WO1992019594A1 - Pyrrolidinones - Google Patents

Pyrrolidinones Download PDF

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Publication number
WO1992019594A1
WO1992019594A1 PCT/US1992/003613 US9203613W WO9219594A1 WO 1992019594 A1 WO1992019594 A1 WO 1992019594A1 US 9203613 W US9203613 W US 9203613W WO 9219594 A1 WO9219594 A1 WO 9219594A1
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WIPO (PCT)
Prior art keywords
formula
cyclopentyloxy
methoxyphenyl
substituted
pyrrolidinone
Prior art date
Application number
PCT/US1992/003613
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English (en)
French (fr)
Inventor
Paul Elliot Bender
Siegfried Benjamin Christensen, Iv
Original Assignee
Smithkline Beecham Corporation
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Publication date
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Priority to JP4511481A priority Critical patent/JPH06507405A/ja
Publication of WO1992019594A1 publication Critical patent/WO1992019594A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to novel pyrrolidinones, 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.
  • cromoglycate are inadequate to control the disease; none of them modify all three phases of asthma and nearly all are saddled with limiting side effects. Most importantly, none of the agents, with the possible exception of steroids, alter the course of progression of chronic asthma.
  • Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones
  • Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the
  • PDEs cyclic nucleotide phosphodiesterases
  • PDE cyclic nucleotide phosphodiesterase
  • Isozymes Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd. (1989). Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV 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 IV 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.
  • the compounds of this invention also inhibit production of Tumor Necrosis Factor (TNF), a serum
  • TNF production is implicated in mediating or exacerbating a number of diseases including 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 sacroidosis, 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
  • AIDS 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.
  • TNF has been implicated in various roles with the human acquired immune deficiency syndrome (AIDS) .
  • AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • T lymphocytes implicated in the infection of T lymphocytes with HIV by playing a role in maintaining T lymphocyte activation. Furthermore, once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be
  • TNF is also associated with yeast and fungal infections. Specifically Candida Albicans has been shown to induce TNF production in vitro in human
  • This invention comprises benzyl pyrrolidinones represented by Formula (I), and pharmaceutical
  • compositions containing these compounds are provided.
  • This invention further constitutes a method of inhibiting phosphodiesterase IV in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of
  • Phosphodiesterase IV 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
  • PDE IV inhibitors are useful in the treatment of
  • This invention further constitutes a method of inhibiting the production of TNF in an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of formula (I).
  • This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), AIDS Related Complex (ARC) or any other disease state associated with an HIV infection, which comprises administering to such a human an effective TNF inhibiting amount of a compound of Formula (I).
  • HIV human immunodeficiency virus
  • ARC AIDS Related Complex
  • the present invention also provides a method of preventing a TNF mediated disease state in an animal in need thereof, including humans, by prophylactically administering an effective amount of a compound of
  • the compounds of the present invention are also useful in the treatment of additional viral infections
  • 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,
  • CMV Cytomegalovirus
  • Influenza Influenza
  • adenovirus adenovirus
  • Herpes group of viruses such as. Herpes Zoster and Herpes Simplex.
  • the compounds of Formula I are also useful in the treatment of 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 the Formula (I) may be administered in conjunction with other drugs of choice, either simultaneously or in a consecutive manner, 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
  • the preferred organism for treatment is the Candida organism.
  • the compounds of the Formula (I) may be co-administered in a similar manner with anti-viral or anti-bacterial agents.
  • the compounds of the Formula (I) 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 the Formula (I) to a mammal in need of such treatment.
