JP2001506230A - New piperazine-containing compounds - Google Patents

Abstract

  (57) [Summary] Novel 3-carboxyindole piperazinamide-containing compounds and compositions for use in therapy as anti-inflammatory agents, inhibitors of cytokine p38 / MAP kinase-mediated diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION                         New piperazine-containing compoundsField of the invention   The present invention relates to a novel class of indole-containing compounds, their preparation, their cytokines Use in the treatment of intervening diseases and pharmaceutical compositions for use in such treatment About things.Background of the Invention   Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are Biological material produced by various cells such as clophages. IL-1 Is thought to be important in other physiological conditions such as immune regulation and inflammation It has been demonstrated to mediate various biological activities [Dinarello et al.,Rev . Infect. Disease ,6, 51 (1984)]. Countless known sources of IL-1 Physical activities include activation of T helper cells, induction of fever, prostaglandin Or stimulation of collagenase production, neutrophil chemotaxis, induction of acute phase proteins and And suppression of plasma iron concentration.   Excessive or unregulated IL-1 production is involved in disease progression and / or pathogenesis There are many conditions. For example, rheumatoid arthritis, osteoarthritis, endotoxemia and And / or toxic shock syndrome, inflammatory response or inflammation induced by endotoxin Other acute or chronic inflammatory conditions, such as sexual bowel disease; tuberculosis, atherosclerosis, myopathy Sex, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, outside These include traumatic arthritis, rubella arthritis and acute synovitis. Recently, IL-1 activity Sex has also been shown to be associated with diabetes and pancreatic beta cells.   DinarelloJ . Clinical Immunologv, 5 (5), 287-297 (1985). Report a biological activity attributable to -1. Some of these effects are: Note that others have described as an indirect effect of IL-1 It is.   Excessive or unregulated TNF production is associated with rheumatoid arthritis, rheumatoid spondylitis, Osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, Endotoxin shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome , Cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion Susceptibility to injury, graft-versus-host reaction, allograft rejection, influenza Fever and muscle pain due to infection, cachexia secondary to infection or malignancy, acquired immunity Cachexia, AIDS, ARC (AIDS-related) secondary to the epidemic deficiency syndrome (AIDS) Complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis Or it is involved in the mediation or exacerbation of many diseases, including fever.   AIDS results from infection of T lymphocytes with human immunodeficiency virus (HIV) . At least three types of HIV, namely HIV-1, HIV-2 and HIV-3, have been identified. It has been certified. HIV infection results in impaired T-cell mediated immunity and infection Individuals present with severe opportunistic infections and / or abnormal tumors. HIV is T lymph T lymphocytes must be activated to enter the sphere. HIV-1, HI Other viruses, such as V-2, infect T lymphocytes after T cell activation, Viral protein expression and / or replication is mediated by such T cell activation. Be present or maintained. Once activated T lymphocytes become infected with HIV, HI T lymphocytes are activated to express the V gene and / or replicate HIV. It must be maintained in a sexual state. Monokine, especially TNF, is a T lymphocyte Activated T cell mediated HIV protein by playing a role in maintaining activation Involved in quality expression and / or virus replication. Therefore, infected with HIV Monokine activity in an individual, such as inhibiting the production of monokines, especially TNF Interference helps limit the maintenance of T cell activation, thereby reducing HIV infectivity Of HIV to uninfected cells is reduced, resulting in immune dysfunction caused by HIV infection Progression is delayed or eliminated. Monocytes, macrophages, and cup fur cells Related cells such as vesicles and glial cells are also involved in maintaining HIV infection. these Cells, like T cells, are targets for viral replication and The bell depends on the activation state of the cell. [Rosenberget al., The Immunopathoge nesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)] . Monokines, such as TNF, are used in monocytes and / or macrophages to produce HIV. It has been proven to activate replication [Poli,et al., Proc. Natl. Acad. Sci ., 87: 782-784 (1990)]. Therefore, monokine production or activation Inhibition helps to limit HIV progression as described for T cells.   TNF is also used for cytomegalovirus (CMV) for similar reasons as described. And other viral infections, such as influenza virus and herpes virus Involved in various roles.   Interleukin-8 (IL-8) was first identified and characterized in 1987 It is a chemotactic factor. IL-8 is expressed in mononuclear cells, fibroblasts, endothelial cells and keratinocytes. Produced by several types of cells, including noocytes. Its production from endothelial cells is IL -1, induced by TNF or lipopolysaccharide (LPS). Human IL-8 is mouse Has been shown to act on neutrophils in guinea pigs, rats and rabbits. IL-8 includes neutrophil attractant / activating protein-1 (NAP-1), monocyte-derived Neutrophil chemotactic factor (MDNCF), neutrophil activator (NAF) and T-cell phosphorus Many different names have been given, such as papocyte chemotactic factors.   IL-8 stimulates various functions in vitro. IL-8 is neutrophil, T It has been shown to have chemoattractant properties for emphocytes and basophils. In addition, the substance may be found to be a hista from basophils from both normal and atopic individuals. Release of lysozyme from neutrophils and respiratory burst Trigger. IL-8 can also be expressed on neutrophils without synthesizing new proteins. Increased the surface expression of Mac-1 (CD11b / CD18). This may increase neutrophil adhesion to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. With increasing IL-8 production Symptoms (involved in neutrophil chemotaxis to inflammatory sites) suppress IL-8 production Improved by some compounds.   IL-1 and TNF affect a wide range of cells and tissues, Itokine and other leukocytes derived from cytokines have a wide range of conditions and symptoms. It is an important and critical inflammatory mediator. Inhibition of these cytokines It is useful in controlling, reducing, and alleviating many of these conditions.   In this field, for therapeutic use, cytokine-suppressing anti-inflammatory drugs, ie, IL- 1. Compounds having the ability to inhibit cytokines such as IL-6, IL-8 and TNF Things are needed.Summary of the Invention   The present invention relates to novel compounds of formula (I) or (II), as well as compounds of formula (I) or (II). And a pharmaceutically acceptable diluent or carrier.   The invention also requires the inhibition of cytokines and the treatment of cytokine-mediated diseases. The inhibitory method and the therapeutic method in a mammal, wherein the method is effective for the mammal. A method comprising administering an amount of a compound of formula (I) or (II).   In particular, the present invention requires treatment of CSBP / RK / p38 kinase-mediated disease. The method of treatment in a mammal.   The invention is more particularly directed to mammals in need of inhibition of IL-1 production. Administering to the mammal an effective amount of a compound of Formula (I) or (II). And a method comprising:   The invention is more particularly directed to mammals in need of inhibiting IL-8 production. Administering to the mammal an effective amount of a compound of Formula (I) or (II). And a method comprising:   The invention more particularly relates to a method for inhibiting TNF production in a mammal in need thereof. The method of inhibiting, wherein the mammal is administered an effective amount of a compound of Formula (I) or (II). And a method comprising:   Accordingly, the present invention provides a compound of formula (I) or formula (II): (Where   R₁Is hydrogen, alkyl, aryl, heteroaryl, aryloxy, Lowaryloxy, nitro, amino, cyano, carboxy, carboxyalkoxy Or carboxamide or halogen, wherein aryl, heteroaryl Or heteroaryloxy or aryloxy groups are optionally substituted May be   R_TwoIs aryl, heteroaryl, arylalkyl, heteroaryl Alkyl, cycloalkyl, or cycloalkylalkyl, where Wherein all of these groups may be optionally substituted) Or a pharmaceutically acceptable salt thereof.Detailed description of the invention   In a compound of formula (I) or (II), R₁Is suitably hydrogen, alkyl, ant , Heteroaryl, aryloxy, heteroaryloxy, nitro, amine , Cyano, carboxy, carboxyalkoxy, carboxamide, or ha Where aryl, heteroaryl, heteroaryloxy, or Or aryloxy group is halogen; haloalkyl (CF_ThreeEtc.); alkyl; Ano; carboxy, carboxyalkoxy, carboxamide, nitro; alcohol Hydroxy; amino; mono- or di-substituted alkylamino; or S (O)_mAlkyl (where m is 0, 1 or 2; methylthio, methyls Lufinyl or methylsulfonyl, etc.), optionally 1-3 times independently It may be substituted. Preferably, R₁The group is at the 5-position on the indole ring. A Reel, heteroaryl, aryloxy, and heteroaryloxy groups are described herein. It may be optionally substituted one or more times as defined in the text. R₁Is allie When R is₁Is phenyl; R₁Is an aryloxy If preferred, R₁Is benzyloxy.   