JPH06503349A - New CSAIDS - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] New C5AIDS technology of invention The present invention provides novel compounds represented by formula (1), pharmaceutical compositions, and formulas (1) to (II). The present invention relates to various methods of using the compounds indicated by +).

This is then converted into prostanoid CPGE, TXA! and prosta It is metabolized to cyjl/). These products include polymorphonuclear leukocytes, mast cells and Produced by a variety of cells including monocytes. 5-lipokingenase (5-LO) The mediated pathway first converts arachidonic acid into 5-hydroperoxy-eicosatetraene. oxidized to acid (5-, HPETE), which was further oxidized to LTA4, peptide protein. Precursors to icotrienes (LTC, LTD, and LTE) and L Metabolizes to B4.

Furthermore, 5-HPETE is 5-hydroxyeicosatetraenoic acid (5-HETE ) is converted to

Fig. Products oxidized with arachidonic acid are mesoietors of various inflammatory conditions. − was identified. Various inflammatory disease symptoms are caused by these mesoietors. Many other symptoms that occur and are discussed herein include both CO and 5-LO. All conditions in which dual inhibitory factors are indicated.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are is a biological substance produced by various cells such as macrophages.

IL-1 and TNF affect a wide range of cells and tissues, and these Cytokines and other leukocyte-inducing cytokines are associated with a wide range of disease states and symptoms. is an important and decisive inflammatory mesoietor. Inhibition of these cytokines is , are useful in controlling, alleviating and alleviating many of these cases of deafness. .

Compounds that are anti-inflammatory drugs (hereinafter referred to as C3AID's) That is, it can inhibit cytokines such as IL-1, IL-6 and TNF. and lipogingenase, especially 5-lipoxygenase (5-■ , 0) and enzymes such as chlorooxygenase (CO). It can inhibit the oxidation of donic acid, thereby inhibiting the production of various leukotrienes and Compounds that can prevent the formation of prostaglandins and However, it is still needed for treatment.

Summary of the invention The present invention provides for administering an effective amount of a compound of formula (I) to an animal in need of treatment. Oxidized polyunsaturated fatty acid mediated disease (hereinafter referred to as oP) in the animal consisting of (noted as IFA).

The present invention provides compounds of formula (TI) or (III) for animals in need of treatment. administration of an effective amount of 1'1. It also relates to treatment methods.

Specifically, the present invention provides interleukin-1 (hereinafter referred to as IL-1) for animals in need of treatment. of a compound of formula (n) or (Ill) sufficient to inhibit A method of inhibiting IL-1 production in an animal, comprising administering an effective amount. Ru. More specifically, ■ inhibition of L-1 production is associated with excessive or unregulated IL-1 production. any disease condition in mammals that is aggravated or caused by childbearing It is also useful for prophylactic or therapeutic treatment of conditions.

Specifically, the present invention provides tumor necrosis factor (hereinafter referred to as TNF) to animals in need of treatment. administering an effective amount of a compound of formula (n) or (I[[) sufficient to inhibit The present invention relates to a method for inhibiting TNF production in the animal, the method comprising administering to the animal. More details Specifically, inhibition of TNF production is exacerbated by excessive or uncontrolled TNF production. prophylactic treatment or treatment of any disease condition in mammals that is caused by or caused by or therapeutic treatment.

Compounds represented by formulas (I) to (II[) are involved in the oxidation of polyunsaturated fatty acid metabolism. Compounds of formula (m) and (I[[) are useful for inhibiting enzymes such as It was found to be useful in inhibiting tocaine.

Detailed description of the invention The present invention provides novel compounds represented by formula (I) and compounds represented by formula (I) and a pharmaceutically acceptable carrier.

Compounds of formula (II) or (I[[) are also useful in the treatment of Lysul infections. It is.

Here, such viruses are upregulated by TNF. ) or induce TNF production in vivo. child The viruses intended for treatment here are those that produce TNF as a result of infection; or directly by a TNF inhibitor represented by formula (II) or (III). or indirectly, by making it susceptible to inhibition, such as by reducing replication. It is something to do. Examples of infectious viruses include HIV-1, HIV-2, and HIV-3, cytomegalovirus (CMV), influenza, adenovirus infections, such as, but not limited to, herpes zoster and herpes simplex. Examples include, but are not limited to, the herpes group of viruses.

In addition, the present invention particularly provides an effective TNF-inhibiting amount of the compound represented by formula (I) in humans. such method comprising administering to a mammal afflicted with immunodeficiency virus (HIV). Concerning methods of treating mammals.

Additionally, compounds of formulas (n) and (III) require inhibition of TNF production. It may also be used for veterinary treatment of mammals other than humans. in animals TNF-mediated diseases for therapeutic or prophylactic treatment include those mentioned above. These include disease states, especially viral infections. Examples of such viruses Feline immunodeficiency virus (FIV) or equine infectious anemia virus, goat such as arthritis viruses, visnaviruses, mesoviruses and other lentiviruses. Examples include, but are not limited to, eel and other pituitary virus infections.

Preferred methods of the invention particularly provide an effective amount of formula (n) or (III) compound or most preferably 5,6-sihydro-2(4-methylthiophenyl) -3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imidazol-7-o or 5゜6-sihydro-2-(4-methylthiophenyl)-3-(2- Methyl-4-pyridinyl)-78-pyrrolo[1,2-a]imidazol-7-o By administering the drug or a pharmaceutically acceptable salt thereof, the virus can be sensitive to upregulation by NF or IL-1 or in vivo Therapeutic treatment of viral infections that induces TNF or IL-1 production in or It is a preventive treatment.

The compound of the present invention of formula (1) has the structural formula [In the formula, W is -(CR4Rs)-1 or -(CRIR3)(CR8R7):R4 or and R5 together are oxo, or one of R4 and R6 is OH, The other of R and R5 is hydrogen.

R2, R3, R6, R7, Rs and Ro are hydrogen; or R2, R5, R6, One or two of R7, R@ and R8 are independently hydrogen or C1-2 Alkyl.

One of R7 and Ro is 4-pyridyl or Cl-4alkyl-4-pyridyl. Lysyl, the other of R3 and R6 is (a) Phenyl.

(b) The lf substituents are independently Cl-4 alkyl, halo, hydroxy, Cl-4 a Lucoquine, aryloxy, heteroaryloxy, 01-3 alkylthisu, C 1-3 alkylsulfinyl, C2-5l-alkenyl-1-thio, Cz, s 2-alkenyl-1-thio, C741-alkenyl-1-sulfinyl, C21 2-alkenyl-1-sulfinyl, arylthio, arylsulfinyl, C l-3 alkylamino, C1-3 dialkylamino, CF,,N (CI-3 a alkanamide), N-(CI-3alkyl)-N(CI-, alkanamide), N-pyrrolidino, N-piperidino, proper 2-en-1-oxo, 2.2.2 - trihaloethoxy, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkyl ruthio, alkoxycarbonylthio, alkoxythionothio, alkoxyalkyl ruthio, alkoxyalkylsulfinyl, alkylthioalkylthio, acyl Consists of oxyalkylsulfinyl, acyloxyalkylthio or Z A group represented by: disubstituted or disubstituted phenyl;

Y is or selected from.

t is 0 or 1. W and R1, R2, R3, R4, R6, R6, R7, R8 and and R1 are the same as defined above.

A is -CRs=CRT-1-N=CR, -1-8- or -0-1R1 and R1 is independently selected from hydrogen, C1-, alkyl, aryl or hetylaryl. selected.

Z is -5-(CR,Rb)1S-Z+: Zl is a functional group: however, a) When R, is 4-pyridyl and WI is -(CR4Rs)-, R, is 4- other than methoxy-substituted phenyl; b) When R is pyridyl or C1-4 alkyl-4-pyridyl, R1 is N　(CI-i alkyl)alkanamide or N-(C,-3 alkanamide ) is a phenyl substituted with something other than or a pharmaceutically acceptable salt thereof.

Preferred monosubstitutions of the compound of formula (I) are 01-4 alkyl, C1-4 alkyl, Lukyl S (Ol (where m is O or 1), C3-4 alkoxy, halo , N-(C,,alkyl)alkanamide, or N(C,-3alkanamide ).

Preferred disubstitution on the phenyl ring of the compound represented by formula (I) is characterized in that (a) the substituents are unique; C7-3 alkylthio, Cl-4 alkoxy, halo, or CI-1a Disubstituted phenyl that is rukyl.

(b) one of the substituents is Cl-3 alkoxy, halo, C1-4 alkyl or CF , and the other substituents are 01-, alkylamino, N-(C,, alkyl)-N (CI-3 alkanamide), C1-3 alkylamino, amino, N-pyrroli dino or N-piperidino, thiol, alkylsulfinyl, acylthio, di Thioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkyl Thio, carboalkoquinoalkylthio, alkokyne-carbonylthio, alkoxy Notionothio, phenylthio, phenylsulfinyl, alcoquinoalkylthio , alkoxyalkylsulfinyl, alkylthioalkylthio, acyloxy disubstituted phenyl that is alkylthio or Z; (C) one of the substituents is amino, Cl-3 alkylamino or CI-S dialkyl other substituents are 01-3 alkylsulfinyl, C2-51-a alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, Cs-s 2-alkenyl-1-thio, Ctra2-alkenyl-1-sulfinyl, thio , acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkyl carbonylalkylthio, carbalkoxyalkylthio, alkoxycarbony ruthio, alkoxythionothio, phenylthio, phenylsulfinyl, alco xyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio O, acyloxyalkylthio, acyloxyalkylsulfinyl or Z Certain disubstituted phenyl (d) substituents are the same, halo, C1-4 alkoxy, C l-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino, N-pipe lysino, 2,2,2-trihaloethoxy, prop-2-en-1-oxy, Cl -3 alkylthio, C1-3 alkyl-sulfonyl, thiol, acylthio, di Thioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkyl Thio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxy thionothio, arylthio, irisulfinyl, alkoxyalkylthio, Consisting of alkoxyalkylsulfinyl, alkylthioalkylthio or Z is a disubstituted phenyl.

A particularly preferred group of compounds is R, is 4-pyridyl or C1-4alkyl-4- pyridyl, Ro is monosubstituted phenyl, and the substituent is Cl-5 alkyl group. A compound represented by formula (I) which is C, C1-3 alkylsulfinyl, or halo It is a subgenus of things. This preferred group of compounds is useful in the treatment of cytokine-mediated diseases. It is also useful.

A particularly preferred compound represented by formula (I) is a compound in which W is -(CRa　Rs　)- It is a compound. More preferred are compounds in which the phenyl substituent is in the para position. most Also preferably, 01-, alkyl moiety of 01-4alkyl-4-pyridyl of R1 is at the 2-position of the pyridyl ring, and the alkyl group is methyl.

The present invention also relates to a novel compound represented by formula (II). formula( The compounds represented by II) are useful for the treatment of cytokine-mediated diseases and for the treatment of 0PUFA-mediated diseases. Useful in treating diseases. The compound represented by formula (II) has the structural formula: [wherein, W is -(CR4R5): R4 and R5 together are oxo, or one of R4 and R5 is O H9 The other is selected from H.

R2, R8, R8 and Ro are independently hydrogen or C1,□2 alkyl: R , and one of R8 is 4-pyridyl or C3-4alkyl-4-pyridyl provided that when R or Ro is C1-4 alkyl-4-pyridyl , the alkyl substituent is located at the 2-position of the pyricine ring, and the other of R1 and R6 is ( a) Phenyl, or the substituent is Cl-3 alkylthio, C1-3 alkylsul Finyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1- Sulfinyl, C,, 2-alkenyl-1-thio, C5-52-alkenyl-1 -sulfinyl, 1-a/ruoxy-1-alkylthio, C12 alkoxy, ha monosubstituted phenyl that is b, Cl-4 alkyl or Z, or (b) substituent is independently C1-3 alkylthio, C1-2 alkokyne, halo or CI-1 Disubstituted phenyl which is alkyl, or one of the substituents (C) is C1-3 alkyl Rusulfinyl, C2-51-alkenyl-1-thio, Cl-51-alkenyl -1-sulfinyl, C5-52-alkenyl-1-thio, C3-52-alke nyl-1-sulfinyl or 1-acyloxy-1-alkylthio, and others 21-substituted phenyl in which CI-Z alkoxy, halo or C1-4 alkyl ,or (d) The substituents are the same, C1-, alkylsulfinyl, C2-51-al Kenyl-1-thio, C! -11-alkenyl-1-sulfinyl, Cs-52- alkenyl-1-thio, Cs-52-alkenyl-1-sulfinyl or 1- acyloxy-1-alkylthio or the substituents together are methylene disubstituted phenyl forming a dioxy group; or (e) The substitution is A monosubstituted phenyl that is: t is 0 or 1, Wl, R3, R3, R3, R1, R3, R6, R7, R, and and Ro are the same as defined above.

However, R1 is 4-pyrinol, Wl is -(CR4Rs　)-1R4 and R5 If one of them is OH and the other is Hl or together oxo, then R6 is 4 -other than methquino-substituted phenyl.

Z is -5-S-Z, Z is C1-, alkyl or phenyl] or a pharmaceutically acceptable salt thereof.

A preferred substituent of the compound represented by formula (II) is R, is 4-pyridyl or C0 -4alkyl-4-pyridyl, Ro is monosubstituted phenyl, and the substituent is selected from 01-3 alkylthio, C1-3 alkylsulfinyl, or halo It will be done. Particularly preferred are compounds in which W is =(CR,R5)-. more preferred Alternatively, the phenyl substituent is in the para position. Most preferably, R1 C1-, 01-, alkyl moiety of alkyl-4-pyridyl is at the 2-position of the pyridyl ring and the alkyl group is methyl.

The present invention also relates to a novel compound represented by formula (III) shown below. There is also. Compounds of formula (I) are also useful in the treatment of 0PUFA-mediated diseases or are useful in inhibiting cytokine production.

The compound represented by the formula Cm) has the structural formula [In the formula, W2 is -(CR4Rs) or -(CR,R5)-(CR6R7)-; R4 and R5 together is OH1 or one of R4 and R5 is OH1 and the other is OH1. hydrogen.