  • a compound of the Formula (I) is
  • R 1 is C 1-12 alkyl unsubstituted or substituted by 1 or more halogens, C 3-6 cyclic alkyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group; C 4-6 cycloalkyl containing one or two unsaturated bonds;
  • X 1 is 0 or S
  • X 2 is 0 or NR 14 ;
  • X 3 is hydrogen or X
  • X is YR 2 , halogen, nitro, NR 14 R 14 , or formamide; Y is 0 or S(O)m;
  • R 2 is -CH 3 or -CH 2 CH 3 , each may be
  • R 3 is hydrogen, halogen, CN, C 1-4 alkyl, halo-substituted C 1-4 alkyl, cyclopropyl unsubstituted or substituted by R 9 , OR 5 , -CH 2 OR 5 , -NR 5 R 16 ,
  • R 3' is hydrogen, halogen, C 1-4 alkyl, halosubstituted C 1-4 alkyl, cyclopropyl unsubstituted or
  • n is an integer from 0 to 2;
  • n is an integer from 1 to 4.
  • q is an integer from 0 to 1;
  • r is an integer from 1 to 2;
  • s is an integer from 2 to 4.
  • x is an integer from 2 to 6;
  • y is an integer from 1 to 6;
  • z is an integer from 0 to 6;
  • R 5 and R 16 may together with the nitrogen form a 5 to 7 membered ring optionally
  • R 5 is independently hydrogen or C 1-4 alkyl, unsubstituted or substituted by one to three fluorines;
  • R 7 is OR 5 , -NR 5 R 16 , or R 12 ;
  • R 8 is hydrogen, C(O)R 7 , (2-, 4- or 5- imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5- triazolyl-[l,2,3]), (3- or 5-triazolyl[1,2,4]), (5- tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5- isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2- oxadiazolyl[l,3,4]), (2-thiadiazolyl[l, 3,4]), (2- ,4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl),
  • R 9 is hydrogen, F or R 12 .
  • R 10 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1-3 alkyl, halo
  • cycloalkyl and heterocyclic moieties may be
  • R 11 is 2-tetrahydropyran or 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2-tetrahydrothiophene unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;
  • R 12 is C 1-4 alkyl unsubstituted or substituted by one to three fluorines
  • R 14 is independently hydrogen or a
  • R 15 is C 1-4 alkyl unsubstituted or substituted by one or more halogens; -C(O)C 1-4 alkyl, unsubstituted or substituted by one or more halogens; oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, or pyrrolyl, and each of the heterocyclics may be unsubstituted or substituted by one or two C 1-2 alkyl groups;
  • R 16 is OR 5 or R 5 ;
  • Z is O, -NR 12 , -NOR 5 , NCN, -C(-CN) 2 ,
  • m is 2 when R 10 is OH in (CR 14 R 14 )n-C(O)O- (CR 14 R 14 ) m -R 10 , (CR 14 R 14 ) n - (C(O)NR 14 ) - (CR 14 R 14 ) m -R 10, or C(R 14 R 14 ) s O(CR 14 R 14 ) m R 10 and further provided that at least one of the R 4 or R 14 groups on (a) or (b) is not hydrogen when q is O, R 3 , R 3' , R 8 and X 3 are H; X is OR 2 , X 2 is O and X, is O or S.
  • All defined alkyl groups can be straight or branched.
  • 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.
  • the term "halogen" is used to mean chloro, fluoro, bromo or iodo. Alkyl groups may be substituted by one or more halogens up to being
  • cycloalkyl as used herein is meant to include groups of 3-6 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl or
  • aryl or “aralkyl”, unless specified otherwise, as used herein is meant an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl.
  • aryl is monocyclic, i.e., phenyl.
  • C 7-11 polycycloalkyl examples include bicyclo [2.2.1]-heptyl, bicyclo [2.2.2] octyl,
  • rings when R 5 and R 16 in the moiety -NR 5 R 16 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/ and S include, but are not limited to
  • the invention further provides for the novel pharmaceutical compositions of the compounds of Formula I.
  • the invention provides a method of inhibiting PDE IV which comprises administering to a subject in need thereof, a compound of Formula (I).
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a subject in need thereof, an effective amount of a compound of Formula (I).
  • the invention also provides a method for the treatment of asthma which comprises administering to a subject in need thereof, an effective amount of a
  • the compounds of Formula (I) are useful in treating, prophylactically or therapeutically, disease states in humans which are exacerbated or caused by excessive or unregulated TNF production.
