JPH06501708A - imidazolidinone compounds - 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] The present invention relates to novel compounds, pharmaceutical compositions containing these compounds, and is used in the treatment of allergic and inflammatory diseases, and is also used in the treatment of tumor cyclic factor (TNF). Concerning its use in inhibiting production.

Background of the invention Bronchial asthma is caused by reversible narrowing of the airways and hyperresponsiveness of the airways to external stimuli. It is a well-characterized symptomatic multifactorial disease.

Identifying new treatments for asthma is important because a large number of mesoieta are responsible for disease development. is made difficult by the fact that Therefore, the influence of a single mesoiator is eliminated. It is unlikely that diagnosing all three components of chronic asthma would have a substantial effect on all three components of chronic asthma. stomach. The “mesoieta approach” and alternative methods are responsible for the pathophysiology of this disease. It is to regulate the activity of cells that become

One such method involves the use of cAMP (adenosine cyclic 3', 5'-monophosphorus). This is by increasing the level of Fate). Cyclic AMP has a wide range of A second metusene that mediates biological responses to hormones, neurotransmitters, and drugs The Krebs Endocrinology Procedure ings of the force international combination exercise Krebs Endocrinology Procedurein gs of the 4th International Co Shi■Nitsu■Tang■ Excelpta Medica), 17-29.1973. a suitable antagonist Upon binding to specific cell surface receptors, adenylate cyclase is activated. , converts Mg''''ATP to cATP at a rapid rate.

Cyclic AMP is among the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. , regulates the activity of most, if not all, cells. Therefore, cAMP 1) airway smooth muscle relaxation, 2) inhibition of mast cell mesoieta release, 3) Suppression of neutrophil degranulation, 4) Suppression of basophil degranulation, and 5) Single cell and tumor Beneficial effects may be obtained including inhibition of clophage activation. Therefore, Ade Compounds that activate nilyl cyclase or inhibit PDEs can improve airway smoothness. It should be effective in suppressing inappropriate activation of muscle and various inflammatory cells.

The major cellular mechanism for cAMP inactivation is the cyclic nucleotide phosphorylation by one or more of the isoenzymes called gesterases (PDEs). This is the hydrolysis of the 3′-phosphodiester bond.

Currently, another cyclic nucleotide phosphogesterase (PDE) enzyme PDE mV is responsible for cyclic AMP degradation in airway smooth muscle and inflammatory cells. It has been found that [Torphy, r-phosphogesterase] Phosphodiester: A Valid Target for Novel Anti-Asthma Drugs ase Isozymes: Potential Targets for Novel Anti-asthmatic Agents) J, New 8Dra Tsugus ψ Fouken Az 7 (New Drugs for Asthma), Ba Barnes (ed.), IBC Technical Services Limited (I BC Technical 5 services Ltd) (1989)] c+ research According to Inhibits neutrophil activation and suppresses degranulation of mast cells, basophils, and neutrophils. control Furthermore, the beneficial effects of PDE rV inhibitors, as in vivo, Adenylate cyclase activity in target cells is stimulated by appropriate hormones or autocoids. When it rises, it is significantly strengthened. Therefore, PDE TV inhibitors Levels of grandin E2 and prostacyclin (activator of adenylate tucrase) Elevating Bell may be beneficial for asthmatic lungs. Such compounds may cause bronchial asthma would provide a unique approach to drug therapy and would provide a unique approach to drug therapy may have significant therapeutic advantages over other drugs.

The compounds of the present invention have been shown to inhibit the in vivo production of tumor necrosis factor (TNF), a serum glycoprotein. It also suppresses production. Excessive or uncontrolled TNF production is associated with rheumatoid arthritis, Myelitis, osteoarthritis, gout arthritis and other arthritic conditions 1 sepsis, septicemia shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, human respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammation, silicosis, pulmonary sarcoidosis, Bone resorption, reperfusion injury, graft-versus-host reaction, allograft rejection, influenza fever and myalgia due to infections such as fever, cachexia due to infections or malignant diseases, acute Cachexia associated with immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related diseases) syndrome), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or can transmit or exacerbate a number of diseases, including pyresis. Related.

AIDS was caused by the infection of 1,928 cells by the human immunodeficiency virus (HIV). be. For HIV, there are at least three types or strains: HrV-1° HIV-2 and HIV-3 have been identified. As a result of HIVg staining, Tm cells were detected. mediated immunity is reduced, and infected individuals develop severe immunocompromise and/or abnormal tumors. Express. In order for HIV to invade the 1928 bulb, activation of the 1928 bulb is required. be. Other viruses such as HIV-1 and HIV-2 produce 1 928 cells, and the expression and/or replication of such viral proteins is mediated or maintained by T cell activation such as Activated 1928 ball becomes HIV Once infected, these 1928 spheres are capable of HIV gene expression and/or HIV replication. must remain activated in order to remain active. monocaine, especially TNF stimulates activated T cells by playing a role in maintaining T lymphocyte activation. associated with mediated HIV protein expression and/or viral replication. Therefore, H.I. By inhibiting the production of monokines, especially TNF, in individuals infected with V. Interfering with monokine activity helps limit maintenance of T cell activation, thereby This reduces the progression of HIV infectivity to uninfected cells, resulting in As a result, the progression of immunodeficiency caused by HIV infection is delayed or eliminated. single Globules, macrophages, and related cells such as Kutzpar cells and Dahlia cells also Associated with maintenance of IV infection. These cells, like T cells, are responsible for viral replication. target, and the level of viral replication depends on the activation state of the cell [robot]. -Rosenberg et al., The Immunophysiology of H. IM Infection, Atopancies in Immunology (The Im munopathogenesis of HIV infection, Ad Vances in Immunology), 57. (1989) ]. Monokines such as TNF induce HI in single cells and/or macrophages. It has been shown to activate V replication [Poli et al. Goods of National Academy of Sciences (Proc, N atl ＾ cad, sci, ), 87: 782-784 (1990) Therefore, inhibition of monokine production or activity is not limited to the methods described above for T cells. As mentioned above, it helps limit the progression of HIV.

TNF has been linked to cytomegalovirus (C) for reasons similar to those described here. MV), influenza virus, and other viruses such as herpes virus It has been associated with a variety of roles with respect to infectious diseases.

The ability to control the adverse effects of TNF is important in mammals requiring such use. Facilitated by the use of compounds that inhibit TNF. excessive and/or uncontrolled TNF-mediated disease states that are exacerbated or caused by TNF production. There remains a need for compounds that are useful for treatment.

Summary of the invention The present invention relates to a novel compound of formula (I) shown below, which has tumor necrosis factor inhibitory activity. related. The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof; It also relates to pharmaceutical compositions containing an acceptable carrier or diluent.

The present invention also relates to a method of inhibiting TNF production in mammals including humans; The method comprises administering an effective TNF-inhibiting amount of a compound of formula (I) to a mammal in need of such treatment. It consists of administering something. This method is useful for several TNF-mediated diseases that can be amenable to it. It may be used in the prophylactic treatment or prophylaxis of diseased conditions.

The invention also relates to methods of treating humans suffering from human immunodeficiency virus (HIV). and the method comprises administering to such a human an effective TNF-inhibiting amount of a compound of formula (I). It consists of things.

Compounds of formula (I) are also useful in the treatment of other viral infections. Here, viruses that are susceptible to upregulation by TNF. or induce TNF production in vivo. What is expected from the treatment here Viruses that contain viruses can be treated with a TNF inhibitor of formula (I), e.g. without reducing their replication. It is sensitive to any direct or indirect inhibition. Such viruses Examples include the above-mentioned HI V-1, HIV-2 and HIV-3, cytomegalore virus (CMv), influenza, and viruses of the herpesvirus family, e.g. Herpes simplex (herpes simplex) and herpes sister (herpes zoster) These include, but are not limited to.

The present invention is a subgenus of compounds of formula (I) having TNF activity, Novel compounds of formula (Ia) useful for mediating or inhibiting PDE rV (PDE rV) It also relates to compounds and pharmaceutical compositions.

The present invention provides a method for inhibiting phosphogesterase in mammals including humans. The method also relates to administering to a mammal in need thereof an effective amount of formula (Ia) as shown below. of the compound.

Furthermore, the present invention provides methods for treating allergic and inflammatory diseases, The method comprises administering to a mammal in need thereof an effective amount of a compound of formula (Ia). Consists of things.

The invention also provides a method of treating asthma, which method comprises treating asthma in a mammal in need thereof. comprising administering an effective amount of a compound of formula (Ia).

The compound of formula (1) has a structure.

[Wherein, R, is -(CR9R10), -(C(0)O), -(CRQRIO) ,, -R8, -(CR*R+o)-(C(○)NRa), -(CR*R+o), , -Ra, or -(CR9R10)-(0), -(CR9R10)-Rg (here and the alkyl moiety is optionally substituted with one or more halogens. good); n is a number having a value of O to 4.

m is a number having a value of O~2: r is a number with a value of O or 1: S is a number with a value of O or 1: R9 and RIG are independently selected from hydrogen or C1-2 alkyl.

R6 is hydrogen, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran , tetrahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl , or C41 cycloalkyl having one or two unsaturated bonds (where cycloalkyl Loalkyl and heterocyclic moieties optionally contain 1 to 3 methyl groups or 1 ethyl group. (optionally substituted with a thyl group); provided that a) when r is 1, n is 1 to 4: or b) When s is 1, n is 2 to 4: or c) R, is hydroxyl, r is 1, when n is 1 to 4, m is 2: or d) Rs is hydroxyl, r or S is 0; When, the sum of n+m is 2 to 6. or e) (CReR+o)--(C(0)○), -(CRs　R+　o)-When m in Ra is O and r is 1, n is 1 to 4: or teeth f) R, is 2-tetrahydrobilane or 2-tetrahydrothiopyran, 2-tetho lahydrofuran or 2-tetrahydrothiophene, when r or S is 0, n+m The sum is 1 to 6. or g) Rs is 2-tetrahydrobyran, 2-tetrahydrothiopyran, 2-tetra Hydrofuran or 2-tetrahydrothiophene, when n is 1 to 4 and r is 1, m must be between 1 and 2, or h) R, is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetra Hydrofuran or 2-tetrahydrothiophene, when n is 2 to 4 and S is 1, m must be between 1 and 2.

X is YRt, halogen, nitro, NR, R, or formylamine; Y is O or 5(0),,I: m' is a number having a value of 0 to 2; R2 is 1CH, optionally substituted with one or more halogens, or -CH .

CHs; R3 is H, CH3, CN, CHtF, CHF2, or CF3゜R4 Hasan, C, -C4 alkyl, 0HSOCHs, OCH2CHs, or ○Ac;R 5 is HloH, -(CH2), Ar, or C1-6 alkyl (where (CH z) aAr or Cl-6 alkyl group is optionally F, Br, CI, -NO2 , -NR8R7, -COtR@, -OR,, -QC(0)R,, C(0)Rs, CN, -C(0)-NR6R7, -C(S)-NR,R,, -NRs-C(0) -NRsRi, -NRa-C(S)-NR,R,, -NR, -C(0)-R,, -NRe-C(S)-R11, -NR, -C(0)-OR6, C(=NRs) -N RaRt, -C(=NCN)-NRaRt, -C(=NCN)-8Rg, -NRa-C(=NCN)-SRs, -NRe-C(=NCN)-NRgRt, -C(=NR@R?)SR6, -NRs-S(0)z-Re, -3(0), =- R,, -NRaSOt-CFs, -NRsC(0)-C(0)-NRsRt, - NR4-C(0)-C(0)-0Ra, 1-imidazolyl, or 1-(NRs) Substituted one or more times with -2-imidazolyl: Ar is 2-13- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, moly Ruphorino, 4- or 5-thiazolyl, trizolyl, 2- or 3-chenyl, 2- Thiafene or phenyl: R6 and R7 are independently hydrogen or optionally one or more halogens. C1-4 alkyl substituted with

q is a number having a value of 0 to 2], and its pharmaceutically acceptable It is salt.

Detailed description of the invention The compound of formula (Ia) has the structure: [Wherein, R1 is -CHz-Cs cyclic alkyl, -CH, -C5-, cyclic alkyl] C1-6 cyclic alkyl, tetrahydrofuran, cyclopentenyl, optionally -01-1 alkyl monosubstituted with one or more fluorines, -(CH2)2 -40H, -(CH2), -C(○)○(CH2),, -CH3, -(CH2) -O-(CHz),,CH3, all of which optionally contain 1 to 3 optionally substituted with a methyl group or one ethyl group: m has a value of 0 to 2 number; n is a number having a value of 1 to 3: p is a number having a value of 2 or 3.

X is YR2; Y is O or S: R2 is CH3 or CH2 optionally substituted with one or more fluorine CH3゜ R1 is HSCH3, CN, CH2F SCHF 2 or CF3:R, HaH, c+-,'y alkyl○HSOCH3,0CH2CH, and ha○AC: R5 is H , OH, -(CH2)aAr, CI-a alkyl: Kyl is unsubstituted or or may be replaced with one or more of the following: F, Br, CL NO2, NR, R,, CO. R6, -NH-C(=NCN)- SCH3, -NHC(0)NR. R7, - C (0) N R a R 7 , -NHC(0)CH3, -NH-(=NCN)-N R s R? ,− N H C (0) C (0) N R a R t, -NHS○2CH 3, -S (○),, CH3, - N H C (0) C (0) - 0 Rs, -OR. , -CN, -C(=NR6)-NR8R7, -NHSO2Ar is 2-, 3- or 4-birinol, pyrimidyl, pyrazyl, imidazolyl, morpho Reno, or phenyl; R6 and R7 are independently hydrogen or CI-4 alkyl; q has a value of 0 to 2; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a subspecies of formula (1) which also has activity as a TNF inhibitor. This is a novel compound of formula (I[).

The compound of formula (ff) has the structure: [In the formula, R1, n, m, rSsSqSRs, R,, R4, R,, Ar, R6, and R, have the same meaning as formula (I): Xl is represented by halogen, nitro, NR, R, or formylamine; and its pharmaceutically acceptable salts.

R in the compounds of formulas (1) and (II) is one or more halogens; When substituted alkyl, halogen is preferably fluorine and chlorine. , more preferably one or more fluorine, even more preferably one or more fluorine CI-4 alkyl substituted with the above fluorine. The most preferred chain length is 1 or 2 carbon atoms, most preferably -CF3, CH2F, -CHF2, -CF2CHF2, CH2CH3, or -CH2CHF2 part Ru. More preferably, R1 is -CF3, -CHFz, or CH3. It is a compound. The term R1 refers to the (CRe R+.) moiety (where R9 and and Rlfl are independently hydrogen or alkyl). As a result, (C Branching of individual methylene units, such as ReR+o)- or (CR,R,.) is possible: each repeating methylene unit is independent of the other, for example ( CRgR+o)- (where n is 2) is -CH2CH(CH,)- can be obtained. The individual hydrogen atoms of repeating methylene units or branched hydrocarbons are Substituted with an independent fluorine to provide a preferred RJ substituent, e.g. as described above. Can be done.

Preferred R3 groups of compounds of formula (Ia) are -CH2-C5 cyclo-alkyl, - CH2-C6-6cycloalkyl, C4-6cycloalkyl, tetrahydrofura cyclopentenyl, 1C optionally substituted with one or more fluorines I-7C5 cyclic alkyl (CHz)z-40H. R1 is fluorine if desired In the case of Cl-7 alkyl substituted with , more preferred groups are -CFs, -CH2 F, CHF2, -CF2CHF2, CH.

CF, or -CH2CHF2.

Preferred X groups of both formula (I) and formula (Ia) are those in which X is YR2 and Y is oxygen. It is something that Both formula (I) and formula (TI), as well as compounds of formula (Ia), are preferred. A desirable R2 group.

Applicable here are those optionally substituted with one or more halogens. Cl-2 alkyl. Halogen atoms are preferably fluorine and chlorine, and more Preferably it is chlorine. More preferred R2 groups are those in which R2 is methyl or fluoro. substituted alkyl, especially C1-2 alkyl, such as -CF3, CHF2, or =CH, This is the CHF2 portion. Most preferred are the CHF2 and C83 moieties. be.

Preferred R6 groups include an optionally substituted -(CI4z)aAr moiety, where q is preferably 1), or optionally substituted C1-6 alkyl , more preferably when R6 is argyl, even more preferably when R5 is C3,5 argyl. This is the case with Lukiru. Preferred substituents on the alkyl and aryl moieties are F, Br , CI, NO2, NR6R,, CO2R6, -NH-C(=NCN)-5CH, , -NHC(0)-NR,R,, -〇(○)R,R,, -NHC(0)CH3, -NH-(=NCN)-NR6R7, -NHC(0)C(0)-NRaRt, - NH302CH3, -8(0)=CH3, -NHC(0)C(0)-0Ra, More preferred substituents are -NH2, -N(CH3)2, -8(0), CH3, -N H-C(0)-CH3, -CO2CHs, OCH3, C02H, No2, -NH -C(=NCN)-3CH3, -NH-C(=NCN)-N)(2, -NH-C (0)-NH2, -NH-C(0)-C(0)-CR6, or NH-C(0)- C(0)-NRaRt. Preferably the Ar moiety is phenyl.