In a compound of formula (I) or (II), R_TwoIs suitably an aryl, hetero Aryl, arylalkyl, heteroarylalkyl, alkyl, cycloal Or a cycloalkylalkyl group. Each of these groups is a halogen ; Haloalkyl (CF_ThreeAlkyl; cyano; carboxy, carboxyl Coxy, carboxamide, nitro; alkoxy; hydroxy; amino; Or disubstituted alkylamino; or S (O)_mAlkyl (where m is 0, 1 or Is 2. Methylthio, methylsulfinyl or methylsulfonyl) If desired, it may be independently substituted one or more times.   Preferably R_TwoR is aryl_TwoIs phenyl, preferably R_Two Is an arylalkyl group,_TwoIs benzyl, phenethyl or naphthyl Methyl. Preferably R_TwoIs heteroaryl or heteroarylalkyl If R_TwoIs a pyridyl or pyrimidine group. Arylalkyl group Is also a halogen, hydroxy, alkoxy, alkyl, a Reel, heteroaryl, arylalkyl, or heteroarylalkyl groups It may be optionally substituted by, for example.   As used herein, “optionally substituted” means, unless otherwise specified. Halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy Substitution C_1-10Alkyl; C_1-10Alkoxy, such as methoxy or ethoxy; Ano; carboxy, carboxyalkoxy, carboxamide, S (O)_mArchi (Where m is 0, 1 or 2), for example, methylthio, methylsulfur Nyl or methylsulfonyl; amino, mono & di-substituted amino; C_1-10Alkyl , Cycloalkyl, or cycloalkylalkyl groups such as methyl, ethyl , Propyl, isopropyl, t-butyl and the like, or cyclopropylmethyl; B substitution C_1-10Alkyl, for example CF_ThreeA hete which may be optionally substituted Loaryl, aryl, e.g., phenyl, or optionally substituted Heteroarylalkyl, arylalkyl such as benzyl or phenethyl Where these aryl groups are also halogen; hydroxy; Substituted alkyl; C_1-10Alkoxy; cyano; carboxy, carboxyalkoxy, Carboxamide, S (O)_mAlkyl; amino, mono- and di-alkyl-substituted amino; Alkyl, or halo-substituted alkyl, for example CF_ThreeMay be replaced by Means a group.   Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric acid, hydrobromic acid , Sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid , Citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, Basic salts of inorganic and organic acids such as lylic acid, phenylacetic acid and mandelic acid Include. In addition, for example, if the substituent comprises a carboxy group, it is pharmaceutically acceptable Pharmaceutically acceptable salts of the compounds of formula (I) with cations may be formed. Appropriate Pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, Ammonium and quaternary ammonium cations.   The following terms, as used herein, mean the following:   "Halo" or "halogen" is halogen: chlorine, fluorine, bromine and iodine Element.   ・ "C_1-10"Alkyl" or "alkyl" means that the chain length is not specified, Straight-chain and branched groups having 1 to 10 carbon atoms, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- Including, but not limited to, butyl, n-pentyl, and the like.   -"Aryl" refers to phenyl and naphthyl.   "Cycloalkyl" as used herein, preferably from 3 to 8 Means a cyclic group having two carbon atoms, cyclopropyl, cyclopentyl, cyclopropyl But not limited thereto.   "Heteroaryl" (alone or "heteroaryloxy" or " Pyrrole, pyrazole, phenyl) Orchid, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pirimi Gin, oxazole, thiazole, thiadiazole, triazole, imidazo One or more, such as, but not limited to, benzimidazole One or more heteroatoms wherein the ring is selected from the group consisting of N, O or S Means a 5- to 10-membered aromatic ring system, including the ring.   ・ "Heterocyclic" (alone or heterocyclylalkyl) (In any combination) is pyrrolidine, piperidine, piperazine, morpholine, Up to one such as, but not limited to, tetrahydropyran or imidazolidine One or more rings are selected from the group consisting of N, O or S A saturated or partially unsaturated 4- to 10-membered ring system containing the above heteroatoms .   ・ "Aralkyl" or "heteroarylalkyl" or "heterocyclyl" The term "alkyl" as used herein refers to the aryl as defined above unless otherwise specified. The above C attached to a hetero, heteroaryl or heterocyclic group_1-4Al Used to mean kill.   “Sulfinyl” refers to the oxide S (O) of the corresponding sulfide, and “thio” The term “sulfonyl” refers to sulfide and the term “sulfonyl” (O)_TwoMeans a group.   Examples of compounds of formula (I) include:   1- (1H-indol-3-ylcarbonyl) -4- (benzyl) piperazine   1- (1H-indol-3-ylcarbonyl) -4- (phenyl) piperazine   1- (1H-indol-3-ylcarbonyl) -4- (2-pyridinyl) pipera gin   1- (1H-indol-3-ylcarbonyl) -4- (2-pyrimidinyl) pipe Razine   1- (1H-indol-3-ylcarbonyl) -4- (diphenylmethyl) pipe Razine   1- (1H-indol-3-ylcarbonyl) -4- (4-pyridinylmethyl) Piperazine   1- (1H-indol-3-ylcarbonyl) -4- (4-trifluoromethyl (Ruphenylmethyl) piperazine   1- (1H-indol-3-ylcarbonyl) -4- (4-fluorophenyl Methyl) piperazine   1- (1H-indol-3-ylcarbonyl) -4- (methyl) piperazine   1- (1H-indol-3-ylcarbonyl) -4- (cyclohexyl) pipera gin   1- (1H-indol-3-ylcarbonyl) -4- (cyclopropylmethyl) Piperazine   1- (1H-indol-3-ylcarbonyl) -4- (4-methylbenzyl) pi Perazine   1- (1H-indol-3-ylcarbonyl) -4- (4-cyanobenzyl) pi Perazine   1- (1H-indol-3-ylcarbonyl) -4- (2-naphthyl) piperazi N   1- (1H-indol-3-ylcarbonyl) -4- (2-phenylethyl) pi Perazine   1- (1H-indol-3-ylcarbonyl) -4- (4-methoxybenzyl) Piperazine   1- (1H-5-bromoindol-3-ylcarbonyl) -4- (benzyl) pi Perazine   1- (1H-5-methylindol-3-ylcarbonyl) -4- (benzyl) pi Perazine   1- (1H-5-chloroindol-3-ylcarbonyl) -4- (benzyl) pi Perazine   1- (1H-5-benzyloxyindol-3-ylcarbonyl) -4- (be Ndil) Piperazine   1- (1H-5-nitroindol-3-ylcarbonyl) -4- (benzyl) Piperazine   1- (1H-5-fluoroindol-3-ylcarbonyl) -4- (benzyl) Piperazine   1- (1H-5-aminoindol-3-ylcarbonyl) -4- (benzyl) pi Perazine   1- (1H-5-phenylindol-3-ylcarbonyl) -4- (benzyl) Piperazine.   Compounds of formula (I) or (II) are described herein, some of which are Scheme I It is obtained by applying a synthesis method described below. Synthesis of these schemes Is a reaction employing any appropriately protected substituent, and the reaction is outlined in this specification. Various different R's are consistent with the response shown.₁And R_TwoFormula (I) having a group or It can be applied to the production of the compound (II). In this case, then deprotect and disclose to the public To obtain a compound of the specified properties. Once the nucleus has been established, further (I) or (II) Compounds are applied by applying standard techniques for functional group transformations well known in the art. Can be manufactured.       Scheme 1-General Method   Substituted indole-3-carboxylic acids (formula (I)) From trifluoroacetic anhydride (TFAA) with THF or DMF To give 3-trifluoroacetylindole 3 (Scheme 1) Katner [Katner, A .; S. Organic Preps and Procs. 1970, 2 (4), 297-303] Method. Trifluoroacetylindole followed by strong alkaline conditions To give 4. Piperazinylamide 5 is used as a binder with thionyl chloride. The reaction between amine and carboxylic acid 4 using Build. Another analog, in some cases after the amide formation, is₁And R_Twoof Obtained by further modification.   Indole-4-carboxylic acid (formula (II)) is prepared similarly, Scheme 2 below reference.       Scheme 2-Indole 4-carboxamide   A commercially available piperazine is converted to an amine from 4-BOC-piperazine with an electrophile. By reacting with the substance and then removing the BOC protecting group with TFA. (Scheme 3).       Scheme 3-Preparation of Substituted Piperazines   Suitable protecting groups for use on hydroxyl and the like are well known in the art and include, for example, Protecting Groups in Organic Synthesis, Greene TW, Wiley-Interscience, New It is described in many documents such as York, 1981. Suitable examples of hydroxy protecting groups Include silyl ethers such as t-butyldimethyl or t-butyldiphenyl And alkyl ethers such as variable linking groups, (CR_TenR₂₀)_nArchi Methyl and the like linked by a single chain.   Pharmaceutically acceptable acid addition salts of compounds of formula (I) or (II) include, for example, Known methods, such as by reacting with an appropriate amount of an acid in the presence of an appropriate solvent Can be obtained byMethod of treatment   The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may be human or other. Cells of the mammal, such as monocytes and / or macrophages (Including but not limited to) excessive or unregulated cytokine production In the manufacture of a medicament for the prophylactic or therapeutic treatment of a disease state Can be.   