R2, R3, R6, R1, R8 and R8 are hydrogen, or R2, R3, R6, One or two of R7, R8 and Ro are independently hydrogen or C1-2 Alkyl: R, is 4-pyrinol or Cl-4alkyl-4-pyridyl.

R, is (a) Phenyl, or the substituent is C1,□3alkylamino, C1-3alkylamino Kylamino, CF3, N-pyrrolidino, N-piperidino, 2.2.2-thiohalo Ethoxy, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocal Bamil, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkylcarbonylalkylthio, alkoxycarbonylthio, alkoxycarbonylthio, phenylthio, phenylsul finyl, alkoquinoalkylthio, alkoquinoalkylsulfinyl, acyl Oxyalkylsulfinyl, alkylthioalkylthio or Z One of the substituted phenyl (b) substituents is Cl-3 alkokene, halo, Cl-4 alkyl or cFs, and the other substituents are thiol, alkylsulfinyl, acylthiol, E, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonyl Lukirchi tag carbalcoquine alkylthio, alcoquine carbonylthio, alco xythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio O, alkoxyalkylsulfinyl, alkylthioalkylthio, acyloxy Sialkylthio, acyloxyalkylsulfinyl, Cl-3 alkylamino %C13 dialkylamino, amino, N-pyrrolidino, N-piperidino or Z with the proviso that one of the substituents is alkylsulfinyl or acyloxyalkaline If kylthio, the other substituents must be CF3 or C3 alkokyne Not disubstituted phenyl: or (d) one of the substituents is amino, Cl-3 alkylamino or C3-, dialkyl other substituents are 01-3 alkylsulfinyl, C2-51-a alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, Cs-52 -alkenyl-1-thio, C5-52-alkenyl-1-sulfinyl, thio , acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkyl carbonylalkylthio, carbalkoxyalkylthio, alkoxycarbony ruthio, alkoxythionothio, phenylthio, phenylsulfinyl, alco xyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio O, acyloxyalkylthio, acyloxyalkylsulfinyl or Z a disubstituted phenyl, or (e) The substituents are the same, halo, C1-3 alkoxy, 2.2.2-triha loetokino, C1-3 alkylthio, thiol, acylthio, dithioacyl, thiol Ocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carboa Rukoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyal Kylsulfinyl, acyloxyalkylsulfinyl or alkylthioal kylthio, provided that phenyl is substituted with C3 alkokino, Disubstituted phenyl substituted at positions other than para.

(f) The following formula Any one group shown in

Y is or There is.

1 is Omaj2 is 1. W2, R4, R2, R3, R4, R3, R6, R7, R8 and R, are the same as the definitions in n1j.

' is -CR, =CR7-1-N=CR7-1-8- or -0-; R1 and 1 stone is independently hydrogen, optionally substituted C3-, alkyl, optional Aryl optionally substituted with 'C' or optionally substituted with selected from different heteroaryls.

Z is -3-(CR,Rゎ)+SZ+: Z is a functional group.

however, a) When t is 0, Zl is other than -8 or tuunyl.

b) Only one of R and R1 is hydrogen; or a pharmaceutically acceptable salt thereof.

Preferred compounds represented by formula (I[I) are compounds in which W is -(CR+Rs)- It is a thing.

More preferred are compounds in which the phenyl substituent is in the para position. most preferably , the C1-4 alkyl moiety of 01-4 alkyl-4-pyridyl in R1 is a pyridine ring. This is a compound in which the alkyl group is methyl.

Preferably, R0 substitution is 01-3 alkylamino, Cl-3 alkylamino, CF3, N-pyrrolithin N-piperidino, thiol, acylthio, dithioacyl , thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbamyl Boalcoquine alkylthio, alcoquinecarbonylthio, alkoxythionothio , alcoquinoalkylthio, alcokynealkylsulfinyl, acyloxia Rukylsulfinyl, or alkylthioalkylthio.

Zl generates 38 moieties without interfering with disulfide bond cleavage in vivo. It is a functional group. Z in formula (II) is a subgenus of Zl. 71 part is aryl , optionally substituted aryl, C1-, alkyl, optionally substituted optionally substituted alkyl, heteroaryl, optionally substituted Preferably, it is a heteroaryl, chain or glutathione. as desired The substituents are the same as Ro or R1 phenyl moieties described above for formula (I). There may be.

R1 and R5 are independently hydrogen, optionally substituted C1-, a optionally substituted aryl, or optionally substituted selected from optionally heteroaryls. Aryl and heteroaryl rings Optional substituents for formula (I), other than Z, include the above-mentioned R0 and R1 for formula (I). Same as phenyl moiety. Preferred R5 and Rb are unsubstituted or C1-4 a It has been replaced by Lukiru.

A preferred compound represented by formula (1) is 5,6-nohydro-2-(4-methylthi (phenyl)-3-(4-pyridinyl)=7))-pyrrolo[12-a]imidazo Rule-7-ol.

5.6-Sihydro-2-(4-methylsulfinylphenyl)-3-(4-bilylphenyl) nyl)-7H-pyro+][1,2-mycoimidazol-7-ol.

5.6-Sihydro-2-(4-methylthiophenyl)-3-(2-methyl-4- pyridinyl)-7H-pyrrolo[1,2-mycoimidazol-7-ol.

5.6-Sihydro-2-(4-methylsulfinylphenyl)-3-(2-methylphenyl) -4-pyridinyl)-7H-pyrrolo[1,2-mycoimidazol-7-ol .

5.6-hydro-2-(4-methylthiophenyl)-3-(4-pyridinyl) -7H-pyrrolo[1,2-a coimidazol-7-one 15.6-sihydro2 -(4-methylsulfinylphenyl)-3-(4-pyridinyl)-7H-piO D[1,2-mycoimidazol-7-one; ruthiophenyl)-3-(2-methyl-4-pyrinonyl)-7H-pyrrolo[1, 2-Mycoimidazol-7-one: 5.6-nohydro-2-(4-methylsulf ynylphenyl)-3-(2-methyl-4-pyrinonyl)-7H-pyrrolo[1, 2-Mycoimidazol-7-one.

5.6-7hydro2-(4-fluorophenyl)-3-(4-pyridinyl)- 711-py00[1,2-mycoimidazol-7-ol: or 5,6-nohy Draw 2-(4-fluorophenyl)-3-(2-methyl-4-pyridinyl)- 7H-pyroO[1,2-mycoimidazol-7-ol.

R1 or R8 is C1-3 alkylsulfinyl, C2-51-alkenyl-1 -sulfinyl, C2-52-alkenyl-1-sulfinyl, alcoquinal In phenyl substituted with killsulfinyl and phenylsulfinyl moieties The compound represented by formula (1) which may be present in the corresponding alkyl group in vivo may serve as a prodrug that is reductively converted to the halogen or alkenylthio form. It should be noted that

R1 or Ro is a/ruthio, /thioar/ru, thiocarbamyl, notiocarbami , alkylcarbonylalkylthio, carbalkoquinoalkylthio, alco Quinocarbonylthio, alkokinothionothio or anoloxyalkylthio The compound represented by formula (I) which may be substituted phenyl is il Vi As a prodrug that is hydrolytically converted to the corresponding sulfhydryl form at VO It should be noted that it can be served as

Phylphenates in which R1 or Ro is substituted with any of the disulfide moieties described herein. The compound of formula (I), which may be phenyl, in vivo Note that it may serve as a prodrug that is oxidatively converted to the rufuhydryl form. You should be aware of it.

As used herein, the term "halo" refers to all halogens, i.e. bromo, fluoro, bromo and iodo.

As used herein, the term "Cto9alkyl" or "alkyl" group refers to means straight or branched groups of 1 to 9 carbon atoms, chain length methyl, ethyl, n-propyl, isopropyl, n -butyl, 5ec-butyl, isobutyl, tert-butyl, etc. (but not limited to) (not available).

As used herein, the term "alkenyl" refers to a straight chain of 1 to 9 carbon atoms. or branched groups, unless the chain length is limited thereto. , vinyl, 1-propenyl, 2-propenyl, or 3-methyl-2-propenyl Examples include (but are not limited to)

When used herein in combination such as "aryloxy", "aryloxy" '' means phenyl or naphthyl.

When used in this specification in combination such as "heteroaryloki 7", "heteroaryloki7" The term "teroaryl" refers to quinoline, isoquinoline, pyridine, pyrimidine, Like xazole, thiazole, thiadiazole, triazole, imidazole (including, but not limited to), one or more rings selected from the group consisting of N, 0, or S 5-10 membered aromatic system containing one or more heteroatoms.

As used herein, the term "sulfinyl" refers to the corresponding sulfide option. It means oxidation. As used herein, the term "thio" refers to sulfide. means. Furthermore, for the sake of clarity, R5 of the compound of formula (I) and The atomic structural formulas of the Roffi substituents are outlined in the table below.

Table 1 Note: A and A1 are hydrogen or alkyl.

Table 2 Sho D and DI are hydrogen, Cl-9 alkyl, or phenyl, t is Omatoko1 11; B is C3-, alkyl or aryl, R1, R1 and Zl are aryl , heteroaryl or C1-, alkyl (optionally substituted) It is.

The hydrogen atom of the CH2 group listed in Table 2 is independently optionally a C1-4 alkyl moiety. may be replaced by

As used herein, the term "lipoxygenase" refers to 5-lipoxygenase 12-lipoxygenase or 15-ribokinogenase enzyme.

The term "inhibiting the production of rlL-1" refers to a) monocytes or macrophages ( In vivo release of IL-1 by all cells, including but not limited to Inhibition of excess IL-rebel in humans can be normalized by inhibiting b) at the genomic level, in humans. Normal or below normal levels of excess in vivo I-L-rubel or C) post-translational events means down-regulation by inhibition of direct synthesis of IL-1.

The term "inhibiting the production of rTNF" refers to a) monocytes or macrophages (which Inhibition of in vivo release of TNF by all cells, including but not limited to By harm, excessive in vivo TNF levels in humans can be reduced to normal levels. b) at the genomic level; In vivo TNF levels decline to normal or below normal levels. down regulation; or C) TN as a post-translation event Downregulation by inhibition of direct synthesis of F.

The term ``rTNF-mediated disease or disease condition'' refers to a condition in which TNF is or other services such as (but not limited to) IL-1 or IL-6. refers to any disease state in which TNF plays a role in releasing itokine . That is, IL-1 is the main component, and its production or action worsens in response to TNF. A disease state in which TNF is secreted or secreted is therefore a disease mediated by TNF. It is considered to be a diseased state.

As used herein, the term "cytokine" refers to cytokines that affect the function of other cells. molecules that regulate interactions between C cells and influence immune or inflammatory responses. means any polypeptide that is. As 1 Night Cain, Monokines and lymphokines are produced regardless of which cells produce them. These include, but are not limited to. In other words, mo, tsukain is generally , macro7γ-7〉 and/or produced and secreted by mononuclear cells such as monocytes Natural killer cells, fibroblasts, basophils, neutrophils , endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and β-phosphorus Many other cells, such as lymphocytes, produce monokines. Lymphokines are usually This refers to the substance produced by lymphocytes. As an example of su-itkine, interleukino-1, (IL-1), interleugin-6 (IL-6), tumor Tumor necrosis factor-alpha (TNFα) and tumor necrosis factor beta (TNFβ) are listed. These include, but are not limited to:

The term "cytokine inhibition or cytokine suppressive amount" refers to excessive or uncontrolled any disease condition exacerbated or caused by cytokine production Cytokines in when administered for prophylactic or therapeutic treatment of Formula (1) ~ which will reduce the in vivo level to normal or subnormal levels means an effective amount of the compound represented by (m).

Inhibition of cytokines contemplated by the present invention for use in the treatment of HIV-infected humans (a) initiation of T cell activation and/or activation of T cell-mediated HIV genetic initiation and/or maintenance of offspring expression and/or replication; and/or (b) For any problems associated with cytokine-mediated diseases such as cachexia or muscle degeneration Must be a relevant cytokine.

TNF-β (also known as lymphotoxin) Also known as TNF-α and and TNF-β are both inhibited by the compounds of the invention, and thus collectively referred to as rTNFJ.

The term "rOPUFA-mediated disease or disease condition" refers to the oxidation of polyunsaturated fatty acids, especially refers to any disease state mediated (regulated) by the arachidonic acid metabolic pathway. Taste. enzymes such as lipokingecase enzyme or cytooxygenase enzyme. The oxidation of arachidonic acid by is particularly targeted by the present invention. Such an enzyme Examples include 5-Lo, 12-Lo, 15-LO and CO. (but not limited to), these include PGE2, LTB4, LTC4, LTD, Contains rostagranone, thromboxane and prostocyclin (these include (without limitation) producing a mesoiator.

The term "rOPUFA inhibitory amount" refers to the in vivo amount of oxidized arachidonic acid metabolism. means an effective amount of a compound of formula (I) that exhibits a reduction in levels.

The compounds represented by formulas (i) to (I[I) are represented by formula (A) as shown below. It can be produced from known intermediates. The compound represented by formula (A) is a known compound and Bender et al., filed on October 11, 1988. U.S. Patent Application No. 07/255.816: Published November 20, 1979 U.S. Patent No. 4.175.127 to Bender et al.; filed July 10, 1987 Bender et al., U.S. Patent Application No. 07/106.199; February 1989 U.S. Patent No. 4.803.279 to Bender et al., issued on September 9, 1988 U.S. Pat. No. 4,719,218+19 to Bender et al., issued January 12th. No. 4,715,310 to Bender et al., issued January 14, 1988. Manufactured at The contents of all these patent documents are cited and described in this specification. It will be done.

Alternatively, all compounds of formula (A) can be prepared as described herein: They can be manufactured by those skilled in the art in similar ways that can be easily adapted to the science in question.

