KR19990077166A - Novel Cycloalkyl Substituted Imidazoles - Google Patents

Abstract

Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy are provided.

Description

Novel Cycloalkyl Substituted Imidazoles

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are biological substances produced in various cells such as monocytes or macrophages. IL-1 has been described as mediating a variety of biological activities that are thought to be important in immune regulation, and other physiological abnormalities such as inflammation (see, for example, Dinarello et al., Rev. Infect. Disease, 6, 51 (1984). Numerous known biological activities of IL-1 include activation of T helper cells, causing fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, acute phase protein induction, and inhibition of plasma iron concentrations.

There are many disease states in which excessive or unregulated IL-1 production is associated with exacerbating and / or causing the disease. These diseases include rheumatoid arthritis, osteoarthritis, endotoxin and / or toxic shock syndrome, other acute inflammatory disease states such as inflammatory bowel disease or inflammatory bowel disease caused by endotoxins; Tuberculosis, atherosclerosis, myopathy, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, trauma arthritis, rubella arthritis and acute synoviitis. There is evidence that recent activity of IL-1 is also related to diabetes and pancreatic β cells.

Dinaello, J. Clinical Immunology, 5 (5), 287-297 (1985) outlines biological activities due to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.

Excessive or unregulated TNF production may include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint abnormalities; Sepsis, sepsis shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, brain malaria, chronic lung inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease, reperfusion injury, transplantation Host reactions against, graft rejection, fever and myalgia from infections such as influenza, cachexia dependent on infection or malignant disease, cachexia dependent on AIDS, AIDS, AIDS-related complications, keloids It is involved in mediating or aggravating numerous diseases including formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis.

AIDS is caused by infection of T-lymphocytes with human immunodeficiency virus (HIV). At least three types or strains of HIV have been identified, namely HIV-1, HIV-2 and HIV-3. As a result of HIV infection, T-cell mediated immunity is impaired, and infected patients show severe opportunistic infections and / or abnormal neoplasms. Activation of T lymphocytes is required for HIV to invade T lymphocytes. Other cells, such as HIV-1, HIV-2, infect T lymphocytes after T cells are activated, and expression and / or replication of the viral protein is mediated or maintained by the T cell activation. Once activated T lymphocytes are infected by HIV, T lymphocytes must remain activated to allow expression of the HIV gene and / or replication of HIV. Monokines, specifically TNFs, are involved in the expression of activated T-cell mediated HIV proteins and / or viral replication by playing a role in keeping T lymphocytes active. Thus, in HIV-infected patients, for example, disrupting monokine activity by inhibiting monokine production, in particular TNF production, may help to limit T cells from staying active, thus preventing the previously uninfected cells. Reduces the progression of HIV infection, thereby slowing or eliminating the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as Cooper cells and glia cells, are also involved in the maintenance of HIV infection. Like T-cells, these cells are targets for viral replication, and the level of viral replication depends on the active state of these cells. Monocaine, such as TNF, has been shown to activate HIV replication in monocytes and / or macrophages (Poli et al., Proc. Natl. Acad. Sci., 87: 782-784). (1990)), therefore, inhibiting the production or activity of monocaine helps to limit the progression of HIV as described above for T-cells.

TNF also plays a variety of roles in other viral infections such as cytomegalovirus (CMV), influenza virus, and herpes virus for similar reasons as described.

Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced in several types of cells, including monocytes, fibroblasts, endothelial cells and keratinocytes. Production in endothelial cells is caused by IL-1, TNF or lipopolysaccharide (LPS). Human IL-8 has been shown to act on neutrophils in mice, guinea pigs, rats and rabbits. IL-8 is called many different names such as neutrophil attractant / activating protein-1 (NAP-1), monocyte-induced neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF) and T-cell lymphocyte chemotactic factor.

IL-8 stimulates numerous functions in vitro. IL-8 has been shown to be chemoattractant for neutrophils, T-lymphocytes and basophils. In addition, IL-8 induces histamine release from basophils in both normal human and atopic patients, as well as lysosomal enzyme release and respiratory explosion from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b / CD18) on neutrophils without de novo protein synthesis, which can increase the adhesion of neutrophils to vascular endothelial cells. Many diseases are characterized by massive infiltration of neutrophils. Compounds that inhibit the production of IL-8 in abnormal conditions associated with increased production of IL-8 (causing neutrophil chemotaxis as inflammatory sites) would be beneficial.

IL-1 and TNF affect numerous cells and tissues, and these cytokines as well as other leukocyte-induced cytokines are important and essential inflammatory mediators of numerous disease states and abnormalities. Inhibiting these cytokines is beneficial in controlling, reducing and alleviating the majority of these disease states.

There is still a need in the art for cytokine inhibitory anti-inflammatory compounds, ie compounds capable of inhibiting cytokines such as IL-1, IL-6, IL-8 and TNF.

Summary of the Invention

The present invention relates to novel compounds of formula (I) and pharmaceutical compositions containing a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.

The present invention relates to a method of treating a CSBP / RK / p38 kinase mediated disease in a mammal comprising administering an effective amount of a compound of Formula I to a mammal in need of treatment for a CSBP / RK / p38 kinase mediated disease.

The present invention also relates to a method for the inhibition of cytokine and cytokine mediated diseases in a mammal comprising administering to a mammal an effective amount of a compound of formula (I) that requires inhibition of cytokines and treatment of cytokine mediated diseases. will be.

More specifically, the present invention relates to a method for inhibiting the production of IL-1 in a mammal comprising administering an effective amount of the compound of formula I to a mammal in need of inhibiting the production of IL-1.

More specifically, the present invention relates to a method for inhibiting the production of IL-8 in a mammal comprising administering an effective amount of a compound of formula I to a mammal in need of inhibiting the production of IL-8.

More specifically, the present invention relates to a method for inhibiting production of TNF in a mammal, comprising administering an effective amount of a compound of formula (I) to a mammal in need of inhibition of production of TNF.

Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Where

R ₁ is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, each of which is C _1-4 alkoxy Or substituted with a C _1-4 alkylthio group, and also independently C _1-4 alkyl, halogen, hydroxyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR ₁₂ , amino, C _1-6 alkyl, one to-and-substituted amino, N (R ₁₀₎ C (O) Rc, or N- heterocyclyl ring (the ring is a 5 to 7 membered ring, optionally an oxygen, sulfur, Or an additional hetero atom selected from NR ₁₅ );

R ₄ is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which are optionally substituted by one or two substituents, each substituent being 4-phenyl, 4-naphth- For substituents of 1-yl, 5-naphth-2-yl or 6-naphth-2-yl, halogen, cyano, nitro, -C (Z) NR ₇ R ₁₇ , -C (Z) OR ₁₆ , -(CR ₁₀ R ₂₀ ) vCOR ₁₂ , -SR ₅ , -SOR ₅ , -OR ₁₂ , halo substituted C _1-4 alkyl, C _1-4 alkyl, -ZC (Z) R ₁₂ , -NR ₁₀ C ( Z) R ₁₆ , or-(CR ₁₀ R ₂₀ ) vNR ₁₀ R _{20 is} selected independently, and for substituents in other positions, halogen, cyano, -C (Z) NR ₁₃ R ₁₄ , -C (Z) OR ₃ ,-(CR ₁₀ R ₂₀ ) m "COR ₃ , -S (O) mR ₃ , -OR ₃ , halo substituted C _1-4 alkyl, -C _1-4 alkyl,-(CR ₁₀ R ₂₀ ) m "NR ₁₀ C (Z) R ₃ , -NR ₁₀ S (O) m'R _8, -NR ₁₀ S (O) m'NR ₇ R ₁₇ , -ZC (Z) R ₃ or-(CR ₁₀ R ₂₀ m ”NR ₁₃ R _{14 is} selected independently;

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

m is 0 or an integer of 1 or 2;

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

m "is 0 or an integer having a value of 1-5;

Rc is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl-C _1-4 alkyl, all of which may be optionally substituted;

R ₂ is optionally substituted C _3-7 cycloalkyl, or C _3-7 cycloalkyl-C _1-10 alkyl;

R ₃ is heterocyclyl, heterocyclyl-C _1-10 alkyl or R ₈ ;

R ₅ is hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or NR ₇ R ₁₇ , -SR ₅ is -SNR ₇ R ₁₇ , and -SOR ₅ is -SOH Is excluded;

R ₇ and R ₁₇ are each independently selected from hydrogen or C _1-4 alkyl, or R ₇ and R ₁₇ together with the nitrogen to which they are attached form a 5-7 membered heterocyclic ring, which ring is optionally oxygen Further sulfur atoms selected from sulfur or NR ₁₅ ;

R ₈ is C _1-10 alkyl, halo-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, -C _1-10 alkyl, heteroaryl, heteroaryl-C _1-10 alkyl, (CR ₁₀ R ₂₀ ) nOR ₁₁ , (CR ₁₀ R ₂₀ ) nS (O) mR ₁₈ , (CR ₁₀ R ₂₀ ) n NHS (O ) ₂ R ₁₈ , (CR ₁₀ R ₂₀ ) nNR ₁₃ R ₁₄ , wherein aryl, arylalkyl, heteroaryl, heteroarylalkyl may be optionally substituted;

n is an integer having a value of 1 to 10;

R ₉ is hydrogen, —C (Z) R ₁₁ or optionally substituted C _1-10 alkyl, S (O) ₂ R ₁₈ , optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl;

R ₁₀ and R ₂₀ are each independently selected from hydrogen or C _1-4 alkyl;

R ₁₁ is hydrogen or R ₁₈ ;

R ₁₂ is hydrogen or R ₁₆ ;

R ₁₃ and R ₁₄ are each independently selected from hydrogen or optionally substituted C _1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl, or together with the nitrogen to which they are attached Forms a heterocyclic ring, the ring optionally comprising an additional hetero atom selected from oxygen, sulfur or NR ₉ ;

R ₁₅ is hydrogen, C _1-4 alkyl or C (Z) -C _1-4 alkyl;

R ₁₆ is C _1-4 alkyl, halo-substituted C _1-4 alkyl, or C _3-7 cyclo alkyl;

R ₁₈ is C _1-10 alkyl, C _3-7 cycloalkyl, heterocyclyl, aryl, aryl-C _1-10 alkyl, heterocyclyl, heterocyclyl-C _1-10 alkyl, heteroaryl or heteroarylalkyl Is;

Z is oxygen or sulfur.

The present invention relates to a novel group of imidazole compounds, methods for their preparation, their therapeutic use in cytokine mediated diseases, and pharmaceutical compositions for use in such treatment.

The novel compounds of formula (I) can also be used in connection with veterinary treatment of mammals other than humans, which require inhibition of cytokines or inhibition of production. Specifically, cytokine mediated diseases to be treated therapeutically or prophylactically in animals include disease states as described in the Methods of Treatment section herein, but in particular viral infections. Examples of such viruses are lentivirus infections (eg horse infectious anemia virus, goat arthritis virus, visna virus or maedi virus) or retrovirus infections (eg feline immunodeficiency). Viruses (FIV), bovine immunodeficiency virus or canine immunodeficiency virus), or other retroviral infections.

In Formula I, suitable R ₁ residues are 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolinyl, 4-quinazolinyl, 1-imidazolyl and 1-benzimidazolyl Among these, 4-pyridyl, 4-pyrimidinyl and 4-quinolyl are preferable. More preferred are substituted 4-pyrimidinyl or substituted 4-pyridyl residues, most preferred substituted 4-pyrimidinyl rings. R ₁ residue is substituted one or more times with C _1-4 alkoxy or C _1-4 alkylthio residues. Preferred ring configurations of the R ₁ substituents on the 4-pyridyl derivatives are 2-positions, such as 2-methoxy-4-pyridyl. Preferred ring configurations on the 4-pyrimidinyl ring are also in the 2-position, such as 2-methoxy-4-pyrimidinyl.

Suitable additional substituents for the R ₁ heteroaryl ring are C _1-4 alkyl, halo, OH, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR ₁₂ , amino, _Mono- and di-substituted amino, N (R ₁₀ ) C (O) Rc or N-heterocyclyl rings, which are 5- to 7-membered rings, optionally oxygen, sulfur or NR _An additional hetero atom selected from ₁₅ ; Alkyl groups in the mono- and di-substituted moieties with C _1-6 alkyl may be substituted with halo, such as trifluoro-, ie trifluoromethyl or trifluoro.

When any substituent of R ₁ is N (R ₁₀ ) C (O) Rc, Rc is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, Heteroaryl-C _1-4 alkyl, heterocyclyl or heterocyclyl-C _1-4 alkyl-C _1-4 alkyl, Rc is preferably C _1-6 alkyl; Preferably, R ₁₀ is hydrogen. The Rc residue, in particular the C _1-6 alkyl group, may optionally be substituted one to three times, preferably as described above. Preferably, R c is C _1-6 alkyl substituted with halogen such as fluorine such as trifluoromethyl or trifluoroethyl.

Suitably, R ₄ is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which are optionally substituted with one or two substituents. More preferably R ₄ is a phenyl or naphthyl ring. When R ₄ is a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl moiety, suitable substituents for this are halogen, -SR ₅ ,- 1 or 2 substituents independently selected from SOR ₅ , -OR ₁₂ , CF ₃ or-(CR ₁₀ R ₂₀ ) vNR ₁₀ R ₂₀ , and preferred substituents for the substituents at other positions on these rings are halogen, -S (O mR ₃ , -OR ₃ , CF ₃ ,-(CR ₁₀ R ₂₀ ) m "NR ₁₃ R ₁₄ , -NR ₁₀ C (Z) R ₃ and -NR ₁₀ S (O) m'R ₈ . Preferred substituents for the 4-position in naphthyl-1-yl and for the 5-position in naphthyl-2-yl are halogen, in particular fluoro and chloro, and -SR ₅ and -SOR ₅ , wherein R ₅ Is preferably C _1-2 alkyl, more preferably methyl), of which fluoro and chloro are more preferred, and fluoro is most preferred 3- in the phenyl and naphthyl-1-yl rings. Preferred substituents for the position are halogen, in particular fluoro and Ro, -OR ₃ , in particular C _1-4 alkoxy; CF ₃ , NR ₁₀ R ₂₀ , for example amino, -NR ₁₀ C (Z) R ₃ , in particular -NHCO (C _1-10 alkyl); -NR ₁₀ S (O) m'R ₈ , in particular -NHSO ₂ (C _1-10 alkyl); and -SR ₃ and -SOR ₃ , wherein R ₃ is preferably C _1-2 alkyl, more preferably Methyl) If the phenyl ring is disubstituted, it is preferably two independent halogen moieties, for example fluoro and chloro, preferably di-chloro, more preferably 3,4- In addition, for the 3-position of both —OR ₃ and —ZC (Z) R ₃ residues, it is preferred that R ₃ may also include hydrogen.

Preferably, the R ₄ moiety is an unsubstituted or substituted phenyl moiety. More preferably, R ₄ is phenyl or phenyl substituted in the 4-position and / or substituted in the 3-position with fluoro, chloro, C _1-4 alkoxy, methane-sulfonamido or acetamido. Or R ₄ is phenyl di-substituted independently at the 3,4-position to chloro or fluoro, more preferably chloro. Most preferably R ₄ is 4-fluorophenyl.

In formula (I), Z is suitably oxygen or sulfur.

Suitably, R ₂ is optionally substituted C _3-7 cycloalkyl or optionally substituted C _3-7 cycloalkyl-C _1-10 alkyl. Preferably R ₂ is C _3-7 cycloalkyl, a double cycloalkyl group is preferably a C _4-7 ring, more preferably a C ₄ or C ₆ ring, most preferably a C ₆ ring, The ring is optionally substituted.

