BG63362B1 - New substituted imidazoles - Google Patents

Abstract

The invetnion relates to new 1,4,5-substituted imidazoles and compositions to be used as cytokin inhibitors. 24 claims

Description

The invention relates to a new group of imidazoles, to a method for their preparation and to their use for the treatment of cytokine mediator diseases, as well as for pharmaceutical compositions for use therein.

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are biological substances produced by various cells such as monocytes or macrophages. IL-1 is known to mediate various biological activities considered important in immunoregulation and other physiological conditions such as inflammation [see, e.g. Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The many known biological activities of IL-1 include activation of T helper cells, induction of inflammation, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute protein phase, and suppression of plasma iron levels.

There are many conditions in which excessive or unregulated production of IL-1 is involved in exacerbating and / or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock syndrome, other acute or chronic inflammatory conditions such as endotoxin-induced inflammatory response or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. New data link the effect of IL-1 on diabetes and pancreatic β-cells.

Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985) provides an overview of the biological activities inherent in IL-1. It should be noted that some of these effects have been described by other authors as indirect actions of IL-1.

Excessive or unregulated THF production is involved in the mediation or exacerbation of many diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammation, silicosis, pulmonary sarcoisosis, transfusion disease, transfusion disease, transfusion disease, allograft rejection, fever and myalgia due to infection such as influenza, cachexia due to infection or malignancy, cachexia due to acquired immune deficiency syndrome (C SO), HIV (AIDS), AIDS related complex (ARC), AIDS related complex (ARC), keloid formation tsikatriksizatsionna tissue disease, Crohn, ulcerative colitis or pyresis.

AIDS is the result of human immunodeficiency virus (HIV) infection of Tymphocytes.

At least three types of HIV strains have been identified,

ie HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, immunity with mediator T cells is impaired and infected individuals show severe opportunistic infections and / or unusual neoplasms. The entry of HIV into T lymphocytes requires activation of T lymphocytes. Other viruses such as HIV-1, HIV-2 infect T lymphocytes after T cell activation, and such viral protein expression and / or replication is mediated or maintained by T cell activation. Once activated T-lymphocyte is infected with HIV, the T-lymphocyte can continue to be maintained in an activated state to allow expression of the HIV gene and / or HIV replication.

Monokines, especially TNF, are involved in the expression of HIV protein and / or the replication of viruses with mediator-activated T cells, playing a role in maintaining the activation of T lymphocytes. Therefore, interference with the activity of monokines, for example by inhibiting the production of monokines, in particular TNF, in HIV-infected individuals helps to limit the maintenance of T-cell activation, thereby reducing the progression of HIV infection in uninfected cells, leading to a delay or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages and related cells, such as Kupffer and glial cells, are also involved in the maintenance of HIV infection. These cells, like T cells, are targets for virus replication and the level of viral replication depends on the activated state of the cells.

Monokines, such as TNF, have been shown to activate HIV replication in monocytes and / or macrophages [See Poli et al., Proc. Natl. Acad, Sci., 87: 782-784 (1990)], therefore, inhibiting the production of monokines or activity helps to limit the progression of HIV, as stated for T cells above.

TNF implements various functions with other viral infections such as cytomegaly virus (CMV), influenza virus and herpes virus for the same reasons as noted.

Interleukin-8 (11-8) is a chemotaxis factor identified and characterized for the first time in 1987. IL-8 is produced by several cell types, including mononuclear cells, fibroblasts, endothelial cells and keratinocytes.

Its production by endothelial cells is induced by IL-1, TNF or lipopolysaccharide (LPS). Human IL-8- has been found to act on the neutrophils of mouse, guinea pig, rat and rabbit. Many different names are given to IL-8, such as neutrophil attracting protein (NAP-1), derived from monocyte neutrophil chemotaxis factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotaxis factor.

IL-8 stimulates many functions in vitro. It has been shown to have chemoattractive properties for neutrophils, T-lymphocytes and basophils. In addition, it induces the release of histamine from basophils by normal and atopic individuals, as well as the release of lysosomal enzyme and respiratory impulse from neutrophils. IL-8 is known to increase the expression surface of Mas-1 (CDIb / CD18) on neutrophils without new protein synthesis, which may promote adhesion of eutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration.

Conditions associated with increased production of IL-8 (which is responsible for the chemotaxis of neutrophil cells at the site of inflammation) can be ameliorated by compounds that suppress IL-8 production.

IL-1 and TNF refer to different cells and tissues, and these cytokines, as well as others derived from leukocyte cytokines, are important and critical mediators of inflammation in a wide variety of diseases and conditions. Inhibition of these cytokines is useful in controlling, reducing, and alleviating many of the disease states.

In this area there is always a need for treatment and for compounds that are anti-cytokine anti-inflammatory drugs, i. compounds that are capable of inhibiting cytokines such as IL-1, IL-6, IL-8 and TNF.

SUMMARY OF THE INVENTION

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

The invention also relates to a method of treating mammalian diseases with a CSBP / RK / p38 kinase mediator, which comprises administering to the mammal in need an effective amount of a compound of formula (I).

The invention relates to a method for inhibiting cytokines and treating mammalian diseases with a cytokine mediator, which comprises administering to the mammals in need of treatment an effective amount of a compound of formula (I).

The invention particularly relates to a method of inhibiting the production of IL-1 in a mammal in need of treatment, which comprises administering to these mammals an effective amount of a compound of formula (I).

The invention particularly relates to a method of inhibiting the production of IL-8 in a mammal in need of treatment, which comprises administering to these mammals an effective amount of a compound of formula (I).

The present invention relates in particular to a method of inhibiting the production of TNF in mammals in need, which consists in administering to these mammals an effective amount of a compound of formula (I). 5

The present invention accordingly relates to compounds of formula (I)

wherein

R 1 represents a 4-pyridyl ring substituted with C ₁₄ alkoxy and optionally optionally substituted with C ₁₄ alkyl, halogen, hydroxy, C ₁₄ alkoxy, C ₁₄ alkylthio, C ₁₄ alkylsulfinyl, CH ₂ OR ₁₂ , amino , mono and di-C ₁₆ alkyl substituted amino, N (R ₁₀ ) C (O) R _c or N-xe-20 ring having a ring having from 5 to 7 atoms and optionally containing an additional heteroatom - oxygen, sulfur or NR _tJ ;

R ₄ stands for phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally 25 substituted by one or two substituents, each of which is independently selected and which is a substituent on 4-phenyl, 4-naphth-1 -yl, 5-naphth-2-yl or 6 naphth-2-yl is halogen, cyano, nitro, C (Z) NR ₇ R ₁₇ , C (Z) OR ₁₆ , (CR ₁₀ R ₂₀ ), COR ₁₂ , SR , sor ,, or ₁₂ , ₃₀ substituted with halogen C ₁ . ₄ alkyl, C _1-4 alkyl, ZC (Z) R ₁₂ , NR ₁₀ C (Z) R ₁₆ or (CR _ie R ₂₀ ) _r NR ₁₀ R ₂ , and which substituent on the other substitution is halogen, cyano, C (Z) NR ₁₃ R _14, C (Z) OR _3, (CR ₁₀ R _{20) b} "COR _3, S (O) _b R _3, OR, substituted c halo C _{| 4} alkyl, C _1h alkyl, ( CR ₁₀ R ₂₀ ) _b . NR ₁₀ (Z) R ₃ , NR _ie S (O) _B , R 'NR ₁₀ S (O) _b , NR ₇ R ₁ ' ZC (Z) R ₃ or (CR 10 Rjj) _b . NR ₁₃ R ₁₄ ;

n is 1 to 10;

m is 0, 1 or 2;

m 'is 1 or 2 m' is 0 or 1 to 5;

ν is 0 or 1 or 2;

R ₂ is an optionally substituted heterocycle or optionally substituted heterotsikli- 45 chen _C1-10 alkyl radical;

Z is oxygen or sulfur;

R _c is hydrogen, C ₁ . ₆ alkyl, C ₃ . ₇ cycloalkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroaryl C ₁₄ alkyl, heterocycle or heterocyclic C _1-4 alkyl;

R ₃ is heterocyclyl, heterocyclyl C _{1 | 0} allyl or R ,;

R ₃ is hydrogen, C ₁₄ alkyl, C ₂₄ alkenyl, C ₂ . ₄ alkynyl or NR ₇ R ₁₇ , except when SR ₃ is SNR ₇ R ₁₇ and SOR ₃ is SOH;

R 1 and R ₁₇ are independently hydrogen or C ₁₄ alkyl or R 1 and R ₁₇ together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 atoms, which ring optionally contains additional heteroatom oxygen, sulfur or NR ₁₃ ;

R, is C _1-10 alkyl, halosubstituted C ,. ₁₀ alkyl, C 1-3. _1o alkenyl, C _{2. 10} alkynyl, C ₃ . ₇ cycloalkyl, C ₅ _. cycloalkenyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C ₁₁₀ alkyl, (CR ₁₀ R ₂₀ ) OR _H ), (CR ₁₀ R ₂₀ ) _n S (O) _B R _lg , (CR ₁₀ R _M ) NHS (O) ₂ R 1, (CR 1 NR 6A, such as aryl, arylalkyl, heteroaryl, heteroarylalkyl may optionally be substituted;

R 1 is hydrogen, C (Z) R _U or optionally substituted C ₁₁₀ alkyl, S (O) ₂ R ₁₃ optionally substituted aryl or optionally substituted aryl C _1-4 alkyl;

R _I0 and R ₂₀ are each independently hydrogen or

C, _ ₄ alkyl;

R _n is hydrogen, _b10 alkyl, C _{3. 7} cycloalkyl, heterocyclyl, heterocyclyl _C1-10 alkyl, aryl, aryl C _{1 | 0} alkyl, heteroaryl or heteroaryl C _1-10 alkyl;

R ₁₂ is hydrogen or R ₁₆ ;

R ₁₃ and R _I4 are all independently hydrogen or optionally substituted C, _ ₄ alkyl, optionally substituted aryl, or optionally substituted aryl C _1-4 alkyl, or together with the nitrogen atom to which they are attached, form a heterocyclic ring of 5 to 7 atoms, which ring optionally contains an additional heteroatom - oxygen, sulfur or NR3;

R ₁₃ is R ₁₀ or C (Z) -C ₁₄ alkyl;

R ₁₆ is C ₁₄ alkyl substituted with halogen C _1-4 alkyl or C ₃ . _; cycloalkyl;

R _1g is C ₁ . ₁₀ alkyl, C ₃ . ₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl C] _-C10 alkyl, heteroaryl or heteroaryl _C1-10 alkyl;

or pharmaceutically acceptable salts thereof.

The novel compounds of formula I, except in humans, may also be used in the treatment of mammals; that need to inhibit cytokine inhibition or production. In particular, diseases with a cytokine mediator that will be treated therapeutically or prophylactically in animals include disease states such as those noted here in the Methods of treatment section, especially for viral infections.

Examples of such viruses include, but are not limited to, lentiviral infections such as equine infectious anemia virus, goat arthritis virus, visna virus, or maedi virus, or retroviral infections such as, but not limited to, cats immunodeficiency (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.

In formula IR ₍ (4-pyridyl ring) is substituted at least once with a C ₁₄ alkoxy group.

Preferred is _{C] 4} alkoxy group such as n-butyl, isopropoxy, ethoxy or methoxy. The preferred site of the substituent in the 4-pyridyl ring R is the 2-position as 2-methoxy-4-pyridyl.

Suitable other substituents for the R, heteroaryl ring are C ₁₄ alkyl, halogen, OH, C ₁₄ alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR ₁₂ , amino, mono- and di-C ₁₆ alkyl substituted amino, N ( R ₁₀ ) a C (O) R _c or N-heterocyclyl ring having a ring having 5 to 7 atoms and optionally containing an additional heteroatom - oxygen, sulfur or NR ₁₃ . The alkyl group in the mono- and _di-1b alkylsubstituted moiety may be halo such as trifluoro, e.g. trifluoromethyl or trifluoroethyl.

Where, in one case, the substituent of R ₁ is N (R ₁₀ ) C (O) R _c , where R _c is hydrogen, C ₁₆ alkyl, C ₃₇ cycloalkyl, aryl, aryl C _{| 4} alkyl, heteroaryl C _1-4 alkyl, heterocyclyl or heterocyclyl C _b4 alkyl C ₁₄ alkyl, R _c is preferably C ₁₆ alkyl; R ₁₀ is preferably hydrogen.

It should be appreciated that R _c , in particular a C ₁₆ alkyl group may optionally be substituted, preferably from one to three times, preferably by halogen such as fluorine such as trifluoromethyl or trifluoroethyl.

Suitably, R ₄ is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one or two substituents.

