1,4,5-triple-substituted imidazole derivatives, processes for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to a method for producing derivatives of imidazole of formula A, where R1represents a substituted heterocycle, R4is phenyl, optionally substituted, R2represents the N3, -(CR10R20)nOR9further as stated in the description. The method includes the interaction of the compounds of formula II with poetential formula III. The invention includes methods of obtaining (a) the compounds of formula IV by reacting R4-CHO with a formamide, an acid catalyst and a dehydrating agent, b) the compounds of formula IV, which consists in the interaction of the compounds of formula I with p-toluensulfonate acid, an acid catalyst, with an organic solvent. Connection on p. 1 possess inhibitory activity against cytokines and therefore can be used as active compounds in pharmaceutical compositions. 7 C. and 23 C.p. f-crystals, 1 PL.

< / BR>
< / BR>
< / BR>
< / BR>

The invention relates to a new group, imidazole derivatives, to processes for their preparation, to their use in the treatment mediated by cytokines diseases, and to pharmaceutical compositions and for whom the tumor (name) are biological substances produced by various cells, such as monocytes or macrophages. IL-1, as shown, mediates many kinds of biological activity and is assumed to be important in the immunoregulation and other physiological conditions such as inflammation [see, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. Many known types of biological activity of IL-1 include the activation of T cells-helper cells, the initiation of fever, stimulation of the production of prostaglandin and collagenase, chemotaxis of neutrophils, activation of acute phase proteins and lower levels of iron in the blood plasma.

There are many pathological States in which excessive or unregulated production of IL-1 causes an exacerbation and/or disease. These diseases include rheumatoid arthritis, osteoarthritis, groove toxins and/or toxic shock syndrome, other acute or chronic painful inflammatory conditions such as inflammatory reaction induced by endotoxin or inflammatory bowel; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, arthritis rubella and acute synovitis. Recently recip is, . Clinical Immunology, 5(5), 287-297 (1985) doing a review of the kinds of biological activity that is associated with IL-1. It should be noted that some of these effects have been described by other authors as indirect effects of IL-1.

Excessive or unregulated production of TNF implied by mediating or exacerbation of a number of diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, arthritis rubella, and other conditions with arthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, syndrome ailments in adults with colds, cerebral malaria, chronic pneumonia, silicosis, sarcoidosis of the lungs, diseases of the resorption of bone tissue, reperfusion injury, reaction to vaccination, transplant rejection, fever, and muscle pain caused by infection, such as influenza, secondary kahalu after infection or malignant disease, kahalu after acquired immunodeficiency syndrome (AIDS), AIDS, KOS (complex due to AIDS), the formation of keloid tissue, scar tissue, Crohn's disease, ulcerative colitis or fever.

AIDS is caused by infection with T-lymphocytic-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cells mediating the immune system is weakened, and the infected individuals show severe accidental infection and/or unusual neoplasms. The introduction of HIV in T-lymphocytes requires the activation of T-lymphocyte. Other viruses, such as HIV-1, HIV-2, infect T-lymphocytes after activation, T cells, and this expression and/or replication protein of the virus is supported or mediated using such activated T cells. As soon as activated T-lymphocytes infected with HIV, the T-lymphocyte needs to continue to be in the activated state, to make possible the expression of a gene of HIV and/or HIV replication. Monokini, in particular TNF, assumed to be involved in mediated activated T-cell expression of the protein of HIV and/or viral replication, playing a role in maintaining activation of T-lymphocyte. For this reason, the influence on the activity of monokine, such as the inhibition of the production of monokine, in particular TNF, among HIV-infected individual helps in limiting the maintenance of activated T-cells, thereby reducing the progression of HIV infection not previously infected cells, resulting in slowing or eliminating the spread of the immune di is, also, as expected, support of HIV infection. These cells, like T cells, are targets for viral replication, and viral replication depends on the activated condition of the cells [see, Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57 (1989)]. Monokini, such as TNF, as shown, to activate HIV replication in monocytes and/or macrophages [see , Poli, et al., Proc. Natl. Acad. Sci., 87:782-784 (1990)] , therefore, inhibition of the production or activity of monokines helps in limiting the spread of HIV, as shown above for T cells.

TNF also, as shown, plays a variety of roles with other viral infections, such as cytomegalovirus (CMV), influenza virus and herpes virus, for the same reasons that have already been marked.

Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types, including menagerie cells, fibroblasts, endothelial cells and keratinocytes. Its production by endothelial cells is induced by IL-1, TNF, or lipopolysaccharide (LPS). IL-8 person, as shown, acts on neutrophils mouse, Guinea-pig, rat and rabbit. With respect to IL-8 used the th factor of neutrophils, derived from monocytes (HRRM), activating factor in neutrophil (FSA) and a chemotactic factor for lymphocytes T-cells.

IL-8 stimulates a number of functions in vitro. As shown, it has properties of chemoattractant for neutrophils, T-lymphocytes and basophils. In addition, it induces the release of histamine from basophils as normal and allergic individuals, as well as the release of lysosomal enzymes and quick selection with respiratory diseases from neutrophils. IL-8 also, as shown, increases the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, which may contribute to increased adhesion of neutrophils to endothelial cells of blood vessels. Many diseases are characterized by a massive infiltration of neutrophils. Conditions associated with increased production of IL-8 (which is responsible for the chemotaxis of neutrophils in inflammation) could be alleviated with compounds that are suppressors production of IL-8.

IL-1 and TNF affect a wide variety of cells and tissues, and these cytokines, together with other cytokines from leukocytes, are important and critical inflammatory mediators in a wide variety of pain alleviating many of these disease conditions.

In this area in the treatment remains a need for compounds that are anti-inflammatory drugs for suppressive cytokines, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.

Brief description of the invention

This invention relates to new compounds of the formula (I) and (II) and to pharmaceutical compositions containing the compounds of formula (I) or (II) and a pharmaceutically acceptable diluent or binder.

This invention also relates to a method of inhibiting cytokines and the treatment of diseases mediated by cytokines in a mammal, in need thereof, which includes an introduction to the specified mammal an effective amount of the compounds of formula (I) or (II).

This invention more specifically relates to a method of inhibiting the production of IL-1 in a mammal, in need thereof, which includes an introduction to the specified mammal an effective amount of the compounds of formula (I) or (II).

This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal, in need thereof, which includes the century is finding, more specifically relates to a method of inhibiting production of TNF in a mammal, in need thereof, which includes an introduction to the specified mammal an effective amount of the compounds of formula (I) or (II).

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

< / BR>
where R1is 4-pyridyl, pyrimidinyl, hinely, ethanolic, hinzelin-4-yl, 1-imidazolyl or 1-benzimidazolyl, where the heteroaryl ring is substituted with N(R10)C(O)Raor halogen-substituted mono - or di-C1-6-alkyl substituted amino and the ring is additionally optionally substituted C1-4by alkyl, halogen, hydroxyl, C1-4alkoxy, C1-4alkylthio,1-4alkylsulfonyl, CH2OR12, amino, mono - and di-C1-6alkyl substituted amino or N-heterocyclyl ring which has from 5 to 7 members, NR15;

R4represents phenyl, naphthas-1-yl or naphthas-2-yl, or heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, to the Deputy 4-phenyl, 4-naphthas-1-yl, 5-naphthas-2-yl or 6-naphthas-2-yl, represents halogen, cyano, nitro, -C (Z)NR7R17, -C(Z)OR16, - (CR10R20)vCOR12, -NR10C(Z)R16or - (CR10R20)vNR10R20and which, for other positions of substitution, is halogen, cyano,

-C(Z)NR13R14, -C(Z)OR3, - (CR10R20)m-COR3, -S(O)mR3, -OR SIG3,

-OR12, halogensubstituted-C1-4alkyl, C1-4alkyl,

- (CR10R20)mNR10C(Z)R3, -NR10S(O)m'R8, -NR10S(O)m'NR7R17,

-ZC(Z)R3, -ZC(Z)R12or - (CR10R20)mNR13R14;

v is 0 or an integer having a value of 1 or 2;

m is 0 or an integer 1 or 2;

m' is an integer having a value of 1 or 2;

m is 0 or an integer having a value of from 1 to 5;

R2represents C1-10alkyl N3, -(CR10R20)n'OR9, heterocyclyl, heterocyclyl1-10alkyl, C1-10alkyl, halogen-substituted C1-10-alkyl, C2-10alkenyl,2-10quinil,3-7cycloalkyl,3-7cycloalkyl1-10alkyl, C5-7cycloalkenyl,5-7cycloalkenyl-C1-10alkyl, aryl, arils1-10alkyl, heteroaryl, heteroaryl-C1-10alkyl, (CR10R20)nOR11, (CR10)nNR13R14, (CR10R20)nNO2, (CR10R20)nCN, (CR10R20)n'SO2R18,

(CR10R20)nS(O)m'NR13R14, (CR10R20)nC(Z)R11, (CR10R20)nOC(Z)R11, (CR10R20)nC(Z)OR11, (CR10R20)nC(Z)NR13R14, (CR10R20)nC(Z)NR11OR SIG9,

(CR10R20)nNR10C (Z) R11, (CR10R20)nNR10C(Z)R13R14, (CR10R20)nN(OR6)WITH(Z)R13R14, (CR10R20)nN(OR6)WITH(Z)R11, (CR10R20)nC(= NOR6R11,(CR10R20)nNR10C(=NR19) NR13R14, (CR10R20)nOC(Z)NR13R14, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nNR10C(Z)OR10, 5-(R18)-1, 2, 4-oxadiazol-3-yl or 4-(R12)-5-(R18R19)-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl; where the aryl, arylalkyl, heteroaryl, heteroallyl, cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;
Z is oxygen or sulfur;

Rarepresents hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, arils1-4alkyl, heteroaryl, heteroaryl1-4alkyl, heterocyclyl, or heterocyclyl1-4alkyl;

R3is heterocyclyl, heterocyclyl1-10alkyl, or R8;

R5represents hydrogen, C1-4alkyl, C2-4alkenyl,2-4quinil or NR7R17except for a residual-SR5which-SNR7R17and-S(O)R5which is S;

R6represents hydrogen, a pharmaceutically acceptable cation, C1-10alkyl, C3-7cycloalkyl, aryl, arils1-4alkyl, heteroaryl, heteroaryl1-10alkyl, heterocyclyl, aroyl, or C1-10alkanoyl;

R7and R17each independently selected from hydrogen or C1-4the alkyl, or R7and R17together with the nitrogen to which they are attached, form a 5-7-membered heterocyclic ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR15;

R8represents C1-10alkyl, halogen-substituted - C1-10alkyl, C2-10alkenyl,2-10quinil,3-7cycloalkyl,5-7CIC
, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14where aryl, arylalkyl, heteroaryl, heteroaromatic may be optionally substituted;

R9represents hydrogen, -C(Z)R11, optionally substituted C1-10alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryls1-4alkyl;

R10and R20each independently selected from hydrogen or C1-4of alkyl;

R11represents hydrogen, C1-10alkyl, C3-7cycloalkyl, heterocyclyl, heterocyclyl1-10alkyl, aryl, arils1-10-alkyl, heteroaryl or heteroaryl1-10alkyl;

R12represents hydrogen or R16;

R13and R14each independently selected from hydrogen or optionally substituted C1-4the alkyl, optionally substituted aryl or optionally substituted aryls1-4-alkyl or together with the nitrogen to which they are attached, form a 5-7-membered heterocyclic ring which optionally includes an additional heteroatom selected from oxygen, sulfur or NR9;

R15is R10or(Z) -CAlkyl;

R18represents C1-10alkyl, C3-7cycloalkyl, heterocyclyl, aryl, arils1-10alkyl, heterocyclyl, heterocyclyl1-10alkyl, heteroaryl, or heteroaryl1-10alkyl;

R19represents hydrogen, cyano, C1-4alkyl, C3-7cycloalkyl or aryl;

or its pharmaceutically acceptable salt.

Detailed description of the invention

The new compounds of formula (I) can also be used in connection with the veterinary treatment of mammals, other than humans, in need of the inhibition of the production or inhibition of cytokines. In particular, mediated by cytokines diseases in animals subject to therapeutic or prophylactic treatment include painful conditions, such as those specified here under medical treatment, but particularly viral infections. Examples of such viruses include, but are not limited to, infection by lentiviruses, such as a virus infectious anemia horses, the virus goat arthritis, visna or maedi virus, or retrovirus infections, such as, but not limited to, human immunodeficiency virus cats (VIC), human immunodeficiency virus bull or human immunodeficiency virus dogs, or other retroviral infections.

Heteroaryl ring R1is replaced by N(R10)C(O)Raor halogen-substituted mono - or di-C1-6alkyl substituted amino. When the substituent R1is N(R10) C(O)Ra, Rarepresents hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, arils1-4alkyl, heteroaryl, heteroaryl1-4alkyl, heterocyclyl or heterocyclyl1-4alkyl, C1-4alkyl, Rapreferably is C1-6by alkyl; preferably R10is hydrogen. Also observed that the radicals Rain particular, C1-6the alkyl group may be optionally substituted, preferably from one to three times, preferably halogen, such as fluorine, as in trifluoromethyl or triptoreline.

When the substituent R1is a halogen-substituted mono - and dis1-6alkyl substituted amino, preferably where the amino group is montemesola halogen-substituted, such as trifter-, that is, a trifluoromethyl or triptorelin.

Heteroaryl ring R1may contain additional replacement group, such as1-4alkyl, halogen, HE1-4alkoxy, C1-4alkylthio,1-4alkylsulfonyl, CH2OR12, amino, mono - and dis1-6alkyl substituted amino, or N-heterocyclic ring which consists of 5-7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15.

The preferred position in the ring substituent R14-peredelnogo is derived position 2, such as 2-methyl-4-pyridyl. The preferred position in the ring at 4-pyrimidinium ring is position 2, such as 2-methylpyrimidine, 2-aminopyrimidine or 2-methylaminopropyl.

Accordingly, for compounds of formula (II) R1is a 4-pyridium or pyrimidinium ring, substituted C1-4alkyl-amino group. WITH1-4alkylamino is, accordingly, methylamino, ethylamino, isopropylamino, n-butylamino or tert-butylamino. Preferably, the ring is a 4-pyrimidinium ring. The preferred position in the ring at 4-pyrimidinecarbonitrile R14-piridinovogo is derived position 2, such as 2-methylamino-4-pyridyl. Peregrinae or pyrimidinyl ring may contain additional surrogate group, such as1-4alkyl, halogen, hydroxyl, C1-4alkoxy, C1-4alkylthio,1-4alkylsulfonyl, CH2OR12, amino, mono - and dis1-6alkyl substituted amino, or N-heterocyclic ring is 5-7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15.

Accordingly, R4for compounds of formula (I) and (II) is a phenyl, naphthas-1-yl or naphthas-2-yl or heteroaryl, which is optionally substituted by one or two substituents. More preferably R4is phenyl or nafcillin ring. Suitable substituents R4when he is 4-phenyl, 4-naphthas-1-ilen, 5-naphthas-2-ilen or 6-naphthas-2-ilen radical, are one or two deputies, each of which is independently selected from halogen, -SR5, -SOR5, -OR12, CF3or - (CR10R20)vNR10R20and for other positions of substitution on these rings are preferred by the Deputy is halogen, -S(O)mR3S(O)m'R8. Preferred substituents for the 4-position in phenyl and naphthas-1-yl, and to position 5 in naphthas-2-yl include halogen, mainly, fluorine and chlorine, and-SR5and-SOR5where R5is preferably C1-2the alkyl, more preferably stands; of which fluorine and chlorine are preferred and most preferred is fluorine. Preferred substituents for position 3 of the phenyl and naphthas-1-ilen ring include halogen, mainly, fluorine and chlorine; -or SIG3mainly WITH1-4alkoxy; CF3; NR10R20such as amino; -NR10C(Z)R3mainly, -NHCO-(C1-10alkyl); -NR10S(O)m'R8mainly, -NHSO2(C1-10alkyl); and-SR3and SOR3where R3is preferably1-2the alkyl, more preferably the stands. When the phenyl ring is disubstituted, preferably these substituents represent two independent halogen radical, such as fluorine or chlorine, preferably di-chloro, and more preferably in position 3, 4. It is also preferable that at position 3 for-or SIG3and-ZC(Z)R3the radicals R3may also include hydrogen.

Accordingly, for compounds of formula (I) and (II) Z is oxygen or sulfur, preferably oxygen.

Accordingly, for compounds of formula (I) and (II) R2represents C1-10alkyl N3, -(CR10R20)n'OR9, heterocyclyl, heterocyclyl1-10alkyl, C1-10alkyl, halogen-substituted C1-10-alkyl, C2-10alkenyl,2-10quinil,3-7cycloalkyl,3-7cycloalkyl1-10alkyl, C5-7cycloalkenyl,5-7cycloalkenyl1-10alkyl, aryl, arils1-10alkyl, heteroaryl, heteroaryl1-10alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18,

(CR10R20)nNR13R14, (CR10R20)nNO2, (CR10R20)nCN, (CR10R20)n'SO2R18<>0R20)nOC(Z)R11, (CR10R20)nC(Z)OR11, (CR10R20)nC(Z)NR13R14, (CR10R20)nC(Z)NR11OR9,

(CR10R20)nNR10C(Z)R11, (CR10R20)nNR10C(Z)R13R14, (CR10R20)nN(OR6)WITH(Z)R13R14, (CR10R20)nN(OR6)WITH(Z)R11, (CR10R20)nC(= NOR6R11, (CR10R20)nNR10C(=NR19)NR13R14, (CR10R20)nOC(Z)NR13R14, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nNR10C(Z)OR10, 5-(R18)-1,2,4-oxadiazol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; where cycloalkenyl, cycloalkylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylboronic, heterocyclic and heterocyclic alkyl radicals may be optionally substituted; where n is an integer having values from 1 to 10, m is 0 or an integer 1 or 2; n' is 0 or an integer having values from 1 to 10; and m' is 1 or 2. Preferably n is 1-4.

Preferably R2is optional salamasina C1-10the alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-7cycloalkyl1-10the alkyl group (CR10R20)nC(Z)OR11, (CR10R20)nNR13R14, (CR10R20)nNHS(O)2R18, (CR10R20)nS(O)mR18, optionally substituted aryl; optionally substituted aryl-C1-10the alkyl, (CR10R20)nOR11, (CR10R20)nC(Z)R11or group (CR10R20)nC(= NOR6R11. More preferably R2is optionally substituted heterocyclyl ring and optionally substituted heterocyclic1-10the alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C3-7cycloalkyl - C1-10the alkyl, optionally substituted aryl group (CR10R20)nNR13R14or (CR10R20)nC(Z)OR11.

