EP1071645A1 - Composes inhibant l'isoenzyme phosphodiesterase 4 (pde 4) - Google Patents

Composes inhibant l'isoenzyme phosphodiesterase 4 (pde 4)

Info

Publication number
EP1071645A1
EP1071645A1 EP99919814A EP99919814A EP1071645A1 EP 1071645 A1 EP1071645 A1 EP 1071645A1 EP 99919814 A EP99919814 A EP 99919814A EP 99919814 A EP99919814 A EP 99919814A EP 1071645 A1 EP1071645 A1 EP 1071645A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
cr4r5
unsubstituted
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99919814A
Other languages
German (de)
English (en)
Other versions
EP1071645A4 (fr
Inventor
Siegfried Benjamin Christensen, Iv
Cornelia Jutta Forster
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1071645A1 publication Critical patent/EP1071645A1/fr
Publication of EP1071645A4 publication Critical patent/EP1071645A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/47—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • 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

Definitions

  • This invention covers certain ketones and amines represented by the likes of 3-(3- cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclobutan-l-one. These ketones are selective for inhibiting the catalytic site in the phosphodiesterase isoenzyme denominated 4 (PDE 4 hereafter) while exhibiting little or no affinity for a second binding site on the PDE 4 isoenzyme denominated the high affinity rolipram binding site.
  • PDE 4 phosphodiesterase isoenzyme denominated 4
  • a method for treating diseases related to inhibiting the catalytic site in the PDE 4 isoenzyme e.g., asthma, COPD, etc. is also disclosed.
  • Area of the Invention is also disclosed.
  • Cyclic nulceotide phosphodiesterases represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5'-monophosphate (cGMP) to their corresponding inactive 5 - monophosphate metabolites.
  • PDEs Cyclic nulceotide phosphodiesterases
  • cAMP adenosine 3',5'-monophosphate
  • cGMP guanosine 3',5'-monophosphate
  • At least five distinct PDE isoenzymes are believed to exist, each possessing unique physical and kinetic charactersitics and each representing a product of a different gene family. Also the distribution of these isoenzymes appears to differ markedly among cell types.
  • Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli. Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma.
  • An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One such way is by elevating levels of 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, 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.
  • 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 degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
  • 2 compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
  • the principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3 -phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
  • PDE cyclic nucleotide phosphodiesterase
  • PDE 4 inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
  • PDE 4 inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
  • Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
  • 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 sarcoidosis
  • 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 human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • AIDS acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • HIV Human Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation.
  • T lymphocyte Once an activated T 3 lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
  • Cytokines are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
  • Monocytes, macrophages, and related cells such as kupffer and glial 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.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus for similar reasons as those noted.
  • TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al, Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al, Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al, Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al, Journal of Infectious Diseases, 162:211-214,1990].
  • CMV cytomegalovirus
  • novel compounds of this invention are represented by Formula (I):
  • Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, - (CR4R5)nO(CR4R5) m R6, or -(CR4R5) r R6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 1 to 4; r is 0 to 6;
  • R4 and R5 are independently hydrogen or Ci-2 alkyl
  • R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyC ⁇ .3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety may be unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to
  • r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5) n O(CR4R5) m R6; X is VR2, halogen, nitro, NR4R5, or formyl amine;
  • V is O or S(O) m '; m' is 0, 1, or 2;
  • X2 is O or NR8;
  • R2 is -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines;
  • R3 is COOR14, C(O)NR4Ri4 or R7;
  • W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • Z is O, NR 9 , NORg, NCN, C(-CN) 2 , CRgCN, CR 8 NO 2 , CR 8 C(O)OR 8 , CR 8 C(O)NR 8 R 8 , C(-CN)NO 2 , C(-CN)C(O)OR 9 , C(-CN)C(O)NR 8 R 8 ;