Preferably, when R ₄ is a phenyl or naphthyl ring. Suitable substituents for R ₄ when 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl are one or two substituents, each of which is independently halogen , -SR _3, -SORj, -OR _12, CF ₃ or- (CR _i "R _{20) v} NR ₁₀ R _20, and for other positions of substitution on these rings preferred substitution is halogen, -S (O) _m R ₃ , -OR ₃ , CF ₃ , - (CR ₁₀ R ₂₀ ) _m . NR ₁₃ R _{| 4} , -NR _IO C (Z) R ₃ and-NR _lo S (O) _m , R _s .

Preferred substituents for the 4th position in the phenyl and naphth-1-yl ring and the 5th place in the naphth-2-yl ring are halogen, in particular fluorine and chlorine and -SR ₃ and -SOR ₃ , where R ₃ is preferably _{C) 2} alkyl, more preferably methyl, of which fluorine and chlorine are more preferred, and especially preferred is fluoro. Preferred substituents for the 3rd position in the phenyl and naphthyl-1-yl rings are halogen, in particular fluorine or chlorine, -O R ₃ , in particular C _{1j (} alkoxy; CF ₃ , NR ₁₀ R _M as amino; -NR ₁₀ C (Z) R ₃ , in particular - NHCO (C ₁₁₀ alkyl); -NR ₁₀ S (O) _m , R ₈ , in particular -NHSO ₂ (C _1-10 alkyl) and -SR ₃ and -SOR, where R ₃ is preferably a C, _ ₁₂ alkyl, improvements methyl. When the phenyl ring is disubstituted preferably it is two independent halogen moieties, such as fluoro and chloro, preferably di-chloro and improvements of 3,4myasto. Preferred for 3rd site are also two -0R ₃ and -ZC (Z) R ₃ substituents, a R ₃ may e also be hydrogen.

Preferably R ₄ is an unsubstituted or substituted phenyl radical. More preferably, R ₄ is phenyl or phenyl substituted in the 4th place with fluorine and / or substituted in the 3rd place with fluorine, chlorine, C ₁₄ alkoxy, methanesulfonamido or acetamido or R ₄ is phenyl disubstituted in 3,4- place it independently with chlorine or fluorine, better chlorine. It is particularly preferred that R ₄ be 4-fluorophenyl.

In formula I, Z is oxygen or sulfur, preferably oxygen.

It is recommended that R ₂ is an optionally substituted heterocycle or heterocyclic Cj ₁₀ alkyl radical.

When R ₂ is optionally substituted heterocycle, the ring is preferably in the group of morpholino, pyrrolidinyl or piperidinyl. When the ring is optionally substituted, the substituent may be directly attached to the free nitrogen, either in the piperidinyl group or in the pyrrole ring or in the ring itself. Preferably, the ring is piperidine or pyrrole, more preferably piperidine. The heterocyclic ring may optionally be substituted one or four times independently by halogen; C ₁₄ alkyl, aryl such as phenyl; arylalkyl such as benzyl, where the aryl or arylalkyl radical itself may be optionally substituted (as defined below); C (O) OR _H as C (O) C ₁₄ alkyl or C (O) OH groups; C (O) H C (O) C ₁₄ alkyl, hydroxy substituted C _1-4 alkyl, C ₁₄ alkoxy, S (O) m C ₁₄ alkyl where m is 0,1 or 2), NR ₁₀ R ₂₀ (where R ₁₀ and R _M are independently hydrogen or C ₍₄ alkyl).

Preferably, if the ring is piperidine, it is attached to the imidazole in the 4th position and the substituents are directly attached to the nitrogen atom, for example 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4- piperidine, ethoxycarbonyl-4-piperidine. If the ring is substituted with an alkyl group and the ring is attached in the 4th position, it is preferable that the substituent be in the 2nd or 6th position or both, such as 2,2,6,6-tetramethyl-4-piperidine . Similarly, if the ring is pyrrole, it is attached to the imidazole in the 3rd position and all substituents are directly bonded to the nitrogen atom.

When R ₂ is optionally substituted heterocyclic C 1-3. ₀ alkyl group, the ring is preferably morpholine, pyrrolidinyl or piperidinyl. Preferably, the alkyl group has 1 to 4 carbon atoms, more preferably 3 or 4 and most preferably 3, as in the propyl group. Preferably, heterocycloalkyl groups include, but are not limited to, morpholinoethyl, morpholinopropyl, pyrrolidinylpropyl and piperidinylpropyl. The heterocycle ring herein is also optionally substituted in a similar manner to that indicated above for the direct binding of the heterocycle.

In all cases, where there is an alkenyl or alkynyl radical as a substituent, the unsaturated bond, for example the vinylene or acetylene bond, is preferably not directly bonded to nitrogen, oxygen or sulfur, for example in 0R ₃ or in some R ₂ residues.

As used herein, "optionally substituted", unless otherwise indicated, means that halogen groups such as fluorine, chlorine, bromine or iodine; hydroxy substituted _C1-10 alkyl; С ,. ₁₀ alkoxy such as methoxy or ethoxy; S (O) _B alkyl, wherein n is 0,1 or 2 such as methylthio, methylsulfinyl or methylsulfonyl; amino, mono & disubstituted amino, such as NR, R _l7 group; or wherein R ₇ R ₁₇ may, together with the nitrogen to which they are attached, cyclize to form a 5 to 7 atomic ring which optionally includes an additional heteroatom selected from O / N / S; With a ₁₁₀ alkyl, cycloalkyl or cycloalkylalkyl group such as methyl, ethyl, propyl, isopropyl, tert-butyl, etc. or cyclopropylmethyl; halogen substituted C ₁₁₀ alkyl such as CF ₂ CF ₂ H or CF ₃ ; halogen substituted _C10-10 alkoxy such as OCF ₂ CF ₂ H; optionally substituted aryl such as phenyl or optionally substituted arylalkyl such as benzyl or phenethyl, where the aryl substituent may also be substituted one or two times by halogen; hydroxy; hydroxy substituted alkyl; C _10-10 alkoxy; S (O) m alkyl; an amino, mono- or disubstituted amino such as the NR ₇ R ₁₇ group; alkyl, or CF _3.

In a preferred embodiment of the compound of formula I, R 1 is 2-alkoxy-4-pyridyl; R ₂ is morpholinylpropyl, piperidinyl, N-benzyl-4-piperidinyl or N-methyl-D-piperidinyl and R ₄ is phenyl or mono- or disubstituted phenyl with fluorine, chlorine, C _{| 4} alkoxy, -S (O) _m alkyl, methanesulfonamido or acetamido.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include alkali salts of inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, acetic, malic, tartaric, citric, lactic, oxalic, succinic, succinic, succinic maleic, benzoic, salicylic, phenylacetic and almond acids. In addition, pharmaceutically acceptable salts of compounds of formula I may also be formed with a pharmaceutically acceptable cation, for example, if the substituent group contains a carboxy moiety. Suitable pharmaceutically acceptable cations are well known in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to:

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

- "C _11alkyl " or "alkyl", both straight or branched chain radicals having 1 to carbon atoms, unless the chain length is otherwise limited, include, but are not limited to, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and the like.

- The term "cycloalkyl" is used herein to refer to cyclic radicals, preferably with 3 to 8 carbon atoms, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.

- The term "cycloalkenyl" is used herein to refer to cyclic radicals, preferably with 5 to 8 carbon atoms having at least one bond, including, but not limited to, cyclopentyl, cyclohexyl and the like.

- The term "alkenyl" used herein in all cases means a straight or branched chain 2-10 carbon atom, unless the chain length is broken includes, but not limited to, ethenyl, 1-propenyl, 2- propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

- "aryl" means phenyl or naphthyl.

- "heteroaryl" (as such or in combination as "heteroaryloxy" or "heteroarylalkyl") means an aromatic ring system of 5-10 atoms in which one or more rings contain one or more heteroatoms selected from N, O or S as, but not only pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole or benzimidazole.

- "heterocyclic" moiety (as such or in combination as "heterocyclylalkyl) means a saturated or partially unsaturated 4-10 atomic ring system in which one or more rings contain one or more heteroatoms - N, O, or S as, but not limited to them, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine.

- The designation "aralkyl" or "heteroarylalkyl" or heterocycloalkyl, "as used herein refers to C _1h alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety as also defined herein unless otherwise stated:

- "sulfinyl" refers to the S (0) of the corresponding sulfide, the term "thio" refers to the sulfide and the term "sulfonyl" refers to the fully oxidized S (O) ₂ residue.

- "aroyl" refers to C (O) Ar, where

Ar means phenyl, naphthyl or arylalkyl as defined above, including but not limited to benzyl and phenethyl.

- "alkanoyl" refers to C (O) C ₁₁₀ alkyl, where alkyl is defined above.

The compounds of the invention may contain one or two asymmetric carbon atoms and may exist in racemic or optically active forms. All of these compounds are within the scope of the invention.

Examples of compounds of formula I are:

5- (2-methoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole

5- (2-Isopropoxy-4-pyridinyl) -4- (4fluorophenyl) -1- (4-piperidinyl) imidazole.

A preferred group of compounds of formula I have the following structure:

wherein R, is pyridyl substituted with _b4 alkoxy, and optionally further substituted one or more times independently by _b4 alkyl, halogen, hydroxy, _b4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR _12, amino, mono or di C _1-4 alkyl substituted _{amino, N (R l0) C (} O) R c or an N-heterocyclyl ring having 5 to 7 ring atoms and optionally containing a further heteroatom - oxygen, sulfur or NR _I5;

R ₂ is optionally substituted heterocyclyl or optionally substituted heterocyclyl C. ₁₀ alkyl residue;

R ₄ is phenyl which is optionally substituted by halogen;

R ₁₀ is independently selected from hydrogen or C ₁₄ alkyl;

R _c is hydrogen, C ₁₆ alkyl, C ₃ _, cycloalkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C, ₄ alkyl, heterocyclyl or heterocyclyl C _{| 4} alkyl C _1-4 alkyl, all of which may be optionally substituted;

R ₁₂ is hydrogen or R ₁₆ ;

R ₁₆ is C ₁₄ alkyl, C _1-4 alkyl substituted with halogen or C _3-7 cycloalkyl;

R ₁₃ is hydrogen, C ₁₄ alkyl or C (Z) -C ₍ C _1-4 alkyl;

Z is oxygen or sulfur or their pharmaceutically acceptable salts.

Preferably R ₂ is piperidine, 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine, 2,2,6,6-tetramethyl-4 -piperidine, morpholinoethyl, morpholinopropyl, pyrrolidinylpropyl or piperidinylpropyl.

The compounds of formula I can be prepared using syntheses, some of which are illustrated in the following schemes applicable to the preparation of compounds of formula I, with different R 1, R ₂ and R ₄ substituent groups which are reacted using optionally substituents that are suitably protected to be compatible with the reaction described below. Subsequent removal of the protecting group, in these cases, provides compounds with generally described properties. Once the imidazole nucleus is formed, other compounds of formula I can be prepared using standard functional group conversion techniques well known to those skilled in the art.

For example, -C (O) NR ₁₃ R ₁₄ can be obtained from CO ₂ CH ₃ by heating, in the presence or absence of a catalyst, of metallic cyanide, e.g. NaCN and HNR ₁₃ R ₁₄ in CH ₃ OH; -OC (O) R ₃ is obtained from -OH e.g. CIC (O) R ₃ in pyridine; -NR ₁₀ -C (S) NR ₁₃ R ₁₄ is prepared from -NHR ₁₀ with alkylisocyanate or thiocyanic acid; NR _i C (O) OR ₆ was prepared from -NHR ₆ with the alkyl chloroformate; -NR ₁₀ C (O) NR ₁₃ R ₁₄ is obtained from -NHR ₁₀ by reaction with isocyanate, for example HN-C-O or R ₁₀ NCO; -NR ₁₀ -C (O) R _g is obtained from -NHR ₁₀ by reaction with C 1 -C (O) R ₃ in pyridine; C (= NR ₁₀ ) NR ₁₃ R ₁₄ is obtained from -C (NR ₁₃ R ₁₄ ) SR ₃ with H ₃ NR ₃ ⁺ OA _c - by heating in alcohol; C (NR ₁₃ R ₁₄₎ SR ₃ was prepared from - C (S) NR _I3 R ₁₄ with R ₆ -I in an inert solvent, e. acetone; C (S) NR _I3 R ₁₄ (wherein R _l3 or R ₁₄ is not hydrogen) from -C (S) NH ₂ with HNR ₁₃ R _14; -C (NCN) -NR ₁₃ R ₁₄ is obtained from -C (= NR ₁₃ R ₁₄ ) -SR ₃ with NH ₂ CN by heating in anhydrous alcohol, alternatively from -C (= NH) NR ₁₃ R ₁₄ by reaction with BrCN and NaOEt in EtOH; -NR ₁₀ -C (“NCN) SR, if it receives from NHR _{10 an} interaction with (R _g S) ₂ C = NCN; NR ₁₀ SO ₂ R ₃ is obtained from -NHR ₁₀ by reaction with -NR ₁₀ C (O) R, by reaction with a Lawesson reagent [2,4-bis- (4methoxyphenyl) -1,3,2,4-dithiadiphosphetane -2,4 disulfide];

-NR ₁₀ SO ₂ CF ₃ is prepared from NHR ₆ with triflicanhydride and a base, where R ₃ , R ₆ , R ₁₀ , R ₁₃ and R ₁₄ are defined in formula I herein.