When R2is optionally substituted by heterocyclyl, the ring is preferably of morpholino, pyrrolidinyl or piperidinyl group. When the ring is optionally substituted, the substituents can be directly pickup. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. Heterocyclyl ring may be optionally substituted one to four times, independently by halogen; C1-4by alkyl; galazalinum C1-4the alkyl, such as trifluoromethyl or triptorelin; aryl, such as phenyl; arylalkyl, such as benzyl, where the aryl or arylalkyl radicals can themselves be optionally substituted (as the definition section below); WITH(O)OR11such as radicals C(O)1-4alkyl or C(O)HE; S(O)H; C(O)1-4the alkyl, replacement WITH1-4the alkyl, C1-4alkoxy, S(O)mWITH1-4the alkyl (where m is 0, 1 or 2), NR10R20(where R10and R20are independently hydrogen or C1-4by alkyl).

Preferably, if the ring is a piperidine ring attached to the imidazole in position 4, and the substituents are located directly on an available nitrogen, that is, form 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxy-carbonyl-4-piperidine, 2,2,2-Cryptor-ethyl-4-piperidine or 1-TRIFLUOROACETYL-4-piperidine. If the ring is substituted by an alkyl group and ring attached in position 4, it is preferable hall, the ring is attached to the imidazole in position 3 and all deputies are directly available nitrogen.

When R2is optionally substituted heterocyclyl1-10alkyl group, the ring is preferably of morpholino, pyrrolidinyl or piperidinyl group. Preferably those alkyl radicals have from 1 to 4, more preferably 3 or 4, and most preferably 3, as in through the group. Preferred heterocyclic alkyl groups include, but are not limited to them, morpholinoethyl, morpholinopropan, pyrrolidinylcarbonyl, and piperidinophenyl radicals. Heterocyclic ring is also optionally substituted similarly as above, for direct attachment heterocyclyl.

When R2is optionally substituted C3-7cycloalkyl or optionally substituted C3-7cycloalkyl1-10the alkyl, cycloalkyl group is preferably C5-C6ring, and this ring may be optionally substituted 1 or more times, independently, by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C1-10alkoxy, such as labels is amino, mono - and di-substituted amino, such as in the group NR7R17; or where R7R17can be cyklinowanie together with the nitrogen to which they are attached, with the formation of a 5-7-membered ring that optionally includes an additional heteroatom selected from O/N/S; C1-10the alkyl, such as methyl, ethyl, propyl, isopropyl or tert-butyl; halogen-substituted by alkyl, such as CF3or triptorelin; replacement C1-10the alkyl, C(O)or SIG11such as the free acid or a derivative complex methyl ester; optionally substituted aryl such as phenyl; optionally substituted arylalkyl, such as benzyl or phenethyl; and further, where the aryl radicals can also be substituted one or two times by halogen; hydroxy; C1-10alkoxy; S(O)mby alkyl; amino, mono - or di-substituted amino, such as group NR7R17; alkyl or halogen-substituted by alkyl.

When R2is (CR10R20)nNR13R14, R13and R14are as defined in formula (I), that is, R13and R14are, each independently, selected from hydrogen, optionally substituted C1-4the alkyl, optional sameselena, form a 5-7-membered heterocyclic ring, optionally containing an additional heteroatom selected from oxygen, sulfur or NR9. It has been observed that in some cases it can give the same radical as heterocyclic C1-10alkyl radical, noted above, which is also suitable as R2. If the ring NR13R14cyclosiloxane, he may be optionally substituted as herein defined. Preferably R13and R14are, independently, hydrogen, C1-4by alkyl, preferably by stands or benzyl. The value of n is preferably from 1 to 4, more preferably equal to 3 or 4 and most preferably equal to 3, as through the group. Preferred groups include, but are not limited to, aminopropyl, N-methyl-N-benzyl)aminopropyl, N-phenylmethyl)amino-1-propyl or diethylaminopropyl.

When R2is a group (CR10R20)nC(Z)OR11, R11is, respectively, hydrogen, C1-4the alkyl, mainly stands. The value of n is preferably from 1 to 4, more preferably equal to 2 or 3, as in through the group. Preferred groups include, but are not limited to the rd (CR10R20)nS(O)mR18, m is 0, 1 or 2 and R18preferably is aryl, especially phenyl or C1-10the alkyl, mainly stands. The value of n is preferably from 1 to 4, more preferably equal to 2 or 3 as ethyl or through the group.

When R2is a group (CR10R20)nOR11, R11is, respectively, hydrogen, aryl, mainly by phenyl, or C1-10the alkyl, mainly stands or ethyl. The value of n is preferably from 1 to 4, more preferably equal to 2 or 3 as ethyl or through the group.

When R2is a group (CR10R20)nNHS(O)2R18, R18is, respectively, alkyl, mainly stands. The value of n is preferably from 1 to 4, more preferably equal to 2 or 3 as ethyl or through the group.

When R2is optionally substituted by aryl, aryl is preferably phenyl. The aryl ring may be optionally substituted one or more times, preferably one or two substituents, independently selected from C1-4of alkyl, halogenated10R20)tOR11, -(CR10R20)tNR10R20mainly amino or mono - or di alkylamino -(CR10R20)nS(O)mR18where m is 0, 1 or 2; -SH-, -(CR10R20)nNR13R14, -NR10C(Z)R3(such as the N(C1-10alkyl)); -NR10S(O)mR8(such as-NHSO2(C1-10alkyl)); and t is 0 or an integer from 1 to 4. Preferably the phenyl is substituted in the 3 or 4 position - (CR10R20)tS(O)mR18and R18preferably is C1-10the alkyl, mainly stands.

When R2is optionally substituted heteroaryl or heteroarylboronic group, the ring may be optionally substituted one or more times, preferably one or two substituents, independently selecting one or more times, WITH1-4by alkyl, halogen-substituted C1-4the alkyl, such as trifluoromethyl or foretel, halogen, especially fluorine or chlorine, (CR10R20) tOR11, -(CR10R20)tNR10R20mainly amino or mono - or di alkylamino -(CR10R20)nS(O)mR18where m is 0, NR10S(O)mR8(such as-NHSO2(C1-10alkyl)); and t is 0 or an integer from 1 to 4.

The person skilled in the art will easily notice that when R2is radical (CR10R20)nOC(Z)R11or (CR10R20)nOC(Z)R13R14or any other similarly substituted group, preferably n is at least 2, which allows the synthesis of stable compounds.

Preferably R2is1-4alkyl (branched and unbranched), mainly methyl, metaltipped, methylsulfinylpropyl, aminopropyl, N-methyl-N-benzylaminopurine group, diethylaminopropyl, cyclopropylmethyl, morpholinylmethyl, morpholinopropan, morpholinylmethyl, piperidine or substituted piperidine. More preferably R2represents methyl, isopropyl, butyl, tert-butyl, n-propyl, metaltipped or methylsulfinylpropyl, morpholinopropan, morpholinylmethyl, phenyl, substituted by halogen, thioalkyl or sulfonylation, such as methylthio, methylsulfinyl or methylsulfonyl radical; piperidinyl, 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxy-carbonyl-4-piperidine, 2,2,2-triptorelin-4-piperid is hiccuping as a substitute group, unsaturated bond, i.e venelinova or acetylene linkage is preferably not directly linked to a nitrogen, oxygen or sulfur radicals, for example in or SIG3or for some of the radicals R2.

As used here, the term "optionally substituted" if it is not specifically defined shall mean such groups as fluorine, chlorine, bromine or iodine; hydroxy; replacement C1-10alkyl, C1-10alkoxy, such as methoxy or ethoxy; S(O)malkyl, where m is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulphonyl; amino, mono - and di-substituted amino, such as in group NR7R17; or where R7R17can together with the nitrogen to which they are attached, to collisionality with the formation of a 5-7-membered ring that optionally includes an additional heteroatom selected from O/N/S; C1-10alkyl, cycloalkyl or cycloalkenyl group, such as methyl, ethyl, propyl, isopropyl, tert-butyl and the like or cyclopropylmethyl; halogen-substituted C1-10alkyl, such as CF3; or triptorelin, optionally substituted aryl, such as phenyl, or optionally substituted arylalkyl, such as benzyl or phenethyl, where these and1-10alkoxy; S(O)malkyl; amino, mono - and di-substituted amino, such as in group NR7R17; alkyl or CF3.

In a preferred subgroup of compounds of formula (I) R2is morpholinopropan, aminopropyl, piperidinyl, N-benzyl-4-piperidinyl, N-methyl-4-piperidinyl or 2,2,6,6-tetramethylpiperidine-4-yl, 2,2,2-triptorelin-4-piperidine or 1-TRIFLUOROACETYL-4-piperidine; and R4represents phenyl or phenyl substituted once or twice by fluorine, chlorine, C1-4alkoxy, S(O)malkyl, methanesulfonamide or ndimethylacetamide.

In a preferred subgroup of compounds of formula (II) R1is 2-methylamino-4-pyrimidinyl or 2-methylamino-4-pyridyl; R2is morpholinopropan, aminopropyl, piperidinyl, N-benzyl-4-piperidinyl, N-methyl-4-piperidinyl or 2,2,6,6-tetramethylpiperidine-4-yl; and R4represents phenyl or phenyl substituted once or twice by fluorine, chlorine, C1-4alkoxy, S(O)mthe alkyl, methanesulfonamide or ndimethylacetamide.

Appropriate pharmaceutically acceptable salts are well known to specialists in this field and include basic salts of inorganic and organic acids, such as chloride-hydrogen acid, methyl -, in SNA acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed with pharmaceutically acceptable cation, for example, if the replacement group includes carboxylation. Appropriate pharmaceutically acceptable cations are well known to specialists in this field and include the cations of alkali metals, alkaline earth metals, ammonium and Quaternary ammonium.

The following terms as they are used here, refer to:

"halo" or "halogen" include Halogens: chlorine, fluorine, bromine and iodine.

"C1-10alkyl" or "alkyl" radicals with a straight or branched chain of from 1 to 10 carbon atoms, unless the chain length is not limited otherwise, include, but are not limited to, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl, ISO-butyl, tert-butyl, n-pentyl and the like.

The term "cycloalkyl" is used here to denote the cyclic radicals preferably 3-8 carbons, who"cycloalkenyl" is used here to denote the cyclic radicals preferably 5-8 carbons, which have at least one connection including, but not limited to, cyclopentenyl, cyclohexenyl and the like.

The term "alkenyl" is used here in all cases to refer to radicals with a straight or branched chain with 2 to 10 carbon atoms, unless the chain length is not limited otherwise, including, but not limited to, ethynyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

"Aryl" is phenyl and naphthyl.

"Heteroaryl" (alone or in any combination, such as "heteroaromatic" or "heteroaromatic") - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group comprising N, O or S, such as, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, hintline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole or benzimidazole.

"Heterocyclic" (on its own or in any combination, such as "geterotsiklicheskikh") - saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group comprising N, O CLASS="ptx2">

The term "aralkyl" or "heteroaromatic", or "heterocyclic alkyl" is used here to denote a1-4of alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic radical, as well as defined here, unless otherwise stated.

"Sulfinil - oxide, S(O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized to S(O)2the radical.

"Aroyl" - C(O)AG, where AG is derived phenyl, naphthyl or arylalkyl, such as defined above, such group includes, but is not limited to, benzyl and phenethyl.

"Alkanoyl" - C(O) C1-10alkyl, where alkyl is as defined above.

For the purposes of the present invention the "core" 4-pyrimidinyl radical for R1or R2referred to as formula

< / BR>
Compounds of the present invention can include one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All these compounds are included in the scope of the present invention.

Examples of compounds of formula (I) include:

5-(2-acetamido-4-pyrimidinyl)-4- (4-forfinal)-1-(4-morpholino-3-propyl)imida the developments of the formula (II) include:

5-[4-(2-methylamino)pyrimidinyl] -4- (4-forfinal)-1-(1-methyl-piperidine-4-yl)imidazole;

5-[4-(2-methylamino)pyrimidinyl] -4- (4-forfinal)-1-(4-morpholine-3-propyl)imidazole;

5-[4-(2-methylamino)pyrimidinyl] -4- (4-forfinal)-1-(piperidine-4-yl)imidazole;

5-[(2-ethylamino)pyrimidine-4-yl] -4- (4-forfinal)-1-(1-methylpiperidin-4-yl)imidazole;

4-(4-forfinal)-5-[2-(isopropyl)aminopyrimidine-4-yl] -1-(1-methylpiperidin-4-yl)imidazole;

5-[4-(2-methylamino-4-pyrimidinyl)] -4- (4-forfinal)-1-(2,2,6,6-tetramethylpiperidine-4-yl)imidazole;

5-(2-methylamino-4-pyrimidinyl)-4- (4-forfinal)-1-(2-cyanoethyl)imidazole;

5-(2-methylamino-4-pyrimidinyl)-4- (4-forfinal)-1-[1-(2,2,2-tryptophanyl)-4-piperidinyl]imidazole;

5-(2-amino-4-pyrimidinyl)-4- (4-forfinal)-1-[1-(2,2,2-triptorelin)-4-piperidinyl]imidazole;

5-(2-amino-4-pyrimidinyl]-4- (4-forfinal)-1-[(1-TRIFLUOROACETYL) -4-piperidinyl]imidazole.

Preferred compounds of formula (II) include:

5-[4-(2-methylamino)pyrimidinyl] -4- (4-forfinal)-1-(4-morpholino-3-propyl)imidazole;

5-[4-(2-methylamino)pyrimidinyl] -4- (4-forfinal)-1-(1-methylpiperidin-4-yl)imidazole;

5-[4-(2-methylamino)pyrimidinyl]-4- (4-forfinal)-1-(4-piperidine)imidazole.

The present invention also includes a new connection is l)-1-(1-methylpiperidin - 4-yl)-5-(2-methylthio-4-pyrimidinyl)imidazole;

4-(forfinal)-1-(1-methylpiperidin - 4-yl)-5-(2-methylsulfinyl-4-pyrimidinyl)imidazole;

1-tert-butyl-4-(4-forfinal)-5-(2-methylsulfinyl-4-pyrimidinyl)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-dipiradol)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4 - forfinal)-1-(tetrahydro-4-pyranyl)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4 - forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4 - forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4 - forfinal)-1-(1-TRIFLUOROACETYL-piperidine-4-yl)imidazole;

5-(4-pyridyl)-4-(4-forfinal)-1- (4-piperidinyl) imidazole;

5-(4-pyridyl)-4-(4-forfinal)-1- (1-tert-butoxycarbonyl-4-piperidinyl)imidazole.

For the purposes of the present invention dose rate, details of preparation and methods of making compounds of the formula (II) are similar to those that relate to compounds of formula (I). In addition, the dose and details of the preparation with the use of compounds of the formula (A) as inhibitors SOH-2 and PGHS are similar to those that relate to compounds of formula (I) as described here.

In a further aspect the present invention concerns a method which provides 4-pyridyl, pyrimidinyl, hinely, ethenolysis, hinzelin-4-yl, 1-imidazolyl or 1-benzimidazolyl, where heteroaryl ring optionally substituted by one or two substituents, each of which, independently, selected from C1-4of alkyl, halogen, hydroxyl, C1-4alkoxy, C1-4alkylthio,1-4alkylsulfonyl, CH2OR12, amino, mono - or di-C1-6alkyl substituted amino, N(R10)C(O)Raor N-heterocyclyl ring, and the ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; and where all replacement group in R1, R2and R4are the same as in formulas (I) and (II). For use in the description section of the synthesis the synthesis of compounds of formula (I)" will also refer to this broader description R1.

In a further aspect, the present invention relates to the compounds of formula (IIA) having the structure

< / BR>
where p is 0 or 2; R4is as defined for formula (I), and ar represents optionally substituted aryl, as defined here. Accordingly, AG represents phenyl optionally substituted C1-4the alkyl, C1-4alkoxy or halogen. Prefer the (II) can be obtained by synthesis methods, some of which are illustrated in schemes I-XI (see the end of the description). The synthesis provided for in these schemes can be applied to obtain the compounds of formula (I), with many different groups of R1, R2and R4that interact with the use of optional substituents, suitably protected for compatibility with the reactions outlined here. Subsequent withdrawal of protection in these cases, then network connections usually described properties. Once formed imidazole nucleus, other compounds of formula (I) and (II) can be obtained by standard methods of mutual transformations of functional groups is well known in this field.

For example: -C(O)NR13R14of CO2CH3by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR13R14in CH3HE; OC(O)R3from IT, for example, with l(O)R3in pyridine; -NR10-C (S) NR13R14from other10with allylisothiocyanate or titanoboa acid; NR6C(O)OR6from NR6with alkylchlorosilanes; -NR10C(O)NR13R14from other10by treating the isocyanate, for example, HN= C= O, or R10N=C=O; -NR10C(O)R8R3with H3NR3+SLA-by heating in alcohol; -C(NR13R14)SR3from-C(S)NR13R14with R6-I in an inert solvent, for example acetone; -C(S)NR13R14(where R13or R14is not hydrogen) from C(S)NH2with HNR13R14-C(=NCN)-NR13R14from-C(=NR13R14)-SR3with NH2CN by heating in anhydrous alcohol, alternatively from-C(=NH)-NR13R14by processing the Enrichment and NaOEt in EtOH; -NR10-C (=NCN) SR8from other10by treating (R8S)2C= NCN; -NR10SO2R3from other10by processing lSO2R3by heating in pyridine; -NR10C(S)R3NR10C(O)R8by treatment with reagent Lawesson (Lawesson''s reagent) [2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithia-diphosphate-2,4-disulfide] ; -NR10SO2CF3from other6with anhydride triftormetilfullerenov acid and base, where R3, R6, R10, R13and R14such as defined here for the formula (I).

Predecessors of the groups R1, R2and R4can be other groups of R1, R2and R4that can be mutually transformed into each other by standard means mutual p is th C1-10alkyl, can be converted into the corresponding1-10the N3derived by interacting with the corresponding azide salt, and then, if desirable, may be restored to the appropriate1-10N2connection, which, in turn, can interact with R18S(O)2X, where X represents a halogen (e.g. chlorine), to obtain the corresponding compound WITH the1-10NS (O)2R18.

The alternate connection of the formula (I), where R2represents a halogen-substituted C1-10alkyl, can interact with aR13R14NH to obtain the corresponding compound WITH the1-10NR13R14or can interact with the salt of an alkali metal, R18SH to obtain the corresponding compound WITH the1-10SR8.