In formula (A), R or R1 is phenyl substituted with a substituted disulfide moiety; The compound shown is where R or R1 is phenyl substituted with a sulfhydryl group. It is prepared by mild air oxidation of a compound of formula (A). Z is -5 -S, -Z, and Zl is aryl, heteroaryl or alkyl; In contrast, nosulfide (Z) is a suitable sulfhydryl compound in an ethereal solvent. One or more of Ro or R1 is reacted with a halogenated sulfenyl. Formula (A ) can be produced by obtaining the compound shown in

Mukaiyah? (MukaiyaIIla) et al., Tetrahedron Letters (T) etrahedron Letters), 56:5907-08 (1968) in a solvent at room temperature according to the method of attachment by the use of the desired aryl-8H or alkyl-8H reagent treated with The additive is obtained, and then it is converted into a 1.1 ratio of the mercaptan of the compound represented by formula (A). Process with. By this method, the amount of disulfide of the compound represented by formula (A) You will also receive a body. The disulfide bond is R6 of the compound represented by formula (A). It is preferable that the

Formula (A ) can be prepared as described above using mineral acid or Lewis acid catalytic conditions. Similar sulfhydryl compounds produced are treated with formaldehyde, acetone or acetone. By reacting with a suitable carbonyl moiety such as cetaldehyde, a symmetrical dithioketyl Manufactured by obtaining a core. Under the acid catalyzed conditions, hydroxyalkyl groups The intermediate, which is a sulfhydryl-containing compound, is reacted with other sulfhydryl-containing compounds to form an alkyl One obtains what is essentially a "His" type compound, differing only in the strand insertion. This method is , the his disulfide moiety of the process inlet of claim 1), i.e., the formula (A)-5-CR R''-3 formula (A) is produced.R or R1, which is a substituent of alkyl, is determined by the carbonyl functional group [where R or R1 is C1-, a alkyl, aryl or heteroaryl (all optionally substituted) ).

Asymmetric thioketals can be obtained by adding metal mercaptan salts prepared as described above. 1 or R1 is 1 or more alkylthioether by reacting with menalthioether. To obtain a compound represented by 2(A) which is phenyl substituted with alkylthio group. It can be manufactured by. The metal salt is a halomethane with independently different alkyl chain lengths. -[CRR,]-thioalkyl[aryl/heteroaryl] compounds. Then, a “non-His” type compound [formula (A)-S-CRR-3-RIF (where R and R1 are as defined above for "bis" compounds, and R2 is optionally C1-9 alkyl, aryl or heteroaryl group which may be substituted ) is obtained. Mixtures of Ro and R3 bonds are contemplated as part of this invention. However, preferably the bonds are at both R8 positions of the compound represented by formula (A).

Alternatively, only one component is a compound of formula (A) and disulfide unpaired where the other half of the bond is an alkyl, aryl or heteroaryl derivative A typical disulfide compound is a sulfhydride compound of formula (A) in an ethereal solvent. A drill compound is reacted with a suitable sulfenyl halide to form a compound in which R or R1 is 1. represented by formula (A), which is phenyl substituted with at least 3 [alkyl]-dithio groups; compound, i.e., [Formula (A)-3-8-R''] (where R-R is the above-mentioned (same as the definition). Intended alkyl, a The halogenated sulfenyl derivative of the aryl or heteroaryl group may be may be replaced.

The disulfide compound is prepared in a solvent, preferably chloroethylene, methylene chloride or in chlorinated solvents such as chloroform, methylsulfinyl, propyls Corresponding alkyl sulfoxides like rufinyl, isopropylsulfinyl compounds (where alkyl is a straight-chain or branched chain having 1 to 9 carbon atoms) trifluoroacetic anhydride or acetic anhydride). Add a carboxylic acid anhydride such as Pummerer rearrangement anti- The reaction may be heated slightly before adding the alkali metal hydroxide, such as thorium hydroxide. It requires that Similarly, when using acetic anhydride, the iodine solid (12) Before addition, heating is required during the hydroxide treatment and then, as before, the symmetric A typical disulfide compound is obtained. A mixture of sulfokit compounds is present in solution. Different substitutions may be present in the 25-heteroarylimidazole system of the present invention. obtain a compound that is "symmetric" except that it has a group Using the compound represented by formula (A) as an intermediate, Gallag her) et al., Tetrahedron Letters, Vol. 30, No. 48, No. 6599-6. 602 (1989) by a similar manufacturing method to that disclosed in Droxyl or forms a 7-keto moiety. The contents of this document are cited in this specification. Ru.

Preferable compounds obtained from the compound represented by formula (A) according to the disclosure of Galafer et al. The new intermediate has the formula (B): In formula 1, R0 to R8 are the same as defined for formula (I), R3゜ is alkyl, phenyl phenyl, substituted phenyl, preferably 4-nitrophenyl]. Formula (B ) is a corresponding 7-keto derivative or a compound represented by formula (I) one of R4 or R5 becomes hydroxy The corresponding 7-hydroxy derivative of formula (I) is obtained. Such oxidizing agent and reducing agents are well known to those skilled in the art. Preferred for use herein A strong oxidant is a Jones test in an organic solvent such as acetone, THF, or dioxane. drugs, solvents like ether/water, t-butanol/water, or other alcohol-based Potassium permanganate in solvent (buffer solution): as well as Sarrez tts) reagent. Preferred reducing agents are dichloromethane/methanol, dichloromethane Organic solvents that provide a proton source, such as tyrene, or other alcoholic solvents. Sodium borohydride in solvents or mixtures thereof, especially in chlorinated solvents May be sodium borohydride, lithium borohydride, chlorinated Perhydrides in organic solvents such as hydrocarbons/alcohols etc. lithium chloride), and hydrogenated oxides, which may be in ethereal or chlorinated solvents. Hydride reagents such as aluminum or lithium hydride: or in organic solvents. It is boron.

All methods for producing the remaining compounds represented by formula (I) not described herein If the art is well known (and the method outlined above or the example below) It can be easily performed by a person skilled in the art according to the method in .゛ The compounds of the present invention may contain one or more asymmetric carbon atoms, and may include racemic and optical May exist in active form. All of these compounds are considered within the scope of this invention. intended.

The compound represented by formula (A) has the structural formula: [wherein, W, -(CR4Rs)- or -(CR4R1)(CRsRl):R2, R3, R4, R3, R6, R7, R6 and R, are independently -H or C1 -2 alkyl: One of R1 and R is 4-pyridyl or Cl-4alkyl-4-pyridyl Jill: The other of R1 and Ro is (a) Phenyl, or the substituent is Cl-4 alkyl, halo, hydroxy, C, -4 alkokino, Cl-3 alkylthio, Cl-3 alkylsulfinyl, Cl -3alkylsulfonyl, C2~, 1-alkenyl-1-thio, C2-52-a alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C2-52 -alkenyl-1-sulfinyl, C2-51-alkenyl-1-sulfonyl, C5-52-alkenyl-1-sulfonyl, C1-3 alkylamino, C3-, dialkylamino, CF3, N (CI-3 alkanamide), N (CI-3 alkyl) N (CI-3 alkanamide), N-pyrroli/no, N-piperidino , proper 2-en-1-oxy, 2.2.2-trihaloethoquino, thiol , acylthio, notioacyl, thiocarbamyl, dithiocarbamyl, alkylka rubonylalkylthio, carbalcoquinalkylthio, alcoquinecarbonyl Thio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxy noalkylthio, alcokynealkylsulfinyl, alkylthioalkylthio , Z or alkylalkylthio.

(b) the ffi substituent is independently C3-3 alkylthio, C1-3 alkokino, Halo, Cl-4 alkyl, C1-3 alkylamino, N (CI-3 alkyl) -N (CI-3 alkanamide), C1-3 alkylamino, amino, N-pi Disubstituted phenyl that is loridino or N-piperidino.

(c) One of the ffifta groups is 01-, alkokene, halo, C1-, alkyl or or CF3, and the substituents are thiol, alkylsulfinyl, acylthio , dithioanlu, thiocarbamyl, dithiocarbamyl, alkylcarbonylal Kylthio, carbalkoquinoalkylthio, alcoquinecarbonylthio, alco Quinthionothio, phenylthio, phenylsulfinyl, alkoquinoalkylthio O, alkoxyalkylsulfinyl, alkylthioalkylthio, Zl or Disubstituted phenyl that is alkylalkylthio.

(d) one of the substituents is amine, Cl-3 alkylamino or C1-, dialkyl other substituents are Cl-3 alkylsulfinyl, C2-51-a alkenyl-1-thio, C-alkenyl-1-sulfinyl, C5-52 -alkenyl-1-thio, C5-52-alkenyl-1-sulfinyl, thio alkyl, acylthio, dithioanlu, thiocarbamyl, dithiocarbamyl, alkyl Carbonylalkylthio, Carbalkoquinoalkylthio, Alcoquinecarbony ruthio, alcoquinthionothio, phenylthio, phenylsulfinyl, alco Quinoalkylthio, alfkyl/alkylsulfinyl, alkylthioalkylthio Disubstituted phenyl which is Zl or acylox/alkylthio.

(e) The substituents are the same, halo, C13 alkoxy, C1-3 alkylamino , Cl-3noalkylamino, N-pyrrolidino, N-piperidino, 2,2.2- 1-lihaloethoxy, prop-2-en-1-oxy, hydroxy, C,-3a Lukylthio, C1-3 alkylsulfonyl, thiol, acylthio, thioacyl , thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbonyl Ruboalkoxyalkylthio, Alcoquinecarbonylthio, Alkoxythionothio O, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxy Noalkylsulfinyl, alkylthioalkylthio or di-composed of Z Substituted phenyl.

or (In the formula, t is O or 1.W, and R1 to R0 are the same as defined above.) or a pharmaceutically acceptable compound thereof It is salt that can be used.

Alternatively, compounds of formula (A) can be prepared as outlined in the reaction scheme below. Preferably, it can be manufactured in a vacuum. Although only the 5-membered ring pyrrole is shown, the synthesis It can also be applied to nitrogen-containing rings of members. Desired R2~R, alkyl represented by formula (A) The R substituted compound is produced from the corresponding R7 to R1 substituted compound represented by formula (3). It will be done.

This method uses equation (3).

Formula (3) [wherein A is (CH, n is 1 or 2, R3 and Ro are related to formula (I)] Same as definition] It consists of cyclizing the compound shown in Preferred Ro is Cl-4 alkylthi substituted by halogen, C9-4 alkyl or Cl-4 alkoxy It is phenyl.

The compound represented by formula (3) is obtained by reacting the compounds represented by formulas (1) and (2). Formula (1) Formula (2) Formula (3) Suitable bases include, but are not limited to, n-butyllithium, potassium t-butyl oxide, lithium diisopropylamide, lithium hexamethylnryl azide alkyl lithium, optionally a phase such as tetraethylammonium bromide. Sodium or potassium hydride or potassium hydroxide, optionally with a transfer catalyst or suitable mixtures thereof, such as n-butyl-lithium and potassium Examples include t-butokid. The compound represented by formula (1) is represented by formula (2) 1 to 2 molar equivalents, preferably 14 to 1.7 molar equivalents, of It is convenient to react with a base.

The reaction for forming the compound represented by formula (3) includes, but is not limited to, THF, Dialkyl ether, dimethylformamide, toluene, dimethylethylidene urine organic or organic compounds such as tetramethylethylenediamine or suitable mixtures thereof. carried out in a solvent. The reaction is conducted within a temperature range of about -80°C to about 100°C. Should. Preferably, the reaction is first cooled and the temperature is increased to Optimize the reaction time.

The compound of formula (3) is isolated after treatment and then converted to formula (3) with a suitable base as described above. It can be cyclized to the compound represented by (A). An example of such a preparation is 11 Synthesis Example 3 It can be seen in

Preferably, the compound of formula (3) is not isolated but is formed in 5 situ. and directly cyclized to the compound of formula (A) under basic conditions of the reaction mixture.

An example of such a preparation can be found in Synthesis Example 4.

In the presence of a base, the compound represented by formula (1) can be converted to formula (4): R, CH, L. Formula (4) [wherein R is the same as defined above and L is a suitable leaving group] or or its acid salt by formula (5): formula (5) Reaction with a compound represented by [wherein A is the same as the above definition for formula (3)] Manufactured by

Examples of suitable bases include, but are not limited to, potassium carbonate, sodium hydride, Mention may be made of sodium hydroxide or lithium diisopropylamide. suitable separation Deradicalization (L) is well known to those skilled in the art and involves the removal of groups such as bromine or chloride. Mention may be made of rogene or tosylate or methylate groups.

The reaction is carried out in a solvent, preferably THFSDMF or a mixture thereof.

The reaction is optionally carried out in conjunction with a phase transfer catalyst, if appropriate, e.g. as a base. If solid sodium hydroxide is used, it may be carried out in the presence of water. The reaction takes place in a chamber Conveniently it is carried out at warm or slightly elevated temperatures. The conversion shown by formula (5) Gradually add an aqueous solution of the acid addition salt of the compound represented by formula (4) to the aqueous solution of the compound and base. It is preferable to add it to

Using the compound represented by formula (A) itself as an intermediate, other compounds represented by formula (A) Compounds of can be produced. Such manufacture was made on October 11, 1988. U.S. Patent Application No. 07/255,816 of Bender et al., filed in 1979. U.S. Pat. No. 4.175.127 to Bender et al., issued Nov. 20; 19 U.S. Patent Application No. 07/106, 19 filed on July 10, 1987 by Bender et al. No. 9: U.S. Pat. No. 4.803.2 to Bender et al., issued February 9, 1989. No. 79: U.S. Patent No. 4.719.218, issued January 12, 1988: Best disclosed in U.S. Pat. No. 4.715.310, issued January 14, 1988. has been done.

The entire contents of these patent documents are incorporated herein by reference.

R, or R1 is 01-3 alkylsulfinyl or C1-, alkenylsulfinyl is mono- or di-substituted phenyl with phenyl; or R or R less than 1 (both 1 Cl-3alkylsulfinyl or Cl-, alkenyl - disubstituted phenyl with sulfinyl, or R or R1 is less at least one alcokynealkylsulfinyl, alcokynealkylsulfinyl Mono- or di-substituted phenyl with nyl or phenyl-sulfinyl substituents The compound of formula (A) which is Further, the application was filed on October 11, 1988. Tabender et al., U.S. patent application Ser. No. 07/255.816; November 20, 1979 Bender U.S. Pat. No. 4.175.127, issued July 1, 1987; U.S. Patent Application No. 07/106.199 of Bender et al. filed on 0; 198 No. 4,803,279 to Bender et al., issued February 9, 1999; No. 4,719,218 to Bender et al., issued January 12, 988. ; U.S. Pat. No. 4,715.3 to Bender et al., issued January 14, 1988. No. 10: and Adams et al., filed June 12, 1990. U.S. Patent Application No. 071537°195 (Attorney Docket No. SB 14506) ) is disclosed.

