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WO1993015045A1 - Derives d'acide n-(3-phenylpropyle) oxamique, d'oxamate et d'oxamide - Google Patents

Derives d'acide n-(3-phenylpropyle) oxamique, d'oxamate et d'oxamide Download PDF

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Publication number
WO1993015045A1
WO1993015045A1 PCT/US1993/000557 US9300557W WO9315045A1 WO 1993015045 A1 WO1993015045 A1 WO 1993015045A1 US 9300557 W US9300557 W US 9300557W WO 9315045 A1 WO9315045 A1 WO 9315045A1
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substituted
hydrogen
unsubstituted
formula
compound
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PCT/US1993/000557
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Siegfried Benjamin Christensen, Iv
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-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

Definitions

  • the present invention relates to novel oxamides, 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 hyperactivity of the respiratory tract to external stimuli. It is now understood that the symptoms of chronic asthma are the manifestations of three distinct processes: 1) an early response to antigen, 2) a delayed or late response to antigen, and 3) chronic inflammation and airway hyperactivity. Cockcroft, Ann. Allergy 55:857-862, 1985; Larsen, Hosp. Practice 22:113-127, 1987.
  • 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 sooth 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.
  • 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.
  • 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
  • Torphy "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.
  • 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.
  • 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 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
  • monokines, specifically TNF are implicated in the infection of T lymphocytes with HIV by playing a role in maintaining T lymphocyte activation.
  • monokines, specifically TNF are implicated in activated T cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation.
  • Monokines such as TNF have been shown to activate HTV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad. Sri.. 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells. It has now been discovered that monokines are implicated in certain disease- associated problems such as cachexia and muscle degeneration.
  • TNF monokine activity
  • an HTV-infected individual aids in enhancing the quality of life of HIV-infected patients by reducing the severity of monokine-mediated disease associated problems such as cachexia and muscle degeneration.
  • 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, Vol. 58, No. 9, p. 2750-54 (1990); and Jafari et al.. Journal of Infectious Diseases, Vol. 164, p. 389-95 (1991).
  • Rl s Cj.12 aikyl unsubstituted or substituted by 1 or more halogens, C3.6 cyclic alkyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group, C4.6 cycloalkyl containing one or two unsaturated bonds, C7.11 polycycloalkyl, - (CRi4Ri4) n C(O)-O-(CRi4Ri4) m -R ⁇ o, .(CR 14 Ri4) n C(O)-O-(CRi4Ri4) r -R ⁇ ⁇ , -(CR 14 R 14 ) x OH, -(CR ⁇ 4 Ri4) s O(CRi4R 14 ) m -R ⁇ o.
  • X is YR2. halogen, nitro, NR14R 4, or formamide; X2 is O or NRi4; X3 is hydrogen or X;
  • Y is O or S(O) m ;
  • R2 is -CH3 or -CH2CH3, each may be unsubstituted or substituted by 1 to 5 fluorines;
  • R4 is independently hydrogen, Br, F, Cl, -NR5R16, NR6 R 16 > - N0 2 > -C(Z)R 7 , -S(O) m R 12 , -CN, OR5, -OC(O)NR 5 R ⁇ 6 , (1 or l-(R 5 )-2-imidazolyl), -C(NR 16 )NR 5 R ⁇ 6 , -C(NR 5 )SR 12 , -OC(O)R 5 , -C(NCN)NR 5 R 16 , -C(S)NR 5 R 16 , N(R 16 )C(O)R 15 , oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl, or when R5 and R 15 are NR5R1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S;
  • R5 is independently hydrogen or C ⁇ _4alkyl, unsubstituted or substituted by one to three fluorines;
  • R 6 is R 5 , -C(0)R 5 , -C(0)C(0)R 7 , -C(0)NR 5 R 16 , -S(0) m R 12 , -C(NCN)SR 12 ,
  • R 7 is OR5, -NR5R 6, or R 12 ;
  • Rg is hydrogen or A