About the scheme I, the compounds of formula (I) is appropriately obtained by the interaction of the compounds of formula (IIA) with the compound of the formula (III), where p is 0 or 2, R1, R2and R4such as defined here for the formula (I), or are precursors of the groups R1, R2and R4, and ar represents optionally substituted penloup R1, R2and R4. As found, R2NH2that interacts with R1CHO with the formation of the imine, the radical R2formula (III), when it contains a reactive functional group such as a primary or secondary amine, alcohol or tilne connection, this group should be appropriately protected. Appropriate protective groups can be found in Protecting Groups Organic Synthesis, Green T. W., Wiley-Interscience, New York, 1981, the disclosure of which is incorporated herein by reference. For example, when2represents a heterocyclic ring, such as piperidino the ring nitrogen is protected with groups such as tert-Vos, CO2R18or substituted arylalkyl radical.

The reaction is conveniently carried out at ambient temperature or under cooling (for example, -50oup to 10o), or by heating in an inert solvent such as methylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile or dimethoxyethane, in the presence of a suitable base, such as2CO3, tert-N2, 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU) or guanidine bases, such as 1,5,7-diazabicyclo[4,4,0]Dec-5-ene (LDP). Intermediate compounds of formula (II), as found, are about the>The interaction of the compounds of formula (IIA), where p=2, with the compound of formula (III), scheme I, gives significantly higher yields compounds of formula (I), than where p=0. In addition, the interaction of the compounds of formula (IIA), where p= 2 is more attractive from the point of view of the environment and the economy. When p=0, the preferred solvent used is methylene chloride, which is unattractive from the point of view of the environment for production in an industrial scale, preferred basis biodiesel fuel is also more expensive and gives some side products and impurities than when using commercially attractive synthesis (p=2), as described below.

As noted, according to the scheme I use 1,3-dipolar cyclopamine anion substituted aristotelician (when p=0) to imine. More specifically, this collaboration requires a strong base such as an amine base, for use on stage deprotonation. Commercially available biodiesel fuel is preferred, although it can also be used tert-piperonyl, Li+ or Na+, or K+ hexamethyldisilazide. Although methylene chloride is the preferred solvent, can be used and the others who MOF, diethyl ether, tert-butyl methyl ether; and acetonitrile, toluene or mixtures thereof. The reaction may take place at from about -20oWith up to approximately 40oC, preferably from about 0oWith up to 20oS, more preferably from about 0oWith up to about 10oWith and most preferably about 4oFor reactions involving R1a group of pyrimidine. For compounds where R1is pyridine, discovered that may be necessary to change the reaction conditions, such as temperature and solvent, such as reducing the temperature to about -50oWith or replacement of the solvent to THF.

In the further process, the compounds of formula (I) can be obtained by attaching the corresponding derivative compounds of formula (IX)

< / BR>
where T1is hydrogen, and T4is R4or alternative T1is R1and T4represents H, in which R1, R2and R4such as defined above; to the connection, which represent: (i) when T1is hydrogen, the corresponding derived heteroaryl ring R1H, in terms of the binding rings to bind heteroaryl ring R1red ring R4H, in terms of the binding rings to effect the binding of the aryl rings R4with the imidazole nucleus at position 4.

Such reactions join aryl/heteroaryl well known to specialists in this field. Usually ORGANOMETALLIC synthetic equivalent of the anion of one component is associated with a reactive derivative of the second component in the presence of an appropriate catalyst. Anionic equivalent can be formed in any of the imidazole of formula (IX), in this case, the aryl/heteroaryl connection provides a reactive derivative, or aryl/heteroaryl compounds, in this case, the imidazole provides reactive derivative. Accordingly, suitable derivatives of the compounds of formula (IX) or aryl/heteroaryl rings include ORGANOMETALLIC derivative, such as magyarkanizsa, tsinkorganicheskih, and ORGANOTIN derivatives of boric acid, and a suitable reactive derivatives include derivatives with bromine, iodine, PERSULPHATES and triftoratsetata. Corresponding methods are described in WO 91/19497, the description of which is incorporated herein by reference.

Sootvetstvenno, PERSULPHATES or triflates derived heteroaryl or aryl ring in the presence of a catalyst linking rings, such as palladium (0) or palladium (II) catalyst, following the way Kumada et al., Tetrahedron Letters, 22, 5319 (1981). Convenient such a catalyst include tetrakis(triphenylphosphine)palladium and PdCl2[1,4-bis(diphenylphosphine)butane], optionally in the presence of lithium chloride and a base such as triethylamine. In addition, Nickel (II) catalyst, such as Ni (II) CL2(1, 2-biphenylphosphine) ethane can also be used for linking the aryl ring, following the way Pridgen et al. , J. Org. Chem, 1982, 47, 4319. Suitable reaction solvents include hexamethylphosphoramide. When the heteroaryl ring is a 4-pyridyl, corresponding derivatives include 4-bromo - and 4-iodine-pyridine and persulphate and triflate esters of 4-hydroxypyridine. Similarly, the corresponding derivatives in the case where the aryl ring is phenyl, include bromine, persulfonic, triplet and preferably improsoned. Appropriate magyarkanizsa and tsinkorganicheskih derivatives can be obtained by treating the compounds of formula (IX) or bromo derivatives of alkylsilane respectively. Lithium intermediate compound can then be treated with an excess of halogen derivatives of magnesium or zinc to obtain the corresponding ORGANOMETALLIC reagent.

Derived triamcinolone the compounds of formula (IX) may be treated with bromine-, Floralife, triplet - or preferably improsoned aryl or heteroaryl ring in an inert solvent, such as tetrahydrofuran, preferably containing 10% hexamethylphosphoramide, in the presence of an appropriate catalyst connection, such as palladium (0) catalyst, such as tetrakis-(triphenylphosphine)palladium, using the method described in Stille, J. Amer. Soc, 1987, 109, 5478, in U.S. patents 4719218 and 5002942, or by use of palladium (II) catalyst in the presence of lithium chloride, optionally with addition of a base, such as triethylamine, in an inert solvent, such as dimethylformamide. Derivatives triamcinolone can be conveniently obtained by metallation-corresponding compounds of formula (IX) of the corresponding agent to attach lithium, such as second-utility or n-utility, in the ether solvent, such as tetragidrofuran, or by treating the bromo derivatives soutetsu. Alternative bromo derivatives of compounds of formula (IX) may be treated heteroaryl or aryl derivative triamcinolone in the presence of a catalyst, such as tetrakis(triphenylphosphine)palladium, in conditions similar to the conditions described above.

Derivatives of boric acid are also usable. Therefore, the corresponding derivative compounds of formula (IX), such as a derivative bromine, iodine, triflate or PERSULPHATES can interact with heteroaryl or airborne acid in the presence of palladium catalyst such as tetrakis(triphenylphosphine)palladium or PdCl2[1,4-bis(diphenylphosphine)butane] , in the presence of a base such as sodium bicarbonate, in the conditions of heating under reflux in a solvent such as dimethoxyethane (see Fisher and Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439, 1965, Snieckus., Tetrahedron Lett., 29, 2135, 1988 and Terashimia, M. , Vhem. Pharm. Bull., 11, 4755, 1985). Can also be used in non-aqueous conditions, for example a solvent, such as DMF, at a temperature of about 100oIn the presence of Pd(II) catalyst (see W. J. Thompson et al., J. Org. Chem, 49, 5237, 1984). Suitable derivatives of boric acid can be obtained by processing magniv accordance with standard methods.

In such reactions attaching it is easy to see that it is necessary to consider the presence of functional groups in compounds of formula (IX). Thus, as a rule, deputies with the amino group or with sulfur must be oxidized or protected.

The compounds of formula (IX) are imidazoles and can be obtained using any of the methods described previously, to obtain compounds of formula (I). In particular, halogenation or other correspondingly activated ketones R4COCH2Hal (for compounds of formula (IX), where T1represents hydrogen, or R1COCH2Hal (for compounds of formula (IX), where T4represents hydrogen), can interact with amidino formula R2NH-C=NH, where R2is the same as defined in formula (I) or its salt in an inert solvent such as a halogenated hydrocarbon solvent, for example chloroform, at a moderately elevated temperature, and, if necessary, in the presence of an appropriate condensing agent such as a base. Obtaining relevant-halogenated described in WO 91/19497. Appropriate reactive esters include the esters of strong organic acids, such as lower alkanol used in the form of a salt, the easy way cleaners containing hydrochloride salt, which then can be converted into a free amicin in situ by using a two-phase system in which the reactive ester is in an inert organic solvent such as chloroform, and salt is in aqueous phase, to which is added slowly an aqueous solution of the base depolama quantity and with vigorous stirring. Relevant amidine can be obtained using standard methods, see, for example, Garigipati, R., Tetrahedron Letters, 190, 31, 1989.

The compounds of formula (I) can also be obtained by using a method that involves reacting the compounds of formula (IX), where T1represents hydrogen, N-acylethanolamines salt in accordance with the method described in U.S. patent 4803279, U.S. patent 4719218 and U.S. patent 5002942, to obtain the intermediate compounds, in which the heteroaryl ring is attached to the imidazole nucleus and is present as its 1,4-dihydroprogesterone, and this derivative can then be subjected to oxidation conditions-diallylamine (scheme II). Heteroaryl salt, for example pyridinium salt, can either be obtained in advance, or more preferably obtained in situ put formity ether or preferably alkylhalogenide ether, such as acetylmuramic, benzoyl chloride, benzylchloride or preferably ethylchloride) to a solution of the compounds of formula (IX) heteroaryl connection R1H or in an inert solvent such as methylene chloride, to which is added heteroaryl connection. Appropriate conditions of diallylamine and oxidation are described in U.S. patents 4803279, 4719218 and 5002942, these references are hereby incorporated in their entirety. The corresponding system of oxidizing agents include sulfur in an inert solvent or solvent mixture, such as decalin, decalin and diglyme, t-cimen, xylene or mesitylene, while heating under reflux, or preferably tert-piperonyl potassium tert-butanol with dry air or oxygen.

In the further process, illustrated in scheme III, the compounds of formula (I) can be obtained by treating the compounds of formula (X) thermally or using cycleroute agent such as phosphorus oxychloride or pentachloride phosphorus (see Engel and Steglich, Leibigs Ann. Chem, 1978, 1916 and Strzybny et al., J. Org. Chem, 1963, 28, 3381). The compounds of formula (X) can be obtained, for example, by acylation of the corresponding-ketoamine activated derivative of formate, such as the corresponding anhydride, is of alocen from the main ketone by examinerbonnie and recovery and the desired ketone may, in turn, be obtained by decarboxylation of beta-keeeper, obtained by condensation of aryl(heteroaryl)acetic ether with reagent R1-SOH.

Scheme IV illustrates the next two (2) different ways, using ketone (formula XI) to obtain the compounds of formula (I). Heterocyclic ketone (XI) is obtained by adding the anion Alkylglucoside, such as 4-methyl-quinoline (produced by processing alkyllithium, such as n-utility) to N-alkyl-O-alkoxybenzenes, complex ether and other suitably activated derivative in the same oxidized state. Alternative anion may be condensed with benzaldehyde to obtain alcohol, which is then oxidized to the ketone (XI).

In the following way N-substituted derivatives of formula (I) can be obtained by treatment of the amide anion of formula (XII)

R1CH2NR2SON (XII)

where R1and R2:

(a) a nitrile of the formula (XIII)

R4CN (XIII)

where R4defined above, or

(b) excess acylhalides, such as acylchlorides, formula (XIV)

R4COHal (XIV)

where R4defined above and Hal represents halogen, or sootvetchikom ammonium, such as ammonium acetate.

One of the varieties of this approach is illustrated in scheme V above. Primary amine (R2NH2) process halogenoarylation formula R1CH2X with obtaining a secondary amine, which is then converted into amide in the usual way. Alternative amide can be obtained as shown in scheme V, by alkylation of formamide R1CH2X. the Deprotonation of this amide strong amide base, such as diisopropylamide lithium or bis(trimethylsilyl)amide, sodium, followed by the addition of excess Aronhold gives misalliance connection, which is then close to the imidazole compounds of formula (I) by heating in acetic acid containing ammonium acetate. Alternative amide anion can interact with substituted arylnitrenes obtaining imidazole of the formula (I) directly.

The following description and diagrams are further examples of the technique originally described above in scheme I. Different pyrimidinediamine derivatives 6, 7 and 8, as shown in scheme VI can be obtained by modification of methods Bredereck et al. (Chem. Ber 1964, 97, 3407), this description is included here as a reference. These Piri is shimanoe aminoaldehyde derivative, for example, 8 can be somewhat unstable. The method of acetolysis as described in scheme VI, where the aldehyde 7 is isolated in the form of acetamide derivative (compound 3 is converted into 7 via the intermediate product 4), leads to a more stable connection for use in the reaction, the addition of the cycle to produce compounds of formula (I).

For this reaction, using conventional conditions acetolysis, and they are well known to specialists in this field. Appropriate conditions are presented, for example, in example 83. In more detail, in the reaction using heat 2-aminophenylacetate with acetic anhydride in the presence of catalytic amounts of concentrated sulfuric acid, which simultaneously acetylase Amin and leads to the replacement of one of alkoxygroup on acetochlor. The resulting compound is converted into the aldehyde by deacetylation with a catalytic amount of alkoxide salt in an appropriate alcoholic solvent such as Na+ methoxide and methanol. Alternative higher outputs can be obtained by first amine acetylation with acetic anhydride, and then the exchange by adding con is obscene van Leusen (van Leusen, et al., J. Org. Chem. 1977, 42, 1153). Been reported following conditions: tert-butylamine(tert-uN2in dimethoxyethane (DME), K2CO3in Meon and NaH in DME. When checking these conditions as it may find any, get low outputs. The desired product, for example, 5-[(2-(1-methylamino)pyrimidine-4-yl] -4-(4-forfinal)-1-(1-methylpiperidin-4-yl)imidazole, allocate with outputs of less than 50%, using tert-BuNH2in DME at room temperature, but can also be used for the second reaction path, including amine exchange with obtaining tert-Butylimino with subsequent interaction with isocyanides 1 to obtain tert-Diimidazole. Probably, this can be done using any of a primary amine as the base. Secondary amines, although not preferred, can be used, but they can also slow decomposing isonitrile. Probably for the reaction requires about 3 equivalents of amine to reach completion, receiving about 50% of the energy outputs of the selected products. Secondary amines with steric constraints (diisopropylamino), although it can be used to react very slow and usually not very effective. The use of tertiary and aromatic amines such as pyridine and triethylamine,nepizdin (DMAP), although react slowly, give some outputs and therefore can be suitable here.

As indicated in schemes VII and VIII, pyrimidinylidene scheme VI can be condensed with a primary amine with getting imine, which may be selected appropriately, or can interact in situ with the desired isonitrile in the presence of a variety of appropriate bases and solvents, as described here, giving 5-(4 - pyrimidinyl)imidazoles, where R2and R4are such as are here described for compounds of formula (I).

A preferred method of preparing compounds of formula (I) is shown in scheme VII. Imine received and allocated to individual phases are often resins that may be difficult to apply. Black color is often tolerated well as on the final product. Output when receiving Iminov changes, and when they are received often use less acceptable from the point of view of environmental solvents such as CH2CL2.

For this reaction, where p=2 requires an appropriate basis for the reaction. For the reaction requires a base strong enough to deprotonation of isonitrile. Appropriate osnovaniya, but not limited to, potassium carbonate, sodium carbonate, primary and secondary amines, such as tert-butylamine, Diisopropylamine, morpholine, piperidine, pyrrolidine, and other dinucleophiles bases, such as DBU, DMAP and 1,4-diazabicyclo[2,2,2]octane (DABCO).

Appropriate solvents for use here include, but are not limited to, N, N-dimethylformamide (DMF), MeCN, halogenated solvents such as methylene chloride or chloroform, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, such as methanol or ethanol, benzene, toluene, dimethyl ether or EtOAc. Preferably the solvent is DMF, DME, THF or MeCN, more preferably DME. The selection of product is usually achieved by the addition of water and filtration of the product in the form of a transparent substance.

Although not very convenient for operation on an industrial scale, adding NaH instead of tert-butylamine to isonitrile temperatures, possibly below the 25o(In THF) is probably necessary. In addition, BuLi also, reportedly, is an effective base for the deprotonation of todiversification at -50oC. (DiSanto, R. ; Costi, R; Massa, S.; Artico, M. Synt. Commun. 1995, 25, 795).

Can be used in a variety UB>CO3/Meon, try to carry out the reaction at 0 room temperature, 40, 64 and 80oC. At temperatures above 40oWith the outputs can fall to about 20%, although not observed little difference between the 0oC and room temperature. Using2CO3in DMF, try to have interaction at 0oAnd the 25oWith no apparent difference in the product quality or yield. Therefore, the temperature ranges below 0oC and above 80oWith, as expected, are also within the present invention. The preferred temperature range is from about 0oup to about 25oC. For the present purpose the room temperature is equal to 25oBut, as has been observed, it may vary from the 20oWith up to 30oC.

As shown in scheme VIII, Imin preferably formed in situ in the solvent. This preferred synthesis method is implemented as a synthesis in one vessel. Conveniently, when a primary amine is used in the form of a salt, such as dihydrochloride salt, for example, the reaction may further include a base, such as potassium carbonate, before adding isonitrile. Alternative nitrogen of the piperidine may be necessary C is th, aryl, arylalkyl radicals, known to experts in this field. Reaction conditions such as solvent, base, temperature and the like, such as those illustrated and discussed above to highlight the imine as shown in scheme VII. The person skilled in the art will easily find that in some circumstances the formation of the imine in situ may require dehydrogenation conditions or may require acid catalysis.

Another method of preparing compounds of formula (I) shown below in scheme VIIIa. To avoid difficulties associated with the separation of pyrimidinediamine 8, it is possible hydrolysis of the acetal 3 to aldehyde 8, as described in example 3, part (b). Aldehyde 8, obtained in situ, can be processed sequentially by the primary amine, ethyl acetate and Panso3to obtain the corresponding imine in situ, which is extracted with ethyl acetate. Adding isonitrile, carbonate base and DMF makes possible the formation of 5-(4 - pyrimidinyl)imidazoles, where R2and R4are such as here defined for compounds of formula (A).

A preferred method of synthesis of compounds of formula (I) also provides for appropriate and over, -methylthiopyrimidine derived as described in the section of examples. Below in scheme IX compound 1 (X=S, methyl), although it is the final product, can also be used as a precursor, as noted previously, to obtain further compounds of the formula (I). In this particular case, methylthiouracil oxidizes to methylsulfonyl radical, which optionally may be further modified to a substituted amino group.