R ₂ residues, ie, C _3-7 cycloalkyl rings, are halogens such as fluorine, chlorine, bromine or iodine; Hydroxy; C _1-10 alkoxy, for example methoxy or ethoxy; S (O) m alkyl, where m is 0, 1, or 2, for example methylthio, methylsulfinyl or methyl sulfonyl; S (O) m aryl; Cyano; Nitro; Amino; Mono- and di-substituted amino, eg, NR ₇ R ₁₇ groups, wherein R ₇ and R ₁₇ are as defined in Formula I or R ₇ and R ₁₇ are cyclized with the nitrogen to which they are attached To form a 5 to 7 membered ring, which ring optionally comprises oxygen, sulfur or an additional hetero atom selected from NR ₁₅ , wherein R ₁₅ is as defined for Formula I. together}; N (R ₁₀ ) C (O) X ₁ , wherein R ₁₀ is as defined for Formula I and X ₁ is C _1-4 alkyl, aryl or aryl-C _1-4 alkyl; N (R ₁₀ ) C (O) aryl; C _1-10 alkyl, for example methyl, ethyl, propyl, isopropyl or t-butyl; Optionally substituted alkyl wherein the substituents are halogen (eg, as in CF ₃ ), hydroxy, nitro, cyano, amino, mono- and di-substituted amino (eg, NR ₇ R ₁₇ groups As is), S (O) m alkyl and S (O) m aryl, where m is 0, 1 or 2}; Optionally substituted C _1-10 alkylene such as ethylene or propylene; Optionally substituted C _1-10 alkynes such as acetylene (ethynyl) or 1-propynyl; C (O) OR ₁₁ , wherein R ₁₁ is as defined in Formula I, for example free acid or methyl ester derivatives; Ra group; -C (O) H; = O; = N-OR ₁₁ ; -N (H) -OH (or alkyl or aryl derivatives substituted on nitrogen or oxime residues); -N (ORb) -C (O) -R ₆ ; Oxirane; Optionally substituted aryl such as phenyl; Optionally substituted aryl-C _1-4 alkyl such as benzyl or phenethyl; Optionally substituted heterocycle, or may be substituted one to three times with heterocyclic C _1-4 alkyl, and these aryl, arylalkyl, heterocyclic, and heterocyclic alkyl moieties listed herein are all optionally halogen , Hydroxy, C _1-10 alkoxy, S (O) m alkyl, cyano, nitro, amino, mono- and di-substituted amino (for example as in NR ₇ R ₁₇ group), alkyl, halo Independently substituted one or two times with substituted alkyl.

Suitably Ra is a 1,3-dioxyalkylene group of the formula -O- (CH ₂ ) sO-, wherein s is 1 to 3, preferably s is 2, preferably 1, 3-dioxyethylene residues.

Suitably Rb is hydrogen, a pharmaceutically acceptable cation, aroyl or C _1-10 alkanoyl group.

Suitably R ₆ is NR ₁₉ R ₂₁ ; Alkyl C _1-6 ; Halo substituted alkyl C _1-6 ; Hydroxy substituted alkyl C _1-6 ; Alkenyl C _2-6 ; Aryl or heteroaryl optionally substituted with halogen, alkyl C _1-6 , alkyl substituted with halo C _1-6 , hydroxyl or alkoxy C _1-6 .

Suitably R ₁₉ is H or alkyl C _1-6 .

Suitably R ₂₁ is H; Alkyl C _1-6 ; Aryl; benzyl; Heteroaryl; Alkyl substituted with halogen or hydroxyl; Or phenyl substituted with a substituent selected from the group consisting of halo, cyano, alkyl C _1-12 , alkoxy C _1-6 , halo substituted alkyl C _1-6 , alkylthio, alkylsulfonyl or alkylsulfinyl;

R ₁₉ and R ₂₁ together with the nitrogen to which they are attached form a 5 to 7 membered ring, wherein the ring members may be optionally substituted by a hetero atom selected from oxygen, sulfur or nitrogen. The ring may be saturated or may contain one or more unsaturated bonds. Preferably R ₆ is NR ₁₉ R ₂₁ and R ₁₉ and R ₂₁ are preferably hydrogen.

When the R ₂ residue is substituted with an NR ₇ R ₁₇ group, or an NR ₇ R ₁₇ C _1-10 alkyl group, and R ₇ and R ₁₇ are as defined in Formula I, the substituent is preferably amino, amino alkyl, or optionally Substituted pyrrolidinyl residues.

Preferred ring configurations on the cyclohexyl ring (particularly when the C ₆ ring) is the 4-position.

When the cyclohexyl ring is disubstituted, it is preferable that

(Wherein R ^{1 '} and R ^2' are independently any substituents indicated for R ₂ above) in the 4-position. Preferably, R ^{1 '} and R ^2' are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkynyl, aryl, arylalkyl, NR ₇ R ₁₇ , and N (R ₁₀ ) C (O) R ₁₁ is. Suitably, alkyl is C _1-4 alkyl, for example methyl, ethyl or isopropyl; NR ₇ R ₁₇ and NR ₇ R ₁₇ alkyl, such as amino, methylamino, aminomethyl, aminoethyl; Substituted alkyls such as cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; Optionally substituted alkynyl, such as propynyl or ethynyl; Aryl such as phenyl; Arylalkyl, for example benzyl, or R ^{1 ′} and R ^{2 ′} together are one keto functional group.

Preferred groups of formula (I) include compounds of formula (Ia) or pharmaceutically acceptable salts thereof.

Where

R ₁ is pyrimidinyl substituted with C _1-4 alkoxy and is also independently C _1-4 alkyl, halogen, hydroxyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl , CH ₂ oR _12, amino, C _1-6 alkyl-yl-and a-substituted amino, N (R ₁₀₎ C (O) Rc, or N- heterocyclyl ring (the ring is a 5 to 7-membered ring and Optionally comprises one or more times optionally substituted with oxygen, sulfur or an additional hetero atom selected from NR ₁₅ ;

R ₂ is an optionally substituted C ₆ cycloalkyl ring;

R ₄ is phenyl, which is optionally substituted with halogen;

R ₁₀ is independently selected from hydrogen or C _1-4 alkyl;

Rc is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl-C _1-4 alkyl, all of which may be optionally substituted;

R ₁₂ is hydrogen or R ₁₆ ;

R ₁₆ is C _1-4 alkyl, halo-substituted C _1-4 alkyl, or C _3-7 cyclo alkyl;

R ₁₅ is hydrogen, C _1-4 alkyl or C (Z) -C _1-4 alkyl;

Z is oxygen or sulfur.

Other preferred groups of formula (I) include compounds of formula (Ib) or pharmaceutically acceptable salts thereof.

Where

R ₁ is pyridyl substituted with C _1-4 alkoxy, and also independently C _1-4 alkyl, halogen, hydroxyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ oR _12, amino, C _1-6 alkyl-yl-and a-substituted amino, N (R ₁₀₎ C (O) Rc, or N- heterocyclyl ring (the ring being 5 to 7 membered ring, Optionally further one or more times with oxygen, sulfur or an additional hetero atom selected from NR ₁₅ ;

R ₂ is an optionally substituted C ₆ cycloalkyl ring;

R ₄ is phenyl, which is optionally substituted with halogen;

R ₁₀ is independently selected from hydrogen or C _1-4 alkyl;

Rc is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl-C _1-4 alkyl, all of which may be optionally substituted;

R ₁₂ is hydrogen or R ₁₆ ;

R ₁₆ is C _1-4 alkyl, halo-substituted C _1-4 alkyl, or C _3-7 cyclo alkyl;

R ₁₅ is hydrogen, C _1-4 alkyl or C (Z) -C _1-4 alkyl;

Z is oxygen or sulfur.

The term "optionally substituted" as used herein, unless defined otherwise herein, includes halogens such as fluorine, chlorine, bromine or iodine; Hydroxy; Hydroxy substituted C _1-10 alkyl; C _1-10 alkoxy, for example methoxy or ethoxy; S (O) m alkyl, wherein m is 0, 1 or 2, for example methyl thio, methylsulfinyl or methyl sulfonyl; Amino, mono- and di-substituted amino {eg, NR ₇ R ₁₇ groups, where R ₇ and R ₁₇ can be cyclized with the nitrogen to which they are attached to form a 5 to 7 membered ring, This ring optionally comprises an additional hetero atom selected from O / N / S); C _1-10 alkyl, cycloalkyl or cycloalkyl alkyl groups such as methyl, ethyl, propyl, isopropyl, t-butyl and the like, or cyclopropyl methyl; Halo substituted C _1-10 alkyl such as —CF ₂ CF ₂ H or —CF ₃ ; Will mean a group such as optionally substituted aryl, eg phenyl, or optionally substituted arylalkyl, eg benzyl or phenethyl, wherein the aryl moiety is also halogen; Hydroxy; Hydroxy substituted alkyl; C _1-10 alkoxy; S (O) m alkyl; Amino, mono- and di-substituted amino (eg, as in NR ₇ R ₁₇ ); It may be substituted once or twice with alkyl or CF ₃ .

In a preferred subclass of compounds of formula I, R ₁ is 2-methoxy-4-pyridyl or 2-methoxy-4-pyrimidinyl, R ₂ is optionally substituted C ₄ or C ₆ cycloalkyl, R ₄ is phenyl or optionally substituted phenyl. In a more preferred subclass, R ₄ is phenyl or phenyl substituted one or two times with fluoro, chloro, C _1-4 alkoxy, —S (O) m alkyl, methanesulfonamido or acetamido; R ₂ is cyclohexyl or methyl, phenyl, benzyl, amino, acetamide, aminomethyl, aminoethyl, cyanomethyl, cyanoethyl, hydroxy, nitroethyl, hydroxy, nitroethyl, pyrrolidinyl, ethynyl , _{1-propynyl, = O, O- (CH 2} ) 2 O-, = NOR 11 ( here, R ₁₁ is hydrogen, alkyl or aryl), NHOH or N (OH) -C (O) -NH Cyclohexyl substituted with ₂ ;

Pharmaceutically acceptable suitable salts are well known to those skilled in the art and include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid. Base salts of inorganic and organic acids such as acids, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed using pharmaceutically acceptable cations, for example where the substituents comprise carboxy moieties. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium and quaternary ammonium cations.

The terminology used herein has the following meanings:

"Halo" or "halogen" includes halogens: chloro, fluoro, bromo and iodo.

"C _1-10 alkyl" or "alkyl"-unless otherwise limited, both straight and branched chain radicals of 1 to 10 carbon atoms, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

As used herein, the term "cycloalkyl" preferably means a cyclic radical of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term "cycloalkenyl" means a cyclic radical having one or more double bonds, preferably of 5 to 8 carbon atoms, and includes, but is not limited to, cyclopentenyl, cyclohexenyl, and the like. It is not limited.

As used herein, the term "alkenyl" always means a straight or branched chain radical of 2-10 carbon atoms, and unless the chain length is limited thereto, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

"Aryl"-phenyl and naphthyl.

"Heteroaryl" (by itself or in any combination, such as "heteroaryloxy", or "heteroarylalkyl")-a 5-10 membered aromatic ring system, wherein at least one ring is N At least one hetero atom selected from the group consisting of O and S, for example, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole , Thiadiazole, triazole, imidazole or benzimidazole.

"Heterocyclic" (by itself or in any combination, such as "heterocyclylalkyl")-a saturated or partially unsaturated 4-10 membered ring system wherein at least one ring is N , At least one hetero atom selected from the group consisting of O or S, including but not limited to pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine Do not.

As used herein, “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is also as defined above bound to an aryl, heteroaryl or heterocyclic moiety as defined herein unless otherwise indicated. Same C _1-4 alkyl.

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

“Aroyl” —C (O) Ar, wherein Ar is phenyl, naphthyl, or an arylalkyl derivative as defined above and these groups include but are not limited to benzyl and phenethyl.

"Alkanoyl"-C (O) C _1-10 alkyl, wherein alkyl is as defined above.

It is recognized that the compounds of the present invention may exist as stereoisomers, regioisomers or diastereomers. These compounds may include one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.

Exemplary compounds of formula I are

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole;

Cis-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole;

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole;

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylthio) pyrimidin-4-yl] imidazole;

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylthio) pyrimidin-4-yl] imidazole;

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-hydroxy) pyrimidin-4-yl] imidazole;

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole;

1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole;

Trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole;

Cis-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole;

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole.

Compounds of formula (I) can be obtained by applying the synthetic procedures, some of which are illustrated in Schemes I-VII below. The syntheses provided in these schemes can be applied to produce compounds of formula I having very different R ₁ , R ₂ and R ₄ groups to react with any substituents suitably protected to suit the reactions outlined herein. have. Subsequently, in the case described above, subsequent deprotection yields a compound of the generally disclosed properties. Once the imidazole nucleus is formed, other techniques of formula I can be prepared by applying standard techniques for functional group transformation known in the art.

For example, from HNR ₁₃ R ₁₄ and -CO ₂ CH _{3 in} CH ₃ OH to —C (O) NR ₁₃ R ₁₄ in CH ₃ OH by heating with or without a catalytic metal cyanide such as NaCN; From -OH to -OC (O) R ₃ using ClC (O) R ₃ in pyridine; From -NHR ₁₀ to -NR ₁₀ -C (S) NR ₁₃ R ₁₄ using alkylisothiocyanate or thiocyanic acid; From -NHR ₆ to -NR ₆ C (O) OR ₆ using alkyl chloroformate; Treating isocyanate, such as NH = C═O or R ₁₀ N═C═O, from -NHR ₁₀ to -NR ₁₀ C (O) NR ₁₃ R ₁₄ ; Treatment with Cl-C (O) R ₃ in pyridine from -NHR ₁₀ to -NR ₁₀ -C (O) R ₈ ; From -C (NR ₁₃ R ₁₄ ) SR ₃ to -C (= NR ₁₀ ) NR ₁₃ R ₁₄ using H ₃ NR ₃ ⁺ OAc ^- by heating in alcohol; From -C (S) NR ₁₃ R ₁₄ to -C (NR ₁₃ R ₁₄ ) SR ₃ using an inert solvent such as R ₆ -I in acetone; C (S) NH ₂ to C (S) NR ₁₃ R ₁₄ , wherein R ₁₃ and R ₁₄ are not hydrogen using HNR ₁₃ R ₁₄ ; Treatment with -C (= NR ₁₃ R ₁₄ ) -SR ₃ using NH ₂ CN by heating in anhydrous alcohol, alternatively with BrCN and NaOEt in EtOH, -C (= NH) -NR ₁₃ R ₁₄ from -C ( = NCN) -NR ₁₃ R ₁₄ ; (R ₈ S) ₂ C = NCN to -NR ₁₀ -C (= NCN) SR ₈ from -NHR ₁₀ ; Treatment with ClSO ₂ R ₃ by heating in pyridine from -NHR ₁₀ to -NR ₁₀ SO ₂ R ₃ ; From -NR ₁₀ C (O) R ₈ by treatment with Loweson's reagent [2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide] -NR ₁₀ C (S) R ₃ ; Triplexic anhydride and base are used to convert from -NHR ₆ to -NR ₁₀ SO ₂ CF ₃ , wherein R ₃ , R ₆ , R ₁₀ , R ₁₃ and R ₁₄ are as defined herein in formula (I). same).

In a further aspect of the invention, there is provided a compound of formula II.

In which p is 0 or 2; R ₄ is as defined for Formula I and Ar is optionally substituted aryl as defined herein. Suitably Ar is phenyl optionally substituted with C _1-4 alkyl, C _1-4 alkoxy or halo. Preferably, Ar is phenyl or 4-methylphenyl, ie tosyl derivative. When Ar is tosyl and p is 0 or 2, if R ₄ is not unsubstituted phenyl, the compound of formula II is believed to be novel.

The precursors of the R _1, R ₂ and R ₄ groups can be other R _1, R ₂ and R ₄ groups which can be converted by applying standard techniques for functional group conversion. For example, a compound of formula (I) wherein R ₂ is halo substituted C _1-10 alkyl can be converted to the corresponding C _{1-10 alkylN 3} derivative by reacting with a suitable azide salt and, if desired, corresponding Can be reduced to a C _1-10 alkylNH ₂ compound, which in turn is reacted with R ₁₈ S (O) ₂ X where X is halo (eg chloro) to correspond to the corresponding C _1-10 alkyl NHS (O) ₂ R ₁₈ compound can be obtained.

Alternatively, compounds of formula I wherein R ₂ is halo substituted C _1-10 alkyl may be reacted with amine R ₁₃ R ₁₄ NH to obtain the corresponding C _1-10 alkylNR ₁₃ R ₁₄ compound, or R ₁₈ SH Can be reacted with an alkali metal salt of to give the corresponding C _1-10 alkylSR ₁₈ compound.