Pharmaceutically acceptable salts and methods for their preparation are well within the skill of those skilled in the pharmaceutical sciences. Are known. Pharmaceutical compounds of formulas (I) to (DI) useful in the present invention Pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, sulfate; Or phosphates. Pharmaceutically acceptable compounds of formula (I) The salt is preferably as described in U.S. Pat. No. 4,175.127 may be manufactured by known techniques. This record The contents are cited in this specification.

Method of treatment All compounds of formulas (I) to (m) can be used in the process of the invention, i.e. in particular 5 - Useful in methods of treating 0PUFA disease states with LO and CO enzymes. Compounds of formula (II) and (m) are suitable for use in humans, including those in need of treatment. For inhibiting the production of cytokines, especially IL-1 or TNF, in animals It is useful for

Oxidation of 0PUFA's, especially arachidonic acid metabolism that induces inflammatory mesoietors The pathway may be regulated by the 5-LO enzyme, among others. The compound represented by formula (I) The discovery that compounds of formula (I) are inhibitors of the 5-lipoxygenase pathway production of 5-lipoxygenase products in the blood ex vivo and based on its effect on 5-lipoxygenase in vitro. There is. Some of these are listed below. 5 of the compound represented by formula (1) -Lipoxygenase pathway inhibitory effects indicate that they are leucoproteins induced by RBL-1 cell supernatants. Decreasing production of 5-lipoxygenase products such as triene B4 production Confirmed by showing.

The pathophysiological role of arachidonic acid metabolites has been the focus of recent intensive research.

Well-described inflammatory activity of prostaglandins (i.e., general inflammatory activity) In addition to more recent descriptions of similar activities for eicosanoids, There has been widespread interest in these products as mesoiators of inflammation. These methods Zoie Iter suffers from rheumatoid arthritis, osteoarthritis, bronchitis, and inflammatory bowel disease. , ulcerative colitis, asthma, cardiovascular disorders, glaucoma, emphysema, acute respiratory distress syndrome, wolf Healing, gout, psoriasis, dermatitis, pyrcsis, pain and allergies – other conditions such as rhinitis, allergic conjunctivitis, food allergies and hives. Produces inflammatory symptoms similar to disorders originating from allergies.

Additional symptoms such as platelet aggregation, and total or partial thrombosis, coronary thrombosis Significant symptoms resulting from thrombosis, including venous thrombosis, phlebitis, and venous thrombosis, are also associated with arachidon. Involved in the acid pathway. Other disease states in which 5-LO inhibitors are useful include myocardial infarction, organ transplant rejection, tissue damage, multiple sclerosis, atherosclerosis, vasculitis , in the treatment of glomerulonephritis and immune complex diseases, and in the field of ophthalmology. corneal preposition due to postoperative inflammation or diseases such as uveitis or surgery. and suffix (corneal, anterior, and posterior) Its use is for general inflammation.

Compounds of formula (I) may be used to treat arachis in animals, including humans, in need of treatment. Treating disease states mediated by the cyclooxy/genase pathway metabolism of donate It was also found to be useful. The compound represented by formula (I) is cyclooxy The discovery that PG of compounds of formula (I) are inhibitors of genase products Effect on E2 product production and based on human monocyte data, the assay are described herein.

Disease states associated with CO metabolic pathways are typically treated with non-steroidal anti-inflammatory drugs (n Saids), and the dominant mode of their action is C This is due to O inhibition. Important primary diseases include, but are not limited to, various joint inflammations. symptoms, pyresis and pain.

Interleukin-1 (IL-1) plays a role in immunoregulation and other physiological functions such as inflammation. have been shown to mediate a variety of biological activities thought to be important in clinical symptoms. [For example, Dinarello et al. Rev, Tnfect, Disease s), 6.51, (1,984)]. Known Biology of Myriad II,,-1 Activities include activation of T helper cells, induction of trajectory, prostaglandin and stimulation of collagenase production, neutrophil chemotaxis, acute phase protein induction and plasma These include suppressing iron levels.

The compounds represented by formulas (II) and (nT) inhibit cytokines, particularly TL-1. The discovery that the compounds of formulas (■) and (II[) are harmful to humans Based on the effect on in vitro production of L-1 in monocytes-L. This assay A is described below.

Excessive or unregulated IL-1 production exacerbates and/or causes disease There are many forms of deafness that are associated with deafness. Seven of these include rheumatoid arthritis , osteoarthritis, endotoxemia, and/or Tokinkunyoseok syndrome, endotoxin other acute or chronic inflammatory disease states, such as inflammatory responses induced by is inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriasis Arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella joints inflammation, and acute synovitis. Recently, IL-1 activity has been shown to be associated with diabetes and kidney disease. They tend to combine β cells.

Dinarello, Journal of Clinical Immunology (J, C11n) ical Immunology), 5(5), 287-297 (1985) discloses biological activities attributable to IL-1. These effects include IL It should be noted that there are also things disclosed in other documents as a direct effect of -1. Ru.

In particular, the discovery of compounds that inhibit TNF production has allowed this molecule to be synthesized, processed and secreted. In addition to understanding how to It will also provide therapeutic research on the disease.

Excessive or uncontrolled TNF production can cause rheumatoid arthritis, rheumatoid arthritis, and spondylitis. Plastic arthritis, gouty arthritis and other arthritic conditions: sepsis, septic shock, Endotoxic/Yoseok, Gram-negative sepsis, Toxic shock syndrome, Adult Inspiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sulcoidonosis , bone resorption disease, reperfusion injury, host versus graft rejection, allograft rejection, Fever and muscle pain due to infections such as influenza, infection or malignant disease Cachexia, cachexia associated with acute immunodeficiency syndrome (AIDS), AIDS, ARC ( AIDS-related syndrome), keloid formation, scar tissue formation, Crohn's disease, ulcerated colon transmits many diseases, including inflammation, or pyresis, or Related to aggravating.

AIDS is caused by infection of T lymphocytes with the human immunodeficiency virus (HIV). occurs. For HIV, there are at least three types or strains, namely 81- r-1, HIV-2 and HIV-3 have been identified. As a result of HIV infection, T Cell-mediated immunity is reduced and infected individuals become severely immunocompromised and/or infected. or develop an abnormal tumor. In order for HIV to invade T lymphocytes, T lymphocytes must be Ball activation is required. Pond viruses such as HIV-1 and HIV-2 are T cells. After activation, T lymphocytes are infected and the expression of such viral proteins and/or Reproduction is mediated or maintained by such T cell activation.

When infected with activated T lymphocytes and IV, these T lymphocytes express HIV genes. and/or 1 item must remain active to enable replication. Must be. Seven cytokines, especially TNF, play a role in maintaining T lymphocyte activation activated T cell-mediated HIV protein expression and/or viral Replication (this is associated with Interfering with monokine activity, such as by inhibiting the production of , which helps control the maintenance of T-cell activation, thereby ensuring that those who are still infected This prevents the progression of H1% JIJ staining on cells with no delay or eliminate the progression of immunodeficiency caused by monocytes, macrophages ge, and related cells such as kunono (- cells and clear cells) related to the maintenance of infection). These cells are called Tit! Like cells, viruses Replication target, the level of viral replication depends on the activation state of the cell in question [Rosenberg et al., The Immunophysiology Off HIV Infection, Advances in Immunology (The 　I　mwunopathygenesis　of　HI　V　nfect ion.

Advances in I +u+uno1ology), Volume 57, (1989 )]. Monokines, such as TNF, stimulate monocytes and/or macrophages. have been shown to activate HIV replication in [Poli et al. Seedinges Off National Academy of Sciences (Pro c, Natl, Acad, Sei,), 87, 782-784 (199 0)], therefore, inhibition of monokine production or activity may As mentioned above, this can help limit the progression of HIV. Further research is Identification of TNF-α as a common factor in HIV activation in vitro The mechanism of action of nuclear factor mediated by nuclear regulatory proteins found in the cytoplasm of B1 cells. [Osborn et al., PNAS (86) 23 36-23401゜This evidence suggests that reduced TNF synthesis is associated with transcriptional and consequent Possesses antiviral effects in HIV infection by reducing virus production suggests.

TNF has been linked to cytomegalovirus (C) for reasons similar to those described here. htV), influenza virus, adenovirus, and herpesvirus It has been implicated in a variety of roles with respect to other viral infections, such as Virus.

TNF also alters the properties of endothelial cells and, for example, induces tissue factor procoagulant activation. increase pro-coagulant activity and anti-U fixation protein. resulting in inhibition of the white C pathway as well as thrombomodulin (thrombpm) down-regulating the expression of It has various procoagulant activities such as. TNF, if:, along with its initial production. (during the early stages of the inflammatory event), myocardial infarction, stroke and cardiovascular shock (this Similar mechanisms of tissue damage in several important diseases, including but not limited to Pro-inflammatory activity (pro-infla + mmators・acti) ity). Intercellular adhesion molecule (ICAM) or endothelial leukemia on endothelial cells Of particular importance is the TNF-induced expression of adhesion molecules such as bulbar attachment molecule (ELAM). It is.

TNF is also an important mesoeater of many inflammatory conditions or diseases. I think that the. Therefore, inhibition of TNF production means that abnormal levels of TNF are produced. It has utility in any inflammatory condition or disease. Abnormal levels of TNF is more than or equal to 1 picogram per liter per month. 2) any cell-associated TNF, or 3) TNF produced by Level of presence of TNF mRNA above basal level in cells or tissues Configure. Additionally, the present invention provides that many of the effects described herein on Tl--1 activity Attributable to physical diseased ducts. These disease states are characterized by the presence of appropriate disease states of TNF activity. Therefore, compounds of formula (II) and (I[[) are suitable for their treatment. It should not be limited to IL-1 activity alone.

Compounds of formula (II) and (I[I) may be used to treat mammals in need of treatment. For the treatment of disease states mediated by cytokines, TNF, in animals, including Found to be useful. The compounds represented by formulas (U) and (III) are The discovery that compounds of formulas (II) and (I) are inhibitors of cytokines, particularly TNF, Effect of the compound shown in II) on the in vitro production of TNF on human monocytes Based on effectiveness. This assay is described herein.

pharmaceutical composition The present invention further provides that PUFA metabolizing enzymes such as 5-LO or CO any disease or disease in animals, including humans, that is caused or aggravated Formula (1) in the formulation of drugs for the prophylactic or therapeutic treatment of conditions. or a pharmaceutically acceptable salt thereof.

The present invention further provides that excessive or unregulated IL-1 or TNF production any disease state in animals, including humans, that is caused or caused by Formula (n) and in the formulation of drugs for the prophylactic or therapeutic treatment of Concerning the use of the compound represented by (I[I).

The present invention also provides effective non-toxic doses and compounds of formulas (1) to (III). and a pharmaceutically acceptable carrier or diluent. Formula (I) by mixing the compound represented by with standard pharmaceutical carriers according to conventional methods. The compound of formula (1) is administered in a conventional dosage form. Ru. A compound of formula (I) can be combined with a known second therapeutically active compound. It can also be administered using conventional medication. These methods are suitable for the desired preparation It involves mixing, granulating, and compressing or dissolving the ingredients so that the

The pharmaceutical carrier used may be, for example, solid or liquid. Examples of solid carriers are , lactose, white clay, euclose, talc, gelatin, agar, pectin, aluminum Examples include gum labia, magnesium stearate, and stearic acid. liquid Examples of carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, carrier or or diluents include glyceryl monosterate or glyceryl nistearate. time delays well known in the art, such as alone or in combination with waxes. A delay material (ti+se delay material) may be included.

Various pharmaceutical forms can be used. Thus, when using a solid support, The preparation may be tabletted or placed in hard gelatin capsules in powder or pellet form. or in the form of a troche or lozenge. The amount of solid support can vary Although it can take any value, it is preferably about 25 to about 1 g. using a liquid carrier If the It may be in the form of a sterile injectable solution, such as a suspension.

In order to obtain stable water-soluble dosing of insoluble compounds of formula (1), formula (1) A pharmaceutically acceptable salt of the compound represented by 0.3M succinic acid or citric acid Dissolved in aqueous solutions of organic or inorganic acids such as

However, the compounds represented by formulas (Ia), (11) and (I[I) are represented by formula (1). As a subgenus of compounds indicated, all applicable dosage ranges and formulations etc. , unless otherwise indicated, apply to compounds of formula (II) and (I[[). Ru.

Compounds of formula (I) may be administered topically. Thus, equation (1) Compounds shown in the table have been shown to be effective in the treatment of inflammation and in animals, including humans and other mammals. can be administered locally in prophylaxis to treat rheumatoid arthritis, rheumatoid arthritis, spondylitis, osteoarthritis, gouty arthritis, and other arthritic conditions, inflamed joints, eczema , other inflammatory skin conditions such as psoriasis or sunburn, and inflammatory ophthalmological conditions including keratitis. : 5-reactive diseases such as pyresis, pain and other symptoms associated with inflammation. It can be used to relieve or prevent pokingenase pathway mediated diseases.

For all methods of use described herein, for therapeutic effects on topical administration. The amount of compound of formula (I) required will, of course, depend on the selected compound, the flame nature and severity of symptoms, whether eicosanoid-mediated or cytokine-mediated. This will vary depending on the animal being treated and is ultimately at the discretion of the physician. action A suitable topical anti-inflammatory dose of the ingredient, i.e. the compound of formula (1), is 0. The dosage is 9 to 150 doses per day, 1 to 4 times, preferably 2 or 3 times daily.

Local administration means non-systemic administration of the compound represented by formula (I) to the epidermis, preoral cavity, etc. including garden application and instillation of the compound into the eyes, ears and nose, where the The compound does not enter the bloodstream significantly. Systemic administration includes oral, intravenous, and intraperitoneal administration. and intramuscular administration.