Another embodiment of the present invention is a new method of hydrolysis of 2-dimethylpyrimidin acetal to 2-dimethylpyrimidin aldehyde as shown in scheme X. hydrolysis of the acetal to the aldehyde using a variety of known reaction conditions, such as formic acid, do not give a satisfactory yield of aldehyde, receive <13%. One method of synthesis involves the use of Asón (fresh) as a solvent and concentrated H2SO4in terms of heating, preferably with a catalytic amount of sulfuric acid. The heating conditions include a temperature from about 60oup to 85oC, preferably from about 70oto about 80oC, as higher temperatures give a darkening of the reaction mixtures or the GTC. The preferred method comprises heating the acetal 3 N. HCl at 40oC for 18 h, cooled and neutralized extraction bicarbonate solution EtOAc. Examples of these two ways described herein in examples 6 (b) and 25.

Target derivatives of 2-aminopyrimidine-4-elimidate formula (I), and pyridine containing such compounds can be obtained through one of three ways: 1) direct interaction of 2-aminopyrimidine with isonitriles; 2) the condensation of 2-acetaminophenodeine with isonitriles with the subsequent removal of acetamidoxime; and 3) oxidation of 2-methylthiopyrimidine derivative to the corresponding sulfoxide with subsequent substitution of the desired amine.

Although these schemes are presented, for example, optionally substituted piperidinyl radical for end position2or 4-florfenicol for R4any suitable organic radical R2or R4can be added this way, if he turns on the primary Amina. Similarly, any suitable R4can be added to the method using isonitrile.

The compounds of formula (IIA) in scheme I can be obtained using the methods of van Leusen et al., higher Ar, R4and p are as described here.

Appropriate dehydrating agents include phosphorus oxychloride, oxalicacid, thionyl chloride, phosgene or taillored in the presence of an appropriate base, such as triethylamine or diisopropylethylamine, or similar reasons, and so forth, such as pyridine. Appropriate solvents are dimethoxyethan, tetrahydrofuran or a halogenated solvent, preferably THF. The reaction is most effective when the temperature of the reaction support between -10oC and 0oC. At lower temperatures, there is an incomplete response, and at higher temperatures, the solution becomes dark and the yield decreases.

The compounds of formula (IV), scheme I, can be obtained by reacting the compounds of formula (V), scheme I, R4CHO, where R4defined here, with ArS(O)pH and formamide with removal of water or without removal, preferably in the conditions of dehydrogenation at room or elevated temperature, for example from 30o150oWith conveniently under reflux, optionally in the presence of an acid catalyst. Alternatively, instead of the acid catalyst may be rabinow acid, p-toluensulfonate acid, hydrogen chloride and sulfuric acid.

The best way to get isonitrile formula (IIA) is illustrated in scheme XI and in the examples section, example 10.

The conversion of the substituted aldehyde in torbensen-formamide can be achieved by heating the aldehyde, 1 - scheme XI, with acid, such as p-toluensulfonate acid, formic acid or camphorsulfonic acid; with formamide and p-toluensulfonate acid [reaction conditions of about 60oC for about 24 h]. It is preferable not to use any solvent. The reaction can give low yields (<30%) when using solvents, such as DMF, DMSO, toluene, acetonitrile or an excess of formamide. Temperature less than 60oWith usually are bad at getting the desired product, and temperature significantly above the 60oWith can give a product which decomposes, or to give benzyl bis-formamide 2 - scheme XI. In example 23 (a) describes the synthesis of 4-florfenicol-methylformamide, the compounds of formula (IV), scheme I, where p=2, described in WO 95/02591 Adams et al. This method differs from that described in example 10, the following terms and conditions: the use of sodium soprovodite, than the present invention, as here described, which use sulinowo acid and are able to use non-aqueous conditions.

Conditions for obtaining -(p-toluensulfonyl)-4-farbenindustrie as described in example 23(b), described in WO 95/02591 Adams et al., as solvent for the extraction of product use Cl and DME as solvent. The present invention improves on this method by using the less expensive solvents such as THF or EtOAc, for the extraction. Even higher yields are obtained by re-crystallization in alcohol, such as 1-propanol, although other alcohols such as methanol, ethanol and butanol, are acceptable. Previously the connection was partially purified chromatographic methods, as well as hazardous solvents for additional purification.

Another embodiment of the present invention is the synthesis thailandinformative derived, which is carried out by reacting bis-formamide intermediate 2 - scheme XI with p-toluensulfonate acid. In this preferred method of obtaining bis-formamide of the aldehyde is accomplished by heating the aldehyde with formamide clonicel, DMF and DMSO, or a mixture thereof. Acid catalysts are catalysts that are well known in this field, and include, but are not limited to, chloride-hydrogen acid, p-toluensulfonate acid, camphorsulfonic acid and other anhydrous acid. The reaction is carried out at a temperature in the range from about 25oWith up to 110oWith, preferably about 50oWith, preferably for from about 4 to about 5 hours are acceptable to longer reaction times. At higher temperatures (>70oC) and longer reaction time may cause decomposition of the product and lower outputs. Complete metamorphosis of a product usually requires the removal of water from the reaction mixture.

Preferred conditions for the conversion bisformamide derived in coseventcomm achieved by heating bisformamide in an appropriate solvent with an acid catalyst and p-toluenesulfonic acid. Solvents for use in this reaction include, but are not limited to them, toluene and acetonitrile and mixtures thereof. In addition, can also be used mixtures of these solvents with DMF or DMSO, but they can lead to lower output is SUP>With higher than 60oWith, is not preferred because of reduced output and speed of reaction. Preferably the range is from about 40oWith up to 60oS, most preferably about 50oC. the Optimal time is between about 4 to 5 hours, although it can be longer. Preferred acids include, but are not limited to, toluensulfonate acid, camphorsulfonic acid and chloride-hydrogen acid, and other anhydrous acid. Most preferably bis-formamide heated in a mixture of toluene:acetonitrile in the ratio of 1:1 with the p-toluensulfonate acid and hydrogen chloride.

Another embodiment of the present invention is the preferred method of obtaining thailandinformative connections, which carry out the process in a single vessel. This method first converts the aldehyde in bis-formamide derived, and then interact bisformamide derived from toluensulfonate acid. This method combines the optimized conditions in a single efficient process. This method can be achieved in high yields >90%, aryl(tosyl)benzylbromide.

Phnom solvent, a mixture of toluene:acetonitrile, preferably at a ratio of 1:1. It is preferable reagent, such as TMS, which interacts with the water formed in the process, and at the same time forms a hydrogen chloride to catalyze the reaction. Also preferred is the use of hydrogen chloride and p-toluensulfonate acid. Therefore, the three respective reaction conditions used here include 1) the use of a dehydrating agent, which also supplies hydrogen chloride, such as l or p-toluensulfonate acid; or 2) using an appropriate dehydrating agent and the corresponding source of the acid source, such as, but not limited to them, camphorsulfonic acid, chloride-hydrogen acid or p-toluensulfonate acid; and 3) alternative dehydrogenation conditions, such as azeotropic removal of water and the use of an acid catalyst and p-toluensulfonate acid.

The compounds of formula (IIA), where p=2, can also be obtained by reacting in the presence of a strong base, the compounds of formula (VI), scheme I, R4CH2NC, with the compound of formula (VII), scheme I, ArSO2L1where R4and AG are the two who testwuide strong bases include, but not limited to, alkyllithium compounds such as utility or sitedisability (Van Leusen et al., Tetrahedron Letters No. 23, 2367-68 (1972)).

The compounds of formula (VI), scheme I, can be obtained by reacting the compounds of formula (VIII), scheme I, R4CH2NH2with alkylphosphates (for example, ethyl formate) to give the intermediate amide, which can be converted to the desired isonitrile by interacting with well known dehydrating agent such as, but not limited to, oxalicacid, phosphoroxychloride or tailhold, in the presence of an appropriate base, such as triethylamine.

Alternatively, the compound of formula (VIII), scheme I, can be converted to the compound of formula (VI), scheme I, by interacting with chloroform and sodium hydroxide in aqueous solution with dichloromethane catalysis of the transfer phase.

The compounds of formula (III), scheme I, can be obtained by reacting the compounds of formula R1CHO with a primary amine R2NH2.

The amino compounds of the formula (VIII), scheme I are known or can be obtained from the corresponding alcohols, oximo or amides using standard mutual priobe groups and the imidazole nitrogen is well known in this field and described in many references, for example, Protecting Groups in Organic Synthesis, Greene, T. W. , Wiley-Interscience, New York, 1981. Examples hydroxylamine groups include silyl ethers, such as tert-butultimately or tert-butylbiphenyl, and alkyl ethers, such as methyl, connected in the form of an alkyl chain of variable length (CR10R20)n. Examples of protective groups for the nitrogen of the imidazole include tetrahydropyranyl.

Pharmaceutical salts add acid compounds of the formula (I) can be obtained in a known manner, for example by processing the appropriate amount of acid in the presence of an appropriate solvent.

Treatment

The compounds of formula (I) or (II) or its pharmaceutically acceptable salt can be used to obtain drugs for prophylactic or therapeutic treatment of any painful condition in man or other mammal, which is exacerbated or called excessive or unregulated production of cytokines such mammalian cells, such as, but not limited to, monocytes and/or macrophages.

The compounds of formula (I) or (II) is able to inhibit Pro-inflammatory cytokines, such as IL-1, AND snoopie cells and tissues, and these cytokines, as well as other cytokines produced by leukocytes, are important and critical inflammatory mediators of a wide variety of painful conditions and symptoms. Inhibition of these Pro-inflammatory cytokines can be used for controlling, reducing and alleviating many of these disease conditions.

Accordingly, the present invention relates to a method of treatment of diseases mediated by cytokines, which includes the introduction of effectively influencing cytokines amount of the compounds of formula (I) or (II), or their pharmaceutically acceptable salts.

In particular, the compounds of formula (I) or (II) or its pharmaceutically acceptable salt can be used in the prevention or treatment of the disease condition in humans or other mammal, which is exacerbated or called excessive or unregulated production of IL-1, IL-8 or TNF, such mammalian cells, such as, but not limited to, monocytes and/or macrophages.

Another aspect of the present invention is that the compounds of formula (A), of the formula (I) and formula (II) is able to inhibit inducible Pro-inflammatory proteins, such SOH-2 KJV the rank can be used in therapy. These Pro-inflammatory lipid mediators cyclooxygenase (COX) pathways responsible for the generation induced by enzyme SOH-2. Therefore, regulation of MOR-2, which is responsible for these products, derived from arachidonic acid, such as prostaglandins, have an impact on a wide variety of important cells and tissues, and critical inflammatory mediators of a wide variety of painful conditions and symptoms. The expression of MOR-1 is not exposed to compounds of formula (I). Selective inhibition of MOR-2 may weaken or reduce the tendency to ulceration, associated with inhibition of MOR-1, thereby inhibiting the prostaglandins, the most important impact on the protection of the cells. This inhibition of these Pro-inflammatory mediators is useful for controlling, reducing and alleviating many of these disease conditions. More significantly, these mediators of inflammation, including prostaglandins are essential for pain, such as with acute sensitivity of pain receptors or swelling. Therefore, this aspect of pain management includes treatment of neuromuscular pain, headache, pain in cancer and pain of arthritis. The compounds of formula (I) or their FARMACIJA by inhibiting the synthesis of the enzyme SOH-2.

Accordingly, the present invention relates to a method of inhibiting the synthesis of MOR-2, which is the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt. The present invention also relates to a method of prophylactic treatment of a human or other mammal by inhibiting the synthesis of the enzyme SOH-2.

Accordingly, in another aspect this invention relates to a method of inhibiting the production of IL-1 in a mammal that is in need, which includes an introduction to the specified mammal an effective amount of the compounds of formula (I) or (II) or their pharmaceutically acceptable salts.

There are many pathological States in which excessive or unregulated production of IL-1 is involved in the exacerbation and/or the call of the disease. They include rheumatoid arthritis, osteoarthritis, irritation, groove toxins and/or toxic shock syndrome, other acute or chronic painful inflammatory conditions such as inflammatory reaction induced by endotoxin or inflammatory bowel, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, Kakhetia, bone resorption, psoriatic synovitis. Recent data also link the activity of IL-1 diabetes, the cells of the pancreas and disease Alzheimer.

In a further aspect the present invention relates to a method of inhibiting production of TNF in a mammal that is in need, which includes an introduction to the specified mammal an effective amount of the compounds of formula (I) or (II) or its pharmaceutically acceptable salt.

Excessive or unregulated production of TNF is involved in mediating or exacerbation of a number of diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, arthritis, gout and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, syndrome ailments colds in adults, irritation, cerebral malaria, chronic pneumonia, silicosis, sarcoidosis of the lungs, diseases of bone resorption, such as osteoporosis, reperfusion injury, reactions to vaccinations, allograft rejection, fever, and convulsions caused by infection, such as influenza, secondary kahalu after infection or malignant disease, secondary kahalu in the syndrome priorie scar tissue, Crohn's disease, ulcerative colitis and fever.

The compounds of formula (I) can also be used in the treatment of viral infections, where such viruses are sensitive to increase their level by regulating with TNF or install production of TNF in vivo. Viruses targeting here for treatment, are viruses that produce TNF as a result of infection or viruses, which are sensitive to inhibition, for example, by using a reduced replication, directly or indirectly through inhibiting TNF compounds of formula (I) or (II). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the viruses of the Herpes group, such as, but not limited to, Herpes Zoster and Negres Simplex. Accordingly, in a further aspect the present invention relates to a method of treatment of a mammal suffering from human immunodeficiency virus (HIV), which includes the introduction of such mammal effectively inhibiting TNF amount of the compounds of formula (I) or (II), or their pharmaceutically acceptable salts.

The compounds of formula (I) or (II) may also be used in connection with the veterinary treatment of mammalian what iesa for therapeutic or prophylactic treatment of animals, include painful conditions, such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to them, lentivirinae infection, such as virus infectious anemia horses, the virus arthritis goat, visna or maedi virus or retrovirus infections, such as, but not limited to, feline immunodeficiency virus (FIV), human immunodeficiency virus bull or human immunodeficiency virus dogs or other retroviral infections.

The compounds of formula (I) or (II) can also be used topically in the treatment or prevention of local pathological States mediated or exacerbated by excessive production of cytokines, such as IL-1 or TNF, respectively, such as inflammation of the ligaments, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory condition of the eye including conjunctivitis; increased temperature, pain and other symptoms associated with inflammation.

The compounds of formula (I) or (II), as shown, also inhibit the production of IL-8 (Interleukin-8, BAN). Accordingly, in this aspect the present invention relates to a method of inhibiting the production of IL-8 in a mammal, guideuse (I) or its pharmaceutically acceptable salt.

There are many pathological States in which excessive or unregulated production of IL-8 is involved in the exacerbation and/or is the cause of the disease. These diseases are characterized by a massive infiltration of neutrophils, such as psoriasis, inflammatory bowel, asthma, cardiac and renal reperfusion injury, syndrome ailments colds in adults, thrombosis and glomerulonephritis. All these diseases are associated with increased production of IL-8, which is responsible for the chemotaxis of neutrophils in inflammation. In contrast to other inflammatory cytokines (IL-1, TNF and IL-6), IL-8 have the unique property of the promoter of the chemotaxis and activation of neutrophils. Therefore, inhibition of production of IL-8 led to a direct reduction in the infiltration of neutrophils.

The compounds of formula (I) or (II) is administered in an amount sufficient for inhibiting the production of cytokines, in particular IL-1, IL-6, IL-8 or TNF, so it falls under the regulation to normal levels or, in some cases, to subnormal levels, so as to weaken or prevent the disease state. Abnormal levels of IL-1, IL-6, IL-8 or TNF, for example, in the context of nastoyashyuyu 1 picograms per ml; (ii) any amount of IL-1, IL-6, IL-8 or TNF-related cells; or (iii) the presence of mRNA of IL-1, IL-6, IL-8 or TNF at levels higher than the basal, in cells or tissues that produce IL-1, IL-6, IL-8 or TNF, respectively.

The discovery that the compounds of formula (I) or (II) are inhibitors of cytokines, in particular IL-1, IL-6, IL-8 and TNF is based on the effect of the compounds of formula (I) on the production of IL-1, IL-8 and TNF in in vitro studies, which are described here.

As used here, the term "inhibiting the production of IL-1 (IL-6, IL-8 or TNF)" refers to the following phenomena:

(a) reducing excessive levels in vivo cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or subnormal levels by inhibiting the release of in vivo cytokine of all cells, including, but not limited to monocytes or macrophages;

b) adjustable lowering with genetically determined level of excess levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in vivo in humans to normal or subnormal levels;

c) adjustable lowering by inhibition of the direct synthesis of the cytokine (IL-1, IL-6, IL-8 or TNF) as a posttranslational event; or

d) adjustable lowering when Tr is malinich levels.

As used here, the term "induced by TNF disease or disease state" refers to any and all painful States in which TNF plays a role, either by production of TNF, either due to TNF release another monokine, such as, but not limited to, IL-1, IL-6, IL-8. A painful condition in which, for example, IL-1 is the main component, and the production or action of which is exacerbated or secreted in response to TNF, must therefore be regarded as a painful condition mediated by TNF.

As used here, the term "cytokine" refers to any Sekretareva the polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. Cytokine includes, but is not limited to this, Monokini or lymphokines, regardless of what cells produce them. For example, is usually mentioned that manokin is produced and secreted managerno cell such as a macrophage and/or monocyte. However, many other cells also produces Monokini, such as natural killer cells, fibroblasts, bezopastnosti and B-lymphocytes. Lymphokines, as commonly referred to, are produced by cells-lymphocytes. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF-) and tumor necrosis factor (TNF-).

As used here, the term "influencing cytokines" or "the vast cytokines amount" refers to an effective amount of the compounds of formula (I) or (II), which causes reduced levels of cytokines in vivo to normal or subnormal levels, when it is given to a patient for prevention or treatment of a pathological state, which is exacerbated or called excessive or unregulated production of cytokines.

As used here, the cytokine referred to in the phrase "inhibition of cytokine for use in the treatment of HIV-infected person", is a cytokine that is involved in (a) initiating/maintaining activation of T-cells and/or expression and/or replication of the HIV gene, activated T-cell, and/or (b) issue any mediated cytokine disease, such as Kakhetia or muscle degeneration.

Because TNF - a (also known as lymphotoxin) has similar structural g is IKI and binds to the same cellular receptor, as TNF-and TNF-, inhibited by compounds of the present invention, and, therefore, are referred to here collectively as "TNF" unless specifically stated otherwise.

