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WO1992007567A1 - Composes d'imidazolidinone - Google Patents

Composes d'imidazolidinone Download PDF

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Publication number
WO1992007567A1
WO1992007567A1 PCT/US1991/008229 US9108229W WO9207567A1 WO 1992007567 A1 WO1992007567 A1 WO 1992007567A1 US 9108229 W US9108229 W US 9108229W WO 9207567 A1 WO9207567 A1 WO 9207567A1
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WIPO (PCT)
Prior art keywords
cyclopentyloxy
methoxyphenyl
imidazolidinone
formula
compound
Prior art date
Application number
PCT/US1991/008229
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English (en)
Inventor
Paul Elliot Bender
Siegfried Benjamin Christensen, Iv
Original Assignee
Smithkline Beecham Corporation
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Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to CA002095429A priority Critical patent/CA2095429A1/fr
Priority to JP4500935A priority patent/JPH06501708A/ja
Priority to KR1019930701375A priority patent/KR930703262A/ko
Publication of WO1992007567A1 publication Critical patent/WO1992007567A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing these compounds and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
  • TNF Tumor Necrosis Factor
  • Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
  • cAMP adenosine cyclic 3',5 ! - monophosphate
  • Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, pgs 17- 29, 1973).
  • adenylate cyclase is activated which converts Mg+2-ATP to cAMP at an accelerated rate.
  • Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil de-granulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
  • compounds that activate adenylate cyclase or inhibit PDE should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
  • PDEs cyclic nucleotide phosphodiesterases
  • TNF Tumor Necrosis Factor
  • rheumatoid arthritis rheumatoid spondylitis
  • osteoarthritis gouty arthritis and other arthritic conditions
  • sepsis septic shock, endotoxic shock, gram negative sepsis
  • toxic shock syndrome adult respiratory distress syndrome
  • cerebral malaria chronic pulmonary inflammatory disease
  • silicosis pulmonary sarcoisosis
  • bone resorption diseases reperfusion injury, graft vs.
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.
  • AIDS cachexia secondary to infection or malignancy
  • cachexia secondary to acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis or pyresis.
  • HIV Human Immunodeficiency Virus
  • Monocytes, macrophages, and related cells have also been implicated in maintenance of the HIV infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al.. The Immunopath ⁇ genesis of HTV Infection, Advances in Immunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown.to activate HIV replication in monocytes and/or macrophages [See Poli, et al.. Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalia virus
  • influenza virus influenza virus
  • herpes virus herpes virus
  • This invention relates to the novel compounds of Formula (I), as shown below, having Tumor Necrosis Factor inhibitory activity.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I).
  • This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
  • This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HTV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).
  • HTV human immunodeficiency virus
  • the compounds of Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or
  • viruses contemplated for treatment herein are those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I).
  • viruses include, but are not limited to; HIV-1, HIV-2 and HIV-3 as noted above, Cytomegalovirus (CMV), Influenza, and the Herpes family of viruses, such as Herpes Simplex & Herpes Zoster.
  • This invention also relates to the novel compounds and pharmaceutical compositions, of Formula (la), a sub-genus of the compounds of Formula (I) having
  • TNF activity but also are useful in the mediation or inhibition of phosphodiesterase IV
  • the invention also relates to a method of inhibiting phosphodiesterase IV in a mammal, including humans, which comprises administering to an mammal in need thereof an effective amount of a compound of Formula (la), as shown below.
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal in need thereof, an effective amount of a compound of Formula (la).
  • the invention also provides a method for the treatment of asthma which comprises administering to an a mammal in need thereof, an effective amount of a compound of Formula (la).
  • R! is - (CRoRlO)n- (C(0)0) r -(CR9 l ⁇ )m-R8- -(CRoRl ⁇ )n- (C(0)NR6)r-(CR9RlO)m-R8, or- (CR9Rio) n - (0) s -(CR9Ri ⁇ )m-R8 wherein the alkyl moieties may be optionally substituted with one or 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 Rio are independently selected from hydrogen or a Ci-2 alkyl
  • R8 is hydrogen, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, or a C .-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;
  • SUBSTITUTE SHEET 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) when Rs is hydroxyl, r is 1, and n is 1 to 4, then m is 2; or d) when R ⁇ is hydroxyl, and r or s is 0, then the sum of n + m is 2 to 6; or e) when m is 0, r is 1 in -(CR9R ⁇ o) n - (C(0)0)r -(CR9R ⁇ o)m-R8- then n is 1 to 4; or f) when Rg is a 2-tetrahydropyran or 2-tetrahydrothiopyran, 2-tetrahydrofuran or
  • 2-tetrahydrothiophene n is 1 to 4, and r is 1, then m must be 1 to 2; or h) when _ is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2-tetrahydrothiophene, n is 2 to 4, and s is 1, then m must be 1 to 2;
  • X is YR2, halogen, nitro, NR6R7, or formyl amine;
  • Y is O or S(0) m -;
  • m 1 is a number having a value of 0 to 2;
  • R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;
  • 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 Cj.g alkyl wherein the (CH2) q Ar or C g alkyl group is optionally substituted one or more times by F, Br, Cl, -NO2, -NR5R7,
  • Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, 4- or 5- thiazolyl, triazolyl, 2- or 3- thienyl, 2-thiaphene, or phenyl; R ⁇ and R7 are independently hydrogen, or C1. alkyl optionally substituted by one or more halogens; q is a number having a value of 0 to 2; and the pharmaceutically acceptable salts thereof.