Compounds of formula (I) or (II) are pro-inflammatory cytokines such as IL-1, I L-6, IL-8 and TNF can be suppressed and therefore used in therapy Can be. IL-1, IL-6, IL-8 and TNF have a wide range of cells and These tissues, which affect tissues, as well as other leukocyte-derived sites Cain is an important and critical inflammatory mediator of a wide range of conditions and symptoms It is. Inhibition of these proinflammatory cytokines controls many of these conditions, Useful for mitigating and mitigating.   Accordingly, the present invention is a method of treating cytokine-mediated An effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable A method is provided that comprises administering a salt.   For the purposes of this specification, the compounds of formulas (I) and (II) are all on the same dosage , Formulas (I) are used interchangeably in the present invention.   The compounds of formula (I) have many other names, for example, prostaglandin endoperon. Inducibility of COX-2 and the like, also called oxide synthase-2 (PGHS-2) Proinflammatory proteins can be inhibited and therefore used in therapy. Proinflammatory lipid mediators of these cyclooxygenase (CO) pathways trigger Produced by the sex COX-2 enzyme. Therefore, such as prostaglandins The regulation of COX-2 associated with these products from rachidonic acid is extensive. Affects critical cells and tissues and is critical for a wide range of conditions and symptoms. He is an inflammatory mediator. COX-1 expression is affected by the compound of formula (I). I can't. This selective inhibition of COX-2 is associated with ulcer induction associated with inhibition of COX-1. Prostaglandins that reduce or eliminate trends and are thus essential for cytoprotective effects Inhibits. Thus, inhibition of these proinflammatory mediators could Useful for many adjustments, alleviation and alleviation of qi. Most notably, these Inflammatory mediators, especially prostaglandins, Sensitization or edema. This aspect of pain treatment is therefore Includes the treatment of transmyalgia, headache, cancer pain, and arthritis pain. A compound of formula (I) or Its pharmaceutically acceptable salts are derived from human or other humans by inhibiting the synthesis of the COX-2 enzyme. Useful for prevention or treatment in mammals.   Accordingly, the present invention is directed to a method of inhibiting the synthesis of COX-2, comprising an effective amount of a compound of formula (I) Or a pharmaceutically acceptable salt thereof. The present invention further provides humans or other mammals with inhibition of COX-2 enzyme synthesis. To provide preventive treatment in   A new member of the MAP kinase family, CSBP, p38, or RK Some have also been separately identified in some laboratories recently. This new tag Activation of protein kinases by dual phosphorylation can be caused, for example, by physicochemical stress and And proinflammatory such as lipopolysaccharide or interleukin-1 and tumor necrosis factor Different cell lines stimulated by a wide range of stimuli, such as treatment with cytokines Has been observed in A cytokine biosynthesis inhibitor of the present invention, a compound of formula (I) Is a potent and selective inhibitor of CSBP / p38 / RK kinase activity It is shown. These inhibitors modulate signaling pathways associated with the inflammatory response. It will help you. In particular, for the first time, a definitive signal transduction pathway Regulation on the effect of lipopolysaccharide on cytokine production in macrophages Wear.   Subsequently, cytokine inhibitors were used in many animal models for anti-inflammatory activity. Tested. To elucidate the unique activity of cytokine inhibitors, a model system Those that were relatively insensitive to rhoxygenase inhibitors were selected. Inhibitors Many such in vivo studies have shown significant activity. Most notable Shows efficacy in collagen-induced arthritis model and endotoxin shock model Inhibition of TNF production. In the latter study, the decrease in plasma levels of TNF was , Associated with survival and protection from death associated with endotoxin shock. Rat womb Compounds useful for inhibiting bone resorption in infant long bone organ culture systems are also very important. You. 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, 533-53 8; Lee et al., (1993). B Ann. IV. Y. Acad Sci. 696, 149-170.   Therefore, another aspect of the present invention is directed to CSBP / RK / p38 kinase mediated diseases. The treatment of a mammal in need thereof, comprising administering an effective amount of a compound of formula (I). A method comprising administering to said mammal. Suitable diseases include IL-1, I Including those described for L-6, IL-8 and TNF, and more particularly, The disease is a CSBP / RK / p38 kinase-mediated disease. These include chronic Rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joints Inflammation, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxicity Shock syndrome, asthma, adult respiratory distress syndrome, seizures, reperfusion injury, openness and non-perfusion CNS injuries such as neurotrauma and ischemia, including both open head injuries, psoriasis, coronary blood Restenosis as occurs after tube formation, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoid Dosis, bone resorption, osteoporosis, graft-versus-host reaction, allograft rejection , Crohn's disease, ulcerative colitis, or other anti-inflammatory bowel disease (IBD), or fever Diseases include, but are not limited to.   CNS injury as defined herein refers to an open or penetrating head Includes both injuries or non-open head injuries, such as due to head injuries. Especially to the brain Also, ischemic stroke is included within the scope of this definition.   Ischemic stroke is usually the result of a local atheromatous closure of an embolus, thrombus or blood vessel Is defined as focal neuropathy caused by insufficient blood supply to a particular brain You. Here, the role of inflammatory cytokines has been elucidated. Provides an effective method of treating these injuries. For acute damage like these For that reason, relatively few treatment methods are available.   TNF-α is a cytokine that has pro-inflammatory effects, including endothelial leukocyte adhesion molecule expression. It is. Leukocytes infiltrate into ischemic brain lesions and thus inhibit TNF Compounds that reduce or reduce the levels thereof are useful for treating ischemic brain injury. Liuet al., Stoke, Vol. 25, No. 7, pp 1481-88 (1994) (cited See).   A model of non-open head injury and treatment with a mixed 5-LO / CO agent is described in Shoham i et al., J. Amer. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No . 2, pp. 99-107 (1992), which is incorporated herein by reference. You. Treatments that reduce edema formation improve functional outcome in these treated animals It turned out to be.   In particular, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be a human or other mammal. Animal cells, such as, but not limited to, monocytes and / or macrophages Exacerbated by excessive or unregulated IL-1, IL-8 or TNF production Prevention or treatment of such diseases in mammals that cause or cause Useful for   Thus, in another aspect, the invention requires the inhibition of IL-1 production. A method for inhibiting IL-1 production in a mammal, comprising administering to said mammal an effective amount of a formula ( A method comprising administering a compound of I) or a pharmaceutically acceptable salt thereof. .   Excessive or unregulated IL-1 production is involved in disease progression and / or development There are many diseases. These diseases include rheumatoid arthritis, osteoarthritis, seizures Endotoxemia and / or toxic shock syndrome, inflammation induced by endotoxin Other acute or chronic inflammatory conditions such as sexual response or inflammatory bowel disease, tuberculosis, atherosclerosis Sclerosis, muscle degeneration, muscle sclerosis, cachexia, bone resorption, psoriatic arthritis, lighter Syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovium Includes flame. Recently, IL-1 activity has been demonstrated in diabetes, pancreatic beta cells and Alzheimer's disease. It has been shown to be associated with Myr disease.   In yet another aspect, the invention provides a mammal in need of inhibiting the production of TNF. For inhibiting the production of TNF in a mammal, comprising administering to said mammal an effective amount of a compound of formula (I). Or a method comprising administering a pharmaceutically acceptable salt thereof.   Excessive or unregulated TNF production is associated with rheumatoid arthritis, rheumatoid spondylitis, Osteoarthritis, gouty arthritis and other arthritis; sepsis, septic shock, endotoxin Elementary shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, Crops, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, bones such as osteoporosis Resorption, reperfusion injury, graft-versus-host reaction, allograft rejection, flu Fever and muscle pain from infections such as enza, cachexia secondary to infection or malignancy ー, cachexia, AIDS, ARC secondary to acquired immunodeficiency syndrome (AIDS) (AIDS-related syndrome), keloid formation, scar tissue formation, Crohn's disease, ulcerative colon It is involved in the mediation or exacerbation of many diseases, including inflammation or fever.   