The precursors of the groups R 1, R 2 and R ₄ may be other groups R _p R ₂ and R ₄ , which can be transformed using standard functional group conversion techniques. For example, a compound of formula I wherein R ₂ is substituted with halogen C ₁₁₀ alkyl may be converted to the corresponding ϋ ,,, θ alkyl Ν ₃ derivative by reaction with a suitable azidosol and then optionally reduced to the corresponding C _b10 alkyl ΝΗ ₂ compound which can be reacted with R _lg S (O) ₂ X wherein X is halogen (eg. chlorine), to yield the corresponding C ,. ₁₀₀ alkyl NHS (O) ₂ R _t , compound.

Alternatively, a compound of formula I, wherein R ₂ halosubstituted C _{| -C10} alkyl can be reacted with an amine R _{| 3} R _{| 4} NH, to yield the corresponding C _1-10 alkyl NR _l3 R ₁₄ or can be reacted with an alkali metal salt of R | _g SH to give the corresponding C _6-10 alkyl SR 1 compound.

SCHEME I

R4CHO (V) +

ArS (O) pH

R4CH2NH2 (Vlll)

H 2 NCHO 'X ^ formylate agent

R ₄ CH ₂ NHCHO

a median (IV) dahydmtirair agent

R ₄ CH ₂ NC (VI)

ArS (O) ₂ U (VH)

According to Scheme I, the compounds of formula I are prepared by reacting a compound of formula II with a compound of formula III, wherein p is 0 or 2, R _p R ₂ and R ₄ are as defined above in formula I or are the precursors of the groups R _p R ₂ and R ₄ and Ar is optionally substituted phenyl group and then, if necessary, converting the precursors R _P R ₂ and R ₄ into the groups R _p R ₂ and R ₄ .

It is recommended that the reaction be carried out at room temperature or under cooling (eg -50 ° C to 10 ° C) or heated in an inert solvent such as methylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile or dimethoxyethane in the presence of a suitable base such as 1, 8-diazabicyclo [5.4.0] undec7-ene (DBU) or guanidine base such as 1,5,7-triaza-bicyclo [4.4.0] dec-5-ene (TBD).

The intermediates of formula II have been found to be very stable and can be stored for a long time. Preferably p is 2. PTC is defined as a 35 phase transfer catalyst.

The compounds of formula II have a structure

ArS (O) _p

wherein p is 0 or 2; R ₄ is as defined in 45 of Formula I and Ar is optionally substituted aryl as defined herein.

It is recommended that Ar be phenyl, optionally substituted by C ₁₄ alkyl, C ₁₄ alkoxy or halogen. Preferably Ar is phenyl or 5® 4-methylphenyl, e.g. tosyl derivative.

The interaction of a compound of formula II, wherein p = 2 with a compound of formula III in Scheme I, yields substantially higher yields of a compound of formula I than when p = 0. The interaction of the compounds of formula II, where p = 2, is more acceptable in terms of environmental pollution and economically.When p = 0, the preferred solvent used is methylene chloride, which is not acceptable in terms of environmental pollution. for many processes, and the preferred base, TBD, is also costly and produces by-products and impurities with respect to the synthesis used (p = 2) as described herein.

As noted, in Scheme I, 1,3-dipolar cyclodealdehyde anion of substituted thiomethylisocyanide (when p = 0) to imine is used. In particular, this interaction requires a strong base, such as an amino base, for the deprotonation step. Commercially available TBD is preferred, although tert-butoxide, Li ⁺ or Na ⁺ , or K ⁺ hexamethyldisilazide may also be used. Although methylene chloride is the preferred solvent, other halogenated solvents such as chloroform or carbon tetrachloride may be used; ethers such as THF, DME, DMF, diethyl ether, tert-butyl methyl ether; as well as acetonitrile, toluene or mixtures thereof. The reaction may be carried out at about -20 ° C to about 40 ° C, preferably at about 0 ° C to about 23 ° C, more preferably at about 0 ° C to about 10 ° C. In some cases, it may be necessary to vary the reaction conditions, temperature and solvent, more precisely lowering the temperature to -50 < 0 > C or changing the solvent with THF.

In another embodiment, compounds of formula I may be prepared by coupling a suitable derivative of a compound of formula IX

in which T ₍ is hydrogen and T ₄ is R _t or alternatively, T | is R, is T ₄ is hydrogen, where R _{p is} R ₂ , and R ₄ is defined above as follows:

(i) when T, is hydrogen, a suitable derivative of the heteroaryl ring R, H, under ring formation conditions, by coupling the heteroaryl ring R1 to the imidazole nucleus at the 5 position; and (ii) when T ₄ is hydrogen, a suitable derivative of the aryl ring R ₄ H, under conditions of ring bonding, the bonding of the aryl ring R 4 to the imidazole nucleus at the 4 position is carried out.

Such aryl / heteroaryl coupling reactions are well known in the art. In general, the organometallic synthetic equivalent of the anion of one component is coupled to a reactive derivative of the other component in the presence of a suitable catalyst. The anionic equivalent may be formed either from the imidazole of formula IX, in which case the aryl / heteroaryl compound provides the reactive derivative, or from the aryl / heteroaryl compound, in which case imidazole provides the reactive derivative. Accordingly, suitable derivatives of the compound are Formula IX, or of the aryl / heteroaryl ring are organometallic derivatives such as organomagnesium, organotin zinc, organotin, and boric acid derivatives, and the appropriate reactive derivatives are bromine, iodine, trifluorosulfonate and trifluoromethanesulfonate. Suitable procedures are described in WO 91 / 19497A.

Suitable organomagnesium and organotin zinc derivatives of Formula IX may be reacted with a halogen, fluorosulfonate or triflate derivative of the heteroaryl or aryl ring in the presence of a ring coupling catalyst such as palladium 0 or palladium II catalyst, following the procedure of Kumada et al. Tetrahedron Letters, 22, 5319 (1981). Such suitable catalysts are tetrakis- (trienylphosphine) -palladium and PdCl ₂ [1,4-bis (diphenylphosphino) -butane], optionally in the presence of lithium chloride and a base such as triethylamine. A nickel II catalyst such as Ni II Cl ₂ (1,2-biphenylphosphino) ethane may also be used to bond the aryl ring following the procedure of Pridgen et al., J. Org.Chem., 1982, 47, 4319. A suitable reaction solvent is hexamethylphosphoramide. Suitable derivatives are 4-bromo and 4-iodopyridine and 4-hydroxypyridine fluorosulfonate and triflate esters. Suitable derivatives, when the aryl ring is phenyl, are bromine, trifluorosulfonate, triflate, and preferably iodine derivatives. Organomagnesium and organotin zinc derivatives can be obtained by reacting a compound of formula IX or a bromine derivative with an alkyl lithium compound to give the corresponding lithium compound by deprotonation or transmutation, respectively. This lithium intermediate may then be reacted with excess magnesium halide or zinc halide to give the corresponding organometallic reagent.

A trialkyl tin derivative of a compound of formula IX may be reacted with bromine, trifluorosulfonate, triflate or, preferably, an aryl or heteroaryl ring derivative compound, in an inert solvent such as tetrahydrofuran, preferably containing 10% hexamethasilate with palladium 0 catalyst, for example tetrakis- (triphenylphosphine) palladium, by the method described by Stille, J.Amer.Chem Soc., 1987, 109, 5478, US 4 719 218 and 5 002 942, or using a palladium II catalyst in presence of lit. hydrochloride, optionally by addition of a base such as triethylamine, in an inert solvent such as dimethylformamide. The trialkyl tin derivative can be obtained in the usual way by metallizing the corresponding compound of formula IX with a lithium agent such as sec-butyllithium or norm-butyllithium in an ether solvent such as tetrahydrofuran, or reacting the bromine derivative of the corresponding compound of formula IX with alkylithium, and then , in each case, reaction with a trialkyl tin halide. Alternatively, the bromine derivative of a compound of formula IX may be reacted with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetrakis (triphenylphosphine) -palladium under conditions similar to those described above.

Boric acid derivatives can also be used. Hence, the appropriate derivative of the compound of formula IX as a bromine, iodine, triflate or fluorosulfonate derivative can be reacted with heteroaryl or arylboronic acid in the presence of a palladium catalyst such as tetrakis- (triphenylphosphine (palladium or P (1Cl ₂ [1,4 -bis- (di-phenylphosphino) -butane] In the presence of a base such as sodium bicarbonate, under reflux conditions, in a solvent such as dimethoxyethane (see Fischer 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). a, for example a solvent such as DMF, at a temperature of about 100 ° C, in the presence of a Pd II catalyst (see Thompson WJet al., J. Org. Chem., 49, 5237, 1984). is obtained by reacting a magnesium or lithium derivative with a trialkylborate ester such as triethyl-, triisopropyl- or tributylborate, by a standard procedure.

In such coupling reactions it can easily be appreciated that the functional groups present in the compounds of formula IX should be considered. Amino substituents and sulfur substitutes must not be oxidized or protected.

The compounds of formula IX are imidazoles and can be prepared by any of the schemes described hereinabove for the preparation of compounds of formula I. In particular, α-halogenketone or other suitably activated ketones R ₄ COCH ₂ Hal (and compounds with formula IX in which T is hydrogen) or R ^ OCHjHal (for compounds of formula IX in which T ₄ is hydrogen) can be reacted with an amidine of formula R ₂ NH-C = NH, where R ₂ is defined in Formula I, or a salt thereof, in an inert solvent such as a halogenated hydrocarbon solvent, e.g. chloroform, at a moderate increase in temperature minutes and, if necessary, in the presence of a suitable condensing agent such as a base. The preparation of suitable α-halogen ketones is described in WO91 / 19497A. Suitable reactive esters are esters of strong organic acids such as lower alkanesulfonic or arylsulfonic acid, e.g. methane or p-toluenesulfonic acid. Amidine is preferably used as a suitable hydrochloride salt, which can then be converted to free amidine in situ, using a two-phase system in which the reactive ester is in an inert limited solvent such as chloroform and the salt is in the aqueous phase to which an aqueous solution of the base is slowly added in a dimolar amount with vigorous stirring. Suitable amidines can be prepared by standard methods, see, for example, Garigipati R., Tetrahedron Letters, 190, 31, 1989. 5

Compounds of formula I can be prepared by a method which consists in reacting a compound of formula IX in which T is hydrogen, with an N-acylheteroaryl salt according to the method described in US 4 803 279, US 4 719 218 and US 5 002 942 to give an intermediate in which the heteroaryl ring is attached to the imidazole nucleus and is present as its 1,4-dihydro derivative, which intermediate may then be subjected to oxidative deacylation conditions (Scheme II).

The heteroaryl salt, for example the pyridinium salt, may be either pre-prepared or preferably obtained in situ by the addition of a suitable carbonyl halide (such as acyl halide, aroyl halide, arylalkyl halogenformate ester, or, preferably, alkylhalogenoformatenebenzoateformatene benzeneformatene benzeneformatene benzeneformatenebenzoateformate) or preferably ethyl chloroformate) to a solution of a compound of formula IX of the heteroaryl compound R1 or in an inert solvent such as methylene chloride to which heteroaryl is added compound. Suitable deacylating and oxidizing conditions are described in US 4 803 279 A _p 4 719 218 A, and 5002 942A _D Suitable oxidizing systems include sulfur in an inert solvent or solvent mixture such as decalin, decalin and diglyme, p-cement, xylene or mesitylene, under reflux conditions, or preferably potassium tert-butoxide in tert-butanol in dry air or oxygen.