  • Rl is -CH2-C3 cyclic alkyl, -CH2-C5-6 cyclic alkyl, C4-6 cyclic alkyl, tetrahydrofuran, cyclopentenyl,-Ci-7 alkyl optionally substituted by 1 or more fluorines,
  • m is a number having a value of 0 to 2
  • n is a number having a value of 1 to 3
  • p is a number having a value of 2 or 3;
  • R2 is -CH3 or CH2CH3 optionally substituted by 1 or more fluorines;
  • R3 is H, CH3, CN, CH2F, CHF2 or CF3;
  • R4 is H, Cl-4 alkyl, OH, OCH3, OCH2CH3, or OAc;
  • R5 is H, OH, -(CH2)q Ar, Ci-6 alkyl; wherein Ar and Cl-6 alkyl may be unsubstituted or substituted by one or more of the following:
  • Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, or phenyl;
  • R and R7 are independently hydrogen, or C ⁇ _4 alkyl ; q is a number having a value of 0 to 2; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention is the novel compounds of
  • Formula (H) also a sub-genus of Formula (I) having activity as an inhibitor of TNF.
  • Ri, n, m, r, s, q, R8, R3 , R4 , R5, Ar, Rg, and R7 are as defined for
  • Xl is halogen, nitro, NR6R7, or formyl amine; and pharmaceutically acceptable salts thereof.
  • Rl for the compounds of Formula (I) and (II) is an alkyl substituted by 1 or more halogens
  • the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines, more preferably 1 or more times by fluorine.
  • the most preferred chain length is one or two carbons, and most preferred is a -CF3, CH2F, -CHF2, -CF2CHF2, CH2CF3, or -CH2CHF2 moiety. More preferred are those compounds in which Ri is cyclopentyl,
  • H THhe Ri te.rm ⁇ 0 contains the moiety (CR9R10) wherein the R9 and Rio are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR9R ⁇ o)n or (CR9R ⁇ o)mJ each repeating methylene unit is independent of the other, e.g. (CR9R ⁇ o)n wherein n is 2 can be -CH2CH(CH3)-, for instance.
  • the individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can be substituted by fluorine independent of each other to yield, for instance, the preferred Rl substitutions, as noted above.
  • Preferred Ri groups for the compounds of Formula (la) are -CH2-C3 cyclo- alkyl, -CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, tetrahydrofuran, cyclopentenyl, -
  • Rl is a C 1 - 7 alkyl optionally substituted by fluorine the more preferred groups are -CF3, - CH2F, CHF2, -CF2CHF2, CH2CF3, or -CH2CHF2.
  • Preferred X groups for both Formulas (I) and (la) are those wherein X is
  • YR2 is oxygen.
  • Preferred R2 groups for the compounds of both Formula (I) and (II), and (la) where applicable is a Cl-2 alkyl optionally substituted by 1 or more halogens.
  • halogens atoms arc prcferably fluorine and chlorine, more preferably fluorine.
  • More preferred R2 groups those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Cl-2 alkyl, such as a -CF3, CHF2, or -CH2CHF2 moiety. Most preferred are the CHF2 and CH3 moieties.
  • Preferred R5 groups are the optionally substituted -(CH2)qAr moiety, wherein q is preferably 1, or an optionally substituted Ci-6 alkyl, more preferably when R5 is an alkyl and more preferred when R5 is a C3-5 alkyl .
  • the Ar moiety is phenyl.
  • R4 substituents for the compounds of Formulas (I), (la) and QI) are H, Cl-2 alkyl or OCH3.
  • Ri is -CH2-C3 cyclic alkyl, -CH2-C5-6 cyclic alkyl, C4-6 cyclic alkyl, tetrahydrofuran, cyclopentenyl, -Cl-7 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH;
  • R2 is methyl or fluro substituted alkyl
  • R3 is CN, CHF2, CF3, or H;
  • R4 is H, Ci- 4 alkyl or OCH3;
  • Y is oxygen.
  • More preferred compounds are those Ri, R2, and Y are as described above, and R5 is Ar is optionally substituted -(CH2)qAr, q is 1 and Ar is phenyl; R3, is H, CN, methyl or CHF2 and R4 is H or Ci-4 alkyl.
