-methyl-2-thiouracil; intermediate compound B3, 5-ethyl-2-thiouracil; intermediate connection B4, 5-propyl-2-thiouracil; intermediate compound B5, 5,6-dimethyl-2-thiouracil.

Nigel is butoxy-2-thiouracil (J. Amer.Chem.Soc. 794, 64 (1942));

the intermediate connection V7, 5,6-grimetime-2-thiouracil (J. Amer. Chem. Soc. 3108, 81 (1959));

intermediate compound B8, 5,6-tetramethylene-2-thiouracil (J.Org. Chem. 133, 18 (1953));

the intermediate connection B9, 5-methoxy-2-thiouracil (J. Chem. Soc. 4590 (1960)).

intermediate compound B10 - 5-(2-hydroxyethyl)-2-thiouracil

The solution ethylformate (33,1 ml, 2.1 EQ.) and-butyrolactone (15 ml, 1 EQ.) in ether (400 ml) dropwise, with stirring, are added to a solution of tert-butoxide potassium (52,5 g, 2.4 EQ.) in tetrahydrofuran (400 ml). The mixture is left to warm to room temperature and stirred over night. The solvent is removed in vacuo, add 2-propanol (600 ml) and thiourea (29,7 g, 2 EQ.) and the mixture is refluxed for 5 hours After cooling to room temperature the precipitate is filtered off, dissolved in water (500 ml) and washed twice with ether. The aqueous solution is acidified to pH 5.5 by addition of acetic acid and the precipitate is filtered off, thoroughly washed with water and dried in vacuum; yield 23,85,1H-NMR (DMSO-d6): a 2.36 (2H, t), 3,47 (2H, m), of 4.57 (1H, m), 7,24 (1H, s), and 12.2 and 12.4 (each 1H, Shir.C); MS (APCI-) for C6H8N2O2S: found (M-N)=171, calculated 172.

Intermediate soya acid (10 g, 1 EQ.) in dimethylformamide (30 ml) was added dropwise to a suspension of sodium hydride (2,45 g, 60% in mineral oil, 1 EQ.) in dimethylformamide (70 ml) at room temperature. The reaction mixture is stirred for 1 hour, and then add ethylbromoacetate (6.8 ml, 1 EQ.) and the resulting mixture is stirred for 16 hours. The solvent is evaporated, the residue suspended in water and the solid collected. Specified in the title compound is obtained by crystallization from ethyl acetate (10.5 g).1H-NMR (CDCl3): of 1.29 (3H, t), 4,27 (2H, square), 4,82 (2H, s), of 6.96 (1H, d), 7,33 (1H, t), 7,74 (1H, dt), 8,19 (1H, DD).

The intermediate connection P - Ethyl(4-oxo-2-thioxo-3,4-dihydro-2H-hinzelin-1-yl)acetate

The intermediate connection B111 (2.64 g, 1 EQ.) and thiourea (2,42 g, 4 EQ.) 1-methyl-2-pyrrolidinone (40 ml) is heated to 180C for 2 hours. After cooling, the mixture obrabotayut water, and the resulting solid collected by filtration. This solid is subjected to column chromatography (silica, 2% methanol/dichloromethane) to obtain the specified title compound as a colourless solid (0,169 g).1H-NMR (CDCl3): [3-(1-phenylethanol)-touraid]thiophene-2-carboxylate

Methyl-3-amino-2-thiophenecarboxylate (30 g, 1 EQ.) and benzoylisothiocyanate (46 ml, 1.8 EQ.) in acetone (250 ml) is heated to 65C for 30 minutes. After cooling, the solution is concentrated and the resulting solid is filtered off and dried (40,54 g).1H-NMR (CDCl3): 3,98 (3H, s), 7,54 (4H, m), 7,94 (2H, m), 8,81 (1H, d), to 9.15 (1H,Shir.C); MS (APCI+) for C14H12N2O3S2found: (M+1)=321, calculated 320.