With reference to Scheme I, a compound of Formula I suitably reacts a compound of Formula II with a compound of Formula III, wherein p is 0 or 2 and R ₁ , R ₂ and R ₄ are as stated above, or, R _1, is a precursor of R ₂ and R ₄ group, Ar is optionally a substituted phenyl group), the R _1, the precursor of R ₂ and R _4, if necessary, R _1, R ₂ and R ₄ groups Prepared by conversion. In R ₂ NH ₂ , which reacts with R ₁ CHO to form an imine of formula III, the R ₂ residue requires a suitable protecting group if it contains a reactive functional group, such as a primary or secondary amine, alcohol, thiol compound. can do. Suitable protecting groups can be found in Protecting Groups in Organic Synthesis, Greene TW, Wiley-Interscience, New York, 1991. For example, when R ₂ comprises a heterocyclic ring such as a piperidine ring as a substituent, the nitrogen is protected with a group such as t-Boc, CO ₂ R ₁₈ or substituted arylalkyl moiety.

Suitably, the reaction is carried out with a suitable base such as 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU), or a guanidine base such as 1,5,7- In an inert solvent such as methylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile or dimethoxyethane in the presence of triaza-bicyclo [4.4.0] des-5-ene (TBD), or cooled Or by heating (eg, -50 ° C to 10 ° C). It has been found that intermediate compounds of formula II are very stable and can be stored for a long time. Preferably, p is two.

The reaction of the compound of formula II (p = 2) with the compound of formula III (Scheme I) provides a consistently higher yield of the compound of formula I than when p = 0. In addition, the reaction of the compound of formula II (p = 2) is more environmentally and economically preferred. As described further herein, when using p = 0, the preferred solvent used is methylene chloride, which is less environmentally preferred for large-scale processing, and is a preferred base than when using a commercially preferred synthesis method (p = 2). Phosphorus TBD is also expensive and produces some byproducts and impurities.

As stated, Scheme I utilizes a reaction in which an anion of substituted aryl thiomethylisocyanide (when p = 0) adds 1,3-dipolar cycloaddition to imine. More specifically, the reaction requires a strong base such as an amine base for use in the deprotonation stage. t-butoxide, Li + or Na + or K + hexamethyldisilazide can also be used, but commercially available TBD is preferred. Methylene chloride is the preferred solvent, but other halogenated solvents such as chloroform or carbon tetrachloride; Ethers such as THF, DME, DMF, diethyl ether, t-butyl methyl ether; In addition, acetonitrile, toluene or mixtures thereof can be used. For reactions comprising a R ₁ group that is pyrimidine, the reaction is about -20 ° C to about 40 ° C, preferably about 0 ° C to about 23 ° C, more preferably about 0 ° C to about 10 ° C, most preferably May occur at about 4 ° C. It is recognized that for compounds where R ₁ is pyridine, it may be necessary to change both temperature and reaction conditions of the solvent, such as, for example, by lowering the temperature to about -50 ° C or changing the solvent to THF.

In a further process, the compound of formula (I) may be a suitable derivative of the compound of formula (IX)

(i) when T ₁ is hydrogen, bond reaction with a suitable derivative of heteroaryl ring R ₁ H under ring bonding conditions to bond heteroaryl ring R ₁ to position 5 of the imidazole nucleus;

(ii) when T ₄ is hydrogen, it can be prepared by binding reaction with a suitable derivative of the aryl ring R ₄ H under ring bonding conditions to bind the aryl ring R ₄ to position 4 of the imidazole nucleus.

Wherein T ₁ is hydrogen and T ₄ is R ₄ or, alternatively, T ₁ is R ₁ and T ₄ is H, wherein R _1, R ₂ and R ₄ are as defined above.

Such aryl / heteroaryl bonding reactions are well known to those skilled in the art. Generally, organometallic synthesis equivalents of one component of anion are combined with reactive derivatives of the second component in the presence of a suitable catalyst. Anionic equivalents can be formed from both imidazoles of formula IX, in which case aryl / heteroaryl compounds provide reactive derivatives, or aryl / heteroaryl compounds, in which case imidazole provides reactive derivatives. Thus, suitable compounds of formula IX or derivatives of aryl / heteroaryl rings include organometallic derivatives such as organomagnesium, organozinc, organotin and boronic acid derivatives, and suitable reaction derivatives include bromo, iodo, Fluorosulfonate and trifluoromethanesulfonate derivatives. Suitable procedures are described in WO91 / 19497, which is incorporated herein by reference.

Suitable organomagnesium and organozinc derivatives of compounds of formula (IX) are prepared according to the procedures of Kumada et al., Tetrahedron Letters, 22, 5319 (1981), for example, ring-bonding catalysts such as palladium (0) or It can be reacted with a halogen, fluorosulfonate or triflate derivative of a heteroaryl or aryl ring in the presence of a palladium (II) catalyst. Such suitable catalysts are tetrakis- (triphenylphosphine) palladium and PdCl ₂ [1,4-bis- (diphenylphosphino) -butane], optionally in the presence of lithium chloride and a base such as triethylamine. It includes. Nickel (II) catalysts, such as Ni (II) Cl ₂ (1,2-biphenylphosphino) ethane, are also described by Prizen et al., J. Org. Chem. 1982, 47, 4319, can be used to link aryl rings. Suitable reaction solvents include hexamethylphosphoramide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4-iodo-pyridine, and fluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly, suitable derivatives when the aryl ring is phenyl include bromo, fluorosulfonate, triflate and preferably iodo-derivatives. Suitable organomagnesium and organozinc derivatives can be obtained by treating compounds of formula IX or bromo derivatives thereof with alkyllithium compounds to obtain the corresponding lithium reagents by deprotonation or transmetallating, respectively. This lithium intermediate can then be treated with excess magnesium halide or zinc halide to obtain the corresponding organometallic reagent.

Trialkyltin derivatives of compounds of Formula (IX) are described in Steille, J. Amer. Chem. Soc., 1987, 109, 5478, by the methods described in US Pat. Nos. 4,719,218 and 5,002,942, suitable palladium (0) catalysts such as tetrakis- (triphenylphosphine) -palladium Bromide, fluorosulfonate, triflate or preferably of aryl or heteroaryl ring compounds in an inert solvent, for example tetrahydrofuran, in the presence of a bonding catalyst, preferably comprising 10% hexamethylphosphoramide Treatment with iodide derivatives or by using a palladium (II) catalyst in an inert solvent such as dimethyl formamide, optionally in the presence of lithium chloride with the addition of a base such as triethylamine. Trialkyl tin derivatives conveniently metalize the corresponding compounds of formula (IX) in an ether solvent, for example tetrahydrofuran, with a lithium agent such as s-butyl-lithium or n-butyllithium, or the corresponding compounds of formula (IX) The bromo derivatives of the compounds can be obtained by treatment with alkyl lithium and in each case with trialkyltin halides. Alternatively, the bromo-derivatives of the compounds of formula IX can be treated with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetrakis- (triphenyl-phosphine) -palladium under conditions similar to those described above. have.

Boronic acid derivatives may also be used. Thus, suitable derivatives of the compounds of formula (IX), for example bromo, iodo, triflate and fluorosulfonate derivatives, are tetrakised in the presence of a base such as sodium bicarbonate in a solvent such as dimethoxyethane under reflux conditions. Can be reacted with heteroaryl- or aryl-boronic acid in the presence of a palladium catalyst such as-(triphenylphosphine) -palladium or PdCl ₂ [1,4-bis- (diphenylphosphino) -butane] Fisher and Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439, 1965, Snieckus, V., Tetrahedron Lett., 29, 2135, 1988 and Terashimia, M., Chem. Pharm. Bull., 11, 4755, 1985). Solvents such as DMF can also be used in the presence of a Pd (II) catalyst at non-aqueous conditions, for example, at a temperature of about 100 ° C. (Thomson, Thompson, WJ et al., J. Org. Chem , 49, 5237, 1984). Suitable boronic acid derivatives can be prepared by treating magnesium or lithium derivatives with trialkylborate esters such as triethyl, tri-iso-propyl or tributylborate according to standard procedures.

In the above coupling reaction, it will be readily understood that proper attention should be paid to the aspect of the functional groups present in the compound of formula (IX). Thus, in general, amino and sulfur substituents must be unoxidized or protected.

The compound of formula (IX) is imidazole and may be obtained by any of the procedures described above for preparing compounds of formula (I). In particular, α-halo-ketone or other suitably activated ketone R ₄ COCH ₂ Hal (for compounds of formula IX wherein T ₁ is hydrogen) or R ₁ COCH ₂ Hal (for compounds of formula IX wherein T ₄ is hydrogen) ) At a suitable elevated temperature in a halogenated hydrocarbon solvent such as chloroform, if necessary, in the presence of a suitable condensing agent such as a base, where R ₂ NH-C = NH (wherein R ₂ is As defined) or salts thereof. Preparation of suitable α-halo-ketones is described in WO 91/19497. Suitable reactive esters include esters of lower alkane sulfonic acids or aryl sulfonic acids, for example strong organic acids such as methane or p-toluene sulfonic acid. Amidine is preferably used as a salt, suitably a hydrochloride salt, and then the reactive ester is present in an inert organic solvent such as chloroform, and the salt is present in the aqueous phase with the slow addition of 2 molar amounts of aqueous base solution with vigorous stirring. By using a two-phase system, the free amidine can be converted in situ. Suitable amidines can be obtained by standard methods (see, eg, Garipatipati R, Tetrahedron Letters, 190, 31, 1989).

Compounds of formula I are also described in US Pat. No. 4,803,279; Compounds of formula IX (wherein T ₁ is hydrogen) are reacted with an N-acyl heteroaryl salt according to the methods described in US Pat. Nos. 4,719,218 and 5,002,942, wherein the heteroaryl ring is bonded to the imidazole nucleus, Intermediates present as 1,4-dihydro derivatives thereof can be obtained and then prepared by a process comprising treating the intermediate under oxidative-deacylating conditions (Scheme II). The heteroaryl salts, for example pyridinium salts, are substituted carbonyl halides (e.g. acyl halides, aroyl halides, arylalkyl haloformate esters or preferably alkyl haloformate esters, e.g. Acetyl bromide, benzoyl chloride, benzyl chloroformate or preferably ethyl chloroformate) to a solution of a compound of formula IX in a heteroaryl compound R ₁ H or in an inert solvent such as methylene chloride, with addition of a heteroaryl compound By addition or more preferably in situ. Suitable deacylation and oxidation conditions are described in US Pat. Nos. 4,803,279, 4,719,218 and 5,002,942, which are incorporated herein by reference in their entirety. Suitable oxidation systems are sulfur in inert solvents or solvent mixtures, for example decalin, decalin and diglyme, p-cymene, xylene or mesitylene under reflux conditions, or potassium in t-butanol, preferably under dry air or oxygen t-butoxide.

In a further procedure illustrated in Scheme III, compounds of formula I can be prepared by treating compounds of formula X thermally or with the aid of cyclizing agents such as phosphorus oxychloride or phosphorus pentachloride (eg, See Engel and Steglich, Liebigs Ann Chem, 1978, 1916 and Strzybny et al., J. Org. Chem. 1963, 28, 3381. Compounds of formula (X) are obtained, for example, by acylating the corresponding α-keto-amines with activated formate derivatives such as the corresponding anhydrides under standard acylation conditions, followed by the formation of imines with R ₂ NH ₂ . can do. Amino ketones can be derived from oxamines and reductions from the parent ketones and the essential ketones are prepared by decarboxylation of beta-ketoesters obtained from the condensation reaction of aryl (heteroaryl) acetic esters with the R ₁ COX component. Can be.

In Scheme IV below, two (2) different routes are illustrated using ketones (Formula XI) to prepare compounds of Formula (I). Heterocyclic ketones (formula XI) form N-alkyl-O-alkoxybenzamides of anions of alkyl heterocycles such as 4-methyl-quinoline (prepared by treating alkyl heterocycles with alkyl lithium such as n-butyl lithium) , Esters or any other suitably activated derivative in the same oxidation state. Alternatively, the anion can be condensed with benzaldehyde to give an alcohol, which can then be oxidized to a ketone (XI).

In a further process, the N-substituted compounds of formula I are

R ₁ CH ₂ NR ₂ COH

Wherein an anion of the amide of R ₁ and R ₂ is as defined above,

(a) Formula XIII

R ₄ CN

Nitrile, wherein R ₄ is as defined above; or

(b) Excess formula XIV

R ₄ COHal

Treatment with an acyl halide, for example acyl chloride, or the corresponding anhydride of (wherein R ₄ is as defined above and Hal is halogen) yields a bis-acylated intermediate which is then combined with ammonium acetate It can manufacture by treating with the same ammonia source.

One variation of the method is illustrated in Scheme V above. The primary amine (R ₂ NH ₂ ) is treated with a halomethyl heterocycle of the formula R ₁ CH ₂ X to give a secondary amine which is then converted to the amide by standard techniques. Alternatively, the amide can be prepared as illustrated in Scheme V by alkylating formamide using R ₁ CH ₂ X. The amide is deprotonated with an amide strong base such as lithium di-iso-propyl amide or sodium bis- (trimethylsilyl) amide, and then excess aroyl chloride is added to give a bis-acylated compound. Next, the ring is closed by heating in acetic acid containing ammonium acetate to obtain an imidazole compound of formula (I). Alternatively, the anion of the amide can be reacted with a substituted aryl nitrile to directly prepare the imidazole of formula (I).

The following description and schemes are further examples of the process as described above in Scheme I. The various pyrimidine aldehyde derivatives 6, 7 and 8, shown in Scheme VI, are described in Bredereck et al., Chem. Ber. 1964, 97, 3407 can be prepared by changing the procedure. The pyrimidine aldehyde is then used as an intermediate in the synthesis as further described herein.

The reaction of imine with tosylmethyl isonitrile is described by van Leusen et al., J. Org. Chem. 1977, 42, 1153. Conditions such as tertiary butyl amine (tBuNH ₂ ) in dimethoxyethane (DME), K ₂ CO _{3 in} MeOH, and NaH in DME have been reported. Each of these conditions was retested to obtain a low yield. A second route was also carried out comprising preparing t-butyl imine by amine exchange followed by reaction with isocyanide to produce 1-tBu imidazole. This route will probably be carried out using any primary amine as the base. Although not preferred, secondary amines can be used, but they can also degrade the isonitrile slowly. The reaction will probably require about 3 equivalents of amine to be completed, yielding an isolation yield of approximately 50%. Protected secondary amines (diisopropylamine) are usable but are very slow and generally not very effective. Tertiary amines such as pyridine and triethylamine and aromatic amines do not occur under specific test conditions, and more basic types such as DBU and 4-dimethylamino pyridine (DMAP) are slower, but have yielded some yields. Thus, it may be suitable for use herein.

As illustrated in Schemes VII and VIII, the pyrimidine aldehydes of Scheme VI can be condensed with primary amines to produce imines, which are suitably isolated or as described herein with various suitable bases in situ. In the presence of a solvent, reaction with the desired isonitrile can yield 5- (4-pyrimidinyl) -imidazole, wherein R ₂ and R ₄ are as defined for the compound of formula (I).

One preferred method for preparing compounds of formula I is shown in Scheme VII below. Immigration is often made and isolated in separate steps as tars that are difficult to handle. Also often black is carried over into the final product. Yields for preparing imines vary, and less environmentally acceptable solvents such as CH ₂ Cl ₂ are often used in their preparation.

In the reaction (p = 2), a suitable base is required to proceed the reaction. The reaction requires a strong base sufficient to deprotonate the isonitrile. Suitable bases include amines, carbonates, hydrides or alkyl or aryl lithium reagents; Or mixtures thereof. Bases include potassium carbonate, sodium carbonate, primary and secondary amines such as t-butylamine, diisopropyl amine, morpholine, piperidine, pyrrolidine and other nonnucleophilic bases such as DBU, DMAP and 1,4-diazabicyclo [2.2.2] octane (DABCO).