  • R7 is -(CR4R5)qRi2 or C g alkyl wherein the R 12 or C ⁇ . alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted 5 by 1-3 fluorines, -F, -Br, -Cl, -NO 2 , -NR 10 R ⁇ , -C(O)R 8 , -CO2R8, -O(CH 2 ) q R8, -CN, - C(O)NR ⁇ oRl l, -O(CH 2 ) q C(O)NR ⁇ oRl l, -O(CH 2 ) q C(O)R 8 , -NR ⁇ 0 C(O)NR ⁇ 0 Rl l, - NRi ⁇ C(O)Rn, -NRl ⁇ C(O)OR9, -NR ⁇ oC(O)Rl3, -C(NR ⁇ o)NR ⁇
  • Rl2 is Ri3 ⁇ C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl;
  • R 8 is hydrogen or R9;
  • R > is R or fluorine
  • R9 is C 4 alkyl unsubstituted or substituted by one to three fluorines; Rl ⁇ is OR 8 or Rn;
  • R ⁇ 1 is hydrogen, or Ci .4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S;
  • Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C ⁇ _2 alkyl groups;
  • Rl4 is hydrogen or R7; or when R 8 and R14 are as NR 8 Ri4 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; provided that: R15 is C(O)Ri4, C(O)NR4R 14 , S(O)2R7, or S(O) 2 NR 4 R 14 ; or a pharmaceutically acceptable salt thereof.
  • a second set of compounds of this invention are represented by Formula (II)
  • Y is -(CR4R5) q Z';
  • Z' is OR14, OR15, SR 14 , S(O) m R 7 , S(O) 2 NR 10 R ⁇ 4 , NR10R14, NR 14 C(O)R 9 , NRloCOORi ⁇ NR ⁇ 0 C(O)OR 7 , NR 10 C(Y')NR ⁇ oRi4, NR 10 S(O) 2 NR ⁇ 0 Ri4, NR 10 C(NCN)NR ⁇ 0 Ri4, NR 10 S(O) 2 R7, NR 10 C(CR4NO2)NR 10 R 14 , NR 10 C(NCN)SR 9 , NR ⁇ oC(CR 4 NO 2 )SR9, NR 10 C(NR 1 o)NR 10 Rl4, NR 10 C(O)C(O)NR 10 Ri4, or NR ⁇ 0 C(O)C(O)OR ⁇ 4 ; 6 Y' is O or S;
  • the invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE 4 in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) and (LI) as shown below.
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) and (LI).
  • the invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) and (II).
  • 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) and (II).
  • 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 (HLV), which comprises administering to such human an effective
  • Compounds of Formula (I) and (II) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • compounds of Formula (I) and (LI) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • Phosphodiesterase 4 inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • PDE 4 inhibitors are useful in the treatment of 7 diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I) and (II).
  • viruses include, but are not limited to HLV-1, HLV-2 and HLV-3, cytomegalovirus (CMV), influenza, adeno virus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HLV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) and (IL).
  • HBV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline immunodeficiency virus (F V) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lenti viruses.
  • the compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of Formula (I) and (LI) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
  • Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.
  • polymixins such as Polymycin B
  • imidazoles such as clotrimazole, econazole, miconazole, and ketoconazole
  • triazoles such as fluconazole, and itranazole
  • Amphotericins in particular Amphotericin B and liposomal Amphotericin B.
  • the compounds of Formula (I) and (II) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) and (II) to a mammal in need of such treatment.
  • a compound of Formula (I) and (II) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • alkyl or "alkyl” groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, 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. 8
  • Alkenyl means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2- propenyl, or 3-methyl-2-propenyl.
  • cycloalkyl or "cycloalkyl alkyl” means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
  • Aryl or “aralkyl”, unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl.
  • the alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.
  • Heteroaryl means an aromatic ring system containing one or more heteroatoms.
  • Halo means all halogens, i.e., chloro, fluoro, bromo, or iodo.
  • “Inhibiting the production of LL-1” or “inhibiting the production of TNF” means: a) a decrease of excessive in vivo LL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of LL-1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcriptional level, of excessive in vivo LL-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 LL-1 or TNF levels as a postranslational event.
  • TNF mediated disease or disease states means 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 LL-1 or LL-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 means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses.
  • a cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them.
  • the cytokine inhibited by the present invention for use in the treatment of a HLV-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 HLV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • his cytokine is TNF- ⁇ .