The intermediate connection V - 2-Thioxo-2,3-dihydro-1H-thieno[3,2-a]pyrimidine-4-one

Potassium hydroxide (13,83 g, 2 EQ.) dissolved in ethanol (1000 ml), and then stirring, pour in the intermediate connection V (40,54 g, 1 EQ.). The mixture is refluxed for 1 hour, and after cooling, get mentioned in the title compound by filtration (17,32 g).1H-NMR (CDCl3): 6,87 (1H, d), to 7.77 (1H, d), 10,46 (2H, Shir.C); MS (APCI-) for C6H4N2OS2found: (M-1)=183 computed 184.

The following intermediate compounds were obtained by the method described for intermediate 10 (see tab.10).

The intermediate connection in20 - 2-(4-forbesii)-5-methylpyrimidin-4-one

Mixture about formamide (100 ml) was stirred at 90C in argon atmosphere for 16 h DMF is removed in vacuo, water is added and the product extracted with ethyl acetate. The organic layer is dried and evaporated, whereupon the residue is triturated with petroleum ether and receive specified in the title compound as a white solid (8,76 g).1H-NMR (CDCl3): 2,02 (3H, s), to 4.38 (2H, c), 6,97 (2H, m), 7,35 (2H, m), 7,74 (1H, s); MS (APCI+) for C12H11FN2OS: found: (M+1)=251, 250 calculated.

The following intermediate compounds were obtained by the method described for intermediate B20 (see tab.11).

The following intermediate compounds were obtained by the method described for intermediate B20, and using appropriate benzylchloride (see tab.12).

The intermediate connection V - 2-(4-forbesii)-5-hydroxyethylpyrrolidine-4-one

The complex of borane-tetrahydrofuran (143 ml, 2.2 EQ., 1.0 M in THF) dropwise in an argon atmosphere add, stirring, to a cooled solution of intermediate compounds In 24 (20 g, 1 EQ.) in dry THF (700 ml). After stirring for a further 30 minutes at 0With that, the mixture is left to warm to room temperature and stirring is continued over night. The solvent vapour is t hot water (500 ml) for 5 minutes, and then the solid is filtered off. The obtained solid material and the filtrate is extracted with dichloromethane, and the organic extracts are combined and purified by chromatography (silica, 2-8% methanol in dichloromethane). Fraction of the product is evaporated and receive a white solid (6,14 g).1H-NMR (DMSO-d6): of 4.25 (2H, c), 4,39 (2H, c), 7,14 (2H, t), was 7.45 (2H, m), 7,82 (1H, Shir.C); MS (APCI+) for C12H11FN2O2S: found: (M+1)=267 calculated 266.

The intermediate connection V - 2-(4-forbesii)-5-isopropoxycarbonyloxymethyl-4-one

A mixture of intermediate compound B11 (2,60 g, 1 EQ), 4-ftorangidridy (1,74 ml, 1 EQ.) and 2-propanol (50 ml) stirred at the boil under reflux for 3 h, and then concentrated in vacuo to obtain a suspension, and diluted with ether. The solid is filtered off, washed with ether and dried; yield 2,87,;1H-NMR (DMSO-d6): 1,17 (6H, d), and 3.31 (2H, c), and 4.40 (2H, c), 4,89 (1H, m), 7,14 (2H, t), was 7.45 (2H, m), to 7.84 (1H, s); MS (APCI+) for C15H17FN2O3S: found: (M+1)=325, 324 calculated.

The intermediate connection in40 - 1-(tert-butoxycarbonylmethyl)-2-(4-forbesii)-5-methylpyrimidin-4-one

A mixture of intermediate compound B20 (6,30 g, 1 EQ), the room temperature in an argon atmosphere for 16 h, then the solution was washed with aqueous ammonium chloride and aqueous sodium bicarbonate, dried and evaporated. After conducting chromatography (silica, ethyl acetate + 0,5%/about Aqua ammonia) followed by crystallization from ethyl acetate receive specified in the title compound as a white solid (3,36 g);1H-NMR (CDCl3): the 1.44 (9H, s), a 2.01 (3H, d), 4,36 (2H, c), 4,51 (2H, c), 6,98 (3H, m), of 7.36 (2H, m); MS (APCI+) for C18H21FN2O3S: found: (M+1)=365 calculated 364.

The following intermediate compounds were obtained by the method described for intermediate connection in40 (see tab.13).