SCHEME II

In another embodiment of the process illustrated in Scheme III below, compounds of formula I may be prepared by reacting a compound of formula X upon heating or by the addition of a cyclizing agent such as phosphorus oxychloride or phosphorus pentachloride (see Engel and Steglich, Liebids Ann. Chem., 1978, 1916 and Strzybny et al., J. Org. Chem., 1963, 28, 3381). The compounds of formula X can be prepared, for example, by acylation of the corresponding α-ketoamine with an activated formate derivative such as the corresponding anhydride, under standard acylation conditions and subsequent imine formation with R 2 NH 2. The amino ketone can be obtained from the starting ketone by oxidation and reduction, and the necessary ketone can be obtained by decarboxylation of the β-ketoester obtained by the condensation of an aryl (heteroaryl) acetic ester with an R ₍ COX component).

SCHEME III

Scheme IV below lists two different ways in which a ketone (Formula XI) is used to prepare a compound of Formula I. The heterocyclic ketone XI is prepared by the addition of an alkylheterocycle anion such as 4-methylquinoline (obtained by reacting it with alkyllithium as normal butyllithium) to an N-alkyl-O-alkoxybenzamidester or any other suitably activated derivative in the same oxidized state.

Alternatively, the anion may be fused with benzaldehyde to give an alcohol, which is then oxidized to ketone XI.

SCHEME IV

(XI)

In another embodiment of the method, an N-substituted compound of formula (I) can be obtained by reacting the anion of an amide of formula

RjCHjNRjCOH (XII) in which R 1 and R ₂ are defined above with:

a) nitrile of formula

R ₄ CN (XIII) wherein R ₄ is as defined above, or

B) an excess of alkyl halide, for example acyl chloride of formula

R ₄ COHal (XIV) wherein R ₄ is as defined above and Hal is halogen or the corresponding anhydride to give a bis-acylated intermediate, which is then reacted with an ammonia source such as ammonium acetate.

SCHEME V

One embodiment of this approach is illustrated in Scheme V. A primary amine (R ₂ NH ₂ ) is reacted with a halogenmethyl heterocycle R 1 H 2 X to give a secondary amine, which is converted to the amide in the usual way. Alternatively, the amide may be prepared, as described in Scheme V, by alkylation of the formamide R 1 H 2 X. Deprotonation of this amide with a strong amide base such as lithium diisopropylamide or sodium bis- (trimethylsilyl) amide, followed by the addition of excess aroyl chloride, yields a bisacylated compound, which is then cyclized to imidazole by formula (I) in acetic acid containing ammonium acetate. Alternatively, the amide anion may be reacted with substituted arylnitrile to give imidazole of formula (I) directly.

The interaction of imines with tosylmethylisonitrile was first reported by Leusen (van Leusen et al., J. Org. Chem., 1977, 42, 1153). The following conditions are indicated: Tert-butylamine (tert-butCH ₂ ) in dimethoxyethane (DME), K ₂ CO ₃ in MeOH and NaH in DME. Reproducing these examples shows that they produce low yields. The second method, involving an amine exchange reaction to produce tert-butylamine, followed by reaction with isocyanide to give 1-tertiary imidazole, is also effective. It is appropriate to use any primary amine as a base. Secondary amines, although not preferred, may also be used but may also decompose isonitrile slowly. The reaction takes about 3 equivalents of amine to complete the reaction, yielding approximately 50% isolated yield. Prohibited secondary amines (diisopropylamine), when used, act very slowly and are not as effective. The use of tertiary and aromatic amines such as pyridine and triethylamine did not interact under some of the conditions tested, but more basic species such as DBU and 4 dimethylaminopyridine (DMAP), although to a small extent, produced the product and may thus be suitable for their application here.

The pyridinaldehyde can be condensed with a primary amine to give an imine that can be easily isolated or reacted in situ with the desired isonitrile in the presence of various suitable bases and solvents as described herein to give 5 (4-pyridyl) ) substituted imidazoles, wherein R ₂ and R ₄ have the meanings defined for the compounds of formula (I).

The imine obtained and isolated in a separate step is often resinous, which makes it difficult to process. Black is often transferred to the final product. The yield for imine preparation varies and often solvents, such as CH ₂ Cl _2, are used to obtain environmentally acceptable pollution.

For the reaction, where p = 2, a suitable base is required to effect the reaction. The reaction requires a strong enough base to deprotonate isonitrile. Suitable bases are amine, carbonate, hydride or alkyl or aryl lithium reagent; or mixtures thereof. The bases include, but are not limited to, potassium carbonate, sodium carbonate, primary and secondary amines such as morpholine, piperidine, pyrrolidine, and other non-nucleophilic bases.

Suitable solvents include, but are not limited to, N, N-dimethylformamide (DMF), MeCN, halogenated solvents such as methylene chloride or chloroform, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), alcohols such as methanol or ethanol, benzene or toluene. Preferably the solvent is DMF, DME, THF or MeCN, most preferably DMF. Isolation of the product may generally be completed by the addition of water or filtration of the product as a pure compound.

Although not suitable for large scale operation, the addition of NaH to isonitrile at temperatures below 25 ° C (in THF) would be beneficial. BuLi is also known as an effective base for deprotonation of tosylbenzylisonitriles at -50 ° C (DiSanto et al., Synth. Commun., 1995, 25, 795).

Different deprotonation temperature conditions may be used depending on the preferred base. For example, tertBuNH ₂ / DME, K ₂ CO ₃ / MeOH, K, CO ₃ in DMF at temperatures above 40 ° C, the yield may drop to about 20%, but a small difference is expected between 0 ° C and 25 ° C. Therefore, temperatures below 0 ° C and above 80 ° C are also contemplated within the scope of the present invention. Preferably, the temperature ranges are from 0 ° C to 25 ° C.

Preferably the imine is formed in situ in a solvent. This preferred synthesis is carried out in a single reactor. It is recommended that, when using a primary amine as the salt, the reaction includes a base such as potassium carbonate prior to the addition of isonitrile. The piperidine nitrogen atom may be required to be protected. Reaction conditions such as solvent, base, temperatures, etc. are similar to those discussed above for the isolation of imine. One of ordinary skill in the art will appreciate that under some conditions the in situ imine formed may require dehydration conditions or may require acidic catalysis.

An alternative way of preparing compounds of formula (I) is to oxidize an alkylthio residue to an alkylsulfinyl or alkylsulfonyl residue which is reacted with a suitable alkoxy residue.

Although in the schemes described herein, for example, optionally with a piperidine radical for R ₂ or 4-fluorophenyl for R _4, any suitable R ₂ or R ₄ can be included in this way if obtained on the basis of a primary amine . Any suitable R ₄ can be added by isonitrile.

The compounds of formula (I) in Scheme I can be prepared by the method of Leusen et al., Supra. For example, compounds of formula (II) can be prepared by dehydrating a compound of formula (IV) - Scheme I, wherein Ar, R ₄ and p have the meanings indicated. Suitable dehydrating agents are phosphorus oxychloride, oxalyl chloride, thionyl chloride, phosgene or tosyl chloride in the presence of a suitable base such as triethylamine or diisopropylethylamine, or similar bases, e.g. pyridine. Suitable solvents are dimethoxyether, tetrahydrofuran or halogenated solvents, preferably THF. The reaction is most effective when the reaction temperature is maintained between -10 ° C and 0 ° C. At lower temperatures, the reaction is incomplete, and at higher temperatures the solution darkens and the yield of the product decreases.

The compounds of formula (IV) - Scheme I can be prepared by reacting 10 compound of formula (V) - Scheme I, R ₄ CHO, where R ₄ is defined herein, with ArS (O) _p H and formamide, with removal or without removal of water, preferably under dehydration conditions, at room temperature or at 15 elevated temperatures, e.g. 30 ° C to 150 ° C, refluxed, optionally in the presence of an acid catalyst. Alternatively, trimethylsilyl chloride may be used in place of the acid catalyst. Examples of acid catalysts are camphor-10-sulfonic acid, formic acid, p-toluenesulfonic acid, hydrochloric acid or sulfuric acid.

The most advantageous method for preparing isonitrile of formula (II) is illustrated below in Scheme VI below.

The conversion of the substituted aldehyde to tosylbenzylformamide can be accomplished by heating the aldehyde, 1-Scheme VI, with an acid such as p-toluenesulfonic, formic or camphorsulfonic acid; with formamide and toluenesulfinic acid [at reaction conditions of about 60 ° C for about 24 hours]. Preferably, no solvent is used. The reaction can be carried out in low yield (<30%) when solvents such as DMF, DMSO, toluene, acetonitrile or excess formamide are used. Temperatures below 60 ° C are generally unfavorable to obtain the desired product, and temperatures above 60 ° C can give rise to a product which decomposes or results in benzyl bisformamide, Scheme VI.

Tosylbenzylformamide compound can be prepared by reacting the bisformamide intermediate, 2-Scheme VI with ρ-toluenesulfinic acid. In this preferred embodiment, the preparation of bisformamide from the aldehyde is accomplished by heating the formamide aldehyde in a suitable solvent with an acid catalyst. Suitable solvents are toluene, acetonitrile, DMF and DMSO or mixtures thereof. Acid catalysts are those well known to those skilled in the art and include, but are not limited to, hydrochloric acid, phthalenesulfonic acid, camhosulfonic acid, and other anhydrous acids. The reaction may be carried out at temperatures in the range of about 25 ° C to 110 ° C, preferably about 50 ° C, for about 4 to about 5 hours, with longer reaction times also acceptable. Decomposition of the product or lower yields may occur at elevated temperatures (<70 ° C) over a long reaction time. Removal of water from the reaction mixture is necessary for complete conversion of the product.

Preferred conditions for the conversion of the bis-formamide derivative to tosylbenzylformamide are carried out by heating the bisformamide in a suitable solvent with an acid catalyst and p-toluenesulfinic acid. The solvents used for this interaction include, but are not limited to, toluene and acetonitrile or mixtures thereof. Other mixtures of these solvents with DMF or DMSO may also be used, but lower yields may be obtained. The temperature ranges from about 30 ° C to about 100 ° C. Temperatures lower than 40 ° C and higher than 60 ° C are not recommended as yield and speed decrease. A preferred range is 40 to 60 ° C, especially about 50 ° C. The optimum time is about 4 to 5 hours, although it may be longer. Preferably the acids used include, but are not limited to, toluenesulfonic acid, camphorsulfonic acid and hydrochloric acid and other anhydrous acids. It is particularly preferred that the bisformamide be heated in a mixture of toluene: acetonitrile in a 1: 1 ratio with p-toluenesulfinic acid and hydrogen chloride.

The preferred synthesis of the tosylbenzylformamide compound is carried out in a single reactor. In this method, the aldehyde is initially converted to a bisformamide derivative, after which the bisformamide derivative is reacted with toluenesulfonic acid. This procedure combines optimal conditions in a single, effective process. In this way high yields (<90%) of arylbenzylformamide are realized.

A catalyst such as trimethylsilyl chloride (TMSCl), in a preferred solvent toluene: acetonitrile in a 1: 1 ratio, is used under the preferred reaction conditions. A reagent such as TMSC1 is preferred because it reacts with the resulting water and at the same time releases hydrogen chloride to catalyze the reaction. The use of hydrogen chloride and p-toluenesulfonic acid is also preferred. Therefore, three recommended reaction conditions are included: 1) use of a dehydrating agent that provides hydrogen chloride together with TMSC1; or 2) use of a suitable dehydrating agent and a suitable acid source such as, but not limited to, camphorsulfonic acid, hydrochloric acid or toluenesulfonic acid; and 3) alternative dehydrating conditions such as azeotropic removal of water and use of an acid catalyst and p-toluenesulfinic acid.

Compounds of formula (II) wherein p is 2 may be prepared by reacting in the presence of a strong base with a compound of formula (VI) - Scheme I, R ₄ CH ₂ NC with a compound of formula (VII) - Scheme I, ArSO ₂ L _p where R ₄ and Ar are as defined and L 1 is a leaving group such as halogen, for example fluorine. Suitable strong bases include, but are not limited to, alkyllithium such as butyllithium or lithium diisopropylamide (Van Leusen et al., Tetrahedron Letters, No. 23, 2367-68 (1972)).

Compounds of Formula (VI) - Scheme I can be prepared by reacting a compound of Formula (VIII) - Scheme I, R ₄ CH ₂ NH ₂ with alkyl formate (eg ethylformate) to give an intermediate which can be converted in the desired isonitrile by reaction with a well-known dehydrating agent such as, but not limited to, oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.

Alternatively, a compound of formula (VIII) - scheme I can be transformed into a compound of formula (VI) - scheme I by reaction with chloroform and sodium hydroxide in aqueous dichloromethane in the presence of a phase transfer catalyst.

The compounds of formula (III) - Scheme I can be prepared by reacting a compound of formula R ₍ CHO with primary amine R ₂ NH ₂ .

