Claims
- 1. A compound of Formula (1.0.0):
- 2. A compound according to claim 1 wherein the group G2 and the substituents R1 and R2 attached thereto are selected in such a way that the resulting portion of a compound of Formula (1.0.0) is represented by partial Formulas (2.5.1) through (2.5.50):
- 3. A compound according to claim 1 wherein E comprises partial Formulas (1.1.4) and (1.1.10) through (1.1.14), and the meaning of R7B of partial Formula (1.1.4) where v is 0 or 1, or the meaning of R7C of partial Formulas (1.1.10) through (1.1.14) is defined as a member selected from the group consisting of partial Formulas (1.4.1) through (1.4.32):
- 4. A compound according to claim 1 wherein E comprises partial Formulas (1.1.4) and (1.1.9) through (1.1.13) and the meanings of R7B and R7C in said partial Formulas are each independently a member selected from the group consisting of partial Formulas (1.5.1) through (1.5.29):
- 5. A compound according to claim 1 wherein E comprises partial Formula (1.1.15) and is a member selected from the group consisting of partial Formulas (1.7.1) through (1.7.46):
- 6. A compound according to claim 1 wherein m is 1; n is 1; W1 is —O—; W2 is absent; Y is ═C(R1a)—; R1a is —H, —F, —Cl, —CH3, —CF3, or —OCH3; RA and RB are independently —H or —CH3; or RA and RB are taken together to form a —(C3-C7) cycloalkyl-spiro moiety; RC and RD are both —H; and R5 and R6 are taken together to form a moiety selected from the group consisting of partial Formulas (1.3.1) through (1.3.4), (1.3.11), (1.3.12), (1.3.14), and (1.3.15):
- 7. A compound according to claim 1 wherein said compound is a member selected from the group consisting of the following:
4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid 4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (8.5.1); 4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (8.5.2); 4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid 4-(1-hydroxy-cyclobutyl)-benzylamide of Formula (8.5.3); 4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid 4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (8.5.4); 4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (8.5.5); Trans-4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid [4-(1-hydroxy-m-1-methyl-ethyl)-cyclohexylmethyl]-amide of Formula (8.5.6); Trans-4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid [4-(1-hydroxy-ethyl)-cyclohexylmethyl]-amide of Formula (8.5.7); 4-(Pyridin-3-yloxy)-thiazole-5-carboxylic acid 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (8.5.8); 4-({[4-(4-fluoro-phen-4-yloxy)-[1,3]thiazole-5-carbonyl]-amino}-methyl)-benzoic acid of Formula (8.5.9); 4-([{4-Benzo[1,3]dioxol-5-yloxy)-[1,3]thiazole-5-carbonyl]-amino]-methyl}-benzoic acid of Formula (8.5.10); 4-({[4-(Benzo[1,3]dioxol-5-yloxy)-[1,3]thiazole-5-carbonyl]-amino}-methyl)-3-fluoro-benzoic acid of Formula (8.5.11); [4-({[4-(Benzo[2,1,3]thiadiazol-5-yloxy)-[1,3]thiazole-5-carbonyl]-amino}-methyl)-phen-4-yloxy]-acetic acid of Formula (8.5.12); [4-({[4-(Benzo[2,1,3]oxadiazol-5-yloxy)-[1,3]thiazole-5-carbonyl]-amino}-methyl )-phenyl-4-yloxy]-acetic acid of Formula (8.5.13); (±)-2-[4-({[4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid of Formula (8.5.14); (±)-2-[4-({[4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl )-cyclohexyloxy]-propionic acid of Formula (8.5.15); 4-(3-Methoxy-phenoxy)-thiazole-5-carboxylic acid 2-fluoro-4-(pyridin-2-yl methoxy)-benzylamide of Formula (8.5.16); (±)-4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid 2-fluoro-4-[1-(1H-tetrazol-5-yl)-ethoxy]-benzylamide of Formula (8.5.17); (±)-4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid 4-(1-carbamoyl-ethoxy)-2-fluoro-benzylamide of Formula (8.5.18); (±)-2-[3-Fluoro-4-({[4-(3-nitro-phenoxy)-thiazole-5-carbonyl]-amino}-methyl )-phenoxy]-propionic acid of Formula (8.5.19); (±)-4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid 4-[1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethoxy]-benzylamide of Formula (8.5.20); [4-({[4-(3-Cyano-phenoxy)-thiazole-5-carbonyl]-amino}-methyl)-3-fluoro-phenyl]-acetic acid of Formula (8.5.21); 2-[4-({[4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl )-3-fluoro-phenyl]-2-methyl-propionic acid of Formula (8.5.22); 4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid 4-carbamoylmethyl-2-fluoro-benzylamide of Formula (8.5.23); 4-(3-Methoxy-phenoxy)-thiazole-5-carboxylic acid 4-[1-methyl-1-(1H-tetrazol-5-yl)-ethyl]-benzylamide of Formula (8.5.24); 4-(3-Nitro-phenoxy)-thiazole-5-carboxylic acid 4-[(2-cyano-benzoylamino)-methyl]-benzylamide of Formula (8.5.25); Pyridine-2-carboxylic acid 4-({[4-(benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl)-3-fluoro-benzylamide of Formula (8.5.26); 4H-[1,2,4]Triazole-3-carboxylic acid 3-fluoro-4-({[4-(3-methoxy-phenoxy)-thiazole-5-carbonyl]-amino}-methyl)-benzylamide of Formula (8.5.27); 4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid 2-fluoro-4-[(2-methoxy-benzoylamino)-methyl]-benzylamide of Formula (8.5.28); 4-(4-Fluoro-phenoxy)-thiazole-5-carboxylic acid 4-{[(3H-imidazole-4-carbonyl)-amino]-methyl}-benzylamide of Formula (8.5.29); 4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid 4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-fluoro-benzylamide of Formula (8.5.30); (±)-2-[4-({[4-(Benzo[2,1,3]thiadiazol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl)-phenoxy]-propionic acid of Formula (8.5.31); 4′-({[4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-am ino}-methyl)-3′-fluoro-biphenyl-3-carboxylic acid of Formula (8.5.32); 4′-({[4-(3-Cyano-phenoxy)-thiazole-5-carbonyl]-amino}-methyl)-3′-fluoro-biphenyl-4-carboxylic acid of Formula (8.5.33); (±)-2-[4′-({[4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl)-2-fluoro-biphenyl-4-yloxy]-propionic acid of Formula (8.5.34); [2-Fluoro-4′-({[4-(4-fluoro-phenoxy)-thiazole-5-carbonyl]-amino}-methyl)-biphenyl-4-yl]-acetic acid of Formula (8.5.35); 2-[3′—Fluoro-4′-({[4-(3-methoxy-phenoxy)-thiazole-5-carbonyl]-amino}-methyl)-biphenyl-4-yl]-2-methyl-propionic acid of Formula (8.5.36); (±)-4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid {3,2′-difluoro-4′-[1-(1H-tetrazol-5-yl)-ethoxy]-biphenyl-4-ylmethyl}-amide of Formula (8.5.37); 4-(4-Fluoro-phenoxy)-thiazole-5-carboxylic acid {4′-[(2-cyano-benzoylamino)-methyl]-3-fluoro-biphenyl-4-ylmethyl}-amide of Formula (8.5.38); Pyridine-2-carboxylic acid [4′-({[4-(benzo[1,3]dioxol-5-yloxy)-thiazole-5-carbonyl]-amino}-methyl)-3′-fluoro-biphenyl-4-ylmethyl]-amide of Formula (8.5.39); 4-(4-fluoro-phenoxy)-thiazole-5-carboxylic acid [4′-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2′-fluoro-biphenyl-4-ylmethyl]-amide of Formula (8.5.40); 4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid {3-fluoro-4′-[(2-methoxy-benzoylamino)-methyl]-biphenyl-4-ylmethyl}-amide of Formula (8.5.41); 4-(3-Cyano-phenoxy)-thiazole-5-carboxylic acid {2′-fluoro-4′-[1-methyl-1-(1H-tetrazol-5-yl)-ethyl]-biphenyl-4-ylmethyl}-amide of Formula (8.5.42); 4-(3-Chloro-4-fluoro-phenoxy)-thiazole-5-carboxylic acid (4′-carbamoylmethyl-3-fluoro-biphenyl-4-ylmethyl)-amide of Formula (8.5.43); and 4-(Benzo[1,3]dioxol-5-yloxy)-thiazole-5-carboxylic acid (3-fluoro-4′-{[(3H-imidazole-4-carbonyl)-amino]-methyl}-biphenyl-4-ylmethyl)-amide of Formula (8.5.44).