Suitable solvents for use in the present invention are N, N-dimethyl-formamide (DMF), MeCN, halogenated solvents such as methylene chloride or chloroform, tetrahydrofuran (THF), dimethoxysulfoxide (DMSO) , Alcohols such as methanol or ethanol, benzene, toluene, DME or EtOAc. Preferably, the solvent is DMF, DME, THF, or MeCN, more preferably DMF. Isolation of the product can generally be carried out by adding water and filtering the product as a pure compound. The mixture is non-nucleophilic and therefore no isonitrile decomposition occurs.

While not convenient for large scale operations, it may be necessary to add NaH instead of t-butylamine to isonitrile (in THF), perhaps lowering the temperature below 25 ° C. In addition, BuLi has also been reported to be an effective base for deprotonating tosyl benzylisonitrile at −50 ° C. [DiSanto et al., Synth. Commun. 1995, 25, 795].

Various temperature conditions may be used depending on the preferred base. For example, at temperatures above t-BuNH ₂ / DME, K ₂ CO ₃ / MeOH, K ₂ CO _{3 in} DMF, about 40 ° C., the yield may drop to about 20% but differ between 0 ° C. and 25 ° C. Is hardly expected. In conclusion, it is contemplated that temperature ranges below 0 ° C. and above 80 ° C. are also within the scope of the present invention. Preferably, the temperature range is about 0 ° C to about 25 ° C. For the purposes of the present invention, it is recognized that the room temperature described in 25 ° C may vary from 20 ° C to 30 ° C.

As shown in Scheme VIII, imine is preferably formed in situ in a solvent. This preferred synthesis is a process that takes place in one-reaction vessel synthesis. Suitably, when primary amines are used as salts, such as hydrochloride salts in the examples below, the reaction may further comprise a base such as potassium carbonate before the addition of isonitrile. Reaction conditions such as solvent, base, temperature, etc., are similar to those exemplified and discussed above for isolated imines as shown in Scheme VIII. Those skilled in the art will readily appreciate that under some circumstances, dehydration conditions may be required in in situ imine formation, or an acid catalyst may be required.

Another method for preparing the compound of formula I is shown in Scheme VIIIa. To avoid the difficulties associated with isolating pyrimidine aldehyde 8, acetal 3 can be hydrolyzed to aldehyde 8 as described herein. Aldehyde 8 formed in situ can be treated successively with primary amine, ethyl acetate and NaHCO ₃ to form the corresponding imine in situ, which is extracted into ethyl acetate. Isonitrile, carbonate base and DMF are added to form 5- (4-pyrimidinyl) -imidazole, wherein R ₂ and R ₄ are as defined for compounds of formula (I) herein.

In addition, preferred methods of synthesizing the compounds of formula (I) include S (O) m alkyl on pyrimidines (R ₁ groups), for example, using 2-methylthio pyrimidine aldehyde derivatives, as also described in the Examples section. Provide a suitable and reliable method for introducing residues.

In Scheme IX (X = S methyl) below, the final product may also be used as a precursor, as described above for preparing other compounds of formula (I). In this particular example the methylthio moiety can be oxidized to methyl sulfinyl or sulfonyl moiety, which can also be further modified with alkoxy. ROH is a suitable nucleophile for R ₁ substitution as claimed herein.

Another embodiment of the present invention is novel hydrolysis of 2-thioalkyl or alkoxy pyrimidine acetal to 2-thioalkyl or alkoxy pyrimidine aldehyde (s), as shown in Scheme X below. Hydrolysis of the aldehyde of acetal with various known reaction conditions, such as formic acid, is not satisfactory in yield of aldehyde and less than 13% is obtained. Preferred synthesis involves the use of AcOH (fresh) and concentrated H ₂ SO ₄ , preferably catalytic amount of sulfuric acid, as a solvent under heating conditions. Since the high temperature darkens the reaction mixture, the heating conditions include a temperature of about 60 to 85 ° C, preferably about 70 to about 80 ° C. After the reaction is complete, the mixture is cooled to about room temperature and acetic acid is removed. An alternative procedure for this involves heating the acetal in 3N HCl at 40 ° C. for about 18 hours, cooling and extracting the bicarbonate neutralization solution into EtOAc.

The final 2-alkoxy and alkylthiopyrimidin-4-yl imidazole compounds of the general formula (I) as well as similar pyridine-containing compounds include: 1) direct reaction of 2-alkoxypyrimidine imines with isonitrile, 2) 2-alkylthiopyrimidines After oxidation of the derivative to the corresponding sulfoxide or sulfone, it can be prepared by one of two methods of substitution with the desired alcohol.

These schemes herein provide, for example, a cyclohexyl residue optionally substituted for the resulting R ₂ position, or ₄ -fluoro phenyl for R ₄ , but any suitable R ₂ residue or R ₄ residue is 1 If it can be prepared on a tertiary amine it can be added to this process. Similarly, any suitable R ₄ can be added via the isonitrile route.

Compounds of formula (II) in Scheme I can be prepared by the method of van lucene et al. For example, a compound of formula II can be prepared by dehydrating a compound of formula IV (Scheme I, where Ar, R ₄ and p are as defined herein).

Suitable dehydrating agents include phosphorus oxychloride, oxalyl chloride, thionyl chloride, phosgene or tosyl chloride in the presence of a suitable base such as triethylamine or diisopropylethylamine or similar base such as pyridine. Suitable solvents are dimethoxy ether, tetrahydrofuran, or halogenated solvents, preferably THF. The reaction is most effective when the reaction temperature is maintained between -10 ° C and 0 ° C. At low temperatures, the reaction occurs incompletely, at high temperatures the solution darkens and the yield of the product decreases.

Compounds of formula IV (Scheme I) are those of formula (V) that do not remove or remove water, preferably in dehydration conditions, conveniently at reflux at ambient temperature or elevated temperature, for example 30 to 150 ° C., optionally in the presence of an acid catalyst Compound (Scheme I) R ₄ CHO, where R ₄ is as defined herein, can be prepared by reacting with ArS (O) pH and formamide. Alternatively, trimethylsilylchloride can be used instead of the acid catalyst. Examples of acid catalysts include camphor-10-sulfonic acid, formic acid, p-toluenesulfonic acid, hydrogen chloride or sulfuric acid.

The optimal process for preparing isonitrile of formula II is illustrated in Scheme XI below.

Conversion of substituted aldehydes to tosylbenzyl formamide can be achieved by combining aldehyde (1) (Scheme XI) with p-toluenesulfonic acid, formic acid or camphorsulfonic acid; Heating with formamide and p-toluene-sulfonic acid can be achieved [under reaction conditions at about 60 ° C. for about 24 hours]. Preferably, no solvent is used. The yield of the reaction is poor (less than 30%) when using a solvent such as DMF, DMSO, toluene, acetonitrile, or excess formamide. At temperatures below 60 ° C. it is generally poor for the preparation of the desired product and at temperatures above 60 ° C. it is possible to prepare a product which decomposes, or to obtain benzylic bis-formamide (2) (Scheme XI). In Example 23 (a) described in European Patent Publication No. WO95 / 02591 (Adams et al.), 4-fluorophenyltosylmethylformamide (compound I of Scheme IV, wherein p = 2) Was synthesized. The procedure differs from that described herein by the following conditions using the sodium salt of toluene sulfinic acid, and the process is more heterogeneous than described herein as described herein where sulfinic acid is used and non-aqueous conditions may be used. One heating, low yield and low regeneration rate are obtained.

Solvent for extracting the product under the conditions of preparation of α- (p-toluenesulfonyl) -4-fluorobenzylisonitrile as described in Example 23 (b) of European Patent Publication No. WO95 / 02591 (Adams et al.) CH ₂ Cl _{2 as} and DME as solvent. The present invention improves this process by using less expensive solvents such as THF and EtOAc for extraction. In addition, other alcohols such as methanol, ethanol and butanol are acceptable, but higher yields are obtained by recrystallization with alcohols such as 1-propanol. Earlier, the compounds are partially purified using chromatographic techniques and harmful solvents for further purification.

Another embodiment of the present invention is the synthesis of tosyl benzyl formamide compounds obtained by reacting bisporamide intermediate (2) (Scheme XI) with p-toluenesulfinic acid. In this preferred route, the preparation of bisformamide from aldehydes is accomplished by heating the aldehydes with formamide in an appropriate solvent with an acid catalyst. Suitable solvents are toluene, acetonitrile, DMF and DMSO or mixtures thereof. Acid catalysts are well known in the art and include, but are not limited to, hydrogen chloride, p-toluenesulfonic acid, camphorsulfonic acid, and other anhydrides. The reaction can be carried out at a temperature in the range of about 25 to 110 ° C., preferably about 50 ° C., suitably for about 4 to about 5 hours, and longer reaction times are also acceptable. At higher temperatures (greater than 70 ° C.), product degradation and low yields can be observed at extended reaction times. In general, complete conversion of the product requires the removal of water from the reaction mixture.

Preferred conditions for the conversion of bisformamide derivatives to tosyl benzyl formamide are achieved by heating the bisformamides together with the acid catalyst and p-toluenesulfinic acid in a suitable solvent. Solvents for use in this reaction include, but are not limited to, toluene and acetonitrile or mixtures thereof. Further mixtures of these solvents with DMF or DMSO can also be used but yields may be lowered. The temperature ranges from about 30 to about 100 ° C. Temperatures below 0 ° C. and above 60 ° C. are undesirable because yields and speeds decrease. Preferably, the range is about 40 to 60 ° C, most preferably about 50 ° C. The optimal time may be longer but is about 4-5 hours. Preferably, the acids used include, but are not limited to toluenesulfonic acid, camphorsulfonic acid and hydrogen chloride and other anhydrous acids. Most preferably, bisporamide is heated with p-toluenesulfinic acid and hydrogen chloride in a 1: 1 ratio of toluene: acetonitrile.

Another embodiment of the present invention is a preferred synthetic route for the synthesis of tosylbenzyl formamide achieved using a one-reaction vessel procedure. The procedure first converts the aldehyde to a bisporamide derivative and then reacts the bisporamide derivative with toluenesulfinic acid. The procedure combines the optimized conditions into one efficient process. In this way high yields of aryl benzylformamide in excess of 90% can be obtained.

Preferred reaction conditions use a catalyst such as trimethylsilyl chloride in a preferred solvent, preferably toluene: acetonitrile in a 1: 1 ratio. Preferred are reagents such as TMSCl, which react with the water produced therein and simultaneously produce hydrogen chloride to catalyze the reaction. Preference is also given to using hydrogen chloride and p-toluenesulfonic acid. Thus, three suitable reaction conditions for use herein include 1) the use of a dehydrating agent such as TMSCl, which also provides hydrogen chloride, 2) a suitable dehydrating agent and a suitable acid source, such as camphorsulfonic acid, hydrogen chloride or toluenesulfonic acid (ie 3) alternative dehydration conditions such as azeotropic removal of water, and the use of acid catalysts and p-toluene sulfinic acid.

In addition, compounds of formula II, wherein p is 2, are compounds of formula VI in the presence of a strong base (Scheme I) R ₄ CH ₂ NC are compounds of formula VII (Scheme I) ArSO ₂ L ₁ (wherein R ₄ and Ar As defined herein, L ₁ can be prepared by reacting with a halo, leaving group such as, for example, fluoro). Suitable strong bases include, but are not limited to, alkyl lithiums such as butyl lithium or lithium diisopropylamide (Van Lucene et al., Tetrahedron Letters, No. 23, 2367-68 (1972)).

Compounds of formula VI (Scheme I) may be prepared by reacting compounds of formula VIII (Scheme I) R ₄ CH ₂ NH ₂ with alkyl formate (eg ethylformate) to obtain intermediate amides. It can be converted to the desired isonitrile by reaction with, but not limited to, well known dehydrating agents such as oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.

Alternatively, the compound of formula VIII (Scheme I) can be converted to the compound of formula VI (Scheme I) by reaction with chloroform and sodium hydroxide in aqueous dichloromethane under a phase transfer catalyst.

Compounds of formula III can be prepared by reacting compounds of formula R ₁ CHO with primary amines R ₂ NH ₂ .

The amino compounds of formula (VIII) (Scheme I) are known or can be prepared from the corresponding alcohols, oximes or amides using standard functional group transformations.

Cycloalkanones (Scheme XII) (Aldrich Chemical Co., Milwaukee, WI), such as compound (1), are reductive amination such as oxime formation with hydroxylamine in H ₂ O. It can then be converted to a cycloalkylamine (Scheme XII) such as compound (2) by the usual procedure for reducing oxime to amine by standard conditions such as catalytic hydrogenation with Raney Ni under H ₂ atmosphere. have. Cycloacylamines (Scheme XII), such as Compound (2), are reacted with aryl aldehydes such as 2-alkylthio or alkoxypyrimidinyl-4-carboxaldehyde in a non-hydroxyl organic solvent to react with Compound (3) It can form the same imine (Scheme XII). Depending on the degree of activation of the aldehyde for imine formation, catalytic acid (eg toluenesulfonic acid) and dehydration conditions (eg azeotropic removal of water in reflux benzene) may or may not be necessary. Imines such as compound (3) (Scheme XII) are in the presence of a base such as 1,5,7-triazabicyclo [4.4.0] -des-5-ene (TBD) in an organic solvent such as CH ₂ Cl _2. It can be converted to 1,4-diaryl imidazole alkylated with a cycloalkyl group by reacting with isonitrile such as 4-fluorophenyl-tolylthiomethylisocyanide. In this way, compound (3) (Scheme XII) is converted to compound (5) (Scheme XII). Cycloalkyl ketal substituted imidazoles such as compound 5 (Scheme XII) are hydrolyzed with aqueous acid (eg aqueous HCl) and then neutralized with base (eg aqueous Na ₂ CO ₃ ) to give compound (6 To a ketone (Scheme XII). Compound (6) (Scheme XII) is converted to oxime (7) (Scheme XII) using hydroxylamine in H ₂ O. Compound (7) (Scheme XII) is converted to hydroxylamine (8) (Scheme XII) by reduction with sodium cyanoborohydride in methanol. Compound (8) (Scheme XII) is converted to hydroxyurea (9) (Scheme XII) by the procedure of Adams et al. (European Patent Publication WO91 / 14674, published October 3, 1991).

In the above scheme, alcohol (10) (Scheme XIII) can be prepared by reducing ketone (6) (Scheme XIII) with a suitable reducing agent such as NaBH ₄ .

The alcohol (10) (Scheme XIII) and related alcohols can also be prepared naturally, as shown in Scheme XIV and Schemes XV and XVI below.

Specific examples are illustrated in Scheme XVI below (Example 11 of the synthesis experiment).

Ketone (1) (Scheme XVII) is reacted with any organometallic reagent (R ₁ M) to give the corresponding alcohol (2) (wherein R ₁ is hydrogen or optionally substituted alkyl aryl, arylalkyl, heterocyclic , Heterocyclic alkyl, or the like). Alcohol (2) can be converted to neopentyl amine (3) using classical Ritter reactions well known to those skilled in the art. The amine (3) may be acylated or sulfonylated. Ketone (1) can be converted to spirooxirane (4) by reagents such as dimethylsulfonium methylide and dimethyl sulfoxium methylide. The oxirane (4) can ring open with excess nucleophiles, such as hydroxides, thiolides, amines, organometallic reagents (e.g., well known organolitate or organoaluminum reagents, etc.).

Ketone (1) (Scheme XVII) may also be subject to reductive amination with any primary or secondary amine to afford amine (6) (Scheme XVII).

Suitable protecting groups for use with hydroxyl groups and imidazole nitrogen are well known in the art and are described in many references, such as, for example, Protecting Groups in Organic Synthesis, Green Tea W., Wiley-Interscience, New York, 1981. ]. Suitable examples of hydroxyl protecting groups include silyl ethers such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers such as methyl linked by alkyl chains (CR ₁₀ R ₂₀ ) _n of various linking groups. Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.

Pharmaceutical acid addition salts of compounds of formula (I) can be obtained by known methods, for example by treatment with an appropriate amount of acid in the presence of a suitable solvent.