  • All of the compounds of Formula (I) and (LI) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formula (I) and (LI) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE 4 and in treatment of disease states mediated thereby.
  • Preferred compounds are as follows:
  • the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines.
  • the preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, - CH2CF3, and -CH2CHF2.
  • Preferred Ri substitutents for the compounds of Formula (I) and (LI) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4.6 cycloalkyl unsubstituted or substituted with OH, C7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH 2 )0-2CH 3 , -(CH 2 )l-3O(CH2)0-2CH 3 , and -(CH 2 )2-4OH.
  • the R4 and R5 terms are independently hydrogen or alkyl.
  • the individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can be unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.
  • Ri is a C7-11 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1. ⁇ 2»6]clecyl, etc. additional examples of which are described in Saccamano et al, WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.
  • Preferred Z terms are O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, 2-(l,3- dithiane), dimethylthio ketal, 2-(l,3-dioxolane), or dimethyl ketal. More preferred are O, NR7, NOR14, NOR15, and 2-(l,3-dioxolane).
  • Preferred X groups for Formula (I) and (II) are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group for Formula (I) and (II) is that wherein X2 is oxygen.
  • the preferred X3 group for Formula (I) and (LI) is that wherein X3 is hydrogen.
  • R2 groups where applicable, is a Ci-2 alkyl unsubstituted or substituted by 1 or more halogens.
  • the halogen atoms are preferably fluorine and chlorine, more preferably fluorine.
  • More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
  • R7 moieties include R 3, unsubstituted or substituted -(CH2)0-2(2-, 3- or 4- pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4-piperazinyl), 10
  • Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R 8 )-l-imidazolyl, 1 -pyrazolyl, 3-(R 8 )-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R 8 )-l-triazolyl, 5-(R 8 )-2-triazolyl, 5-(R 8 )-l-tetrazolyl, 5-(R 8 )-2-tetrazolyl, 1- tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R 8 )-l-piperazinyl, or pyrrolyl ring.
  • Preferred rings when R 8 and R14 in the moiety -NR 8 Ri4 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 1 -pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl.
  • the respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I) and (LI).
  • Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l-imidazolyl, 4-(R7)-l-imidazolyl, 5-(R7)-l-imidazolyl, 3-(R7)-l -pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l-triazolyl, 5-(R7)-l-triazolyl, 5-(R7)-l-tetrazolyl, and 5-(R7)-2-tetrazolyl.
  • R7 Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l-tetrazolyl, 4-(R7)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
  • Preferred groups for NR 8 Ri4 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(R ⁇ 4)- 1 -piperazinyl, or 4-(R 15)- 1 -piperazinyl .
  • Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or
  • the heterocyclic ring itself may be unsubstituted or substituted by R 8 either on an available nitrogen or carbon atom, such as l-(R 8 )-2-imidazolyl, l-(R 8 )-4-imidazolyl, l-(R 8 )-5-imidazolyl, l-(R 8 )-3-pyrazolyl, l-(R 8 )-4-pyrazolyl, l-(R 8 )-5-pyrazolyl, l-(R 8 )-4-triazolyl, or l-(R 8 )-5-triazolyl.
  • W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present. It is most preferred that W is ethynyl or 1,3-butadiynyl. 1 1
  • R is -CH2- cyclopropyl, -CH2-C5.6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH;
  • R2 is methyl or fluoro-substituted alkyl
  • R, is R, where R, is an unsubstituted or substituted aryl or heteroaryl ring
  • X is YR2
  • Z is O, NR7.
  • those compounds of Formula (I) are those wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is VR2; V is oxygen; X2 is oxygen; R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, R3 is a substituted or unsubstituted pyrimidinyl ring, and Z is O or NR7.
  • preferred compounds of Formula (LI) they are the same as for those of Formula (I) where Formula (LI) shares a group in common with Formula (I).
  • the preferred embodiment is where R4 and R5 are hydrogen, q is 0 or 1 and Z' is OR14, OR15, or NR 0R14, most particularly NR10R14.
  • Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • Pharmaceutically acceptable salts are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid. If the parent compound is an acid, it is treated with an inorganic or organic base dissolved in a suitable solvent.
  • compositions of the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the Formula (I) and (LI).
  • the compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended.
  • These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
  • compositions and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
  • topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, or nose.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension. 12