  • Rl is cylopentyl, methyl or CF2H
  • R3 is H
  • CN or CH3 R4 is hydrogen
  • X is YR2
  • Y is oxygen
  • R2 is CF2H or methyl
  • l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- imidazolidinone l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-2- imidazolidinone;
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.
  • Ci. ⁇ alkyl or “alkyl” groups as used herein is meant to include both straight or branched chain radicals of 1 to 7 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkenyl as used herein is meant to include, but not limited to vinyl, 1-pr ⁇ penyl, 2-propenyl, 2-propinyl or 3-methyl-2-propenyl.
  • cycloalkyl or "cycloalkyl alkyl” as used herein is meant to include groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl orcyclohexyl.
  • aryl or “aralkyl”, unless specified otherwise, as used herein is meant an aromatic ring or ring system of 6-10 carbon atoms, preferably monocycle, such as phenyl, benzyl, phenethyl or naphthyl.
  • halo as used herein is meant all halogens, i.e., chloro, fluoro, bromo and iodo.
  • SUBSTITUTE SHEET a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL- 1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcription level, of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL- 1 or TNF levels as a postranslational event.
  • TNF mediated disease or disease states any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1, or IL-6.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • TNF- ⁇ also known as cachectin
  • both TNF- ⁇ and TNF- ⁇ are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
  • TNF- ⁇ is inhibited.
  • cytokine any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in the immune or inflammatory response.
  • a cytokine includes, but is not limited to monokines and lymphokines regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and ⁇ - lymphocytes.
  • Lymphokines are generally referred to as being produced by lymphoctye cells. Examples of cytokines for the present invention include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6
  • EL-6 Interleukin-8
  • TNF- ⁇ Tumor Necrosis Factor-alpha
  • TNF- ⁇ Tumor Necrosis Factor beta
  • a cytokine contemplated by the present invention, for use in the treatment of a HIV-infected human, must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HTV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • the cytokine specifically desired to be inhibited is TNF- ⁇ .
  • All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes in a human in need thereof. All of the compoimds of Formula (la) are useful in the method of inhibiting PDE IV and in treatment of disease states mediated thereby.
  • the mammal is preferably a human, afflicted with a disease state selected from endotoxic shock, adult respiratory distress syndrome, cachexia secondary to infection or malignancy, cachexia secondary to acute immune deficiency syndrome (AIDS), AIDS, reperfiision injury, pulmonary inflammatory disease, cerebral malaria, graft vs. host reaction, bone resorption diseases, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, eczema, psoriasis, sunburn, conjunctivitis, or pyresis.
  • a disease state selected from endotoxic shock, adult respiratory distress syndrome, cachexia secondary to infection or malignancy, cachexia secondary to acute immune deficiency syndrome (AIDS), AIDS, reperfiision injury, pulmonary inflammatory disease, cerebral malaria, graft vs. host reaction, bone resorption diseases, rheumatoid arthritis, rheumatoi
  • Ri represents Ri as defined in relation to a compound of Formula (I) or a group convertible to Ri
  • X represents X as defined in relation to a compound of Formula (I) or a group convertible to X, with trimethylsilyl cyanide and a suitable catalyst, such as anhydrous zinc iodide, either neat or in the presence of a suitable non-reacting solvent, such as a halocarbon, at ambient temperature under an inert atmosphere.
  • a suitable catalyst such as anhydrous zinc iodide
  • the solvent if present, is removed and the residue is reacted with the amine (NH2R4) , in which R4 represents R4 as defined in relation to a compound of Formula (0 or a group convertible to R4, in a suitable solvent, such as an alcohol, at about 40°C under an inert atmosphere in a sealed vessel to provide a compound of the Formula (3)
  • SUBSTITUTE SHEET which may be converted to an appropriate acid salt form, such as a hydrochloride.
  • compounds of Formula (3) may be prepared by a Strecker synthesis in which a compound of Formula (2) is reacted with sodium cyanide and the amine as its hydrochloride salt in an appropriate non-reacting solvent, such as an alcohol, at ambient temperature.
  • a suitable alkyl or aralkyl haloformate such as ethyl, benzyl or menthyl chloroformate
  • a non-reacting solvent such as methylene chloride
  • an appropriate acid scavenger such as saturated aqueous sodium bicarbonate
  • these compounds may be obtained by reduction of the nitrile of a compound of the Formula (3) with an appropriate reductant, such as lithium aluminum hydride in a non-reacting solvent, such as ethyl ether, THF, or hydrogen in a non-reacting solvent, such as ethyl ether, THF, or hydrogen in a non-reacting solvent, such as ethyl ether, THF, or hydrogen in a non-reacting solvent, such as ethyl ether, THF, or hydrogen in
  • TITUTE SHEET the presence of a suitable catalyst, such as a noble metal or Raney nickel, in an alcoholic solvent to provide a diamine of the Formula (6) in which R5 is H
  • a solvent such as toluene
  • R5 is OH
  • compounds of Formula (I) wherein R5 is OH are prepared by oxidation of the corresponding Formula (5) compound where R5 is H to an aldehyde oxime with, e.g., sodium tungstate and hydrogen peroxide at 0°C followed by reduction of the oxime intermediate with, e.g., sodium cyanoborohydride in presence of acid to give the corresponding Formula (5) compound wherein R5 is hydroxyl.