  • the present invention also provides a method for the inhibition of the production of tumor necrosis factor (TNF) in an animal in need thereof, including humans, which comprises administering to the animal in need of such treatment an effective amount of a compound of Formula I.
  • TNF tumor necrosis factor
  • TNF mediated 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.
  • IL-1 for instance is a major component, and whose
  • TNF tumor necrosis factor
  • cytokine any secreted polypeptide that affects the functions of other cells, and is a molecule which modulates
  • 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, epidermal keratinocytes, and ⁇ -lymphocytes.
  • monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and ⁇ -lymphocytes.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines for the present invention include, but are not limited to
  • Interleukin-1 Interleukin-1
  • Interleukin-6 Interleukin-6
  • Tumor Tumor
  • TNFGC Tumor Necrosis Factor-alpha
  • TNF ⁇ Tumor Necrosis Factor beta
  • a preferred subgroup of formula I is formula (lb):
  • R 1 is C 4 -C 6 cyclic alkyl, unsubstituted or substituted by one to three methyl or ethyl groups;
  • C 1-7 alkyl unsubstituted or substituted by 1 to 3 fluorines; -(CH 2 ) s C(O)O- (CH 2 ) m CH 3 ; -(CH 2 ) s O (CH 2 ) m CH 3 ;
  • s 2 to 4.
  • n 0 to 2;
  • X is -YR 2 , halogen, nitro, amine, C 1-2 dialkylamine, C 1-2 monoalkylamine, or formyl amine;
  • Y is 0 or S(O) m ;
  • R 2 is -CH 3 or -CH 2 CH 3 , each may be
  • R 3 is H, CH 3 , CN, F, OH, -C ⁇ CR 9 or CF 3 ;
  • X 1 is O or S
  • q is 0 or 1
  • R 4 is independently hydrogen, Br, F, C1l -NR 5 R 16 , NO 2 , -C(Z)R 7 , -S(O) m C 1-3 alkyl, CN, OR 16,
  • R 5 is independently hydrogen or C 1-4 alkyl unsubstituted or substituted by one to three fluorines;
  • R 6 is H, R 12 , -C(O)R 12 , -C(O)C(O)R 7 ,
  • R 7 is OR 5 , NR 5 R 16 or R 12 ;
  • R 8 is H or -C(O)R 7 ;
  • R 9 is hydrogen, F or R 12 ;
  • R 12 is C 1-4 alkyl unsubstituted or substituted by one to three fluorines
  • R 14 is H or a C 1-2 alkyl unsubstituted or substituted by one or more fluorines;
  • R 15 is C 1-4 alkyl unsubstituted or substituted by one or more halogens; -C(O)C ⁇ -4 alkyl, unsubstituted or substituted by one or more halogens; oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morphollinyl, piperidinyl, piperazinyl, or pyrrolyl, and each of the heterocyclics may be unsubstituted or substituted by one or two C ⁇ _2 alkyl groups;
  • R 16 is OR 5 or R 5; or a pharmaceutically acceptable salt thereof;
  • Preferred compounds are those in which R 1 is
  • R 3' is hydrogen; X 3 is hydrogen; A is (a); R 4 is H, Br, OR 16 , CN, NR 5 R 6 , NO 2 , C(O)R 7 , S(O) m R 12 , 1- or 2- imidazolyl, -OC(O)CH 3 or NHC(O)R 15 ; R 8 is C(O)OH, H or C(O)OEt; R 14 is hydrogen, CH 3 , NH 2 or NHC(O)CH 3 .