A new member of the family of MAP kinases, called alternative CSBP, R or RK, was recently identified independently by several laboratories. Activation of this new protein kinase via dual phosphorylation was observed in different cell systems during stimulation with a wide range of incentives, such as physico-chemical stress and treatment with lipopolysaccharide and Pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor. Inhibitors of the biosynthesis of cytokines of the present invention, the compounds of formula (I), (II) and (A), as defined, are potent and selective inhibitors of the activity of CSBP/p38/RK kinase. These inhibitors can be used when determining the signaling pathways involved in inflammatory responses. In particular, the first time a specific transmission signal can be attributed to the effect of lipopolysaccharide on the production of cytokines in macrophages.

Inhibitors of cytokines were subsequently investigated for anti-inflammatory activity in several animal models. Modelka receive activity only agents suppressing against cytokines. Inhibitors showed significant activity in many of these studies in vivo. Most notable are their activity on the model collagenbinding arthritis and inhibition of production of TNF in a model of endotoxic shock. In the latter study, the decrease in the level of TNF in plasma correlates with survival and protection from mortality associated with endotoxic shock. Also of great importance is the effectiveness of the compounds in the inhibition of resorbtive bone tissue in the culture of differentiated cells in the tubular bones of the rat embryo. Griswold et al. (1988) Arthritis Rhum. 31: 1406-1412; Badger, et al. (1989) Circ. Shock 27, 51-61; Votta et al. (1994) in vitro. Bone 15, 533-538: Lee et al. (1993). Ann. N. Y. Acad. Sci. 696, 149-170.

To use the compounds of formula (I), (II) or (A) or their pharmaceutically acceptable salts in the treatment, they are usually included in the pharmaceutical composition in accordance with conventional pharmaceutical practice. The present invention therefore also relates to pharmaceutical compositions containing an effective non-toxic amount of compound of formula (I) or (II) and pharmaceutically acceptable binder or diluent. For the purposes of the present invention soorae (I).

The compounds of formula (I), their pharmaceutically acceptable salts and pharmaceutical compositions comprising them, can conveniently be administered using any of the methods commonly used for administration of drugs, for example, oral, local way, parenterally or by inhalation. The compounds of formula (I) can be administered in conventional dosage forms obtained by combining the compounds of formula (I) with standard pharmaceutical binders in accordance with customary methods. The compounds of formula (I) can also be entered in conventional dosages in combination with known second therapeutically active compound. These methods may include mixing, granulating and compressing or dissolving the ingredients in accord with the requirements of the desired drug. It should be noted that the form and character of the pharmaceutically acceptable binder or diluent is dictated by the amount of active ingredient with which they should be combined, the route of administration and other well-known parameters. Binder (binder) must be "acceptable" in the sense of being compatible with other ingredients of the product and is not to be vrednymi solid, or liquid. Examples of solid binders include lactose, white earth, sucrose, talc, gelatin, agar, pectin, Arabic gum, magnesium stearate, stearic acid and the like. Examples of liquid binders are syrup, peanut oil, olive oil, water and the like. Similarly, binder or diluent may contain a material to increase the time of release, well known in this field, such as glycerylmonostearate or glycerylmonostearate, by itself or with wax.

Can be used with a wide variety of pharmaceutical forms. So, if you use solid binder, the drug can be prepared in the form of tablets, placed in a hard gelatin capsule in powder or pellet form or in the form of pills or pellets. The amount of solid binder may vary within wide limits, but preferably is from about 25 mg to about 1 g When using a liquid binder, the drug may be in the form of a syrup, emulsion, soft gelatin capsule, sterile water for injection, such as ampoules or nonaqueous liquid suspension.

The compounds of formula (I) is of formula (I) externally to the epidermis or in the oral cavity and instillation of such a compound into the ear, eyes and nose, so that the connection is not introduced to in large quantities in the blood stream. In contrast, systemic introduction refers to oral, intravenous, intraperitoneal and intramuscular introduction.

Preparations suitable for topical administration, include liquid or semi-liquid preparations suitable for penetration through the skin to the area of inflammation, such as liquid ointments, lotions, creams, lubricating ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient can be prepared by the local introduction of from 0.001% to 10% wt./wt., for example from 1% to 2% by weight of the preparation. He may, however, contain up to 10% wt./wt., but preferably contains less than 5% wt./wt., more preferably from 0.1% to 1% wt./wt. drug.

Lotions of the present invention include lotions, suitable for application to the skin or eyes. Lotion for the eyes may contain a sterile aqueous solution, optionally containing a bactericide, and can be obtained using methods similar to the methods for the preparation of drops. Lotions or liquid ointment for application to the skin may also include an agent to accelerate the drying or cooling of the skin, such as IPN is about.

Creams, lubricating ointments or pastes according to the present invention are semi-solid preparations, the active ingredient for external application. They can be obtained by mixing the active ingredient in finely ground or powdered form, alone or in solution or suspension in aqueous or non-aqueous liquid fat or nairboi basis by appropriate technical means. The core can include hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax or soap-based metal; an adhesive material; an oil of natural origin such as almond, corn, peanut, castor or olive oil, the fat of wool or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol, or a macrogel. The drug can include any appropriate surface-active agent, such as anionic, cationic or non-ionic surfactant, such as arbitarily ether or polyoxyethylene derived. May also be included suspendresume agents such as natural gums, cellulose derivatives or inorganic materials, such Karetniy can include sterile aqueous or oily solution or suspension, and can be prepared by dissolving the active ingredient in an appropriate aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably include a surface-active agent. The resulting solution may then be cleaned to transparency by filtration, placed in an appropriate vessel, which is then hermetist and sterilized by autoclaving or maintaining at 98-100oWith in half an hour. Alternatively, the solution may be sterilized by filtration and placed in a vessel using any aseptic techniques. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops, are nitrate - or acetylphenyl mercury (0,002%), benzylaniline (0,01%) and chlorhexidine (0,01%). Appropriate solvents for the preparation of oil solution include glycerol, diluted alcohol, and propylene glycol.

The compounds of formula (I) can be administered parenterally, that is by intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal, or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Cootie formula (I) can also be entered via inhalation, that is by intranasal or oral inhalation administration. Appropriate dosage forms for such administration, such as aerosol medication or an inhaler with a fixed dose, can be prepared using conventional techniques.

For all methods of use described herein for compounds of formula (I), daytime running oral dosage is preferably from about 0.01 to about 30 mg/kg of total body weight, preferably from about 0.01 mg/kg to 10 mg/kg, more preferably from about 0.01 mg to 5 mg Daily mode parenteral dosage is from about 0.001 to about 30 mg/kg of total body weight, preferably from about 0.01 to about 10 mg/kg, and more preferably from 0.01 mg to 5 mg/kg Daily dosage regimen in the local application is preferably from 0.1 mg to 150 mg, applied from one to four, preferably two to three times a day. Daily dosage inhalation is preferably from about 0.01 mg/kg to about 1 mg/kg / day. The person skilled in the art will also notice that the optimal quantity and spacing of individual dosages of the compounds of formula (I) or its pharmaceutically acceptable salts are determined by the nature and is gaudemus treatment, and that such optimums can be determined using conventional techniques. The person skilled in the art will also notice that the optimal course of treatment, that is, the number of doses of the compounds of formula (I) or its pharmaceutically acceptable salt, given per day for a certain number of days, can be determined by the person skilled in the art using conventional research to establish the course of treatment.

Hereinafter the invention will be described with reference to subsequent biological examples which are purely illustrative and are not intended to limit the scope of the present invention.

BIOLOGICAL EXAMPLES

Effects of inhibition of cytokines, compounds of the present invention is determined using the following in vitro tests:

Interleukin-1 (IL-1): Monocytes from peripheral human blood isolate and purify any of the fresh blood from voluntary donors, or from a light layer of stored supply of blood, in accordance with the method Colotta et al. J. Immunol., 132, 936 (1984). These monocytes (1106) are placed on a 24-hole tablets at a concentration of 1-2 million/ml per well. The cells give the opportunity to adhere for 2 h, after this time unattached cells are removed with the aid of which polysacharide (50 ng/ml), and the culture incubated at 37oC for an additional 24 hours At the end of this period supernatant cultures delete and clear to transparency from the cells and all residues. Supernatant cultures then directly assess the biological activity of IL-1 or by using the method of Simon et al., J. Immunol. Methods, 84, 85 (1985) (based on the ability of IL-1 to stimulate cell line producing interleukin-2 (EL-4) secretion of IL-2 in cooperation with iodoform A), or by the method of Lee et al., J. Measurement Therapy, 6(1), 1-12 (1990) (the ELISA analysis). The compounds of formula (I), as demonstrated by the examples 1-24 are, as shown, inhibitors of IL-1 produced in vitro by human monocytes.

The tumor necrosis factor (TNF): Monocytes from peripheral human blood isolate and purify any of the bright layers of blood from stored reserves, or from residues from thrombocytopenia, in accordance with the method Colotta, R. et al., J. Immunol., 132(2), 936 (1984). Monocytes are placed at a density of 1x106cells/ml of medium/well in 24-well plates. The cells give the opportunity to adhere for 1 h, after this time the supernatant is sucked off and add fresh medium (1 ml RPMI-1640, Whitaker Biomedical Products, Whitaker, CA, USA) containing 1% fetal calf serum plus penicillin and streptomycin (10 ezone doses (1 nm - 10 mm (compounds dissolved in dimethyl sulfoxide/ethanol, so that the final concentration of solvent in the culture medium is 0.5% dimethyl-sulfoxide/0.5% ethanol). Then add bacterial lipopolysaccharide (E. coli 055: B5[FSC] from Sigma Chemical Co.) (100 ng/ml in 10 ml of saline phosphate buffer), and the culture incubated for 16-18 h at 37oC in an incubator with 5% CO2. At the end of the incubation period supernatant cultures separated from the cells, centrifuged at 3000 rpm to remove residual cells. Then the supernatant appreciate on the activity of TNF using either radioimmunoassay analysis or ELISA, as described in WO 92/10190 and Becker et al., J. Immunol. , 1991, 147, 4307. The compound of formula (I), as demonstrated by the examples 1-24 are, as shown, inhibitors of TNF produced in vitro by human monocytes.

Inhibiting the activity of IL-1 and TNF, apparently, does not correlate with properties of the compounds of formula (I) when the mediating inhibition of the metabolism of arachidonic acid. In addition, the ability to inhibit the production of prostaglandin and/or leukotriene synthesis of nonsteroidal anti-inflammatory drugs with strong inhibitory activity against cyclooxygenase and/and oksidnyh doses.

Interleukin-8 (IL-8): Primary endothelial cells of human umbilical cord (PAKC) (Cell Systems, Kirland, Wa) incubated in culture medium with added 15% fetal calf serum and 1% contrasuppression-HBGF consisting of afgf and heparin. Then, cells 20-fold diluted before use (250 μl) at gelatinising 96-well plates. Before using the culture medium replaced with fresh medium (200 μl). Buffer or investigational compound (25 μl at concentrations from 1 to 10 μm) were then added to each well for 4 holes at once and tablets incubated for 6 h in a humidified incubator at 37oC in an atmosphere with 5% CO2. At the end of the incubation period, the supernatant removed and assess the concentration of IL-8 using ELISA kit for IL-8 obtained from R&D Systems (Minneapolis, MN). All data are presented as mean value (ng/ml) for multiple samples based on the standard curve deviations. The values of the IC50where they are visible, are obtained by nonlinear regression analysis.

Analysis of specific binding proteins cytokines

Was developed analysis Radiocontrast binding to provide primary screening with high reproducibility for research for the RCM analysis, using a newly allocated

the human monocytes as a source of cytokines and ELISA assays for quantitative data. In addition, this analysis is much easier, the proposed analysis of binding has been extensively tested and showed high degree of correlation with the results of the biological analysis. Specific and reproducible analysis of inhibition of binding of the cytokine was developed using soluble cystoscopically fraction of cells TNR.1 and radioactively labeled compounds. Application for U.S. patent USSN 08/123175 Lee et al., registered in September 1993; Lee et al., PCT 94/10529 registered on September 16, 1994 and Lee et al., Nature 300, p(72), 739-746 (Dec. 1994), the description of which is included here by reference in their entirety, describe the above method of screening drugs to identify compounds that interact and bind with protein, specifically binds the cytokine (hereinafter BSSC). However, for the purposes of the present invention binding protein can be selected as in solution or in immobilized form, or can use genetic engineering to be expressed on the surface of recombinant host cells, such as the system may be used in the screening process. Regardless of the type of binding protein, a lot of connections in contact with the binding protein under conditions sufficient for the formation of a complex connection/binding protein, and are defined compounds capable of forming, increase or interact with these complexes.

Shows zero compounds of formula (I), examples 3-27, all demonstrated positive inhibitory activity, such as IC50linking from about 0.18 to 5 μm in this assay, binding, except for example 12, where the connection has not been studied.

Analysis using prostaglandiinireseptoreita-2 (SGPP-2):

The following analysis describes how to determine the inhibitory effects of compounds of the formula (I) on the expression of the protein human SGPP-2 in LPS-stimulated monocytes.

Method: Monocytes in human peripheral blood emit light layers by zentrifugenbau in a gradient of Ficoll and Percoll. Cells were seeded at 2106/well in 24-hole plates and let to adhere for 1 h in RPMI plus 1% serum AB man, 20 mm L-glutamine, penicillin-streptomycin and 10 mm HEPES. Connection type at various concentrations and incubated at 37<'s what the night at 37oC. the Supernatant is removed and cells are washed once with cold SPR. Cells are lysed in 100 ál of cold lyse buffer (50 mm Tris/Hcl pH 7.5, 150 mm NaCl, 1% NP40, 0.5% of deoxycholate sodium, 0.1% of VAT, 300 µg/ml Gnkazy, 0,1% TRITON X-10, 1 mm PMSF, 1 mm leupeptin, 1 mm pepstatin). The lysate centrifuged (10000 g for 10 minutes at 4o(C) to remove residual cells and soluble fraction is subjected to analysis for VAT using PAGE (12% gel). The protein separated on a gel, transferred to a nitrocellulose membrane by electrophoresis for 2 h at 60 C. the Membrane pretreated for 1 h SFR/0,1% Tween 20 with 5% non-fat dry milk. After three times washing in buffer SFR/Tween, the membrane is incubated with diluted in a ratio of 1:2000 monospecific serum antibodies to SGPP-2 or diluted in a ratio of 1:1000 serum antibodies to SGPP-1 SFR/Tween with 1% BSA for 1 h with continuous shaking. The membrane washed three times in SFR/Tween and then incubated with diluted in a ratio of 1:3000 conjugate serum antibodies ass to rabbit Ig (Amersham) and horseradish peroxidase in SFR/Tween with 1% BSA for 1 h with continuous shaking. The membrane is then washed three times in SFR/Tween, and use immunodetectable the ECL system (Amersham) for detectionisdone, and, as discovered, they are active (inhibited LPS-induced expression of protein PGHS-2 in extent, notable for ranking, similar to that observed with the inhibition of the production of cytokines in these analyses):

1-[3-(4-Morpholinyl)propyl] 4-(4-forfinal)-5-(4-pyridyl)imidazole, an illustrative compound of formula (I); 6-(4-Forfinal)-2,3-dihydro-5-(4-pyridinyl)[2,1-b]thiazole; Dexamethasone

Several compounds have been investigated and proved to be inactive (up to 10 μm);

2-(4-Methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-(5H)-pyrrolo[1,2-a] imidazole, rolipram; feniton and NDGA. None of the investigated compounds, as found, did not inhibit the levels of proteins SGPP-1 or cPLA2in similar experiments.

Examples of the synthesis of

Hereinafter the invention is described with reference to the following examples, which are illustrative only and are not intended to limit the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are of the highest available purity, and all reactions take place in anhydrous conditions in an argon atmosphere, unless otherwise stated.

In the examples all temperatures are given in degrees Celsius (oC). Mass spectra are obtained from the using the/SUP>H-NMR (hereinafter NMR) recorded at 250 MHz using a spectrometer Bruker AM 250 or Am 400. The multiplicity indicated as follows: s=singlet, d=doublet, t=triplet, q=Quartet, m=multiplet and user. indicates broadened signal. The feast upon. means a saturated solution, EQ. means the proportion of the molar equivalent of the reagent with respect to the main participant reactions. Flash chromatography is carried out on Merck Silica gel 60 (230-400 mesh mesh.).

Example 1

1-[3-(4-Morpholinyl)propyl]-4-(4-forfinal)-5-(4-pyridyl)-imidazol

a) 4-Forfinal-colistimethate

A solution of p-forventelige (13.1 ml (hereinafter ml), 122 millimole (hereinafter mmol)), thiocresol (16,64 grams (next g), formamide (15.0 ml, 445 mmol) and toluene (300 ml) are combined and heated to the boiling point of toluene with azeotropic removal of H2About for 18 hours the Cooled reaction mixture is diluted with EtOAc (500 ml) and washed with saturated aqueous PA2CO3(3100 ml), saturated aqueous NaCl (100 ml), dried (PA2SO4) and concentrate. The residue is triturated with petroleum ether, filtered and dried in vacuum to obtain 28,50 g specified in the title compound as a white solid (85%). Melting point (hereinafter referred to so square) = 119>
Cl2(300 ml) is cooled to -30oWith and under mechanical stirring is added dropwise l3(11 ml, 110 mmol) followed by adding dropwise Et3N (45 ml, 320 mmol), keeping the temperature below -30oC. Stirred at -30oC for 30 min and 5oC for 2 h, diluted with CH2Cl2(300 ml) and washed with 5% aqueous solution of Na2CO3(3100 ml), dried (Na2SO4) and concentrated to 500 ml of This solution is filtered through a cylindrical layer of quartz 12 x 16 cm in a large crucible (funnel) with a filter of sintered glass with CH2Cl2to obtain 12.5 g (53%) of the pure isonitrile in the form of a light brown, resinous solid product. IR (CH2Cl2) 2130 cm-1.

c) Pyridine-4-carboxaldehyde[4-morpholinyl-3-yl] Imin

Pyridine-4-carboxaldehyde (2.14 g, 20 mmol), 4-(3-aminopropyl)morpholine (2,88 g, 20 mmol), toluene (50 ml) and gSO4(2 g) are combined and stirred in an argon atmosphere for 18 hours gSO4filtered off and the filtrate is concentrated and the residue is re-focusing of CH2Cl2to obtain 4.52 g (97%) indicated in the title compound as a yellow oil comprising less than 5% of aldehyde based on d) 1-[3-(4-Morpholinyl]-4-(4-forfinal)-5-(4-pyridyl)imidazole

The compound of example 1(b) (1,41 g, 5.5 mmol) and the compound of example 1(C) (1,17 g, 5.0 mmol), and CH2Cl2(10 ml) is cooled to 5oC. Add 1,5,7-diazabicyclo[4,4,0] Dec-5-ene, hereinafter referred to as (LDP) (0.71 g, 5.0 mmol) and the reaction mixture was kept at 5oC for 16 h, diluted with EtOAc (80 ml) and washed with saturated aqueous Na2CO3(215 ml). Extracted with EtOAc 1 N. HCl (315 ml) and the acidic phase was washed with EtOAc (225 ml), layer EtOAc (25 ml) and make alkaline by adding a solid TO a2CO3to pH 8.0, and then 10% NaOH to pH 10. The phases are separated and the aqueous extracted with additional EtOAc (325 ml). The extracts are dried (K2CO3), concentrated and the residue crystallized from acetone/hexane to obtain 0,94 g (51%) specified in the connection header. So pl. = 149-150oC.