  • R9 is hydrogen, F or R ⁇ 2 ; Rio is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi_3alkyl, halo substituted arIyoxyC ⁇ _3alkyl, indanyl, indenyl, C ⁇ _ ⁇ polycyclo-alkyl, furanyl, pyranyl, thienyl, thiopyranyl, (3- or 4-tetrahydropyranyl), (3- or 4-tetrahydrothiopyranyl), 3-tetrahydrofuranyl, 3-tetrahydrothienyl, C3.6 cylcoalkyl, or a C4.gcycloalkyl containing one or two unsaturated bonds, wherein the cylcoalkyl and heterocyclic moieties may be unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;
  • R is 2-tetrahydropyranyl or 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydro ⁇ ienyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;
  • R 2 is C ⁇ _4al yl unsubstituted or substituted by one to three fluorines
  • Rl4 is independently hydrogen or a C _ alkyl unsubstituted or substituted by fluorine;
  • R 5 is 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 Cj_ 2 alkyl groups;
  • R g is OR5 or R5 or when R5 and R g are NR5R6 they may, together with the nitrogen, form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;
  • Rl7 and R 2 6 are independentiy hydrogen, halogen, C1.4a-.kyl, halo-substituted C ⁇ _ 4--lkyl, cyclopropyl unsubstituted or substituted by R9, -CH 2 OR5, -CH2NR5R16, -C(0)OR 5 , -C(0)NR 5 R ⁇ 6 or -C(Z)H;
  • R 20 is -0(CH2) q R 8 , -NR 5 OR 5 , -NR 5 NR 5 R 8 , -NR 5 (CH 2)q R 8 , -OCH 2 NR 5 C(0)R 2 ⁇ , -OCH 2 C(0)NR 22 R 2 3, -OCH(R 5 )OC(0), C ⁇ . 4 alkyl, -OCH(R 5 )C(0)OC ⁇ .3- ⁇ lkyl;
  • R 2 1 is CH3 orphenyl
  • R 22 is hydrogen, CH3, CH 2 CH3, or CH CH 2 OH
  • R 23 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, or CH 2 CONH 2 ;
  • - 4 - A is C ⁇ _6alkyl (2-, 3-, or 4-pyridyl), 4-morpholinyl, 4-piperidinyl, (1-, 2-, 4- or 5- imidazolyl), (2- or 3-thienyl), (2- or 5-pyrimidyl), (4 or 5-thiazolyl), triazolyl or quinolinyl, all of which may be unsubstituted or substituted by one or more R4 groups; or A is -(CH2) r SRi2. or A is a formula of (a) or (b)
  • R4 and R 4 groups on the naphtyl ring may be substituted at any open position;
  • Z is O, NR12, NOR5, NCN, C(-CN) 2 , CR 5 NO 2 , CR 5 C(O)OR 5 , CR 5 C(O)NR 5 R 5 , -C(-CN)NO2, C(-CN)C(O)ORi2 or C(-CN)C(O)NR 5 R 5 ;
  • m is 0 to 2; n is 1 to 4; q is O to 1; r is 1 to 2; s is 2 to 4; x is 2 to 6; y is 1 to 6; z is 0 to 6; or a pharmaceutically acceptable salt thereof; provided that: m is 2 when RIQ is OH in (CRi4Ri4) n -C(O)O-(CRi4Ri4) m -R ⁇ o, (CR14R14 (C(O)NRi4)-(CRi4Ri4)-(
  • Z is 2-6 in -C(R 4Ri4) z R ⁇ o when RJQ is OH.
  • This invention further comprises a method of inhibiting phosphodiesterase TV in an animal, including humans, which method comprises administering to an animal in need thereof an effective amount of a compound of Formula (I).
  • This invention further comprises a method of inhibiting the production of TNF in an animal, including humans which method 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 (HTV), AIDS Related Complex (ARC) or any other disease state associated with an HTV infection, which comprises administering to such a human an effective TNF inhibiting amount of a compound of Formula (I).
  • HTV 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 Formula (I).
  • the compounds of the present invention 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.
  • the 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, HTV-2 and HIN-3, Cytomegalovirus (CMV), Influenza, adenovirus and the 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 T ⁇ F or will elicit T ⁇ F 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 imidaozles, 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.
  • 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 administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • 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.
  • halogen is used to mean chloro, fluoro, bromo or iodo.
  • Alkyl groups may be substituted by one or more halogens up to being perhalogenated.
  • cycloalkyl as used herein is meant to include groups of 3-6 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.
  • 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.
  • the aryl is monocyclic, i.e., phenyl.
  • C7.11 polycycloalkyl examples include bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo [5.2.1.0 2 ' 6 ]decyl, 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.
  • rings when R5 and R ⁇ in the moiety -NR5R1 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 1-imidazolyl, 1-pyrazolyl, 1-triazoly, 2-triazolyl, tetrazolyl, 2-tetrazoyl, morpholinyl, piperazinyl, or pyrrolyl ring.