Compounds of formula (I) further provide for up-regulation of the virus by TNF. Viruses that are susceptible to or cause TNF production in vivo It is also useful in treating infectious diseases. The virus associated with the treatment of the invention may be an infectious virus. Or a TNF inhibiting compound of formula (I) That are sensitive to inhibition, such as reduced replication, directly or indirectly. Such viruses include HIV-1, HIV-2 and HIV-3, Tomegalovirus (CMV), influenza, adenovirus and herpes Loop viruses such as herpes zoster and herpes simplex It is not limited to. Thus, in a further aspect, the invention relates to a human immunodeficiency A method of treating a mammal afflicted with a virus (HIV), wherein the mammal has TNF inhibition. Administering a harm-effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Containing methods.   The compound of formula (I) may further comprise a non-human mammal in need of inhibiting TNF production. Can be used for veterinary treatments. Therapeutic or prophylactic in animals TNF-mediated diseases to be treated include the conditions described above, but are particularly It is a stain. Examples of such viruses include, for example, equine infectious anemia virus, goat Lentivirus, such as arthritis virus, visna virus, or maedi virus Infection or retroviral infection, such as, but not limited to, feline immunity Deficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus. Or other retroviral infections.   Compounds of formula (I) may further be subjected to excess support such as IL-1 or TNF, respectively. Local conditions mediated or exacerbated by itokine production, such as inflammation Awake joints, eczema, contact dermatitis, psoriasis and other inflammatory, such as sunburn Cutaneous symptoms; inflammatory symptoms of the eye, including conjunctivitis; fever, pain and other inflammation-related It can be used topically in the treatment or prevention of symptoms and the like.   The compounds of formula (I) also inhibit the production of IL-8 (interleukin-8, NAP). It has been shown to harm. Therefore, in a further aspect, the present invention provides A method of inhibiting IL-8 production in a mammal in need of inhibiting L-8 production, Administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to said milk animal. And a method comprising:   Excessive or unregulated IL-8 production is involved in its deterioration and / or development. There are many diseases. These diseases include psoriasis, inflammatory bowel disease, asthma, heart and kidney Large amounts of neutrophils such as reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis Characterized by infiltration. All these diseases are neutrophil chemistry to inflammatory sites It is associated with increased IL-8 production, which is responsible for chemotaxis. Other inflammatory cytokines (I In contrast to L-1, TNF and IL-6), IL-8 is neutrophil chemotaxis and And has the property of promoting activation. Therefore, by inhibiting IL-8 production, Neutrophil infiltration is directly reduced.   The compounds of formula (I) may be cytokines, in particular IL-1, IL-6, IL-8 or Inhibits TNF production and reduces it to normal, or sometimes normal, levels It is administered in an amount sufficient to ameliorate or prevent the condition as adjusted below. For example a book Abnormal levels of IL-1, IL-6, IL-8 or TNF according to the invention can be expressed as ( i) 1 picogram / ml or more of free (not bound to cells) IL-1, IL-6 , IL-8 or TNF levels; (ii) any cell-bound IL-1, IL-6 , I L-8 or TNF; or (iii) IL-1, IL-6, IL-8 or Is IL-1, IL above basal levels in cells or tissues where TNF is produced -6, consisting of the presence of IL-8 or TNF mRNA.   Compounds of formula (I) may be cytokines, in particular IL-1, IL-6, IL-8 and T The finding that it is an inhibitor of NF has been identified in the in vitro assays described herein. Of the compound of formula (I) on the production of IL-1, IL-8 and TNF in Good.   As used herein, “IL-1 (IL-6, IL-8 or TNF) The term "inhibits the production of   (a) by all cells, including but not limited to monocytes or macrophages In vivo release of cytokines (IL-1, IL-6, IL-8 or TNF) Excessive in vivo levels of cytokines in humans by inhibiting Or reduced below normal levels;   (b) At the genome level, cytokines (IL-1, IL-6, IL-6) in humans -8 or TNF) to normal or subnormal levels. Unregulating;   (c) cytokines (IL-1, IL-6, IL-8 or Down-regulation by inhibiting direct synthesis of TNF); Or   (d) At the translation level, cytokines (IL-1, IL-6, IL- 8 or TNF) down to normal or below normal levels in vivo To regulate Means   The term “TNF-mediated disease or condition” as used herein refers to TNF Produce TNF itself, or TNF is produced by another monokine, such as IL- 1, to be able to release (but not limited to) IL-6 or IL-8 Means any and all diseases that play a role in. For example, if IL-1 Diseases that are the main component and whose production or action worsens or is secreted in response to TNF state Is considered to be a condition mediated by TNF.   As used herein, the term “cytokine” affects cell function. Are molecules that regulate cell-cell interactions in the immune, inflammatory or hematopoietic response , Means a secreted polypeptide. Which cells produce cytokines Including but not limited to monokines and lymphokines No. For example, monokines are commonly found in macrophages and / or monocytes and the like. It is produced and secreted by mononuclear cells. However, many other cells are also Natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, stellate brain Monocytes such as cells, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes Produce Lymphokines generally refer to those produced by lymphocytes. Examples of cytokines include interleukin-1 (IL-1), interleukin -6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor-beta (TNF-β) Not done.   As used herein, “cytokine interference amount” or “cytokine The term `` inhibitory amount '' refers to a condition exacerbated by excessive or unregulated cytokine production. Or when administered to patients to prevent or treat Formula (I) for reducing in vivo levels of tocaine to normal or below normal levels An effective amount of the compound is meant.   As used herein, "sites used in the treatment of humans infected with HIV" Cytokines in the phrase "inhibition of Cain" include (a) initiation of T cell activation and And / or maintaining and / or activating T cell mediated HIV gene expression and / or And / or (b) problems associated with cytokine-mediated diseases, such as cachexia Or a cytokine involved in muscle degeneration.   TNF-β (also called lymphotoxin) is called TNF-α (also called cachectin). Organisms with close structural homology, each of which is similar to the same cellular receptor TNF-α and TNF-β both elicit a biological response and bind Inhibited by the given compounds and therefore, unless otherwise noted herein, inclusive This is referred to as "TNF".   To use a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy, It is usually formulated into pharmaceutical compositions according to standard pharmaceutical practice. Therefore, The present invention further provides an effective, non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier. And a pharmaceutical composition comprising a body or a diluent.   The compound of the formula (I), a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same, Conveniently, by the conventionally used routes for dosing, for example, orally, topically It can be administered parenterally or by inhalation. The compounds of the formula (I) are prepared in a customary manner. It is thus prepared by combining a compound of formula (I) with a standard pharmaceutical carrier. It can be administered in any conventional dosage form. The compounds of the formula (I) are further known as second therapeutically It can be administered in conventional dosages in combination with the active compound. These methods use the ingredients Mix, granulate and compress or dissolve as appropriate for desired preparation Including doing. The form and characteristics of the pharmaceutically acceptable carrier or diluent Determined by the amount of active ingredient to be administered, the route of administration and other well-known variables. Will be recognized. The carrier (s) is compatible with the other ingredients of the formulation and Must be "acceptable" in the sense that it is not harmful to   The pharmaceutical carrier employed can be, for example, either a solid or liquid. Solid carrier Examples are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, Gum arabic, magnesium stearate, stearic acid and the like. Liquid carrier Examples are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or The diluent is glyceryl monostearate or glyceryl distearate May be included, alone or with a wax, as is well known in the art.   