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

Suitable protecting groups for use with hydroxyl groups and imidazole nitrogen are well known to those skilled in the art and have been described in many literature, for example, Protective Groups in Organic Synthesis, Greene TW, Wiley-Interscience, New York. 1981. Suitable examples of protecting hydroxyl groups are silyl ethers such as tertbutyldimethyl or tert-butyldiphenyl and alkyl ethers such as methyl bonded via an alkyl chain with a variable bond (CR ₁₀ R _{2 ((} ) _n . A suitable example of protecting groups for imidazole nitrogen is tetrahydropyranyl.

Pharmaceutically acceptable acid addition salts of compounds of formula (I) may be prepared in a known manner, for example, by treatment with an appropriate amount of acid in the presence of a suitable solvent.

Examples of application and implementation of the invention

Treatment methods

The compounds of formula (I) or their pharmaceutically acceptable salts may be used for the manufacture of medicaments for the prophylaxis or treatment of any disease condition in a human or other mammal that is exacerbated or caused by excessive or unregulated cytokine production by the cells of that mammal , such as monocytes and / or macrophages, not limited to.

The compounds of formula (I) inhibit inflammatory cytokines such as IL1, IL-6, IL-8 and TNF and are therefore useful as medicaments. IL1, IL-6, IL-8 and TNF affect a large number of cells and tissues and these cytokines, as well as other leukocyte-produced cytokines, are important and critical mediators of inflammation in a wide variety of disease states and conditions. Inhibition of these inflammatory cytokines is useful for controlling, limiting and ameliorating these disease states.

In this connection, the present invention relates to a method of treating diseases with a cytokine mediator, which consists in administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, incorporated into the cytokine.

The compounds of formula (I) are able to inhibit excitable pro-inflammatory proteins such as COX-2, also known by various names, such as prostaglandin endoperoxide synthase-2 (PGHS-2) and are therefore useful as medicaments. These pro-inflammatory lipid mediators of the cyclooxygenase pathway (CO) are produced by the induced COX-2 enzyme. Therefore, the regulation of COX-2, which is the cause of these arachidonic acid products, such as prostaglandins, affects a large number of cells and tissues and is an important mediator of inflammation in various disease states. COX2 expression is not performed by the compounds of formula (I). This selective inhibition of COX-2 attenuates or attenuates the ulcerogenic action associated with the inhibition of COX-1, thereby inhibiting prostaglandins, which are important cytoprotectants. Thus, inhibition of these pro-inflammatory mediators is applied to control, reduce and alleviate many of these disease states. Of particular note is that these inflammatory mediators, in particular prostaglandins, influence pain or edema by sensitizing pain receptors. This aspect influences pain, therefore, includes the treatment of neuromuscular pain, headache, tumor-related pain, and arthritis pain. The compounds of formula (I) or their pharmaceutically acceptable salts are used for the prophylaxis or treatment of humans or other mammals by inhibiting the synthesis of the COX-2 enzyme.

Accordingly, the present invention relates to a method of inhibiting the synthesis of COX-2, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for the prophylactic treatment of humans or other mammals by inhibiting the synthesis of COX-2 enzyme.

In particular, the compounds of formula (I) or their pharmaceutically acceptable salts are used for the prophylaxis or treatment of any disease condition in a human or other mammal that is exacerbated or caused by excessive or unregulated production of IL-1, IL-8 or TNF from the cells of this mammal, including, but not limited to, monocytes and / or macrophages.

In this connection, in another aspect, the present invention relates to a method of inhibiting the production of IL-1 in a mammal in need thereof, which comprises treating the mammal with an effective amount of the compound of formula (I) or a pharmaceutical thereof acceptable salt.

There are a number of diseases in which excessive or unregulated production of IL-1 affects the exacerbation or causing of the disease. These include rheumatoid arthritis, osteoarthritis, stroke, endotoxemia or toxic shock syndrome, other acute or chronic inflammatory conditions such as inflammatory reaction caused by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, musculoskeletal disease, muscular disease , psoriasis arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent studies have also linked IL-1 action to diabetes, pancreatic β-cells and Alzheimer's disease.

In another aspect, the present invention relates to a method of inhibiting the production of TNF in mammals in need of which method consists in treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production is involved in the mediation or exacerbation of many diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic syndrome, endotoxic syndrome, respiratory distress in adults, stroke, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease such as osteoporosis, reperfusion injury, reaction transplant / receiver, allograft response, fever and myalgia due to infection, such as influenza, cachexia due to infection or malignancy, cachexia due to acquired immune deficiency syndrome (AIDS), AIDS (AIDS), complex, AIDS (AIDS), complex, , keloid formation, cicatrix tissue formation, Crohn's disease, ulcerative colitis and pyresis.

The compounds of formula (I) are also used to treat viral infections in viruses that are susceptible to regulation by TNF or abolish TNF production in vivo. Such viruses are those that produce TNF as a result of infection or those that are susceptible to inhibition, thereby reducing replication, either directly or indirectly, by a compound of formula (I) that inhibits TNF. Such viruses include, but are not limited to, HIV-1, HIV-2, and HIV-3, cytomegaliovirus (CMV), influenza, adenovirus, and Herpes group viruses, such as, but not limited to, Herpes Zoster and Herpes Simplex. Therefore, in another aspect the present invention relates to a method of treating mammals affected by human immunodeficiency virus (HIV), which comprises treating that mammal with an effective TNF-inhibiting amount of a compound of formula (I) or a compound thereof a pharmaceutically acceptable salt.

The compounds of formula (I) may also be used for the veterinary treatment of non-human mammals in need of inhibition of TNF production. Diseases with a TNF mediator for treatment, therapeutic or prophylactic in animals, include disease states as noted above, but in particular viral infections. Examples of such viruses include, but are not limited to, lentiviral infections such as equine anemia virus, goat arthritis virus, visna virus, maedi virus, or retroviral infections such as, but not limited to, immune deficiency virus in cats (FIV), bovine immunodeficiency virus, or dog immunodeficiency virus or other retroviral infections.

The compounds of formula (I) may also be used topically for treating or preventing disease states caused or exacerbated by excessive cytokine production such as IL-1 or TNF, respectively as inflammatory joints, eczema, psoriasis, and other inflammatory conditions. skin as sunburn; inflammatory conditions of the eyes, including conjunctivitis; pyresis, pain, and other conditions associated with inflammation.

The compounds of formula (I) have also been shown to inhibit the production of IL-8 (interleukin-8, NAP). Accordingly, in another aspect, the invention provides a method of inhibiting the production of IL-8 in mammals in need thereof, which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable thereof salt.

Disease conditions exist in which excessive or unregulated production of IL-8 is involved in exacerbating or causing the disease. These diseases are characterized by massive neutrophil infiltration such as psoriasis, bowel inflammation, asthma, cardiac or renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these conditions are associated with increased production of IL-8, which causes the chemotaxis of neutrophils to the site of inflammation. Contrary to other inflammatory cytokines (IL-1, TNF and IL-6), IL-8 has the unique property of accelerating the chemotaxis and activation of neutrophils. Due to this, inhibition of IL-8 production results in a direct decrease in neutrophil infiltration.

The compounds of formula (I) are administered in an amount sufficient to inhibit the production of the cytokine, in particular IL-1, IL-6, IL-8 or TNF, so that it is regulated to a normal level and is improved or prevented door disease state. Abnormal levels of IL-1, IL-6, IL-8, or TNF for example in the context of the present invention are: (i) concentrations of free (unrelated to cells) IL-1, IL-6, IL-8, or TNF- large than or equal to 1 picogram per ml; (ii) any cell-bound IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1, IL-6, IL-8 or TNF mRNA above baseline concentrations in the cells or tissues in which IL-1, IL-6, IL-8 or TNF are produced, respectively.

The finding that compounds of formula (I) are inhibitors of cytokines, in particular IL-1, IL-6, IL-8 or TNF, is based on the effects of the compounds of formula (I) on the production of IL-1, IL-8 or TNF in the in vitro assays described below.

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

a) reducing the extremely high in vivo cytokine concentration (IL-1, IL-6, IL-8 or TNF) in humans to normal or subnormal levels by inhibiting in vivo cytokine release in all cells, including, but not limited to, to them, monocytes and macrophages;

b) regulating, at the genomic level, the excessive in vivo concentrations of the cytokine (IL-1, IL-6, IL-8 or TNF) in humans to normal or subnormal levels;

c) regulation by inhibition of direct cytokine synthesis (IL-1, IL-6, IL-8 or TNF) as a posttranslational action; or

d) regulating, at the translational level, the extremely high in vivo concentrations of cytokines (IL-1, IL-6, IL-8 or TNF) in humans to normal or sub-normal concentrations.

As used herein, the term "disease or disease condition with a TNF mediator" refers to any or all disease states in which TNF plays a role, either by producing TNF itself or as TNF causes the release of another monokine such as, but not limited to, IL -1, IL-6 or IL-8. A disease state in which, for example, IL-1 is a major component and whose production or action is enhanced in response to TNF, is therefore considered a disease state with a TNFz mediator.

As used herein, the term "cytokine" refers to any produced polypeptide that affects cell function and is a molecule that modulates the interaction between cells in an immune, inflammatory or haematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines, no matter which cells produce them. For example, the monokine is generally considered to be produced and secreted by a mononuclear cell, such as a macrophage and / or monocyte. However, many other cells also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and B lymphocytes. Lymphokines are generally considered to be produced by lymphocyte cells. Examples of cytokines include, but are not limited to, 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).

As used herein, the term "cytokine inhibitory" or "cytokine inhibitory amount" refers to an effective amount of a compound of formula (I) that causes the in vivo concentrations of the cytokine to fall to normal or subnormal levels when administered to a patient for prevention or treatment of a disease condition that is exacerbated or caused by excessive or unregulated production of cytokines.

As used herein, the cytokine referred to in the expression &quot; cytokine inhibition for use in the treatment of an HIV infected person &quot; is a cytokine that is involved in a) initiating and / or maintaining T-cell activation and / or HIV gene. mediator T cell expression and / or replication and / or b) any cytokine mediated disease problem, such as cachexia or muscle degeneration.

Because TNF-β (also known as lymphotoxin) has a similar structural homology to TNF-α (also known as cachectin) and because each of them elicits similar biological responses and binds to the same cellular receptor, both TNF-α and TNF-β is inhibited by the compounds of the present invention and is therefore generally referred to in the specification as "TNF" unless specifically stated otherwise.

Recently, in several laboratories, a new member of the MAP kinase family, alternatively called CSBP, p38 or RK, has been independently identified [see Lee et al., Nature, vol. 300 n (72), 739-746 (1994)]. Activation of this novel protein kinase by dual phosphorylation has been observed in various cellular systems after stimulation with a wide range of stimulants such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. The cytokine biosynthesis inhibitors of the present invention, the compounds of formula (I), have been identified as potent and selective inhibitors of CSBP / p38 / RK kinase activity. These inhibitors are used to determine the activation of signaling pathways in the inflammatory response. In particular, for the first time a specific transduction signaling pathway may be attributed to the action of lipopolysaccharide · in the production of cytokines in macrophages. C, in addition to those already mentioned, includes = also the treatment of stroke, neurotrauma, sr- _; infant and renal impairment, thrombosis, gl- = - merulonephritis, diabetes and pancreatic β-cells, multiple sclerosis, muscle degeneration, eczema, psoriasis, sunburn, and conjunctivitis.

Cytokine inhibitors have been consistently tested in a number of animal models for anti-inflammatory activity. Model systems have been selected to be relatively insensitive to cyclooxygenase inhibitors in order to detect the unique activities of cytokine inhibiting agents. Inhibitors have shown significant activity in many such in vivo studies. Most notable is their efficacy in a model of collagenase-induced arthritis and inhibition of TNF production in a model of endotoxic shock. In the last study, a decrease in plasma TNF concentration correlated with survival and protection against endotoxic shock-related mortality. Also of great importance is the efficacy of the compounds in inhibiting bone resorption in a long-embryonic rat embryonic organ system. (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. Ν. Y. Acad. Sci. 696, 149-170.

In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof as a therapeutic agent, it is usually processed into a pharmaceutical composition according to standard pharmaceutical practice. This invention therefore also relates to pharmaceutical compositions containing an effective non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I), their pharmaceutically acceptable salts and the pharmaceutical compositions containing them, can be conveniently administered by any of the commonly used routes of administration, for example orally, topically, parenterally or by inhalation. The compounds of formula (I) can be administered in conventional dosage forms prepared by mixing the compound of formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of formula (I) may also be administered in conventional doses in combination with a known second therapeutically active compound. These procedures may include mixing, granulating and tabletting or dissolving the components as is customary for the desired preparation. The form and nature of the pharmaceutically acceptable carrier or diluent is determined by the amount of active ingredient with which it is to be combined, the route of administration and other well known variables. The carrier (s) should be "acceptable" in the sense that they are compatible with the other components of the dosage form and are not harmful to the patient.