How to treat

A compound of formula (I) or a pharmaceutically acceptable salt thereof is human or aggravated or developed by excessive or unregulated cytokine production by mammalian cells, such as, but not limited to, monocytes and / or macrophages. It can be used for the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states of other mammals.

Compounds of formula (I) are useful for treatment because they can inhibit pre-inflammatory cytokines such as IL-1, IL-6, IL-8 and TNF. IL-1, IL-6, IL-8, and TNF affect a wide range of cells and tissues, as well as their cytokines, as well as other leukocyte-induced cytokines, and are important and critical inflammatory mediators of a wide range of disease states and disorders. Inhibiting these proinflammatory cytokines is beneficial in controlling, reducing and alleviating most of these disease states.

Compounds of formula (I) are useful for treatment because they can inhibit inducible proinflammatory proteins such as COX-2, also called many other names, such as prostaglandin endopeperoxide synthase-2 (PGHS-2). These proinflammatory lipid mediators of the cyclooxygenase (CO) pathway are produced by inducible COX-2 enzymes. Thus, the regulation of COX-2 that contributes to these products derived from arachidonic acid, such as prostaglandins, affects a wide range of cells and tissues and is an important and critical inflammatory mediator of a wide range of disease states and disorders. Expression of COX-1 is not affected by the compound of formula (I). Such selective inhibition of COX-2 can alleviate or eliminate the ulcer-inducing propensity associated with inhibition of COX-1, inhibiting prosoglandins which are essential for cell protective effects. Thus, inhibition of these proinflammatory mediators is useful in controlling, reducing and alleviating the majority of these disease states. Most notably, these inflammatory mediators, particularly prostaglandins, are associated with pain, or edema, as in the sensitization of pain receptors. Thus, aspects of such pain management include treatment of neuromuscular pain, headaches, cancerous pain and joint pain. Compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for prophylaxis or treatment in humans or other mammals by inhibiting COX-2 enzyme synthesis.

Accordingly, the present invention provides a method of inhibiting COX-2 synthesis, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides methods of prophylactic treatment in humans or other mammals by inhibiting COX-2 enzyme synthesis.

Accordingly, the present invention provides a method of treating a cytokine mediated disease, comprising administering an effective cytokine inhibitory amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In particular, the compounds of formula (I) or pharmaceutically acceptable salts thereof are excessive or unregulated IL-2, IL-8 or TNF by mammalian cells, such as, but not limited to, monocytes and / or macrophages. Useful for the prevention and treatment of disease states in humans or other mammals, aggravated or developed by production.

Thus, in another aspect, the invention inhibits the production of IL-1 in a mammal comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof. It is about a method.

There are many disease states in which excessive or unregulated IL-1 production is associated with exacerbating and / or developing the disease. These disease states include rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and / or toxic shock syndrome, other acute inflammatory disease states such as inflammatory reactions caused by endotoxins or inflammatory bowel disease, tuberculosis, atherosclerosis, Muscle degeneration, multiple sclerosis, cachexia, osteoporosis, psoriatic arthritis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. According to recent evidence, IL-1 activity is also associated with diabetes, pancreatic β cells and Alzheimer's disease.

In another aspect, the present invention relates to a method for inhibiting the production of TNF in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production can lead to rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, sepsis shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, brain Malaria, chronic lung inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, such as osteoporosis, reperfusion injury, host reaction to transplantation, tagase rejection, fever and myalgia from infections such as influenza, infections or malignant diseases Secondary cachexia, secondary cachexia secondary to AIDS, AIDS, ARC (AIDS-related complications), mediates many diseases including keloid formation, scar tissue formation, inflammatory bowel disease, Crohn's disease, ulcerative colitis and fever Or worsen.

Compounds of formula (I) are also useful for the treatment of infections of viruses that are sensitive to upregulation by TNF or that induce TNF production in vivo. Viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those that are sensitive to inhibition, such as by TNF inhibition of a compound of Formula (I), either directly or indirectly by reducing replication. Such viruses include HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenoviruses and viruses of the Herpes group (eg Herpes Zoster and Herpes Simplex). ), But is not limited to such). Thus, in another aspect, the present invention relates to a method of treating a mammal comprising administering to the mammalian infected human immunodeficiency virus (HIV) a TNF inhibitory effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. will be.

The compounds of formula (I) can also be used in connection with veterinary treatment of mammals other than humans, which require inhibition of TNF production. TNF mediated diseases for therapeutic or prophylactic treatment in animals include disease states as described above, in particular viral infections. Examples of such viruses include, but are not limited to, equine infectious anemia virus, goat arthritis virus, lentiviral infections such as bisna virus or Medi virus, or feline immunodeficiency virus (FIV), bovine immunodeficiency virus or canine immunodeficiency virus. Not) retroviruses, or other retroviral infections.

The compounds of formula (I) also have local disease states that are mediated or exacerbated by excessive cytokine production, for example by IL-1 or TNF, for example joint inflammation, eczema, contact dermatitis, psoriasis and sunlight Other inflammatory skin diseases such as burns; Inflammatory eye disease, including conjunctivitis; It can be used externally for the treatment and prevention of fever, pain and other diseases associated with inflammation.

Compounds of formula I also appear to inhibit the production of IL-8 (interleukin-8, NAP). Thus, in another aspect, the present invention comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof, wherein the mammal is in need of inhibiting the production of IL-8. It is about a method.

There are many disease states associated with excessive or unregulated IL-8 production that exacerbate and / or develop the disease. These diseases are characterized by neutrophil mass infiltration, such as psoriasis, inflammatory bowel disease, asthma, mental and physical reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with increased production of IL-8, which causes neutrophil chemotaxis to sites of inflammation. Unlike other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has unique properties that promote chemotaxis and activation of neutrophils. Thus, inhibiting IL-8 production can directly reduce neutrophil infiltration.

Compounds of Formula I inhibit cytokine, in particular IL-1, IL-6, IL-8, or TNF production, down to normal levels, or in some cases below normal levels, in order to alleviate or prevent disease states. Is administered in a sufficient amount. For example, abnormal levels of IL-1, IL-6, IL-8 or TNF in the context of the present invention may be: (i) at least 1 picogram / ml of free (non-cell bound) IL-1, IL-6, IL -8 or TNF levels, (ii) any cell bound IL-1, IL-6, IL-8 or TNF, or (iii) cells in which IL-1, IL-6, IL-8 or TNF is produced, respectively Or the presence of IL-1, IL-6, IL-8 or TNF mRNA above the basal level in tissue.

The discovery that compounds of formula I are inhibitors of cytokines, specifically IL-1, IL-6, IL-8, and TNF, has been described as a formula for the production of IL-1, IL-8 and TNF in the in vitro assays described herein. Based on the effects of the compounds of I.

As used herein, the term "inhibition of IL-1 (IL-6, IL-8 or TNF) production"

a) excessive in vivo of cytokines (IL-1, IL-6, IL-8 or TNF) in humans by inhibiting in vivo release of cytokines by all cells, including but not limited to monocytes or macrophages Reducing the level to normal or subnormal levels,

b) at the genome level, down-regulating excessive in vivo levels of cytokines (IL-1, IL-6, IL-8 or TNF) in humans to normal or subnormal levels,

c) post-translational events, down-regulation by inhibition of direct synthesis of cytokines (IL-1, IL-6, IL-8 or TNF), or

d) At the translational level, it means down-regulating excessive in vivo levels of cytokines (IL-1, IL-6, IL-8 or TNF) in humans to normal or subnormal levels.

As used herein, the term "TNF mediated disease or disease state" refers to the release of TNF by other production of TNF itself or other monokines such as, but not limited to, IL-1, IL-6 or IL-8. By any disease condition is meant to act. Thus, for example, a disease state in which IL-1 is a major component and whose production or activity is exacerbated or secreted in response to TNF is considered a disease state mediated by TNF.

As used herein, the term "cytokine" refers to any secreted polypeptide that is a molecule that affects the function of a cell and modulates intercellular interactions in an immune, inflammatory or hematogenous response. Cytokines include, but are not limited to, monocaine and lymphokine, regardless of which cell produces it. For example, monocaine is generally meant to be produced and secreted by mononuclear cells, such as macrophages and / or monocytes. However, many other cells also produce monokillers such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, cerebral astrocytic cells, myeloid stromal cells, skin keratinocytes and B-white blood cells. Lymphokine is generally meant to be produced by white blood cells. Examples of cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor-beta (TNF) -β), but is not limited thereto.

As used herein, the term “cytokine inhibition” or “cytokine inhibitory amount” when used in a patient to prevent or treat a disease state that is exacerbated or caused by excessive or unregulated cytokine production, is a biomarker of cytokines. An effective amount of a compound of formula (I) that will lower the level within normal or below normal.

Cytokines, as used herein in the phrase “inhibition of cytokines for use in the treatment of HIV-infected persons,” refer to (a) T cell activation, and / or expression of activated T cell mediated HIV genes and (Or) initiation and / or maintenance of replication, and / or (b) cytokines involved in any cytokine mediated disease associated with problems such as cachexia or myopathy.

TNF-β (also known as lymphotoxin) has close structural homology with TNF-α (also known as capetine), each of which induces a similar biological response and binds to the same cellular receptor, Both -α and TNF-β are inhibited by the compounds of the present invention and are therefore collectively referred to herein as "TNF" unless specifically stated otherwise.

In recent laboratories, new members of the MAP kinase family, generally referred to as CSBP, p38 or RK, have been independently identified. In different cell systems upon stimulation by physicochemical stress and lipopolysaccharide or by extensive stimulation such as treatment with proinflammatory cytokines such as interleukin-1 and tumor necrosis factor, activation of the novel protein kinase via dual phosphorylation Was observed. Compounds of formula (I), which are cytokine biosynthesis inhibitors of the invention, have been determined to be potent and selective inhibitors of CSBP / p.38 / RK kinase activity. These inhibitors help to determine signal pathway involvement in the inflammatory response. In particular, the first complete signal transduction pathway can be defined as the action of lipopolysaccharide in the cytokine production of macrophages. In addition to the diseases already mentioned, it also includes the treatment of stroke, neurotrauma, mental and reperfusion injury, thrombosis, renal glomerulonephritis, diabetes and pancreatic β cells, multiple sclerosis, myopathy, eczema, psoriasis, sunburn and conjunctivitis.

Cytokine inhibitors were then tested in many animal models for anti-inflammatory activity. The model system is chosen to be relatively insensitive to cyclooxygenase inhibitors to reveal the intrinsic activity of cytokine inhibitors. The inhibitor has shown significant activity in many such in vivo studies. Most notable is its effect in collagen-induced arthritis models and inhibition of TNF production in endotoxin shock models. In the latter study, the decrease in plasma concentration of TNF correlates with survival and protection from endotoxin shock-related deaths. In addition, the effectiveness of compounds that inhibit bone resorption in fetal iliac organ culture systems is very important [Griswold et al., (1988) Arthritis Rheum. 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). B Ann. N.Y. Acad. Sci. 696, 149-170.

Compounds of formula (I) or pharmaceutically acceptable salts thereof are usually formulated into pharmaceutical compositions according to standard pharmaceutical practice for use in therapy. Accordingly, the present invention also relates to pharmaceutical compositions containing a nontoxic effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same may conveniently be administered by any route conventionally used for drug administration, eg, oral, external, parenteral or inhalation. have. The compounds of formula (I) may be administered in conventional dosage forms prepared by combining the compounds of formula (I) with standard pharmaceutical carriers in accordance with conventional procedures. In addition, the compounds of formula (I) can be administered in conventional dosage forms in combination with known second therapeutically active compounds. These procedures may include mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired formulation. The form and properties of the pharmaceutically acceptable carrier or diluent are defined by the amount of active ingredient to be formulated, the route of administration and other well known variables. The carrier (s) must be "acceptable" in that they are compatible with the other ingredients of the formulation and are not toxic to their recipients.

The pharmaceutical carrier used may be, for example, solid or liquid. Examples of solid carriers include lactose, white clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may comprise a time retardant known in the art, for example glyceryl mono-stearate or glyceryl distearate, alone or in combination with a wax.

A wide range of pharmaceutical formulations can be used. Thus, when a solid carrier is used, the preparation can be enclosed in hard gelatin capsules in powder or pellet form or tableted in the form of troches or lozenges. The amount of solid carrier varies widely but will preferably be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or non-aqueous liquid suspension.

The compounds of formula (I) can be administered externally, ie by non-systemic administration. This includes administering the compound of formula (I) externally to the epidermis or oral cavity, or dropping the compound into the ears, eyes and nose, so that the compound is substantially not introduced into the bloodstream. Systemic administration, on the other hand, represents oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for external administration include liquid or semi-liquid formulations suitable for penetration into the site of inflammation through the skin, such as linens, lotions, creams, ointments or pastes, and for administration to the eyes, ears or nose. And dorps. The active ingredient may comprise 0.001 to 10 w / w%, for example 1% to 2% by weight of the formulation for external administration. However, this may constitute about 10% by weight of the formulation, but will preferably comprise less than 5 w / w%, more preferably 0.1 to 1 w / w%.

Lotions according to the present invention include those suitable for administration to the skin or eyes. Ophthalmic lotions may optionally include sterile aqueous solutions containing bactericides and may be prepared in a similar manner as for the preparation of drops. Skin lotion or lining agents may also include active agents such as alcohol or acetone to dry and cool the skin quickly, and / or wetting agents such as glycerol, or oils such as castor oil or arachis oil.

Creams, ointments or pastes according to the invention are semisolid formulations of the active ingredient for external administration. These may be prepared by mixing the active ingredient alone or in powder or powder form with an oily or non-oily base with the aid of a suitable machine in a solution or suspension in an aqueous or non-aqueous fluid. Bases include hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal soaps; Plant mucus; Natural oils such as almond oil, corn oil, arachis oil, castor oil or olive oil; Wool or derivatives thereof, or fatty acids such as stearic acid or oleic acid may be included with alcohols or macrogels such as propylene glycol. The formulation may comprise any suitable surfactant, such as anionic, cationic or nonionic surfactants such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives, or inorganic materials (eg, silicon silica), and other ingredients such as lanolin may also be included.

Drops according to the invention may comprise sterile aqueous or oily solutions, or aqueous suspensions or oily suspensions, and the active ingredient is dissolved in a suitable aqueous solution of fungicides and / or fungicides and / or any other suitable preservatives Preferably, it can manufacture by including surfactant. The resulting solution can then be filtered to clarify, transferred to a suitable container, then sealed and autoclaved at 98-100 ° C. or maintained for half an hour to sterilize. Alternatively, the solution can be filtered and sterilized and transferred to the container by aseptic technique. Examples of suitable fungicides and fungicides for inclusion in drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for preparing the oily solution include glycerol, dilute alcohol and propylene glycol.

The compounds of formula (I) can be administered parenterally, ie by intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Suitable dosage forms for such administration may be prepared by conventional techniques. The compounds of formula (I) can also be administered by inhalation, i.e., intranasal and oral inhalation administration. Dosage forms suitable for such administration, eg, aerosol formulations or metered dose inhalers, can be prepared by conventional techniques.

For all methods of use of the compounds of formula (I) disclosed herein, the daily oral dosage is preferably about 0.1 to about 80 mg / kg (gross body weight), preferably about 0.2 to 30 mg / kg, more preferably Will be about 0.5-15 mg. The daily parenteral dosage is about 0.1 to about 80 mg / kg (gross body weight), preferably about 0.2 to 30 mg / kg, more preferably about 0.5 to 15 mg / kg. The daily external dosage will preferably be from 0.1 to 150 mg administered 1 to 4 times daily, preferably 2 or 3 times daily. The daily inhalation regimen will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. In addition, the optimal amount and interval of each dosage of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the disease to be treated, the form, route and site of administration, and the particular patient to be treated. It will be appreciated by those skilled in the art that one optimal condition can be determined by conventional techniques. In addition, those skilled in the art will understand that the optimal course of treatment, ie, multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, provided daily can be ascertained by one skilled in the art using conventional procedures of treatment determination testing. .

The invention will be described by reference to the following biological experiments, which are merely illustrative and should not be construed as limiting the scope of the invention.

Biological experiment

The cytokine inhibitory effect of the compound of the present invention was measured by the following in vitro test.