Preferred R,ll substituents of compounds of formula (I), formula (Ia) and formula (n), H, C,-2 alkyl or OCH3.

Preferred are formula (I) and formula (Ia) [wherein R6 is optionally substituted -] (CH2)aA　r　(Q is 0 or 1), or optionally substituted C5-5 Alkyl: R1 is =CH2-C5 cyclic alkyl, -CHz-Cs-s cyclic alkyl C4-6 cyclic argyl, tetrahydrofuran, cyclopentyl, as desired -CI-,C5 cyclic alkyl (CHJ2) replaced with one or more fluorine -40H: R1 is methyl or alkyl replaced with fluorine, R1 is CN, CH F2, CF3, or HER, is H, Cl-5 alkyl or OCH, Y is oxygen This is a compound represented by

A more preferred compound is one in which R1, R2, and Y have the same meanings as above, and R1 is Ar. or optionally substituted -(CH2), Ar, q is 1, Ar is phenyl , R3 is H, CN, methyl or CHF2, R4 is H or C3-4 alkyl It is something that

Optionally present substituents include -NH-C(0)-CHs, -NH-C(=NC N)-8CH3, -NH-C(=NCN)-NH2, -NH-C(0)-NHz , -NHz, -N(CH3)2, -NH-C(0)-C(0)-NH2, and bar N　HC(0)　CO2CHs　Basic color selection Sarel.

Most preferably, R1 is cyclopentyl, methyl or CF2H, R3 is H, C N or CH3, R4 is hydrogen, X is YR2, Y is oxygen, R2 is CF, H or methyl , R5 is -NH-C(0)-CH3, -NH-C(=NCN)-3CHs, - NH-C(=NCN)-N H2, -NH-C(○)-NH2, -NH2, -N (CHs)! , -NH-C(0)-C(○)-N H2, or -NHC(0)C ○2CH, is a compound that is benzyl substituted with a group.

Particularly preferred are the following compounds: 1-(4-aminobenzyl)-4-( 3-Fuclobentyloxy-4-methquinphenyl)-2-imidazolidinone: 1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxy phenyl) = 3-methyl-2-imidapurinone; 4-(3-cyclopentyl) xy-4-methquinphenyl)-1-(4-tmethylaminobenzyl)-2=i Midazolinonone.

4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidi Non; 1-(4-acetamidobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone: R-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidazolidinone, S-(+)-4-(3-cyclopentyloxy-4-methquinphenyl)-2- imidazolidinone, 5-(-)-1-(4-aminobenzyl)-4-<3-cyclopentyloxy -4~methquinphenyl)-2-imidazolidinone.

R(+)-1-(4-aminopencyl)-4-(3-cyclopentyloxy-4 -methoxyphenyl)-2-imidazolidinone: 5-(-)4-(4-benzylpyridyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone.

R-(+)-1-(4-benzylpyridyl)-4-C3-cyclopentyloxy -4-methquinophenyl)-2-imidazolidinone; 5-(-)-1-(4-a cetamidobenzyl)-4-(3-fuclopentyloxy-4-methquinophenyl) R)-2-imidazolidinone; R-(+)-1-(4-acetamidobenzyl) -4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazoly Dinone; 5-(-)-1-(4-oxamidobenzyl)-4-(3-cyclopene Tyloxy-4-methquinphenyl)-2-imidazolidinone: R-(+)-1 -(4-oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxy Cyphenyl)-2-imidazolidinone: R~(+)-1-(4-formamidobe) ndyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-y Midashirinnon.

5-(-)-1-(4-formamidobenzyl)-4-(3-cyclopentyl) xy-4-methoxyphenyl)-2-imidazolidinone; 1-(4-acetaminyl) do-3-pidylmethyl)-4-(3-cyclopentyloxy-4-methoxyf phenyl)-2-imidazolidinone: 5-(-)-4-(3-cyclobenthyloxy C-4-methoxyphenyl)-1-(2,4-diaminobenzyl)-2-imida Zolidinone: 5-(-)-4-(3-cyclopentyloxy-4-methoxyphene) Nyl)-1-(2,4-diacetamidobenzyl)-2-imidazolidinone: R -(+)-4-(3-cyclopentyfuroxy-4-methoxyphenyl)-1- (2,4-diaminobenzyl)-2-imidazolidinone: or R-(+)-4- (3-cyclopentylleoxy-4-methquinphenyl)-1-(2,4-dia (cetamidobenzyl)-2-imidazolidinone.

Another aspect is the novel intermediates for use herein, especially of formula (5) and formula (6). .

Examples of preferred compounds of formula (5) include (2R)- and (2S)-1-benzi hydroxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyf) phenyl)-2-[(-)-menthyloxycarbonylaminoconitane.

The compounds of the invention may contain one or more asymmetric carbon atoms, and may contain one or more asymmetric carbon atoms. It can exist in semi- and optically active forms. All of these compounds are within the scope of the present invention. It is thought that it is inside.

As used herein, the term "rC+-t alkyl" or "alkyl" group refers to Unless otherwise specified, it is meant to include linear or branched groups having 1 to 7 carbon atoms. methyl, ethyl, n-propyl, isopropyl, n-butyl, 5eC-butyl butyl, isobutyl, tert-butyl, and the like.

As used herein, the term "alkenyl" refers to vinyl, 1-propenyl, 2-propenyl, including lopenyl, 2-propynyl or 3-methyl-2-propenyl; Not limited.

The term "cycloalkyl" or "cycloalkylalkyl" as used herein means containing a group having 3 to 7 carbon atoms, for example, cyclopropyl, cyclopropyl, Such as lopropylmethyl, cyclobentyl or cyclohexyl.

As used herein, the term "aryl" or "aralkyl" refers to , means an aromatic ring or a ring system having 6 to 10 carbon atoms, preferably a monocyclic ring, e.g. , phenyl, benzyl, phenethyl or naphthyl.

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

The term "rl-(NR6)-2-imidazolyl or 1-imidazolyl" respectively , means.

The term "inhibits the production of rlL-1" or "inhibits the production of rTNF" means a) By all cells including but not limited to monocytes or macrophages By inhibiting the in vivo release of IL-1 by or reducing TNF levels to normal levels or below normal levels; b) excess in vivo IL-1 or TNF levels at the translational or transcriptional level, respectively. or C) as a post-translational event. It is intended to down-regulate IL-1 or TNF levels by inhibiting direct synthesis. Taste.

The term ``rTNF-mediated disease or disease condition'' refers to Thus, 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 the production or action worsens in response to TNF; Alternatively, the disease state in which it is secreted may therefore be considered a disease state mediated by TNF. available. TNF-β (also known as lymphotoxin) It has strict structural homology to cachectin (also known as cachectin). Also, each induces similar biological responses and binds to the same cellular receptors. Therefore, both TNF-α and TNF-β are inhibited by the compounds of the present invention. and thus collectively referred to as rTNFJ unless otherwise specified. Preferably, TNF-α is inhibited.

As used herein, the term "cytokine" refers to a cytokine that affects the function of cells and , any molecule that modulates interactions between cells in an immune or inflammatory response. Also meant is a secreted polypeptide. As cytokines, which cells produce them? Monokine and lymphin may be mentioned, but these is not limited to. For example, monokines generally target macrophages and/or or produced and secreted by mononuclear cells such as monocytes, but natural Lucilla cells, fibroblasts, basophils, neutrophils, endothelial cells, stratified cells, intermedullary cells Many other cells such as plasma cells, epidermal keratinocytes, and β-lymphocytes are monocarboxylic. Produce in. Lymphoids are normally produced by lymphoid cells. It is called. Examples of cytokines related to the present invention include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (I L-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor beta (T NF-β), but are not limited to these.

Inhibition of cytokines contemplated by the present invention for use in the treatment of HIV-infected humans (a) initiates and/or maintains T cell activation and/or activates T cell-mediated H IV gene expression and/or replication, and/or (b) such as cachexia or muscle degeneration. Must be a cytokine associated with any problem associated with cytokine-mediated disease. Must be. A cytokine that is particularly desired to inhibit is TNF-α. .

All of the compounds of formula (I) are suitable for use in a method of inhibiting the production of TNF, preferably by inhibiting the production of TNF. by the necessary human macrophages and monocytes, or macrophages and monocytes Useful in methods of inhibiting TNF production. All of the compounds of formula (Ia) are PD Useful in methods of inhibiting E■ and treating disease states mediated thereby.

The mammal is preferably suffering from endotoxic shock, adult respiratory distress syndrome, infection or Cachexia associated with malignant disease, cachexia associated with acute immunodeficiency syndrome (AIDS), AIDS S, reperfusion injury, pulmonary inflammation, cerebral malaria, graft-versus-host reaction, bone resorption, chronic Rheumatoid arthritis, rheumatoid arthritis, myelitis, osteoarthritis, gout arthritis, eczema, psoriasis, sunburn, A human suffering from a disease condition selected from conjunctivitis or viresis.

Preparation method: For the preparation of compounds of formula (I), one skilled in the art can follow the methods outlined in the Examples below. Can be implemented. The preparation of the remaining compounds of formula (I) not described herein is disclosed herein. It may be prepared by a method similar to that described above.

R1 is other than CN, and X is BrS I, No□, amine, formylamine, or For compounds other than S(○), ・(however, m' is 1 or 2), inactive Under a positive atmosphere at room temperature, formula (2): [wherein R, is the same R as defined for the compound of formula (I), or convertible to R3] group, where X is the same X as defined for the compound of formula (I) or a group convertible to X. A compound represented by With a suitable catalyst such as zinc oxide, either neat or with a suitable non-reactive material such as a halocarbon. The reaction is carried out in the presence of a reactive solvent. Formation of intermediate trimethylsilylcyanohydrin Once complete, remove the solvent, if present, and store in a closed container under an inert atmosphere. The residue is purified with an amine (NR 1R2), where R4 has the same definition as for the compound of formula (I). means R4 or a group convertible to R4) to obtain a compound represented by formula (3). . This may be converted into a suitable acid salt such as hydrochloride.

Alternatively, the compound of formula (3) can be prepared by combining the compound of formula (2) with a suitable solvent such as an alcohol. react with sodium cyanide and the amine in its hydrochloride form in a suitable non-reactive solvent at room temperature. It may be prepared by the Strecker synthesis method. heavy The compound of formula (3) or is its salt, such as ethyl chloroformate, benzyl chloroformate or menthyl chloroformate. By reaction with any suitable alkyl haloformate or aralkyl haloformate, formula (4 ): [wherein R6 is alkyl, optionally substituted benzyl, or (-)-menthyl] is obtained.

In the presence of excess ammonia, RII is optionally substituted benzyl For example, hydrogen and a Raney nickel catalyst of the nitrile of the compound of formula (4) which is other than By reduction with a catalyst such as A compound is obtained.

Hydroxylation in a suitable solvent such as alcohol or dimethyl sulfoxide (DMSO) A compound of formula (5) in which Rs is H in the presence of a suitable base such as an aqueous sodium solution The cyclization of gives compounds of formula (I) in which R5 is H and R3 is other than CN. It will be done.

Alternatively, these compounds can be prepared in non-reactive solvents such as ethyl ether, THF, etc. , in a suitable reducing agent such as lithium aluminum hydride, or in an alcoholic solvent. (3) with hydrogen in the presence of a suitable catalyst such as a noble metal or Raney nickel. By reducing the nitrile of the compound, formula (6) It may be prepared by obtaining a diamine of the formula [wherein R3 is H] stomach.

Toluene, etc. at low temperature in the presence of an acid scavenger such as a saturated aqueous solution of sodium bicarbonate. By reacting the diamine of formula (6) in which R1 is H with phosgene in the solvent of Compounds of formula (I) are obtained in which 5 is H and R3 is other than CN. alternatively is N,N-carbonyldiimidazole or 1,1-carbonyl in a suitable solvent. - Sheiko.

2,4- The use of triazoles avoids the use of phosgene and acid scavengers. comparable amounts of these compounds are obtained.

Alternatively, in compounds of formula (6) where R6 is H and R5 is other than CN, of α-NH, such as t-butyloxycarbonyl or benzyloxycarbonyl. Selective protection with a nyl group followed by a suitable aldehyde and Imine formation with imine or iminium ion reduction followed by removal of α-N protecting group By removing, a compound of formula (6) in which R5 is other than H and R3 is other than CN is obtained. It will be done.

In the same way as described above regarding the compound of formula (6) when R3 is H, when R5 is H or more, The reaction of the diamine of the compound of formula (6) when R6 is other than H A compound of formula (I) is obtained.

For compounds of formula (I) in which R6 is OH, for example, tungsten Corresponding compounds of formula (5) where R3 is H by sodium acid and hydrogen peroxide to an aldehyde oxime and then oxidize it to an aldehyde oxime, e.g. The oxime intermediate is reduced by sodium dihydride to ensure that R3 is hydroxyl. It is prepared by obtaining the corresponding compound of formula (5).

Compounds of formula (1) in which R3 is CF, CHF2 or CH2F are as described below. is prepared from the corresponding compound of formula (2) using a method described below.

Compounds of formula (2) in which R3 is CF3 are derived from compounds of formula (2) in which R8 is H. Electrochemically, Shono et al., Journal of Organic Research Mistry (J, Org, Chew,), 56.204 (1991). Obtained by method.

The compound of formula (2), in which R3 is CF or CHF, undergoes metal ringing at -78°C. agent, then Nad et al., Izvest, (1959 ) Page 71: Chemical Abstracts (Chem, Abstract, ), The method of Volume 53, No. 14877 and Volume 53, No. 17933 (1959) A compound represented by formula (2a) by trifluoroacetic acid or difluoroacetic acid Obtained by processing things.

Compounds of formula (2) in which R3 is CH, F are described by Rozen et al. SynthesisX6 665. (1985), R8 is obtained by treatment of a compound of formula (2) where is CH3.

The compound of formula (2) in which X is R2S and R3 is H is 3-hydroxy-4- Nitrobenzaldehyde with the desired halogenation R+ (where R2 is as defined above) the same) followed by treatment with sodium SR2 in DMF. Manufactured by science.

The compound of formula (2) in which X is F or CI and R3 is H is (2-fluoro or is the alkylation of chloro)-5-methylphenol with the desired halogenation R3. , followed by the formation of benzyl bromide with N-promosuccinimide, then ethyl Desired aldehyde with 2-nitropropane and sodium etquinide in alcohol produced by conversion to

The novel compound of formula (2) in which R5 is CH3 is methyl metal, and R3 is hydrogen. addition to a compound of formula (2), followed by acidification, e.g. with pyridinium dichromate. It can be manufactured by chemical reaction.

For compounds of formula (I) where R, O and X are as defined in formula (I): , R1 and R, (when X is YR2) are both hydrogen, corresponding to formula (2) Bases of compounds, such as metal carbonates, metal hydroxides, metal hydrides and alkyl agent Q-L (where Q is R1 or R2 as defined above, and L is any suitable leaving group known in the field, such as C1, Br, ■, tosyl, mesyl, or trifuryl) or by fluorinated ethylene, e.g. tetrafluoroethyl Produced by alkylation with ren.

Alternatively, compounds of formula (I) may be prepared in which R1 and/or R2 are for the compound of formula (2). Pencil or methquin methyl, ethquin, which is alkylated as described above. Prepared from compounds of formula (I) that are protecting groups such as methyl or acetonide. X For compounds of formula (I) where is an amine, monoalkylamine or formylamine, and such alkylation is performed when X is a nitro or protected amine, e.g. or no N-t-butoxycarbonyl or mono- or di-N-benzyl carried out with a compound of formula (2) or protected R,/R2 formula (I) which is The protecting group is then removed by methods known to those skilled in the art.

For compounds of formula (I) where R3 is other than CN, X is Br5ISNO2, amino other than ion, formylamine or S(0)m, where mo is 1 or 2, and R5 is other than H, in a suitable solvent such as chloroform at reflux temperature, R5 is A suitably substituted aryl or alkylalk of the amine of formula (5) reaction with a dehyde, followed by the formation of a suitable acid salt such as hydrochloride or acetate, iminium By reduction of the salt, e.g. with sodium cyanoborohydride in methanol, A compound of formula (5) in which R3 is other than CN and R5 is other than H is obtained. alternative method Noble metal metal catalytic reduction of imine or iminium functional groups may be used as . For most of these compounds, formulas in which R6 is other than H due to the cyclization described above Compound (I) is obtained. Containing a base-sensitive functional group in R3 such as a nitro group For certain compounds of formula (5) with The conversion takes place before cyclization.

Such amines may then be optionally functionalized.