A wide variety of pharmaceutical forms can be used. Therefore, using a solid carrier If desired, the preparation may be tableted or hard gelatine in powder or pellet form. It can be in capsules or in the form of a troche or lozenge. Solid charge Body mass will vary widely but preferably is from about 25 mg to about 1 g. liquid If a carrier is used, the preparation should be syrup, emulsion, soft gelatin capsule , In the form of a sterile injectable solution such as an ampoule or a non-aqueous liquid suspension.   The compounds of formula (I) can be administered locally, ie, by non-systemic administration. This These include external application of the compound of formula (I) to the epidermis or oral cavity and the ear of the compound, Eye and nasal inhalation, so that the compound significantly enters the bloodstream. do not do. In contrast, systemic administration includes oral, intravenous, intraperitoneal and intramuscular administration. Indicates intramuscular administration.   Formulations suitable for topical administration are liquids suitable for penetrating the site of inflammation through the skin Or semi-liquid preparations such as liniments, lotions, creams, ointments or paints And drops suitable for administration to the eye, ear or nose. The active ingredient is For topical administration, 0.001% to 10% w / w of the formulation, for example 1% to 2% % By weight. However, the amount is like 10% w / w of prescription But preferably less than 5% w / w, more preferably 0.1% to 1% w / w. w.   The lotions of the present invention include those suitable for application to the skin or eyes. Eyes The solution contains a sterile aqueous solution which may optionally contain a bactericide. Prepared by a similar method. Lotion or linimen for application to skin Is an agent that promotes drying and cooling of the skin, such as alcohol or acetone. And / or moisturizing oils such as glycerol or castor oil or peanut oil Agents may be included.   The cream, ointment or paste according to the invention is a semi-solid active ingredient for external application. Body prescription. These can be used alone or in the form of finely divided or powdered active ingredients. Are in the form of solutions or suspensions in aqueous or non-aqueous fluids, and It is prepared by mixing with a leasing or non-greasy base. The base is charcoal Hydrogen, such as solid, soft or liquid paraffin, glycerol, beeswax, gold Genus soap; Serous; almond, corn, peanut, castor oil or olive oil Oils of natural sources such as wool fat or its derivatives or alcohols, such as propyle Such as stearic acid or oleic acid with glycol or macrogel Fatty acids and the like may be included. Formulations may contain suitable surfactants such as anions, clicks On or non-ionic surfactants, such as sorbitan esters or their poly An oxyethylene derivative may be included. Suspending agents such as natural gums, cellulose Derivatives or inorganic substances such as siliceous silica and other components such as lanolin May be included.   Drops of the invention may comprise a sterile aqueous or oily solution or suspension, and may contain an active ingredient. The components are preferably selected from fungicides and / or fungicides and / or other suitable preservatives. Or by dissolving in a suitable aqueous solution containing a surfactant. One The resulting solution is then clarified by filtration, transferred to a suitable container, which is sealed, Autoclave or maintain at 98-100 ° C for half an hour Treat with bacteria. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. You may. Examples of fungicides or fungicides suitable for inclusion in drops are nitric acid or Are phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and And chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution are Includes glycerol, dilute alcohol and propylene glycol.   The compounds of formula (I) may be administered parenterally, i.e., intravenously, intramuscularly, subcutaneously, intranasally, rectally. , By intravaginal or intraperitoneal administration. Parenteral in subcutaneous and intramuscular forms Administration is generally preferred. Dosage forms suitable for such administration are prepared by conventional techniques. It is. The compounds of formula (I) may further be administered by inhalation, i.e., by intranasal or oral inhalation. Can also be administered. Suitable dosages for such administration, such as aerosol formulations or metered dose inhalers The dosage forms are prepared by conventional techniques.   For any method of use disclosed herein with respect to compounds of formula (I) The daily oral dose is preferably from about 0.01 to about 8 / kg of total body weight. 0 mg, preferably about 0.1-30 mg / kg, more preferably about 0.2 mg to 15 mg. The daily parenteral dose is about 0.1 / kg of total body weight. To about 80 mg, preferably about 0.1 to about 30 mg / kg, more preferably Is about 0.2 mg to 15 mg / kg. The daily topical dose is preferably about 0.1 mg to 150 mg, 1 to 4 times per day, preferably 2 times Or three times. The daily inhalation dose is preferably about 0.01 mg / k per day g to about 1 mg / kg. A compound of formula (I) or a pharmaceutically acceptable salt thereof The optimal amount and the interval between doses will depend on the nature and extent of the condition to be treated, the mode of administration, and the route And the site, and the particular patient to be treated, such optimal values It will be understood by those skilled in the art that it can be determined by conventional techniques. Also, the best Therapeutic methods, i.e., a compound of Formula (I) or a compound thereof administered daily for a predetermined number of days. The frequency of administration of a pharmaceutically acceptable salt can be determined by one of ordinary skill in the art using routine therapeutic determination tests. It will also be appreciated by those skilled in the art.   The novel compounds of formula (I) may further be used for inhibiting cytokines or inhibiting production. It can be used for veterinary treatment of non-human mammals. Especially for animals Cytokine-mediated diseases undergoing therapeutic or prophylactic treatment in Conditions, such as those described herein, but especially for viral infections. is there. Examples of such viruses include, for example, equine infectious anemia virus, goat arthritis Lentiviral infection, such as a virus, visna virus, or maedi virus Disease or retroviral infection, such as, but not limited to, feline immunodeficiency Irus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other , But not limited to, retroviral infections.   The present invention will be described with reference to the following biological examples, which are merely illustrative. It is not intended to limit the scope of the present invention.Biological examples   The cytokine inhibitory effect of the compound of the present invention was measured by the following in vitro assay. Decided: Interleukin-1 (IL-1)   Human peripheral blood monocytes were prepared according to the method of Colotta et al, J Immunol, 132, 936 (1984). Therefore, a fresh blood preparation from a volunteer donor or at a blood bank Isolate from buffy coat and purify. These monocytes (1 × 10⁶) For 24 wells Plate at a concentration of 1-2 million / ml per well. 2:00 cells The non-adherent cells are then removed by gentle washing. About The test compound for 1 hour before adding lipopolysaccharide (50 ng / ml). To the cells and incubate the culture for an additional 24 hours at 37 ° C. At the end Remove the culture supernatant and clarify the cells and all tissue pieces. Simo culture supernatant n et al. Immunol. Methods, 84, 85, (1985) (A23187A of IL-1) Stimulate interleukin-2 producing cell line (EL-4) in cooperation with onophore to stimulate IL -2 based on the ability to secrete -2, or Lee et al., J. ImmunoTherapy, 6 (1 ), 1-12 (1990) (ELISA assay). Assay for biological activity. Tumor necrosis factor (TNF):   Human peripheral blood monocytes were obtained from Colotta, R .; et al., J Immunol, 132 (2), 936 (1984) Blood bank buffy coat or platelet pheresis residue as required Isolate from it and purify. 1 × 10 monocytes⁶At the density of cells / ml medium / well Plate in a 24-well multi-dish. Allow cells to attach for 1 hour, then Aspirate the supernatant and add 1% fetal calf serum + penicillin and streptomycin (10 Medium (1 ml, RPMI-1640, Whitaker Biome dical Products, Whitaker, CA). Cells are treated with 1 nM to 101 mM Dose range (compound dissolved in dimethylsulfoxide / ethanol The final solvent concentration will be 0.5% dimethyl sulfoxide / 0.5% ethanol. Incubate for 45 minutes in the presence or absence of the test compound. Then, bacterial lipopolysaccharide (E. coli 055: B5 [LPS], Sigma Chemicals Co. (100 ng / ml in 10 ml phosphate buffered saline). 