The pharmaceutical carrier used may for example be either solid or liquid. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, agar, pectin, arabic gum, magnesium stearate, stearic acid and the like. Similarly, the carrier or diluent may include a release retardant component well known to those skilled in the art such as glyceryl monostearate or glyceryl distearate alone or in combination with wax.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be tableted, placed in hard gelatin capsules, in powder or pallet form, or in the form of pastilles or sugar dragees. The amount of solid carrier varies widely, but is preferably from about 25 mg to 1 g. When using a liquid carrier, the preparation is in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solutions, or non-aqueous liquid suspensions.

The compounds of formula (I) may be administered topically, i.e. through on-site application. This includes administering the compound of formula (I) externally to the epidermis or oral cavity and the addition of such compound into the eye, ear and nose so that it does not substantially enter the bloodstream. In contrast, non-local administration includes oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include a liquid or semi-liquid preparation suitable for penetrating the skin to the site of inflammation, such as liniments, lotions, creams, ointments or pastes and drops, suitable for use in the eyes, ears or nose. The active ingredient for topical administration is from 0.001% to 10% by weight, for example from 1% to 2% by weight of the formulation. However, it may also contain 10% by weight, but it is recommended to contain less than 5% by weight, most preferably 0.1 to 1% by weight of the form.

Lotions according to the invention include those suitable for application to the skin or eyes. The eye lotion may contain a sterile aqueous solution, optionally containing a bactericidal agent, and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may include a drying agent and a skin cooling agent such as alcohol or acetone and / or moisturizers such as glycerol or oil such as castor or peanut oil.

The creams, ointments or pastes of the present invention are semi-solid dosage forms of the active ingredients for external use. They may be prepared by mixing the active ingredients in a finely divided or powdered form, alone or in solution or suspension on an aqueous or non-aqueous basis, using a suitable apparatus, with an oil or non-oil base. The base may contain hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal soap; mucous solution; oil of natural origin, such as almond, corn, peanut, castor or olive oil; lanolin or its derivatives or fatty acids such as stearic or oleic acid in combination with an alcohol such as propylene glycol or macrogel. The form may include any suitable surfactant such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspension agents such as natural rubber, cellulose derivatives or inorganic silicates and other ingredients such as lanolin may also be used.

The drops according to the present invention may contain sterile aqueous or oily solutions or suspensions of a bactericidal and / or fungicidal agent and / or any other suitable preservative and preferably include a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized by autoclaving or sterilizing at 98-100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the droplets are phenylmercurinitrate or acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, dilute alcohol and propylene glycol.

The compounds of formula (I) may be administered parenterally, i. intravenous, intramuscular, subcutaneous, nasal, rectal, vaginal or ultraperitoneal. The 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) may also be administered by inhalation, i.e. nasally or orally. Suitable dosage forms for such administration as aerosol forms or metered dose inhalers may be prepared by conventional techniques.

For all the methods of use described herein for the compounds of formula (I), the daily dosage regimen is preferably from about 0.1 to about 80 mg / kg body weight, preferably from about 0.2 to 30 mg / kg, preferably from about 0.5 mg to 15 mg. The daily parenteral dose regimen is about 0.1 to about 80 mg / kg of total body weight, preferably about 0.2 to about 30 mg / kg, and more preferably about 0.5 mg to 15 mg. The daily topical dosage regimen is preferably from 0.1 mg to 150 mg administered once to four times, preferably two or three times daily. The daily inhalation dose regimen is preferably from 0.01 mg / kg to about 1 mg / kg per day. It will be known to those skilled in the art that the optimal amount and distribution of individual daily doses of the compounds of formula (I) and their pharmaceutically acceptable salts are determined by the nature and condition of the patient, the form, method and site of administration and for each individual patient, and that this optimum is determined by conventional techniques. It is also appreciated by those skilled in the art that the optimal course of treatment, i. the number of doses of the compound of formula (I) or pharmaceutically acceptable salt thereof per day for a specified number of days, which can be confirmed by one skilled in the art using conventional tests to determine the course of treatment.

The novel compounds of formula (I) may also be used for the veterinary treatment of non-human mammals in need of inhibition of cytokine production. In particular, diseases with a cytokine mediator for the therapeutic or prophylactic treatment of animals include diseases such as those listed in the "Treatment methods" section, particularly viral infections. Examples of such viruses include, but are not limited to, lentiviral infections such as infectious anemia virus in horses, goat arthritis virus, visna virus, or maedi virus, or retroviral infections such as, but not limited to, the virus cats immunodeficiency virus (FIV), bovine immunodeficiency virus or dog immunodeficiency virus, or other retroviral infections.

The invention is described with reference to the following biological examples, which are merely illustrative and do not limit the scope of the present invention.

Biological examples

The cytokine inhibitory action of the compounds of the present invention is determined by the following in vitro studies:

Interleukin-1 (IL-1)

Human peripheral blood monocytes are isolated and purified either from fresh blood from donor volunteers or from blood banks according to the procedure of Colotta et al., J. Immunoi. 132, 936 (1984). These monocytes (1 x 10 ⁶ ) were placed in 24-well plates at a concentration of 1-2 million / ml per well. The cells were allowed to adhere to the bottom for 2 h, after which the non-adherent cells were removed by gentle washing. The test compounds were then added to the cells for 1 h before the addition of lipopolysaccharide (50 ng / ml) and the cultures were incubated at 37 ° C for a further 24 h. At the end of this period, the clear liquid from the culture is removed and purified from cells and all fragments. The clear liquid from the culture was then tested immediately for IL-1 biological activity or by the method of Simon et al., J. Immunoi. Methods, 84, 85 (1985) (based on the ability of IL-1 to stimulate interleukin-2 producing cell lines (EL-4) to secrete IL-2 together with the A23187 ionophore) or by the method of Lee et al., J .Immuno Therapy, 6 (1), 1-12 (1990) (ELISA analysis).

The test compound of formula (I) shows a positive inhibition in this assay.

Tumor necrosis factor (TNF):

Human peripheral blood monocytes are isolated from leukocyte membranes from blood banks or thrombopheresis residues according to the procedure of Colotta R. et al., J. Immunol. 132 (2), 936 (1984). Monocytes were placed at a density of 1 x 10 'cells / ml medium / well in 24-well multi-views. The cells were allowed to adhere to the bottom for 1 h, after which the clear liquid was aspirated and fresh medium (1 ml,

RPMI-1640, Whitaker Biomedical Products, Whitaker, CA) containing 1% calf fetal serum plus penicillin and streptomycin (10 units / ml). The cells were incubated for 45 min in the presence or absence of the test compound at the order of 1 nM-10 mM (the compounds were dissolved in dimethyl sulfoxide / ethanol so that the final solvent concentration in the culture medium was 0.5% dimethyl sulfoxide / 0 , 5% ethanol). Bacterial lipopolysaccharide (E.coli 055: B5 [LPS] from Sigma Chemicals Co) (100 ng / ml) in 10 ml phosphate buffered saline) was then added and the cultures incubated for 16-18 h at 37 ° C in 5 % CO ₂ incubator. At the end of the incubation period, clear culture fluid was removed from the cells, centrifuged at 3000 rpm to remove the cell fragments. The clear fluid was then assayed for TNFactivity using either radio-immunoassay or ELISA as described in WO 92/10190 and by Becker et al., J. Immunol., 1991, 147, 4307.

IL-1 and TNF inhibitory activity do not appear to correlate with the properties of the compounds of formula (I) as mediators of inhibition of arachidonic acid metabolism. Moreover, the ability to inhibit the production of prostaglandin and / or the synthesis of leukotriene by non-steroidal anti-inflammatory drugs with potent cyclooxygenase and / or lipoxygenase inhibitory activity does not mean that the compound also necessarily inhibits the production of TNF or IL-1 in non-toxic ones.

In vivo TNF analysis:

The above tests are in vitro, but the compounds of formula (I) can also be tested in an in vivo system as described in:

1) Griswold et al., Drugs Under Exp. and Clin. Really. XIX (6), 243-248 (1993) or

2) Boehm et al., Journal of Medicinal Chemistry 39, 3929-3937 (1996).

Interleukin-8 (IL-8):

Human umbilical cord (HUVEC) primary endothelial cells (Cell Systems, Kirland, Wa) were maintained in culture medium supplemented with 15% calf fetal serum and 1% CSHBGF consisting of a FGF and heparin. The cells were then diluted 20-fold before being placed (250 μΐ each) in gelatin-coated 96-well plates. The culture medium is replaced with fresh medium (200 μΐ) before use. Then, a buffer or test compound (25 μ 25, at concentrations between 1 and 10 μΜ) in four replicates was added to each well and the plates incubated for 6 h in a humidified incubator at 37 ° C, in an atmosphere of 5% CO ₂ . At the end of the incubation period, clear liquid was separated and tested for IL-8 concentrations using an IL-8 ELISA instrument obtained from R&D Systems (Mineapolis, MN). All data are presented as mean values (ng / ml) of multiple samples, based on a standard curve. Where appropriate, IC ₅₀ is determined by nonlinear regression analysis.

Cytokine specific protein binding assay.

Radiocompetitive linkage analysis has been developed to provide highly reproducible primary screening for structure-activity studies. This assay provides many advantages over conventional bioassays that use freshly isolated human monocytes as a source of cytokine and an ELISA assay to quantify it. In addition to being much easier, linkage analysis is widely recognized as highly correlated with bioassay results. A specific and reproducible cytokine inhibitor binding assay was developed using a soluble cystosolic fraction of THP-1 cells and a radiolabeled compound. Patent Application US SN 81/123175 Lee et al., Filed September 1993, USSN; Lee et al., PCT 94/10529, filed Sept. 16, 1994, and Lee et al., Nature 300, n (72), 739-746 (Dec. 1994) describe a characteristic method for drug screening to identify compounds that interact and bind to a cytokine specific binding protein (hereinafter referred to as CSBP). However, for the purposes herein, the binding protein may be isolated in solution or in immobilized form or may be expressed by genetic engineering on the surface of recombinant host cells as a phage display system or as fusion proteins. Alternatively, whole cells or cytosolic fractions containing CSBP may be used in screening. Regardless of the form of the binding protein, most of the compounds are contacted with the binding protein under conditions sufficient to form a compound / binding protein complex and compounds capable of forming, enhancing or inhibiting said complex are identified.

A representative final compound of formula (I), example 1, exhibits a positive inhibitory activity with IC 50 <50 μΜ in this binding assay.

CSBP kinase assay:

This assay measures the CSBP catalyzed transfer of ³² P from [α- ³² P] ATP to the threonine residue in the epidermal growth factor receptor (EGFR) -npoflyimpaH peptide (T669) in the following sequence: KRELVEPLTPS GEAPNQALLR (REMAINS) 661-68. (See Gallagher et al., “Regulation of Stress Induced Cytokine Production by Pyridinyl Imidasoles: Inhibition of CSBP Kinase,” Bioorganic & Medicinal Chemistry, To be published 1996).

The kinase reaction mixtures (total volume 30 µl) contain: 25 mM Hepes buffer, pH 7.5; 10 mM MgCl ₂ ; 170 [mu] M ATP ⁰¹ ; 10 μM Na-ορτοvanadate; 0.4 mM T 669 peptide; and 20-80 ng expressed from yeast purified CSBP 2 (see Lee et al., Nature 300, η (72) 739-746 (Dec. 1994). The compounds (5 µl of [6X] stem ^<2> ) were pre-incubated with the enzyme and peptide 20 min on ice to start reactions with ³² P (MgATP) The reaction mixtures were incubated at 30 ° C for 10 min and the reactions were stopped by adding 10 µl of 0.3 M phosphoric acid. with ³² P peptide was separated on phosphocellulose (Watman, p81) filters by dropwise addition of 30 µl of reaction mixture The filters were washed 3 times with 75 mM phosphoric acid followed by 2 washes with H ₂ O and read at ³² P.

The CSBP Km for ATP is determined to be 170 µM. Therefore, the compounds were screened at Km value of ATP.

^<2) Compounds are usually dissolved in DMSO and diluted in 25 mM Hepes buffer to give a final DMSO concentration of 0.17%.

Representative final compounds of Formula (I), Example 2, demonstrated positive inhibitory activity of an IC _J0 <50 uM in this binding assay.

Analysis of prostaglandin endoperoxide synthase-2 (PGHS-2):

The following study relates to the inhibitory effect of compounds of formula (I) on human PGHS-2 protein expressed in human LPS-stimulated monocytes.