Formula (I ) of the compound of formula (2) in which R3 is H in a suitable solvent. Reaction with lithium genide and silyl halide, then reaction with a suitable siloxane, etc. The initiation of the sequence by reduction with a reducing agent indicates that Xl is a halide. A compound of formula (7) is obtained. Alternatively, compounds of formula (2) where R3 is H By reduction of Xl with a suitable reducing agent such as sodium borohydride, Xl becomes OH A compound of formula (7) is obtained. For example, of such a compound of formula (7), Phosphorus trichloride, thionyl chloride, phosphorus tribromide, cupric bromide or carbon tetrabromide and trif A compound represented by phenylphosphine [wherein Xl is a halide] is obtained. Then, by halide substitution with anide, formula (8)・ A compound of the formula [wherein R3 and R8 are H] is obtained, which is an inert compound. LDA or alkyllithium or lithium hexamethylsin under atmosphere at low temperature reacted with a strong base such as radide and then reacted with e.g. By reaction with Ro and appropriate work-up, R3 is C0NH, and Ro is H. A compound of formula (8) is obtained; or, for example, methyl chloroformate. By reaction with which alkyl haloformate or aryl haloformate, R3 becomes C00R A compound of formula (8) is obtained in which s is H and Ro is H: The COOR8 group of , may be converted to CONH2 groups at this stage or at a later stage. Alternatively, , R3 is 000R8 and R, is H, the compound of formula (8) is a secondary acid alkyl or a secondary aryl acid, e.g. methyl secondary acid, under an inert atmosphere at room temperature or is sodium hydride or a compound of formula (8) in which R3 and Ro are H at high temperature. It may also be obtained by reaction with a metal hydride such as potassium hydride. R3 is H The compound of formula (2) is methyl methyl sulfinyl methyl sulfide and hydroxyl. A number of known methods are known, such as reaction with a base such as sodium chloride, followed by e.g. By treatment with cholic acid, the compound of formula (7) in which Xl is COOR4 is Compounds of formula (7) in which Xl is COOR4 with a suitable base, which may be mologated generation of the anion of the product, then e.g. By reaction with talolobenzyl, the formula ( Compound 8) is obtained.

Generation of the tertiary anion with a suitable base in a suitable solvent followed by e.g. azide 2.4.6-Doliisobropyrubenzenesulfonyl or other electron sources of azide A compound of formula (8) in which R8 is CONH2 and R8 is N, You can get things. For example, by hydrogenation using noble metal or Raney nickel catalysts. By reduction of the azide and nitrile groups, R1 is H and R8 is CONH2. A compound of formula (6) is obtained. Cyclization of this diamine as before, then For example, by amide dehydration with trifluoroacetic anhydride, R4 and R5 are H. A compound of formula (I) in which R3 is CN is obtained.

Alternatively, for compounds of formula (8) where R3 is CONH2 and R, is N3, For example, 10% palladium on carbon and 1 equivalent of acetic acid, or alternatively Contact with triphenylphosphine in a suitable solvent such as tetrahydrofuran/water. Selective reduction of the azide group to the amine using catalytic hydrogenation, followed by similar R4 is H by reaction with a suitable alkyl haloformate or aralkyl haloformate. , and a compound of formula (4) in which R8 is C0NH, is obtained. Nito as above By lyle reduction, formula (5) where R4 and R5 are H and R3 is CONH2 The compound is obtained. By cyclization of the ring, dehydration of the R3 amide to the nitrile, R4 and compounds of formula 1 are obtained, in which R5 is H and R1 is CN.

Alternatively, the formula (5) in which R4 and R3 are H and R1 is C0NHz The amino group of the compound is preferably a compound made as known in the art. It may also be protected with a lobobenzyloxy or t-butyloxycarbonyl group (as skilled in the art). Dehydration of the R3 amide to the nitrile is carried out by methods well known to those skilled in the art. A compound of formula (5) in which amine is deprotected, R4 and R5 are H, and R8 is CN You can get things. The amine group of such a compound of formula (5) is homologous as described above. Compounds of formula (5) in which R5 is other than H are obtained. Cyclization, then suitable By appropriate functional group manipulation (e.g. reduction, acylation, deprotection, oxidation, etc.), R3 can be CN, R4 is H and R5 is other than H. Compounds of formula (I) are obtained .

A compound of formula (I) is prepared from another compound of formula (I) and is For example, when R4 is 0-acetate, hydroxy It may also be functionally modified by acetylation from R4 as a syl. R5 is ( Compounds that are CH2)qAr or C2-6 alkyl are substituted as follows: For example, NH by oxidation using peroxide, NO□ from derivative: catalytic metal cyanide with or without compounds such as NaCN, and HNR in CH30H, -CO2CH3 by heating with R, C(0)NR8R,; e.g. 10H to 10C(0)R6:alkyl using CI C(0)R8 in pyridine -NHRa to -NRa- using lysothiocyanate or thioanic acid C(S　)　N　Rs　R7; -NHR, to NR using alkyl chloroformate , C(○)OR,: For example, Isonana such as HN=C=○ or R, N=C=O -NHRa to -NR,C(0)NRIIR, ;pyridine by treatment with -NHR6 to -NR6-C(0)R6 by treatment with C1-C(0)R6 in ; -C(NReR 7) SRa to -C(=NRa)NReR7; in an inert solvent, e.g. acetone, -C(S)NR6R2 to -C(NRaRt)SRa; HNR using R6-I 11R7 is used to convert C(S)NH, to 1C(S) in which R6 or R7 is other than hydrogen. ) N Rs Rt: Using NH, CN by heating in absolute alcohol -C("NRaRt) from SRs or Br-CN and NaEtO in EtOH - By processing C(=NH)-NR,R, to C(=NCN)-NR,R? ;(RaS)2C=NCN processing changes HNR6 to NR6-C(=NCN ) SR6; HNR by treatment with CI5OzRe by heating in pyridine 6 to -NR, SO□R6, Lawesson's reagent [2,4-bis(4-methoxyphenylene) treatment with -NR,C(○)Ra to -NR,C(S)Re: Anhydrous triflic HNR6 to NRaSO2CF3 using acids and bases; for example, methyl chloride -NHR, to NR6 using bases such as luoxalyl and trimethylamine C(0)-C(○)-0Ra; -NR6C(0)-C(0 )-0R6 to -NRaC(0)-C(0)-NReRt: in chloroform, 2 -C(=NH)NHR, to 1(N Ra)-2-imidazolyl.

For compounds where X is 5(0), -01-6 alkyl and m is 1 or 2 The final compound is obtained after dehydrating the CONH2 group in the synthesis step (C) to an ano group. , under conditions well known to those skilled in the art, e.g. -5-C+-a by oxidizing the intermediate -8-alkyl product using acid Obtained from an alkyl group. X is Br1 L Not, amine or formylamine For compounds that are, the synthesis of these compounds involves using a suitably protected amine using any of the steps described above. Such protecting groups can be determined by those skilled in the art. Greene, T., is known for its conservation in organic synthesis. Protective Groups in Organic 5ynth esis), Wisoe Publishers, New York (1981). It is shown. This content is incorporated herein by reference.

In particular, for compounds of formula (I) where X is formylamine, in the last step is formed by formylating a compound in which is NH2, and the protecting group, amino obtained by removal from the carbon functional group. The use of deprotected amines in the case of poly( is suitably acylated to the NHCH○ group or it is oxidized to the NO2 group.

The desired Br or The I group is obtained. That is, compounds of formula (I) in which X is Br or PCT/US91 on Protected Amines, Diazotization of Amines, and Diazonium Substitution 104795; or, where X is NO, For compounds of I), similar deprotection of amines by oxidation of the amine to the nitro group It may be manufactured using the technology of PCT/US91104795.

Method of treatment Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals For use, it is usually formulated as a pharmaceutical composition according to standard pharmaceutical practice. do.

The compound of formula (I) or a pharmaceutically acceptable salt thereof is suitable for use in humans or other mammals. such human cells, such as, but not limited to, monocytes and/or macrophages. Disease conditions exacerbated by or caused by TNF production (especially Prophylactic or therapeutic treatment of disease states caused by excessive or uncontrolled TNF production. It can be used in the manufacture of drugs for treatment. Compounds of formula (I) can be used for TNF production. to control and return to normal levels, and in some cases even normal levels. Administered in amounts sufficient to inhibit TNF production to ameliorate or prevent this disease state. Ru.

Abnormal levels of TNF are defined in the present invention as 1)], greater than 1 picogram per ml; or equivalent free (non-cell-bound) TNF: 2) TNF-related cells: or 3) TNF above the basal level in the cells or tissues where TNF is produced. It constitutes the level of existence of RNA.

The compound of formula (Ia) or a pharmaceutically acceptable salt thereof is suitable for use in humans or other mammals. disease states mediated by inhibition of PDE rV, such as asthma, allergy prophylactically or therapeutically treat inflammatory or inflammatory diseases, including but not limited to It can be used in the production of drugs for. Compounds of formula (Ia) may be used in humans or other administered in an amount sufficient to treat such disease in a mammal.

When the compounds of the present invention are administered in accordance with the present invention, unacceptable toxicological effects may occur. The results are completely unpredictable.

Compounds of formula (I) may be used to treat disease states mediated by excessive or unregulated TNF production. For example, rheumatoid arthritis, rheumatoid arthritis, myelitis, osteoarthritis, etc. inflammation, gout arthritis and other arthritic conditions: sepsis, septic shock, endotoxic shock. ,・ri, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, large Cerebral malaria, chronic pulmonary inflammation, silicosis, pulmonary sarcoidosis, wound resorption, reperfusion injury , graft-versus-host reactions, allograft rejection, and infections such as influenza. fever and myalgia, cachexia associated with infection or malignancy, and acute immunodeficiency syndrome (AI). Cachexia associated with DS), AIDS, ARC (AIDS-related syndrome), keloid formation , scar tissue formation, Crohn's disease, ulcerative colitis, virus 7, AIDS, and site Megalovirus (CMV), influenza virus, and herpetoviridae infections caused by other viruses, such as viruses.

Compounds of formula (I) may be mediated by or exacerbated by excessive TNF production. Inflammatory local diseases such as rheumatoid arthritis, rheumatoid arthritis, osteoarthritis , gout arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis, and sunburn. Other inflammatory skin conditions such as 1 Inflammatory eye conditions including conjunctivitis: Virens ( pyresis), pain, and other symptoms related to inflammation (including, but not limited to) ) can also be used topically to treat or prevent good.

Compounds of formula (I) are used in the field of veterinary medicine to treat TNF-mediated diseases such as viral infections. May be used to treat diseases. Examples of such viruses include Feline Immunodeficiency Virus. virus (FIV) or other retroviral infections, such as equine infectious anemia virus. goat arthritis virus, visna virus, ovine chronic progressive pneumonia virus and Examples include other lentiviruses.

Furthermore, among cytokinins, TNF production precedes IL-1 and other cytokinins. While increasing the function of kinin, what relationship between these molecules is involved in inflammation? There is no clear data on whether it contributes to associated disease states. In the present invention, many The biological disease state of interleukin-1 (I This is considered to be due to L-1) activity. A comprehensive list of IL-1 activities is available at , Dinarello [Journal of Clinical Impressions] Nology (J, C11nical Immunology), 5(5), 287-297 (1985)].

Some of these effects have been described by others as indirect effects of IL-1. It should be noted that The myriad of known biological activities of IL-1 Activation of T helper cells, induction of fever, prostaglandin and collagen stimulation of iron production, neutrophil chemotaxis, induction of acute phase proteins and plasma iron levels. Examples include suppression. These disease states are also the appropriate disease states for TNF activity. It is believed that the compounds of formula (I) are therefore also useful for the treatment of The use of compounds of formula (I) is specifically limited to the TNF-mediated disease conditions described herein. should not be assumed to be fixed. The compound of formula (I) is a compound of formula (I) in which TNF and IL-1 are compatible. Since it acts multiplicatively, it should have efficacy in II,-1 mediated disease states. T.N.F. may likewise mediate the release of IL-1 and thus reduce TNF levels. The following may be useful in treating disease states in which IL-1 is a major component. therefore, The present invention provides an effective TNF production inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable amount thereof. The salt contained in Aggravated by or caused by L-1 production, especially IL-1 is the main component, which is useful for prophylactically or therapeutically treating such human disease conditions. Ru.

infected with HIV exhibiting problems associated with immune dysfunction or cytokine-mediated diseases Methods for treating and monitoring humans are described by Hanna [WO90/ No. 15534, dated December 27, 1990]. In general, early treatment Methods of inhibiting TNF activity in other TNF-mediated disease states by compounds of formula (1) methods that are known to be effective can be imitated. treated Individuals have T cell counts and T4/T8 ratios, and/or reverse transcriptase and viral proteins. measurements of viremia, such as levels of Regularly check the progress of problems related to nocaine-mediated diseases. normal treatment If no effect is seen even after continuing the treatment, the dosage of the monokine activity inhibitor may be changed, e.g. increase by 50% per week.

Compounds of formula (I) can be used to treat TNF-mediated disease states using such agents according to conventional procedures. or, in the case of compounds of formula (Ia), as PDE TV inhibitors. with a standard pharmaceutical carrier in an amount sufficient to produce the desired therapeutic activity for the use. Orally (this route is (if active) may be administered topically, parenterally, or by inhalation.

A compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals. For use in medicine, it is usually formulated as a pharmaceutical composition according to standard pharmaceutical practice. Ru.

The pharmaceutical compositions of the present invention contain an effective non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable amount. Contains a carrier or diluent. Compounds of formula (1) can be prepared according to conventional procedures by formula ( I) in an amount sufficient to produce TNF production inhibitory activity, respectively, in a standard manner. Administered in conventional dosage forms prepared by combining with standard pharmaceutical carriers. It will be done.

These steps include mixing, granulating, and pressing the ingredients to suit the desired formulation. This may include shrinking or dissolving.

The pharmaceutical carrier used may be, for example, solid or liquid. Examples include lactose, terra alba, sucrose, talc, gelatin, agar, pectin. Magnesium stearate, gum arabic, magnesium stearate, stearic acid, etc. . Examples of liquid carriers include syrup, peanut oil, olive oil, water, and the like. Ru. Similarly, carriers or diluents include glycerin monostearate or glycerin Time delays known in the art, such as distearate alone or in combination with waxes. A substance may also be included.

Of the compounds of formula (1) and their pharmaceutically acceptable salts (if any), Some are orally active, but they can be used in a wide variety of drug forms.

Preparation of pharmaceutically acceptable salts is determined by the nature of the compound itself and is within the skill of the art. It can be prepared by conventional techniques readily available to those skilled in the art. Therefore, solid If a carrier is used, the preparation can be made into tablets, powder or pellets, and hard gelatin. It can be placed in capsules or as lozenges. ). The amount of solid carrier can vary, but is preferably The amount is about 25 mg to about 1 g. If a liquid carrier is used, the formulation may include syrup, Sterile injectable liquid forms such as emulsions, soft gelatin capsules, ampoules and non-aqueous suspensions It is a state. If the composition is in the form of a capsule, for example a hard gelatin capsule Conventional encapsulation using the carrier described above in a shell of is suitable. The composition is soft When in the form of latin shell capsules, it is commonly used in preparing dispersions and suspensions. Possible pharmaceutical carriers include, for example, aqueous gums, cellulose, silicates or oils. It can be placed inside the shell of a soft gelatin capsule. The syrup formulation is one Generally, in a liquid carrier such as ethanol, glycerin or water, It consists of a suspension or solution of the above compound or salt containing flavorings and colorants.

The amount of compound of formula (1) required for therapeutic effect upon topical administration is, of course, a matter of choice. Values vary depending on the compound chosen, the nature and severity of the symptoms, and the treatment the animal receives. However, the final decision is at the discretion of the doctor.

Systemic administration means oral, intravenous, intraperitoneal and intramuscular administration.

Topical administration is non-systemic administration, in which the compound is applied outside the epidermis or into the oral cavity. or to prevent such compounds from entering the ears, eyes, nose, or the bloodstream. Including inhalation into the wrong area.

As used herein, the term "parenteral" includes intravenous, intramuscular, subcutaneous, nasal Includes intracavitary, intrarectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular injections It can be prepared by technique.

Typical parenteral compositions optionally include a parenterally acceptable oil, e.g. Contains tyrene glycol, polyvinylpyrrolidone, lectin, peanut oil or sesame oil. A solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier with Consists of a cloudy liquid. The daily dose for inhibition of TNF production by parenteral administration is: Calculated as the free base of the compound of formula (I) or a pharmaceutically acceptable salt thereof, approximately 1001 mg/Kg ~ approx. 40 mg approx. 0,001 mg/Kg ~40 mg/Kg is appropriate.

Compounds of formula (1) may be administered orally. Each dosage unit for oral administration is , the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. , 111g to 100ll1g is appropriate, preferably 1omg to 30! I Contains g.

The daily dosage for oral administration is a compound of formula (I) or a pharmaceutically acceptable dosage thereof. Approximately 0.001 mg/Kg to 100 mg/Kg, calculated as the free base. , preferably 0.01 mg/Kg to 40 mg/Kg. Active ingredient may be administered 1 to 6 times per day, sufficient to exhibit activity.

Compounds of formula (I) may be administered by inhalation. “Inhalation” refers to intranasal and Indicates oral inhalation administration. Dosage forms suitable for such administration, e.g. Agents or metered dose inhalers and the like may be prepared by conventional techniques. intranasal The daily dosage of a compound of formula (I) for oral and inhalation administration is from about 10 to about 120 0 mg is appropriate.