Although the active ingredient can be administered alone as a raw chemical, it can also be used in pharmaceutical compositions. Preferably, it exists as For topical administration, the active ingredient may be added to the formulation at 0° 001% to 10% w/w, for example 1% to 2% by weight, but 1 It may consist of as much as 0% w/w, preferably more than 5% w/w of the formulation. It does not matter, and more preferably consists of 01% to 1% W/W.

The topical formulations of the present invention contain, together with the active ingredient, one or more acceptable carriers and Optionally, it consists of therapeutic components of either pond. The carrier is compatible with the other ingredients of the formulation must be ``acceptable'' in the sense of being able to do so and not be harmful to the recipient. No.

Formulations suitable for topical administration include liquids suitable for penetration through the skin to the site of inflammation. liquid or semi-liquid preparations, e.g. liniments, lotions, creams, ointments formulations or pastes, and drops suitable for administration to the eyes, ears, and nose. .

The drops of the invention may consist of a sterile aqueous or oil solution or suspension, Bactericides and/or fungicides and/or fungicides, preferably containing surfactants. by dissolving the active ingredient in a suitable aqueous solution of any other suitable preservative. It can be prepared by The resulting solution is then clarified by filtration and placed in a suitable container. This is then sealed and autoclaved or 98-100 Sterilize by keeping for half an hour at °C. Alternatively, the solution may be filtered. sterilize it and transfer it to a container using aseptic technique. Contained in drops Examples of suitable disinfectants and fungicides include phenylmercuric nitrate or phenylmercuric acetate. Nil water! ! (0°002%), benzalkonium chloride (001%) and sodium acetate Lorhequindin (001%) is mentioned. Solvents suitable for the preparation of oily solutions Lotions of the present invention include those suitable for application to the skin or eyes. Ru. Ophthalmic lotions are sterile aqueous solutions that may optionally contain bactericides. It can be prepared by a method similar to that for preparing drops. Skin Lotions or rinsing agents for application to the skin may also dry more quickly and cooling agent, such as alcohol or acetone, and/or glycerin. Contains moisturizers like celerol, or oils like castor oil or peanut oil. It's okay.

The cream, ointment or paste of the present invention is a semi-solid product for external use containing an active ingredient. It is a drug. They contain the active ingredient in finely ground or powdered form, by itself. or as a solution or suspension in an aqueous or non-aqueous liquid using a suitable machine. It can be prepared by mixing it with a base with or without oil. ), the bases include hard, soft or liquid paraffin, glycerol, beeswax , metallic soaps, demulcents, almond oil, corn oil, peanut oil, linseed oil or Oils of natural origin, such as wool fat or its derivatives, or propylene Stearic acid or in combination with alcohol such as recall or macrogel It may consist of hydrocarbons such as fatty acids such as oleic acid. This formulation includes Suitable surfactants, such as sorbitan esters or their polyoxyethylene Containing anionic, cationic or nonionic surfactants such as derivatives Good too. Mat:, turbidifying agents, such as natural rubber, cellulose derivatives, or Inorganic substances such as silicaceous 5ilicas Other ingredients may also be included, such as lanolin and lanolin.

The method of the present invention involves parenterally delivering monokine activity inhibitors. It can be done. As used herein, "parenteral" refers to intravenous, intramuscular Intra, subcutaneous, intranasal, rectal, intravaginal or intraperitoneal administration. Generally subcutaneous and intramuscular parenteral administration forms are preferred. Suitable dosage for such administration Forms can be prepared by conventional techniques.

All uses described herein for compounds of formula (1)-(Ill) In one method of administration, the daily oral dose is about 0.1 to 80 mg per 111 g of total body weight, preferably Preferably 0.5 to 30 goods/'hti, more preferably about 9 to 15 goods/'hti. . The parenteral daily dose is about 0.1 to 80 m9 per 14 g of total body weight, preferably about 0.5 m9 per 14 g of total body weight. to about 3019/J19, more preferably about 119 to 15 9/J19.

Compounds of formula (Ill) may be administered by inhalation. "Inhalation" means intranasal inhalation administration and oral inhalation 19 administration. Aerosol formulation or use Metered dose inhalers, etc. 11 may be prepared by conventional techniques. described herein For all methods in which a compound of formula (I) is administered by inhalation, A preferred daily dose is about 0.01 9/h9 to about 1 ay/h9 per day.

The form and characteristics of the pharmaceutically acceptable carrier or diluent are effective to combine. Depends on ingredients, route of administration, and other well known variables, will be determined by those skilled in the art. This is what I understand.

Regarding the administration of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof The appropriate amount and interval will depend on the nature and severity of the condition being treated, the form of administration, route and and site, as well as the individual patient being treated. It will be recognized by those skilled in the art that the subject can be administered by conventional techniques.

The optimal treatment, i.e., formula (1 ) or a pharmaceutically acceptable salt thereof may be administered according to conventional therapeutic procedures. This is ascertained by one skilled in the art using standard test methods.

Example Without further elaboration, one skilled in the art can, using the preceding description, place the present invention in its fullest scope. It seems that it can be used up to the limit. Therefore, the examples below are simply It should be construed as illustrative and does not limit the scope of the invention in any way. .

Example A Expression (1) for in vitro L-1 production by human monocytes Inhibitory effects of compounds Compound represented by formula (1) for inv1tro production of IL-1 by human monocytes The effect of the substance was tested using the following protocol.

IL-1 by human peripheral blood monocytes using bacterial lipopolysaccharide (LPS) induced production. Simon et al. [Journal of Immunology Cal Melins (J, Immunol, Methods), 84.85 (1985) to produce an interleukin cell line (EL-4) according to the method of Kin2 (11-2) stimulates IL- IL-1 activity was measured by the ability to secrete 2. Colott a) et al. [Journal of Immunology (J, I m5uno1.), 132.936 (1984)] from volunteer donors. Isolation of human peripheral blood monocytes from fresh blood preparations or blood bank buffy coats and purified. 1 to 2 million such monocytes/well Plated in 24-well plates at a concentration of I11. Allow cells to attach for 2 hours , then unattached cells were removed by gentle washing. Next, test The compound was added to the cells for 1 hour before the addition of lipopolysaccharide (50 nq/ml'), Cultures were incubated for an additional 24 hours at 37°C. Incubation time Afterwards, the culture supernatant was removed and cells and all debris were removed. culture supernatant, Immediately assayed for IL-1 biological activity in a manner similar to that described above, radio prostaglasins and/or leukotrienes at once by immunoassay. I then assayed it.

These results demonstrate that human peripheral blood monocytes are highly susceptible to bacterial endotoxins. and showed. Nanogram or picogram amounts of LPS produce high levels of IL-1 production. However, leukotrienes stimulated production and prostaglandin production. were only slightly, if at all, detected in such performances□ These observations are consistent with various reports [Humes et al. Null Off Biological Chemistry (J, Biol, Chew, ), 257.1591 (1982)].

Expression (1) for in vitro IL1 production by human monocytes The results of the effects of the compounds are shown in Table 1. As shown in Table 1, represented by formula (I) The compound is an effective inhibitor of in vitro IL1 production by human monocytes. be. The compound represented by formula (I) was tested in vitro by monocytes. The exact mechanism that inhibits production is currently unknown. Effective cyclooxy Other non-steroidal agents with genease and/or lipoquine genease inhibitory activity This inhibitory activity is due to the fact that anti-inflammatory drugs do not inhibit TL-1 production at non-toxic doses. Properties and relationships of the compound represented by formula (1) in mediating inhibition of chydonate metabolism I don't think it's related. Furthermore, prostagranone production and/or The ability of the compound to inhibit leukotriene synthesis inhibits 11,-1 production. That doesn't mean it's necessary.

non-inflammation responses and other disease states in causing or exacerbating them. Regulation (i.e., excess) in vivo'11. -1 Broad range of production roles Based on the reliability maintained in [e.g. Fontana et al. Ide, Wood et al., supra, Akejima and Dina Shinoro (D1narello), supra, Habicht and Beck et al., supra; Chesque et al., supra; See Benjain et al., supra: and Dinarello, supra], and the compound represented by the formula Cl0) is used in human macrophages and/or monocytes. (see Table 1) ), the compounds of formulas (Ir) to (m) can be prepared according to the method of the present invention. When used, monocytes and/or macrophages in humans in need It will inhibit in vivo IL-1 production.

Utility Example B Inhibition of compounds of formula CI) on in vitro TNF production by human monocytes Effect Section 1; Assay mechanism Effect of compound of formula (1) on in vitro production of TNF by human monocytes was experimented using the following protocol.

Co1otta, R. et al., Journal of Immunology. G (J.

I Dragon uno1. ), 132 (2): 936 (1984). human peripheral blood from blood bank buffy coat or platelet ference remnants. Monocytes were isolated and purified. Monocytes were placed in a 24-well multi-purpose bowl. Cells were plated at a density of 1X10' cells per 141 medium per well. the cell concerned After 1 hour of attachment, the supernatant was aspirated and added with 1% fetal serum and 10 units/'l. A new medium containing veninoline and streptomycin [RPMI-16 40. Whitaker Biomedical, Whitaker, California Products (Whitaker Biomedical Products)] 1++/ was added. The cells were treated with a test compound at a dosage range of lnM-10ttM. (Compounds were incubated for 45 minutes in the presence or absence of dimethyl sulfonate. Dissolved in dimethyl oxide/ethanol, the final solvent concentration in the culture medium was 0.05% dimethyl sulfoxide 105% ethanol). Next, bacterial lipopolysaccharide Sig+sa Chemicals Co. E coli (E. coli 055: B5 [LPS]) from phosphate 1100n/ml in 10m/buffered saline (PBS)! and culture. Incubated for 16-18 hours at 37°C in 5% CO, Ink, Beta.

After this incubation, the culture supernatant was removed from the cells and rotated at 3000 rpm/ Cell debris was removed by centrifugation at rp. 0.0517 of the supernatant was assayed for TNF activity using the following procedure.

Section ■: Radioimmunoassay method for TNF activity The assay buffer is 7.4, 0.01M NaPO4, 0.15M NaCLO.

025M EDTA and 0.1% sodium azide. Cheno ( Chen) et al., Nature, 330:581-583 ( 1987) (7) Human recombinant TNF (rhTNF) obtained using the method , was iodinated by the modified chloramine-T method described in Section 1 below. Sample (culture) 50 μl of supernatant) or rhTNF standards, polyclonal rabbit anti-rhTNF (Genzyme, Boston, Massachusetts) 1/900 0 dilution and “I-TNF8000 cp■ in a final volume of 400 μl buffer. and incubated overnight (18 hours) at 4°C. normal rabbit serum and goat anti-rabbit IgG (Calbioche). were added dropwise against each other for maximum precipitation of rh-TNF. carrier normal Appropriate dilution of rabbit serum (1/200), appropriate dilution of goat anti-rabbit IgG Precipitate the solution (1/4) and 25 units heparin (Calbiochem) and place in an assay tube. 200 μl of this complex was added per plate and incubated overnight at 4°C. tube Centrifuge at 200 rpm for 30 minutes, carefully aspirate the supernatant, and remove the pellet. Beckman Gamma 5500 counter - Measured with For calculation, logit-1logi line transformation curve (logit- 1oglinear transformation curve) was used. . The concentration of TNF in the sample was determined linearly in the range of 157 to 20.000 pg/m/. The readings were taken from a standard curve of rhTNF.

Section ■ Radioiodination of rhTNF Frolik et al., Journal on Biological Chemistry Tory (J, Biol, Chew), 259:10995-110 Iodination of rhTNF using a modified chloramine-T method of 00 (1984). went. i.e. 5m rhTNF in 5wl 20MM Tris (pH 7,5) g of 0.5M KPO315m/and carrier-free "'I (100mC1/++ l; ICN) diluted with 10 ml. 100 n/d to start the reaction (Aqueous solution) Aliquots 5++4' of chloramine-T solution were added. 2 minutes at room temperature Afterwards, add another 5vsl aliquot and after 1.5 minutes, add the last chloramine-T. 5mf was added. The reaction was stopped, and after 1 minute, 501M sodium metabisulfite was added. Um 20d, 12 (1+M potassium iodide 1001N and 1.2me/ml urine Element 2001Z was added. Mix the contents and pour the reaction mixture into a pre-filled, flat container. Equilibrated Sephadex (S ephadex) G-25 column (PD 1 0 Pharmacia (Pharacia) and 0.25% gelatin. Elution was carried out with phosphate buffered saline (pH 7.4). peak radioactivity Both containing fractions were pooled and stored at -20°C. ``The specific activity of 1-TNF is 8 It was 0-100 sCi/s+g protein. Biological activity of iodinated TNF , Neale, M.

L.) et al., European Journal on Cancer and Clinical ・Oncology (Eur, J, Can, C11n, 0nco1.), 25 ( 1): 133-137 (1989) as determined by the L929 cytotoxicity assay. and was found to be 80% of that of unlabeled TNF.

1st Vi'i: Measurement of TNF - ELISA Winston et al. Current Protocols in Molecular Biology in Molecular Biology), page 11.2.1, Ausbel (Ausubel) et al. (1987) John Wiley & Sons (Ausubel) et al. Basic Santoy Noci ELIS disclosed in New York, USA Levels of TNF were measured using the A assay method. The ELISA method The following murine monoclonal anti-human TNF was used as a cupture antibody. The following polyclonal rabbit anti-human TNF antibody was used as the second antibody.

For detection, goat anti-rabbit antibody conjugated with peroxidase (Pehringer Manno 1, Indianapolis, Indiana, USA) im (Boehringer Mannheim, Catalog #605222) and then the substrate for peroxidase (containing 0.1% urea peroxide) 1 g/wl orthophenylene diamine) was added. The TNF level in the sample is Recombinant human TNF produced in E. coli (E, Co11) (American SmithKline Beecham, King-on-Prussia, Pennsylvania, United States Pharmaceuticals (SmithKline Beecham Phar Calculated from a standard curve generated by (obtained from Aaceuticals).