Interleukin-1 (IL-1)

Isolation of human peripheral blood mononuclear cells from volunteers or from fresh blood preparations obtained in a blood bank buffy coat, according to the procedures of Colotta et al., J Immunol, 132, 936 (1984). And purified. These monocytes (1 × 10 ⁶ ) were plated on 24-well plates at a concentration of 1-2 million / ml per well. The cells were left to attach for 2 hours and then gently washed to remove non-adherent cells. The test compound was then added to the cells for about 1 hour before lipopolysaccharide (50 ng / ml) was added and the cultures were incubated at 37 ° C. for an additional 24 hours. At the end of this period, the culture supernatant was recovered and the cells and all debris washed. The culture supernatant was then reviewed by Simon et al., J. Immunol. Methods, 84, 85 (1985) (based on the ability of IL-1 to stimulate interleukin 2 producing cell line (EL-4) to secrete IL-2 in cooperation with A23187 ionophores) or other literature The biological activity of IL-1 was immediately analyzed by the method of Lee et al., J. Immuno Therapy, 6 (1), 1-12 (1990) (ELISA assay). Representative compounds of Formula (I) (Example 2) exhibited positive inhibitory activity against IL-1.

Tumor Necrosis Factor (TNF)

According to the procedure of Colotta, R. et al., J Immunol, 132 (2), 936 (1984), peripheral blood mononuclear cells of humans were collected from blood bank buffy coat or platelet peressis residues. Isolated and purified. The monocytes were plated at a density of 1 × 10 ⁶ cells / ml medium / well in a 24-well multiple dish. After allowing the cells to adhere for 1 hour, the supernatant is aspirated to fresh medium (1 ml, RPMI-1640, Whittaker Biomedical Products) containing 1% fetal calf serum and penicillin and streptomycin (10 units / ml). Whitaker Biomedical Products, Whitaker, Calif.). The cells were dissolved or dissolved in dimethyl sulfoxide / ethanol such that the final solvent concentration in the culture medium was 0.5% dimethyl sulfoxide / 0.5% ethanol in the presence or absence of test compound in the range of 1 nM-10 mM dose. Incubate for minutes. Then bacterial lipopolysaccharide (E. coli 055: B5 [LPS], Sigma Chemical Co.) was added (100 ng / ml in 10 ml phosphate buffered saline) and the culture Incubation was for 16-18 hours at 37 ° C. in a 5% CO ₂ incubator. At the end of the incubation period, the culture supernatant was removed from the cells and centrifuged at 3000 rpm to remove cell debris. The supernatant was then analyzed for TNF activity using radioimmunoassay or ELISA assay, as described in WO92 / 10190 and Becker et al., J Immunol, 1991, 147, 4307. . Representative compounds of formula I (Example 2) showed positive inhibitory activity against TNF.

IL-1 and TNF inhibitory activity does not appear to be related to the properties of the compounds of formula (I) that mediate arachidonic acid metabolism inhibition. In addition, the ability to inhibit the production of prostaglandins and / or the synthesis of leukotrienes by a nonsteroidal anti-inflammatory drug with potent cyclooxygenase and / or lipoxygenase inhibitory activity, results in non-toxic administration of the compound. A dose does not necessarily mean that it will inhibit TNF or IL-1 production.

In vivo TNF analysis

In contrast to the assays shown above in vitro assays, compounds of formula I are also described in (1) GreaseWorld et al., Drugs Under Exp. and Clinical Res., XIX (6), 243-248 (1993)] or other documents (2) Boehm et al., Journal Of Medicinal Chemistry 39, 3929-3937 (1996), the full text of which is hereby incorporated by reference. May be tested in an in vivo system as described herein.

Using the assay described above, representative compounds of Formula I (Examples 1 and 6-11) showed positive inhibitory activity below 50 μM in this assay.

Interleukin-8 (IL-8)

Culture medium supplemented with 15% fetal calf serum and 1% CS-HBGF containing aFGF and heparin from endothelial cells (HUVEC) (Cell Systems, Kerland, WA) of the first human umbilical cord conduit Maintained at. The cells were then diluted 20-fold and then plated (250 μL) on gelling coated 96 well plates. Prior to use, the culture medium was replaced with fresh medium (200 μl). Buffer or test compound (25 μl, concentration of 1-10 μM) was then added to each well in 4-fold wells and the plates were incubated for 6 hours in a humidified incubator at 37 ° C. under 5% CO ₂ atmosphere. Supernatants were harvested at the end of the incubation period and analyzed for IL-8 concentration using an IL-8 ELISA kit obtained from the R & D system (Minneapolis, Minn.). All data are expressed as mean values (ng / ml) of multiple samples based on standard curves. Where appropriate, IC ₅₀ was calculated by nonlinear regression analysis. Representative compounds of formula I (Example 2) showed positive inhibitory activity against IL-8.

Cytokine Specific Binding Protein Analysis

Radiocompetitive binding assays have been developed that provide a highly reproducible primary screen for structural activity studies. This assay provides many advantages over conventional bioassays that use ELISA assays to use and quantify newly isolated human monocytes as a source of cytokines. In addition to being much easier to analyze, it has been widely found that the binding assays are highly correlated with the results of bioassays. Reproducible specific cytokine inhibitor binding assays were developed using soluble cytosolic fluid fractions from THP.1 cells and radiolabeled compounds. U.S. Patent Application No. 08/123175 (Lee et al., Filed Sep. 1993), U.S. Patent Application PCT 94/10529 (Lee et al., Sep. 16, 1994, incorporated herein by reference in its entirety. And Lee, et al., Nature 300, n (72), 739-746 (1994. 12.), screen for drugs to identify compounds that react with and bind to cytokine specific binding proteins (CSBP). The method is described. However, for the purposes of the present invention, the binding protein may be in isolated or immobilized form in solution or may be genetically engineered to be expressed genetically in phage display systems or on the surface of recombinant host cells such as fusion proteins. . Alternatively, cytosolic fractions or whole cells comprising CSBP can be used in the screening protocol. Regardless of the form of the binding protein, a number of compounds were contacted with the binding protein under conditions sufficient to form the compound / binding protein complex and compounds that could form, enhance or interfere with the complex were detected.

Representative compounds of formula (I) (Examples 1-8) all exhibited positive inhibitory activity of IC ₅₀ of less than ₅₀ μM in this binding assay.

CSBP Kinase Analysis

This assay measures ³² P of CSBP-catalyst delivery from [a- ³² P] ATP to threonine residues in epithelial growth factor receptor (EGFR) inducing peptide (T669) having the sequence: KRELVEPLTPSGEAPNQALLR (residues 661-681) ( See Galllagher et al., "Regultion of Stress Induced Cytokine Production by Pyridinyl Imidazoles: Inhibition of CSPB Kinase", BioOrganic & Medicinal Chemistry, 1996.

Kinase reactions (total volume 30 μl) were 25 mM Hepes buffer (pH 7.5); 10 mM MgCl ₂ ; 170 μM ATP ⁽¹⁾ ; 10 μM Na ortho vanadate; 0.4 mM T669 peptide; And 20-80 ng of yeast expressed purified CSBP2 (see Lee et al., Nature 300, n (72), 739-746 (1994. 12.). Compounds (5 μl from [6 ×] stock ⁽²⁾ ) were preincubated with enzymes and peptides on ice for 20 minutes before starting the reaction with 32 P / MgATP. The reaction was incubated at 30 ° C. for 10 minutes and stopped by addition of 10 μl 0.3 M phosphoric acid. 32 P-labeled peptide was separated on a phosphocellulose (Wattman, p81) filter by dropwise addition of 30 µl of the reaction mixture. The filter was washed three times with 75 mM phosphoric acid and then twice with H ₂ O and counted for 32P.

⁽¹⁾ The Km of CSBP for ATP was determined to be 170 μM. Thus, compounds were screened at the Km value of ATP.

^{(2) The} compounds were generally dissolved in DMSO and diluted in 25 mM Hepes buffer to give a final concentration of DMSO of 0.17%.

Representative compounds of formula (I) (Examples 9 and 10) showed positive inhibitory activity of IC ₅₀ of less than 50 μM in this kinase assay.

<Prostaglandin Endopeperoxide Synthase-2 (PGH-2) Assay>

The following assay describes a method of measuring the inhibitory effect of a compound of formula (I) on human PGHS-2 protein expression in LPS stimulated human monocytes.

Methods: Human peripheral blood mononuclear cells were isolated from buffy coat by centrifugation through Ficoll and Percoll gradients. Cells were seeded at 2 × 10 ⁶ / well in 24 well plates and allowed to attach for 1 hour in RPMI supplemented with 1% human AB serum, 20 mM L-glutamine, penicillin-streptomycin and 10 mM HEPES. Compounds were added at various concentrations and incubated at 37 ° C. for 10 minutes. LPS was added at 50 ng / well (to induce enzyme expression) and incubated overnight at 37 ° C. The supernatant was removed and the cells washed once in cold PBS. The cells were treated with 100 μl of cold lysis buffer (50 mM Tris / HCl, pH 7.5), 150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300 μg / ml DNAse, 0.1% Triton X-100, 1 mM PMSF, 1 mM leupetin, 1 mM pepstatin). The lysate was centrifuged (10,000 × g, 10 min at 4 ° C.) to remove debris and the soluble fractions were analyzed by SDS PAGE (12% gel). Proteins isolated on the gel were transferred onto nitrocellulose membranes by electrophoretic means at 60 volts for 2 hours. The membrane was pretreated for 1 hour in PBS / 0.1% Tween 20 containing 5% fat free milk. After washing three times in PBS / Twin buffer, the membranes were washed for 1 hour with 1: 2000 dilution of single specific antiserum: PGHS-2 or 1: 1000 dilution of antiserum: PGHS-1 in PBS / Twin containing 1% BSA. Incubation was continued while shaking. The membranes were washed three times in PBS / Twin buffer, followed by a 1: 3000 dilution of horseradish peroxidase binding donkey antiserum: rabbit Ig (Amersham) in PBS / Twin containing 1% BSA. Incubation was continued while shaking for hours. The membrane was then washed three times in PBS / twin and the expression level of prostaglandin endoperoxide synthase-2 was detected using an ECL immunodetection system (Amersham).

Result: The following compound: 4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole, 6- (4-fluorophenyl) -2,3 -Dihydro-5- (4-pyridinyl) imidazole [2,1-b] thiazole and dexamethasone were tested and found to be active (to inhibit cytokine production as stated in the indicated assays). Similar to that in order to inhibit LPS induced PGHS-2 protein expression. Some of the following compounds: 2- (4-methylsulfinylphenyl) -3- (4-pyridyl) -6,7-dihydro- (5H) -pyrrolo [1,2-a] imidazole, rolipram , Phenidone and NDGA were tested and found to be inactive (<10 μΜ). All of these compounds tested were either PGHS-1 or cPLA in similar experiments.₂ It was found not to inhibit protein levels.

TNF-α Analysis in Traumatic Brain Injury

In this assay, rats were experimentally induced lateral fluid-collision traumatic brain injury (TBI) and then tested for the expression of tumor necrosis factor mRNA at specific brain sites. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg, ip) and moderate (2.4 atm) lateral to the center on the left parietal cerebral cortex. Fluid-impact brain injury was applied (n = 18) or "sham" treatment (anesthesia and surgery without damage, n = 18). At 1, 6 and 24 hours after the injury, the animals were sacrificed, the brain removed, the left (injured) parietal cortex (LC), the corresponding area in the opposite right cortex (RC), damaged Tissue samples of the cerebral cortex (LA) adjacent to the cerebral cortex of the head, the corresponding contiguous region (RA), the left hippocampus (LH), and the right hippocampus (RH) in the right cortex were prepared. Total RNA was isolated, Northern blot hybridization was performed and quantified for TNF-α positive control RNA (macrophages = 100%). One hour after injury, TNF-α mRNA expression in traumatic cerebral hemispheres was reduced to LH (104 ± 17% of the positive controls, p <0.05 compared to Siamese), LC (105 ± 21%, p <0.05 ) And LA (69 ± 8%, p <0.01). In addition, at 6 hours after injury, TNF-α mRNA expression was expressed in LH (46 ± 8%, p <0.05), LC (30 ± 3%, p <0.01), and LA (32 ± 3%, p <0.01). ) Was observed, which resolved 24 hours after injury. In the opposite cerebral hemisphere, TNF-α mRNA expression increased to RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (22 ± 8%) 1 hour after injury, 6 The time increased to RH (28 ± 11%), RC (7 ± 5%) and RA (26 ± 6%, P <0.05), but not to 24 hours. For siamese (surgery without injury) or untreated animals, no consistent changes in TNF-α mRNA expression were observed at any time in any of the six brain regions in both cerebral hemispheres. These results indicate that after parasagittal fluid-impact brain injury, transient expression of TNF-α mRNA is altered in certain brain regions, including the intact cerebral hemisphere. Since TNF-α can induce neuronal growth factor (NGF) and stimulate the release of other cytokinins from activated astrocytes, these post-injury alterations in the gene expression of TNF-α may be an acute response to CNS trauma. Plays an important role in both and and regenerative reactions.

CNS impairment model for IL-β mRNA

In this assay, we characterized the local expression of interleukin-1β (IL-1β) mRNA in specific brain regions following experimental lateral fluid-impact traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg, ip) and moderate (2.4atm) lateral fluid-impact brain injury in the middle on the left parietal cortex. Was added (n = 18), or “shammed” (anesthesia and surgery were performed without damage). Animals were sacrificed at 1, 6 and 24 hours post-injury, brain removed, left (injured) parietal cortex (LC), corresponding areas in opposite right cortex (RC), damaged parietal cortex Tissue samples of cerebral cortex (LA) adjacent to, corresponding contiguous regions (RA), left hippocampus (LH) and right hippocampus (RH) in the right cortex were prepared. Total RNA was isolated, Northern blot hybridization was performed, and expressed as a percentage of radioactivity of IL-1β positive macrophage RNA loaded with the amount of brain tissue IL-1β mRNA on the same gel. One hour after brain injury, the expression of IL-1β mRNA in the damaged cerebral hemisphere was reduced by LC (20.0 ± 0.7% in the positive control group, n = 6, p <0.05 compared to Siamese animals), LH (24.5 ± 0.9 A significant increase in%, p <0.05) and LA (21.5 ± 3.1%, p <0.05) was observed, LC (4.0 ± 0.4%, n = 6, p <0.05) and 6 hours after injury. An increase in LH (5.0 ± 1.3%, p <0.05) was maintained. In Siamese or untreated animals, expression of IL-1β mRNA was not observed in any of the respective brain regions. This result indicates that after TBI, transient expression of IL-1β mRNA is locally stimulated at specific brain regions. These local changes in cytokinins such as IL-1β play an important role in pathological or regenerative sequelae after injury to brain injury.

The invention will now be described with reference to the following examples which are intended merely for illustration and should not be construed as limiting the scope of the invention. All temperatures are in degrees Celsius, all solvents are of the highest purity available, and all reactions are performed under anhydrous conditions in an argon atmosphere unless otherwise indicated.

In the examples below, all temperatures are in degrees Celsius (° C.). Mass spectra were performed on a VG Zab mass spectrometer using rapid atomic collisions unless otherwise indicated. ¹ H-NMR (hereinafter “NMR”) spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. Multiplicity represents s = single, d = double, t = triple, q = quad, m = multi, and br stands for broad signal. Sat. represents the labeled solution and eq. Represents the ratio of molar equivalents of the reagents to the main reactants.

Flash chromatography was done on Merck Silacagel 60 (230-400 mesh).