  • a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension. 12
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • the pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
  • the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient.
  • the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
  • a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor.
  • Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area.
  • the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
  • Cyanocyclobutanone 1 -Scheme 1 prepared as described in an accompanying patent application filed on even date herewith may be protected, for example, as a ketal, by treatment with suitable reagents, such as bis(trimethylsilyloxy)ethane and catalytic trimethylsilyl trifluoromethanesulfonate, in a suitable solvent, such as dichloromethane.
  • suitable reagents such as bis(trimethylsilyloxy)ethane and catalytic trimethylsilyl trifluoromethanesulfonate
  • a suitable solvent such as dichloromethane.
  • the nitrile may then be reduced by a suitable reagent, such as diwobutylaluminum hydride, in a suitable solvent, such as toluene or an ether, such as tetrahydrofuran and tetrabutyl methyl ether.
  • Aldehyde 2-Scheme 1 may be homologated to the alkyne by treatment with an appropriate reagent, such as dialkyl diazomethylphosphonate, [Seyferth et al, J. Org. Chem., 36: 1379, 1971 and a suitable base, such as potassium t-butoxide, in a suitable solvent, such as tetrahydrofuran.
  • an appropriate reagent such as dialkyl diazomethylphosphonate, [Seyferth et al, J. Org. Chem., 36: 1379, 1971 and a suitable base, such as potassium t-butoxide, in a suitable solvent, such as tetrahydrofuran.
  • Deprotection of the ketal may be achieved by treatment with an acidic reagent, such as hydrogen chloride or/?-toluenesulfonic acid, in an aqueous solvent, such as tetrahydrofuran, at temperatures from room temperature to reflux, preferably at 60
  • Terminal alkyne 3-Scheme 1 may be coupled with an aryl bromide or iodide, such as iodobenzene, using an appropriate catalyst system, such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide, in a suitable solvent, such as triethylamine, at elevated temperature, preferably at 85°C, to provide the phenylethynylcyclobutanone 4 Scheme 1.
  • an appropriate catalyst system such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide
  • a suitable solvent such as triethylamine
  • Reagents a) T SOCH 2 CH 2 OT S, TMSOTf, CH 2 CI 2 , -78°C to RT; b) DIBAL-H, THF, TBME; c) N 2 CHP(0)(OMe) 2 , KO'Bu, THF, -78°C to RT; d) HCI, H 2 0, THF, 60°C; e) Phi, (PPh 3 ) 4 Pd, Cul, Et j N, 85°C.
  • Phenylethynylcyclobutanone 1 Scheme 2 may be treated with a suitable reagent, such as methoxymethyldiphenylphosphonium chloride, and a suitable base, such as phenyllithium, in a suitable solvent, such as ether or tetrahydrofuran.
  • a suitable solvent such as ether or tetrahydrofuran.
  • the resulting methyl vinyl ether 2z Scheme 2 may be hydrolyzed by treatment with an acidic reagent, such as p-toluenesulfonic acid, in a suitable aqueous solvent, such as w ⁇ propanol, at elevated temperature, preferably at reflux.
  • Aldehyde 3a- or 3b-Scheme 2 may be transformed into the amine by, for example, reductive amination by treatment with suitable reagents, such as ammonium acetate and sodium cyanoborohydride, followed by hydrogen chloride, in a suitable solvent, such as methanol, to provide the aminomethylcyclobutane 4a- or 4b-Scheme 2
  • Reagents a) CH 3 OCH 2 PPh 3 + CI-, PhLi, Et 2 0, 0°C to RT; b) pTsOH, IPrOH, H 2 0, reflux; c) i. NH 4 OAc, NaBH 3 CN, MeOH, 4 A sieves; ii. HCI, MeOH.
  • Terminal alkyne 1 -Scheme 3 may be reduced to the alcohol by a variety of reagents, such as a borohydride, especially lithium borohydride, in a suitable solvent, such as an alcohol, such as ethanol, or an ether, such as dimethoxyethane or tetrahydrofuran, at temperatures from -78°C to room temperature.
  • a borohydride especially lithium borohydride
  • a suitable solvent such as an alcohol, such as ethanol, or an ether, such as dimethoxyethane or tetrahydrofuran
  • the mixture of cis and trans alcohols may then be subjected to Mitsunobu reaction conditions [Mitsunobu, Synth, 1, 1981], for example with diethyl azodicarboxylate, triphenylphosphine and phthalimide, in a suitable solvent, such as tetrahydrofuran, to give a mixture of phthalimidocyclobutanes, the cis and trans isomers of which may conveniently be separated.
  • Trans-phthalimidocyclobutane 2-Scheme 3 may be elaborated to the amine, for example with hydrazine, in a suitable solvent, such as ethanol and tetrahydrofuran, and protected, for example as the t-butylcarboxylate, by treatment with a suitable reagent, such as di-t-butyldicarboxylate, in a suitable solvent, such as dichloromethane.
  • a suitable solvent such as ethanol and tetrahydrofuran
  • a suitable reagent such as di-t-butyldicarboxylate