  • Formula (2) compounds where R3 is CF3 or CHF2 are obtained by treatment of the Formula (2a) compound with a metalling agent at -78°C followed by trifluoroacetic acid or difluoroacetic acid by the method of Nad et al., Izvest, (1959) page formula (2a) compound with a metalling agent at -78 °C followed by trifluroacetic
  • Formula (2) compound where R3 is CH2F are obtained by treatment of the Formula (2) compounds where R3 is CH3 according to the method of Rozen et al., Synthesis (6) 665, (1985).
  • Formula (2) compounds where X is R2S and R3 is H are prepared by alkylation of 3-hydroxy 4-nitrobenzaldehyde with the desired Ri-halide, where Rl is as described above, followed by treatment with sodium SR2 in DMF.
  • Formula (2) compounds wherein X is F or Cl and R3 is H are prepared by alkylation of the (2-fluoro or chloro)-5-methyl phenol with the desired Ri-halide, followed by formation of the benzyl bromide with N-bromo succinimide and subsequent transformation to the required aldehyde with 2-nitropropane and sodium ethoxide in ethanol.
  • Novel Formula (2) compounds where R3 is CH3 can be made by addition of a methyl metal to the Formula (2) compounds where R3 is hydrogen, followed by oxidation, e.g. with pyridinium dichromate.
  • Ri and/or R2 are protecting groups, such as benzyl or methoxymethyl, ethoxymethyl or acetonide, and are removed by methods well known in the art and subsequently alkylated as described above for the Formula (2) compounds.
  • X is amine, monoakylamine or formylamine
  • such alkylation is performed on Formula (2) or protected R1/R2
  • ET R5 is other than H
  • reaction of an amine of the Formula (5) wherein R5 is H with a suitably substituted aryl or alkyl aldehyde in a suitable solvent, such as chloroform at reflux temperature, followed by suitable acid salt formation, such as a hydrochloride or acetate, and reduction of the iminium salt with, for example, sodium cyanoborohydride in methanol provides a compound of the Formula (5) in which R3 is other than CN and R5 is other than H; alternatively nobel metal catalytic reduction of the imine or iminium function may also be employed.
  • cyclization as described above provides compounds of Formula (I) in which R5 is other than H.
  • certain compounds of Formula (5) which contain a base-sensitive functionality in R5, such as a nitro group conversion to a base stable functionality, such as an amine, is conducted prior to cyclization; such amines may then be functionalized as desired.
  • TUTE SHEET a compound of Formula (8) wherein R3 is COORs and R9 is H; this COORg group of such a compound may be transformed either at this stage or at a later stage to a CONH2 group by any of the standard techniques well known to those skilled in the art.
  • a compound of Formula (8) wherein R3 is COOR8 and R9 is H may also be obtained by reaction of a compound of Formula (8) wherein R3 and R9 are H with a metal hydride, such as sodium or potassium hydride, at ambient or elevated temperature under an inert atmosphere in the presence of an alkyl or aryl dicarbonate, for example methyl dicarbonate.
  • a metal hydride such as sodium or potassium hydride
  • a compound of Formula (2) wherein R3 is H may be homologated to a compound of the Formula (7) wherein Xi is COOR4 by any number of known processes, such as reaction with a methyl methyl sulfinylmethyl sulfide and a base, such as sodium hydroxide, followed by treatment with, for example, alcoholic acid; generation of an anion of a compound of Formula (7) wherein Xi is COOR4 with a suitable base, followed by reaction with, for example, cyanogen chloride or 2- chlorobenzyl thiocyanate, provides a compound of Formula (8) wherein R3 is COOR4 and R9 is H.
  • Nitrile reduction as described above provides a compound of the Formula (5) wherein R4 and R- are H and R3 is CONH2. Cyclization of the ring and dehydration of the R3 amide to a nitrile then provides a compound of the Formula I wherein R4 and R5 are H and R3 is
  • ami o moiety of a compound of the Formula (5) wherein R4 and R5 are H and R3 is CONH2 may be suitably protected, e.g. with a carbobenzyloxy or t-butyloxycarbonyl group, prepared as known in the art, dehydration
  • Compounds of Formula (I) may be prepared from other Formula (T) compounds and functionally modified, as known in the art, e.g. where R4 is O-acetate, by acetylation from R4 as hydroxyl.
  • R5 is (CH2)qAr or C2-6 alkyl substituted by: NO2 from the NH2 derivative by oxidation, e.g. with a peracid; C(0)NR6R7 from the -CO2CH3 by heating with or without catalytic metal cyanide, e.g.