The following intermediate compounds were obtained by the method described for intermediate B20 (see tab.14).

The intermediate connection V - 1-(tert-butoxycarbonylmethyl)-2-(4-forbesii)-5-chloropyrimidine-4-one

A mixture of intermediate compound B41 content (7,45 g, 1 EQ.), N-chlorosuccinimide (2,84 g, 1 EQ.) and carbon tetrachloride (150 ml) was stirred at. boiling under reflux in an argon atmosphere for 2H, and then the solution is evaporated. After conducting chromatography (silica, ethyl acetate) followed by rubbing with ether get mentioned in the title compound in the form of be is 35 (2H, m), 7,40 (1H, s); MS (APCI+) for C17H18ClFN2O3S: found: (M+1)=385/387 calculated 384/386.

The intermediate connection V - 1-(tert-butoxycarbonylmethyl)-2-(4-forbesii)-5-chloropyrimidine-4-one

Specified in the header of the get connection as well as the intermediate connection V, except that instead of N-chlorosuccinimide using N-bromosuccinimide;1H-NMR (CDCl3): to 1.45 (9H, s), and 4.40 (2H, c), of 4.49 (2H, c), of 6.99 (2H, m), 7,35 (2H, m), 7,53 (1H, s); MS (APCI+) for C17H18BrFN2O3S: found: (M+1)=429/431 calculated 428/430.

The intermediate connection V - 1-(tert-butoxycarbonylmethyl)-2-(4-forbesii)-5-methylsulfonylamino-4-one

m-Chloroperbenzoic acid (0,93 g) added to ice the suspension of intermediate compounds V (1.50 g) in dichloromethane (20 ml). The resulting solution was left to warm to room temperature and stirred for 30 minutes and then washed with aqueous sodium bicarbonate. After conducting chromatography (silica, 3-8% methanol in ethyl acetate) get mentioned in the title compound as a white solid (1,15 g);1H-NMR (CDCl3): 1,46 (N, C) to 2.94 (3H, s), 4,51 (4H, m), 7,01 (2H, m), 7,37 (2H, m), 7,60 (1H, s); MS (APCI+) for C18H-(4-forbesii)-5-methylpyrimidin-4-one

The intermediate connection in40 (3.88 g) are added to a solution triperoxonane acid (10 ml) in dichloromethane (20 ml) in an argon atmosphere and the mixture is stirred over night at room temperature. After evaporation of the solvent and trituration with ether get mentioned in the title compound as a white solid (3.04 from g).1H-NMR (DMSO-d6): is 1.81 (3H, d), 4,42 (2H, c), of 4.66 (2H, c), 7,14 (2H, m), 7,47 (2H, m), 7,63 (1H, m); MS (APCI+) for C14H13FN2O3S: found: (M+1)=309 calculated 308.

The following intermediate compounds were obtained by the method described for intermediate connection B60 (see tab.15).

The intermediate connection B80 - 1-(N-methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5-(2-azidoethyl)pyrimidine-4-one

A mixture of compound of example 39 (1.88 g, 1 EQ.), methanesulfonamido anhydride (0,713 g, 1.2 EQ.), triethylamine (0,665 ml) and dichloromethane (20 ml) stirred at 0C for 4 h the Solution was washed with water, dried and evaporated to obtain a light foam (2.4 g). The resulting substance was dissolved in dimethylformamide (20 ml), add sodium azide (0,266 g, 1.2 EQ.) and the mixture is stirred in the atmosphere of aylormade, and the organic layer dried and evaporated. After conducting chromatography (silica, ethyl acetate) get mentioned in the title compound as white solids;1H-NMR (CDCl3): to 2.66 (2H,m), is 2.88 (3H, s), of 3.60 (2H, m), 4,46 with 4.64 (6N, m), 6,84-7,50 (N, m), 8,02 (1H, s); MS (APCI+) for C29H26lFN6O2S: found: (M+1)=577/579 calculated 576/578.

The following intermediate compounds were obtained by the method described for intermediate connection B80 (see tab.16).