  • inhibiting the production of TNF means: a) a decrease of excessive in vivo TNF levels in a human to normal levels or below normal levels by inhibition of the in yivo release of TNF 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 TNF levels in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of TNF as a postranslational event.
  • TNF mediated 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 EL-1, or IL-6.
  • cytokine as used herein means any secreted polypeptide that affects the functions of other 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 refe ⁇ -ed 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.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines examples include, but are not limited to Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF ⁇ ) and Tumor Necrosis Factor beta (TNF ⁇ ).
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • TNF ⁇ Tumor Necrosis Factor-alpha
  • TNF ⁇ Tumor Necrosis Factor beta
  • a preferred subgroup of Formula (I) is Formula (lb):
  • Rl is phenyl, benzyl or C _2 alkyl unsubstituted or substituted by 1 or more fluorines, C4.6 cycloalkyl, CH2-cyclopentyl, CH2-cyclopropyl, C7.11 polycycloalkyl, 3-tetrahydrofuranyl, cyclopentenyl, -(CH2) n C(O)-O-(CH 2 ) m CH3, -(CH 2 )2-4OH, -(CH2) s O(CH2) m -CH 3 , -(CH 2 )n-(C(O)NR ⁇ 4 )-(CH2) m -CH3, all of which may be unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group; s is 2 to 4; m is 0 to 2; n is 1 to 3;
  • X is YR2, halogen, nitro, amine, C ⁇ .2dialkylamine, C ⁇ _2monoalkylamine or formamide;
  • Y is O or S(O) m ;
  • R2 is -CH3 or -CH2CH3, each may be unsubstituted or substituted by 1 to 4 fluorines;
  • A is (2-, 3-, or 4-pyridyl), 4-morpholinyl, 4-piperidinyl, (1- or 2-imidazolyl), (2- or 3-thienyl) or (4- or 5-thiazolyl), all of which may be unsubstituted or substituted by one or more: Br, F, Cl, -NR5R6, NR 5 R 16 , NR ⁇ Rifr NO2, -COR7, -S(O) m Ri2, CN, OR 5 , -OC(O)NR5Ri6, (1- or 2-imidazolyl), -C(NRi6)NR5Ri6, -C(NR 5 )SR 2 , -OC(O)R 5 , -C(NCN)NR 5 R 6, -C(S)NR5Ri6, -NRi6C(O)Ri5, oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl; or when R5 and Ri are
  • R5 is independently hydrogen or C ⁇ _4alkyl, unsubstituted or substituted by one to three fluorines;
  • R6 is R 5 , -C(O)R 5 , -C(O)C(O)R 7 , -C(O)NR 5 R ⁇ 6 , -S(O) m R ⁇ 2 , -C(NCN)SR ⁇ 2 or -C(NCN)NR 5 R 6;
  • R7 is OR5, NR5R16 or R 5 ;
  • Rg is H or A;
  • R9 is R5;
  • R 4 is independently hydrogen or a C ⁇ _2 lkyl unsubstituted or substituted by fluorine;
  • R 5 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, mo ⁇ holinyl, piperidinyl, piperazinyl or pyrrolyl, and each of these heterocyclic rings is connected at a carbon atom and may be unsubstituted or substituted by one or two C ⁇ _ 2 alkyl groups;
  • Rj6 is OR5 or R5. or a pharmaceutically acceptable salt thereof;
  • Rl7 and R 2 g are independently hydrogen, halogen, C ⁇ - -dkyl, halo-substituted C ⁇ _ 4alkyl, cyclopropyl unsubstituted or substituted by R9, -CH 2 OR5, -CH NR5R16, -C(0)OR 5 , -C(0)NR 5 R 16 or -C(Z)H;
  • Rig, R 2 4 and R 2 5 are independently H, CN, and C1-.4 alkyl optionally substituted by one or more fluorines;
  • R 19 is hydrogen, -(CH 2 ) m A, or -CH 2 0(CH 2 ) m A;
  • R 20 is 0(CH 2 ) q Rg, -NR 5 OR 5 , NR 5 (CH 2 ) q Rg, -OCH 2 NR 5 C(0)R 2 ;
  • R 2 1 is CH3 or phenyl
  • R 22 is hydrogen, CH3, CH 2 CH 3 , or CH 2 CH 2 OH;
  • R 2 is hydrogen, CH3, CH 2 CH 3 , CH 2 CH 2 OH, or CH 2 CONH 2 ; when A is morpholin-4-yl, piperidin-4-yl, imidazol-4-yl, piperidin-4-yl or imidazol- 1-yl, then q is not 1.
  • Preferred compounds are those in which Rj is CH 2 -cyclopropyl, CH 2 -C5_g cycloalkyl, C4. cycloalkyl, phenyl, tetrahydrofuran-3-yl, 3- or 4-cyclopentenyl, -C ⁇ _ 2 alkyl optionally substituted by one or more fluorines, -(CH 2 ) n C(0)-0-(CH 2 ) m CH3,
  • X 2 is oxygen;
  • X3 is hydrogen;
  • X is YR 2 and Y is 0;
  • R 2 is a C _ 2 alkyl optionally substituted by one or more fluorines;
  • R3 is hydrogen, C ⁇ CR9, CN, C(0)H, CH 2 OH, CH 2 F, CF 2 H, or CF3;
  • Rig is hydrogen, CN or C ⁇ alkyl optionally substituted by one or more fluorines;
  • R 9 is hydrogen or (CH ) m A;
  • R 2 Q is 0(CH 2 ) q R 8 , NR 5 OR 5 , or NR 5 (CH 2 ) q Rg.
  • Ri is C ⁇ _ 2 alkyl substituted by 1 or more fluorines, CH 2 -cyclopropyl, CH -cyclopentyl, cyclopentyl or cyclopentenyl;