Method: Human peripheral blood monocytes are isolated from leukocyte membranes by centrifugation through Ficoll and Percoll gradients. Cells were seeded at 2 x KP / wells in 24-well plates and allowed to adhere to the bottom for 1 h in RPMI supplemented with 1% human AB serum, 20 mM Lglutamine, penicillin-streptomycin and 10 mM Hepes . The compounds were added at various concentrations and incubated at 37 ° C for 10 min. 50 Lg / well LPS (enzyme expression excitation) was added and incubated overnight at 37 ° C. The clear liquid was separated and the cells were washed once with cold PBS. Cells were lysed in 100 μΐ 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, ImM PMSF, 1 mM leupeptin, 1 mM pepstatin). The lysate was centrifuged (10,000 x g for 10 min at 40 ° C) to remove the fragments and the soluble fraction was subjected to SDS PAGE analysis (12% gel). The gel-separated protein was transferred to the nitrocellulose membrane by electrophoretic means for 2 h at 60 V. The membrane was pre-treated in PBS / Tween buffer, the membrane incubated with 1: 2000 dilution from monospecific antiserum to PGHS-2 or 1: 1000 dilution of antiserum to PGHs-Ι in PBS / Tween with 1% BSA for 1 h with continuous shaking. The membrane was washed 3X in PBS / Tween and then incubated with a 1: 3000 dilution of horseradish peroxidase conjugated with donkey antisera to rabbit Ig (Amersham) in PBS / Tween with 1% BSA for 1 hour with continuous shaking. The membrane was then washed 3X in PBS / Tween and an ECL immune detection system (Amersham) was used to demonstrate the expression level of prostaglandin endoperoxide synthase-2.

Results: The following compounds were tested and found to be active in this assay (i.e., inhibit LPS-induced PGHS-2 protein expression in a power order similar to that of inhibiting cytokine production, as noted in the above analyzes):

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.

Several compounds have been tested and found to be inactive (up to M):

2- (4-methylsulfinylphenyl) -3- (4-pyridyl) -6,7-dihydro- (5H) -pyrrolo [1,2-a] imidazole; rolipram; phenidone and NDGA.

None of the tested compounds inhibited PGHS-1 or cPLA ₂ protein concentrations in similar experiments.

TNF-α in traumatic brain injury trials.

The present experience relates to the study of tumor necrosis factor mRNA expression in specific brain regions that follow experimentally induced lateral fluid percussion traumatic injury (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg ip) and subjected to moderate-lateral fluid percussion brain injury (2.4 atm) centered on the left temporal parietal cortex 18) or “sham''TpeTHpaHe (anesthesia and surgery without damage, n = 18). Animals are killed by decapitation at 1, 6, and 24 h after injury, the brains are removed and samples are prepared from the left (damaged) parietal cortex (LC), corresponding areas from the contralateral right cortex (RC), left hippocampus (LH), and right hippocampus (RH). Total RNA was isolated and Northern blot hybridization was performed and quantified for TNF-α positive control RNA (macrophage = 100%). There was a significant increase in TNF-α mRNA expression in LH (104 ± 17% of positive control, p <0.05 vs. sham), LC (105 ± 21%, p <0.05) and LA (69 ± 8%, p <0.01) in the traumatized hemisphere 1 h after injury. Increased expression of HaTNF-α mRNA was also observed in LH (46 ± 8%, p <0.05), LC (30 ± 3%, p <0.01) and LA (32 ± 3%, <0.01). at 6 h, which disappears at 24 h after injury. In the contralateral hemisphere, TNF-α mRNA expression was increased in RN (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (22 ± 8%) at 1 h and in RH (28 ± 11%), RC (7 ± 5%) and RA (26 ± 6% p <0.05) at h but not at 24 h after injury. No significant changes in TNF-α mRNA expression were observed in sham (surgery without damage) or untreated animals in any of the 6 brain regions, in any of the hemispheres, at any time. The results show that after parasagittal fluid-percussion brain damage, the temporal expression of TNF-α mRNA changes in specific brain regions, including those in the non-traumatized hemisphere. Because TNF-α is capable of inducing nerve growth factor (NGF) and stimulating the release of other cytokines by activated astrocytes, this post-traumatic change in TNF-α gene expression plays a significant role in both acute and regenerative responses for CNS injury.

CNS damage model for IL-β mRNA.

This experiment characterized the regional expression of interleukin-ΐβ (IL-β) mRNA in specific brain regions after experimental lateral fluid percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pantobarbital (60 mg / kg, ip) and subjected to moderate-lateral fluid percussion brain injury (2.4 atm) centered on the left temporal cortex (18 atm) ), or sham treatment (anesthesia and surgery without damage). Animals are killed 1, 6, and 24 h after injury, the brain is separated and samples are prepared from tissues of the left (damaged) parietal cortex (LC), corresponding areas in the contralateral right cortex (RC), the cortex adjacent to the damaged parietal cortex (LA), the adjacent area in the right cortex (RA), left hippocampus (LH), and right hippocampus (RH). Total RNA was isolated and Northern blot hybridization was performed and the amount of IL-Ιβ in brain tissue was presented as a percentage of the radioactivity of IL-1 Makpophage RNA applied to the same gel. At 1 h after brain injury, there was a significant and noticeable increase in the expression of IL-Ιβ mRNA in LC (20.0 ± 0.7%) of the positive control, n &apos; 6, p <0.05 compared to sham animal ), LH (24.5 ± 0.9%, p <0.05) and LA (21.5 ± 3.1%, p <0.05) in the damaged hemisphere, which remains elevated until 6 h after damage in the LC (4.0 ± 0.4%, n-6, p <0.05) and LH (5.0 ± 1.3%, p <0.05). No expression of IL-Ιβ mRNA was observed in any of the relevant brain regions in sham or untreated animals. These results indicate that after TBI, the temporal expression of IL-Ιβ mRNA is regionally stimulated in specific brain regions. These regional changes in cytokines such as IL-Ιβ play a role in the post-traumatic or regenerative residual phenomenon of brain damage.

Examples of synthesizing compounds

The invention is illustrated by the following examples which serve to illustrate and should not be construed as limiting the scope of the present invention. All temperatures are given in ° C, all solvents are of an available purity and all interactions are carried out in the absence of water in argon atmosphere unless otherwise stated. Mass spectral analyzes were performed on a VG Zab mass spectrometer using rapid atomic bombardment, unless otherwise stated. Ή-NMR (hereinafter NMR) spectra were recorded at 250 MHz using a Broker AM 250 or At 400 spectrometer. The indicated multiplets are: s = singlet, d “doublet, t triplet, q ^g quartet, m = multiplet and br stands for broad signal. The designation eq represents the molecular equivalents of the reagent with respect to the parent reagent.

Flash chromatography was performed on Merck Silica gel 60 (230-400 mesh).

Example 1.

5- (2-methoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole

a) 2-Chloropyridine-4-carboxyaldehyde-1-tert-butoxycarbonyl-4-aminopiperidinimine

2-Chloropyridine-4-carboxaldehyde was prepared as described in (WPI Ass. No. 88258820/37). This aldehyde was reacted with the product of Example 1 (d) according to the procedure of Example 1 (g) to give the title compound as a yellow oil, a mixture of NMR based iminoisomers. Ή NMR (CDCl ₃ ): δ 8.49, 8.35 (2d, ΙΗ), 8.22 8.21 (2, s, 1), 7.57, 7.29 (2s, 1H), 7. 45, 7.12 (2d, 1H), 2.93 (m, 1), 2.70 (m, 3), 1.64 (m, 3), 1.42, 1.40 (2s, 9) , 1.17 (m, 2).

b) 5- (2-chloro-4-pyridinyl) -4-fluorophenyl) -1- (1-tert-butoxycarbonylpiperidin-4-yl) imidazole

The product of Example 1 (a) interacts with the product of Example 1 (f) using the technology of Example 1 (h). The crude product was filtered through silica gel, eluting with 0-2% MeOH in CH ₂ Cl ₂ to give the title compound as a slightly yellow solid. MS ES + m / z = 457, 459 (MH ⁺ ).

c) 5- (2-methoxy-4-pyridinyl) -4-fluorophenyl) -1- (1-tert-butoxycarbonylpiperidin-4-yl) imidazole

The product of the previous example (1.0 g, 2.19 mmol) was dissolved in 25% NaOMe in MeOH (20 ml) and refluxed for 1 h, cooled and mixed with water and stirred. extracted with EtOAc (2x). The extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was flash chromatographed (0-30% EtOAc in hexane) to give 300 mg (32%) of the title compound as a brown solid. Crystals were obtained from acetone / hexane. MS ES + m / z = 453 (MH ^{&lt; + &gt;} ).

d) 5- (2-methoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole

The product of the preceding example is reacted according to the procedure of Example 1 (I). The crude product was triturated with 1:10 Et ₂ O / hexane, filtered and dried to give the title compound as a white solid. M.P. 136-137 ° C.

Example 2.

5- (2-isopropoxy-4-pyrimidinyl) -4- (4fluorophenyl) -1- (4-piperidinyl) imidazole

The product was prepared according to the procedure of Example 1 using sodium isopropoxide and isopropanol instead of sodium methoxide and methanol. MS ES + m / z = 381 (MH ^{&lt; + &gt;} ).

Reference example 1

5- (2-methoxy-4-pyrimidinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole

a) 2-14-methylthiopyrimidine-4-carboxaldehyde dimethylacetal

Pyrogenic aldehyde dimethylacetal (60 ml, 459 mmol) and N, N-dimethylformamide dimethylacetal (60 ml, 459 mmol) were stirred together at 100 ° C for 18 h, then the mixture was cooled.

Methanol (300 ml), thiourea (69.6 g) and sodium methoxide (231 ml, 25% by weight in MeOH) were added to the above mixture and stirred at 70 ° C for 2 h. After cooling, iodomethane (144 ml) was added dropwise and the mixture was stirred for 3 hours at room temperature. After dilution with EtOAc and H ₂ O, the organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a brown oil (75.5 g, 82% yield). 1 H-NMR (CDCl 3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).

b) 2-methoxypyrimidine-4-carboxaldehyde dimethylacetal

The product of the previous example (5.0 g, 25 mmol) was dissolved in methanol (100 ml), cooled to 4 ° C and a solution of oxonium salt (9.21 g) in water (100 ml) was added dropwise ( T <15 ° C). It was heated to 23 ° C, stirred for 2 h, poured into 10% aqueous NaOH solution (250 ml) and extracted with EtOAc. The extracts were washed with 10% aqueous NaOH solution, dried (Na ₂ SO ₄ ), filtered, concentrated and flash chromatographed (70% hexane / EtOAc) to give 1.66 g (36%) of the compound according to the title. ESP + (Mass Spec) m / z 185 (MH ⁺ ).

c) 2-methoxypyrimidine-4-carboxaldehyde The product of the previous example (0.54 g, 2.93 mmol) was dissolved in 3M HCl (2.17 ml, 6.5 mmol) and stirred at 23 ° C for 3 days. , cooled to 4 ° C, separated with EtOAc and basified slightly by the addition of Na ₂ CO ₃ . Extraction with EtOAc (5 x 40 ml) gave 0.309 g (76%) of the title compound as a white solid. 1 H NMR (CDCl ₃ ): d 9.96 (s. 1), 8.78 (d, 1), 7.46 (d, 1), 4.10 (s, 3).

d) 1-tert-butoxycarbonyl-4-aminopiperidine

-tert-butoxycarbonyl piperidin-4-one (commercially available by Lancaster Chem) (39.9 g, 0.20 mol), THF (150 ml), H ₂ O (300 ml) and H ₂ NOH HCl (55.2 , 0.80 mol) were dissolved together and Na ₂ CO ₃ (55.2 g, 0.53 mol) was added in small portions. The mixture was stirred at 23 ° C for 14 h, most of the THF was evaporated in vacuo, adjusted to pH> 10 with 50% aqueous NaOH, extracted with EtOAc (5 x 50 ml) ) and concentrated to a white foam. It was converted to a powder with hexane, filtered and the solid dried in vacuo to give 40.31 g of the title compound.

The above residue was dissolved in EtOH (absolute, 1 L) and pre-nickel (50 ml suspension in EtOH) was added and the mixture was reduced to an atmosphere of H ₂ (50 psi 50x6,895 kN / m ² ) for 3.5 h. The catalyst was filtered off and washed with EtOH. Concentration gave 38.44 g (96% total) of the title compound as a colorless oil, which solidified upon standing at -20 ° C.

c) 4-fluorophenyl-tolylsulfonomethylformamide

To a suspension of sodium p-toluenesulfinate (30 g) in water (100 ml) was added methyl tert-butyl ether (50 ml) and then concentrated HCl (15 ml) was added dropwise. After stirring for 5 min, the organic phase was removed and the aqueous phase was extracted with methyl tert-butyl ether. The organic phase was dried (Na ₂ SO ₄ ) and concentrated almost to dryness. Hexane was added and the resulting precipitate was collected to give p-toluenesulfinic acid; yield 22 g.