Example 1 Bitartrate 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-triptoreline)benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5-ethylpyrimidine-4-one

A mixture of intermediate compound A30 (0,403 g, 1 EQ.), the intermediate V (0,371 g, 1 EQ.), HATU (0,426 g, 1.2 EQ.), di-isopropylaniline (0,482 ml, 2.4 EQ.) and dichloromethane (15 ml) was stirred at room temperature overnight, then washed with aqueous ammonium chloride and aqueous sodium bicarbonate. The organic layer is dried and evaporated and the product purified by chromatography (silica, 5% methanol in dichloromethane). Fraction of the product is evaporated to obtain a white foam (0,627 g). This free base (0,612 g) dissolved in methanol (10 ml), add sour wine is atnow salt as a white solid (0,622 g).1H-NMR (d6-DMSO; sa 1:1 mixture of rotamers)as 0.96 (3H, m) 1,07 (6N, m), and 2.27 (2H, m), 2,59 (2H, m), 2,84 (2H, m), 3,37/a 3.50 (4H, m), 4.26 deaths (2H, c), 4,39/4,43 (2H, 2x s), with 4.64/4,72 (2H, 2x s), 4,94/5,09 (2H, 2x s), 7,11/7,14 (2H, 2 m), was 7.36-7,49 (5H, m), 7,63/7,72 (2H, 2 d), to 7.84 (4H, m); MS (APCI+) for C34H38F4N4About2S: found: (M+1)=655 calculated 654.

Example 2 - Bitartrate 1-(N-(2-(diethylamino)ethyl)-N-(2-(4-triptoreline)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5-ethylpyrimidine-4-it

Specified in the title compound is obtained from intermediates A31 and V the method described in example 1.

1H-NMR (d6-DMSO; sa 1:2 mixture of rotamers): 0,93 (6N, m) a 1.08 (3H, m), and 2.27 (2H, m) to 2.66 (4H, m), 3,39/of 3.45 (4H, m), is 4.21 (2H, c), 4,39/was 4.42 (2H, 2x s), 4,66/4,77 (2H, 2x s), equal to 4.97/5,10 (2H, 2x s), 7,09/for 7.12 (2H, 2 t), 7,42/7,49 (2H, 2 t), 7,79/7,86 (1H, 2x DD), 7,87 (2H, d), 7,97/of 8.06 (1H, 2x DD), of 8.28 (2H, d), 8,62/8,71 (2H, 2x s); MS (APCI+) for C34H37F4N5O2S: found: (M+1)=656 calculated 655.

Example 3(s) - 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-triptoreline)benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylenediamine-4-one

The intermediate connection V (87,1 g, 0/26 mol) is suspended in dichloromethane (2,9 liters). Then add Gil) and the suspension is stirred for 45 minutes, during which receives the solution is completely dissolved substances. The intermediate connection A30 (91,2 g, 0.26 mol) for 5 minutes add in the form of a solution in dichloromethane (100 ml) and the resulting solution was stirred for 4 hours. Then add the mixture a saturated solution of ammonium chloride: water (1:1, 1 liter) and the solution stirred for 10 minutes. The organic phase is separated and extracted with a mixture of saturated ammonium chloride water (1:1, 1 liter) and receive extracts with pH 6. The organic phase is separated and extracted with water (1 liter) containing acetic acid (10 ml) to obtain the extract with a pH of 5. The dichloromethane layer is separated and extracted with a mixture of "a saturated solution of sodium carbonate: water: saturated solution of the salt (1:3:0,2, 1 liter), pH to 10.5, and then the mixture a saturated solution of salt: water (1:1, 1 liter). The brown solution is dried over anhydrous sodium sulfate, in the presence of decolorizing charcoal (35 g), filtered and the solvent is removed in vacuum to obtain a dark brown foam. The resulting foam is dissolved in isopropylacetate (100 ml) and the solvent is removed in vacuum. Dark brown resinous residue is dissolved in boiling isopropylacetate (500 ml), cooled to room temperature, precipitated and stirred over night. According to the scientists, the solid is dried by vacuum filtration funnel fused glass within 1 hour and then recrystallized from isopropylacetate (400 ml). After stirring overnight, the resulting solid is filtered off, washed with isopropylacetate (80 ml) and dried in vacuum to obtain specified in the connection header, 110 g, the yield of 63.5%.