  • methyloxalyl chloride and a base such as triethylamine
  • -NR6C(0)-C(0)-NR6R7 from -NR6C(0)-C(0)-OR6 with HNR6R7
  • the final compound is made from the -S-Ci-6 alkyl moiety by oxidizing the intermediate -S-alkyl product with, e.g. a peracid such as 3-chloroperbenzoic acid, under conditions well known those skilled in the art, after the CONH2 moiety in synthesis step (c) is dehydrated to the cyano moiety.
  • a peracid such as 3-chloroperbenzoic acid
  • compounds of Formula CO wherein X is Br or I may be prepared using the techniques of PCT/US91/04795 on a similarly deprotected amine, diazotization of the amine, and diazonium displacement; or for compounds of Formula (I) wherein X is NO2 may be prepared using the techniques of PCT/US91/04795 on a similarly deprotected amine by oxidation of the amine to the nitro group.
  • a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by TNF production by such human's cell, such as but not limited to monocytes and/or macrophages, especially caused by excessive or unregulated TNF production.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit TNF production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state.
  • Abnormal levels of TNF constitute levels of 1) free (not cell bound) TNF, greater than or equal to 1 picogram per ml; 2) any cell associated TNF; or 3) the presence of TNF mRNA above basal levels in cells or tissues in which TNF is produced.
  • the compounds of Formula (la), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic treatment of any disease state, in a human, or other mammal, which is mediated by inhibition of PDE IV, such as but not limited to asthma, allergic or inflammatory diseases.
  • the compounds of Formula (la) are administered in an amount sufficient to treat such a disease in a human or other mammal.
  • the compounds of Formula (I) may be used in the treatment of any disease states mediated by excessive or unregulated TNF production, such as but not limited to rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfiision injury, graft vs.
  • TNF production such as but not limited to rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
  • sepsis septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silico
  • AIDS cytomegalia virus
  • influenza virus a virus that causes fever and myalgias due to infection
  • AIDS cachexia secondary to infection or malignancy
  • cachexia secondary to acquired immune deficiency syndrome
  • AIDS secondary to acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, AIDS and other viral infections, such as cytomegalia virus (CMV), influenza virus, and the herpes family of viruses.
  • CMV cytomegalia virus
  • the compounds of Formula (I) may also be used topically as well in the treatment or prophylaxis of inflammatory topical disease states mediated or exacerbated by excessive TNF production respectively, such as for rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • inflammatory topical disease states mediated or exacerbated by excessive TNF production respectively, such as for rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis
  • the compounds of Formula (I) may also be used in association with the veterinary field for treatment of TNF mediated diseases such as viral infections.
  • viruses include but are not limited to, feline immunodeficiency virus (FTV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • FTV feline immunodeficiency virus
  • retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the present invention attributes many of the biological disease states attributable to interleukin-1 (IL-1) activity as being attributable to that of TNF activity as well.
  • IL-1 interleukin-1
  • a comprehensive listing of IL-1 activities can be found in Dinarello, J. Clinical Immunology.5 (5), 287-297 (1985). It should be noted that some of these effects have been described by others as indirect effects of IL-1.
  • IL-1 The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
  • SUBSTITUTE SHEET considered appropriate disease states of TNF activity and hence compounds of Formula (I) are also useful in their treatment as well, and the use of the compounds of Formula (I) should not be considered solely limited to the specifically described TNF mediated disease states herein.
  • the compounds of Formula (I) should be efficacious in an B -1 mediated disease state as TNF and B -1 act in a synergistic manner. TNF as well mediates the release, in some instances, of IL-1, therefore a reduction in the levels of TNF may be useful in the treatment of a disease state wherein IL-1 is a major component.
  • the present invention relates therefore, to an effective, TNF production inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is useful in treating, prophylactically or therapeutically, any disease state in a human which is exacerbated or caused by excessive or unregulated IL-1 production, i.e., where IL-1 is a major component, by such human's monocytes and/or macrophages.
  • an initial treatment regimen can be copied from that known to be effective in interfering with TNF activity for other TNF mediated disease states by the compounds of Formula (1).
  • Treated individuals will be regularly checked for T cell numbers and T4 T8 ratios and/or measures of viremia such as levels of reverse transcriptase or viral proteins, and/or for progression of ⁇ ionokine-mediated disease associated problems such as cachexia or muscle degeneration.
  • the amount of the monokine activity interfering agent administered is increased, e.g., by fifty percent per week.
  • the compounds of Formula (I) may be administered orally (when active by this route), topically, parenterally or by inhalation in conventional dosage forms prepared by combining such agent with standard pharmaceutical carriers according to conventional procedures in an amount sufficient to produce the desired therapeutic activity for treatment of a TNF mediated disease state or in the case of a compound of Formula (la) in their use as a PDE IV inhibitor.