- 8. A pharmaceutical composition for use in treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme, including the D subtype thereof, whereby it regulates the activation and degranulation of eosinophils, comprising a therapeutically effective amount of a compound of Formula (1.0.0) as defined in claim 1, together with a pharmaceutically acceptable carrier therefor.
- 9. A method of treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme, including the D subtype thereof, whereby it regulates the activation and degranulation of eosinophils, comprising administering to said subject in need of said treatment a therapeutically effective amount of a compound of Formula (1.0.0) as defined in claim 1; characterized in that said disease, disorder, or condition comprises one or more members selected from the group consisting of:
asthma of whatever type, etiology, or pathogenesis; or asthma that is a member selected from the group consisting of atopic asthma; non-atopic asthma; allergic asthma, atopic, bronchial, IgE-mediated asthma; bronchial asthma; essential asthma; true asthma, intrinsic asthma caused by pathophysiologic disturbances; extrinsic asthma caused by environmental factors; essential asthma of unknown or inapparent cause; non-atopic asthma; bronchitic asthma; emphysematous asthma; exercise-induced asthma; occupational asthma; infective asthma caused by bacterial, fungal, protozoal, or viral infection; non-allergic asthma; incipient asthma; wheezy infant syndrome; chronic or acute bronchoconstriction; chronic bronchitis; small airways obstruction; and emphysema; obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis; or an obstructive or inflammatory airways disease that is a member selected from the group consisting of asthma; pneumoconiosis; chronic eosinophilic pneumonia; chronic obstructive pulmonary disease (COPD); COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith; COPD that is characterized by irreversible, progressive airways obstruction; adult respiratory distress syndrome (ARDS), and exacerbation of airways hyper-reactivity consequent to other drug therapy; pneumoconiosis of whatever type, etiology, or pathogenesis; or pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease; anthracosis or miners' asthma; asbestosis or steam-fitters' asthma; chalicosis or flint disease; ptilosis caused by inhaling the dust from ostrich feathers; siderosis caused by the inhalation of iron particles; silicosis or grinders' disease; byssinosis or cotton-dust asthma; and talc pneumoconiosis; bronchitis of whatever type, etiology, or pathogenesis; or bronchitis that is a member selected from the group consisting of acute bronchitis; acute laryngotracheal bronchitis; arachidic bronchitis; catarrhal bronchitis; croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; staphylococcus or streptococcal bronchitis; and vesicular bronchitis; bronchiectasis of whatever type, etiology, or pathogenesis; or bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis; sacculated bronchiectasis; fusiform bronchiectasis; capillary bronchiectasis; cystic bronchiectasis; dry bronchiectasis; and follicular bronchiectasis; seasonal allergic rhinitis; or perennial allergic rhinitis; or sinusitis of whatever type, etiology, or pathogenesis; or sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis; acute or chronic sinusitis; and ethmoid, frontal, maxillary, or sphenoid sinusitis; rheumatoid arthritis of whatever type, etiology, or pathogenesis; or rheumatoid arthritis that is a member selected from the group consisting of acute arthritis; acute gouty arthritis; chronic inflammatory arthritis; degenerative arthritis; infectious arthritis; Lyme arthritis; proliferative arthritis; psoriatic arthritis; and vertebral arthritis; gout, and fever and pain associated with inflammation; an eosinophil-related disorder of whatever type, etiology, or pathogenesis; or an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia; pulmonary infiltration eosinophilia; Loffler's syndrome; chronic eosinophilic pneumonia; tropical pulmonary eosinophilia; bronchopneumonic aspergillosis; aspergilloma; granulomas containing eosinophils; allergic granulomatous angiitis or Churg-Strauss syndrome; polyarteritis nodosa (PAN); and systemic necrotizing vasculitis; atopic dermatitis; or allergic dermatitis; or allergic or atopic eczema; urticaria of whatever type, etiology, or pathogenesis; or urticaria that is a member selected from the group consisting of immune-mediated urticaria; complement-mediated urticaria; urticariogenic material-induced urticaria; physical agent-induced urticaria; stress-induced