Example 2

5-(2-Aminopyrimidine-4-yl)-4-(4-forfinal)-1-[3-(4-morpholinyl)propyl]imidazol

a) 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal

Dimethylformamide, dimethylacetal (55 ml, 0.41 mol) and pyruvic aldehyde, dimethylacetal (50 ml, 0.41 mol) are combined and heated to 100oC for 18 hours, the Methanol is removed in vacuo to obtain an oil. NaOH solution (18 g, 0, the above-described oil. The resulting mixture was stirred at 23oC for 48 hours Filtering gives 25 g (50%) specified in the connection header.

b) 2-Aminopyrimidine-4-carboxaldehyde

The connection of the previous stage (1,69 g, 10 mmol) and 3 N. model HC1 (7.3 ml, 22 mmol) are combined and heated to 48oC for 14 h, cooled, layer EtOAc (50 ml) and neutralized by adding NaHCO3(2.1 g, 25 mmol) in small portions. The aqueous phase is extracted with EtOAc (550 ml) and the extracts dried (Na2SO4) and concentrate to obtain 0.793 g (64%) specified in the connection header.

c) 2-Aminopyrimidine-4-carboxaldehyde [3-(4-morpholinyl)-propyl]Imin

The connection of the previous stage and 4-(3-aminopropyl)morpholine interact according to the method of example 1(C), above, obtaining specified in the title compound as a yellow oil.

d) 5-(2-Aminopyrimidine-4-yl)-4-(4-forfinal)-1-[3-(4-morpholinyl)propyl] imidazol

According to the method of example 1(d) above, except using the compound of the previous stage as an imine, get mentioned in the title compound as a white solid product.1H-NMR (CD3CL): 8,15 (d, J=5.4 Hz, 1H), 7.62mm (s, 1H), 7,46 (DD, 2H), 7,00 (t, J=8.6 Hz, 2H), 6,50 (d, J=5.4 Hz, 1H), 5,09 (user. s, 2H), 4,34 (t, J=7,0 Hz, 2H), 3,69 (m, 4H), 2,35 (user. C-3-propyl)imidazol

a) 2-Methylaminopropane-4-dimethylacetal

Sodium (3,27 g, 142 mmol) was dissolved in absolute ethanol (425 ml). Add 1-metilprednisolone (15.5 g, 142 mmol) and the resulting suspension is stirred for about 10 minutes Add 1,1-dimethoxy-2-oxo-4-dimethylamino-3-butene (142 mmol) dissolved in ethanol (20 ml), and the mixture is stirred at reflux for 24 hours the Mixture is cooled and filtered. The ethanol is evaporated and the resulting residue triturated with hot EtOAc. Drilling fluid EtOAc combined and the solvent is evaporated to obtain specified in the connection header (23,5 g, 91%) as a yellow oil.1H-NMR (Dl3): 8,35 (d, J=4.5 Hz, 1H), 6,74 (d, 1H), 5,10 (s, 1H), 3,40 (s, 1H), 3.00 and (d, 3H).

b) 2-Methylaminopropane-4-carboxaldehyde

Following the method of example 2 (b), above, except using the compound of the previous stage (of 11.75 g, a 64.6 mmol), get mentioned in the title compound as a yellow foam (of 7.3 g, yield 82.7 per cent). 1H-NMR (CDCl3): 9,85 (d, J=4.5 Hz, 1H), charged 8.52 (s, 1H), 7,03 (d, 1H), 5,52 (s, 1H), 3,10 (d, 1H).

c) 5-[4-(2-Methylamino)pyrimidinyl]-4-(4-forfinal)-1-(4-N-morpholino-1-propyl)imidazol

The connection of the previous stage (5.0 g, of 36.5 mmol) and 4-(3-aminopropyl)morpholine (5,3 ml of 36.5 mmol) imposition of example 1(b) (11.3 g, while 43.8 mmol) and LDP (8,4 g, 61,32 mmol). The mixture is left to stand for about 3 days at about 5oC. the Product is filtered and grind into powder with hot EtOH to obtain specified in the connection header (6,06 g, the output of 41.9%) as a pale-yellow solid product. So pl. = 203-305oS.1H-NMR (CDCl3/MeOD): 8,01 (d, J=4.5 Hz, 1H), 7,60 (s, 1H), 7,37 (kV, 2H), 6,95 (t, 2H), 6,29 (d, 1H), 4,32 (s, 1H), 3,63 (t, 4H), of 3.57 (m, 2H), 2.95 and (s, 3H), 2,33 (m, 4H), of 2.23 (t, 2H), equal to 1.82 (t, 2H).

Example 4

5-[4-(2-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(1-methyl-piperidine-4-yl)imidazol

a) Compound of example 75(a) (4,25 g that 37.2 mmol), obtained as described in WO 95/02591, Adams et al. which description is incorporated here by reference in its entirety, and example 3(b) (5,1 g that 37.2 mmol), obtained as above, join in CH2Cl2(150 ml). This mixture is stirred for about 16 h at room temperature and cooled to 0oC. Add the compound of example 1(b), above, and biodiesel fuel, and the resulting mixture was stirred at room temperature for about 3 days. The mixture is purified directly on a column of silica gel and purified by flash chromatography elwira 0%-5% MeOH/CH2Cl2. The oil obtained is washed in acetone/hexane and the precipitate is filtered, washed with acetone recipS.1H-NMR (Dl3): 8,16 (d, J=4.5 Hz, 1H), to 7.77 (s, 1H), 7,45 (kV, 2H), 6,98 (t, 2H), 6,41 (d, 1H), 5,20 (d, 1H), 4,66 (s, 1H), 3,05 (d, 3H), 2,98 (d, 2H), 2,32 (s, 3H), and 2.14 (m, 2H), 2,01 (m, 4H).

The above conditions is used as a compound of formula (IIA) - scheme I, where p= 0. In the same way part (a), but using the compound of the formula (IIA) - scheme I, where p=2, and isolated Imin use on the table.

In ways similar to those described above, can be obtained following connection.

Example 5

5-[4-(2-Methylamino)pyrimidinyl]-4-(4-forfinal)-1-(4-piperidine)imidazol

a) 5-[4-(2-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(4-N-BOC-piperidine)imidazol

A solution of 2-methylamino-4-pyrimidinecarboxylic (2,47 g 17,99 mmol) and tert-butyl 4-amino-1-piperidinecarboxylate (as described in example 46(a) in WO 95/02591, Adams et al.) (3,96 g, 19,79 mmol) in 36 ml of DMF was stirred at about 25oC for about 5-6 hours After cooling to about 0oTo add isonitrile stage (b) of example 10(b), below (6,24 g, 21.60 mmol) and powdered TO2CO3(2,98 g, 21.60 mmol). The solution is gradually heated to about 25oC for about 3 hours after about 16 h was added 100 ml of N2O and the resulting mixture was filtered, washed with 20 ml of N2O and 50 ml trego powder.1H-NMR (300 MHz, CDCl3): 8,15 (1H, d, J= 5.0 Hz), 7,72 (1H, s), 7,45 (2H, m), of 6.99 (2H, t, J=8.7 Hz), 6,40 (1H, d, J= 5,1 Hz), 5,20 (1H, m), 4,80 (1H, m), 4,28 (2H, m), 3,03 (3H, d, J=5.0 Hz), was 2.76 (2H, t, J=and 12.2 Hz), 2,17 (2H, d, J=12,2 Hz) to 1.86 (2H, DQC, J=4,3, and 12.4 Hz), 1,48 (N, C).

b) 5-[4-(2-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(4-piperidine)imidazol

To a stirred suspension of N-BOC derivative stage (a) above (31 g, 68 mmol) in ethyl acetate (310 ml, 10 volumes) add 3 N. HCl (160 ml, 476 mmol, 7 EQ. ) at 25oC. the Obtained turbid yellow solution was stirred at 25oC for 2 hours the pH of the reaction mixture adjusted to 12-13 by slow addition of 50% aqueous NaOH solution. The phases are separated, and the aqueous phase is extracted twice with methylene chloride (200 ml each time). The combined organic extracts washed with water, dried over MgSO4and evaporated in a rotary evaporator to dryness. The obtained light-yellow residue is suspended in hot ethyl acetate/methylene chloride (200 ml), the mixture 9:1) and allow to cool to 25oC. the Product is collected by filtration by suction and washed with ethyl acetate (25 ml). The white solid product is dried to constant weight at 50o/≪1 mm) to obtain 19 g (54 mmol) described in the header of the product, receiving the output of 79%.1H-NMR (300 MHz, CDCl3): 8,15 (1H, d, J=5J=2,0, to 12.3 Hz), 2,16 (2H, d, J=11.8 Hz), to 1.86 (2H, DQC, J=3,9, and 12.2 Hz).

In an alternative synthesis is mentioned in the title compound can be obtained in the following way:

5-[4-(2-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(piperidine 4 - yl)imidazol

i) 5-[4-(2-Methylamino)pyrimidinyl]-4-(4-forfinal)-1-(4-N - carboxyethylpyrrole)imidazol

A solution of 2-methylaminopropane-4-carboxaldehyde of dimethylacetal (1.88 g, or 10.3 mmol) in 10 ml of 3 N. HCl is heated under 47oC for 14 h before until according to HPLC will not disappear from the source material. The reaction mixture is cooled to 25oand add successively ethyl 4-amino-1-piperidine-carboxylate (1,95 g, 11.3 mmol), ethyl acetate (30 ml) and Panso3(3,45 g, 41,1 mmol). After 7 h add DMF (5 ml), isonitrile stage (b), example 10(b) (2,97 g of 10.3 mmol) and powdered TO2CO3(1.56 g, 11.3 mmol). The reaction mixture is stirred for 14 h, diluted with 50 ml EtOAc, washed with water (250 ml), a saturated solution of K2CO3(50 ml) and brine (30 ml) and the organic phase is concentrated. The product is recrystallized from ethyl acetate to obtain specified in the connection header (1,96 g 45%).1H-NMR (300 MHz, Dl3): 8,16 (1H, d, J=5.0 Hz), 7,72 (1H, s), 7,45 (2H, m), 7,00 (2H, t, J=8.7 Hz), 6,41 (1H, d, J=5,0 GCC).

ii) 5-[4-(2-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(piperidine-4-yl)imidazol

To a stirred solution of the compound obtained above (2.1 g, with 4.64 mmol) in EtOH (40 ml) and water (20 ml) is added NaOH (1.48 g, is 37.2 mmol) and the solution heated under reflux for 36 hours the Solution is cooled to room temperature and add toluene (20 ml). The solution was concentrated in vacuo, add toluene (20 ml) and again concentrated in vacuo. Add water (30 ml) and toluene (30 ml), and the white solid product, which was formed, filtered and dried to obtain specified in the title compound (1.26 g, 77%).1H-NMR (300 MHz, CDCl3): 8,15 (1H, d, J=5.0 Hz), to 7.77 (1H, s), 7,45 (2H, m), of 6.99 (2H, t, J=8.7 Hz), 6,40 (1H, d, J=5,1 Hz), 5,23 (1H, m), was 4.76 (1H, m), up 3.22 (2H, d, J=12,4 Hz), 3,05 (3H, d, J=5,1 Hz) to 2.67 (2H, dt, J= 2,0, to 12.3 Hz), 2,16 (2H, d, J=11.8 Hz), to 1.86 (2H, DQC, J=3,9, and 12.2 Hz).

In another alternative embodiment of the present invention, the protective group is substituted with tert-VOS on carboxyethyl and synthesized using conditions similar to the conditions of parts (a) and (b) above:

5-[4-(2-N-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(4-N-carboxyethylpyrrole)imidazol

A solution of 2-methylamino-4-pyrimidinecarboxylic (2,47 g 17,99 mmol) and ethyl 4-amino-1-piperidinecarboxylate (3.25 g, to 18.9 mmol) in 36 m is g, of 20.7 mmol) and powdered TO2CO3(3.11 g, to 22.5 mmol). After approximately 16 h add 250 ml of N2O, 30 ml TBME and 30 ml of EtOAc, and the resulting mixture is filtered, washed with 200 ml of N2And TBME (2100 ml). The isolated material is re-crystallized from EtOAc/Et2O obtaining of 5.3 g (65%) indicated in the title compound as a white powder. So pl. 205-206o;1H-NMR (300 MHz, CDCl3): 8,16 (1H, d, J=5.0 Hz), 7,72 (1H, s), 7,45 (2H, m), 7,00 (2H, t, J=8.7 Hz), 6,41 (1H, d, J=5.0 Hz), 5,19 (1H, m), 4,84 (1H, m), 4,35 (2H, m) to 4.16 (2H, d, J=7,1 Hz), 3.04 from (3H, d, J= 5.0 Hz), 2,82 (2H, m), of 2.20 (2H, m), a 1.88 (2H, DQC, J=4,4, 12,5 Hz) of 1.28 (3H, t, J=7,1 Hz).

In another alternative embodiment of the present invention using acid hydrolysis ethylcarbamate network specified in the header connection:

5-[4-(2-Methylamino)pyrimidinyl]-4-(4-forfinal)-1-(4-piperidine)-imidazol

Concentrated hydrochloric acid (12 ml) is added to 4 - [[1-(1-etoxycarbonyl)-4-piperidinyl)] -4-(4-forfinal)-1H-imidazol-5-yl] -N-methyl-2-pyrimidinamine (25 g, 0,059 mol) and heated under reflux for 18 hours, the Reaction mixture was cooled to 0oC and neutralized with 50% aqueous sodium hydroxide solution. The precipitate is collected by filtration, washed with water, air-dried and dried in the house to 62%.

Example 6

5-[(2-Ethylamino)pyrimidine-4-yl] -4-(4-forfinal)-1-(1-methylpiperidin-4-yl)imidazol

a) 2-Methylthiopyrimidin-4-carboxaldehyde dimethylacetal

Pyruvic aldehyde, dimethylacetal (19.2 ml, 159,1 mmol) and N,N-dimethylformamide, dimethylacetal (21,12 ml, 159,1 mmol) are combined in a 500 ml flask and heated to 100oC. After 4.5 h, the flask is removed from the heater, add thiourea (11,0 g, 144,5 mmol), NaOMe (25 wt. % solution in Meon, and 39.7 ml, 173 mmol) and 30 ml Meon, and continue heating at 65oC. After 18 h, the solution is cooled to 25oWith and add Me (10,8 ml, 173 mmol) for 5 min (ectoderm.) After 3 h the solution was diluted with 250 ml of N2O and extracted with EtOAc (3 x 100 ml). The combined organic phases, dried over Na2SO4and concentrate to obtain specified in the connection header (26,8 g, 93%) as a brown oil.

b) 2-Methylthiopyrimidin-4-carboxaldehyde

2-Methylthiopyrimidin-4-carboxaldehyde dimethylacetal (30.0 g, 150 mmol) is dissolved in 300 ml ice Asón and 3 ml of conc.2SO4and heated at about 70-80oC. After 10 h, the solution is cooled to 25oWith, and Asón removed in vacuo, leaving a residue in the form of a brown oil. The residue is diluted with 200 ml of CH2CL2and prom is O4and concentrate to obtain 22.1 g (96%) indicated in the title compound as a brown oil.

c) 2-Methylthiopyrimidin-4-carboxaldehyde (1 methylpiperidin-4-yl)Imin

2-Methylthiopyrimidin-4-carboxaldehyde (5.6 g, 36 mmol) and 4-amino-1-methylpiperidin the dihydrochloride (of 6.73 g, 36 mmol) was dissolved in 200 ml of CH2CL2and add Panso3(10.6 g, 126 mmol). After 20 h, the solution was filtered and concentrated to obtain a 8.9 g (98%) indicated in the title compound as a brown oil.

d) 4-(Forfinal)-1-(1-methylpiperidin-4-yl)-5-(2-methylthio-4-pyrimidinyl)imidazol

T-BuNH2(3,90 ml, 37,08 mmol) is rapidly added to a solution of 2-methylthiopyrimidin-4-carboxaldehyde (1 methylpiperidin-4-yl)imine (3,71 g, 14,83 mmol) and 4-forfeitability (5,15 g, 17.8 mmol), dissolved in 50 ml of DME at 25oC. After 14 h, the solution was diluted with 50 ml EtOAc and washed with 50 ml feast upon. Panso325 ml of saline solution. The organic phase is dried over Na2SO4and concentrate. Crystallization of the crude residue using EtOAc/hexane gives 2.85 g (50%) of product as light-brown crystals.1H-NMR (300 MHz, CDCl3): 8,31 (1H, d, J=5,1 Hz), 7,78 (1H, s), 7,40 (2H, m), of 6.99 (2H, t, J=8.7 Hz), 6,76 (1H, d, J=5,2 Hz), of 4.67 (1H, m), 2,97 (2 the haunted reaction conditions with other aminovymi bases and solvents:

a) tert-butylamine and THF; (b) Diisopropylamine and THF; (C) pyrrolidin and THF; (d) potassium carbonate and ethanol.

e) 4-(Forfinal)-1-(1-methylpiperidin-4-yl)-5-(2-methyl-Sul vinyl-4-pyrimidinyl)imidazol

The potassium persulfate (3.2 g, 7.0 mmol) in water (75 ml) are added to a solution of 4-(forfinal)-1-(1-methylpiperidin-4-yl)-5-(2-methylthio-4-pyrimidinyl)imidazole (2.7 g, 7.0 mmol) in ice Asón (150 ml). After stirring at ambient temperature for 72 h, the reaction mixture is neutralized by adding parts of a concentrated aqueous solution of NH4OH and extracted with CH2Cl2. The organic extract was washed with brine, dried (MgSO4) and concentrate. The residue is triturated with ethyl ether to obtain specified in the connection header in the form of not-quite-white solid; yield 2.3 g (83%).

f) 5-[(2-Ethylamino)pyrimidine-4-yl] -4-(4-forfinal)-1- (1-methylpiperidin-4-yl)imidazol

4-(Forfinal)-1-(1-methylpiperidin-4-yl)-5-(2-methylsulfinyl-4-pyrimidinyl) imidazole (0.25 g, of 0.65 mmol) and 70% aqueous solution of ethylamine (2.5 ml) is heated to 120oIn a sealed reaction vessel for 18 hours After cooling to ambient temperature volatile products is evaporated and the residue triturated with these is+) MS m/e= 381 (MH+).