  • a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition,
  • composition of the present invention will comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the compounds of Formula (I) are administered in conventional dosage forms prepared by combining a compound of Formula (I) in an
  • SHEET amount sufficient.to produce TNF production inhibiting activity, respectively, with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Compounds of Formula (J) and their pharmaceutically acceptable salts (when possible), some of which are orally active, can be employed in a wide variety of pharmaceutical forms.
  • the preparation of a pharmaceutically acceptable salt will be determined by the nature of the compound itself, and can be prepared by conventional techniques readily available to one skilled in the art. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • a syrup emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • the amount of a compound of Formula (I) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.
  • systemic administration oral, intravenous, intraperitoneal and intramuscular administration.
  • topical administration non-systemic administration and includes the application of a compound externally to the epidermis, to the buccal cavity
  • parenteral' as used herein includes intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • the daily dosage regimen for inhibition of TNF production, via parenteral administration is suitably about 0.001 mg Kg to 40 mg/Kg, for example about 0.001 mg/Kg to 40 mg Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the compounds of Formula (I) may be administered orally.
  • Each dosage unit for oral administration contains suitably from 1 mg to 100 mg, and preferably from 10 mg to 30 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for oral administration is suitably about .001 mg/kg to lOOmg kg, preferably 0.01 mg Kg to 40 mg Kg, of a compound of Formula
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.
  • the compounds of Formula (I) may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily dosage regimen for a compound of Formula (I) for intranasal administration and oral inhalation is suitably about 10 to about 1200 mg.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
  • the compounds of Formula (I) may also be administered topically.
  • the compounds of Formula (I) may be administered topically in the treatment or prophylaxis of inflammatory topical disease states mediated or exacerbated by excessive TNF production, respectively, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • a suitable dose of a TNF production inhibiting compound of Formula (T) is from about .01 mg to about 100 mg of base for topical administration, the most preferred dosage being about .01 mg to about 30 mg, for example, .003 mg to 10 mg administered two or three times daily.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1 % to 1% w/w of the formulation.
  • the formulations of the present invention comprise an active ingredient together with one or more acceptable carriers) therefor and optionally any other therapeutic ingredients).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C.for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • BSTITUTE SHEET Lotions include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation Of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi- solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as prolylene glycol or macrogols.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient, with which it is to be combined, the route of administration and other well- known variables.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • 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 can be determined by the protocol as described in Badger et al.. EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.
  • the compounds of Formula ( ) displayed an IC50 value of 0.01- to about >3.0 for Inhibition of LPS-Induced Human Monocyte TNF Production in the above noted assay.
  • 4-(3-cyclopentyloxy-4- methoxyphenyl)-2-imidazolidinone demonstrated an IC50 of .2 ⁇ M in the in-vitro assay system described above.
  • 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone demonstrated a positive in-vivo response of about 57 % reduction in serum levels of TNF which were induced by the injection of endotoxin.
  • TNF tumor necrosis factor
  • Formula (la) can be determined using a battery of five distinct PDE isozymes.
  • the tissues used as sources of the different isozymes are as follows: 1) PDE la, canine trachealis; 2) PDE lb, porcine aorta; 3) PDE Ic, guinea-pig heart; 4) PDE HI, guinea-pig heart; and 5) PDE IV, human monocyte.
  • PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques (Toiphy and Cieslinski, Mol. Pharmacol.37:
  • PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography (White et al.. FASEB J. 4: A1987 1990).
  • Formula (la) range from 0.1 ⁇ M to 30 ⁇ M.
  • SUBSTITUTE SHEET B 2-Ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxy-phenvDacetonit ⁇ ile.
  • 2-Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile hydrochloride (2.83 g, 10 mmol) was suspended in saturated aqueous sodium bicarbonate (25 ml) and methylene chloride (25 ml) was added. The mixture was stirred vigorously under an argon atmosphere until all solid dissolved and then ethyl chloroformate (1.9 ml, 19.9 mmol) was added in one portion.
  • 4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane was accomplished with preparative HPLC conditions using a JY-100 chromatospac apparatus equipped with a 8cm x 100cm column packed with 1.8 kg YMC sperical silica gel (15-30 ⁇ ).
  • the mobile phase of 95:5 methylene chloride/ether eluted at a flow rate of 200 mL/min and a load of 13 g per run.
  • the total amount of mixed sample run was 51 g (54% 2R, 46% 2S).
  • TUTE SHEET imder an argon atmosphere for 1.5 h.
  • the mixture was diluted with ethyl acetate and the pH was adjusted to - 6 with ammonium chloride.
  • the aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed five times with water.
  • the organic extracts were dried (sodium sulfate) and evaporated. Purification by flash chromatography, eluting with 97:3 methylene chloride/methanol, provided a white solid (70 mg, 74%): m.p. 135-137°C. Analysis Calc.