Typical compositions for inhalation include solutions, suspensions or emulsions that can be administered as dry powders. form, or traditional forms such as nochlorodifluoromethane and trichlorofluoromethane. It is in the form of an aerosol using a propellant.

The composition may be in unit dosage form, such as tablets, capsules or metered dose aerosols. Preferably, it is a sol or the like, and the patient can administer the unit dose himself.

Compounds of formula (I) may be administered topically. Therefore, the compound of formula (I) is , inflammatory local diseases mediated or exacerbated by excessive TNF production Conditions such as rheumatoid arthritis, rheumatoid arthritis, myelitis, osteoarthritis, gout arthritis and and other symptoms of arthritis, such as inflamed joints, eczema, psoriasis, or sunburn. Inflammatory skin conditions: Inflammatory eye conditions, including conjunctivitis: pyresi s) to treat or prevent pain and other symptoms associated with inflammation, respectively. It can be administered locally.

Suitable doses of compounds of formula (I) that inhibit TNF production are: , about 0.01+ag to about 100 mg of base, with the most preferred dosage being about 0.01+ag to about 100 mg of base. ．． 01+g to about 30+ig, e.g. 0,003mg administered 2 or 3 times daily It is 10+++g.

If an active ingredient can be administered alone as a raw chemical, it is Preferably, it is present as a composition. In the case of topical administration, the active ingredient is It consists of 0.001% to 10% W/V, for example 1% to 2% by weight. It is made It consists of about 10% w/v of the agent, but preferably does not exceed 5% v/v, More preferably it consists of 0.1% to 1% v/v.

The formulations of the present invention may include one or more carriers and optionally other therapeutic ingredients. Contains active ingredients. The carrier can be present with other ingredients of the formulation and its receipt must be ``acceptable'' in the sense of not being harmful to people.

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

The drops according to the invention may consist of a sterile aqueous or oily solution or suspension. , bactericides and/or fungicides and/or other suitable preservatives, preferably Prepared by dissolving the active ingredient in a suitable aqueous solution, preferably containing a surfactant. Shitsuru. The resulting solution is then clarified by filtration and transferred to a suitable container. All you have to do is get it. The container is then sealed and autoclaved or Sterilize by maintaining at 8-100°C for half an hour. Alternatively, filter the above solution sterilize the sample and transfer it to a container using aseptic technique. Contain in drops Examples of suitable disinfectants and fungicides include phenyl acetate or acetic acid (0° 0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate ( 0°01%). Glycerin is a suitable solvent for preparing oil solutions. , dilute alcohol and propylene alcohol.

Lotions according to the present invention include those suitable for application to the skin and eyes. Ru. Ophthalmic lotions consist of sterile aqueous solutions, optionally containing a bactericide. It may be prepared by a method similar to that for preparing drops. apply to the skin Lotions or liniments for dressings may also speed drying and cool the skin. agents such as acetone and/or moisturizers such as glycerin It may also contain an agent or an oil such as castor oil or peanut oil.

The cream, ointment or paste according to the invention is a semi-solid formulation for external use containing an active ingredient. It is a body preparation. They contain active ingredients that are finely ground or powdered, Alternatively, as a solution or suspension in an aqueous or non-aqueous liquid, using a suitable machine. It may be produced by mixing the oil with a base containing or not containing an oil. child Bases include hard, soft or liquid paraffin, glycerin, beeswax, metallic soap. : Demulcent, almond oil, corn oil, peanut oil, castor oil or olive oil, etc. Oils of natural origin, wool fat or derivatives thereof, or propylene glycol or mak Fats such as stearic acid or oleic acid in combination with alcohols such as Rogol Examples include fatty acids. The formulation may contain a suitable surfactant, such as sorbitan ester. anionic, cationic or non-ionic, such as esters or their polyoxyethylene derivatives. An onic surfactant may also be included. Also, suspending agents such as natural rubber, cell loin derivatives, or silicaceous 5i licas) and other ingredients such as lanolin. .

The form and nature of the pharmaceutically acceptable carrier or diluent with which it should be combined Depends on the amount of active ingredient, route of administration and other known variables are within the skill of the art. This is what people understand.

Optimal amounts for individual administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and the interval, the nature and extent of the condition being treated, the route and site of administration, and the This may be determined by the particular patient and such optimal conditions may not be determined by conventional techniques. Those skilled in the art will understand that this can be determined. The perfect place! law, i.e. on a given day a compound of formula (I) or a pharmaceutically acceptable compound thereof given per day for several days. The number of doses of the salt to be administered can be ascertained by one skilled in the art using conventional treatment-determining test methods ( Well, those skilled in the art will recognize this.

Inhibitory effect of compounds of formula (I) on in vitro TNF production by human monocytes The inhibitory effect of compounds of formula (I) on in vitro TNF production by human monocytes is Badger et al. [EPO Publication Application No. 0411754^2.1991 February 6th] and /XX Nana Hanna) [W090/15534.1990 It can be measured according to the protocol described in ``December 27, 2009-''. formula( The compound of I) inhibits LPS-induced TN of human monocytes in the above assay. For inhibition of F production, IC3° values of 0.01 to about >3.0 were shown. for example, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidi Non has an IC50 value of 02 μM in the above in vitro assay system. showed that.

Two models of endotoxic shock are utilized to evaluate the in vivo efficacy of compounds of formula (1). TNF activity was determined. The protocols used for these models are those of Nokutoga (B [EPO Publication Application No. 0411754A2. dated February 6, 1991] and Hanna [WO90/15534. December 27, 1990 date].

4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidi Non reduced serum levels of TNF induced by injection of endotoxin by approximately 57%. showed a positive in vivo response.

The data presented herein demonstrate that the compounds of the invention inhibit TNF production in mammals. It shows. Therefore, the compound of formula (I) is useful for monocytes and macrophages in humans. It is useful for inhibiting tumor necrosis factor (TNF) production by tumor cells.

Utility model B The phosphogesterase inhibitory activity and selectivity of the compound of formula (Ia) is determined by five different It can be determined using a set of PDE isoenzymes. different i The tissues used as the origin of the enzyme are as follows: 1) PDE Ia, tracheal muscle of dog; 2) PDE Ib, aorta of pig; 3) PDE Ic, guinea pig human heart = 4) PDE m, guinea pig heart: and 5) PDE rv, human monocytes. PDEIa, Ib, Ic and Torphy and Cieslinski, Molecular 7 Huma: 10G (Mol, Pharmacol,) 3 7:206-214.1990]. PDErV is , after anion exchange, heparin-sepharose chromatography [white (White) et al., FASEB J, 4^19871990 pieces in a row It is used to purify to kinetic homogeneity.

Phosphogesterase activity was determined by Torphy and Cieslinski. - (Cieslinski) [Molecular Pharmacology (Mo1. Pharmacol, ) 37: 206-214, 1990] protocol. Assay as described in the manual. IC of the compound of formula (Ia). is 0 It is within the range of 1 gM to 30 μM.

Utility Example C Selected PDE rV inhibitors increase cAMP accumulation in untreated tissues The ability to use U, a human monocytic cell line that has been shown to contain large amounts of PDE rV. -937 cells are used for evaluation. Evaluation of PDE TV inhibitory activity in untreated cells To evaluate the PDE inhibitor (001-100 μM) for 1 min, then 1 μM Incubated with prostaglandin E2 of M for 4 minutes. 5 minutes after the start of the reaction, 1 Cells were lysed by the addition of 7.5% perchloric acid and IM potassium carbonate. The pH was neutralized, and the cAMP content was evaluated by RIA. General for this assay A similar protocol is the cyclic AMP and cyclic GMP of Brooker et al. Radioimmunassay of cycle c AMP and cyclic GMP) [Advanced cyclic ・Nucleotide Research (Adv, Cyclic Nucleotide R es, ), 10: 1-33.1979]. Formula (Ia) The EC, , of the compound is in the range of 0.3 uM to >10 uM.

Synthesis examples The following examples are illustrative and do not limit the compounds of the invention.

Example 1 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidi Non-3-cyclopentyloxy-4-methoxybenzaldehyde (10.0g, 45゜4o1), trimethylsilyl cyanide (7.6ml, 57smol) and traces of anhydrous zinc iodide were stirred at room temperature under an argon atmosphere.

After 30 minutes, a cold solution of anhydrous ammonia in methanol (6.2 M, 36 m 1, 223 mmol) and the mixture was heated at 40°C in a sealed reaction vessel. Stirred for 3 hours. The container is vented and the liquid removed under vacuum. Obtained oil Redissolved in methanol and added concentrated hydrochloric acid (5 ml, 60 mmol) and ether. A solid was produced. Wash this thoroughly with ether, dry it, and Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonite Rilu hydrochloride was obtained as an off-white powder (11.8 g, 92%).

Melting point 164-166°C (decomposition).

N9.91; Actual value: C59,30, H6,91, N9.87゜2-amino-2 -(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile hydrochloride (2.83 g, 100111101) was dissolved in a saturated aqueous solution of sodium bicarbonate (25 m methylene chloride (25 ml) was added. Add this mixture to all Stir vigorously under an argon atmosphere until the solids are dissolved, then add ethyl chloride. Roformate (1.9 ml, 19.0 mmol) was added in one portion. Even more erotic (0.5 ml, 5.2 mmol) was added at 1.2 and 3 hours. added. After 4 hours, the mixture was partitioned and the methylene chloride was washed with dilute hydrochloric acid (charcoal). (potassium acid).

Recrystallization from ether/hexane gave the title compound as a solid (3.0 g, 93% ) was obtained: melting point 100-101°C.

Elemental analysis 2 calculated values (C,) as H22N204): C64,13, H6,97 , N8.80: Actual value: C63.89, N7.04. N8.72゜2-ethoxy Carbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl) Acetonitrile (3.0 g, 9.4 a + mol) and concentrated ammonia water (2.5 m1) in ethanol (70 ml) and a suspension of Raney nickel (in water) 30 ml of a 50% suspension in water (washed three times with ethanol). This mixture Hydrogenate at 60 psi for 3 hours, dilute with methylene chloride, filter through Celite, It was subjected to evaporation treatment.

The residue was partitioned between methylene chloride and dilute aqueous hydrochloric acid, and the organic layer was discarded. Carbonate the aqueous layer Basify with saturated aqueous thorium solution, extract with methylene chloride, (with potassium carbonate) Dry. Evaporate the solvent to give 2-ethoxycarbonylamino-2-(3-cy Clopentyloxy-4-methquinphenyl)ethylamine (3.0g, 100 %)・Melting point 79-84°C.

N8.63; Actual value: C62.70, H8.17, N8.47° Ethanol (1 2-ethoxycarbonylamino-2-(3-cyclopentyl) in xy-4-methoxyphenyl)-ethylamine (40mg, 0.12ma+o l) solution and sodium hydroxide aqueous solution (2.5N, 0.5ml) under argon. The mixture was heated under reflux for 5 hours under atmosphere. The mixture is cooled and partitioned between ether and water. Ta. The ether layer was washed with dilute acid, dried (over potassium carbonate) and subjected to evaporation. 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidashi Linnon (16 mg.

48%): melting point 116-118°C.

Elemental analysis: Calculated value (as C+s H2ON203): C65,20,N7. 30. NIO.

14; Actual value: C65.04, N7.19. N10.28゜diphenyl)-1- (4-Nitrobenzylamino)ethane in chloroform as in Example 1 2-Ethoxycarbonylamino-2-(3-cyclopentyloxy) prepared by C-4-methoxyphenyl)ethylamine (1.25g, 3.9ma+ol) and A solution of 4-nitrobenzaldehyde (0.59 g, 3.0 mmol) was The mixture was heated under reflux for 2 hours under a gas atmosphere. Cool the mixture and remove the solvent in vacuo and a solution of anhydrous hydrochloric acid in ether (1.0M, 4ml) was added. child The solution was evaporated to dryness and the residue was redissolved in anhydrous methanol and dissolved in sodium cyanoborohydride. Lium (0.25g, 4.Ommol) was added. This mixture was heated at room temperature for 2 hours. Stir and partition between ethylene chloride and saturated sodium bicarbonate solution, and remove the organic layer (on charcoal). (potassium acid). The residue was subjected to flash chromatography and Purification by elution with 2-ethoxylponylamino-2-( 3-cyclopentyloxy-4-methoxyphenyl)-1-(4-nitrobendi A solid of ruamino)ethane was obtained.

(0.7 g, 4Q%): melting point 112-113°C.

2-Ethoxycarbonyl in acetic acid (2,511) and water (2,5ffi1) Ruamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-( of 4-nitro-benzylamino)ethane (0.4 g, 0.9 IIlff101) The solution was treated with an aqueous solution of titanium trichloride (20%, 4.5 ml). 15 minutes later, Add concentrated aqueous ammonia (6 ml) and 9:1 methylene chloride/methanol; The mixture was filtered through glass fiber filter paper. Separate the methylene chloride layer and add (sodium sulfate) dried). The solvent was evaporated.

Residue (0,31 g) and sodium hydroxide in ethanol (], On+1) (2.5M, 5ml) was heated under reflux for 5 hours. Cool the mixture and add methylene chloride. The aqueous layer was extracted with both methylene chloride and ether. Matching The organic layer was dried (over potassium carbonate) and evaporated. Dilute the residue with methylene chloride Recrystallization from 1-(4-aminobenzyl)-4-(3-cycloether) Lopentyloxy-4-methquinophenyl)-2-imidazolidinone (0,22 g, 66%) of solid matter was obtained. Melting point 127-128°C.

Elemental analysis/calculated values (as CuH2tN303)/C69,27,H7,13, N11゜02, actual measurement C69,51, H7,23, N11.16゜Example 3 4-(3-Fuclobentyloxy-4-methoxyphenyl)-1-(4-dimethy (ruaminobenzylamino)-1-(4-dimethylaminobenzylamino)ethane 2-Ethoxycarbonyl prepared as in Example 1 in loloform Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamide (0,725g, 2.25mmol) and 4-dimethylamine/-benzfur A solution of Dehyde 1’ (0°34 g, 2.25 au Ilol) was added in an argon atmosphere. The mixture was heated under reflux for 2 hours and the solvent was removed by distillation. Furthermore, chloroform (1 0.1) was added, and refluxing was continued for an additional hour. Cool this mixture and remove the solvent under vacuum. The residue was redissolved in tetrahydrofuran (15 ml) and dissolved in ether. A solution of anhydrous hydrochloric acid (1,0M.

5 ml) was added. The solution was evaporated to dryness and the residue was dissolved in anhydrous methanol (10 m 1), cooled to 0°C, and added sodium cyanoborohydride (0.28 g, 4.5+ uol) was added. The mixture was allowed to warm to room temperature and stirred overnight.

The colorless mixture was partitioned between methylene chloride and 10% sodium hydroxide and the organic layer ( dried over potassium carbonate). The residue was subjected to flash chromatography and Elution with first ether and then 5% methanol/ether yielded the title compound. A solid (0.82 g, 80%) was obtained: melting point 94-96°C.

2-ethoxycarbonylamino-2-(3 -cyclopentyloxy-4-methoxyphenyl)-1-(4-dimethylamino benzylamino)ethane (0.40 g, 0.88 mmol) and sodium hydroxide um aqueous solution (2.5M.

A solution of 1ff11) was heated to reflux under an argon atmosphere for 6 hours. this mixture It was cooled, partitioned between methylene chloride and water, and the aqueous layer was extracted with methylene chloride. organic layer was dried (over potassium carbonate) and evaporated. Flash chromatography of the residue Purified by chromatography and eluting with 2% methanol/methylene chloride. and purified by recrystallizing the resulting solid from chloroform/ethanol. to give the title compound as a solid (0.29 g, 80%): mp 171-17. 2℃.

Elemental analysis Calculated value (C2 < Hs + Ns Os・3/111H20 ): C69,25, H7, 69°N10.09; Actual value・C69,29, H7, 50, H9, 95° Example 4 l-(4-acetamidobenzyl)-4-(3-cyclopentyloxy-4-methyl Toxiphemethoxyphenyl)-2-(ethoxycarbonylamino)ethanechlor 2-Ethoxy prepared as in Example 1 in loform (15 ml) Carbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl) Ethylamine (0,725g, 2.25mmol> and 4-acetamidoben A solution of dualdehyde (0.37 g, 2.25 mmol) was added under an argon atmosphere. The mixture was heated to reflux for 3 hours and the solvent was removed by distillation. Furthermore, chloroform (10 m 1) was added and reflux was continued for an additional hour. Cool this mixture and remove the solvent in vacuo. The residue was redissolved in tetrahydrofuran (15 ml) and dissolved in ether. A solution of anhydrous hydrochloric acid (1.0 M, 2.5 ml) was added. Evaporate this solution to dryness , the residue was redissolved in anhydrous methanol (10 ml), cooled to 0°C and diluted with methanol ( Sodium cyanoborohydride (0,28 g, 4,5 mm ol) was added. The mixture was allowed to warm to room temperature and stirred overnight. colorless mixture Partition the material between methylene chloride and 10% sodium hydroxide, and remove the organic layer (potassium carbonate). dried). The residue was subjected to flash chromatography using 3% methanol. Elution with methylene chloride gave the title compound as a foam (0.84 g, 80%). Ta.