  • R2 is methyl or fluoro substituted
  • R 3 is hydrogen, C ⁇ CH or CN; and R 4 is hydrogen, Br, NH 2, -NHC(O)CH 3 , C(O)OH, -NHC(NCN) SCH 3 , -NHC(O)NH 2 , -N(CH 3 ) 2r NHC(O)C(O)OCH 3 , -NHC (O) C (O) OH, -NHS(O) 2 CH 3 , -C(O)OCH 3 , S(O) 2 CH 3 , SCH 3 , -NHC(O)C(O)CH 3 , S(O)CH 3 , -NHC(O)C(O)NH 2 , CN, C(O)NH 2 , NHS(O) 2 CF 3 ,
  • R 1 is cyclopentyl, CF 3 , CH 2 F, CHF 2 , CF 2 CHF 2 , CH 2 CF 3 , CH 2 CHF 2 , CH 3 , CH 2 -cyclopentyl, CH 2 -cyclopropyl or cyclopentenyl;
  • R 2 is CF 3 , CHF 2 , or CH 2 CHF 2 ;
  • one R 3 is hydrogen and the other R 3 is hydrogen, C ⁇ CH or CN and is in the
  • X 2 R 1 , X and X 3 respectively represent X2R 1 , X and X 3 as defined in relation to Formula (I) or groups convertable to X 2 R 1, X and X 3 ; and X 1 is H, with an appropriate malonic acid ester derivative, such as
  • R 3' is H or COOR 17 , typically as a mixture.
  • Formula (2) with, e.g., carboalkoxy- or carboaryloxy-methylene trialkyl- or triarylphosphorane, provides a compound of the Formula (3) wherein R 18 is H.
  • a suitable solvent such as an aqueous alcohol
  • a source of cyanide such as sodium, potassium or tetra-alkylammonium cyanide
  • R 3' is H.
  • R 3' is COOR 17 , which may be hydrolyzed and decarboxylated to provide a compound of the Formula (5) wherein R 3' is H.
  • compounds of the Formula (5) wherein R 3' is H may be derived from first,
  • reaction of a compound of the Formula (9) (as described below) wherein R 20 is H and R 3 is H, R 12 or cyclopropyl unsubstituted or substituted by R 9 with a strong base, followed by reaction with an appropriate alkyl or aryl ⁇ -halo carboxylate, such as methyl ⁇ -bromoacetate, will also provide a compound of the Formula (4) wherein R 3 is H, R 12 or cyclopropyl unsubstituted or substituted by R 9 .
  • Reduction of the nitrile group of such compounds of the above Formula (4) or of the nitro group of the above similar compounds of the Formula (5) provides compounds of Formula (7) wherein R 19 is H.
  • R 19 is H; reaction of appropriate compounds of the Formula (8) wherein R 19 is H with a strong base, such as sodium hydride, followed by reaction of the generated amide anion with an appropriate activated alkylating agent, such as a halide, mesylate or tosylate, also provides the
  • X 4 is chloro or bromo and R 3 and R 20 are H;
  • a compound of the Formula (9) wherein R 3 is COOR 17 ,R 20 is H and X 4 is CN may also be obtained by reaction of a compound of the Formula (9) wherein R 3 and R 20 are H and X 4 is CN with a metal hydride, such as sodium hydride, in the presence of a dialkyl or diary1 carbonate, such as dimethyl carbonate.
  • a metal hydride such as sodium hydride
  • such compounds may be obtained by homologation of a compound of the Formula (2) wherein R 3 is H to a compound of the Formula (9) wherein R 3 is COOR 17 and X4 and R 20 are H by any number of known processes, such as reaction with methyl methylsulfinylmethyl sulfide and a base, e.g., sodium hydroxide, followed by treatment with, e.g., alcoholic acid.
  • a suitable base followed by reaction with, e.g., cyanogen chloride or 2-chlorobenzyl thiocyanate, provides compounds of the Formula (9) wherein R 3 is COOR 17 , R 20 is H and X 4 is CN.
  • Formula (7) compounds wherein R 19 is H and R 3 is the protected or unprotected hydroxyl.