  • HEET dimethylsulfoxide (5 mL) was treated with 10% sodium hydroxide (210 ⁇ L, 0.54 mmol) and stirred for 1 h under an argon atmosphere at 80-85°C.
  • the reaction mixture was cooled and extracted twice with ethyl acetate.
  • the organic extracts were washed 5 times with water, dried (potassium carbonate) and evaporated Purification by flash chromatography, first eluting with 7:3 ethyl acetate/hexanes, then a second column, eluting with 98.5:1.5 methylene chloride/methanol, provided a off-white solid (119 mg, 63%): m.p. 72-74 ⁇ Q
  • Acetic formic anhydride was prepared by heating a mixture of acetic anhydride (5.0 mL, 53 mmol) and formic acid (2.1 mL, 56 mmol) at 40-45°C for
  • Acetic formic anhydride was prepared by heating a mixture of acetic anhydride (5.0 mL, 53 mmol) and formic acid (2.1 mL, 56 mmol) at 40-45°C for 3 h.
  • EET mg 10.6 mmol
  • Addition of acetic acid (405 ⁇ L, 7.1 mmol) was followed by stirring at room temperature for 72 h under an argon atmosphere.
  • Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness.
  • the residue was partitioned between methylene chloride and water, and the organic extract was dried (sodium sulfate) and evaporated in vacuo. Purification by flash chromatography, eluting with from 30 to 50% ethyl acetate in hexane, provided an orange solid (1.25 g, 62%), mp 119-125°C.
  • a compound of Formula (I), (l ⁇ g to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula (I) in polyethylene glycol with heating. This solution is then diluted with water for injection (to 100ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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Abstract

L'invention se rapporte à de nouveaux dérivés d'imidazolidinone, qui ont le pouvoir d'inhiber la production du facteur de nécrose tumorale (FNT) et qui sont utiles pour traiter des maladies dont on a établi qu'elles sont déclenchées ou exacerbées par la production du facteur FNT. Ces composés servent également d'inhibiteurs de l'enzyme PDE IV et sont par conséquent utiles pour traiter des états pathologiques nécessitant un processus médiateur ou inhibiteur.
PCT/US1991/008229 1990-11-06 1991-11-05 Composes d'imidazolidinone WO1992007567A1 (fr)

Priority Applications (3)

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CA002095429A CA2095429A1 (fr) 1990-11-06 1991-11-05 Composes d'imodazolidinone
JP4500935A JPH06501708A (ja) 1990-11-06 1991-11-05 イミダゾリジノン化合物
KR1019930701375A KR930703262A (ko) 1990-11-06 1991-11-05 이미다졸리디논 화합물

Applications Claiming Priority (4)

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US60998190A 1990-11-06 1990-11-06
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Cited By (56)

* Cited by examiner, † Cited by third party
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WO1993025517A1 (fr) * 1992-06-15 1993-12-23 Celltech Limited Derives a groupe phenyle trisubstitue utilises comme inhibiteurs selectifs de la phosphodiesterase iv
WO1994002465A1 (fr) * 1992-07-28 1994-02-03 Rhone-Poulenc Rorer Limited Inhibiteurs de phosphodiesterase d'amp cyclique et du facteur de necrose tumorale
EP0636369A1 (fr) * 1993-07-13 1995-02-01 Pfizer Inc. Pyrimidones et imidazolinones pour le traitement du choc
EP0624159A4 (fr) * 1992-01-13 1995-04-12 Smithkline Beecham Corp Imidazoles a substitution par pyridyle.