2-ethoxycarbonylamino-2-(3-silane) in ethanol (3 ml) clobentyloxy-4-methquinphenyl)-1-(4-acetamidobenzi Ruamino)ethane (0.08g, 0.17mmol) and sodium hydroxide solution The solution (2.5M, 0.2ml) was heated to reflux for 48 hours under an argon atmosphere. It flowed. The mixture is cooled, partitioned between methylene chloride and water, and the aqueous layer is separated from methylene chloride. Extracted with The organic layer was dried (over potassium carbonate) and evaporated. residue was subjected to flash chromatography using 2-5% methanol/chloroform. Gradient elution and recrystallization of the resulting solid from chloroform/ethanol. to give the title compound as a solid (0.05 g, 65%); mp 1 91℃.

Elemental analysis: Calculated value (as C24H29N$04): C68,06, H6,90 , H9,92; Actual value: C67,90, H7,21, H9,86°3-cyclope methyloxy-4-methoxybenzaldehyde (5.5 g, 25 mmol), Limethylsilyl-cyanide (4.2 mL, 31.3 mmol) and traces of anhydride The zinc iodide mixture was stirred at room temperature under an argon atmosphere. After 30 minutes, methano A cold solution of anhydrous methylamine (5M, 25μL, 125mmol ) was added and the mixture was stirred at 40° C. for 3 hours in a closed reaction vessel. this Vent the container and remove the liquid under vacuum. Redissolve the resulting oil in methanol Then concentrated hydrochloric acid (2.3 ml, 27 mmol) and ether were added to produce a solid. Made it happen. This was thoroughly washed with ether and dried to remove the hydrochloride, which turned grayish. White powder (6.5 g.

85%), melting point 123-127°C (decomposition).

Elemental analysis: Calculated value (C+<H+5NfOz, as HCl): C59,47,H 6,77°H9,91+Actual measurement: C59,30,H6,91,H9,87°2- (3-cyclopentyloxo-4-methoxyphenyl)-2-methylaminoacetate Tonitrile hydrochloride (2.0 g, 5.7 mmol) was dissolved in saturated sodium bicarbonate water. The mixture was suspended in liquid (15 ml) and methylene chloride (25 ml) was added. this mixture , stir vigorously under an argon atmosphere until all solids are dissolved, then Ethyl chloroformate (1.35 iL, 14 mmol) was added in one portion. room After 3 hours at room temperature, the mixture was partitioned and the methylene chloride was dried (over potassium carbonate). The solvent was removed in vacuo to give an oil (2.6 g, 100%).

2-ethoxycarbonyl-methylamino-2-(3-cyclopentyloxy-4 -methoxyphenyl)acetonitrile (2.4g, 7.2mmol) and concentrated acetonitrile Aqueous ammonia (2 mL) was added to Raney nickel in ethanol (70 mL). suspension (2.4 mL of 50% suspension in water, washed 3 times with ethanol). added. The mixture was hydrogenated at 60 psi for 3 hours, diluted with methylene chloride, and Filtration through light and evaporation gave an oil. Treat the residue with methylene chloride and dilute salt. The organic layer was discarded. Base the aqueous layer with saturated aqueous sodium carbonate solution. extracted with methylene chloride and dried (potassium carbonate). evaporate the solvent The amine (3.0 g 1100%) was obtained: mp 79-84°C.

Elemental analysis: Calculated value (as CuHzaN204”1/8HzO): C62, 89, H8, 15°N8.63; Actual value: C62,70, H8,17, N8.4 7゜D) 2-ethquincarbonylmethylamino-2-(3-cyclopentyl xy-4-methoxyphenyl)-1-(4-nitrobenzylamino)ethanechlor 2-ethoxycarbonylamino-2-(3-ph) in loform (25 mL) Clobentyloxy-4-methoxyphenyl)ethylamine (1.88g, 5 ．． 6 mmol) and 4-nitrobenzaldehyde (0.89 g, 5.9 mmol) ) was heated to reflux under an argon atmosphere for 6 hours. Cool this mixture and add solvent was removed in vacuo and a solution of anhydrous hydrochloric acid in ether (IM, 5.7 mL) was added. Evaporate this solution to dryness and redissolve the residue in anhydrous methanol (25 WL). Dissolved and added sodium cyanoborohydride (0.71 g, 11.3 mmol). Ta. The mixture was stirred at room temperature for 2 hours, then mixed with ethyl acetate and 10% aqueous sodium hydroxide. The organic layer was dried (sodium sulfate). Flush the residue By chromatography and eluting with 50% hexane/ethyl acetate. The amine (1.11 g.

42%).

E) 1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methyl (toxyphenyl)-3-methyl-2-imidazolidinone acetic acid (6,5a+L) and 2-ethoxycarbonylmethylamino-2- in water (6,511IL) (3-cyclopentyloxy-4-methoxyphenyl)-1-(4-nitrobene A solution of (dylamino)ethane (1.11 g, 2.4 mmol) was added to titanium trichloride. (20%, 12.2 fflL) in water. After 30 minutes, add concentrated ammonia water. (16 mL) and 97:3 methylene chloride/methanol and stirred the mixture. It was filtered through a lath fiber filter paper. Separate the methylene chloride layer and dry (over sodium sulfate) Dry. The solvent was evaporated. Residue (0,99 g, 2.1 mmol) and aqueous sodium hydroxide solution (2.5 M, 2.6+nL ) was heated under reflux for 48 hours. The mixture was cooled and partitioned between ethyl acetate and water; The aqueous layer was extracted with both ethyl acetate and ether. Combined organic layers (nat sulfate) dried (over 100 ml) and subjected to evaporation. Flash chromatography of the residue After eluting with 10% ether/methylene chloride, methylene chloride/ether Purified by recrystallization from 1-(4-aminobenzyl)-1-4- (3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-2-imie A solid of dazolidinone (0.7 g, 88%) was obtained: melting point 143°C.

Elemental analysis: Calculated value (as CCzsHuNsOs): C69,85, N7.39. NIO.

62; Actual value: C69.82, N7.46. N10.52゜Example 6 and 7 (2R)- and (2S)-1-benzyloxycarbonylamino-2-(3- Clopentyloxydi-4-methoxyphenyl)-2-[(-)-menthyloxy carbonylamino] nioxycarbonylamino] acetonitrile methylene chloride ( 2-amino-2-(3-cyclopentyloxy-4-methyl) in quinphenyl)acetonitrile hydrochloride (prepared in Example 1, Bart A) (39g , 137.9 mmol) was added to a saturated aqueous solution of sodium hydrogen carbonate (350 IL ) and stirred under argon until the amine was dissolved. Add to this mixture ( -)-Menthyl chloroformate (44.4 mL, 206.9 mmol) was added. and the mixture was stirred vigorously for 18 hours. Separate the organic layer (potassium carbonate ) and subjected to evaporation. Reconcile the product from methylene chloride and hexane The filtrate was washed with 9.1 hexane/ether (34.7 g, 59%): Melting point: 124-141°C. The mother liquor was evaporated and subjected to flash chromatography. , purified by elution with 6:1:2 hexane/ether/methylene chloride. A solid (21.2 g 136%) was obtained: melting point 114-125°C.

Elemental analysis: Calculated value (as C2sHxsNz04・1/IOH!O): C69, 77, H8,48, N6.51; Actual value: C70,14, H8,41, N6.6 2-(3-Cyclopentyloxy- 4-Methoxyphenyl)-2-[(-)-menthyloxycarbonyl-aminoco A solution of acetonitrile (27.5 g, 64.2 g) was added to Raney nickel 28 WL of 50% suspension washed three times with tanol) and concentrated ammonia water (30+ L). The mixture was hydrogenated at 50 psi for 2 hours and filtered through Celite. , washed with methylene chloride.

The solvent was removed in vacuo to give a solid (27.5g, 99%).

Elemental analysis Calculated value (as CzsH4oN204): C69,41, N9.32 ．． N6.48; Actual value: C68.21, N9.73. N6.06°C) 1- Benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-meth) xyphenyl)-2-[(-)-menthyloxycarbonylaminocoethane chloride 2-(3-cyclopentyloxy-4-methane in methylene (5001 nL)) quinphenyl)-2-[(-)-menthyloxycarbonylaminocoethyl acetate To a solution of amine (272 g, 62.9 mmol) was added triethylamine under an argon atmosphere. Treated with thylamine (9,2a+L, 66.2ms+ol) and cooled to 0°C . Benzyl chloroformate (9.1 mL, 63.7 o 1) was added and the reaction was stirred for 16 hours and slowly warmed to room temperature. This mixture The material was partitioned between methylene chloride and dilute hydrochloric acid.

The organic extracts were dried (magnesium sulfate/rum) and evaporated. flash chroma purified by chromatography and eluting with 97:3 methylene chloride/ether. A solid product was obtained. This was recrystallized from methylene chloride/ether/hexane. A solid (27.1 g, 76%) was obtained. Melting point 154-164°C.

D) (2R)- and (2S)-1-benzyloxycarbonylamino-2-(3 -cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyl- Oxycarbonylaminoconitane 1-benzyloxycarbonylamino-2-(3-cyclopentyloxy-4- methoxyphenyl)-2-EC-)-menthyloxycarbonylaminoconitane diastereomer separation was performed using 1.8 kg of MMC spherical silica gel (15-30μ JY-100 Chromatos equipped with 8CIX 100c+o column packed with ) This was achieved by preparative HPLC conditions using a Pack apparatus. 95:5 methylene chloride /ether mobile phase at a flow rate of 200 mL/min, 13 g per experiment. It eluted at the loading amount. The total amount for the mixed sample experiment was 51 g (54% 2R, 46% 2S) Met. Detection by refractive index of the eluting product was used. The recovery rate of 2R isomer is , 25.2 g (92%): 99.9% HPLC; recovery of 2S isomer is: 20.7g (88%): 99°3% HPLC: Melting point (2R): 178~ 179°C; (2S)+167~14: Actual value: 2R: C69,95, H8,1 9, N4.92; 2S: C69, 55°N7.89. N4.84゜ 2R: [α] o! (0,5, methanol) = -67,2'2 S: [α ]otsco, 5. Methanol) = +9.2° Example 8 R-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidinoridine tyloxylponylamino]ethylamine methanol (20+ (2R)-1-benzyloxycarbonylamino-2-(3-silyl) in L) Clopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxy A solution of carbonylaminocoethane (293+g, Q, 52 mmol) was heated on charcoal. Bare 10% palladium (306g) and ammonium formate (168mg, 2.6 units) o1). The reaction was stirred at 50-55°C for 0.5 h and concentrated ammonia The mixture was basified with aqueous aqueous solution and then filtered through Celite. The solvent was removed in vacuo and the residue Partitioned between 95:5 methylene chloride/methanol and water. Organic extract (Nat sulfate (222+ g, 99%) as a white solid (222+ g, 99%) I got it.

(2R)-2-(3-cyclobenzene in dimethyl sulfoxide (3 mL) luoxo-4-methquinphenyl)-2-[(-)-menthyloxycarbonyl A solution of aminemine (149mgXo.34mmol) was added to 10% sodium hydroxide. Treated with thorium aqueous solution (O15L, 0.14Illaol) and The mixture was stirred for 1.5 hours under a vacuum atmosphere. Dilute this mixture with ethyl acetate and adjust the pH to The concentration was adjusted to about 6 with ammonium chloride. The aqueous phase was extracted with ethyl acetate and the combined organic extracts The output was washed 5 times with water. The organic extract was dried (over sodium sulfate) and evaporated. It made sense. Subjected to flash chromatography, 97 methylene trichloride/methylene Purified by elution with tanol to give a white solid (701 g, 74%) Obtained: melting point 135-137°C.

Elemental analysis Calculated value (as CI, H2ON203): C65.20. H7.30 ．． NIO14, actual value: C65.26, H7.39. N10.14.

[α]. ” (1. 1 3. methanol) = -25.2.

Example 9 ethyloxycarbonylamino]ethylamine in methanol (100+L). (2S)-1-benzyloxycarbonylamino-2-(3-cyclopentyl) (4-methoxyhentyl)-2-[(-)-menthyloxycarbony Ruaminokoethane (1. 6 5 g, 2. 91 mmol) 1 on carbon 0% palladium (1.65g) and ammonium formate (1.0g, 15.8g) 1). The reaction was stirred at 50-55 °C for 0.25 h and then It was filtered through a filter. The solvent was removed in vacuo and the residue was dissolved in 95:5 methylene chloride/methane. and 95:5 water/concentrated aqueous ammonia. Organic extract (sodium sulfate) After drying and evaporation, a white solid (1.21 g, 96%) was obtained. .

(2S)-2-(3-cyclopene in dimethyl sulfoxide (3 mL) methyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonyl Ruaminochoethylamine: / (14 7. 3 tmg. 0. 3 4 mmol ) solution to 10% aqueous sodium hydroxide solution (0.15 mL, 0.4 1) and stirred for 1.5 hours under an argon atmosphere.

The mixture was diluted with ethyl acetate and the pH was adjusted to about 6 with ammonium chloride.

The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed five times with water. organic extraction The material was dried (sodium sulfate) and evaporated. flash chromatog Purified by eluting with 97:3 methylene chloride/methanol. A white solid (80.4 mg, 84%) was obtained. Melting point 134-136℃ .

Elemental analysis: Total "ILM" (as CIsHioNzOs・5/4HzO): C60.28. H6.75.

H9.37; Actual value: C60.35. H6.60. H9.42.

[αko. ” (1. 30. Methanol) = +22’ Example 10 S-(-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphemethoxyphenyl)-2-[(-)-menthyloxycarbonyl (2S)-2-<3-silyl aminocoethane in chloroform (10 mL) Clopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxy Carbonylaminoconitylamine (5 5 3 mg, 1. 2 7 mmol) and a solution of 4-nitrobenzaldehyde (202 mg, 1.33 mmol), The mixture was stirred under reflux for 8 hours and at room temperature for 18 hours under an argon atmosphere. solvent in vacuum and the residue was dissolved in tetrahydrofuran (IOIIIL) and methanol (15 mL). ). Sodium cyanoborohydride (2 4 2 mg, 3. 8 5 mm θ1) was added and the solution was stirred for about 5 hours. Acetic acid (150 μL, 2. After adding 5 mood), the mixture was stirred at room temperature for 2 hours under an argon atmosphere. charcoal Aqueous sodium oxyhydrogen solution was added and the solution was evaporated to dryness. Dilute the residue with methylene chloride partitioned several times between methanol/methanol and water and dried the organic extract (over potassium carbonate). , and subjected to evaporation treatment. Subjected to flash chromatography, 25 nia 5-acetic acid ethyl Purified by eluting with chill/hexane to give a yellow solid (293 mg, 41%) was obtained: fused methquinphenyl)-2-[(-)-menthyloxycarbo Nylaminoconitane methanol (3-cyclobentyloxy-4-methoxyphenyl)-2-(-)-menthyl [oxycarbonylamino]etha: / (2 7 0 mg, o. 5 + u + ol ) was mixed with acetic acid (1.45 mL), water (1.45 mL) and titanium trichloride (2 2.61 L of 0% aqueous solution). The reaction was stirred for 15 minutes, at which time , water (1.45 mL) and concentrated aqueous ammonia (35 mL) were added. this reaction 1.1 Disodium carbonate aqueous solution/methanol/methylene chloride (100OI The mixture was diluted with L) and stirred for 1 hour. The mixture was filtered through Celite and 5% methanol was added. The mixture was thoroughly washed with chlorine/methylene chloride and subjected to evaporation. Pour the residue into water and methylene chloride. The organic extract was dried (over potassium carbonate) and evaporated to give a yellow A colored solid (237 mg, 93%) was obtained: mp 74-75°C.

(2S)-1-(4-aminoben) in dimethyl sulfoxide (5 mL) dylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2 -[(-)-menthyloxycarbonylaminocoethane (232 mg, 0.4 3 mmol) solution, 10% sodium hydroxide (210μ, 0.54 mIIlol) and stirred for 1 hour at 80-85°C under argon atmosphere.

The reaction mixture was cooled and extracted twice with ethyl acetate. Wash the organic extract 5 times with water. , dried (over potassium carbonate) and evaporated.

Flash chromatography, first eluting with 7:3 ethyl acetate/hexane. After that, apply to the second column and add 98.5:1.5 methylene chloride l methanol. Purified by eluting with to give an off-white solid (119-216 3%): melting point 72-74°C.

Elemental analysis: Calculated value (C2zlhtNsOrl/4Hz○T): C68.46 ．． H7.18.

N10.89: Actual +111 value: C68.35. H7.07. N10.52.

[α]. ” (0.99.methanol) = -85.