5% CO at 37 ° C for 6-18 hours_TwoIncubate in incubator . At the end of the incubation period, the culture supernatant was removed from the cells and 3000 rpm Centrifuge at m to remove cell debris. The supernatant is then used for radioimmunoassay or WO92 / 10190 and Becker et al using either of the ELISA assays. al., J Immunol, 1991, 147, 4307. Test.   IL-1 and TNF inhibitor activity are expressed by mediating inhibition of arachidonic acid metabolism It does not appear to be related to the properties of the compound of (I). Furthermore, powerful cyclooxygen Non-steroidal anti-inflammatory having an activity of inhibiting lipase and / or lipoxygenase Inhibits prostaglandin production and / or leukotriene synthesis by drugs The ability of the compound to also produce TNF or IL-1 production at non-toxic doses Means not to inhibit. Interleukin-8 (IL-8)   Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems, Kirland, Wa) 15% fetal calf serum and 1% CS-HBGF (from aFGF and heparin) Maintained in a supplemented culture medium. Then, the cells were diluted 20-fold, and gelatin was Place in coated 96-well plate (250 μl). Before use, remove the culture medium Replace with medium (200 μl). Then buffer or test compound (25 μl, (Concentration between 1 and 10 μM) was added to each well of the four wells and the plate 5% CO_TwoFor 6 hours in a humidified incubator at 37 ° C under an atmosphere of Beate. At the end of the incubation period, the supernatant is removed and the R & D System ( (Minneapolis, MN) using an IL-8 ELISA kit. Assay for degree. All data are based on standard curves, Expressed as an average (ng / ml). IC₅₀Can be obtained by nonlinear regression analysis as appropriate . Cytokine-specific binding protein assay   Developed a radioactive competitive binding assay and developed a highly reproducible one for structure-activity studies. I got the next screen. This assay uses newly isolated human as a source of cytokines. More than conventional bioassays using monocytes and ELISA assays to quantify them To provide the benefits. Apart from the assay being much simpler, the binding assay It has been confirmed that it highly correlates with the result of the test. Specific and reproducible rhino Tokaine inhibitor binding assays were performed using THP. Soluble cytosol flux from one cell And radiolabeled compounds. Patent application USSN08 / 1231 75 (Lee et al, filed September 1993), PCT 94/10529 (Lee et al, (Filed September 16, 1994) and Lee et al, Nature 300, n (72), 739-746 (19). (December 1994) (the disclosure of which is incorporated by reference in its entirety as part of the present invention) Interacts with cytokine-specific binding protein (hereinafter referred to as “CSBP”) The method described above for screening drugs to identify compounds that match ing. However, for the purposes of the present invention, the binding protein is in isolated form in solution. Or immobilized form, or by genetic engineering It is expressed in the stem or as a fusion protein on the surface of the recombinant host cell. Another As a method, whole cells or cytosol fractions containing CSBP are screened. Used in the protocol. Regardless of the form of the binding protein, Multiple compounds can be combined with a binding protein under conditions sufficient to form a combined protein complex. Contact to form the complex and detect compounds that can enhance or interfere with the complex. Put out.   Representative compounds of Formula (I), Examples 1-24, are all in this binding assay. Showed positive inhibitory activity. Prostaglandin endoperoxide synthase-2 (PGHS-2) assay :   The following assay demonstrates human PGHS-2 protein expression in LPS-stimulated human monocytes. A method for determining the inhibitory effect of a compound of formula (I) on The following Say is indicated herein using compounds other than the compound of formula (I).Method: Centrifugation of human peripheral blood monocytes by Ficoll and Percoll gradients Isolated from buffy coat. Cells were plated at 2 × 10 in a 24-well plate⁶Pieces / we 1 hour, 1% human AB serum, 20 mM L-glutamine, penicillin -Adhesion in RPMI supplemented with streptomycin and 10 mM HEPES I let it. Compounds were added at various concentrations and incubated at 37 ° C. for 10 minutes. LPS was added at 50 ng / well (to induce enzyme expression) and incubated at 37 ° C. overnight. Incubated. The supernatant was removed and the cells were washed once with cold PBS. 1 cell 00 ml cold lysis buffer (50 mM Tris / HCl pH 7.5, 150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SD S, 300 μg / ml DNase, 0.1% TRITON X-100, 1 mM  PMSF, 1 mM leupeptin, 1 mM pepstatin). Melt Was centrifuged (10,000 × g for 10 minutes at 4 ° C.) to remove cell debris and Fractions were subjected to SDS PAGE analysis (12% gel). Separated on gel Transfer proteins to nitrocellulose membrane at 60 volts for 2 hours by electrophoresis did. Prevent membrane for 1 hour in PBS / 0.1% Tween 20 with 5% nonfat dry milk Prepared. After washing three times in PBS / Tween buffer, PGHS-2 was washed. To 1: 2000 dilution of monospecific antiserum or 1: 1 against PGHs-1 1 hour in PBS / Tween containing 1% BSA with antiserum at a dilution of 000 While shaking continuously. Membrane 3 times with PBS / Tween After washing, the horseradish was diluted 1: 3000 to rabbit Ig (Amersham). PBS containing 1% BSA with tissue peroxidase-conjugated donkey antiserum Incubation was performed in Tween with continuous shaking for 1 hour. Then put the membrane on P Wash three times in BS / Tween and use the ECL immunodetection system (Amersham) Determine the level of prostaglandin endoperoxidase synthase-2 expression Issued.result: The following compounds were tested and tested in this assay for activity (i.e., L with similar potency to inhibit cytokine production as described in PS-induced PGHS-2 protein expression): 6- ( 4-fluoro-phenyl) -2,3-dihydro-5- (4-pyridinyl) imidazo [2,1-b] thiazole; and dexamethasone.   Some compounds were tested and found to be inactive (up to 10 μM); 2 -(4-methylsulfinylphenyl) -3- (4-pyridyl) -6,7-dihydro -(5H) -pyrrolo [1,2-a] imidazole; lolipran; phenidone and NDGA. Any of these compounds tested showed PGH in similar experiments. S-1 or cPLA_TwoIt was found not to inhibit protein levels.TNF-α traumatic brain injury assay   This assay is based on experimentally induced lateral trauma traumatic brain injury (T Investigate tumor necrosis factor mRNA expression in specific brain regions following BI) Do for you. Adult sprag-Dawley rats (n = 42) were pentobarbitaluna Anesthetized with thorium (60 mg / kg, ip) and collected in left parietal parietal cortex (n = 18). Moderate (2.4 atm) lateral drip brain injury or "pseudo" treatment (wound Anesthesia and surgery were performed without harm. n = 18). Animals injured 1, 6 and 24 After hours, sacrificed by decapitation, brain removed, left (injured) parietal cortex (LC), contralateral right Corresponding site in cortex (RC), cortex adjacent to injured parietal cortex (LA), right cortex The corresponding adjacent sites in the quality (RA), left hippocampus (LH) and right hippocampus (RH) Prepare sample. Isolate total RNA and Northern blot hybridization And quantified against TNF-α positive control RNA (macrophage = 100%) . One hour after injury in the traumatized hemisphere, significant TNF-α mRNA Increase was LH (104 ± 17% of positive control, p <0.05 compared to mock), LC ( 105 ± 21%, p <0.05) and LA (69 ± 8%, p <0.01). Is observed. LH (46 ± 8%, p <0.05), LC (30 ± 3%, <0. 01) and LA (32 ± 3%, p <0.01) also increased TNF-αm RNA expression is observed at 6 hours, which disappears 24 hours after injury. Contralateral half In spheres, the expression of TNF-α mRNA was RH (46 ± 2% , P <0.01), increased in RC (4 ± 3%) and RA (22 ± 8%), At time, RH (28 ± 11%), RC (7 ± 5%) and RA (26 ± 6%, p <0 . 