Section V・Production of anti-human TNF antibodies・ Kohler and Millstein, Neich. 256:495 (1975) (the entire content of which is incorporated herein by reference). Lungs of BALB/c mice immunized with recombinant human TNF using a modification of A monoclonal antibody against human TNF was prepared from. Freund complete adj. Recombinant human T emulsified in Bant (DIFCO, Illinois, USA) Repeated immunization of New Sealant White (NZW) rabbits with NF A polyclonal rabbit anti-human TNF antibody was prepared by

Utility Example C In a test used to determine activity as a 5-lipokingenase pathway inhibitor Male Ba1b/c mice (20-28 g) were used. all mice , 2 - Charles River Breeding Laboratories, Kixton, York. Charles River Breeding Laborato ries). - Mice within the experiment were of the same age.

Reagents were used as follows: The compound of formula (T) was used as a free base. The compound is dissolved in acidic physiological saline. Dissolved in water. At a final volume of 10ne/19, combine by washing with a given volume. administered something.

For in vitro experiments, appropriate concentrations in ethanol (10% final concentration) and then using the 1ili solution given in the text Diluted to final concentration.

Arachidonic acid-induced mouse ear inflammation Arachidonic acid (2 me/20 m/) in acetone was applied to the inner surface of the left ear.

The thickness of both ears was then measured with an automatic micrometer one hour after the procedure, and the data was expressed as the change in thickness between treated and untreated ears (10-3clI).

Prior to topical application of arachidonic acid, the test compound was administered in acid/saline at the specified time. Administered orally. 5.6-Sihydro2-(4-methylthiophenyl)-3-(4 -pyridyl)-[7H]-pyroO[1,2-a]imidazol-7-ol compound showed an ED of 22.3 my/kg and 1 in this assay.

5-Lipokingenase activity assay 5-lipoxygenase (5-LO) was isolated from extracts of RBL-1 cells.

These cells were collected from the American Type Culture Collection (Aeri canType Culture Co11ection) (#CRL 13 78) and supplemented with medium containing 10% heat-inactivated fetal serum. Grow at 37°C with 5% CO in a stirred culture using Eagle Essential Medium (MEM). It has grown. Harvest cells from cultures by centrifugation at 2,000×g for 20 min and then and 50mM sodium phosphate containing 1M EDTA and 0.1% gelatin. The sample was washed twice with pH 7.0.

After this wash, resuspend the cells in fresh phosphate buffer to 5X 10' cells/W. A concentration of 1 was reached. This suspension was heated at 75 Qpsi for 10 minutes in a Pa bomb. by nitrogen cavitation using I crushed it. The disrupted cells were then centrifuged at 10.000×g for 20 min. . The supernatant was collected and centrifuged at 100.000xg for 60 minutes. Collect this supernatant and Stored at -70°C until assay.

Inhibition of 5-lipokingenase activity was determined in one of two assays, viz. Measured after 90 seconds at 0°C or GK Hogaboom (G, K.

Hogaboom et al., Molecular Fur 7 Co., Ltd. Phar+waco1. ) 30.51.0-519 (1986) Radiotracer measured by one-time assay or continuous 02 consumption assay Measured. Compare the results from both assays to see if they are the same. all compounds Materials were dissolved in ethanol with a final concentration of ethanol being 1% in the assay.

Once the radiotracer assay is completed, the assay is performed after 90 seconds of incubation at 20°C. The produced 5-lipoxygenase product [transLTB4 (DI-HETE) , 5HETE and 5HPETE] were tested. Aliquot of supernatant (40 ++/), 11mM EDTA, 1iM ATP, 50++M NaCl, 5% ethylene glycol and 10019/sl! sonicated phosphatide 25 °C MBisTri, J:Si solution (in p[(7,0) (total volume 0.238 ml) for 10 minutes with inhibitor or excipient. It was a cube. CaC12 (2 true M) and 1-C14-arachitoniaic acid ( 25mM; 100. By adding OOOdpmX final volume 0.25 m4), The 5-lipokinogenase reaction was started. After 90 seconds, double the capacity (0,5++f) The reaction was stopped by adding water-cooled acetone. 10 minutes at 1.000xg Samples were deproteinized on ice for 10 minutes before centrifugation. The protein-depleted stage is argon-treated. It was dried at 1,000°C and then redissolved in ethanol 20011. Then these trials No. K. Hogaboom et al., Molecular Pharmacology, 3051 No. 0-519 (1,986), incorporated herein by reference. , analyzed by reverse phase ItPLC. Compounds with 5-lipokinogenase activity Mediated inhibition is described as the concentration of compound that results in 50% inhibition of product synthesis.

A second assay to assess inhibition of 5-lipoxy7 genease activity It was a continuous assay to monitor consumption of 02 as it progressed. 5- Lipo Oxygenase enzyme (200 ml, 1-M EDTA, IIM, ATP, 5 (hMNaCl, 25°C M B15Tri containing 596 ethylene glycol s buffer (pH 70) (total R1 volume 2.9 M) for 2 min at 20°C. or pre-incubated with the vehicle. Arachidonic acid (1 (bM)) and CaCi2 (2mM) were added to start the reaction. 02 decrease Clark type electrode and Yetu Spring O, monitor (type 53) (Oha Using Yellow Springs, Io state. and tracked over time. The optimum speed was calculated from the nine progression lines. 5-Lipoxygener Compound-mediated inhibition of enzyme activity was 50% inhibition of the optimal rate for excipient-treated samples. is expressed as the concentration of the compound produced.

LTC4/PGE2 production from in vitro human monocytes a) Cells prepared by the American Red Cross (Philadelphia, Pennsylvania). Human monocytes were prepared from leukosource pack. Ta.

The leucosource pack was subjected to sequential sedimentation on Ficoll, followed by Ehu D Latta (F, using sedimentation on Pereoll) Co1atta) et al., Journal of Immunology (J, l Huno 132.936 (1984) (the present invention (quoted in the specification).

The monocyte fraction obtained from this technique consisted of >85% monocytes. (The rest are neutrophils and lymphocytes). Monocytes (1,5 x 10’) were inoculated with polypropylene. They were placed in pyrene tubes and used as suspension cultures. Assay buffer was RPMI 1 640 Buffer 1 & [Moore, G, E, et al. JAM A, 199.519 (1967) (herein incorporated by reference)], 1% human A B serum, 21M glutamine, 100U/wing! penicillin/streptomynon, 25 votes M HEPES [4-(2-hydroxyethyl)-1-piperazine-e tansulfonic acid], and 1mM CaClt.

b) LTC4/PGEv production, monocytes (0,911/tube) in 12X75+n poly Distributed into ethylene tubes (as suspension cultures). Compound dissolved in assay medium (chemical 100 μl of a 10× stock of the compound was added per tube (in duplicate).

Cells were placed in a humidified incubator. The mixture was incubated at about 7° C. for about 45 minutes with constant stirring. to stimulate cells The A23187 calcium ionophore used (final concentration 2 μM) was added to monocytes. was inked and incubated for an additional 15 minutes. The stage is then collected from the container and centrifuged. Therefore, it was clarified, divided into two aliquots, and stored at -70°C until assayed. did.

C) Radioimmunoassay Two supernatants were used for LTC4 production by radioimmunoassay. and PGE2. This is from the manufacturer (Boston, Massachusetts). Stone's New England N1c New England no clear leucotri according to the instructions of New England N1 clear Leukotriene ``Hco LTC4 and [''I]-PGE2R1A kits were used.

Compound-mediated inhibition of LTC4 is characterized by concentration of LTC4, a compound that causes 50% inhibition of production. Described as degrees.

TPA-induced mouse ear edema 12-0-tetradecanoylphorbol acetate (TPA) to mouse ears Administration of lipoxygenase (LO) and cyclooxygase (Co) products It was shown that inflammation caused by both was induced. LO and CO products and sa Corticosteroids, which inhibit itokine production, have antiedema activity and are effective against inflammatory cells. Although they also inhibit cyst invasion, CO and LO inhibitors only have anti-edematous activity. TPA (12-0-tetradecanoylphorbol acetate) in setone Sigma Chemical Company (Sigma Che+5ical Co.) ) (411q/20 tin) on the inner surface of the left ear of a BALB/c male mouse. and applied to external surfaces. The thickness of both ears was then automatically measured 2 and 4 hours after the procedure. Measurements were made with an Ichromator (Mitutoyo, Japan). Data is Expressed as the change in thickness (10-'c-) between treated and untreated ears. a Application of setone did not produce a edematous response: therefore, the difference in ear thickness was due to TP It represents the response to A. After measuring the edema, take the inflamed left ear and -70 until assayed for MPO<myeloperoxidase) activity. Stored at °C.

Test compounds are administered orally 15 minutes before application of TPA. The results are in one group. Mean +/- standard deviation values from measurements on 8 mice per day.

A nose of myelobertinase (MPO) in inflamed ear tissue ヱ On the day of the assay, partially thawed ear tissue was minced and then treated with 0.5% H 50mM phosphorage buffer (pH 6) containing TAB ) in a Tissumizer homogenizer (Tissumizer). The mixture was homogenized (10% W/V) using a vacuum cleaner (Tekmar Co.). this The tissue homogenate was frozen-thawed three times, then briefly (10 seconds) Sonicated.

B radely et al., Journal of Investigation Eve Dermatology (J, T best, Derts,), 78 :206.1982 was used with the modifications described herein. 0- Cyanisgin (0,167 mg/ml; Sigma Chemical Company) and and MPO dependence of hydrogen peroxide (0,0005%: Sigma Chemical Company) The appearance of colored products from the reaction was measured spectrophotometrically at 460 nm.

Supernatant MPO activity was measured using a Beckman (B, eckIlan) DU-7 spectrophotometer and and dynamic analysis package (Beckman Instruments, Inc.) Using the code (Beckman I nstruwents, I nc, ) , quantified kinetically (sampled at 15 second intervals and measured over 3 minutes) change in absorbance). One unit of MPO activity is 1 micron per minute at 25°C. Defined as the decomposition of moles of peroxide.

Land: 5.6-Sihydro2-(4-methylthiophenyl)-3-(4-pyridyl)- [7H]-pyrrolo[1,2-a]imidazol-7-ol compound has MPO activity. Edema response (-66%) and inflammatory cell infiltration as indicated by inhibition of Both responses (-66%) were significantly reduced. E of MPO for this compound DS was 21.819/h9 per oral administration. This compound is It had significant anti-inflammatory activity in the model. The potency of this compound is surprisingly It was always bigger than expected.

Table 1 IL-1 (ICs.) data.

Compound number '10.3 Compound number 5 2 22 ° Compound number 1 is 5,6-dihythro-2-(4-fluorophenyl)-3-( 4-pyridyl)-7-ol-5,6-sihydro[7H]-pyrrolo[1,2- a] imidazol-7-ol.

Compound number 2 is 5,6-sihydro-2-(4-methylthiophenyl)-3- (4-pyridyl)-[7H]-pyrrolo[1,2-a]imidazole 7-ol be.

Table 2 TNF (IC,.) data: Compound number ° 1 03 Compound number '22.0 Table 3 LTC4 (IC5゜) data/compound number '12.3 Compound number 1 22.8 Compound number 2 70 Table 5 PGE, data Compound number ° 1 14 Compound number ゝ　2　23 Synthesis examples Example 1 5.6-hydro-2-(4-methylthiophenyl)-3-(4-pyridinyl) -5,6-sihydro-2-(4-fluorophenyl)-3-(4-pyridinyl) -7H-biOO[1,2-a]imidazol-7-ol (085 grams , 9), 29 mmol (hereinafter referred to as mmol)) of DMF (10 mmol) Sodium thiomethquine (0.30v, 4,4 mol) was added. The resulting mixture was heated at 120°C for 48 hours, Then it was cooled. The mixture was concentrated under reduced pressure and the residue was dissolved in HtO and CH2Cl. It was distributed between two. The organic extract was washed with a saturated aqueous solution of Na(J) and dried (Mg S O4). The solvent was removed in vacuo and the residue was recrystallized twice from MeOH to give a pale A tan solid (0,199,20%) was obtained. Melting point 229-230°C.

'HNMR (CDCrs): δ8.59 (d, 2H): 7.40 (d, 2H); 7.19 (2 duplicate d, 4H): 6.18 (br d, IH); 5. 27 (m, IH): 4.27 (m, LH); 3.94 (m, IH): 2.90 (m, LH); 2.63 (m, IH); 2.50 (s, 3H).

CIMS (NHs); mle (tel, int,): 324 [(M +H)', 100], 308(11).

Elemental analysis (Cls H+tNs OS) theoretical value・C,66,85:H, 5,30; N, 12.99: S, 9.91, measured value C, 66,78: H , 5, 55: N, 12.95; S, 9.58° Example 2 5.6-Sihydro2-(4-fluorophenyl)-3-(4-pyridinyl)- 7H-pyrrolo[1,2-a]imidazol-7-ol a) 1-t5.6-cy Hydro-2-(4-fluorophenyl)-3-(4-pyridinyl)-7H-piO O[1,2-a]imidazol-7-yll-1-(4-nitrophenyl)meth Knoll At 0°C, 5,6-hydro-2-(4-fluorophenyl)-3-(4-pyridi nyl)-7H-piOO[1,2-a]imidazole (15,09,0,054 mo mol (hereinafter referred to as mol)) in CHtC4't (50++4') Methoxyethoxymethyl (30*t, 0.26sol) was added. The resulting mixture The mixture was warmed to room temperature and stirred for 1 hour. Add ether and decant the mixture I did (3x). Dissolve the residue in EtOH (400d) and add triethyl to this solution. Amine (40*e, 0.2!J+ol) and 4-nitrobenzaldehyde (10 mol of 15,09° area) was added. The resulting mixture was kept under reflux for 48 hours. Heat, then cool and concentrate under reduced pressure. Residue 1-+10 and CH2 Partitioned between Cl1. Organic extract with NaCl! Washed with saturated aqueous solution and dried ( MgSOt). The solvent was removed in vacuo and the residue was triturated with EtOAc. Ta. The orange solid that formed was collected by filtration to yield the title compound (8, Oy, 34%). I got it. This was used without further purification.