Example 11 R-(+)-1-(4-aminobenzyl")-4-(3-cyclopentyl Oxy-4-methquinphemethoxyphenyl)-2-[(-)-menthyloxy (2R)-2- in carbonylaminocoethane chloroform (15 mL) (3-cyclopentyloxy-4-methquinphenyl)-2-[(-)-menthyl oxycarbonylaminoconitylamine (843 mg, 1, 95 mm ol) and 4-nitrobenzaldehyde (311 mg, 2.

A solution of 4 mmol) was stirred under reflux under an argon atmosphere for 18 hours. solvent Removed in vacuo and the residue was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL). mL). Sodium cyanoborohydride (371+g, 5.8% 1) was added and the solution was stirred for 1 hour. Acetic acid (225 μL% 3.7 mmo After addition of l), the mixture was stirred at room temperature for 48 hours under an argon atmosphere. sodium bicarbonate An aqueous solution of lium was added and the solution was evaporated to dryness. The residue is diluted with methylene chloride/methano. The organic extract was dried (over potassium carbonate) and evaporated. It was attached to. Flash chromatography using 3N ethyl acetate/hexane Purification by elution with gave a yellow solid (704 mg, 64%) : Melting point 62-64°C.

B) (2R)-1-(4-aminobenzylamino-2-(3-cyclopentyl) xy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamine (2R)-1-(4-nitrobenzyl) in ethane methanol (5 mL) Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[( -)-Menthyloxycarbonylaminocoethane (683mg, 1.2mmo The solution of 1) was mixed with acetic acid (4.5 uL), water (4°5+aL) and titanium trichloride (2 7.8 uL of 0% aqueous solution). The reaction was stirred for 15 minutes, at which time , water (4.5 uL) and concentrated aqueous ammonia (10.5 uL) were added. this reaction 1:1:2 sodium carbonate aqueous solution/methanol/methylene chloride (300a+ L) and stirred for 1.5 hours. The mixture was filtered through Celite and 5% methane was added. It was thoroughly washed with alcohol/methylene chloride and subjected to evaporation. The residue was dissolved in water and methichloride. The organic extract was dried (over potassium carbonate) and subjected to evaporation. , a yellow solid (625 mg, 97%) was obtained: mp 71-73°C.

(2R)-1-(4-aminobenzi) in dimethyl sulfoxide (3 mL) Ruamino)-2-(3-cyclobentyloxy-4-methoxyphenyl)-2- [(-)-Menthyloxycarbonylaminoethane (615 mg, 1.2 mmo The solution of l) was treated with 10% sodium hydroxide (600 uL, 2.5 mmol). The mixture was stirred at 85-90°C for 2 hours under an argon atmosphere. Cool this reaction , water was added and extracted twice with ethyl acetate. The organic extract was washed 5 times with water ( (potassium carbonate) and evaporated. flash chromatography and first eluted with 98.5:1.5 methylene chloride/methanol, then the second Purified by column and eluting with 98:2 methylene chloride/methanol. A yellow solid (310 mg, 68%) was obtained: mp 71-73°C.

Elemental analysis: Calculated value CCzxH2FN5Os"5/8HzO, Te): C67, 28, H7, 25°N10.70; Actual value: C67,24, H7,02, N10 ．． 34° [αko,” (1, 22, methanol) = +80° Example 12 S-(-)-1-(4-benzylpyridyl)-4-(3-cyclopentyloxy -4-methoxy4-methoxyphenyl)-2-[(-)-menthyloxycarbo (2S)-2-(3- cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxy Cycarbonylaminoconitylamine (444111g, 1.03mmol) and and 4-pyridine-carboxaldehyde (105μ, 1,08 mmol) The solution was stirred at reflux under an argon atmosphere for 4.5 hours, then at room temperature for 18 hours. Stir for a while. The solvent was removed under vacuum and the residue was dissolved in tetrahydrofuran (8 mL) and Redissolved in methanol (51OL). Sodium cyanoborohydride (198r ng, 3.14 mol) was added and the solution was stirred for 0.5 h. Acetic acid (12 After adding 0 μL% 2.1 mm01), stir at room temperature for 2 hours under an argon atmosphere. Stirred.

Aqueous sodium bicarbonate solution was added and the solution was evaporated to dryness. Treat the residue with chloride Partition between tyrene/methanol and water, dry organic layer (over potassium carbonate) and evaporate. It was then subjected to development processing. Flash chromatography with 98:2 methanol/ Purification by elution with methylene chloride gave the product (353 mg, 66%) I got it.

B) 5-(-)-1-(4-benzylpyridyl)-4-(3-cyclopentyl Oxy-4-methquinphenyl)-2-imidazolidinone dimethyl sulfoxide (2S)-1-(4-benzylpyridylamino)-2 in (5IIIL) -(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-men Tyloxycarbonylaminotriethane (322111g, 0.62mmol) The solution was treated with 10% sodium hydroxide (300 itL, 0.74 mmol). The mixture was stirred at 100 to 105°C for 0.5 hour under an argon atmosphere. This reactant was cooled and extracted twice with ethyl acetate. The organic extract was washed 5 times with water (carbonate (potassium) and evaporated. Attached to flash chromatography and purified by eluting with 97.5:2.5 methylene chloride/methanol. A pale yellow solid (162+g, 71%) was obtained. Grind this with ether and dried (143 mg): mp 146-147°C.

Elemental analysis: Calculated value (as Cz+HzsN30s/3/8H10): c67.4 0. H6,94°N11.23: Actual value: C57,71, H6,82, N11. 05° [α] o” (0,95, methanol) = -64,6° Example 13 R-(+)-1-(4-benzylpyridyl)-4-(3-cyclopentyloxy -4-methoxyphenyl)-2-imidazolidinone A) (2R)-1-(4-benzylpyridylamino')-2-(3-cyclopene methyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonyl (2R)-2-(3-cyclyl)aminocoethane in chloroform (8 uL) Lopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxyca rubonylaminoconitylamine (358 mg, 0.83 mmol) and 4-pyrylic A solution of zinc carboxaldehyde (85 μL, 0.87 μL) was added in an argon atmosphere. Stirred under ambient air and reflux for 6 hours, then at room temperature for 18 hours. Solvent under vacuum and the residue was dissolved in tetrahydrofuran (5+sL) and methanol (5uL). Re-dissolved. Sodium cyanoborohydride (161mg, 2.5ma+ol) and the solution was stirred for 1 hour. Add acetic acid (95 μL, 1°7 ol) After that, the mixture was stirred at room temperature for 18 hours under an argon atmosphere. Sodium bicarbonate in water and the solution was evaporated to dryness. The residue was dissolved in methylene chloride/methanol and water. The organic layer was dried (potassium carbonate) and evaporated. flash Subjected to chromatography and first eluted with 97:3 methanol/methylene chloride. This was followed by a second separation using flash chromatography with a 98:2 ratio. Purified by eluting with ethanol/methylene chloride to give the product (120a+ g, 28%) was obtained.

B) R-(+)-1-(4-benzylpyridyl)-4-(3-cyclopentyl Oxy-4-methoxyphenyl)-2-imidazolidinone dimethyl sulfoxide (2R)-1-(4-benzylpyridylamino)-2-( in (3 mL) 3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyl Solution of oxycarbonylaminocoethane (112 mg, 0, 21 mmol) was treated with 10% sodium hydroxide (110 μL, 0.26 mmol), The mixture was stirred at 80-85° C. for 1 hour under a Rougon atmosphere. Cool the reaction and add water. and extracted twice with ethyl acetate. The organic extract was washed 5 times with water (potassium carbonate dried (over 100 ml) and subjected to evaporation. Subjected to flash chromatography, Purified by eluting with 97:3 methylene chloride/methanol to give a white solid. (41 mg, 52%) was obtained: mp 135-137°C.

Elemental analysis: Calculated value (as Cz+HzsNsOs・0.55Si02): C60 ,33,H6゜03,N10.05+actual value:C60,32,H6,14,H9 , 92° Example 14 S-(-)-1-(4-acetamidobenzyl')-4-(3-cyclopentyl Oxy-4-methoxyphenyl)-2-imidazolidinone A) 5-(-)-1 -(4-acetamidobenzyl)-4-(3-cyclopentyloxy-4-meth xyphenyl)-2-imidazolidinone)S-(-)-1-(4-aminobenzi )-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imida Zolidinone (5011g, 0.13mmol) was added with methylene chloride (1fflL) ) in acetic anhydride (37 ttL, 0.39 mmoD) and pyridine (-1/2 drop ) and the mixture was stirred for 0.5 h at ambient temperature under an argon atmosphere. did.

The reaction mixture was subjected to flash chromatography using 98:2 methylene chloride/methylene chloride. Purified by elution with tanol to give a white solid (51 mg, 93%). Obtained: melting point 98-100°C.

Elemental analysis/calculated value (as C! 4 H2e Ns O4・1/2H20): C66,65, H6,99°N9.72: Actual value: C66,94, H6,89, N9.58゜[αko. ”　(0,90,methanol)=-72゜9゜R-(+) -1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxy Cyphenyl)-2-imidazolidinone (50 mg, 0.13111101) , acetic anhydride (37 μL 10.39+mol) in methylene chloride (1 mL) and pyridine (-1/2 drop) and the mixture was evaporated under argon atmosphere. Stirred at ambient temperature for 0.5 hours. The reaction mixture was subjected to flash chromatography. , purified by eluting with 98.2 dichloride/methanol to give a white Solid (51 mg, 93%) mp 99-102°C.

Elemental analysis calculated value (Ct a H2e N, as 04.1/2H20): C 66,65,H6,99°N9.72; Actual value: C66,89,H6,60,N 9.38° [αko,)” (0,99, methanol) = +75.6° Example 16 S-(-)-1-(4-oxamidobenzyl)-4-(3-noclopentyloxy (4-methquinophenyl)-2-imidazolidinone 5-(-)-1-(4-oxamidobenzyl)-4-(3-cyclobenzyloxy 5-(-)-1-(4- aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) -2-imidazolidinone (76 g, 0.2 g) was added to 0.0 At ℃, trimethylamine (0.03 mL, 0.22 mmol) and methyl Xalyl chloride (0.04 mL, 0.22 maol) was added. 0.5 o'clock After a while, add aqueous ammonium chloride solution and pour the mixture into water. Extracted with tyrene three times. The organic extract was dried (over potassium carbonate) and evaporated. It was attached to. Flash chromatography in 4:1 ethyl acetate/hexane Purification by elution with a white foamy solid (89 mg, 93%) Two melting points: 77-80°C. This method in methanol (1 mL) in a pressure tube Thiloxamate (89 mg, 19 mmol) was added to -7 ml under an argon atmosphere. Cooled to 8°C and anhydrous ammonia (3 mL) was condensed into the snow. seal this tube and the mixture was allowed to return to ambient temperature. After 20 hours, the tube was cooled to -78°C and opened. and returned to ambient temperature under a stream of argon. The residue is dissolved, filtered and subjected to evaporation. did. Trituration with methylene chloride gave a white solid (79 mg, 91%). : Melting point 191-193°C.

Elemental analysis: Calculated value CCtaHtsNsOs・0.6H! (as O): C62,2 2, H6, 35°N12.09; Actual value: C62,25, H6,22, N11. 97° [α], 2s (0,99, dimethyl sulfoxide) = -47,7” carried out Example 17 R-(+)-1-(4-oxamidobenzyl)-4-(3-cyclopentyloxy c-4-methquinphenyl)-2-imidazolidinone R-(+)-1-(4-oxamidobenzyl)-4-(3-cyclopentyloxy c-4-methquinphenyl)-2-imidazolidinone R-(+)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methquinphenyl)-2-imidazolidinone (51 mg, 0.13 mmol ) in methylene chloride (0,5o+L) at 0°C under an argon atmosphere. A solution of remethylamine (0.02 mlS0°14 mmol) and methylene chloride ( Methyloxalyl chloride (0,014 mL, 0.1 4 mmol) of the solution, the mixture was poured into water and diluted with methylene chloride. Extracted twice. The organic extracts were dried (over potassium carbonate) and evaporated. centre Rush chromatography was performed, eluting with 3:1 ethyl acetate/hexane. to give a white sticky solid (58 mg, 96%), melting point 1. 27-131℃. This methyl alcohol in methanol (1 mL) in a pressure tube Xamate (58 mg, 0.12 + mol) was added to -78 ℃ and anhydrous ammonia (2ωL) was condensed into the snow. seal this tube , the mixture was allowed to return to ambient temperature. After 18 hours, the tube was cooled to -78°C, opened, and It was brought back to ambient temperature under a stream of Rougon. The residue was dissolved, filtered and evaporated.

Trituration with methylene chloride gave a white solid (35 mg, 61%): mp. 192-193°C.

Elemental analysis, calculated value (as C24H211N405・1/3H20): C62, 88, H6, 30°N12.22; Actual value: C63,23, H6,27, N11 ．． 78° [α]D” (0,99, dimethyl sulfoxide) = +49.1° carried out Example 18 R-(+)-1-(4-formamidobenzyl)-4-(3-cyclopentyl) xy-4-methquinphenyl)-2-imidazolidinone R-(+)-1-(4- formamidebenzyl)-4-(3-cyclopentyloxy-4-methoxyphene) Nyl)-2-imidazolidinone Acetic anhydride (5, OmL, 53 mmol) and formic acid (2,11IIL, 56 mmol) was heated at 40-45°C for 3 hours. Acetic formic anhydride was prepared by Acetic formic anhydride (37 μL, 0.3 9 mmol) was added with dry tetrahydrofuran (1, R-(+)-1-(4-aminobenzyl)-4-(3-fuku lobentyloxy-4-methoxyphenyl)-2-imidazolidinone (66mg .

0.17 mmol) was added dropwise and the mixture was warmed to ambient temperature for 18 h. Stirred. partitioning the reaction mixture between methylene chloride and aqueous sodium bicarbonate; The organic extracts were washed with water, dried and evaporated. flash chromatog Purified by eluting with 98:2 methylene chloride/methanol. A white solid (1 g 182% of 57II) was obtained, melting point 92-95°C.

Elemental analysis: Calculated value CC25Ht7NsO<): C67,46,H6,65 , NIo.

26: Actual measurement value: C67.09, H6.64, N10.06゜[α]D” (0, 90, methanol) = +89.3° Example 19 S-(-)-1-(4-formamidobenzyl)-4-(3-cyclopentyl) xy-4-methoxyphenyl)-2-imidazolidinone 5-(-)-1-(4- formamidebenzyl)-4-(3-cyclopentyloxy-4-methoxyphene) )-2-imidazolidinone Acetic anhydride (5, OmL, 53 mmol) and A mixture of acids (2.1 mL, 56 mmol) was heated at 40-45 °C for 3 hours. Acetic formic anhydride was prepared by Acetic acid formic anhydride (25μ, 0.27 amol), dry tetrahydrofuran (1,5a 5-(-)-1-(4-aminobenzyl)-4-(3-fucro Bentyloxy-4-methoxyphenyl)-2-imidazolidinone (65 mg.

0.17 mmol) was added dropwise and the mixture was warmed to ambient temperature for 18 h. Stirred. partitioning the reaction mixture between methylene chloride and aqueous sodium bicarbonate; The organic extracts were washed with water, dried and evaporated. flash chromatog Purified by eluting with 98:2 methylene chloride/methanol. to give a white foamy solid (43 mg, 62%): mp 103-106°C. .

Elemental analysis: Calculated value CCuH2yNs04.1. (as IHxO): C64,35 , H6,86°N9.79; Actual value: C64,72, H6,53, N9.31° [α], “(0,90, methanol) = -90,6° Example 20 1-(4-acetamido-3-pyridylmethyl)-4-(3-cyclopentylmethyl) xy-4-methoxyphenyl)-2-imidazolidinone A) 1-(4-aceto Amido-3-pyridylmethylamino)-4-(3-cyclobentyloxy-4- methoxygenyl)-2-imidazolidinone in chloroform (15 mL). (2R,2S)-2-(3-cyclopentyloxy-4-methoxyphenyl) -2-[(-)-menthyloxycarbonylaminocoethylamine (409+g , 95a+mol) and 4-pyridine-carboxaldehyde (15510g , 0.95au++ol) was stirred under reflux for 4 hours under an argon atmosphere. and cooled. The solvent was removed in vacuo and a portion of the residue (1951 g, 0.34 m mol) in tetrahydrofuran (2 mL) and methanol (2 mL). Ta. Add sodium cyanoborohydride (65 mg, 1.0+mol) and The solution was stirred for 0.5 hour.

After adding acetic acid (40μ, Q, 7a + mol) at room temperature under an argon atmosphere. Stirred for 1 hour. Aqueous sodium bicarbonate solution was added and the solution was evaporated to dryness. . The residue was partitioned between methylene chloride/methanol and water, and the organic layer was purified (with potassium carbonate). ) was dried and subjected to evaporation treatment. Firstly, 3 :97 methanol/methylene chloride to give the amine (1 28mg.

65%) with a melting point of 78-81°C.