1H-NMR (d6-DMSO; sa 1,9:1 mixture of rotamers): 0,99 (6N, t) of 2.10 (2H,m) of 2.50 (4H, square), 2,58/2,62 (2H, 2 t), 2,70/2,82 (2H, 2 t), of 2.86 (2H, t), 3,28/to 3.58 (2H, 2 t), 4,45/to 4.52 (2H, 2x s), 4,68/4,70 (2H, 2x s), is 4.93 (2H, c), to 6.95 (2H, m), 7,31 (2H, d), 7,31/7,37 (2H, 2 m) of 7.48/7,52 (2H, d), the 7.65 (2H, m), 7,72 (2H, m); MS (APCI+) (M+N)+667; so pl. 125(DSK - asymmetric of endotherm).

Example 3(b) - Bitartrate 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-triptoreline)benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylenediamine-4-it

Specified in the title compound is obtained from intermediates A30 and V the method described in example 1.

1H-NMR (d6-DMSO; sa 1:1 mixture of rotamers): 0,92/0,99 (6N, 2 t) to 1.99 (2H, m), 2,54 (6N, m), 2,68/2,74 (4H, m) to 3.36(2H, m), is 4.21 (2H, c), 4,37/of 4.44 (2H, 2x s), 4,63/4,74 (2H, 2x s), 4,89/5,13 (2H, 2x s), 7,08/7,14 (2H, 2 m), was 7.36-to 7.50 (4H, m), of 7.64/of 7.70 (2H, 2 d), 7,83 (4H, m); MS (APCI+) for C36H38F4N4O2S: found: (M+1)=667 calculated 666.

Example 3(s) - Hydrochloride, 1-(N-(2-(diethylamino)enoe base of example 3(a) (3.00 g, 0,0045 mol) is suspended, with stirring, in isopropanol (30 ml) and heated to 45With obtaining a light solution. Then the solution is cooled to room temperature and add concentrated hydrochloric acid (0,40 ml, 0.045 mol). The resulting suspension is stirred at room temperature for 35 minutes and then cooled to 0C for 35 minutes. After that, the suspension is filtered and washed with isopropanol (10 ml) and then with heptane (30 ml), and dried in vacuum to obtain specified in the title compound as a white solid (3.00 g, 95%).

1H-NMR (CDCl3)1,38 (6N, t) of 2.08 (2H, m), 2,82 (2H, t) to 2.99 (2H, t), 3,19 (4H, m) to 3.35 (2H, m), of 3.97 (2H, c), 4,42 (2H, c), to 4.81 (2H, c), 4,99 (2H, c), 6,87 (2H, t), 7,26 (2H, t), 7,33 (2H, d), 7,41 (2H, d), 7,53 (2H, d), 7,71 (2H, d), 11,91 (1H, s).

Example 4 - Bitartrate 1-(N-(2-(diethylamino)ethyl)-N-(2-(4-triptoreline)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylenediamine-4-it

Specified in the title compound is obtained from intermediates A31 and V the method described in example 1.

1H-NMR (d6-DMSO; sa 3:1 mixture of rotamers)0,92/0,98 (6N, t), L,99 (2H, m), 2,53 (6N, m), 2,68/a 2.75 (4H, m) to 3.41 (2H, m), 4,22 (2H, c), 4,N, d), 8,61/8,69 (1H, 2x s); MS (APCI+) for C35H37F4N5O2S: found: (M+1)=668 calculated 667.

Example 5 - Bitartrate 1-(N-(2-(diethylamino)ethyl)-N-(2-(4-triptoreline)pyrimid-5-ylmethyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylenediamine-4-it

Specified in the title compound is obtained from intermediates A33 and V the method described in example 1.

1H-NMR (d6-DMSO; sa 3:1 mixture of rotamers)0,92/1,09 (6N, t) a 1.96 (2H, m) 2,60 (6N, m) of 2.75 (4H, m), of 3.48 (2H, m) to 4.23 (2H, c), to 4.38/and 4.40 (2H, 2x s), 4,65/to 4.81 (2H, 2x s), equal to 4.97/5,11 (2H, 2x s), 7,07/7,10 (2H, 2 t), 7,38/7,44 (2H, 2 t), to $ 7.91 (2H, d), to 8.57 (2H, d), 8,84/8,93 (2H, 2x s); MS (APCI+) for C34H36F4N6O2S: found: (M+1)=669 calculated 668.