  • Terminal alkyne 3_r Scheme 3 may be coupled to an aryl bromide or iodide, such as iodobenzene, with an appropriate catalyst system, such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide, in a suitable solvent, such as triethylamine, at elevated temperatures, preferably at 85°C.
  • an appropriate catalyst system such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide
  • a suitable solvent such as triethylamine
  • Terminal alkyne 3-Scheme 3 may be reacted with even unreactive aryl iodides and bromides, such as 2-amino-5-iodopyrimidine, in the presence of a base, such as diethylamine, in a suitable solvent, such as dimethyl sulfoxide, using an appropriate catalyst system, such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide, at elevated temperatures, preferably at 65°C.
  • aryl iodides and bromides such as 2-amino-5-iodopyrimidine
  • a base such as diethylamine
  • a suitable solvent such as dimethyl sulfoxide
  • an appropriate catalyst system such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide
  • the intermediate may be deprotected, for example with trifluoracetic acid, in a suitable solvent, such as dichloromethane, to provide the tra/u-(2-aminopyrimidin- 5-ylethynyl)cyclobutylamine 5-Scheme 3.
  • a suitable solvent such as dichloromethane
  • Reagents a) LiBH 4 , THF, -30°C; b) DEAD, PPh 3 , phthalimide, THF; c) N 2 H 4 H 2 0, THF, EtOH; d) (f-Bu0 2 C) 2 0, CH 2 CI 2 ; e) Phi, (PPH 3 ) 4 Pd, Cul, Et 3 N, 85°C; f) TFA, CH 2 CI 2 ; g) (PPh 3 ) 4 Pd, Cul, 2-amino-5-iodopyrimidine, D SO, Et 2 NH, 65°C.
  • Terminal alkyne 1 -Scheme 4 may be subjected to Mitsunobu [Pearson et al, J. Org. Chem., 54: 4235, 1989] reaction conditions, for example with diphenylphosphoryl azide, diethyl azodicarboxylate and triphenylphosphine, in a suitable solvent, such as 17 tetrahydrofuran, resulting in a mixture of cis and trans azides 2a- and 2b-Scheme 4. which may conveniently be separated.
  • Trans-azide 2a-Scheme 4 may be coupled with an aryl iodide or bromide using a suitable catalyst system, such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide, in a suitable solvent, such as triethylamine, at elevated temperatures, preferably at 85°C.
  • a suitable catalyst system such as tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide
  • a suitable solvent such as triethylamine
  • Azide 3-Scheme 4 may be reduced with a suitable reducing system, such as triphenylphosphine, in the presence of a suitable base, such as pyridine, in a suitable solvent, such as ammoniacal methanol.
  • Salt formation with, for example, ethereal hydrogen chloride provides the amine salts 4-Scheme 4.
  • the coupled aryl group is a benzoate ester 5-Scheme 4.
  • saponification may be achieved by a variety of reaction conditions, for example with potassium hydroxide in tetrahydrofuran, methanol and water.
  • Salt formation with, for example, ethereal hydrogen chloride provides the amine salts 6-Scheme 4
  • Reagents a) LiBH 4 , THF, -78°C; b) DEAD, Ph 2 P(0)N 3 , PPh 3 , THF; c) Arl, (PPh 3 ) 4 Pd, Cul, Et 3 N, 85°C; d) PPh 3 , pyridine, NH 3 , MeOH; e) HCI, Et 2 0; f) KOH, THF, MeOH, H 2 0. 18
  • the reaction was diluted with water and extracted with three portions of 5/95 methanol/dichloromethane. The organic extract was dried (magnesium sulfate) and evaporated to provide crude amine as a colorless oil.
  • the crude intermediate was dissolved in dichloromethane (20 mL) and was treated with ditert.butyl dicarbonate (0.13 g, 0.61 mmol). The reaction was stirred at room temperature under an argon atmosphere for 24h, was partitioned between dichloromethane and water, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:9 ethyl acetate :hexanes provided product as a whitish solid (0.098 g, 44%), m.p.129- 130°C.
  • trans-l-fertbutoxycarbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-3- phenylethvnylcvclobutane A solution of trans- l-tertbutoxycarbonylamino-3-(3- cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutane (0.098 g, 0.25 mmol) in triethylamine (3 mL) was treated with iodobenzene (0.03 mL, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (0.01 g, 4%) and copper(LI) iodide (0.003 g, 6%).
  • inhibitory effect of compounds of Formula (I) and (LI) on in vitro TNF production by human monocytes may 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,
  • Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
  • the phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (I) and (TJ) 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 Lb, porcine aorta; 2) 25 PDE Ic, guinea-pig heart; 3) PDE LH, guinea-pig heart; 4) PDE 4, human monocyte; and 5)
  • PDE V canine trachealis.
  • PDEs la, lb, Ic and ILL are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214,
  • PDE 4 is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy et al, J. Biol. Chem., 267:1798- 1804, 1992].
  • Phosphodiesterase activity is assayed as described in the protocol of Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive ICso's in the nanomolar to ⁇ M range for compounds of the workings examples described herein for Formula (I) and (LI) have been demonstrated.