1-(4-acetamido-3-pyri in dimethyl sulfoxide (3 mL)) (dylmethylamino)-4-(3-cyclopentyloxy-4-methoxyphenyl )-2-imidazolidinone (121 mg, 0.21 mmol) was added to 10 % sodium hydroxide (42+OL, 1.05 mmol) and The mixture was stirred at 90 to 95° C. for 2.5 hours under a vacuum atmosphere. Cool the reaction and add water. and extracted twice with ethyl acetate. The organic extract was washed 5 times with water (potassium carbonate The mixture was dried (in a vacuum) and subjected to evaporation. Subjected to flash chromatography, 9 Purified by eluting with 6:4 methylene chloride/methanol to give a white solid. Obtained a substance (63 mg, 79%): melting point 69N14.31 + actual value C64.30 , H6,86, N14.05°C) 1-(4-acetamido-3-pyridylmethane) methyl)-4-(3-cyclopentyl-4-mepyridine (2 mL)) (4-amino-3-pyridylmethyl)-4-(3-cyclopentyloxy-4- methoxyhentyl)-2-imidazolidinone (36+g, 0.09 mmol ) in methylene chloride (0.5 mL) was prepared as acetyl chloride (0,OO7) in methylene chloride (0,5 mL). 5 mL, 0.11 mol) and the mixture was heated under an argon atmosphere. and stirred for 1 hour at ambient temperature. Acetyl chloride in methylene chloride (0,5d) Further add a known amount of 0.0075 mL, 0.11 ma+ol, and ．． Stirring was continued for 5 hours.

Water was added and the mixture was extracted three times with methylene chloride. Organic layer (sodium sulfate) (2000 ml) and subjected to evaporation. Subjected to flash chromatography, Purified by eluting with 96:4 methylene chloride/methanol to give an off-white color. A white solid (39 mg, 99%) was obtained: mp 184-187°C. This solid The shape was triturated with methylene chloride and ether to give a white solid (10 mg). Obtained.

Elemental analysis: Calculated value (C!sl'hsN<Oco, as 65HzO): C63, 33, H6,77, N12.84; Actual value: C63,34, H6,52, N12 ．． 44° Example 21 S-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1- (2,4-Diazinitrobenzylamino)-2-[(-)-menthyloxycal Bonylaminoconitane (as above) in chloroform (40 mL) 2S)-1-benzyloxycarbonylamino-2-(3-cyclopentyloxy cy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino (2S)-2-(3 -cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyl- oxycarbonylaminocoethylamine and 2,4-dinitrobenzaldehyde ( 762111g, 3.88mmol) under reflux under an argon atmosphere. Stirred for 5 hours. The solvent was removed in vacuo and the residue was purified with tetrafluorocarbons under an argon atmosphere. Redissolved in hydrofuran (38 mL) and methanol (40 mL). Cyanoho Sodium hydride (664a+g, 10.6 mmol) was added and the solution Stirred for 1 hour. After adding acetic acid (404 μL, 7.1 mmol), at room temperature Stirred for 72 hours. Add aqueous sodium bicarbonate solution and evaporate the mixture to dryness. did. Partition the residue between methylene chloride and water and extract the organic extract (with sodium sulfate). It was dried and evaporated in vacuo. Subjected to flash chromatography , purified by elution with a solution of 40-60% ethyl acetate in hexane. A semi-solid (1.7 g, 79%) was obtained.

B) (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1 -(2,4-diaminobenzylamino)-2-[(-)-menthyloxycarbo Nylaminoconitane in methanol (16.6 mL) containing acetic acid (16.6 mL) (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl) in -1-(2,4-dinitrobenzyl)-2-[(-)-menthyloxycarbonyl A solution of ruaminoconitane (1,7 g, 2,8 mmol) was added to water (16,6+ mL) and titanium trichloride (35 mL of a 20% aqueous solution).

The reaction was stirred for 90 minutes, cooled in a water bath, diluted with water (24 mL) and concentrated ammonia. A solution of aqueous water (47 mL) was added. This reaction was mixed with 5% sodium carbonate/methano Diluted with alcohol/methylene chloride (1:1:2) and stirred for 1 hour. Divide this mixture into It was separated and the aqueous phase was extracted with methylene chloride. Dry the organic extract (with potassium carbonate) It was then subjected to evaporation treatment in vacuo. The product was subjected to flash chromatography. by eluting with chloroform (saturated with aqueous ammonia and dried). Purification to give a solid (1.04 g, 68%): mp 150-154°C.

(2S)-2-(3-cyclopene in dimethyl sulfoxide (811L)) Tyloxy-4-methoxyphenyl)-1-(2,4-diaminobenzylamino )-2-[(-)-menthyloxylponylamimeethane (1.0 g, 1.8 A solution of 1 mmol) was diluted with 10% sodium hydroxide (1.0 mmol) and 2.5 Il1 1101) and stirred at 80-85° C. for 3 hours under an argon atmosphere. reaction The mixture was cooled, partitioned between cold water and ethyl acetate, and the organic extracts were washed with water (sulfuric acid). (sodium chloride) and evaporated in vacuo. flash chromatography The product was purified with 0.5-2% methanol (with aqueous ammonia). Purified by elution with chloroform (saturated and dried) to give granular A resinous material (459+eg, 64%) was obtained = [α]D25 (0,609, methano ) = -83,6' Elemental analysis two calculated values (as C!2H21N40.): C6 6,65,H7,12,N14゜13; Actual value: C66,40,H7,04,N 13.97° Example 22 S-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1- (2,4-diacetamidobenzyl)-2-imidazolidinone anhydrous pyridine (5 5-(-)-4-(3-cyclopentyloxy-4-methoxy) in phenyl)-1-(2,4-diaminobenzyl)-2-imidazolidinone (24 Acetic anhydride (340 μL, 3.60a+mol) and the mixture was heated at ambient temperature under an argon atmosphere. Stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in cold 3NHC] and acetic acid. Chill and distributed. Wash the organic extract with water, 5% aqueous sodium bicarbonate solution, and water. , dried over sodium sulfate and concentrated in vacuo. flash chromatograph the product containing 1-2% methanol (saturated with aqueous ammonia). , dried) and purified by elution with chloroform to give a resin (18 0g162%) was obtained: [a]o" (0,600, m/-l) = -61° Elemental analysis: Calculated value (as C2aH3zN40g4/4HtO): C64,38 , H6,75°N11.55; Actual value + C64,61, H6,77, N11.3 8゜Example 23 R-(+)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1- (2,4-diaminobenzyl)-2-imidazolidinone A)(2R)-2-(3 -cyclopentyloxy-4-methoxyphenyl)-1-(2,4-dinitrobe ndylamino)-2-[(-)-menthyloxycarbonylaminocoethanechlor (2R)-1-benzyl chloride in loform (401 nL) as described above. oxycarbonyl-amino-2-(3-cyclopentyloxy-4-methoxyphene) nil)-2-((-)-menthyloxycarbonylamino)ethane (2,00g (2R)-2-(3-cyclopentyloxy- 4-Methoxyphenyl)-2-[(-)-menthyloxycarbonylaminochoe Thylamine and 2,4-dinitrobenzaldehyde (762 mg, 3, 88 mmol) solution was stirred under reflux for 5 hours under an argon atmosphere. vacuum the solvent and the residue was dissolved in tetrahydrofuran (10 mL) and methanol (15II L) was redissolved. Sodium cyanoborohydride (665mg, 10.6+++ mol) was added and the solution was stirred for 1 hour. Acetic acid (405 μL, 7, l mmol) was added, and the mixture was stirred at room temperature for 72 hours under an argon atmosphere. Carbonic acid Aqueous sodium hydrogen solution was added and the solution was evaporated to dryness. Dilute the residue with methylene chloride and water, dry the organic extract (over sodium sulfate) and evaporate in vacuo. Submitted to processing.

Flash chromatography with 30-50% ethyl acetate in hexane. Purification by elution gave an orange solid (1.25 g, 62%): Melting point 119-125°C.

B) (2R)-2-(3-fuclopentyloxy-4-methoxyphenyl)-1 -(2,4-diaminobenzylamino)-2-[(=)-menthyloxycarbo in methanol (12 mL) containing nylaminocoethane acetic acid (12 mL). (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-( 2,4-Dinitrobenzylamino)-2-[(-)-menthyloxycarbonyl A solution of amino]ethane (1.2 g, 2.Q mmol) was added to water (10 mL) and Treated with titanium chloride (20.8 mL of 20% aqueous solution).

The reaction was stirred for 60 minutes, cooled in a water bath, diluted with water (12 mL) and concentrated ammonia. A solution of aqueous water (28 mL) was added. This reaction was mixed with 5% sodium carbonate/methano The mixture was diluted with alcohol/methylene chloride (1:1:2) and stirred for 1 hour. This mixture The materials were separated, the aqueous phase was extracted with methylene chloride containing 5% methanol, and the combined organic matter was extracted with methylene chloride containing 5% methanol. The extract was washed with water, dried (over potassium carbonate) and subjected to base treatment in vacuo. did. Subjected to Frazzini chromatography (saturated with aqueous ammonia and dried) Purified by eluting with chloroform) to give a tan solid (0, 59 g, 54%) was obtained: mp 139-143°C.

(2R)-2-(3-cyclopentyl) in dimethyl sulfoxide (4 mL) (4-methoxyphenyl)-1-(2,4-diaminobenzylamino) -2-[(-)-menthyloxycarbonylaminocoethane (0.59g, 1. 0.07 mmol) was added to 10% sodium hydroxide (0.53 mL, 1.3 m mol) and stirred at 80-85° C. for 3.5 hours under an argon atmosphere. anti The reaction mixture was cooled and partitioned between cold water and ethyl acetate, the organic extracts were washed with water and ( (potassium carbonate) and evaporated in vacuo. flash chromatography The product was quantified with 1-2% methanol (saturated with aqueous ammonia). Purified by elution with chloroform (dehydrated and dried) to give a resinous product ( 352+g, 83%) obtained = [α],” (0°564, methanol) = +8 4゜ Elemental analysis two calculated values (Ct□) (as zar'Log): C66, 65, H7, 12, N14°13; Actual measurement: C66,43, H7,03, N14.11° carried out Example 24 R-(+)-4-(3-fuclopentyloxy-4-methoxyphenyl)-1- (2,4-diacetamidobenzyl)-2-imidazolidinone anhydrous pyridine (4 ml) of R-(+)-4-(3-cyclopentyloxy-4-methoxy phenyl)-1-(2,4-diaminobenzyl)-2-imidazolidinone (17 Acetic anhydride (250 μL, 2.64 mmol) was added to a solution of mol) and the mixture was stirred for 18 h at ambient temperature under an argon atmosphere. did. The reaction mixture was concentrated in vacuo and the residue was partitioned between cold 3N HCI and ethyl acetate. did. The organic extract was washed with water, 2% aqueous sodium carbonate, water, and diluted with sodium sulfate. dried on a platter and concentrated in vacuo. Flash chromatography The product was added to a solution (saturated with aqueous ammonia and dried) containing 1-2% methanol. Purified by elution with loloform to yield a resin (140 mg, 66%). Obtained: [αko,” (0,591, methanol) = 59° Elemental analysis: Calculated value ( C26H32N 40s・1/4H! (as O): C64,38, H6,75 ゜N11.55;Actual value・C64,20,H6,70,N11.43゜The above By the method, the following compounds can be prepared: Example No. Compound 25 1-(4-anobenyl)-4-(3-cyclopentyloxy-4-methyl Toxyphenyl)-2-imidazolidinone 26 1-(4-amidinobenzyl) -4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazoly Dinone 27 4-(3-cyclopentyloxy-4-methoxyphenyl)-1- [4-(2-imidazo)benzyl-2-imidazolidinone 28 4-(3-imidazo) Clopentyloxy-4-methoxyphenyl)-2-imidazolidinone 29 4-(3-cyclopentyloxy-4-methoxyphenyl)=1-[4- (1-imidazo) penzylco-2-imidazolidinone 30 4-(3-[4-but [toxy]-4-methquinphenyl)-2-imida A drug mixed with the compound of the present invention Formulations for use can be prepared in a variety of forms using a number of excipients. mosquito Examples of such formulations are shown below.

Preparations for inhalation Compound of formula (I) (1 μg to 100 mg) is administered from a metered dose inhaler to 1lIJj Nebulize to deliver the desired amount of drug with each use.

Tablet/Ingredients per tablet 1 Active ingredient (compound of formula (I)) 40mg2, Corn starch 20mg 3. Alginic acid 20mg Pharmaceutical compositions for parenteral administration include a suitable amount of a compound of formula (I) in polyethylene glycosylation. It is prepared by dissolving it in a solution with heating. This solution is then poured into Dilute with water (100 nL) for injection. This solution was then applied to a 0.22 micron Sterilize by filtering with a membrane filter and seal in a sterile container.

The above description does not fully disclose the present invention, including preferred embodiments thereof. be. Modifications and improvements in the embodiments specifically disclosed herein are within the scope of the following claims. It is in. Without further elaboration, one skilled in the art can, using the above description, It is thought that it can be used to a certain extent. Therefore, here The examples are merely illustrative and are not intended to limit the scope of the invention in any way. It should be interpreted that there is no such thing. Specific examples of the present invention that claim exclusive rights, that is, monopoly rights, are: , is defined as below.

international search report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A61K 311505 ABF 9360-4C3115359360-4C C07C2171587457-4H 2711027188-4H 271/20 7188-4H 271/34 7188-4H C07D 213/38 6701-4C307/20 7252-4C 309/10 7252-4C 333/32 7252-4C 3351027252-4C 405/12 233 8829-4C405/14 233 8829-4C 409/12 233 8829-4C409/14 233 8829-4C 417/12 233 9051-4C417/14 233 9051-4C I Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IT, LU, NL, SE), A U, CA, JP, KR, US (72) Inventor Christensen, Seekfli To Benjamin, The Force Raisto, Philadelphia, Pennsylvania 19103, United States REIT No. 2216

Claims (36)