  • R is methyl or fluoro substituted C ⁇ _ 2 alkyl;
  • R3 is hydrogen, C ⁇ CH or CN; and
  • A is 2-, 3- or 4-pyridyl, 4-mo ⁇ holinyl, 2-thienyl, 2-imidazole or 4-thiazolyl, each of which may be substituted or unsubstituted by NR5R16 or NR5C(0)R5;
  • R 2 Q is OR5, NR5OR5 or NHCH 2 A.
  • R] is cyclopentyl, CF3, CH 2 F, CHF , CF 2 CHF 2 , CH 2 CF3, CH 2 CHF 2 , CH3, CH 2 -cyclopentyl, CH 2 -cyclopropyl or cyclopentenyl;
  • R 2 is CH3, CF3, CHF 2 , or CH CHF 2 ;
  • one R3 is hydrogen and the other R3 is hydrogen, C ⁇ CH or CN and is in the 4-position.
  • R3 is hydrogen and the other R3 is hydrogen, C ⁇ CH or CN and is in the 4-position.
  • Formula (1) not described therein may be prepared by the analogous processes disclosed herein, which comprises: a) for compounds wherein R3 is H, Ci-2 alkyl optionally substituted by 1 or more fluorines, R17, Rig, R 9, R24, R25 and R26 are H, and wherein Ri represents Ri as defined in relation to a compound of Formula (I) or a group convertible to Ri and X and X3 represents X and X3 as defined in relation to a compound of Formula (I) or a group convertible to X or X3, reacting a compound of the Formula (2)
  • a malonic acid derivative such as malonic acid or a malonic acid half ester
  • a suitable solvent such as pyridine
  • a catalyst at elevated temperatures to provide a compound of the Formula (3), wherein R27 is OH, O-alkyl, O-phenyl, or O-benzyl.
  • Reduction with a suitable reductant such as hydrogen with a catalyst provides a compound of the Formula (4) wherein R3, is as defined above for part a), Ri8, R17 and R24 are H, and R27 is OH, O- alkyl , O-phenyl, or O-benzyl.
  • Convering a compound of Formula (4) wherein R27 is OH to a compound of Formula (4) wherein R27 is NHR19 may be accomplished by any of the standard peptide coupling methods well known in the art, e.g. mixed anhydride formation when R27 is OH followed by reaction with the amine, NH2R19- For those compounds in which R19 does not possess a reducible functionality, reduction of the amide moiety of a compound of the Formula (4) wherein R27 is NHR19 provides a compound of the Formula (5) wherein R3 is as defined above for part a), R17 is H and R19 is as defined in part in Formula (1)
  • Oxidizing a compound of Formula 2' with an oxidizing agent for example pyridium dichromate, provides the ketone of Formula (2) as described above wherein R3 is methyl.
  • This compound is treated with a halogenating agent, for example copper (II) bromide and heated in a suitable solvent to provide the ⁇ -halo ketone of Formula (2") wherein X4 is a halogen, for example, bromide.
  • Displacement of the halogen of Formula (2") by a metal cyanide, such as sodium cyanide, in a suitable solvent, such as dimethylformamide provides, the ⁇ -cyanoketone of Formula (2"), wherein X4 is CN, which is reduced in one or more steps with hydrogen and a catalyst or an appropriate metal hydride to the Formula (5) compound where R3 is OH, and R g, R17, R19 and R24 are H.
  • a metal cyanide such as sodium cyanide
  • a suitable solvent such as dimethylformamide
  • DAST diethylaminosulfur trifluoride
  • Treatment of Formula (1) or Formula (5) compounds where R3 and Rl8 together form a keto moiety with DAST provides the corresponding Formula (1), or Formula (5) compounds where R3 and Rig are both F; which provides the corresponding Formula (1) compounds when treated by any of the methods indicated herein.
  • synthesis of some compounds of Formula (1) when X or X3 are other than Br, I, NO2, or formylamine begins by reaction of a compound of the Formula (2) with a lithium halide and a silyl halide in an appropriate solvent followed by reduction with an appropriate reductant, such as a siloxane, to provide a compound of Formula (6) wherein X5 is halogen.
  • an appropriate reductant such as a siloxane
  • Halide displacement of a compound of Formula (6) by, e.g., the anion of a cyano acetate, provides the compound of the Formula (7) wherein R17 is COOR5 and R5 is other than H.
  • Ester saponifcation and acid decarboxylation provides a compound of Formula (7), wherein R3, R17 and Ri8 are H,
  • R 17 ester group of the above described compounds of Formula (7) may be converted to other compounds of Formula (7) wherein R 7 is, e.g., C(O)OR5, C(O)NR5Ri6, C(Z)H, etc., by standard chemical transformation.