WO1995017392A1 (fr) * 1993-12-22 1995-06-29 Celltech Therapeutics Limited Derives phenyle trisubstitues, leurs procedes de preparation et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase (type iv)
US5491147A (en) * 1992-10-23 1996-02-13 Celltech, Limited Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment
US5502072A (en) * 1993-11-26 1996-03-26 Pfizer Inc. Substituted oxindoles
EP0714397A4 (fr) * 1993-08-19 1996-06-26
US5563143A (en) * 1994-09-21 1996-10-08 Pfizer Inc. Catechol diether compounds as inhibitors of TNF release
WO1996031485A1 (fr) * 1995-04-06 1996-10-10 Janssen Pharmaceutica N.V. Composes 1,3-dihydro-1-(phenylalkyl)-2h-imidazol-2-one ayant une activite anti-pde iv et anti-cytokine
WO1996031486A1 (fr) * 1995-04-06 1996-10-10 Janssen Pharmaceutica N.V. Composes 1,3-dihydro-1-(phenylalcenyl)-2h-imidazol-2-one ayant une activite anti-pde iv et anti-cytokine
US5580888A (en) * 1992-12-23 1996-12-03 Celltech Therapeutics Limited Styryl derivatives as anti-inflammatory agents
US5608070A (en) * 1993-12-22 1997-03-04 Celltech Therapeutics Limited Enantioselective process for the preparation of chiral triaryl derivatives and chiral intermediates for use therein
US5622977A (en) * 1992-12-23 1997-04-22 Celltech Therapeutics Limited Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same
EP0770613A1 (fr) * 1995-10-27 1997-05-02 Grünenthal GmbH Dérivés substitués de l'imidazolidin-2,4 dione comme immunomodulateurs
US5633257A (en) * 1993-03-10 1997-05-27 Celltech Therapeutics Limited Cyclo(alkyl and alkenyl)phenyl-alkenylyl(aryl and heteroaryl)compounds and pharmaceutical compositions containing them
US5665754A (en) * 1993-09-20 1997-09-09 Glaxo Wellcome Inc. Substituted pyrrolidines
US5679696A (en) * 1992-07-28 1997-10-21 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
WO1997040032A1 (fr) * 1996-04-23 1997-10-30 Schering Aktiengesellschaft Phenyldihydrofuranones chirales servant d'inhibiteurs de la pde-iv
US5686434A (en) * 1993-11-26 1997-11-11 Pfizer Inc. 3-aryl-2-isoxazolines as antiinflammatory agents
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JP2009522293A (ja) * 2005-12-30 2009-06-11 メルク エンド カムパニー インコーポレーテッド Ｃｅｔｐ阻害剤
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EP2258689A1 (fr) * 2000-03-16 2010-12-08 Biolipox AB Inhibiteurs benzyles de PDE4
CN104781256A (zh) * 2012-10-29 2015-07-15 霍夫曼-拉罗奇有限公司 3,4-双取代的噁唑烷酮衍生物和其作为钙激活的钾通道的抑制剂的用途

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US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
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WO1997040032A1 (fr) * 1996-04-23 1997-10-30 Schering Aktiengesellschaft Phenyldihydrofuranones chirales servant d'inhibiteurs de la pde-iv
US6011060A (en) * 1996-04-23 2000-01-04 Schering Aktiengesellschaft Chiral phenyldihydrofuranones as PDE-IV inhibitors
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US6093716A (en) * 1996-09-16 2000-07-25 Celltech Therapeutics, Limited Substituted 2-pyrimidineamines and processes for their preparation
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US6048866A (en) * 1997-03-14 2000-04-11 Celltech Therapeutics, Limited Substituted 2-anilinopryimidines useful as protein kinase inhibitors
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DE19732928C2 (de) * 1997-07-31 2000-05-18 Gruenenthal Gmbh Verwendung substituierter Imidazolidin-2,4-dion-Verbindungen als Schmerzmittel
US6579983B1 (en) 1999-06-18 2003-06-17 Celltech R&D Limited 5-cyano-2-aminopyrimidine derivatives
US6600037B1 (en) 1999-10-20 2003-07-29 Celltech R & D Limited 4,5-disubstituted-2-aminopyrimidines
EP2258689A1 (fr) * 2000-03-16 2010-12-08 Biolipox AB Inhibiteurs benzyles de PDE4
US7491739B2 (en) 2000-05-31 2009-02-17 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
EP1568692A1 (fr) * 2000-05-31 2005-08-31 Santen Pharmaceutical Co., Ltd. (pyridin-4-yl)alkyl-amides comme inhibiteurs de la production de TNF-alpha
US7345064B2 (en) 2000-05-31 2008-03-18 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
US7098226B2 (en) 2000-05-31 2006-08-29 Santen Pharmaceutical Co., Ltd. TNF-α production inhibitors
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US7291624B2 (en) 2001-05-29 2007-11-06 Bayer Schering Pharma Ag CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents
US7235561B2 (en) 2001-05-29 2007-06-26 Schering Ag Compound and a composition including such a compound
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JP2009522293A (ja) * 2005-12-30 2009-06-11 メルク エンド カムパニー インコーポレーテッド Ｃｅｔｐ阻害剤
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7652018B2 (en) 2006-08-15 2010-01-26 Wyeth Llc Imidazolidin-2-one derivatives useful as PR modulators
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
US7618990B2 (en) 2006-08-15 2009-11-17 Wyeth Oxazolidone derivatives as PR modulators
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
CN104781256A (zh) * 2012-10-29 2015-07-15 霍夫曼-拉罗奇有限公司 3,4-双取代的噁唑烷酮衍生物和其作为钙激活的钾通道的抑制剂的用途
CN104781256B (zh) * 2012-10-29 2017-09-29 霍夫曼-拉罗奇有限公司 3，4‑双取代的噁唑烷酮衍生物和其作为钙激活的钾通道的抑制剂的用途

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CA2095429A1 (fr) 1992-05-07
KR930703262A (ko) 1993-11-29
PT99442A (pt) 1992-09-30
EP0557408A4 (en) 1993-10-27
JPH06501708A (ja) 1994-02-24
IE913855A1 (en) 1992-05-22
AU9030691A (en) 1992-05-26
EP0557408A1 (fr) 1993-09-01

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