Example 7

4-(4-Forfinal)-5-[2-(isopropyl)aminopyrimidine-4-yl] -1-(1-methylpiperidin-4-yl)imidazol

According to the method of example 6, stage (F), except substituting Isopropylamine receive specified in the connection header in the form of yellowish-korichnevogo solid product with a yield of 20%: ES(+) MS m/e=395 (MH+).

Example 8

5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-(1-methyl-4 - piperidinyl)imidazol

a) 2-Acetamidophenyl-4-carboxaldehyde monomethyl monoacylglycerol

A mixture of 2-aminopyrimidine-4-carboxaldehyde of dimethylacetal (9.0 g, 53 mmol) and acetic anhydride (25 ml) heated to 60oC for 18 hours Add concentrated H2SO4(10 drops) and the solution heated to 100oC for 10 h After cooling to ambient temperature volatile products is evaporated and the residue is filtered using vacuum through a pad of silica gel, elwira 4% Meon in CH2Cl2. Evaporation of the filtrate followed by grinding of the residue with ether complex network specified in the title compound as a white solid; yield 8.6 g (68%).

b) 2-Acetamidophenyl-4-carboxaldehyde

The sodium methoxide (0,056 g, 1.0 mmol) are added to a solution of 2-acetamido-pyrimid is. After stirring at this temperature for 3 h, the reaction mixture is neutralized by adding 3 N. HCl. The resulting solution was concentrated, and the residue is heated with CH2Cl2. The remaining solid product is removed by filtration, and the solvent is evaporated to obtain specified in the title compound as a yellow solid; yield 3.2 g (92%).

c) 2-Acetamidophenyl-4-carboxaldehyde (1 methylpiperidin-4-yl)Imin

Following the method of example 75(b), as described in WO 95/02591, Adams et al., except for the substitution of 2-acetamido-pyrimidine-4-carboxaldehyde receive specified in the title compound in the form of not quite white solid product with a yield of 75%.

d) 5-(2-Acetamido-4-pyrimidinyl)-4-(4-forfinal)-1-(1-methyl-4-piperidinyl)imidazol

Following the method of example 6(d), except substituting 2-acetamidophenyl-4-carboxaldehyde (1 methylpiperidin-4-yl)imine, get mentioned in the title compound as a yellow solid in 51% yield.

e) 5-(2-Amino-4-pyrimidinyl)-4-4(4-forfinal)-1-(1-methyl-4-piperidinyl)imidazol

A solution of 5-(2-acetamido-4-pyrimido-Neil)-4-(4-forfinal)-1-(1-methyl-4-piperidinyl)imidazole (4.0 g, 0,010 mol) in 40 ml of 3 N. HCl heated to 75oC for 18 hours After okhlazhdenii sediment allocate by filtration, washed with water and dried in air to obtain specified in the title compound as a white solid product with a quantitative yield.

Example 9

5-(2-Acetamido-4-pyrimidinyl)-4-(4-forfinal)-1-(4-morpholino-3-propyl)imidazol

A solution of 5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(4-morpholino-3-propyl)imidazole (0.50 g, 1.3 mmol) in acetic anhydride (10 ml) is heated under reflux for 18 hours After cooling to ambient temperature the excess acetic anhydride is evaporated and the residue partitioned between saturated aqueous Panso3and ethyl acetate. The layers are separated and the organic phase concentrated. The residue is dissolved in Meon (10 ml) and added dropwise to 2.5 N. NaOH (1 ml). After stirring at ambient temperature for 2 h, the solution is partially evaporated and the precipitate is collected by filtration, washed with water and dried in air to obtain specified in the title compound as a white solid; yield 0.28 g (51%): ES(+) MS m/e=425 (MH+).

Example 10

(a) -(p-Toluensulfonyl)-4-tormentilline

To a stirred solution of 4-forventelige (124 g, 979 mmol) in acetonitrile (620 ml, 5 volumes) and toluene (620 ml, 5 volumes) add fo the P>oC in nitrogen atmosphere for 5 hours To the resulting white suspension type p-toluensulfonate acid (230 g, 1,47 mol, 1.5 EQ.), and the reaction mixture is heated to 50oC for 5 h, then cooled to ambient temperature. Add methanol (250 ml) and tert-butyl methyl ether (620 ml). After 15 minutes the reaction mixture was poured into water (3 l), pre-cooled to 0oC. After stirring for 30 minutes at 0oThe product is collected by filtration by suction and washed with tert-butylmethylamine ether (250 ml). The product, a white, crystalline solid, which is dried to constant weight at 40o/≪1 mm RT.article to obtain 270 g (879 mmol) of the described product (yield 90%). 1H-NMR (300 MHz, CD3SP): TO 7.99 (1H, s), 7,92 (1H, m), 7,71 (2H, d, J= 8,3 Hz), 7,49 (2H, DD, J=5,3, 8,8 Hz), 7,39 (2H, d, J=8.1 Hz), 7,16 (2H, t, J=8,8 Hz), (1H, m), of 6.31 (1H, d, J=a 10.6 Hz), 2,42 (3H, s).

Conditions, alternative used above in part (a), use:

a) toluene at about 50oWith; (b) acetonitrile at about 50oWith; and (C) using the same conditions as above, but at temperatures of 30, 40, 50, 60 and 70oC.

b) -(p-Toluensulfonyl)-4-forbindelser

Stir the suspension -(p-toluensulfonyl)-4-fluoro-ensiform the UB>3
(46 ml, 487 mmol, 1.5 EQ.). See the jump in temperature in the 1oWith due ekzotermicheskie reaction. After 15 minutes at 0oWith the white suspension is cooled to -5oC. Triethylamine (166 g of 1.62 mol, 5 EQ. ) is added dropwise to the suspension for 45 minutes at such a rate as to maintain the reaction temperature below 0oBut above -5oC. care Must be taken at the beginning of the addition as the reaction tends to be exothermic temperature jump. After adding the yellow suspension is stirred for 30 minutes at 0oC. the Reaction suspension tends to darken during mixing. The reaction suspension was poured into a mixture of saturated aqueous sodium bicarbonate solution (1 l) and ethyl acetate (1 l), both pre-cooled to 0oC. the Organic phase is later washed with water, then brine. The organic phase was concentrated in vacuo by evaporation on a rotary evaporator until then, until there is 10% of the initial volume. Add 1-propanol (200 ml) and again concentrated in vacuo at 35oFrom until, until there is 10% of the initial volume. This process is repeated with fresh 1-propanol (200 ml). the m filtration by suction and washed with 1-propanol (50 ml). Off-white solid product is dried to constant weight at 40o/≪1 mm RT. Art. with obtaining and 65.7 g (227 mmol) of the product described, receiving the output of 70%.1H-NMR (300 MHz, CDCl3): a 7.62 (2H, d, J=6,7 Hz), 7,46 (4H, m), was 7.08 (2H, t, J=8.6 Hz), 5,62 (1H, s) to 2.46 (3H, s).

Use alternative conditions relative to that used above in part (b), such as (a) different solvents: DME, DME/acetonitrile (10:1) using the same reaction conditions; (b) using the reaction conditions described above, but in the temperature range from -30, -15, -10 and 0oC; C) using the reaction temperature at 0oC and -10oWith; (d) the number of dehydrating agents, including triperoxonane anhydride, thionyl chloride and oxalicacid.

Example 11

5-(2-Acetamido-4-pyrimidinyl)-4-(4-forfinal)-1-(1-methylpiperidin-4-yl)imidazol

To a solution of 2-acetamidophenyl-4-carboxaldehyde (0.84 g, 5.08 mmol) and 1-methylpiperidin-4-elementisdeclared salt (1.04 g, 5,59 mmol) in 21 ml of DMF add powdered K2CO3(1.54 g, and 11.2 mmol). After about 6 h add -(p-toluensulfonyl)-4-forbindelser, the product of stage (b) of example 10, above, (1,76 g, 6,10 mmol) and powdered TO2CO3(0.84 g, 6,10 mmol) and walls washed 5e organic phases are washed with H2O (350 ml), dried over Na2SO4and concentrate. Clean the connection specified in the header (0.75 g, 38%), recrystallized from EtOAc as light yellow crystals.1H-NMR (300 MHz, CDCl3): 8,71 (1H, s), 8,39 (1H, d, J=5,2 Hz), 7,81 (1H, s), 7,39 (2H, m), 7,13 (2H, t, J=8.7 Hz), for 6.81 (1H, d, J=5,2 Hz), 4,88 (1H, m) to 2.94 (2H, d, J=10.1 Hz), 2,47 (3H, s), 2,32 (3H, s) 2,07 (6N, m).

Example 12

5-[4-(2-Methylthionine)pyrimidinyl] -4-(4-forfinal)-1-(4-piperidine)imidazol

To a solution of 2-methylthieno-4-pyrimidinecarboxylic (3.4 g, 22,07 mmol) and 4-amino-1 - metilprednisolona salt (4,54 g, a 24.3 mmol) in 44 ml of DMF add powdered TO2CO3(7,02 g, 50.8 mmol). After about 6 h, the solution is cooled to about 0oWith and add isonitrile of example 10, the stage (b), above, (of 7.68 g of 26.5 mmol) and K2CO3(3.57 g, 25,38 mmol), and stirred with gradual heating to about 25oC. After about 16 h, the reaction mixture is diluted with 200 ml EtOAc and washed with 200 ml of N2O. the Aqueous layer was extracted with EtOAc (2100 ml) and the combined organic phases are washed with H2O (3100 ml). The organic phase is dried over Na2SO4and concentrate, and is listed in the title compound is recrystallized from EtOAc/Hex to obtain 5,12 g (61%) of light yellow Cristallo is, is), at 2.59 (3H, s), 2,32 (3H, s) 2,07 (6N, m).

Example 13

5-[4-(2-Methylamino)pyrimidinyl] -4-(4-forfinal)-1-(1-methylpiperidin-4-yl)imidazol

To a solution of 2-methylamino-4-pyrimidinecarboxylic (2,79 g, 20,37 mmol) and 4-amino-1 - metilprednisolona salt (4,19 g, 22,41 mmol) in 41 ml of DMF add powdered TO2CO3(to 6.19 g, 44,82 mmol). The mixture is stirred at room temperature for about 6 hours the Solution is cooled to aboutoWith and add isonitrile example 85, stage (b) (7,07 g, 24,44 mmol) and powdered TO2CO3(3,10 g, 22,41 mmol). Stirred at about 0oC for about 3 h, then slowly warmed to room temperature for 2 hours Add 100 ml of N2Oh and stirred for about 15 minutes. Filtered and washed with 50 ml of N2O and 50 ml TBME. After drying to 5.56 g (74%) indicated in the title compound is isolated in the form of not quite white powder.1H-NMR (300 MHz, CDCl3): 8,15 (1H, d, J=4.9 Hz), 7,76 (1H, s), 7,45 (2H, m), of 6.99 (2H, t, J=8.7 Hz), 6,40 (1H, d, J=5,1 Hz), from 5.29 (1H, m) and 4.65 (1H, user. C), totaling 3.04 (3H, d, J=5,1 Hz), of 2.97 (2H, m), 2,31 (3H, s), 2,13-1,98 (6N, m).

Alternatively, the reaction described above is carried out at room temperature.

Example 14

5-[4-(2-Aminopyrimidine)-4-(4-forfinal)-1-(2,2,6,6-tetramethyl-4-the compound of example 2(b) (0,752 g 6.1 mmol), above, combine 4-amino-2,2,6,6-tetramethyl-piperidine (1,00 g, 6.42 per mmol), CH2CL2(90 ml) and CH3HE (1 ml), stirred overnight and concentrated to obtain specified in the title compound as a yellow solid product.

b) 5-[4-(2-Amino)pyrimidinyl)-4-(4-forfinal)-1-(2,2,6,6-tetramethyl-4-piperidinyl)imidazol

The product from (a) above, and the product of example 4(b) above, (1.86 g, 6.42 per mmol), K2CO3(0,842 g, 6.1 mmol), and DMF (12 ml) are combined and stirred for 3 days. Pour in N2O (25 ml) and extracted with EtOAc (425 ml), dried (Na2SO4) and concentrated to oil. Flash chromatography (0-10% Meon in CH2Cl2gives 0,837 g (35%) specified in the connection header. So pl. 227-230 (decomp.).

Example 15

With methods similar to the methods described above, except using the compound of example 3(b) as the aldehyde precursor imine can be obtained the following link:

5-(2-Methylamino-4-pyrimidinyl)-4-(4-forfinal)-1-(2,2,6,6-tetramethyl-4-piperidine)imidazole; so pl.=184-185oC.

With methods similar to the methods described in example 1, except using the product of example 2(b) or of the product of example 3(b) as the aldehyde and the corresponding the Mino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-dipiradol)imidazole. So pl. 228-230oC.

Example 17

5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-pyranyl)imidazole. So pl. 222-223oC.

Example 18

5-(2-Methylamino-4-pyrimidinyl)-4-(4-forfinal)-1-(2-cyanoethyl)imidazole. So pl. 193-194oC.

In ways similar to those described in example 14 of WO 95/02591 Adams et al. (Attorney Docket P50172-1), except using the product of example 16 as the source of the product, can be obtained the following compounds:

Example 19

5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazole. So pl. 255-265oC (decomp.).

Example 20

5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazol

The product of example 16, above (213 mg, 0.6 mmol), CH2CL2(2.25 ml), CH3HE (0.75 ml) and TN (92 ml, 1.2 mmol) is cooled to 4oWith and add MCPBA (about 80%) (387 mg), heated to 23oC for 20 min, poured into EtOAc (50 ml) and washed with 5% aq. PA2CO3, dried (Na2SO4), concentrated, filtered through a layer of silica (0-4% Meon) to give pure 5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazole (80 mg, 34%). So pl. =228-230oC.

Example 21

5-(2-Methylamino-4-pillaged dimethylacetal

Pyruvic aldehyde, dimethylacetal (277 ml, 2.3 mol) and N,N-dimethylformamide, dimethylacetal (304 ml, 2.3 mol) is stirred together at 100oC for 18 hours the Mixture was concentrated to a brown oil.

Metallic sodium (25 g) is dissolved in EtOH (3 l). Add methylguanine hydrochloride (112 g), and the mixture is stirred for 5 hours Add the above oil (1.15 mmol) and the mixture heated under reflux for 24 h, cooled, filtered and concentrated. The resulting residue triturated with hot EtOAc and filtered through celite. The filtrate is concentrated, getting mentioned in the title compound as a brown oil.1H-NMR (CDCl3): with 8.33 (d, 1H), 6.75 in (d, 1H), 5,10 (s, 1H), 3,40 (C, 6N), of 3.00 (s, 3H).

b) 2-N-Methylaminopropyl-4-carboxaldehyde

A mixture of compound of example 21(a) hydrolyzing by way of example 26(e) to give the compound as a yellow foam.1H-NMR (CDCl3): 9,88 (s, 1H), 7,13 (d, 1H), 7,01 (d, 1H), 2.05 is (s, 3H).

c) 2-N-Methylaminopropyl-4-carboxaldehyde(1- [1- (2, 2, 2-triptorelin)aminopiperidin]Imin

The product of example 26(C) and the product of example 21(b) interact according to the method of example 1(f) obtaining specified in the title compound as a yellow oil.1H-NMR (CDCl3): a 8.34 (-forfinal)-1-[1-(2,2,2-triptorelin)piperidine-4-yl]imidazole

The product of example 21(C) and the product of example 26 (h) interact by way of example 26(i) obtaining specified in the connection header. Crystals from acetone/hexane. So pl. 189-191oC.

Example 22

5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-[(1-Cryptor-acetyl)-4-piperidinyl]imidazol

The product of example 46 (C) (500 mg, 1.12 mmol) described in WO 95/02591 Adams et al. (Attorney Docket P50172-1), suspended in CH2CL2(50 ml) and add Et3N (585 ml, 4.2 mmol), and after 30 seconds, add triperoxonane anhydride (160 ml, 1.12 mmol). After 1 h, the insoluble material is filtered and the filtrate concentrated. The obtained white powder was filtered through a layer of quartz (1-2% CH3HE in CH2Cl2)

obtain 350 mg (72%) specified in the connection header. So pl.=249-250oC.

Example 23

5-(4-Pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazol

a)Pyridine-4-carboxaldehyde(ethyl-4-aminopiperidin-carboxylate)Imin

Following the method of example 26(C), except substituting ethyl-4-aminopiperidines 4-(3-aminopropyl)morpholine, get mentioned in the title compound in quantitative yield.

b) 1-[(1-Etoxycarbonyl)piperidine-4-yl] -4-(4-forfinal)-5-(4-pyridyl)imidazole

Following the method pearsonlloyd(4-etiennetaillet)-Eminem, get listed in the title compound as light-yellow solid product with 71% yield.

C) 4-(4-Forfinal)-5-(4-pyridyl)-1-(4-piperidinyl)imidazol

Concentrated hydrochloric acid (40 ml) are added to 1-[(1-etoxycarbonyl)piperidine-4-yl] -4-(4-forfinal)-5-(4-pyridyl)imidazole (9.4 g, 24 mmol) and the mixture heated under reflux for 18 hours Obtained yellow solution is cooled to ambient temperature and neutralized with 10% aqueous solution of sodium hydroxide. The precipitate is collected, washed with water and dried in air to obtain specified in the title compound as a white solid with a yield of 71%. ESMS=323 [M+H]; so pl. 185-187,0oC.

Example 24

5-(4-Pyridyl)-4-(4-forfinal)-1-(1-tert-butoxycarbonyl-4-piperidinyl)imidazol

Following the method of example 11, except substituting pyridine-4-carboxaldehyde (tert-butoxy-4-aminopiperidines)-imine 2-N-methylamino-4-carboxaldehyde(4-etiennetaillet)Eminem get mentioned in the title compound as a pale yellow solid with a yield of 42%. ESMS=423 [M+H].

Example 25

2-Methylthiopyrimidin-4-carboxaldehyde

A mixture of 2-methylthiopyrimidin-4-carboxaldehyde dimethyl-acetal (3 g, of 15.5 mmol) is italist addition of solid NaHCO3. The aqueous phase is separated and extracted with EtOAc (425 ml). The combined organic extracts dried (Na2SO4) and concentrate. The resulting residue is purified flash chromatography (silica gel, CH2Cl2) and recrystallized in hexane to obtain specified in the connection header in the form of a cream-colored needles (1.12 g, yield 48%).1H-NMR (CDCl3): for 9.95 (s, 1H), 8,77 (d, 1H), 7,43 (d, 1H), 2.63 in (s, 3H).