  • These Formula (7) compounds may be alkylated on nitrogen and cyclized as described above,then treated with diethylaminosulfur trifluoride to provide the
  • compounds of Formula (la) wherein R 3 represents the remaining R 3 groups of Formula (la) may be derived from the compounds of the Formulas (8) or (la) wherein R 3 is CN by protection of the amide and other sensitive functionality, and manipulation of the CN function as, for example, reduction of the R 3 CN moiety to CHO and functional group transformation of the CHO by any of the standard conditions well known in the art.
  • Formula (2) compounds where R 3 is CH 2 F are obtained by treatment of the Formula (2) compounds where R 3 is CH 3 according to the method of Rozen et al.,
  • X is S(O) m R 12
  • m is 1 or 2
  • the final compound is made from the -SR 12 moiety by oxidizing the intermediate -SR 12 product under conditions well known to those skilled in the art, after the appropriate CONH 2 moiety in the synthetic sequence is dehydrated to the cyano moiety.
  • X and/or X 3 are Br, I, nitro, amine or formyl amine
  • synthesis of these compounds is accomplished by any of the steps described above using a suitably protected amine as X and/or X 3 .
  • Such protecting groups are known to those skilled in the art and are readily disclosed in Greene, T., Protective Groups in Organic Synthesis,
  • the deprotected amine is then appropriately acylated to the formyl amine moiety, oxidized to the NO 2 moiety, or diazotized and displaced by methods well known to those skilled in the art to produce the desired Br or I moiety.
  • Compounds of formula (I) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, parenterally, sublingually, transdermally, rectally, via inhalation or via buccal administration.
  • compositions which are active when given orally can be formulated as syrups tablets, capsules and lozenges.
  • a syrup formulation will be formulated as
  • compositions generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
  • aqueous gums celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • 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.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • 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
  • a typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • 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.
  • Each dosage unit for oral administration contains suitably from 0.001 mg to 100 mg/Kg, and preferably
  • parenteral administration contains suitably from 0.001 mg/Kg to 40 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable salt therof calculated as the free base.
  • Each dosage unit for intranasal contains suitably from 0.001 mg/Kg to 40 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable salt therof calculated as the free base.
  • administration or oral inhalation contains suitably
  • topical formulation contains suitably 001 to 1.0% of a compound of formula (I).
  • Each dosage unit for rectal administration contains suitably 0.01 mg to 100 mg of a compound of formula (I).
  • administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of formula (I) or a pharmaceutically
  • the daily dosage regimen for parenteral administration is suitably abut 0.001 mg/Kg to 40 mg/Kg, for example abut 0.001 mg/Kg to 40 mg/Kg, of a compound of the
  • inhalation is suitably about 10 to about 1200 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit antiinflammatory
  • the active ingredient is administered in an amount sufficient to inhibit TNF production such that normal or subnormal levels are achieved which are sufficient to ameliorate or prevent the disease state.
  • selectivity of compounds is determined using a battery of five distinct PDE isozymes.
  • PDEs la, lb, Ic and III are partially purified using standard
  • PDE IV 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)).
  • IC 50 s for compounds of this invention range from 25 nM to 500 ⁇ M..
  • cAMP Accumulation in U-937 Cells The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues is assessed using ⁇ -937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV. To assess the activity of PDE IV inhibition in intact cells, nondifferentiated U-937 cells (approximately 10 5 cells/reaction tube) were incubated with various concentrations (0.01-100 ⁇ M) of PDE inhibitors for one minute and 1 ⁇ M
  • prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by the addition of 1M potassium
  • Monocytes may be determined by the protocol as described in Badger et al., EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534,
  • bromocyclopentane (32 mL, 0.31 mol) in dimethylformamide (0.25 L) was heated under an argon atmosphere at 100°C. After 4 h, additional bromocyclopentane (8 mL, 0.08 mol) was added and heating was continued for 4 h. The mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ether and aqueous sodium carbonate. The organic extract was washed with aqueous sodium carbonate and dried (potassium carbonate). The solvent was removed in vacuo and the residue was
  • tetrahydrofuran (9mL) was treated with ammonium formate (1.04 g, 16.4 mmol) and 10% palladium on carbon (127 mg) in a suspension of methanol (25 mL). The suspension was stirred for three hours. The reaction was then filtered through celite and washed with methanol. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. After extracting, the organic layer was washed two time with water, dried (potassium carbonate) and concentrated in vacuo .