Mix p-toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22 ml, 206 mmol), formaldehyde (20 ml, 503 mmol) and camphorsulfonic acid (4 g, 17.3 mmol) and mix. at 60 ° C for 18 h. The resulting solid was crushed and stirred with a mixture of MeOH (35 ml) and hexane (82 ml) and then filtered. The solid was resuspended in MeOH / hexane (1: 3, 200 ml) and stirred vigorously to break the remaining large pieces. Filtration gave the title compound (27 g, 62% yield): 1 H-NMR (400 MHz CDCl ₃ ): d 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).

f) 4-fluorophenyl-tolylsulfonomethylisocyanide

4-Fluorophenyl-tolylsulfonomethylformamide (2.01 g, 6.25 mmol) in DME (32 ml) was cooled to -10 ° C, POCl ₃ (1.52 ml, 16.3 mmol) was added dropwise. triethylamine (4.6 ml, 32.6 mmol) in DME (3 ml) while maintaining the temperature below -5 ° C. The mixture was gradually warmed to room temperature over a period of 1 hour, poured into water and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO ₃ solution, dried (Na ₂ SO ₄ ) and concentrated. The residue was triturated with petroleum ether and filtered to give the title compound (1.7 g, 90% yield). Ή NMR (CDCl ₃ ) d 7.63 (d, 2H), 7.33 (m, 4H), 7.10 (t, 2H), 5.60 (s, 1H), 2.50 (s, 3H) ).

g) 2-methoxypyrimidine-4-carboxaldehyde [1-tert-butoxycarbonyl-4-aminopiperidine] imine

The product of Example 1 (d) (0.308 g, 2.23 mmol) and the product of Example 1 (c) (0.468 g, 2.34 mmol) were combined in CH ₂ Cl ₂ (50 ml) and stirred at 23 ° C for 16 h. Concentration gave the title compound as a light orange foam. 1 H NMR (CDCl ₃ ): d 8.56 (d, 1), 8.26 (s, 1), 7.57 (d, 1), 4.05 (s and m, 4), 3.5 (m, 2), 3.0 (m, 2), 1.75 (m, 4), 1.46 (s, 9).

h) 5- (2-methoxy-4-pyrimidinyl) -4- (4fluorophenyl) -1 - ((1-tert-butoxycarbonyl) -4piperidinyl] imidazole

The product of the above example, DMF (5 ml), the product of example 1 (f) (0.708 g, 2.23 mmol) and K ₂ CO ₃ (0.308 g, 2.23 mmol) were mixed and stirred for 2 days , diluted with Et ₂ O and filtered. The filtrate was concentrated under high vacuum to give a brown solid. Trituration with Et ₂ O and hexane (1: 1, 200 ml) gave the title compound as a tan solid. Crystallization from acetone / hexane gave 0.505 g (64% of 5- (2-methoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (1-tert-butoxycarbonylpiperidin-4-yl) imidazole). ESP + (Mass Spec) m / z 453 (MH ⁺ ).

i) 5- (2-methoxy-4-pyrimidinyl) -4- (4fluorophenyl) -1- (4-piperidinyl) imidazole

The product of the preceding example (0.505 g, 1.43 mmol) was added to ice-cooled TFA under argon. The resulting solution was warmed to 23 ° C and stirred for 1.5 h. The TFA was removed in vacuo, the residue was dissolved in EtOAc and extracted with water (2 x 20 ml). The combined aqueous phases were separated with EtOAc and cooled to 4 ° C, basified by the addition of 10% aqueous NaOH solution and the aqueous phase extracted with EtOAc (4 x 25 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give a white crystalline solid. Treatment of the solid with hexane gave 165 mg of a white solid. Evaporation of the above filtrate gave an additional 133 mg of light yellow crystals. Total yield 298 mg (59%). For the first amount of crystals collected: m.p. Mp 159-160 ° C.

All publications, including, but not limited to, patents and patent applications cited in this specification, are incorporated herein by reference, as if the individual publications were fully disclosed.

The above description fully discloses the invention, including its preferred embodiments. Modifications and improvements to the embodiments specifically described herein are within the scope of the following claims. Without further elaboration, any person skilled in the art may, using the foregoing description, apply the present invention to its full extent. The examples therefore illustrate the invention but are not limited thereto.

Claims

Claims (24)

Claims 1. Compounds of the formula in which R _I represents a 4-pyridyl ring substituted with C ₁₄ alkoxy and optionally optionally substituted independently by C ₁₄ alkyl, halogen, hydroxy, C ₁₄ alkoxy, C ₁₄ alkylthio, C ₁₄ alkylsulfinyl, CH ₂ OR ₁₂ , amino, mono and di-C ( ₄ alkyl substituted amino, N (R ₁₀ ) C (O) R _c or N-heterocyclyl ring having a ring having from 5 to 7 atoms and optionally containing an additional heteroatom selected from oxygen, sulfur or NR ₁₅ ; R ₄ denotes phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one or two substituents, each of which is independently optionally selected and which substituent on 4-phenyl, 4-naphth-1-yl, 5-naphth-2yl or 6-naphth-2-yl is halogen, cyano, nitro, C (Z) NR ₇ R _t7 , C (Z ) ORj ₆ , (CR ₁₀ R _w ), COR ₁₂ , SR ₅ , SOR, OR ₁₂ substituted with halogen C ₁₄ alkyl, C ₁₄ alkyl, ZC (Z) R ₁₂ , NR ₁₀ C (Z) R ₁₆ or (CR, ^ NR ₁₀ R _m h which substituent for the other substitution site is halogen, cyano, C (Z) NR ₁₃ R ₁₄ , C (Z) OR ₃ , (CR 2 R 4 .CORj, S (O) _m R ₃ , ORj, substituted with halogen C _w alkyl, C ₁₄ alkyl, (CR ₁₀ R ₂₀ ) _b . NR ₁₀ C (Z) R ₃ , NR _{| 0} S (O) _n. R, NR ₁₀ S (O ) _ra .NR ₇ R ", ZC (Z) R ₃ or (CR _t0 R _{20) m} .NR ₁₃ R _l4; ve is 0, 1 or 2; n is 1 to 10; m is 0, 1 or 2; m 'is 1 or 2; m 'is 0 or 1 to 5; R 1 is optionally substituted heterocyclyl or optionally substituted heterocyclyl C 1. _{w is} an alkyl residue; Z is oxygen or sulfur; R _c 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; R ₃ is heterocyclyl, heterocyclyl C, allyl or R _s ; R _s is hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C ₂ . ₄ alkynyl or NR ₇ R ₁₇ , except that -SR ₃ is -SNR 4, and -SOR ₃ is -SOH; R 1 and R ₁₇ are independently selected from hydrogen or C ₁₄ alkyl or R 1 and R ₁₇ together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 atoms, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR ₁₃ ; R ₈ is C ₍₍₀ alkyl substituted with halogen Cj. _Lo alkyl, _C2-10 alkenyl, _{C2. [0} alkynyl, C _{3. 7} cycloalkyl, C _{J 7} cycloalkenyl, aryl, aryl Cj ,,, alkyl, heteroaryl, heteroarylC ₁₀ alkyl, (CR ₁₀ R ₂₀ ) _n OR _H , (CRjJJ.S.S (O) N, (CRjjR R) NHS (O) ₂ R ₁₈ , (CR ₁₀ R ₁₃ NR ₃ R ₁₄ , such as aryl, arylalkyl, heteroaryl, heteroarylalkyl can optionally be substituted; R, is hydrogen, C (Z) R _U or optionally substituted C ,. _1o alkyl, S (O) ₂ R _l8, 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 _tl is hydrogen, C _1-10 alkyl, C ₃ _, cycloalkyl, heterocyclyl, heterocyclyl Cj., 0 alkyl, aryl, aryl Cj. _l0 alkyl, heteroaryl or heteroaryl C _1-10 alkyl; R _l2 is hydrogen or R _16; Rj ₃ and R ₁₄ are each independently selected from hydrogen or an optionally substituted C _1-4 alkyl, optionally substituted aryl, or optionally substituted aryl C _{( -4} alkyl, or together with the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR ,; R ₁₃ is R ₁₀ or C (Z) -C ₁₄ alkyl; R ₁₆ is C _1-4 alkyl substituted with halogen C 1-4 alkyl or C ₃ . ₇ cycloalkyl; R, is C,. _w alkyl, C ₃₇ cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl C _1-10 alkyl, heteroaryl or heteroaryl C, | _O alkyl; or pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ₍ is substituted by isopropoxy, ethoxy or methoxy). A compound according to claim 1, wherein R 1 is optionally substituted phenyl. A compound according to claim 3 wherein the phenyl is mono or polysubstituted independently of halogen, SR _s , S (O) R ₃ , OR ₁₂ substituted with halogen C _1-4 alkyl or C ₁₄ alkyl. 5. A compound according to claim 4 wherein the phenyl is fluorine substituted. A compound according to claim 1, wherein R 1 is morpholinopropyl, piperidine, N-methylpiperidine, N-benzylpiperidine or 2,2,6,6-tetramethylpiperidine. A compound according to claim 1, which is 5- (2-methoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 5- (2-isopropoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier or diluent. A method for treating mammalian inflammation, wherein the mammal in need of treatment is treated with an effective amount of a compound of formula (I) according to claims 1 to 8. A method of treating a mammalian disease with a CSBP / RK / p38 kinase mediator, wherein the mammal is treated with an effective amount of a compound of formula (I) according to claims 1 to 8. 12. The method of claim 11, wherein the disease mediated CSBP / RK / p38 kinase is psoriasis arthritis, Reiter syndrome, rheumatoid arthritis, gout, gouty arthritis, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid arthritis rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic with thawing, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, neurotrauma, respiratory distress syndrome in adults, malaria, adult diseases, silicosis, pulmonary sarcoisosis, bone resorption disease, osteoporosis, restenosis, cardiac or renal reperfusion injury, thrombosis, glomerulonephritis, diabetes, transplant response to host, allograft rejection, colitis, collagen, dermatitis, psoriasis, sunburn and conjunctivitis. A method for preparing a compound of formula (I) as defined in claim 1, wherein the compound of formula ArS (O) _p R4 nc is reacted with a compound of formula Ri NR ₂ V (III) n where ρ is 0 or 2, and a base strong enough to deprotonate the isonitrile residue of formula II R _p Rj and R ₄ are as defined in claim 1 or are precursors for the groups R _t , R j, R ₄ and Ar is optionally substituted phenyl group and then, if necessary, the precursors of the groups R _t , R ₂ and R ₄ are converted to the groups Rp 1 ^ and R ₄ . 14. A method according to claim 13, wherein p is 0. 15. The method of claim 13 wherein p is 2. 16. The process of claim 15, wherein the base is an amine, carbonate, hydride or alkyl or aryl lithium reagent. A method according to claim 13, wherein the imine of formula (III) is isolated before reacting with the compound of formula (II). A method according to claim 13, characterized in that the imine of formula (III) is obtained in situ before reacting with the compound of formula (II). A method according to claim 18, characterized in that the imine is obtained in situ by reacting an aldehyde of formula R 1 HO, in which R 1 has the meanings defined for formula (I), with a primary amine of formula R ₂ NH ₂ , wherein R ₂ has the meanings defined for formula (I). 20. The method of claim 19, wherein dehydration conditions are used to form imine in situ. 21. The method according to claim 15, 19 or 20, wherein the solvent is N, N-dimethylformamide (DMF), halogenated solvent, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), alcohol, benzene, toluene, MeCN or DME . A method according to claim 19, characterized in that the aldehyde R, CHO is a pyridinaldehyde of formula ⁵ wherein X is C _1-4 alkoxy and X is defined as optionally a substituent on R, the residue of formula (I ) according to claim 1. for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Yu A method according to claim 19, wherein the R ₂ residue in the primary amine R ₁ NH ₂ is piperidine, 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1- ethoxycarbonyl-4-piperidine, 1-tert-15bisoxycarbonyl-4-piperidine, 2,2,6,6-tetramethyl-4-piperidine, morpholinoethyl, morpholinopropyl, pyrrolidinylpropyl or piperidinylpropyl. A method according to claim 13, wherein the compound is: 20 5- (2-methoxy-4-pyridinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole or 5- (2-Isopropoxy-4-pyridinyl) -4- (4fluorophenyl) -1- (4-piperidinyl) imidazole or a pharmaceutically acceptable salt thereof. Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, Dr. Γ Blvd. M. Dimitrov 52-B