Example 1

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

a) 4-fluorophenyl-tolylsulfonomethylformamide

To a suspension of sodium p-toluenesulfinic acid salt in H ₂ O (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of concentrated HCl (15 mL). After stirring for 5 minutes, the organic phase is removed and the aqueous phase is extracted with methyl t-butyl ether. The organic phase was dried (Na ₂ SO ₄ ) and concentrated to dryness. Hexane was added and the free acid was filtered off. p-toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL, 503 mmol) and camphor sulfonic acid (4 g, 17.3 mmol) were combined and 18 at 60 ° C. Stir for hours. The resulting solid was triturated and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) and filtered. The solid was resuspended in MeOH / hexanes (1: 3, 200 mL) and stirred vigorously to break up the remaining large mass. Filtration gave the title compound (27 g, 62% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (s, 1H), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d , 1H), 2.45 (s, 3H).

b) 4-fluorophenyl-tolylsulfonomethyl isocyanide

The preceding compound (2.01 g, 6.25 mmol) in ethylene glycol dimethylether (DME) (32 mL) was cooled to -10 ° C. POCl ₃ (1.52 mL, 16.3 mmol) was added, followed by the dropwise addition of triethylamine (4.6 mL, 32.6 mmol) in DME (3 mL) while maintaining an internal temperature below −5 ° C. The mixture was gradually warmed over 1 h, quenched in H ₂ O and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was triturated with petroleum ether and filtered to give the title compound (1.7 g, 90% yield). ¹ H NMR (CDCl ₃ ): δ 7.63 (d, 2H), 7.33 (m, 4H), 7.10 (t, 2H), 5.60 (s, 1H), 2.50 (s, 3H).

c) 2-N-methylthiopyrimidine-4-carboxaldehyde dimethyl acetal

Pyruvaldehyde dimethyl acetal (60 mL, 459 mmol) and N, N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100 ° C. for 18 hours. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt% in MeOH) were added to the mixture and stirred at 70 ° C for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. After diluted with EtOAc and H ₂ O, the organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (75.5 g, 82% yield). ¹ H NMR (CDCl ₃ ): δ 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).

d) 2-methylthiopyrimidine-4-carboxaldehyde

A mixture of the preceding compounds (10.04 g, 55 mmol) in 3N HCl (45 mL) was stirred at 47 ° C. for 24 h. After cooling, EtOAc was added followed by solid NaHCO ₃ . The aqueous phase was extracted with EtOAc (4 × 100 mL). The organic phases were combined, dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a yellow foam. ¹ H NMR (CDCl ₃ ): δ 9.95 (s, 1H), 8.77 (d, 1H), 7.43 (d, 1H), 2.63 (s, 3H).

e) 1-amino-4- (1,3-dioxycyclopentyl) cyclohexane

Na ₂ CO ₃ (49.2 g, 547) in a mixture of 1,4-cyclohexanedione monoethylene ketal (27.6 g, 177 mmol) and hydroxylamine hydrochloride (49.2 g, 708 mmol) in H ₂ O (250 mL) Mmol) was added in portions. After stirring for 1 hour, the mixture was extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and concentrated to give 4- (1,3-dioxycyclopentyl) cyclohexanone oxime (27.5 g, 90% yield). Oxime (27.5 g, 161 mmol), Raney Ni (about 13.5 mL as suspension in EtOH) and EtOH (200 mL) were combined and shaken at 50 psi H ₂ for 4 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound (23.6 g, 93% yield) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 2.64 (m, 1H), 1.75-1.25 (m, 12H).

f) 2-methylthiopyrimidine-4-carboxaldehyde (4-ethylene ketal cyclohexyl) imine

2-methylthiopyrimidine-4-carboxaldehyde (9.5 g, 6.9 mmol) prepared in Example 1 (d) and previous step 1-amino-4- (1,3-dioxycyclopentyl) cyclohexane ( 10.8 g, 6.9 mmol) was stirred in DMF (150 mL) for 18 h. The title compound was used without any purification. ¹ H NMR (CDCl ₃ ): δ 8.51 (d, 1H), 8.21 (s, 1H), 7.53 (d, 1H), 3.93 (s, 4H), 3.40 (m, 1H), 2.55 (s, 3H) , 1.94-1.70 (m, 6H), 1.61 (m, 2H).

g) 1- (4-ethylene ketal cyclohexyl) imidazole-4- (4-fluorophenyl) -5-[(2-methylthio) pyrimidin-4-yl] imidazole

4-fluorophenyl-tolylsulfonomethylisocyanide (26 g, 90 mmol) and K ₂ CO ₃ (15.7 g, 113.6) prepared in Example 1 (b) were added to the crude product of the previous step in DMF cooled to 0 ° C. Mmol). The mixture was stirred at 0 ° C. for 3 hours, then gradually warmed to room temperature and stirred for 18 hours. EtOAc was added and the mixture was filtered and the solid was washed with EtOAc. H ₂ O was added to the filtrate and the organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated. The mixture was evaporated to almost dryness, filtered and washed with 1: 1 EtOAc / to afford the title compound as pale yellow crystals. ¹ H NMR (CDCl ₃ ): δ 8.33 (d, 1H), 7.81 (s, 1H), 7.43 (q, 2H), 7.12 (t, 2H), 6.78 (d, 1H), 4.74 (m, 1H) , 4.00 (s, 4H), 2.59 (s, 3H), 2.18 (dd, 2H), 2.04 (dq, 2H), 1.89 (dd, 2H), 1.70 (dt, 2H).

h) 1- (4-ethylene ketal cyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylsulfoxy) pyrimidin-4-yl] imidazole

To a solution of the preceding compound (0.20 g, 48 mmol) in THF (2 mL) and MeOH (1 mL) at 0 ° C. was added oxone monopersulfate (0.36 g, 0.56 mmol) dissolved in H ₂ O (2 mL). It was. The mixture was stirred for 5 hours, then poured into 10% NaOH and extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was triturated with Et ₂ O and filtered to afford the title compound (0.089 g, 45% yield) as a white solid. ¹ H NMR (CDCl ₃ ): δ 8.36 (d, 1H), 7.82 (s, 1H), 7.42 (q, 2H), 7.02 (t, 2H), 6.79 (d, 1H), 4.80 (m, 1H) , 4.00 (s, 3H), 2.20 (m, 2H), 2.06 (m, 3H), 1.89 (m, 2H), 1.70 (m, 5H).

i) 1- (4-ethylene ketal cyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

Sodium methoxide (5.17 mL, 22.6 mmol, 25% by weight in MeOH) was added to anhydrous THF (33 mL) followed by the compound of the previous example (5 g, 11.3 mmol). The mixture was stirred at rt for 2 h, then layered with EtOAc and diluted with H ₂ O. The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography (silica gel, 5% MeOH / CH ₂ Cl ₂ ). The resulting residue was triturated with EtAOc / hexanes (1: 1) to afford the title compound (3.57 g, 77% yield) as a white solid. ¹ H NMR (CDCl ₃ ): δ 8.34 (d, 1H), 7.81 (s, 1H), 7.40 (q, 2H), 7.00 (t, 2H), 6.78 (d, 1H), 4.79 (m, 1H) , 4.05 (s, 3H), 3.99 (s, 4H), 2.17 (m, 2H), 2.05 (s, 2H), 1.90 (m, 2H), 1.69 (dt, 2H).

j) 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

A mixture of the preceding compounds (10.73 g, 26.23 mmol) in 3N HCl (150 mL) was stirred for 36 h, then neutralized with saturated aqueous Na ₂ CO ₃ and filtered. The solid was washed with water and the aqueous mixture was extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and concentrated to give the title compound as white crystals. Melting point 212-214 ° C.

Example 2

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

To a solution of the compound of Example 1 (j) (0.099 g, 0.27 mmol) in MeOH / THF (1 mL, 1: 1) NaBH ₄ solution [1 mL, NaBH ₄ 10 g, MeOH (2.5 mL) and MeOH (0.2 1M solution prepared by combining 25% NaOMe in mL) was added. After stirring for 10 minutes, the mixture was quenched with saturated Na ₂ CO ₃ and the solvent was evaporated. The residue was recrystallized from MeOH / H ₂ O to give the title compound (0.063 g, 63% yield) as a white needle. Melting point 188-190 ° C.

Example 3

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5 [(2-methylthio) pyrimidin-4-yl] imidazole

The title compound was obtained as white crystals following the procedure of Example 1 (j) except using the compound of Example 1 (f). Melting point 201-203 ° C.

Example 4

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylthio) pyrimidin-4-yl] imidazole

Following the procedure of Example 2 except using the compound of Example 3, the title compound was obtained as white crystals. Melting point 194-196 ° C.

Example 5

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-hydroxy) pyrimidin-4-yl] imidazole

a) 1- (4-ethylene ketal cyclohexyl) -4- (4-fluorophenyl) -5-[(2-hydroxy) pyrimidin-4-yl] imidazole

The title compound was obtained as a white solid following the procedure of Example 1 (h) except that the MeOH was removed and the mixture was allowed to warm to room temperature and the insoluble product was filtered off. ¹ H NMR (CDCl ₃ ): δ 8.03 (dd, 1H), 7.69 (d, 1H), 7.35 (m, 2H), 6.88 (dt, 2H), 6.17 (dd, 1H), 4.35 (m, 1H) , 3.90 (m, 4H), 2.06-1.85 (m, 4H), 1.75 (d, 2H), 1.56 (dt, 2H).

b) 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-hydroxy) pyrimidin-4-yl] imidazole

Following the procedure of Example 1 (j) except using the compound of the previous step, the title compound was obtained as a white solid. Melting point 236-238 ° C.

Example 6

1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole

a) 1- (4-ethylene ketal cyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole

A mixture of sodium metal (0.161 g, 0.7 mmol) and isopropanol (30 mL) was gently stirred until the sodium metal dissolved. 1- (4-ethylene ketal cyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylsulfoxy) pyrimidine-4 prepared in Example 1 (h) in isopropanol (10 mL) -Yl] suspension of imidazole (0.3 g, 0.7 mmol) was added and the mixture was stirred at 90 ° C. for 2 hours. The mixture was cooled, diluted with H ₂ O and extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and concentrated. Recrystallization from EtOH / H ₂ O gave the title compound (0.15 g, 49% yield). ¹ H NMR (CDCl ₃ ): δ 8.35 (d, 1H), 7.81 (s, 1H), 7.43 (q, 2H), 7.01 (t, 2H), 6.73 (d, 1H), 5.30 (m, 1H) , 4.77 (m, 1H), 3.99 (s, 4H), 2.16 (m, 2H), 2.05 (dq, 2H), 1.90 (d, 2H), 1.68 (dt, 2H), 1.45 (d, 6H).

b) 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole

The title compound was obtained as white crystals following the procedure of Example 1 (j) except using the compound of the previous step. Melting point 161-163 ° C.

Example 7

1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole

The title compound was obtained following the procedure of Example 2 except using the compound of Example 6 (b). Melting point 208-211 ° C.

Example 8

Cis / trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

A suspension of the compound of Example 1 (j) (0.25 g, 0.68 mmol) in anhydrous THF (5 mL) was cooled to -78 ° C. Methylmagnesium bromide (3 mL, 9 mmol, 3 M in Et ₂ O) was added and the reaction was gradually warmed to 0 ° C. over 2 h. The reaction was quenched with H ₂ O and extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography (silica gel, 5% MeOH / CH ₂ Cl ₂ ). The resulting residue was triturated with EtAOc / hexanes (1: 1) to afford the title compound (0.06 g, 23% yield) as a white solid. Melting point 170-180 ° C.

Example 9

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole

a) 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole

To a suspension of NaH (0.36 g, 9 mmol) in anhydrous THF (9 mmol) ethanol (2 mL) was added dropwise. When gas evolution stopped, 1- (4-ethylene ketal cyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylsulfoxy) pyrimidine-4- of Example 1 (i) Il] imidazole (1.3 g, 2.9 mmol) was added and the mixture was stirred for 4 hours. The mixture was poured into H ₂ O and extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (1.20 g, 98% yield) as a yellow solid. ¹ H NMR (CDCl ₃ ): δ 8.32 (d, 1H), 7.80 (s, 1H), 7.40 (q, 2H), 7.00 (t, 2H), 6.75 (d, 1H), 4.76 (m, 1H) , 4.45 (q, 2H), 4.00 (s, 4H), 2.17 (m, 2H), 2.03 (dq, 2H), 1.88 (dd, 2H), 1.76 (dt, 2H), 1.48 (t, 3H).

b) 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole

The title compound was prepared following the procedure of Example 1 (j) except using the compound of the previous step as a solid. ¹ H NMR (CDCl ₃ ): δ 8.36 (d, 1H), 7.78 (s, 1H), 7.43 (q, 2H), 7.03 (t, 2H), 6.79 (d, 1H), 5.30 (m, 1H) , 4.49 (q, 2H), 4.09 (q, 1H), 2.55 (m, 6H), 2.10 (m, 2H), 1.50 (t, 3H).

c) trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole

Example 10

Cis-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

Triphenyl phosphine (0.82 g, 3.12 mmol) was added to a solution of the compound of Example 2 (1.0 g, 2.7 mmol) in THF, and the solution was stirred for 15 minutes. Benzoic acid (0.43 g, 3.53 mmol) and diisopropylazo carboxylate (0.66 g, 3.26 mmol) were added. The solution was stirred for 24 hours and the solvent was removed in vacuo. The benzoate was separated by flash chromatography and dissolved in THF. Saturated with aqueous 1M LiOH (4.6 mL) and then chromatographed gave a white solid (0.6 g, 60%) which crystallized from aqueous EtOH. Melting point (145-147 ° C.).

Example 11

Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

a) Synthesis of 2-thiopropyl-4-dimethoxymethylpyrimidine

N, N-dimethylformamide dimethyl acetal (88.7 g, 98.9 ml, 700 mmol) and pyruvaldehyde dimethyl acetal (85.3 g, 86.8) in a 1 l three-neck flask equipped with a stir bar, thermometer, 100 ml addition funnel and reflux condenser Ml, 700 mmol) was heated in an oil bath at 110 ° C. for 3-4 hours. The solution was cooled to 85 ° C. and thiourea (48.9 g, 636.4 mmol) and NaOMe (25% by weight in MeOH, 151.2 g, 160 mL, 700 mmol) were added and stirred at 85 ° C. for 3-4 hours. The solution was cooled to 65 ° C., 1-bromopropane (86.9 g, 64.4 mL, 700 mmol) was added to the addition funnel and slowly added to the reaction over 10-15 minutes and the solution was gently refluxed. After 1 h, 100 mL of EtOAc was added to the reaction and the oil bath was raised to a temperature of 95 ° C. The reflux condenser was replaced with a distillation head and 150-200 mL of solvent was distilled off from the reaction. 400 mL EtOAc and 120 mL H ₂ O were added and stirred at 50 ° C. for 5 minutes. Transfer to a separatory funnel and separate the aqueous phase. 60 mL H ₂ O was added and the aqueous phase was separated. EtOAc solution was analyzed to determine the yield of the title compound.

Alternatively, 1-bromopropane can be replaced with any alkyl halide and alkylated at 0 ° C to 100 ° C.

b) trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-propylthio) pyrimidin-4-yl] imidazole

To a solution of the product of (a) (58.3 g, 255.6 mmol) dissolved in 250 mL of EtOAc was added 213 mL (638 mmol) of 3N HCl, and the resulting solution was added at 55 ° C. until 55% of the starting material disappeared by HPLC. Heated for 3 hours. The solution was cooled to room temperature, diluted with 200 mL of EtOAc and brought to pH 6-7 with 132 mL of 50% NaOH solution. The solution was further neutralized by adding 20 g of solid NaHCO ₃ . The mixture was transferred to a separatory funnel and the bottom water layer was removed. The organic layer was transferred to a 1 L round bottom flask and concentrated to about 100 mL total volume under vacuum on a rotary evaporator. The residue was dissolved in 175 ml of acetonitrile and trans-4-aminocyclohexanol (25.02 g, 217 mmol) was added. The resulting solution was stirred at room temperature for about 20 minutes, at which point HPLC showed that all the aldehyde formed above was consumed. The solution was concentrated on a rotary evaporator to a total volume of about 130 mL and the residue was diluted with 205 mL DMF. Tosylisonitrile (48.0 g, 166.1 mmol) and K ₂ CO ₃ (26.5 g, 191.7 mmol) in Example 1 (b) was added and the resulting solution was stirred at 35 ° C. for 2.5 h, at which point HPLC Showed that immigration no longer exists. The solution was cooled to room temperature, diluted with 400 mL TBME and 250 mL H ₂ O and transferred to a separatory funnel. The mixture was shaken and left to remove the lower water layer. The aqueous layer was extracted twice with 300 ml TBME and the two TBME layers combined and washed with 200 ml H ₂ O. The organic layer was collected and concentrated to a total volume of about 300 ml. About 80 mL of hexane was added and the product crystallized from the solution over 3-4 hours. The product was filtered through a Buchner funnel and dried in a vacuum oven at 60 ° C. to give 44 g (64% yield) of the title compound.

c) trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole

The product of step (b) (10.8 g, 26.2 mmol) is dissolved in 43 mL of MeOH, oxone (trade name Oxone, 12.1 g, 19.6 mmol) is added and the resulting suspension is 4-24 h at RT. Stirred. After HPLC confirmed that no starting material remained, the suspension was filtered through a Buchner funnel to remove residual oxone salts. NaOMe / MeOH solution (25%, 16 mL) was added to the solution until about pH 12. After 20 minutes, the reaction was confirmed to be complete by HPLC, and 100 ml of water was added to the reaction. The resulting solution was stirred at room temperature for 3 hours, then filtered through a Buchner funnel and rinsed with 50 ml of water. The light white solid was dried in a vacuum oven at 60 ° C. for 18 hours to give 6.0 g (62% yield) of the title compound.