urticaria; idiopathic urticaria; acute urticaria; chronic urticaria; angioedema; cholinergic urticaria; cold urticaria in the autosomal dominant form or in the acquired form; contact urticaria; giant urticaria; and papular urticaria; conjunctivitis of whatever type, etiology, or pathogenesis; or conjunctivitis that is a member selected from the group consisting of actinic conjunctivitis; acute catarrhal conjunctivitis; acute contagious conjunctivitis; allergic conjunctivitis; atopic conjunctivitis; chronic catarrhal conjunctivitis; purulent conjunctivitis; and vernal conjunctivitis; uveitis of whatever type, etiology, or pathogenesis; or uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea; anterior uveitis; iritis; cyclitis; iridocyclitis; granulomatous uveitis; nongranulomatous uveitis; phacoantigenic uveitis; posterior uveitis; choroiditis; and chorioretinitis; psoriasis; multiple sclerosis of whatever type, etiology, or pathogenesis; or multiple sclerosis that is a member selected from the group consisting of primary progressive multiple sclerosis; and relapsing remitting multiple sclerosis; autoimmune/inflammatory diseases of whatever type, etiology, or pathogenesis; or an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders; hemolytic anemia; aplastic anemia; pure red cell anemia; idiopathic thrombocytopenic purpura; systemic lupus erythematosus; polychondritis; scleroderma; Wegner's granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Stevens-Johnson syndrome; idiopathic sprue; autoimmune inflammatory bowel diseases; ulcerative colitis; Crohn's disease; endocrin opthamopathy; Grave's disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; primary biliary cirrhosis; juvenile diabetes or diabetes mellitus type l; anterior uveitis; granulomatous or posterior uveitis; keratoconjunctivitis sicca; epidemic keratoconjunctivitis; diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; psoriatic arthritis; glomerulonephritis with and without nephrotic syndrome; acute glomerulonephritis; idiopathic nephrotic syndrome; minimal change nephropathy; inflammatory/hyperproliferative skin diseases; psoriasis; atopic dermatitis; contact dermatitis; allergic contact dermatitis; benign familial pemphigus; pemphigus erythematosus; pemphigus foliaceus; and pemphigus vulgaris; prevention of allogeneic graft rejection following organ transplantation; inflammatory bowel disease (IBD) of whatever type, etiology, or pathogenesis; or inflammatory bowel disease that is a member selected from the group consisting of ulcerative colitis (UC); collagenous colitis; colitis polyposa; transmural colitis; and Crohn's disease (CD); septic shock of whatever type, etiology, or pathogenesis; or septic shock that is a member selected from the group consisting of renal failure; acute renal failure; cachexia; malarial cachexia; hypophysial cachexia; uremic cachexia; cardiac cachexia; cachexia suprarenalis or Addison's disease; cancerous cachexia; and cachexia as a consequence of infection by the human immunodeficiency virus (HIV); liver injury; pulmonary hypertension; and hypoxia-induced pulmonary hypertension; bone loss diseases; primary osteoporosis; and secondary osteoporosis; central nervous system disorders of whatever type, etiology, or pathogenesis; or a central nervous system disorder that is a member selected from the group consisting of depression; Parkinson's disease; learning and memory impairment; tardive dyskinesia; drug dependence; arteriosclerotic dementia; and dementias that accompany Huntington's chorea, Wilson's disease, paralysis agitans, and thalamic atrophies; infection, especially infection by viruses wherein such viruses increase the production of TNF-α in their host, or wherein such viruses are sensitive to upregulation of TNF-α in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1, HIV-2, and HIV-3; cytomegalovirus, CMV; influenza; adenoviruses; and Herpes viruses, including Herpes zoster and Herpes simplex; yeast and fungus infections wherein said yeast and fungi are sensitive to upregulation by TNF-α or elicit TNF-α production in their host, when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but not limited to, polymixins, Polymycin B; imidazoles, clotrimazole, econazole, miconazole, and ketoconazole; triazoles, fluconazole and itranazole; and amphotericins, Amphotericin B and liposomal Amphotericin B; and ischemia-reperfusion injury; autoimmune diabetes; retinal autoimmunity; chronic lymphocytic leukemia; HIV infections; lupus erythematosus; kidney and ureter disease; urogenital and gastrointestinal disorders; and prostate diseases.