Example 6 - Hydrochloride 1-(N-methyl-N-(2-(4-chlorophenyl)-benzyl)-aminocarbonylmethyl)-2-(4-terbisil)thio-5-(2-amino-ethyl)pyrimidine-4-it

A solution of intermediate compound B80 (0,228 g) in ethanol (20 ml) hydronaut in the presence of 10% palladium on carbon (0.09 g) at atmospheric pressure for 2 days. The catalyst is filtered off, the solvent is removed in vacuo and the resulting oil purified by chromatography (silica, 10% methanol solution of ammonia in dichloromethane). Free actuarial removed in vacuum, and the residue triturated with ether; yield 0,132,

1H-NMR (d6-DMSO; sa 2:1 mixture of rotamers)of 2.58 (2H, m), 2,87/2,99 (3H, 2x s) to 2.99 (2H, m), 4,40/of 4.45 (2H, 2x s), 4,57/of 4.66 (2H, 2x s), equal to 4.97/5,00 (2H, 2x s), 7,16 (2H, m), 7,33/7,38 (2H, 2 d), of 7.4 to 7.7 (N, m) 8,0 (2H, Shir.m); MS (APCI+) for C29H28ClFN4O2S: found: (M+1)=551/553 calculated 550/552.

Example 7 - 1-(N-methyl-N-(2-(4-chlorophenyl)benzyl)-aminocarbonylmethyl)-2-(4-terbisil)thio-5-(2-acetamidomethyl)pyrimidine-4-one

A solution of compound of example 6 (0,173 g, 1 EQ.), acetic anhydride (0,033 ml, 1.1 EQ.) and di-Isopropylamine (of 0.066 ml, 1.2 EQ.) in dichloromethane (10 ml) was stirred at room temperature overnight. The solution was washed with aqueous ammonium chloride and aqueous sodium bicarbonate, and then the organic layer is dried and evaporated. The residue is triturated with ether and receive specified in the title compound as a white solid (0.156 g).

1H-NMR (CDCl3; sa 2:1 mixture of rotamers): a 1.96 (3H, s) of 2.64 (2H, m), 2,93/3,10 (3H, 2x s) to 3.49 (2H, m), 4,46 with 4.64 (6N, m), 6,77 (1H, Shir.t), 6,97-7,16 (3H, m), 7,26-7,49 (10H, m); MS (APCI+) for C31H30lFN4O3S: found: (M+1)=593/595 calculated 592/594.

Example 8 - 1-(N-(2-(diethylamino)ethyl)-N-(2-(4-chlorophenyl)-benzyl)aminocarbonylmethyl)-2-(4-CFT is 0,134 g, 1.2 EQ.) added to a solution of compound of example 37 (0.40 g, 1 EQ.) triethylamine (0,124 ml, 1.4 EQ.) in dichloromethane (5 ml) atC, and then stirred at this temperature for 4 hours. The mixture is washed with water, dried and evaporated to receive nelfinavir as a pale yellow solid. This substance is dissolved in a 2 M solution of dimethylamine in THF (10 ml) and stirred at room temperature for 16 hours. The solvent and excess amine is removed in vacuo and the product purified by chromatography (silica, 5-20% methanol in ethyl acetate, and then 1-10% methanol solution of ammonia in dichloromethane) to obtain specified in the connection header.

1H-NMR (CDCl3)0,98 (6N, t), 2,28/2,30 (3H, s), 2,46-2,65 (6N, m), 3,26/of 3.56 (2H, 2 t), 3,33/to 3.36 (2H, 2x with), 4,46/4,53/5,54/4,90 (4H, 4 s) of 4.67 (2H, s), 6,98 (2H, m), 7,21-7,50 (11N, m); MS (APCI+) for C35H41ClFN5O2S: found: (M+1)=650/652 calculated 649/651.