All publications, including but not limited to patents and patent applications cited herein, are hereby incorporated by reference as if each publication were specifically incorporated by reference as if specifically and individually disclosed.

The above description fully discloses the present invention, including the preferred embodiments. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to the widest extent. Accordingly, the embodiments herein are to be construed as merely illustrative and not in any way limiting the scope of the invention. Embodiments of the invention claiming exclusive features or privileges are defined below.

Claims (35)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Where R ₁ is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, each of which is C _1-4 alkoxy Or substituted with a C _1-4 alkylthio group, and also independently C _1-4 alkyl, halogen, hydroxyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR ₁₂ , amino, C _1-6 alkyl, one to-and-substituted amino, N (R ₁₀₎ C (O) Rc, or N- heterocyclyl ring (the ring is a 5 to 7 membered ring, optionally an oxygen, sulfur, Or an additional hetero atom selected from NR ₁₅ ); R ₄ is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which are optionally substituted by one or two substituents, each substituent being 4-phenyl, 4-naphth- For substituents of 1-yl, 5-naphth-2-yl or 6-naphth-2-yl, halogen, cyano, nitro, -C (Z) NR ₇ R ₁₇ , -C (Z) OR ₁₆ , -(CR ₁₀ R ₂₀ ) vCOR ₁₂ , -SR ₅ , -SOR ₅ , -OR ₁₂ , halo substituted C _1-4 alkyl, C _1-4 alkyl, -ZC (Z) R ₁₂ , -NR ₁₀ C ( Z) R ₁₆ , or-(CR ₁₀ R ₂₀ ) vNR ₁₀ R _{20 is} selected independently, and for substituents in other positions, halogen, cyano, -C (Z) NR ₁₃ R ₁₄ , -C (Z) OR ₃ ,-(CR ₁₀ R ₂₀ ) m "COR ₃ , -S (O) mR ₃ , -OR ₃ , halo substituted C _1-4 alkyl, -C _1-4 alkyl,-(CR ₁₀ R ₂₀ ) m "NR ₁₀ C (Z) R ₃ , -NR ₁₀ S (O) m'R _8, -NR ₁₀ S (O) m'NR ₇ R ₁₇ , -ZC (Z) R ₃ or-(CR ₁₀ R ₂₀ m ”NR ₁₃ R _{14 is} selected independently; v is 0 or an integer having a value of 1 or 2; m is 0 or an integer of 1 or 2; m 'is an integer having a value of 1 or 2; m "is 0 or an integer having a value of 1-5; Rc is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl-C _1-4 alkyl; R ₂ is optionally substituted C _3-7 cycloalkyl, or C _3-7 cycloalkyl-C _1-10 alkyl; R ₃ is heterocyclyl, heterocyclyl-C _1-10 alkyl or R ₈ ; R ₅ is hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or NR ₇ R ₁₇ , -SR ₅ is -SNR ₇ R ₁₇ , and -SOR ₅ is -SOH Is excluded; R ₇ and R ₁₇ are each independently selected from hydrogen or C _1-4 alkyl, or R ₇ and R ₁₇ together with the nitrogen to which they are attached form a 5-7 membered heterocyclic ring, which ring is optionally oxygen Further sulfur atoms selected from sulfur or NR ₁₅ ; R ₈ is C _1-10 alkyl, halo-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, -C _1-10 alkyl, heteroaryl, heteroaryl-C _1-10 alkyl, (CR ₁₀ R ₂₀ ) nOR ₁₁ , (CR ₁₀ R ₂₀ ) nS (O) mR ₁₈ , (CR ₁₀ R ₂₀ ) n NHS (O ) ₂ R ₁₈ , (CR ₁₀ R ₂₀ ) nNR ₁₃ R ₁₄ , wherein aryl, arylalkyl, heteroaryl, heteroarylalkyl may be optionally substituted; n is an integer having a value of 1 to 10; R ₉ is hydrogen, —C (Z) R ₁₁ or optionally substituted C _1-10 alkyl, S (O) ₂ R ₁₈ , optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl; R ₁₀ and R ₂₀ are each independently selected from hydrogen or C _1-4 alkyl; R ₁₁ is hydrogen or R ₁₈ ; R ₁₂ is hydrogen or R ₁₆ ; R ₁₃ and R ₁₄ are each independently selected from hydrogen or optionally substituted C _1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl, or together with the nitrogen to which they are attached Forms a heterocyclic ring, the ring optionally comprising an additional hetero atom selected from oxygen, sulfur or NR ₉ ; R ₁₅ is hydrogen, C _1-4 alkyl or C (Z) -C _1-4 alkyl; R ₁₆ is C _1-4 alkyl, halo-substituted C _1-4 alkyl, or C _3-7 cyclo alkyl; R ₁₈ is C _1-10 alkyl, C _3-7 cycloalkyl, heterocyclyl, aryl, aryl-C _1-10 alkyl, heterocyclyl, heterocyclyl-C _1-10 alkyl, heteroaryl or heteroarylalkyl Is; Z is oxygen or sulfur. The compound of claim 1, wherein R ₁ is substituted 4-pyridyl or 4-pyrimidinyl. 3. The compound of claim 2, wherein said substituent is C _1-4 alkoxy. The compound of claim 2, wherein R ₄ is optionally substituted phenyl. The compound of claim 4, wherein the phenyl is independently substituted one or more times with halogen, -SR ₅ , -S (O) R ₅ , -OR ₁₂ , halo-substituted C _1-4 alkyl or C _1-4 alkyl. . The compound of claim 1, wherein R ₂ is selected from optionally substituted C ₄ to C ₆ cycloalkyl. The compound of claim 1, wherein R ₂ is selected from optionally substituted C ₄ to C ₆ cycloalkyl-C _1-4 alkyl. The method according to claim 6 or 7, The cycloalkyl ring is halogen; Hydroxy; C _1-10 alkoxy; S (O) mC _1-10 alkyl, wherein m is 0, 1, or 2; Amino; Cyano, nitro; NR ₇ R ₁₇ group; C _1-10 alkyl; Substituted alkyl, wherein the substituent is selected from halogen, hydroxy, nitro, cyano, NR ₇ R ₁₇ , S (O) mC _1-4 alkyl, C (O) OR ₁₁ ; -O- (CH ₂ ) sO-, where s is 1 to 3; -C (O) H; = O; = N-OR ₁₁ ; -N (R ₁₀ ) -OH; -N (ORb) -C (O) -R ₆ ; Optionally substituted aryl; Or optionally substituted arylalkyl; N (R ₁₀ ) C (O) X ₁ ; C (O) OR ₁₁ ; Optionally substituted alkylene; Or may be independently substituted one to three times with optionally substituted C _1-10 alkynyl; Rb is hydrogen, a pharmaceutically acceptable cation, aroyl or a C _1-10 alkanoyl group; R ₆ is NR ₁₉ R ₂₁ ; Alkyl C _1-6 ; Halo substituted alkyl C _1-6 ; Hydroxy substituted alkyl C _1-6 ; Alkenyl C _2-6 ; Halogen, alkyl C _1-6 , aryl or heteroaryl optionally substituted with halo substituted alkyl C _1-6 , hydroxyl or alkoxy C _1-6 ; R ₁₉ is H or alkyl C _1-6 ; R ₂₁ is H; Alkyl C _1-6 ; Aryl; benzyl; Heteroaryl; Alkyl substituted with halogen or hydroxyl; Or phenyl substituted with a substituent selected from the group consisting of halo, cyano, alkyl C _1-12 , alkoxy C _1-6 , halo substituted alkyl C _1-6 , alkylthio, alkylsulfonyl or alkylsulfinyl; R ₁₉ and R ₂₁ together with the nitrogen to which they are attached form a 5 to 7 membered ring, the ring members may be optionally substituted by a hetero atom selected from oxygen, sulfur or nitrogen; X ₁ is C _1-4 alkyl, aryl or aryl-C _1-4 alkyl; N (R ₁₀ ) C (O) aryl. 9. The compound of claim 8, wherein the optional substituents are hydroxy, aryl, arylalkyl, alkyl, alkynyl, NR ₇ R ₁₇ , NR ₇ R ₁₇ C _1-6 alkyl, ═O, = NOR ₁₁ , —NH (OH ), -N (OH) -C (O) -NH ₂ , cyanoalkyl, nitroalkyl or -O- (CH ₂ ) ₂ O-. The method of claim 1, 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-5- [4- (2-methoxy) pyrimidinyl] -4- (4-fluorophenyl) -1- (4-hydroxycyclohexyl) -imidazole; Cis-5-[(2-methoxy) pyrimidin-4-yl] -4- (4-fluorophenyl) -1- (4-hydroxycyclohexyl) -imidazole; 5- [4- (2-methylthio) pyrimidinyl] -4- (4-fluorophenyl) -1- (4-oxocyclohexyl) imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylthio) pyrimidin-4-yl] imidazole; 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-hydroxy) pyrimidin-4-yl] imidazole; 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole; 1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole; Cis-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole, or a pharmaceutically acceptable salt thereof compound. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier or diluent. Cis-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Cis-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole, or pharmaceutical Acceptable salts thereof. Pharmaceutically acceptable carriers or diluents, and Cis-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Cis-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Compound or pharmaceutical which is trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole Pharmaceutical compositions containing salts thereof as is acceptable. A method for treating a cytokine mediated disease in a mammal comprising administering to said mammal an object in need of the treatment of a cytokine mediated disease according to any one of claims 1 to 13. 15. The method of claim 14 wherein the mammal is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, trauma arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joints Abnormal conditions, sepsis, sepsis shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, brain malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis (sarcososis), bone resorption disease, osteoporosis, restenosis, mental and reperfusion injury, thrombosis, glomerulonephritis, diabetes, host reaction to transplantation, tagase rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Have a cytokine-mediated disease selected from multiple sclerosis, myopathy, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis Way. 15. The method of claim 14, wherein said cytokine mediated disease state is asthma, osteoporosis or arthritis. A method of treating inflammation in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) according to claim 1. A method of treating osteoporosis in a mammal comprising administering to a mammal in need thereof an effective amount of the compound of formula (I) according to claim 1. A mammalian CSBP / RK / p38 kinase, comprising administering an effective amount of a compound of formula (I) according to any one of claims 1 to 13 to a mammal in need of treatment for a CSBP / RK / p38 kinase mediated disease. Method of treatment of mediated diseases. 20. The method of claim 19, wherein the mammal has psoriatic arthritis, Reiter syndrome, rheumatoid arthritis, gout, gouty arthritis, trauma arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joints Abnormal conditions, sepsis, sepsis shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, brain malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption Disease, osteoporosis, restenosis, mental and reperfusion injury, thrombosis, glomerulonephritis, diabetes, host reaction to transplantation, tagase rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact How to develop CSBP / RK / p38 kinase-mediated diseases of sexual dermatitis, psoriasis, sunburn and conjunctivitis. A compound of a compound of formula II formula III, and R a precursor of a formula after sufficient strong base and reacting the following compounds isopropyl deprotonate the nitrile residue of the II, if necessary R _1, R ₂ and R _{4 1,} A process for preparing a compound of formula (I) according to claim 1 which comprises converting to R ₂ and R ₄ groups. <Formula II> Where p is 0 or 2, R ₁ , R ₂ and R ₄ are as defined in claim 1 or are precursors of R ₁ , R ₂ and R ₄ groups, Ar is an optionally substituted phenyl group. The method of claim 21, wherein TBD is used as the base when p = 0 in the reaction. 22. The process of claim 21, wherein an amine, carbonate, hydride, or alkyl or aryl lithium reagent is used as the base when p = 2 in the reaction. The method of claim 21, wherein the imine of formula III is isolated before reacting with the compound of formula II. The method of claim 21, wherein the imine of Formula III is formed in situ prior to reacting with the compound of Formula II. The process of claim 25, wherein the aldehyde of Formula R ₄ CHO, wherein R ₄ is as defined for Formula I, is selected from the formula 1 of Formula R ₂ NH ₂ , wherein R ₂ is as defined for Formula I. Reacting with a secondary amine to form the imine in situ. 27. The method of claim 26, wherein imine is formed in situ using dehydration conditions. The method of claim 27, wherein the solvent is N, N-dimethyl-formamide (DMF), halogenated solvent, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohol, benzene or toluene, or DME. The aldehyde R ₁ CHO of claim 25, wherein the aldehyde R ₁ CHO for obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof is Wherein X is C _1-4 alkoxy or C _1-4 alkylthio and X ₁ is defined as any substituent on the R ₁ residue of formula I according to claim 1. The method of claim 25, wherein the primary amine R ₂ NH ₂ is C _3-7 cycloalkyl amine, C _3-7 cycloalkyl-C _1-10 alkylamine, all of which may be optionally substituted. 30. The compound of claim 29, wherein the R ₂ moiety is 4-hydroxycyclohexyl, 4-ketocyclohexyl, 4-oxyranylcyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-isopropyl-4-hydrate Hydroxy cyclohexyl, 4-pyrrolidinyl-cyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-phenyl-4-hydroxy cyclohexyl, 4-benzyl- 4-hydroxy cyclohexyl, 1-propenyl-4-hydroxy, 4-hydroxy-4-amino-cyclohexyl, 4-aminomethyl-4-hydroxy cyclohexyl or 4- (1,3-dioxy Cyclopentyl) cyclohexyl. The method of claim 21 wherein the compound is 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-5- [4- (2-methoxy) pyrimidinyl] -4- (4-fluorophenyl) -1- (4-hydroxycyclohexyl) -imidazole; Cis-5-[(2-methoxy) pyrimidin-4-yl] -4- (4-fluorophenyl) -1- (4-hydroxycyclohexyl) -imidazole; 5- [4- (2-methylthio) pyrimidinyl] -4- (4-fluorophenyl) -1- (4-oxocyclohexyl) imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methylthio) pyrimidin-4-yl] imidazole; 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-hydroxy) pyrimidin-4-yl] imidazole; 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole; 1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-isopropoxy) pyrimidin-4-yl] imidazole; Cis-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-ethoxy) pyrimidin-4-yl] imidazole, or a pharmaceutically acceptable salt thereof Way. 33. The method of claim 32, wherein said compound is Cis-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Cis-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole; Trans-1- (4-hydroxy-4-methylcyclohexyl) -4- (4-fluorophenyl) -5-[(2-methoxy) pyrimidin-4-yl] imidazole, or pharmaceutical Its salt is acceptable. A prostaglandin endoperoxide synthase in a mammal, comprising administering an effective amount of the compound of formula I according to claim 1 to a mammal in need of inhibition of the synthesis of prostaglandin endoperoxide synthase-2 (PGHS-2) 2 Method of inhibiting synthesis of (PGHS-2). 35. The method of claim 34, wherein the inhibition of PGHS-2 is used to prevent or treat treatment of edema, fever, hyperalgesia, neuromuscular pain, headache, cancer pain, or arthralgia.