- 10. The combination of a compound of Formula (1.0.0) as defined in claim 1 together with one or more members selected from the group consisting of the following:
(a) Leukotriene biosynthesis inhibitors: 5-lipoxygenase (5-LO) inhibitors and 5-lipoxygenase activating protein (FLAP) antagonists selected from the group consisting of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-791 75; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8); 2,6-di-tert-butylphenol hydrazones of Formula (5.2.10); the class of methoxytetrahydropyrans which includes Zeneca ZD-2138 of Formula (5.2.11); the compound SB-210661 of Formula (5.2.12) and the class to which it belongs; the class of pyridinyl-substituted 2-cyanonaphthalene compounds to which L-739,010 belongs; the class of 2-cyanoquinoline compounds to which L-746,530 belongs; the classes of indole and quinoline compounds to which MK-591, MK-886, and BAY×1005 belong; (b) Receptor antagonists for leukotrienes LTB4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-one class of compounds to which L-651,392 belongs; the class of amidino compounds to which CGS-25019c belongs; the class of benzoxaolamines to which ontazolast belongs; the class of benzenecarboximidamides to which BIIL 284/260 belongs; and the classes of compounds to which zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY×7195 belong; (c) PDE4 inhibitors including inhibitors of the isoform PDE4D; (d) 5-Lipoxygenase (5-LO) inhibitors; or 5-lipoxygenase activating protein (FLAP) antagonists; (e) Dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF); (f) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4; (g) Antihistaminic H1 receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; (h) Gastroprotective H2 receptor antagonists; (i) α1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agents administered orally or topically for decongestant use, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethyinorepinephrine hydrochloride; (j) α1- and α2-adrenoceptor agonists in combination with inhibitors of 5-lipoxygenase (5-LO); (k) Anticholinergic agents including ipratropium bromide; (l) β1- to β4-adrenoceptor agonists including isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; (m) Theophylline and aminophylline; (n) Sodium cromoglycate; (o) Muscarinic receptor (M1, M2, and M3) antagonists; (p) COX-1 inhibitors (NSAIDs); COX-2 selective inhibitors including rofecoxib; and nitric oxide NSAIDs; (q) Insulin-like growth factor type I (IGF-1) mimetics; (r) Ciclesonide; (s) Inhaled glucocorticoids with reduced systemic side effects, including flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate; (t) Tryptase inhibitors; (u) Platelet activating factor (PAF) antagonists; (v) Monoclonal antibodies against endogenous inflammatory entities; (w) IPL 576; (x) Anti-tumor necrosis factor (TNF□) agents including Etanercept, Infliximab, and D2E7; (y) DMARDs including Leflunomide; (z) TCR peptides; (aa) Interleukin converting enzyme (ICE) inhibitors; (bb) IMPDH inhibitors; (cc) Adhesion molecule inhibitors including VLA-4 antagonists; (dd) Cathepsins; (ee) MAP kinase inhibitors; (ff) Glucose-6 phosphate dehydrogenase inhibitors; (gg) Kinin-B1- and B2-receptor antagonists; (hh) Gold in the form of an aurothio group together with various hydrophilic groups; (ii) Immunosuppressive agents, e.g., cyclosporine, azathioprine, and methotrexate; (jj) Anti-gout agents, e.g., colchicine; (kk) Xanthine oxidase inhibitors, e.g., allopurinol; (ll) Uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone; (mm) Antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine; (nn) Growth hormone secretagogues; (oo) Inhibitors of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11); (pp) Transforming growth factor (TGFβ); (qq) Platelet-derived growth factor (PDGF); (rr) Fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (ss) Granulocyte macrophage colony stimulating factor (GM-CSF); (tt) Capsaicin cream; (uu) Anti-emetic agents including NK-1 receptor antagonists and D-4418; and (vv) Anti-depressants.
1.0 REFERENCE TO COPENDING APPLICATIONS
[0001] Reference is made to copending International application and US application based thereon, Serial No. PCT/IB98/00315, both filed Mar. 10, 1998 (Attorney Docket No. PC9762A), and published as WO 98/45268 on Oct. 15, 1998; claiming priority from application Serial No. 60/043403 filed Apr. 4, 1997 (Attorney Docket No. PC9762), now abandoned; which discloses nicotinamide derivatives having biological activity as selective inhibitors of the PDE4D isozyme, and thus useful in the treatment of inflammatory, respiratory and allergic diseases and conditions. Nothing that is disclosed in the above-mentioned applications would teach the person of ordinary skill in the pertinent art the novel compounds of the present invention or the unexpectedly high level of inhibitory selectivity for the PDE4D isozyme which said novel compounds possess.
Provisional Applications (1)
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Number |
Date |
Country |
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60265486 |
Jan 2001 |
US |