[Claims] 1. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is -(CR9R10) n-(C(O)O)r-(CR9R10)m-R8, -(CR9R10)n-( C(O)NR6)r-(CR9R10)m-R8, or -(CR9R10)m- (O)a-(CR9R10)m-R8 (where one alkyl moiety is optional) or may be substituted with more halogens); n is a number having a value of 0 to 4; m is a number having a value of 0 to 2; r is a number having a value of 0 or 1; s is a number having a value of 0 or 1; R9 and R10 are independently selected from hydrogen or C1-2 alkyl; R8 is Hydrogen, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran, tet lahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, or C4-6 cycloalkyl having one or two unsaturated bonds (here, cycloalkyl Kyl and heterocyclic moieties optionally contain 1 to 3 methyl groups or 1 ethyl group. ) and; However, a) when r is 1, n is 1 to 4: or b) when s is 1, n is 2 to 4: or c) When R8 is hydroxyl, r is 1, and n is 1 to 4, m is 2; or d) R8 is When hydroxyl, r or s is 0, the sum of n+m is 2 to 6; or e)-(CR9 R10)n-(C(O)O)r-(CR9R10)m-m in R8 is 0, r is 1, n is 1 to 4; or f) R8 is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tet lahydrofuran or 2-tetrahydrothiophene, when r or s is 0, n+m The sum is 1 to 6; or g) R8 is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetra Hydrofuran or 2-tetrahydrothiophene, when n is 1 to 4 and r is 1, m must be between 1 and 2; or h) R8 is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetra Hydrofuran or 2-tetrahydrothiophene, when n is 2 to 4 and s is 1, m must be between 1 and 2; X is YR2, halogen, nitro, NR6R7, or formylamine; Y is O or S(O)m′; m' is a number having a value of 0 to 2; R2 is -CH3 or -CH optionally substituted with one or more halogens 2CH3; R3 is H, CH3, CN, CH2F, CHF2, or CF3; R4 is H, C1- C4 alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH , -(CH2)qAr, or C1-6 alkyl, where (CH2)qAr or The C1-6 alkyl group is optionally F, Br, Cl, -NO2, -NR6R7 , -CO2R6, -OR6, -OC(O)R6, C(O)R6, CN, -C(O )-NR6R7, -C(S)-NR6R7, -NR6-C(O)-NR6R7, -NR6-C(S)-NR6R7, -NR6-C(O)-R6, -NR6-C( S) -R6, -NR6-C(O)-OR6, C(=NR6)-NR6R7, -C (=NCN)-NR6R7, -C(=NCN)-SR6, -NR6-C(=NC N) -SR6, -NR6-C (=NCN) -NR6R7, -C (=NR6R7) SR6, -NR6-S(O)2-R6, -S(O)m1-R6, -NR6SO2 -CF3, -NR6C(O)-C(O)-NR6R7, -NR6-C(O)-C (O)-OR6, 1-imidazolyl, or 1-(NR6)-2-imidazolyl substituted one or more times; Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, moly Ruphorino, 4- or 5-thiazolyl, triazolyl, 2- or 3-thienyl, 2 - thiafene or phenyl; R8 and R7 are independently hydrogen or optionally one or more halogens C1-4 alkyl substituted with: q is a number having a value of 0 to 2] and its pharmaceutically acceptable compounds salt. 2. 2. A compound according to claim 1, wherein the halogen is fluorine. 3. 3. The compound according to claim 1 or 2, wherein X is YR2. 4. 4. A compound according to claim 3, wherein Y is oxygen. 5. R5 is H, optionally substituted -(CH2)qAr, or optionally substituted 4. The compound according to claim 1, 2 or 3, which is C1-6 alkyl. 6. R1 is cyclopentyl, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemistry There are formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, -CF3, CH2 F, -CHF2, -CF2CHF2, CH2CF3, or -CH2CHF2 or The compound according to claims 1 to 5, which is CH3. 7. Claim 6 wherein R2 is methyl, -CF3, CF2H, or -CH2CHF2. Compounds described. 8. R4 is hydrogen, methyl or methoxy, R3 is CN, CHF2, CF3, or H. 8. The compound according to claim 7, which is H. 9. Claim 5, wherein R5 is H or optionally substituted -(CH2)qAr. Compounds listed. 10. Claim 8 or 9, wherein Ar is phenyl or substituted phenyl, and q is 1. Compounds listed. 11. Optionally present substituents include Br, C1, NO2, NR6R7, CO2 R6, -NH-C(=NCN)-SCH3, -NHC(O)-NR6R7, -C (O)R6R7, -NHC(O)CH3, -NH-(=NCN)-NR6R7, -NHC(O)C(O)-NR6R7, -NHSO2CH3, -S(O)mCH 3, -NHC(O)C(O)-OR6, -OR6, -CN, -C(=NR6)- NR6R7, -NHSO2CF3, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Number 11. The compound according to claim 10, which is selected from formulas, chemical formulas, tables, etc. 12. Optionally more present substituents include -NH2, -N(CH3)2, -S(O) mCH3, -NH-C(O)-CH3, -CO2CH3, OCH3, CO2H, NO2, -NH-C(=NCN)-SCH3, -NH-C(=NCN)-NH2 , -NH-C(O)-NH2, -NH-C(O)-C(O)-OR6, or NH 12. A compound according to claim 11 selected from -C(O)-C(O)-NR6R7. 13.4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imida 2. The compound according to claim 1, which is a zolidinone. 14.1-(4-aminobenzyl-4-(3-cyclopentyloxy-4-meth) 2. The compound according to claim 1, which is (xyphenyl)-2-imidazolidinone. 15. The above compound is 1-(4-aminobenzyl)-4-(3-cyclopentyl oxy-4-methoxyphenyl)-2-imidazolidinone; 1-(4-aminobenzene) (3-cyclobentyloxy-4-methoxyphenyl)-4-(3-cyclobentyloxy-4-methoxyphenyl)-3-methyl Tyl-2-imidazolidinone; 4-(3-cyclopentyloxy-4-methoxy phenyl)-1-(4-dimethylaminobenzyl)-2-imidazolidinone; 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidi Non: 1-(4-acetamidobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone; R-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidazolidinone, S-(+)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidazolidinone, S-(-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone; R-(+)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone; S-(-)-1-(4-benzylpyridyl)-4-(3-cyclopentyloxy -4-methoxyphenyl)-2-imidazolidinone; R-(+)-1-(4-beta cyclopentyloxy-4-methoxyphenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) -2-imidazolidinone; S-(-)-1-(4-acetamidobenzyl)-4 -(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidino R-(+)-1-(4-acetamidobenzyl)-4-(3-cyclopentyl S-(-)-1- (4-oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxy phenyl)-2-imidazolidinone: R-(+)-1-(4-oxamidobenzi )-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imida Zolidinone; R-(+)-1-(4-formamidobenzyl)-4-(3-cyclo Lopentyloxy-4-methoxyphenyl)-2-imidazolidinone; S-(- )-1-(4-formamidobenzyl)-4-(3-cyclopentyloxy-4 -methoxyphenyl)-2-imidazolidinone: 1-(4-acetamido-3- pyridylmethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) -2-imidazolidinone; S-(-)-4-(3-cyclopentyloxy-4- methoxyphenyl)-1-(2,4-diaminobenzyl)-2-imidazolidino S-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)- 1-(2,4-diacetamidobenzyl)-2-imidazolidinone; R-(+) -4-(3-cyclobentyloxy-4-methoxyphenyl)-1-(2,4- diaminobenzyl)-2-imidazolidinone; or R-(+)-4-(3-cyclo Lopentyloxy-4-methoxyphenyl)-1-(2,4-diacetamidobe 2. A compound according to claim 1, wherein the compound is selected from the group consisting of (imidazolidinone)-2-imidazolidinone. 16. Inhibition of tumor necrosis factor (TNF) production in animals in need of it 2. A method for treating such animals, comprising the use of an effective amount of the compound according to claim 1 to inhibit TNF production. A method consisting of administering something. 17. 17. The method according to claim 16, wherein X is YR2 and all halogens are fluorine. . 18. Y is oxygen, R5 is H, optionally substituted -(CH2)qAr, or optionally substituted C1-6 alkyl. 19. R1 is cyclopentyl, CH3, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or halo 19. The method according to claim 18, wherein substituted alkyl; R2 is methyl or halo-substituted alkyl. . 20. q is 1, Ar is -NH2, -N(CH3)2, -S(O)mC as desired H3, -NH-C(O)CH3, NHC(O)NH2, CO2CH3, OCH3 , NO2, -NHC(=NCN)NH2, -NHC-(=NCN)SCH3, - NHC(O)-C(O)-OCH3, -NHC(O)-C(O)-NH2 or C 20. The method of claim 19, wherein OOCH3 is substituted. 21. The above compound is 1-(4-aminobenzyl)-4-(3-cyclopentyl Oxy-4-methoxyphenyl)-2-imidazolidinone: 1-(4-aminobenzene) cyclopentyloxy-4-methoxyphenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methoxyphenyl Tyl-2-imidazolidinone; 4-(3-cyclopentyloxy-4-methoxy phenyl)-1-(4-dimethylaminobenzyl)-2-imidazolidinone; 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidi Non; 1-(4-acetamidobenzyl)-4-(3-cyclobentyloxy- 4-methoxyphenyl)-2-imidazolidinone; R-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidazolidinone, S-(+)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidazolidinone, S-(-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone; R-(+)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-imidazolidinone: S-(-)-1-(4-benzylpyridyl)-4-(3-cyclopentyloxy -4-methoxyphenyl)-2-imidazolidinone; R-(+)-1-(4-beta cyclopentyloxy-4-methoxyphenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) -2-imidazolidinone; S-(-)-1-(4-acetamidobenzyl)-4 -(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidino R-(+)-1-(4-acetamidobenzyl)-4-(3-cyclopentyl S-(-)-1- (4-oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxy phenyl)-2-imidazolidinone; R-(+)-1-(4-oxamidobenzi )-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imida Zolidinone; R-(+)-1-(4-formamidobenzyl)-4-(3-cyclo Lopentyloxy-4-methoxyphenyl)-2-imidazolidinone; S-(- )-1-(4-formamidobenzyl)-4-(3-cyclopentyloxy-4 -methoxyphenyl)-2-imidazolidinone; 1-(4-acetamido-3- pyridylmethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) -2-imidazolidinone; S-(-)-4-(3-cyclopentyloxy-4- methoxyphenyl)-1-(2,4-diaminobenzyl)-2-imidazolidino S-(-)-4-(3-cyclopentyloxy-4-methoxyphenyl)- 1-(2,4-diacetamidobenzyl)-2-imidazolidinone; R-(+) -4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4- diaminobenzyl)-2-imidazolidinone; or R-(+)-4-(3-cyclo Lopentyloxy-4-methoxyphenyl)-1-(2,4-diacetamidobe 17. The method according to claim 16, wherein the method is selected from 2-imidazolidinones (imidazolidinones). 22. Inhibition of TNF can cause septic shock, endotoxic shock, and gram-negative bacterial septicemia. 17. The method of claim 16, wherein the method mediates the disease state of blood loss or toxic shock syndrome. 23. Inhibition of TNF may improve cachexia associated with AIDS, cachexia associated with cancer, and acute immunity. syndrome (AIDS), AIDS-related syndrome (ARC), or HIV infection or infection by a virus selected from the group consisting of influenza or CMV; 17. The method of claim 16, wherein the method mediates other disease conditions associated with. 24. Inhibition of TNF has been linked to adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, and chronic pulmonary inflammatory disease. disease states such as necrotizing colitis, necrotizing colitis, bone resorption, or graft-versus-host reaction. The method according to claim 16. 25. An effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition containing. 26. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) [In the formula, R1 is -CH2-C3 ring alkyl, -CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, trahydrofuran, cyclopentenyl, optionally with one or more fluorine Substituted -C1-7 alkyl, -(CH2)2-4OH, -(CH2)n-C (O)O(CH2)m-CH3, -(CH2)p-O-(CH2)mCH3 , all of which are optionally substituted with 1 to 3 methyl groups or 1 ethyl group. m may be a number having a value of 0 to 2; n is a number having a value of 1 to 3; p is a number with a value of 2 or 3: X is YR2; Y is O or S; R2 is -CH3 or CH2 optionally substituted with one or more fluorine CH3; R3 is H, CH3, CN, CH2F, CHF2 or CF3; R4 is H, C1-4 Alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH, - (CH2)qAr, C1-6 alkyl; where Ar and C1-6 alkyl are May be unsubstituted or substituted with one or more of the following: : F, Br, Cl, NO2, NR6R7, CO2R6, -NH-C(=NCN)- SCH3, -NHC(O)NR6R7, -C(O)NR6R7, -NHC(O) CH3, -NH-(=NCN)-NR6R7, -NHC(O)C(O)NR6R 7, -NHSO2CH3, -S(O)mCH3, -NHC(O)C(O)-OR 6, -OR6, -CN, -C(=NR6)-NR6R7, -NHSO2CF3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼;A r is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, mole Horino, or phenyl; R6 and R7 are independently hydrogen or C1-4 alkyl; q has a value of 0 to 2; or a pharmaceutically acceptable salt thereof. 27. R1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CF3, CHF2, C1-7 Al yl, -C1-4alkylOH, or optionally 1 to 3 methyl groups or 1 27. The compound according to claim 26, which is a C4-C5 cyclic alkyl substituted with an ethyl group. 28. an effective amount of a compound according to claim 26 and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition containing. 29. A method of inhibiting PDEIV, comprising administering PDEIV to a mammal in need thereof. from administering an effective amount of the compound of claim 27 sufficient to inhibit IV. How to become. 30. Inhibition of PDEIV may be associated with asthma or other allergic or inflammatory disease conditions. 30. The method of claim 29, wherein the method mediates the 31. A method of treating asthma, comprising administering PDEIV to a mammal in need thereof. A method comprising administering an inhibiting effective amount of a compound according to claim 13 or 14. . 32. A method of inhibiting PDEIV, comprising: administering PDEIV to a mammal in need thereof; administering an effective amount of a compound according to claim 13, 14 or 15 to inhibit IV. A method consisting of 33. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is -(CR9R10) n-(C(O)O), -(CR9R10)m-R8, -(CR9R10)n-( C(O)NR6), -(CR9R10)m-R8, or -(CR9R10)n- (O)5-(CR9R10)m-R8 (where one alkyl moiety is optional) or may be substituted with more halogens); n is a number having a value of 0 to 4; m is a number having a value of 0 to 2; r is a number having a value of 0 or 1; s is a number having a value of 0 or 1; R9 and R10 are independently selected from hydrogen or C1-2 alkyl; R8 is water element, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran, tetra Hydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, or 1 or C4-6 cycloalkyl having two unsaturated bonds (here, cycloalkyl and heterocyclic moieties optionally substituted with 1 to 3 methyl groups or 1 ethyl group. ) and; However, a) when r is 1, n is 1 to 4; or b) when s is 1, n is 2 to 4; or c) When R8 is hydroxyl, r is 1, and n is 1 to 4, m is 2; or d) R8 is When hydroxyl, r or s is 0, the sum of n+m is 2-6: or e)-(CR9 R10)n-(C(O)O)r-(CR9R10)m-m in R8 is 0, r is 1, n is 1 to 4: or f) R8 is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tet lahydrofuran or 2-tetrahydrothiophene, when r or s is 0, n+m The sum is 1 to 6; or g) R8 is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetra Hydrofuran or 2-tetrahydrothiophene, when n is 1 to 4 and r is 1, m is 1-2. must be; or h) R8 is 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetra Hydrofuran or 2-tetrahydrothiophene, when n is 2 to 4 and s is 1, m must be between 1 and 2; X is YR2, halogen, nitro, NR6R7, or formylamine; Y is O or S(O)m′; m' is a number having a value of 0 to 2; R2 is -CH3 optionally substituted with one or more halogens or -CH2CH3; R3 is H, CH3, CN, CH2F, CHF2, or CF3; R4 is H, C1- C4 alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH , -(CH2)qAr, or C1-6 alkyl, where (CH2)qAr or The C1-6 alkyl group is optionally F, Br, C1, -NO2, -NR6R7, -CO2R8-, -OR6, -OC(O)R6, C(O)R6, CN, -C(O )-NR6R7, -C(S)-NR6R7, -NR6-C(O)-NR6R7, -NR6-C(S)-NR6R7, -NR6-C(O)-R6, -NR6-C( S) -R6, -NR6-C(O)-OR6, C(=NR6)-NR6R7, -C (=NCN)-NR6R7, -C(=NCN)-SR6, -NR6-C(=NC N) -SR6, -NR6-C (=NCN) -NR6R7, -C (=NR6R7) SR6, -NR6-S(O)2-R6, -S(O)m'-R6, -NR6SO2 -CF3, -NR6C(O)-C(O)-NR6R7, -NR6-C(O)-C (O)-OR6, 1-imidazolyl, or 1-(NR6)-2-imidazolyl substituted one or more times; Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, moly Ruphorino, 4- or 5-thiazolyl, thiazolyl, 2- or 3-thienyl, 2- Thiafene or phenyl; R6 and R7 are independently hydrogen or optionally one or more halogens C1-4 alkyl substituted with; q is a number having a value of 0 to 2] and its pharmaceutically acceptable compounds A method for producing salt comprising: A. Formula (5) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(5) [In the formula, R1, X, R3, R4, R8 has the same meaning as formula (I), and R5 is H. After oxidation to oxime, the oxime is reduced to give the corresponding formula (5) [wherein R5 is hydroxyl]; then by cyclization using a base and a solvent. Therefore, a compound represented by formula (I) [wherein R5 is H and R3 is other than CN] Do you get: Or B. It is represented by the above formula (5) [wherein R5 is H] The resulting iminium compound is reacted with an aldehyde to form an acid salt. The salt is reduced to form a compound of formula (5) [wherein R3 is other than CN and R5 is other than H] and then by cyclization with a base, a compound of formula (I) [wherein R3 is CN or more] is obtained. outside, R5 is other than H, X is Br, I, NO2, amine, formylamine, or S( O) obtain a compound represented by m′, m is 1 or 2; or C. Formula (5) as above [wherein R4 and R5 are H and R3 is CONH2] ] After cyclizing the compound represented by the formula (I ) [wherein R4 and R5 are H and R3 is CN]; Or D. Formula (5) [wherein R4 and R5 are H and R3 is CONH2] React the appropriately protected amino moiety shown to convert the R3 amide into a nitrile. dehydration and protection of the amine functionality to form a compound of formula (5) [wherein R4 and R5 are H, R 3 is CN], and then cyclized to obtain a compound of the formula (I) [wherein R4 is hydrogen, R5 is other than H, and R3 is CN]; or ,E. The deprotected amine functional group of formula (5) produced in step E above was homologated. After that, cyclization is performed to form a compound of the formula (I) [in air, R4 is hydrogen, R5 is other than H, and R3 is CN] ]; or, F. Formula (6) ▲There are mathematical formulas, chemical formulas, tables, etc.▼The compound shown in (6) is captured in an acid in a solvent. A compound of the formula (I) [wherein R5 is H and R3 is CN or less] is reacted with phosgene in the presence of a or obtain a compound represented by G. Compound represented by formula (6) of N,N'-carbonyldiimidazole or 1,1,-carbonyldiimidazole in a solvent. -1,2,4-triazole to form the formula (5) [wherein R5 is H and R3 is H.CN]; Formula (6) [wherein, R4 is H, R3 is CONH2] after reacting by cyclization, By amide dehydration, formula (I) [wherein R4 and R5 are H and R3 is CN] or to obtain a compound represented by I. Formula (6) as above [where α−N H is protected, R5 is H, R3 is not CN] is reacted. After that, imine formation is performed using a suitable aldehyde, and then imine or imini By reducing the um salt and deprotecting α-NH, the formula (6) [wherein R5 is other than H, R 3 is other than CN] After obtaining the compound represented by; in any of the above steps F to H Thus, a process consisting of obtaining a compound of formula (I). 34. formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(5) [In the formula, R1, X, R3, R4, R5 and R8 have the same meanings as in formula (I). 35. (2R)-1-benzyloxycarbonylamino-2-(3-cyclopene methyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonyl Ruamino]ethane; or (2S)-1-benzyloxycarbonylamino-2-(3-cyclopentyl xy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamine 34. The compound according to claim 33, which is ethane. 36. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(6) [In the formula, X, R1, R4, R3, and R5 has the same meaning as formula (I)].