05) but not after 24 hours. Mock (Surgery without injury ) Or TNF-α mRNA expression in non-experimented animals. Consistent changes were observed in any of the six brain regions in any hemisphere, Not seen at the time. These results indicate that after lateral sagittal brain injury, TNF- Temporary expression of α mRNA is altered in certain brain regions, including the non-traumatic hemisphere. It indicates that TNF-α can induce nerve growth factor (NGF), activates stellate Stimulates the release of other cytokines from the cell, so that TNF-α gene expression Post-traumatic changes in both acute and regenerative responses to CNS trauma Play an important role.CNS injury model for IL-β mRNA   This assay is characteristic of rats following experimental lateral injection traumatic brain injury (TBI). Localized expression of interleukin-1β (IL-β) mRNA in certain brain regions To analyze. Adult sprag-Dawley rats (n = 42) with pentobarbital nato Anesthetized with lium (60 mg / kg, ip), left middle parietal cortex (n = 18) Concentration (2.4 atm) of side-draining brain injury or "pseudo" treatment (no injury) Anesthesia and surgery are performed). Animals were cut off at 1, 6 and 24 hours after injury. Head sacrificed, brain removed, left (injured) parietal cortex (LC), contralateral right cortex (RC) The corresponding area in the cortex (LA) adjacent to the injured parietal cortex, the right cortex Tissue samples of corresponding adjacent sites (RA), left hippocampus (LH) and right hippocampus (RH) Is prepared. Isolate total RNA and perform Northern blot hybridization. The amount of IL-1β mRNA in the brain tissue was determined using the IL-1β positive macrophage R on the same gel. Expressed as% of relative radioactivity of NA. One hour after brain injury, to the traumatized hemisphere In a significant increase in IL-1β mRNA was observed in LC (20.0 ± 0.7% of positive control). , N = 6, p <0.05 compared to sham animals, LH (24.5 ± 0.9%, p < 0.05) and LA (21.5 ± 3.1%, p <0.05) This is by LC (4.0 ± 0.4%, n = 6, p <0.05) until 6 hours after injury. And LH (5.0 ± 1.3%, p <0.05). pseudo Alternatively, in animals that have not undergone experiments, IL-1β mRNA expression is It is not seen in the brain region. These results indicate that after TBI, IL-1βmR Figure 4 shows that transient expression of NA is stimulated locally in certain regions of the brain. I These local changes in cytokines, such as L-1β, are associated with post-traumatic pathology of brain injury. Plays an important role in biological or reproductive sequelae. Synthesis example   It is believed that the invention is merely exemplary in the following and does not limit the scope of the invention This will be described by way of examples. Unless otherwise specified, all temperatures are in degrees Celsius and Solvents are of the highest purity available and all reactions are anhydrous in an argon atmosphere Perform under conditions.   In the examples, all temperatures are degrees Celsius (° C.). Unless otherwise noted, quality Quantitative spectra were performed on a VG Zab mass spectrometer using the fast atom bombardment method. .¹The H-NMR (hereinafter referred to as “NMR”) spectrum was -Recorded using an AM250 or Am400 spectrophotometer. The multiplicity is as follows S = singlet, d = doublet, t = triplet, q = quadruple, m = multiplet, br represents a broad signal. Sat. Means a saturated solution, and eq is The ratio of the molar equivalent of the reagent to the corresponding product is shown.   Flash chromatography was performed on Merck silica gel 60 (230-400 mesh). ).                                 Example 1 1- (1H-indol-3-ylcarbonyl) -4- (benzyl) piperazine   Indole-3-carboxylic acid (161 mg, 1.0 mmol), benzyl pipera Gin (347 μL, 2.0 mmol), triethylamine (278 μL, 2.0 m mol) and CH_TwoCl_Two(4 mL) and CH_TwoCl_Two(4 mL) in SOCl_Two( 146 μL, 2.0 mmol) was added dropwise. The obtained mixture is heated at 23 ° C. for 40 minutes. While stirring, CH_TwoCl_Two(75 mL) and washed with 10% aqueous NaOH (20 mL) Clean, combine with flash silica (40 mL), and slurry in a sintered glass funnel. Flash silica, plus CH_TwoCl_Two0-2% CH in_ThreeEluted with OH, white 297 mg (95%) were obtained as colored crystals. ES + MS m / z = 320 (MH +) .                                 Example 2 1- (1H-indol-3-ylcarbonyl) -4- (phenyl) piperazine   The procedure of Example 1 was repeated, except that phenylpiperazine was used. The title compound was obtained. ES + MS m / z = 306 (MH +).                                 Example 3 1- (1H-indol-3-ylcarbonyl) -4- (2-pyridinyl) piperazi In   Except for using 2-pyridylpiperazine, a white solid was obtained by the method of Example 1. To give the title compound. ES + MS m / z = 307 (MH +).                                 Example 4 1- (1H-indol-3-ylcarbonyl) -4- (2-pyrimidinyl) pipera gin   A white solid was prepared by the method of Example 1 except that 2-pyrimidinylpiperazine was used. To give the title compound. ES + MS m / z = 308 (MH +).                                 Example 5 1- (1H-indol-3-ylcarbonyl) -4- (diphenylmethyl) pipera gin   A white solid was obtained by the method of Example 1 except that diphenylmethylpiperazine was used. To give the title compound. ES + MS m / z = 396 (MH +).                                 Example 6 1- (1H-indol-3-ylcarbonyl) -4- (4-pyridinylmethyl) pi Perazine   Except for using 4-pyridylmethylpiperazine, a white solid was obtained by the method of Example 1. The title compound was obtained as a product. ES + MS m / z = 321 (MH +).Example 7 1- (1H-indol-3-ylcarbonyl) -4- (4-trifluoromethyl Phenylmethyl) piperazine a)1-Tert-butoxycarbonyl-4- (4-trifluoromethylbenzyl Le) piperazine   Acetone (5 ml) of 4-tert-butoxycarbonylpiperazine (250 mg) Potassium carbonate (185 mg) and α-bromomethyl-4-trifluoro Romethylbenzene (320 mg) was added. The mixture was heated to reflux overnight. cold After cooling, the solvent was concentrated and the residue was partitioned between chloroform and water. Dry the organic phase (Na_TwoSO_Four), Filtered and concentrated to give the title compound as an oil (460 mg).¹ HNMR (250 MHz, CDCl_Three) d: 1.48 (s, 9H), 2.40 (t, 4H), 3.45 (t, 4H), 3.57 (s, 2H), 7.45 (d, 2H), 7. 59 (d, 2H). b)1- (4-trifluoromethylbenzyl) piperazine   To the compound of the previous example (460 mg) in dichloromethane (5 ml) was added trifluoromethane. Acetic acid (1 ml) was added dropwise. Stirring was continued for 1 hour under an inert atmosphere. Solvent under vacuum It was concentrated and azeotroped with toluene to finally make TFA a trace amount. Intermediate trifle The salt was dissolved in water (5 ml) and basified by addition of solid potassium carbonate. Play The released base was extracted into dichloromethane. Dry the organic phase (Na_TwoSO_Four), Concentrated The title compound was obtained as an oil (320 mg).¹ HNMR (250 MHz, CDCl_Three) d: 2.36-2.49 (m, 4H); 92 (t, 4H), 3.54 (s, 2H), 7.45 (d, 2H), 7.59 (d, 2) H) c)1- (1H-indol-3-ylcarbonyl) -4- (4-trifluoromethyl (Cylbenzyl) piperazine SB-223877   Example 1 except that 1- (4-trifluoromethylbenzyl) piperazine was used. The title compound was obtained by the method.¹HNMR (250 MHz, CDCl_Three) d: 2. 48 (t, 4H), 3.60 (s, 2H), 3.69-3.80 (m, 4H), 7.1 8-7.22 (m, 2H), 7.26-7.34 (m, 2H), 7.45 (d, 2H) , 7.68 (d, 2H), 7.70 (dd.1H), 9.28 (bs, 1H).                                 Example 8 1- (1H-indol-3-ylcarbonyl) -4- (4-fluorophenylmeth (Chill) piperazine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 2.45 (t, 4H), 3.50 (s, 2H), 3.73 ( t, 4H), 6.99 (t, 2H), 7.15-7.48 (m, 6H), 7.66- 7.72 (m, 1H), 9.09 (bs, 1H).                                 Example 9 1- (1H-indol-3-ylcarbonyl) -4- (methyl) piperazine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 2.38 (s, 3H), 2.49 (t, 4H), 3.78 ( t, 4H), 7.17-7.25 (m, 2H), 7.31-7.37 (m, 2H), 7.68-7.73 (m, 1H), 9.25 (bs, 1H).Example 10 1- (1H-indol-3-ylcarbonyl) -4- (cyclohexyl) piperazi In   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 1.09-1.32 (m, 5H), 1.78-1.91 (m , 4H), 2.25-2.35 (m, 1H), 2.61 (t, 4H), 3.71 (t, 4H), 7.18-7.26 (m, 2H), 7.37-7.41 (m, 1H), 7. 49 (d, 1H), 7.67-7.72 (m, 1H), 8.72 (bs, 1H).Example 11 1- (1H-indol-3-ylcarbonyl) -4- (cyclopropylmethyl) pi Perazine   The title compound was prepared according to the general method of Example 7. M. S .: (CI); MH + 284                                Example 12 1- (1H-indol-3-ylcarbonyl) -4- (4-methylbenzyl) pipe Razine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 2.35 (s, 3H), 2.41-2.52 (m, 4H), 3.52 (s, 2H), 3.67-3.78 (m, 4H), 7.10-7.31 (m, 4H) 8H), 7.65-7.72 (m, 1H), 9.41 (bs, 1H).                                Example 13 1- (1H-indol-3-ylcarbonyl) -4- (4-cyanobenzyl) pipe Razine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 2.41-2.53 (m, 4H), 3.60 (s, 2H), 3.70-3.79 (m, 4H), 7.17-7.39 (m, 4H), 7.46 (d , 2H), 7.62 (d, 2H), 7.66-7.72 (m, 1H), 9.22 (bs , 1H).Example 14 1- (1H-indol-3-ylcarbonyl) -4- (2-naphthyl) piperazine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 2.50-2.59 (m, 4H), 3.61 (s, 2H), 3.62-3.73 (m, 4H), 7.14-7.21 (m, 2H), 7.34-7 . 39 (m, 2H), 7.44-7.54 (m, 3H), 7.68-7.86 (m, 2H) 5H), 9.74 (bs, 1H).                                Example 15 1- (1H-indol-3-ylcarbonyl) -4- (2-phenylethyl) pipe Razine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) d: 2.44-2.70 (m, 6H), 2.78-2.88 ( m, 2H), 3.67-3.82 (m, 4H), 7.12-7.43 (m, 8H), 7.65-7.72 (m, 1H), 9.49 (bs, 1H).                                Example 16 1- (1H-indol-3-ylcarbonyl) -4- (4-methoxybenzyl) pi Perazine   The title compound was prepared according to the general method of Example 7.¹HNMR (250 MHz, CDCl_Three) D: 2.45-2.53 (m, 4H), 3.51 (s, 2H) 3.70-3.76 (m, 4H), 3.81 (s, 3H), 6.86 (d, 2H), 7.18-7.29 (m, 4H), 7.37-7.41 (m, 2H), 7.66-7 . 72 (m, 1H), 9.59 (bs, 1H).                                