Compounds of the following examples get in the way described in example 1 mainly in accordance with the same procedure, except that in some cases, instead of HATU and di-Isopropylamine use EDC (2 EQ.) 1-hydroxybenzotriazol (1 EQ.). Then, where indicated, get salt JV is m, described in example 6 (see tab.18).

The following compound is produced by a method described in example 7 (see tab.19).

The following compound is produced by a method described for intermediate connection B60. Sol obtained by the method described in example 1 (see tab.20).

Biological data

1. Screening for inhibition of Lp-PLA2

Enzymatic activity was determined by measuring the exchange rate of the synthetic substrate (A) at 37With 50 mm HEPES buffer (N-2-hydroxyethylpiperazine-N’-2-econsultancy acid) containing 150 mm NaCl, pH 7,4.

The analysis was carried out in 96-well titration tablets. Recombinant Lp-PLA2was purified to homogeneity from infected with baculovirus Sf9 cells using a column, forming a chelate complex with zinc, affinity chromatographic column with separate Blue and anion-exchange columns. After purification and ultrafiltration enzyme at a concentration of 6 mg/ml was stored at 4C. Analytical tablets with the connection or the carrier and buffer was established on the volume of 170 ál using automated robotics. The reaction was initiated by adding 20 μl of 102.

The reaction was monitored at 405 nm and at 37C for 20 minutes using a tablet reader with automatic stirring. The reaction rate was measured as the rate of change of optical density.

Results

Compounds described in the examples were tested as described above and had the value of the IC50within the <0.1 nm to 10 μm.

Claims

1. 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-triptoreline)-benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylene-pyrimidine-4-one formulas

or its pharmaceutically acceptable salt.

2. Connection on p. 1 in free base form.

3. Connection under item 1 in the form of cleaners containing hydrochloride salt.

4. The compound according to any one of paragraphs.1-3, applicable in the treatment or prevention of a pathological state associated with the activity of the enzyme Lp-PLA2.

5. Connection p. 4, where the specified painful condition is atherosclerosis.

6. Connection p. 4, where the specified disease state is diabetes, hypertension, angina, reperfusion injury, ischemia, rheumatoid arthritis, stroke, Alzheimer's disease, myocardial infarction, sepsis, acute the and, applicable for primary and secondary prevention of acute coronary attacks.

8. The compound according to any one of paragraphs.1-3 for the manufacture of a medicinal product that is applicable for the treatment of painful conditions associated with the activity of the enzyme Lp-PLA2.

9. The compound according to any one of paragraphs.1-3 for the manufacture of a medicinal product, applicable to the treatment of atherosclerosis.

10. Pharmaceutical composition having the effect of inhibitor associated with lipoprotein phospholipase A2(Lp-PLA2) containing the compound according to any one of paragraphs.1-3 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to p. 10, adapted for oral administration.

12. The pharmaceutical composition under item 10 or 11, which further comprises a therapeutically effective amount of an agent that reduces the level of cholesterol.

13. The pharmaceutical composition according to p. 12, where the specified agent that lowers cholesterol, is a statin.

14. The pharmaceutical composition according to any one of paragraphs.10-13, used in the treatment or prevention of a pathological state associated with the activity of the enzyme Lp-PLA2.

15. The pharmaceutical composition according to p. 14, where the specified painful sosie is diabetes, hypertension, angina, reperfusion injury, ischemia, rheumatoid arthritis, stroke, Alzheimer's disease, myocardial infarction, sepsis, acute and chronic inflammation, and psoriasis.

17. The pharmaceutical composition according to any one of paragraphs.10-13 for the manufacture of medicinal products, applicable for primary and secondary prevention of acute coronary attacks.

18. The pharmaceutical composition according to any one of paragraphs.10-13 for the manufacture of drugs suitable for the treatment of painful conditions associated with the activity of the enzyme Lp-PLA2.

19. The pharmaceutical composition according to any one of paragraphs.10-13 for the manufacture of drugs suitable for the treatment of atherosclerosis.

20. A method of obtaining a connection on p. 1, including the interaction of the compounds of formula (II)

with the compound of the formula (III)

in the conditions of formation of the amide.

 

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