  • Certain compounds of Formula (1) wherein R17 is other than CH2NR5R16 unless suitably protected, are prepared by reacting a compound of Formula (5) with an appropriately activated oxamic acid derivative of a Formula (8) compound wherein Xg is an activating group, well known to those skilled in the art, such as those disclosed in Bodansky fl al.. Peptide Synthesis. Wiley & Sons, publishers (1976) pages 99-109.
  • More preferred X groups are Cl, Br, OCH2CH3, OC(O)CH 3 , OC(O)CF 3 ,O-C(O)-OCH 2 CH 3 , O-C(O)- OCH2CH(CH3)2, or O-C(O)-OCH2-C6Hs in the presence of a non-nucleophilic base.
  • 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.
  • 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.
  • Those of skill in the formulation arts will be capable of preparing appropriate formulations targeted to one or more of these routes of administration.
  • 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 from .01 mg to 30 mg/Kg, and each dosage unit for 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 administration or oral inhalation contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a 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).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • 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 Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for intranasal administration and oral 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 activity, or if used as a TNF inhibitor, 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.
  • Phosphodiesterase inhibitory activity and selectivity of compounds is determined using a battery of five distinct PDE isozymes.
  • the characteristics of these PDEs appear in Table 1.
  • 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 III, guinea-pig heart; and 5) PDE IV, human monocyte.
  • PDEs la, lb, Ic and JH are partially purified using standard chromatographic techniques (Torphy and Cieslinski, Mol. Pharmacol.21:206-214, 1990).
  • PDE TV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-
  • IC50S for compounds of this invention range from 25 nM to 500 mM.
  • U-937 cells a human monocyte cell line that has been shown to contain a large amount of PDE IV.
  • nondifferentiated U-937 cells approximately 10 ⁇ cells/reaction tube
  • PDE inhibitors were incubated with various concentrations (0.01-100 mM) of PDE inhibitors for one minute and 1 mM prostaglandin E2 for an additional four minutes.
  • 5 minutes after initiating the reaction cells were lysed by the addition of 1M potassium carbonate and cAMP content was assessed by RIA.
  • a general protocol for this assay is described in Brooker et al., Radioimmunassay of cyclic AMP and cyclic GMP,
  • EXAMPLE 3 Methyl N-r3-G-Cvclopropylmethoxy-4-difluoromethoxyphenyl)propylloxamate 3a.
  • 4-Difluoromethoxy-3-hydroxybenzaldehyde A vigorously stirred mixture of 3,4- dihydroxybenzaldehyde (50 g, 362 mmol) and potassium carbonate (50 g, 362 mol) in dimethylformamide (250 mL) was heated under an atmosphere of chlorodifluoromethane using a -78 C condenser at 100 C for 5.5h. An additional quantity of potassium carbonate (10 g) was added and the reaction was continued for another 0.5h. .
  • reaction mixture was quenched by the successive dropwise addition of ethyl acetate and then aqueous sodium potassium tartrate, was poured into brine and was extracted twice with methylene chloride.
  • the organic extract was dried (potassium carbonate) and d e solvent was revoved in vacuo to provide the amine.
  • T TE SHEET stirred under an argon atmosphere for 0.5 h, was partitioned between acidic water and methylene chloride and was extracted twice. The organic extract was dried (magnesium sulfate) and evaporated. Purifi-cation by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, provided a tan solid: m.p. 33-35 C. Analysis Calc. for C17H21F2NO5: C 57.14, H 5.92, N 3.92; found: C 57.39, H 6.00, N 3.90.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne de nouveaux oxamides de formule (I) qui inhibent la phosphodiestérase IV (PDE IV) et le facteur de nécrose tumorale (FNT).
PCT/US1993/000557 1992-01-29 1993-01-19 Derives d'acide n-(3-phenylpropyle) oxamique, d'oxamate et d'oxamide WO1993015045A1 (fr)