Example 17 1- (1H-5-bromoindol-3-ylcarbonyl) -4 (benzyl) pipera gin a)1H-3-trifluoroacetyl-5-bromoindole   5-bromoindole (0.98 g) 5.0 mmol) and THF (3.0 mL) ) And the resulting solution was cooled to 4 ° C. and TFAA (1.26 g) 6.0 mmol) , And stirred for 16 hours._TwoPour into O, filter, H_TwoWash with O, vacuum Dry in the middle to obtain the title compound. ES-MS m / z = 290 (M−H)^-. b)1H-3-carboxy-5-bromoindole   The product of the previous example was combined with 20% aqueous NaOH and heated to reflux for 15 minutes . Cool to 23 ° C., wash with EtOAc, then acidify with concentrated HCl to <pH 1 Gender. The resulting precipitate was filtered, dried under vacuum and 0.79 g (5-bromo (66% from Indole). ES-MS m / z = 238 (MH)^-. c)1- (1H-5-bromoindol-3-ylcarbonyl) -4- (benzyl) Piperazine SB-241938   The product of the previous example was treated by the method of Example 1 to give the title compound. ES + MS m / z = 398 (MH +).                                Example 18 1- (1H-5-methylindol-3-ylcarbonyl) -4- (benzyl) pipe Razine   5-Methylindole was converted to the title compound according to the general method of Example 17. Was. ES + MS m / z = 333 (MH +).                                Example 19 1- (1H-5-chloroindol-3-ylcarbonyl) -4- (benzyl) pipe Razine   5-Chloroindole was converted to the title compound according to the general method of Example 17. Was. . ES + MS m / z = 354 (MH +).                                Example 20 1- (1H-5-benzyloxyindol-3-ylcarbonyl) -4- (ben Jill) piperazine   5-Benzyloxindole was prepared according to the general method of Example 17 to give the title compound. Was converted to ES + MS m / z = 426 (MH +).Example 21 1- (1H-5-nitroindol-3-ylcarbonyl) -4- (benzyl) pipe Razine   5-Nitroindole was converted to the title compound according to the general method of Example 17. Was. ES + MS m / z = 365 (MH +).                                Example 22 1- (1H-5-fluoroindol-3-ylcarbonyl) -4- (benzyl) pi Perazine   Conversion of 5-fluoroindole to the title compound according to the general method of Example 17 did. ES + MS m / z = 338 (MH +).                                Example 23 1- (1H-5-aminoindol-3-ylcarbonyl) -4- (benzyl) pipe Razine   The product of Example 21 (91 mg, 0.25 mmol), CH_ThreeOH (15 mL), Combine HOAC (100 mL) and PtO (10 mg) in a Parr apparatus, psiH_TwoFor 2 hours. The mixture was filtered through a pad of celite. The filtrate is concentrated and the residue is_TwoO was separated and crystallized from 25 mg of the title compound. Obtained as a white solid. ES + MS m / z = 335 (MH +).                                Example 24 1- (1H-5-phenylindol-3-ylcarbonyl) -4- (benzyl) pi Perazine   The product of Example 17 (200 mg, 0.5 mmol), phenylboronic acid (24 2 mg, 2.0 mmol), Pd (PPh_Three)_Four(20 mg), dimethoxyethane (5 m L) and 2M aqueous Na_TwoCO_Three(1 mL) were combined under argon and the solvent was refluxed for 6 hours And stored at 2 ° C. for 2 days. 30% H_TwoO_Two(0.5 mL), 3 Stirred for 0 minutes. CH_TwoCl_Two(100 mL) was diluted with 10% aqNaOH And washed with CH_TwoCl_TwoThrough a plug of silica (100 mL) with 0-4% MeOH in And filtered to give 158 mg (80%). ES + MS m / z = 396 (MH +) .   The foregoing description fully discloses the invention including preferred embodiments. This specification Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Further Without devising the invention, those skilled in the art should utilize the preceding description to make the most of the present invention. It is thought that it is possible. Thus, the examples herein are merely illustrative, It is not considered to limit the scope of the invention in any way. Exclusive nature and excellence The scope of the invention claiming priorities is as follows.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 209/08 C07D 209/08 401/12 401/12 403/12 403/12 (72) Inventor Adams, Jerry Leroy, United States 19087 Forest Road, 611 (72), Wayne, PA Inventor Baume, Jeffrey Charles United States 19406 Anthony Road, 248 (72) King of Prussia, PA Chan, George Inventor・ Wakin United States 19096 Winwood, PA, Wiltshire Road No. 249 (72) Inventor Rahman, Shirley Kay United Kingdom, Hertfordshire, Bishops Stortford

Claims (1)

[Claims] 1. formula: Wherein R ₁ is hydrogen, alkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, nitro, amino, cyano, carboxy, carboxyalkoxy, carboxamide, or halogen, wherein aryl, heteroaryl, The heteroaryloxy, or aryloxy group may be substituted; R ₂ is aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl, or cycloalkylalkyl, wherein all of these Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ₁ is hydrogen, halogen, methyl, phenyl, benzyloxy, nitro, or amino. 3. R ₂ is benzyl, phenyl, pyridyl, pyrimidinyl diphenylmethyl, pyridylmethyl, benzyl, alkyl, cyclohexyl, naphthylmethyl or compound of claim 1 wherein the phenylethyl. 4. R ₂ is benzyl or haloalkyl, alkyl, halogen, cyano, or 4. The compound of claim 3 wherein a benzyl substituted by alkoxy. 5. R ₂ is phenyl or halogen, haloalkyl, alkoxy, or The compound of claim 3 wherein is phenyl substituted by alkyl. 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or diluent. 7. A method of treating inflammation in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) according to any one of claims 1 to 5. Including methods. 8. A method of treating osteoporosis in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of formula (I) according to any one of claims 1-5. Including methods. 9. A method of inhibiting the synthesis of PGHS-2 in a mammal in need of inhibiting the synthesis of prostaglandin endoperoxide synthase-2 (PGHS-2), wherein the mammal is provided with an effective amount of a PGHS-2. A method comprising administering a compound of formula (I) according to any one of the preceding. 10. 10. The method of claim 9, wherein the inhibition of PGHS-2 is used in the prevention or therapeutic treatment of edema, fever, hypersensitivity, neuromuscular pain, headache, cancer pain or arthritis pain. 11. A method of treating a CSBP / RK / p38 kinase mediated disease in a mammal in need of the treatment of a CSBP / RK / p38 kinase mediated disease, wherein the mammal is provided with an effective amount of any one of claims 1-5. A method comprising administering a compound of formula (I) as described. 12. The mammal is a cytokine mediated disease, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock Syndrome, asthma, adult respiratory distress syndrome, seizures, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, bone resorption, osteoporosis, reperfusion injury, graft-versus-host reaction, allograft rejection, Crohn's disease 12. The method of claim 11, wherein the subject is suffering from a CSBP / RK / p38 kinase-mediated disease selected from ulcerative colitis or fever. 13. formula: Wherein R ₁ is hydrogen, alkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, nitro, amino, cyano, carboxy, carboxyalkoxy, carboxamide, or halogen, wherein aryl, heteroaryl R ₂ is aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl, or cycloalkylalkyl; all of these groups Or a pharmaceutically acceptable salt thereof. 14． R ₁ is hydrogen, halogen, methyl, phenyl, benzyloxy, nitro or claim 13 A compound according is amino. 15. R ₂ is benzyl, phenyl, pyridyl, pyrimidinyl diphenylmethyl, pyridylmethyl, benzyl, alkyl, cyclohexyl, naphthylmethyl or claim 13 A compound according phenylethyl. 16. R ₂ is benzyl or haloalkyl, alkyl, halogen, cyano, or claim 15 A compound according alkoxy is benzyl substituted with,. 17． R ₂ is phenyl or halogen, haloalkyl, alkoxy, or claim 15 A compound according alkyl is phenyl substituted with. 18. A pharmaceutical composition comprising a compound according to any one of claims 13 to 18 and a pharmaceutically acceptable carrier or diluent. 19. A method of treating inflammation in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) according to any one of claims 13 to 18. Including methods. 20. A method of treating osteoporosis in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of formula (I) according to any one of claims 13 to 18. Including methods. 21. A method for inhibiting PGHS-2 synthesis in a mammal in need of inhibiting the synthesis of prostaglandin endoperoxide synthase-2 (PGHS-2), the method comprising administering to said mammal an effective amount of a PGHS-2. A method comprising administering a compound of formula (I) according to any one of the preceding. 22. 22. The method of claim 21, wherein the inhibition of PGHS-2 is used in the prevention or therapeutic treatment of edema, fever, irritability, neuromuscular pain, headache, cancer pain or arthritis pain. 23. 19. A method of treating a CSBP / RK / p38 kinase-mediated disease in a mammal in need of the treatment of a CSBP / RK / p38 kinase-mediated disease, comprising administering to said mammal an effective amount of any one of claims 13-18. A method comprising administering a compound of formula (I) as described. 24. If the mammal is a cytokine mediated disease, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxicity Shock syndrome, asthma, adult respiratory distress syndrome, seizures, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, bone resorption, osteoporosis, reperfusion injury, graft-versus-host reaction, allograft rejection, clone 24. The method of claim 23, wherein the disease is CSBP / RK / p38 kinase mediated disease and is selected from ulcerative colitis or fever.