1-15.6 to a solution of Jones reagent (25 liters) in acetone (250 s+1) -Sihydro2-(4-fluorophenyl)-3-(4-pyridinyl)-7H- Pyrrolo[1゜2-a]imidazol-7-yll-1-(4-nitrophenyl) Methanol (5°0 g, 12 mmol) was added. The resulting mixture was heated at room temperature for 3 Stir for 0 min then adjust pH to 7-8 with 2.5N NaOH. decante Remove the solid material from the acetone solution by washing with 2.5N NaOH and and 1 and 2 CH7Cf2/EtzO. Filter this mixture and separate the layers. I let go. The organic extracts were combined with acetone solution and evaporated under reduced pressure. 2 residues ．． Partitioned between 5N NaOH and CH,C12, the organic extract was dissolved in NaCl saturated aqueous solution. and dried (MgSOg). The solvent was removed in vacuo and the residue was dissolved in Et2 The title compound (159.43%) was obtained as an orange solid. . This was used without further purification.

5.6-7hydro2-(4-fluorophenyl)-3-(4-vininyl)- 7H-pyrrolo[1,2-al imidazol-7-one (crude product prepared above) Sodium borohydride (1,59,40 +ll+*ol) was added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture The mixture was concentrated under reduced pressure and the residue was partitioned between H20 and CH,C42. organic The extracts were washed with a saturated aqueous solution of Na(Jj) and dried (MgSOl). The solvent was removed in vacuo. The residue was triturated slightly with EtOAc and purified with copious amounts of Et20. Triturated to. The solid formed in MeOH for a total yield of 0.909 (26%) Recrystallize the compound in a white solid state for one season.

'HNMR (DMSOds): 8.58 (d, 2H): 7.45 (dd, 2 H): 7°36 (6, 2H): 7.16 (apparent t, 2H); 5.76 (d, IH); 4.99 (m, IH): 4.16 (m, IH): 3.95 ( m, LH); 2.82 (m, IH): 2.30 (m.

LH).

CIMS (NHx); mle (rel, int,): 296 [(M10) ', 100].

6.7-hydro-2-(4-methylthiophenyl)-3-(4-pyridinyl) -5H-pyrrolo[1,2-a]imidazole (formula (A) intermediate) a) at 20°C, Potassium hydroxide (341,09,6,09*ol) and bromide solution were stirred vigorously. Traethylammonium (51,2y, 0.24@ol) in tetrahydrofuran (THF) (2,01) to a suspension in 2-pyrrolidinone (97,2*e, 1. 2811101) was added. A thick white slurry is formed and the temperature is lower than 30 minutes. The temperature rose to 27°C within the day.

After mechanically stirring the reaction mixture for a total of 100 min at 20-30 °C, deionized water was added. 4-picolyl chloride hydrochloride (200, Ov, 1.22*ol) in Cl2O*l ) was added over 25 minutes. The temperature rises up to 40℃, and does not rise higher than this. There wasn't. After this addition, the reaction mixture was stirred for 120 minutes and then celite (C elite). The reaction flask and filtered solids were dissolved in THF ( 400d) and the washings were combined with the filtrate. What amount is retained during filtration? After separating the aqueous substances, the organic solution was reduced to a volume of 800 by atmospheric distillation of THF. Concentrated to ++t'.

After cooling the solution to 20°C, 60-80 gasoline (50k) was added.

After adding another 500 g of 60-80 gasoline, the solution was stirred for 10 minutes. Ta.

After adding the last 600 m/s of 60-80 gasoline, the mixture was stirred for another 10 minutes. Stir for a while. After cooling the mixture to 5°C for 16 hours, the product was removed by filtration. Isolated, washed with 60-80 gasoline (400d), 40°C, 100+Hg It was dried for 24 hours. As a result, a light brown granular crystalline solid tube of 1-(4-pin) was formed. 186.09 (86%) of Cholyl-2-pyrrolidinone was obtained. Melting point 82-84 ℃. HPLC assay 96.1%: M”, 176.0947cC+eHuNtO Theoretical value of 176.0950 + m/z 176, (M"), 147 (M--ct Hs), 119 (147-Co) and 903 (119-HCN): v,, , (KBr)2950.1690<C=O>, 1600.1450.1420. 1300 and 1280tM-'; δH (270MHz, CDC1,) 1.8 5(2H, m, CHtCHtCHt), 2.20(21(,t, -CHtC( 0)), 3.10 (2H, t, -CH2CH?NRR'), 4.25 (2H.

s, PyCH2-), 6.95 (2H, m, Ar(3,5)) and 8.30 ( 2H,m,Ar(2°6)).

b) At 0~10℃,! -(4-picolyl)-2-pyrrolidinone (20,09, 0°114 mol) of n-butyllithium in a solution in dry THF (260 m#) (so, o*l, 0.125 mol of a 2.5 M solution in hexane) was added. Attachment Addition took 10 minutes. Next, THF (65 Add potassium tetrabutoxide (12,79,0,114 mol) in ml) The resulting golden yellow suspension was stirred for 10 minutes. At this point, 5℃ at 0~10℃ 4-Methylthiobenzonitrile (18, 6v, 0125ω01) was added. Once the addition is complete, allow the reaction mixture to reach room temperature. It was heated for 30 minutes. After this time, the reaction mixture was heated under reflux for 120 min and 3 After cooling to 0 °C, 1 liter of deionized water (80%) was added. The resulting fluid solution was stirred for 30 minutes, then the aqueous layer was separated for 30 minutes before it was removed.

put and take distillation The solvent was exchanged with ethyl acetate via n). Here, solvent 14011! remove The mixture was then purified with 140 ml of ethyl acetate. This process continues until the base temperature reaches 77℃. The process continued. Further 45 ml of ethyl acetate was added and the solution was cooled to 50°C. After that, F30-80 gasoline (871'8 sweat was added. After cooling to room temperature, the product was crystallized, and after stirring for 3 hours, the suspension was cooled to 0-5°C and stirred for an additional 2 hours. did. The product was then separated by filtration and 60-80 gasoline (400 mil. After dry-smoking at 40°C and 100I Hg for 24 hours, a pale yellow color formed. 6,7-nohythro-2-(4-methylthiophenyl)-3-(4) in the crystalline solid state -pyridinyl)-5H-pyrrolo[1,2-al imidazole (17,69,50 %) was obtained. Melting point 172°C + HPLC assay 95°6%: δH (270MHz , CDC1g) 2.50 (3 summer (,S, -3Me), 2.70 (2H.

m, -CH2CH2,CHt-), 3.00 (2H,t, -CHtCH1CH! NRR, 4°05 (2H, t, -CHzCHtCHzNRR'), 7.20( 2H, m, MeS Ar), 7°30 (2H, m, 3.5-Py), 7.50 ( 2H,m,Me　Ar) and 8.60(2H1a) at -70°C, 1-(4 -Picolyl)-2-pyrrolidinone (2,01y, 11°4 mmol) in THF (285 ml) of n-butyl lithium (8.7 (8.7) of a 25 M solution in hexane) bj', 21.7+1sol) was added. The resulting yellow suspension = 30 to -7 After stirring at 0°C for 90 min, 4-methylthiol in THF (4(bl)) was added at -65°C. Obenzonitrile (2,729,18,311+*ol) was added. reaction mixture The mixture was allowed to warm to room temperature over 15 minutes and then stirred for a further 21 hours. After this , ammonia (720 μl of 35% W/W aqueous solution) was added, which caused the reaction to The reaction mixture turned from red to yellow. After stirring this solution for 30 minutes, The medium was removed in vacuo and the residue was eluted with ethyl acetate triethylamine (9 6:4) on silica gel. the result , Z-1-amino-1-(4-methylthiophenyl) in the form of a free-flowing yellow powder )-2-(4-pyridyl)-2-(1-(2-pyrrolidinoyl))etheno(12 g, 32%) was obtained.

Melting point 220-222°C (from ethyl acetate). , M'325.1271゜CIs H+sN! The theoretical value of the OS is 325.1249. v−+r　(nu jol mull) 3500-3300 (NH), 1669 (C-0), 1 632 (C-C) and 1566 cm-'; δH (270MHz, ds- DM SO), 2. 1 0 (2H, m, CH2CH2CH!-), 2. 40 (2H, t, CH2CHtCHtC(0)), 2.50 (3H, s, -3M e), 350 (2H, t, CHtCHzCHzC(0)), 5.70 (2H,s , NHt), 650 (2H, m, 3.5-Py), 7.25 (4H, m, Me S Ar) and 8. ．． 05 (2H, m.

2.6-Py); m/z 325 (M'), 308 (M NHs), 268 (M- C,H2O) and 150 (CsHsNS).

b) Z-1-amino-1-(4-methylthiophenyl)-2-(4 -2-tl-(2-pyrrolidinoyl))etheno(11419,03 Add n-butyllithium (hexyl lithium) to a suspension of 51 nmol) in THF (8.8 ml). 249 μl of a 2.5 M solution in Sun, 0.491 s++ aol) was added. Obtained The dark red solution was allowed to warm to room temperature over 30 minutes and then stirred at this temperature for 19 hours. Stirred. After this, the color changed to light yellow. At this point, the reaction mixture was subjected to HPLC. Therefore, it was found that the compound had the title compound 88-9 (82%). .

Example 5 2-(4-fluorophenyl)-6,7-')hydro-3-(4-pyridinyl) -51(-pyrrolo[1,2-a]imidazole (formula (A) intermediate) at -80°C, 1-(4-picolyl)-2-pyrrolidinone (56■9.0.318mm+ol) A solution of n-butyllithium (1.0 M in hexane) in dry THF (8*i) 427 μf, 0.4771101) of liquid was added. The resulting cloudy bright yellow The color solution was stirred at -50--80°C for 50 minutes and then diluted with THF (93°C) at -80°C. p-fluorobenzonitrile (6119,0,8097 mmol) in st') Add t. Then, after the reaction mixture turns dark red, let the reaction mixture cool to room temperature. It was heated with After stirring for 18 hours, the solvent was removed in vacuo and the residue was used as the eluent. Chromatography on Nori gel using ethyl acetate-methanol (41) I'll attach it to you. As a result, the title compound was obtained (719.7%).

Example 6 The seven samurai swords are roaring, and the description of the color work is Maruyoshi - the main animal ← the sleepless yo empty Liu H - Piroro [1, 2-a] Imidazole (formula (A) intermediate) at -40°C, 1-(4-picolyl)-2-pyro A solution of lysinone (2,669,151 gwol) in dry THF (76 m/) n-Butyl 1(Thium (2.5M solution in hexane 7.26*i, 18.1mm o↓) was added. Then potassium tert-butoxide (1,69 g, 15 A solution of 1 o 1) in THF (8,5 liters) was added, resulting in a golden yellow suspension. The mixture was stirred at -40°C for 10 minutes. At this point, at -40°C, 4-bromobenzoni A solution of tolyl (5,509,30,2++ mol) in THF (50++1) was added and the reaction mixture was then allowed to warm to room temperature. After stirring for 18 hours, the reaction The mixture was concentrated to dryness, and the residue was mixed with ethyl acetate/methanol (5:1) as an eluent. ) was used for chromatography on silica gel. As a result, yellow The title compound was obtained in a crystalline solid state (0.71 g, 14%). M’339.037 The theoretical value of 1°CuH+*N3"Br is 339.0371.M"341.0 The theoretical value of 387°CuH+sN3”Br is 341.0351.δH(27 0MHz.

CDC1g) 2.65 (2H, m, -C1-1t, CH, CHt-), 3.00 (2H, t.

CHt CHt CH2N RR, 4.00 (2H, t, CHtCHtCH* NRR'), 7°25 (2H, m, 3.5-Py), 7.40 (4H, m, Br -Ar) and 8. , 60 (2H, m.

2.6-Py); m/z 339 (M"), 341 (M") 259 (M-HBr) , 310 (M C2H3) and 312 (M-C2H,).

The foregoing description fully describes the invention, including specific examples. Items specifically mentioned herein Modifications and improvements to the examples are within the scope of the following claims. without further explanation , one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent, It seems possible. Accordingly, the examples herein are to be construed as illustrative only. However, the scope of the present invention is not limited in any way. exclusive ownership Examples of the invention for which privilege is claimed are as defined below.

international search report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A61K 31/44 A CD AED 9360-4C 311505ABG 9360-4C CO7D471104 108 A 8829-4C (72) Inventor Duyuri Deege Murray Phoenix, Pennsylvania 19460, United States 144 West Ridge Brace South R, Kusville I (72) Inventor: Gallagher, Timothy F. Pennsylvania, USA 255 Manor Road (72), Burleysville, State 19438 Inventor: New -ton, john Frank, West Chester, Pennsylvania 19380, USA ・Road No. 871