Example 26 (see scheme XII at the end of the description)

5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-[1-(2,2,2-triptorelin)-4-piperidinyl]imidazol

a) 1-TRIFLUOROACETYL-4-(1,2-diacetyl)piperidine

4-(1,2-Diacetyl)piperidine (7,15 g, 50 mmol), CH2Cl2(50 ml), Et3N (8,35 ml, 60 mmol) and DMAP (and 0.61 g, 5 mmol) are combined and added dropwise triperoxonane anhydride (11,03 g of 52.5 mmol) in CH2Cl2(50 ml), and maintain at a temperature <30with external cooling. After decay of the initial reaction, the reaction mixture was stirred at 23oC for 16 h, washed with 1 N. HCl (250 ml), dried (Na2SO4) and concentrate to obtain 13,38 g (100%) 1-TRIFLUOROACETYL-4-(1,2-diacetyl)piperidine in the form of a white solid product. IR 1693 cm-1.

b) 1-(2,2,2-Triptorelin)-4-piperidinol

Product preds what holodilniki, and stirred for 5 h, cooled to 4oWith, and add 6 N. HCl (1.5 ml). The mixture is concentrated and alkalinized (pH>12) with 50% aq. NaOH and extracted with Et2O (340 ml). The extract is dried (K2CO3) and concentrated to a colorless oil.

The above oil is dissolved in 1 N. HCl (15 ml) and the solution heated under reflux for 1 h, cooled to 23oC and extracted with Et2O (320 ml), dried (Na2SO4) and concentrate to obtain 0.84 g (93%) 1-three-foradil-4-piperidine in the form of a light yellow oil. IR 1719 cm-1.

(C) the Hydrochloride of 1-(2,2,2-triptorelin)-4-aminopiperidine

The product of the previous stage (3,14 g of 17.35 mmol), N2(29 ml) and H2NOH model HC1 (4,82 g, 69,4 mmol) is dissolved together and add small portions of Na2CO3(4,82 g). The mixture was stirred at 23oC for 2 h, the set pH>10 to 50 percent using aq. NaOH, extracted with Et2O (550 ml) and concentrated to a white foam.

The above residue was dissolved in EtOH (abs.) and added Raney Ni (5 ml suspension in EtOH) and the mixture restore in N2(50 lb/in2) (3100 g/cm2) for 3.5 hours the Catalyst is filtered off and washed with EtOH. Add an ethereal solution of Hcl (1 M) (40 ml), and the solvent Adalet filtered off, washed with an additional amount of Et2O and dried in vacuum to obtain 1,71 g (39%) specified in the connection header.1H-NMR (CD3OD): 4,1 (m, 2), and 3.7 (m, 2), and 3.5 (m, 1), 3,3 (m, 2), 2,3 (m, 2), 2,1 (m, 2).

d) 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal

Dimethylformamide, dimethylacetal (55 ml, 0.41 mol) and pyruvic aldehyde, dimethylacetal (50 ml, 0.41 mol) are combined and heated to 100oC for 18 hours, the Methanol is removed in vacuo to obtain an oil. NaOH solution (18 g, 0.45 mol) in N2About (50 ml) are added to the guanidine Hcl (43 g, 0.45 mol) in H2O (100 ml) and the resulting solution is added to the above oil. The resulting mixture was stirred at 23oC for 48 hours Filtering gives 25 g (50%) specified in the connection header.

e) 2-Aminopyrimidine-4-carboxaldehyde

The connection of the previous stage (1,69 g, 10 mmol) and 3 N. HCl (7.3 ml, 22 mmol) are combined and heated to 48oC for about 14 h, cooled, layer EtOAc (50 ml) and neutralized by adding Panso3(2.1 g, 25 mmol) in small portions. The aqueous phase is extracted with EtOAc (550 ml) and the extracts dried (Na2SO4) and concentrate to obtain 0.793 g (64%) specified in the connection header.

f) 2-Aminopyrimidine-4-Carbo/SUB>CO3(1,21 g, 8,77 mmol) and the product of example 1(e) (0,79 g of 6.45 mmol), and CH2Cl2(100 ml) are combined and stirred in the atmosphere of AG within 14 hours of the Phases are separated and the aqueous phase is extracted with an additional portion of CH2Cl2. The combined organic phases are dried (K2CO3) and concentrate to obtain specified in the title compound as a yellow oil.1H-NMR (CDCl3): at 8.36 (d, 1), 8,13 (s, 1), 7,19 (d, 1), and 5.2 (m, 2), the 3.35 (m, 1), and 3.0 (m, 4), to 2.55 (m, 2), 1,90 (m, 2), a 1.75 (m, 2).

g) 4-Forfinal-tolylsulfochloride

To a suspension of sodium salt of p-toluensulfonate acid (30 g) in N2O (100 ml) add TBME (50 ml), then added dropwise conc. HCl (15 ml). After stirring for 5 min the organic phase is removed and the aqueous phase extracted with TBME. The organic phase is dried (Na2SO4) and concentrated almost to dryness. Add hexane and filtered free acid.

Free acid (22 g, 140,6 mmol), p-forbindelse (22 ml, 206 mmol), formamide (20 ml, 503 mmol) and camphorsulfonic acid are combined and stirred at 60oC for 18 hours resulting solid product paint and stirred with a mixture of Meon (35 ml) and hexane (82 ml), then filtered. The solid product PowerNet specified in the title compound (27 g, yield 62%).1H-NMR (400 MHz, Dl3): 8,13 (s, 1H), 7,71 (d, 2H), 7,43 (DD, 2H), 7,32 (d, 2H), was 7.08 (t, 2H), 6,34 (d, 1H), of 2.45 (s, 3H).

h) 4-Forfinal-tolylsulfochloride

The compound of example 1(f) (2,01 g of 6.25 mmol) in DME (32 ml) cooled to -10oC. Add RO3(of 1.52 ml, 16.3 mmol) and then dropwise added triethylamine (4.6 ml, with a 32.6 mmol) in DME (3 ml), maintaining the internal temperature below -5oC. the Mixture was gradually heated with stirring for 1 h, quenched in N2O and extracted with EtOAc. The organic phase is washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrate. The resulting residue is triturated with petroleum ether and filtered to obtain specified in the title compound (1.7 g, yield 90%).1H-NMR (CDCl3): 7,63 (d, 2H), 7,33 (m, 4H), 7,10 (t, 2H), ceiling of 5.60 (s, 1H), 2,50 (s, 3H).

i) 5-(2-Amino-4-pyrimidinyl)-4-(4-forfinal)-1-[1-(2,2,2-triptorelin)-4-piperidinyl]imidazol

The product of example 1(h) (1,96 g, 6,79 mmol), the product of example 26(f) (<6,45 mmol) and K2CO3(0,89 g of 6.45 mmol), and DMF (14 ml) are combined and stirred in the atmosphere of AG within 2 days. The resulting mixture was diluted with Et2O (100 ml) and filtered. The filtrate is concentrated to a dry residue in a vacuum. The obtained solid product is triturated with Et2oC.

Example 27

5-(2-Methylthio-4-pyrimidinyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazol

a) 1-tert-Butoxycarbonyl-4-aminopiperidin 1-tert-

Butoxycarbonyl-4-aminopiperidine-4-one (commercially available from Lancaster Chem) is converted into the free base specified in the title compound by the method of example 26 (C) with the exception of the processing stages Hcl.

b) 2-Methylthiopyrimidin-4-carboxaldehyde [1-tert-butoxy-carbonyl-4-aminopiperidin]Imin

2-Methylthiopyrimidin-4-carboxaldehyde [Bredereck et al. Chem. Ber. 1964, 3407] (1.51 g, 9.8 mmol), the product of example 27 (a) (2.1 g, 10.5 mmol), MgSO4(about 2 g) and CH2Cl2(75 ml) are combined and stirred at 23oC for 16 h Filtration and concentration of the filtrate gives specified in the title compound as a yellow oil.1H-NMR (CDCl3): to 8.57 (d, 1), of 8.27 (s, 1), 7,58 (d, 1), of 4.05 (m, 2), 3,55 (m, 1), of 3.00 (m, 2), 2,60 (s, 3), a 1.75 (m, 4), to 1.48 (s, 9).

c) 5-(2-Methylthio-4-pyrimidinyl)-4-(4-forfinal)-1-[(1-tert-butoxycarbonyl)-4-piperidinyl)imidazol

Following the method of example 26(i), except using the product of example 27(b) as imine, receive oil from the ether phase. Flash chromatography in 0-1% Meon in CH2Cl2the concentration and rubbing the residue with GE is avago solid product. ESP+MS m/z = 470 (MH+).

d) 5-(2-Methylthio-4-pyrimidinyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazol

The product of the preceding example (469 mg, 1.0 mmol) is suspended in CH3HE (2 ml), cooled to 0oC in an atmosphere of AG and added 4 M Hcl in dioxane. The obtained light yellow solid product is heated to 23oC, stirred for 4 h and diluted with Et2O. Separated resinous solid product, which utverjdayut, rubbing with Et2O within 20 minutes, the Solid product is filtered, re-dissolved in N2O, washed with EtOAc, the second layer portion of EtOAc, and the aqueous phase is alkalinized by adding 50% aqueous NaOH solution. Extraction EtOAc (3x), drying of the combined extracts (K2CO3) and concentration gives a solid product, which was triturated with Et2O and filtered to obtain 168 mg (46%) indicated in the title compound in the form of a whitish solid product. So pl.=182-183oC.

The above description describes the present invention, including its preferred embodiments. Modifications and improvements of the embodiments specifically described herein, are within the scope of the subsequent claims. Without further discussion involves is giving the most complete way. For this reason, the examples are assumed as illustrative only and do not represent any limitation of the scope of the present invention in any way. Embodiments of the present invention, in which formulated the exclusive right and privilege are defined as follows.

1. The method of obtaining 1,4,5-triple-substituted imidazole derivatives of the formula

< / BR>
where R1represents a 4-pyridyl, 4-pyrimidinyl, where heteroaryl ring optionally substituted by one or two substituents, each of which is independently selected from1-4of alkyl, halogen, hydroxyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulfonyl, amino, CH2OR12mono - or di-C1-6alkyl substituted amino, N(R10)C(O)Raor N-heterocyclic ring, where the ring consists of 5 to 7 members and optionally contains an additional heteroatom selected from oxygen or NR15;

R4represents phenyl, optionally substituted by one or more substituents, such as halogen, S(C1-C6)alkyl, cyano, nitro, carboxy;

R2represents a C1-10the N3, -(CR10R20)n' is the system containing one or more heteroatoms selected from the group comprising N or O; C1-6alkyl, halogen-substituted C1-6alkyl, C2-6alkenyl, heteroaryl-C1-6alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNR13R14, (CR10R20)nCN, (CR10R20)nSO2R18, (CR10R20)nS(O)mNR13R14, (CR10R20)nC(Z)R11, (CR10R20)nOC(Z)R11, (CR10R20)nC(Z)OR11, (CR10R20)nC(Z)NR13R14, (CR10R20)nC(Z)NR11OR9,

(CR10R20)nNR10C(Z)R11, (CR10R20)nNR10C(Z)R13R14, (CR10R20)nNR10C(= NR19)NR13R14, (CR10R20)nOC(Z)NR13R14, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nNR10C(Z)OR10;

m' is an integer 1 or 2;

n is an integer having values from 1 to 10;

n' is 0 or an integer having values from 1 to 10;

Z is oxygen or sulfur;

Rais9represents hydrogen or C1-6alkyl;

R10and R20each independently selected from hydrogen or C1-4of alkyl;

R11represents hydrogen, C1-6alkyl, a heterocycle, which is a saturated or partially unsaturated 5 to 6-membered ring system containing one or two nitrogen atom;

R12represents hydrogen or R16;

R13and R14each independently selected from hydrogen or optionally substituted C1-4the alkyl, optionally substituted phenyl or optionally substituted phenyls1-4the alkyl, or together with the nitrogen to which they are attached, form a 5 - to 6-membered heterocyclic ring which optionally contains an additional heteroatom selected from oxygen or NR9;

R15is an R10or(Z)-C1-4alkyl;

R16represents a C1-4alkyl;

R18represents a C1-4alkyl, a heterocycle, which is a saturated or partially unsaturated 5 to 6-membered ring system containing one or two heteroatoms selected from oxygen or nitrogen;

R19represents hydrogen, cyano, Cthe organisations of the formula IIA

< / BR>
with the compound of the formula III

< / BR>
where p is 2;

and base, strong enough to deprotonation isonitriles radical of the formula IIA and where Imin formula III is formed in situ before the reaction with the compound of the formula IIA; R1, R2and R4are as defined for formula A, and ar is optionally substituted phenyl group.

2. The method according to p. 1, where the basis is amine, amide, carbonate, hydride, or alkyl - or abilitiy reagent, or mono-, di - and trehosnovnoy phosphate.

3. The method according to p. 1, where Imin receive in situ by reacting the aldehyde of the formula

R1CHO,

where R1is as defined for formula AND,

with the primary amine of the formula

R2NH2,

where R2is as defined for formula A;

R2may be suitably protected as necessary.

4. The method according to p. 3, where when receiving the imine in situ using dehydrating conditions.

5. The method according to p. 3, where the solvent is N, N-dimethylformamide (DMF), halogenated solvents, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, benzene, toluene or DME.

6. The method according to p. the Deputy R1in the formula As under item 1,

obtaining the compounds of formula a or its pharmaceutically acceptable salt.

7. The method according to p. 3, where the aldehyde R1CHO is pyridinylmethyl formula

< / BR>
where X is defined as the substituent R1in the formula As under item 1,

obtaining the compounds of formula a or its pharmaceutically acceptable salt.

8. The method according to p. 3, where the primary amine R2NH2is optionally substituted heterocyclic amine or heterocyclic1-10alkylamine.

9. The method according to p. 8, wherein the primary amine R2NH2is a 4-aminopiperidine, 1-methyl-4-aminopiperidine or 4-amino-2,2,6,6-tetramethylpiperidine.

10. The method according to p. 3, where the aldehyde of the formula R1CHO is formed in situ.

11. The method according to p. 10, where the aldehyde is formed by hydrolysis of the acetal of the formula

R1CH(ORa)2,

where R1defined in formula A;

Rarepresents alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic.

12. The method according to p. 1 where the compound is 5-(4-pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazole or its pharmaceutically acceptable salt.

13. The method according to p. 1, where the received soedinenii)-4-(4-forfinal)-1-(tetrahydro-4-dipiradol)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-pyranyl)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(tetrahydro-4-sulfonylmethane)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-(1-TRIFLUOROACETYL-4-piperidinyl)imidazole;

5-(2-amino-4-pyrimidinyl)-4-(4-forfinal)-1-[1-(2,2,2-triptorelin)-4-piperidinyl] imidazole or

5-(4-pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazole,

or its pharmaceutically acceptable salt.

14. The method of obtaining the compounds of formula

< / BR>
where p is 0 or 2;

AG represents optionally substituted phenyl or naphthyl;

R4is as defined for compounds of formulas And p. 1,

characterized in that interact aldehyde of the formula

R4-CHO,

where R4is as defined for compounds of formula A,

and the compounds of formula

Ar-S(O)p-H,

where AG is listed above,

with a formamide, an acid catalyst and optionally a dehydrating agent.

15. The method according to p. 14, where the dehydrating agent and an acid catalyst are the same.

16. The method according to p. what about p. 14, where the acid catalyst is an anhydrous acid, trimethylsilane, p-toluensulfonate acid, camphorsulfonic acid or hydrogen chloride.

18. The method according to p. 14, where the process is carried out in an organic solvent.

19. The method according to p. 14, where the solvent is toluene, or acetonitrile, or a mixture.

20. The method according to p. 14, where R in formula IV is 0.

21. The method according to p. 14, where R in formula IV is 2.

22. The method according to p. 14, where the interaction is formed intermediate compound of the formula

< / BR>
where R4is as defined for compounds of formula As in paragraph 1.

23. The compound of the formula I

< / BR>
where R4is as defined for compounds of formula As in paragraph 1, except that a is not unsubstituted phenyl.

24. The method of obtaining the compounds of formula

< / BR>
where p is 2;

AG represents optionally substituted phenyl or naphthyl;

R4is as defined for compounds of formula As in paragraph 1,

namely, that interact compounds of the formula

< / BR>
where R4is as defined for formula AND,

with the connection of foo solvent.

25. The method according to p. 24, where the solvent is toluene, or acetonitrile, or a mixture.

26. 5-(4-Pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazole or its pharmaceutically acceptable salt.

27. Connection on p. 26, which represents 5-(4-pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazole.

28. 5-(4-Pyridyl)-4-(4-forfinal)-1-(1-tert-butoxycarbonyl-4-piperidinyl)imidazole.

29. The pharmaceutical composition inhibiting activity of cytokines, characterized in that it contains an effective amount of 5-(4-pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazole or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent.

30. The pharmaceutical composition according to p. 29, containing as an active ingredient 5-(4-pyridyl)-4-(4-forfinal)-1-(4-piperidinyl)imidazole.

Priority points:

09.01.1995 under item 1;

07.06.1995 on PP. 2-24 - clarification of signs on these points.

 

Same patents:

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl

The invention relates to the field of organic chemistry and oil industry, specifically to the new derived contrasena-2-trimethylammoniumchloride-4-methoxy-6-morpholyl-1,3,5-triazine, which is an intermediate in the synthesis of active additives, inhibiting the oxidation of vegetable oils (antioxidant)

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7

The invention relates to the use as a medicinal substance medications for the treatment of diseases associated with impaired venous function and/or inflammatory edema tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and its new compounds of General formula I, where a is either a sulfur atom, oxygen or the radical R3N, where R3is a hydrogen atom, a C1-C5-alkyl; R1is either1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted group selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, methyl, phenyl; R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, and methoxy; and pharmaceutically acceptable salts

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new chemical compound is 2-(N-morpholin)-4-methylpyridine, which can be used as inhibitors of acid corrosion of steel by acid treatment of wells or refineries

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl

The invention relates to a new 2-{4-[4-(4,5-dichloro-2-Mei-1-yl)butyl]-1-piperazinil}-5-torpedinidae formula I (see

The invention relates to novel azole compounds having antifungal activity, their preparation and application

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to a new polymorphic and hydrated forms of the dihydrochloride of Lesopitron(2-[4-[4-(chloropyrazole-1-yl)butyl] -1-piperazinil] pyrimidine] ), which have effect on the Central nervous system, showing, in particular, anxiolytic, sedative and antidepressant action, and pharmaceutical compositions based on these forms of Lesopitron

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl
Up!