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US82724492A 1992-01-29 1992-01-29
US07/827,244 1992-01-29
US96863692A 1992-10-29 1992-10-29
US07/968,636 1992-10-29

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Cited By (27)

* Cited by examiner, † Cited by third party
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US5591776A (en) * 1994-06-24 1997-01-07 Euro-Celtique, S.A. Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV
US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
US5665737A (en) * 1994-10-12 1997-09-09 Euro-Celtique, S.A. Substituted benzoxazoles
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
US6268373B1 (en) 1995-06-07 2001-07-31 Euro-Celtique S.A. Trisubstituted thioxanthines
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2091955A1 (fr) * 2007-10-05 2009-08-26 Acucela, Inc. Composés d'alcoxy pour le traitement de maladies
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014131024A2 (fr) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et applications associées
EP2776395A2 (fr) 2011-11-09 2014-09-17 Mylan Laboratories, Limited Procédé pour la préparation de roflumilast
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US9447078B2 (en) 2012-01-20 2016-09-20 Acucela Inc. Substituted heterocyclic compounds for disease treatment
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
CN106146296A (zh) * 2015-04-21 2016-11-23 昆药集团股份有限公司 一种咖啡酸衍生物的制备方法
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient

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WO1992000968A1 (fr) * 1990-07-10 1992-01-23 Smithkline Beecham Corporation Oxamides

Patent Citations (1)

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WO1992000968A1 (fr) * 1990-07-10 1992-01-23 Smithkline Beecham Corporation Oxamides

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US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
US5629285A (en) * 1993-08-23 1997-05-13 Immunex Corporation Inhibitors of TNF-α secretion
US5591776A (en) * 1994-06-24 1997-01-07 Euro-Celtique, S.A. Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV
US5665737A (en) * 1994-10-12 1997-09-09 Euro-Celtique, S.A. Substituted benzoxazoles
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
US6268373B1 (en) 1995-06-07 2001-07-31 Euro-Celtique S.A. Trisubstituted thioxanthines
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US9468598B2 (en) 2002-02-20 2016-10-18 Astrazeneca Ab Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US10188615B2 (en) 2007-10-05 2019-01-29 Acucela Inc. Alkoxy compounds for disease treatment
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US9737496B2 (en) 2007-10-05 2017-08-22 Acucela Inc. Alkoxy compounds for disease treatment
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EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators
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US9447078B2 (en) 2012-01-20 2016-09-20 Acucela Inc. Substituted heterocyclic compounds for disease treatment
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