Abstract

L'invention concerne des cétones, alcools et amines, représentés par les analogues d'une 3-(3-cyclopentyloxy-4-méthoxyphényl)-3-phényléthynylcyclobutan-1-one, et utiles en tant qu'antagonistes de PDE 4.
EP99919814A 1998-04-14 1999-04-13 Composes inhibant l'isoenzyme phosphodiesterase 4 (pde 4) Withdrawn EP1071645A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8170298P 1998-04-14 1998-04-14
US81702P 1998-04-14
PCT/US1999/007995 WO1999052847A1 (fr) 1998-04-14 1999-04-13 Composes inhibant l'isoenzyme phosphodiesterase 4 (pde 4)

Publications (2)

Publication Number Publication Date
EP1071645A1 true EP1071645A1 (fr) 2001-01-31
EP1071645A4 EP1071645A4 (fr) 2003-04-02

Family

ID=22165846

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99919814A Withdrawn EP1071645A4 (fr) 1998-04-14 1999-04-13 Composes inhibant l'isoenzyme phosphodiesterase 4 (pde 4)

Country Status (4)

Country Link
EP (1) EP1071645A4 (fr)
JP (1) JP2002511438A (fr)
CA (1) CA2328250A1 (fr)
WO (1) WO1999052847A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3345405A (en) * 1964-03-31 1967-10-03 Smith Kline French Lab 1-amino-2(and 3)-phenylcyclobutane-1-carboxylic acids
WO1991015451A1 (fr) * 1990-04-05 1991-10-17 Smithkline Beecham Pharma Gmbh Nouveaux derives de phenyle-cycloalcanes et de phenyle-cycloalcenes
US5187192A (en) * 1992-03-13 1993-02-16 Abbott Laboratories Cyclobutyl derivatives having lipoxygenase inhibitory activity
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3345405A (en) * 1964-03-31 1967-10-03 Smith Kline French Lab 1-amino-2(and 3)-phenylcyclobutane-1-carboxylic acids
WO1991015451A1 (fr) * 1990-04-05 1991-10-17 Smithkline Beecham Pharma Gmbh Nouveaux derives de phenyle-cycloalcanes et de phenyle-cycloalcenes
US5187192A (en) * 1992-03-13 1993-02-16 Abbott Laboratories Cyclobutyl derivatives having lipoxygenase inhibitory activity
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HONDA T ET AL: "CHIRAL SYNTHESIS OF PHOSPHODIESTERASE INHIBITOR, (R)-(-)-ROLIPRAM, BY MEANS OF ENANTIOSELECTIVE DEPROTONATION STRATEGY" HETEROCYCLES, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 42, no. 1, January 1996 (1996-01), pages 109-111, XP002921368 ISSN: 0385-5414 *
See also references of WO9952847A1 *