  • the solvent was removed in vacuo and the residue was treated with cold water and extracted twice with methylene chloride.
  • the organic layer was washed two times with water, dried (potassium carbonate) and concentrated in vacuo .
  • the resin was purified by flash chromatography, eluting with a gradient of 50-100% ethyl acetate/methylene chloride to provide a colorless oil of the title compound (396 mg, 82%).
  • Methyl 3-cyano-3-(3,4-dimethoxyphenyl)propionate (3.0 g, 12 mmol) and 70% perchloric acid (1.9 g) were added to a suspension of 10% palladium on carbon (0.6 g) in
  • the aqueous layer was extracted, the combined organic phase washed with water and dried (sodium sulfate).
  • the solvent was removed in vacuo, and the residue was dissolved in toluene with a catalytic amount of sodium cyanide and was refluxed for 7 h.
  • the solvent was removed in vacuo the residue was dissolved in ethyl acetate and washed with water two times.
  • the organic layer was dried (sodium sulfate) and evaporated.
  • the solvent was removed in vacuo and the residue was dissolved in toluene with a catalytic amount of sodium cyanide and refluxed for 15 hours.
  • the solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water and the organic layer washed with water two times.
  • the organic layer was dried (sodium sulfate) and evaporated.
  • the residue was purified by flash chromatography, eluting with 1:1% ethyl acetate/hexanes, to provide the product (468 mg, 69%).
  • reaction was quenched by adding solid sodium bicarbonate and the reaction mixture was partitioned between methylene chloride and water.
  • the reaction mixture was concentrated in vacuo, water added and the aqueous phase extracted three times with methylene chloride. The extracts were washed with water two times, dried (sodium sulfate) and evaporated to a yellow residue. The residue was
  • reaction mixture was allowed to stir for 24 h at room temperature under an argon atmosphere, and submitted to another two cycles of treatment with acetic anhydride (200 mL, 2.2 mmol; 400 ⁇ L, 4.4 mmol).
  • acetic anhydride 200 mL, 2.2 mmol; 400 ⁇ L, 4.4 mmol.
  • the reaction was poured into ice cold aqueous hydrochloric acid and extracted twice with methylene chloride. The organic extracts were washed with cold dilute
  • EXAMPLE 48 4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-[4-(4,4- dimethyl-2-oxazolin-2-ylcarbonylamino)benzyl]-2- pyrrolidinone a) 4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-[4-(N-1-hydroxy-2-methyl-2-propylcarbamidocarbamido)benzyl]-2-pyrrolidinone To a solution of 1-(4-N-carbomethoxycarbamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (0.125 g, 0.27 mmol) in alumina-treated chloroform (10 mL) was added 2-amino-2-methylpropanol (0.051 mL, 0.54 mmol) and the mixture was stirred under an argon atmosphere overnight.
  • Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • a compound of formula I, (1 ⁇ g to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Step 1 Blend ingredients No. 1, No. 2, No . 3 and No .
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • Step 4 The wet granules are then dried in an oven at
  • Step 5 The dry granules are lubricated with
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount f a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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PCT/US1992/003613 1991-05-02 1992-05-01 Pyrrolidinones WO1992019594A1 (en)

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MX9202090A (es) 1992-11-01
ZA923210B (en) 1993-03-31
PT100441A (pt) 1993-09-30
CA2102106A1 (en) 1992-11-03
CN1067244A (zh) 1992-12-23
AU1917092A (en) 1992-12-21
EP0584208A4 (enrdf_load_stackoverflow) 1994-03-23

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