Claims (27)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, W is -(CR4R5)-, or -(CR4R5)-(CR6R7)-; R4 or and R5 together are oxo; or one of R4 and R5 is OH, R The other of 4 and R5 is hydrogen; R2, R3, R6, R7, R8 and R9 are hydrogen; or R2, R3, R6, R 7, one or two of R8 and R9 are independently hydrogen or C1-2 alkyl Kyl; one of R1 and R0 is 4-pyridyl or C1-4 alkyl-4 -pyridyl; the other of R1 and R0 is (a) phenyl; (b) The substituents are independently C1-4 alkyl, halo, hydroxy, C1-4 alkyl, Koxy, aryloxy, heteroaryloxy, C1-3 alkylthio, C1 -3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-52- Alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C2-5 2-alkenyl-1-sulfinyl, arylthio, arylsulfinyl, C 1-3 alkylamino, C1-3 dialkylamino, CF3, N-(C1-3 a N-(C1-3 alkyl)-N-(C1-3 alkanamide) , N-pyrrolidino, N-piperidino, prop-2-en-1-oxy, 2,2, 2-trihaloethoxy, thiol, acylthio, dithioacyl, thiocarbamyl , dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyal Kylthio, alkoxycarbonylthio, alkoxythionothio, alkoxyal Kylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, acyl selected from oxyalkylsulfinyl, acyloxyalkylthio or Z mono- or di-substituted phenyl: (c) formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A group represented by; Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Numbers There are formulas, chemical formulas, tables, etc. ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼; selected from; t is 0 or 1; W and R1, R2, R3, R4, R5, R6, R7, R8 and and R9 are the same as defined above; A is -CR5=CR7-, -N=CR7-, -S- or -O-; Ra and R b is independently selected from hydrogen, C1-9 alkyl, aryl or heteroaryl is; Z is -S-(CRaRb)t-S-Z1; Z1 is a functional group: however, a) When R1 is 4-pyridyl and W1 is -(CR4R5)-, R0 is 4-pyridyl. other than toxy-substituted phenyl; b) If R0 is pyridyl or C1-4 alkyl-4-pyridyl, R1 is N-(C1-3 alkyl)alkanamide or N-(C1-3 alkanamide )] A compound represented by or a pharmaceutically acceptable salt thereof. 2. Claim 1 wherein R1 is 4-pyridyl or C1-4alkyl-4-pyridyl. Compounds described. 3. R1 is C1-4 alkyl-4-pyridyl, and the alkyl substituent is pyridine. 3. A compound according to claim 2 in position 2 of the ring. 4. 4. A compound according to claim 2 or 3, wherein one of R4 or R5 is OH. 5. 5. The compound according to claim 4, wherein W1 is -(CR4R5)-. 6. 6. A compound according to claim 5, wherein R0 is monosubstituted phenyl. 7. R0 is substituted by alkyl S(O)m, m is 0 or 1 A compound according to claim 6. 8. 8. A compound according to claim 7, wherein alkyl is methyl or ethyl. 9. 9. A compound according to claim 8, wherein alkyl is methyl and said substituent is in the para position. 10. 11. The compound according to claim 10, wherein R2, R3, R8 and R9 are hydrogen. 11.5,6-dihydro-2-(4-methylthiophenyl)-3-(4-pyridi 7H-pyrrolo[1,2-a]imidazol-7-ol: 5,6-dihy Dro-2-(4-methylsulfinylphenyl)-3-(4-pyridinyl)-7 H-pyrrolo[1,2-a]imidazol-7-ol: 5,6-dihydro-2- (4-methylthiophenyl)-3-(2-methyl-4-pyridinyl)-7H-pi Lolo[1,2-a]imidazol-7-ol: 5,6-dihydro-2-(4- methylsulfinylphenyl)-3-(2-methyl-4-pyridinyl)-7H- Pyrrolo[1,2-a]imidazol-7-ol: 5,6-dihydro-2-(4 -methylthiophenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo [1,2-a]imidazol-7-one; 5,6-dihydro-2-(4-methyl sulfinylphenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo [1,2-a]imidazol-7-one: 5,6-dihydro-2-(4-methyl Thiophenyl)-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imida zol-7-one; or 5,6-dihydro-2-(4-methylsulfinyl phenyl)-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imidazole 2. The compound according to claim 1, which is -7-one. 12. The presence of a compound of formula (I) according to claim 1 in a mammal in need of treatment. OPUF in a mammal in need of such treatment, consisting of administering an effective amount of Methods for treating A-mediated diseases. 13.5-Lipoxygenase enzyme or cyclooxygenase enzyme is inhibited 13. The method according to claim 12. 14. Disease status: rheumatoid arthritis, osteoarthritis, platelet aggregation, thrombosis, veins inflammation, venous thrombosis, or myocardial infarction, inflammation, bronchitis, inflammatory bowel disease, ulcerated colon inflammation, hives, dropsy, psoriasis, dermatitis, multiple sclerosis, atherosclerosis, Vasculitis, glomerulonephritis, immune complex disease, pyresis, allergy Claim 12: Sexual disorder, rhinitis, allergic conjunctivitis, or food allergy. How to put it on. 15. The compound 5,6-dihydro-2-(4-methylthiophenyl)-3-(4-pyridinyl) -7H-pyrrolo[1,2-a]imidazol-7-ol: 5,6-dihydro- 2-(4-methylsulfinylphenyl)-3-(4-pyridinyl)-7H-pyridinyl Lolo[1,2-a]imidazol-7-ol; 5,6-dihydro-2-(4- methylthiophenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo[ 1,2-a]imidazol-7-ol; 5,6-dihydro-2-(4-methyl sulfinylphenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo [1,2-a]imidazol-7-ol; 5,6-dihydro-2-(4-methyl ruthiophenyl)-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imi dazol-7-one; 5,6-dihydro-2-(4-methylsulfinylphenyl )-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imidazole-7 -one: 5,6-dihydro-2-(4-methylthiophenyl)-3-(2-methyl -4-pyridinyl)-7H-pyrrolo[1,2-a]imidazol-7-one; 5,6-dihydro-2-(4-methylsulfinylphenyl)-3-(2-methylphenyl) -4-pyridinyl)-7H-pyrrolo[1,2-a]imidazol-7-one: 5,6-dihydro-2-(4-fluorophenyl)-3-(4-pyridinyl)- 7H-pyrrolo[1,2-a]imidazol-7-ol: or 5,6-dihyde Rho-2-(4-fluorophenyl)-3-(2-methyl-4-pyridinyl)-7 The method according to claim 12, which is H-pyrrolo[1,2-a]imidazol-7-ol. Law. 16. comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition. 17. The compound 5,6-dihydro-2-(4-methylthiophenyl)-3-(4-pyridinyl) -7H-pyrrolo[1,2-a]imidazol-7-ol: 5,6-dihydro- 2-(4-methylsulfinylphenyl)-3-(4-pyridinyl)-7H-pyridinyl lolo[1,2-a]imitazol-7-ol: 5,6-dihydro-2-(4- methylthiophenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo[ 1,2-a]imidazol-7-ol: 5,6-dihydro-2-(4-methyl sulfinylphenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo [1,2-a]imidazol-7-ol: 5,6-dihydro-2-(4-methyl ruthiophenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo[1, 2-a] Imidazol-7-one: 5,6-dihydro-2-(4-methylsulf ynylphenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo[1, 2-a] Imidazol-7-one: 5,6-dihydro-2-(4-methylthiophyl) phenyl)-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imidazole -7-one: or 5,6-dihydro-2-(4-methylsulfinylphenyl )-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imidazole-7- 17. The composition according to claim 16, wherein the composition is on. 18.5,6-dihydro-2-(4-methylthiophenyl)-3-(4-pyridi nyl)-7H-pyrrolo[1,2-a]imidazol-7-ol compound. 19.5,6-dihydro-2-(4-methylthiophenyl)-3-(2-methyl -4-pyridinyl)-7H-pyrrolo[1,2-a]imidazole-7-olation Compound. 20. Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, W1 is -(CR4R5)-; R4 and R5 together are oxo: or one of R4 and R5 is O H the other is selected from H; R2, R3, R8 and R9 are independently hydrogen or C1-2 alkyl: R1 and one of R0 is 4-pyridyl or C1-4alkyl-4-pyridyl , provided that when R1 or R0 is C1-4 alkyl-4-pyridyl , the alkyl substituent is located at the 2-position of the pyridine ring, and the other of R1 and R0 is , (a) phenyl, or the substituent is C1-3 alkylthio, C1-3 alkyl Sulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl- 1-sulfinyl, C3-52-alkenyl-1-thio, C3-52-alkenyl -1-sulfinyl, 1-acyloxy-1-alkylthio, C1-2 alco monosubstituted phenyl which is xy, halo, C1-4 alkyl or Z; or (b ) where the substituents are independently C1-3 alkylthio, C1-2 alkoxy, halo or C Disubstituted phenyl that is 1-4 alkyl: or (c) one of the substituents is C 1-3 alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51 -alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3- 52-alkenyl-1-sulfinyl or 1-acyloxy-1-alkylthi and the other is C1-2 alkoxy, halo or C1-4 alkyl Substituted phenyl: or (d) The substituents are the same, C1-3 alkylsulfinyl, C2-51-alk Kenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52- alkenyl-1-thio, C3-52-alkenyl-1-sulfinyl or 1- acyloxy-1-alkylthio or the substituents are methylene Disubstituted phenyl forming a dioxy group: or (e) The substitution is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A monosubstituted phenyl that is: t is 0 or 1: W1, R1, R2, R3, R4, R5, R6, R7, R8 and and R9 are the same as defined above: Z is -S-S-Z■, Z■ is C1-9 alkyl or phenyl; however, R1 is 4-pyridyl, W1 is -(CR4R5)-, one of R4 and R5 is OH, the other hydrogen or together oxo, R0 is 4-methoxy other than substituted phenyl] Effective cytokine-inhibiting amount of the compound represented by or a pharmaceutically acceptable salt thereof to an animal in need of treatment. How to treat cain-mediated diseases. 20. R2, R3, R6, R7, R8 and R9 are hydrogen, or R2, One or two of R3, R6, R7, R8 and R9 are independently hydrogen or is C1-2 alkyl; R1 is 4-pyridyl or C1-4alkyl-4-pyridyl; R0 is The substituent is C1-3 alkylthio, C1-3 alkylsulfinyl or halo Claim 19 The compound is a monosubstituted phenyl or a pharmaceutically acceptable salt thereof. Method described. 21. The compound 5,6-dihydro-2-(4-methylthiophenyl)-3-(4-pyridinyl) -7H-pyrrolo[1,2-a]imidazol-7-ol: 5,6-dihydro- 2-(4-methylsulfinylphenyl)-3-(4-pyridinyl)-7H-pyridinyl Lolo[1,2-a]imidazol-7-ol: 5,6-dihydro-2-(4- methylthiophenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo[ 1,2-a]imidazol-7-ol; 5,6-dihydro-2-(4-methyl sulfinylphenyl)-3-(2-methyl-4-pyridinyl)-7H-pyrrolo [1,2-a]imidazol-7-ol; 5,6-dihydro-2-(4-methyl ruthiophenyl)-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imi dazol-7-one: or 5,6-dihydro-2-(4-methylsulfinyl phenyl)-3-(4-pyridinyl)-7H-pyrrolo[1,2-a]imidazo 21. The method of claim 20, wherein lu-7-one is lu-7-one. 22. If the cytokine inhibited is IL-1 or if TNF is inhibited, The method according to claim 20. 23. Cytokine-mediated diseases include septic shock, endotoxic shock, and gram negative bacterial sepsis, toxic shock syndrome, acute immunodeficiency syndrome (AIDS), AIDS-related syndrome (ARC) or other disease states associated with HIV infection, cachexia, Cachexia associated with AIDS, cachexia associated with cancer, adult respiratory distress syndrome, asthma, chronic pneumonia Symptomatic diseases, Crohn's disease, ulcerative colitis, inflammatory bowel disease, bone resorption, host-versus graft 21. The person according to claim 20, who has a reaction, acute graft rejection, or chronic rheumatoid arthritis. Law. 24. The compound is 5,6-dihydro-2-(4-methylthiophenyl)-3-(4 -pyridinyl)-7H-pyrrolo[1,2-a]imidazol-7-ol or 5,6-dihydro-2-(4-methylthiophenyl)-3-(2-methyl-4- pyridinyl)-7H-pyrrolo[1,2-a]imidazol-7-ol. The method according to claim 23. 25. a. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R2, R3, R4, R5, R6, R7, R8 and R9 are independently -H or is C1-2 alkyl: n is 0 or 1: One of R1 and R0 is 4-pyridyl or C1-4alkyl-4-pyridyl Jill: The other of R1 and R0 is (a) Phenyl, or the substituent is C1-4 alkyl, halo, hydroxy, C1 -4 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, C1 -3alkylsulfonyl, C2-51-alkenyl-1-thio, C2-52-a alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C2-52 -alkenyl-1-sulfinyl, C2-51-alkenyl-1-sulfonyl, C3-52-alkenyl-1-sulfonyl, C1-3 alkylamino, C1-3 dialkylamino, CF3, N-(C1-3 alkanamide), N-(C1-3 alkyl)-N-(C1-3 alkanamide), N-pyrrolidino, N-piperidino -, prop-2-en-1-oxy, 2,2,2-trihaloethoxy, thiol , acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylka rubonylalkylthio, carbalkoxyalkylthio, alkoxycarbonyl Thio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxy Sialkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio , Z or monosubstituted phenyl which is acyloxyalkylthio; (b) The substituents are independently C1-3 alkylthio, C1-3 alkoxy, halo, C1-4 alkyl, C1-3 alkylamino, N-(C1-3 alkyl)-N- (C1-3 alkanamide), C1-3 dialkylamino, amino, N-pyrroli disubstituted phenyl which is dino or N-piperidino; (c) one of the substituents is C1-3 alkoxy, halo, C1-4 alkyl or is CF3, and other substituents are thiol, alkylsulfinyl, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkyl ruthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxy Cithionothio, phenylthio, phenylthio, phenylsulfinyl, alkoxy Sialkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio , Z or acyloxyalkylthio: (d) substituent group one of which is amino, C1-3 alkylamino or C1-3 dialkylamino Yes: Other substituents are C1-3 alkylsulfinyl, C2-5-1-alkenyl -1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alke Nyl-1-thio, C3-52-alkenyl-1-sulfinyl, thiol, acyl ruthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonyl alkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, Alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyal Kylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, and is acyloxyalkylthio; or (e) the substituents are the same. halo, C1-3 alkoxy, C1-3 alkylamino, C1-3 dia Lucylamino, N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy cy, prop-2-en-1-oxy, hydroxy, C1-3 alkylthio, C1 -3 alkylsulfonyl, thiol, acylthio, dithioacyl, thiocarbami dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxy Lukylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio , phenylsulfinyl, alkoxyalkylthio, alkoxyalkylsulf or a disubstituted phenyl selected from alkylthioalkylthio ] The compound represented by is oxidized to the corresponding 7-keto derivative, and then reduced to the ketone. of the corresponding formula (I) in which one of R4 or R5 is hydroxy; of the compound of formula (I) according to claim 1, Production method. 26. With oxidizing agent or Jones reagent, sodium permanganate or Sarretz reagent 26. The method of claim 25. 27. Reducing agent is sodium borohydride, sodium cyanoborohydride, borohydride With lithium chloride, perhydride, aluminum hydride, lithium hydride or boron 26. The method of claim 25.