Also Published As

Publication number Publication date
EP1071645A4 (fr) 2003-04-02
JP2002511438A (ja) 2002-04-16
CA2328250A1 (fr) 1999-10-21
WO1999052847A1 (fr) 1999-10-21

Similar Documents

Publication Publication Date Title
EP0796096A1 (fr) Monomeres 4,4-(disubstitues)cyclohexan-1-carboxylate et composes correspondants
US5990119A (en) 1,4,4-(trisubstituted)cyclohexane monomers and related compounds
WO1996020157A1 (fr) Dimeres 3,3-(disubstitue)cyclohexan-1-ol et composes apparentes
US6172118B1 (en) Compounds
US5767151A (en) 3,3-(disubstituted) cyclohexan-1-ylidine acetate dimers and related compounds
WO1999052847A1 (fr) Composes inhibant l'isoenzyme phosphodiesterase 4 (pde 4)
WO1996020160A1 (fr) Dimeres 1,3,3-(trisubstitues)cyclohexane et composes apparentes
EP0796091A1 (fr) Monomeres 3, 3-(disubstitues) cyclohexan-1-ol et composes correspondants
WO1996020159A1 (fr) Monomeres d'acetate 3,3-hexamethylene (bisubstitue)-1-ylidine et composes connexes
WO1996019993A1 (fr) Monomeres de 1,3,3-(trisubstitue)cyclohex-1-ene et composes apparentes
EP0799205B1 (fr) Monomeres de 1,4,4-(trisubstitue)cyclohex-1-ene utilises comme inhibiteurs de pde iv et tnf
US5777176A (en) 4,4-(disubstituted)cyclohexan-1-ol dimers and related compounds
US5900417A (en) 1,3,3-(Trisubstituted)cyclohexanemonomers and related compounds
WO1996019983A1 (fr) Dimeres d'acetate 4,4-(disubstitue)cyclohexane-1-ylidine et composes associes
EP0799204A1 (fr) Monomeres de 1,3,3-(trisubstitue)cyclohexane et composes apparentes
EP0801566A1 (fr) Monomeres de 4,4-(disubstitue)cyclohexan-1-ylidine acetate et composes apparentes
EP0796097A1 (fr) Monomeres 3,3-(disubstitues) cyclohexan-1-carboxylate et composes correspondants
EP0802791A1 (fr) Dimeres de 3,3-(disubstitues)cyclohexan-1-ylidine acetate et composes correspondants
WO1996019979A1 (fr) Dimeres de 1,4,4-(trisubstitue)cyclohexane et composes apparentes
EP0799181A1 (fr) Dimeres 3,3-(disubstitues)cyclohexane-1-carboxylate et leurs composes apparentes
EP0794773A1 (fr) Monomeres de 1,4,4-(trisubstitue) cyclohexane et composes apparentes
WO1996019980A1 (fr) Dimeres de 3,3-(disubstitue)cyclohexan-one et composes apparentes

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20001017

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE ES FR GB IT LI NL

A4 Supplementary search report drawn up and despatched

Effective date: 20030220

RIC1 Information provided on ipc code assigned before grant

Ipc: 7C 07D 239/42 B

Ipc: 7C 07C 229/46 B

Ipc: 7C 07C 217/74 B

Ipc: 7C 07C 47/47 B

Ipc: 7C 07C 45/68 B

Ipc: 7C 07C 45/59 B

Ipc: 7C 07C 45/51 B

Ipc: 7C 07C 49/755 B

Ipc: 7C 07C 49/115 B

Ipc: 7C 07C 49/105 B

Ipc: 7C 07C 49/23 A

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20021101