(19I United States (12) Patent Application Publication (10) Pub

llIIlIlllIlIlIllIlIllIllIllIIlllIIlllIlIllIIlllIIllIIlllllIIlIlIlIlIllllIlIIIIIIIIIIIIIIII US 20040067954A1 (19i United StateS (12) Patent Application Publication (10) Pub. No. : US 2004/0067954 A1 Eggenweiler et al. (43) Pub. Date: Apr. 8, 2004

(54) BENZOYLPYRIDAZINES (86) PCT No. : PCT/EP01/15070

(76) Inventors: Hans-Michael Eggenweiler, Darmstadt (30) Foreign Application Priority Data (DE); Michael Wolf, Darmstadt (DE); Norbert Beier, Reinheim (DE); Dec. 23, 2000 (DE)...... 100 64 997.1 Joachim Leibrock, Pfungstadt (DE); Michael Gassen, Munchen (DE); Publication Classification Thomas Ehring, Remscheid (DE) (51) Int. Cl...... A61K 31/501; C07D 43/02 Correspondence Address: (52) U. S. Cl. 514/252. 02; 514/252. 06; 544/238; MILLEN, WHITE, ZELANO R BRANIGAN, 514/247 P.C. 2200 CLARENDON BLVD. SUITE 1400 (57) ABSTRACT ARLINGTON, VA 22201 (US)

(21) Appl. No. : 10/451, 393 This invention relates to compounds of the formula (I) in which R', R, R, X and Q are as defined above and their use (22) PCT Filed: Dec. 19, 2001 as PDE IV inhibitors. US 2004/0067954 A1 Apr. 8, 2004

BENZOYLPYRIDAZINES —CH(Hal) —, —C(Hal)~ —, —CHA' —, —CA'A —,— NH —or —NA' —, [0001] The invention relates to compounds of the formula I [0010] and salts and solvates thereof. [0011] 1-Benzoyltetrahydropyridazines as progesterone receptor ligands are described, for example, in J. Med- .Chem. 38, 4878 (1995). Similar compounds are also disclosed in DE 196 32 549 R' A1. N [0012] The invention had the object of finding novel 0 —Q compounds having valuable properties, in particular those 0 X R which can be used for the preparation of medicaments. [0013] It has been found that the compounds of the formula I and salts and solvates thereof have very valuable [0002] in which pharmacological properties as well as being well tolerated. [0003] R' and R are each, independently of one [0014] Compounds of formula I inhibit the PDE IV another, H, OH, OR, SR, SOR, SO~R or Hal, isozyme and thereby have a wide range of therapeutic where R' and R together may alternatively be applications, because of the essential role which the PDE IV —0— CH~ —0—, family of isozymes plays in the physiology of all mammals. The enzymatic role performed by the PDE IV isozymes is R is NHA', [0004] Hal, OH, OA, NO~, NH~, the intracellular hydrolysis of adenosine 3', 5'-monophos- NA'A, COOH, COOA', CONHA', CN, CONH~, phate (cAMP) within pro-inflammatory leukocytes. cAMP, CONA'A, NHCOA', NHS02A', NHCOOA', in turn, is responsible for mediating the elfects of numerous hormones in the body, and as a consequence, PDE IV inhibition plays a significant role in a variety of physiological processes. There is extensive literature in the art describ- ing the elfects of PDE inhibitors on various inflammatory —N —N NH cell responses, which in addition to cAMP elevation, include inhibition of superoxide production, degranulation, chemo- taxis and tumor necrosis factor (TNF) release in eosinophils, neutrophils and monocytes. [0015] The compounds according to the invention can be employed for the treatment of asthmatic diseases. The antiasthmatic action of PDE IV inhibitors has been described, for example, by T. J. Torphy et al. in Thorax, 46, 512-523 (1991) and can be determined, for example, by the method of T. Olsson, Acta allergologica 26, 438-447 (1971). or [0016] Since cAMP inhibits bone-degrading cells and stimulates bone-forming cells (S. Kasugai et al. , M 681 and —N N —SOPH, K. Miyamoto, M 682, in Abstracts of the American Society for Bone and Mineral Research, 18'" Annual Meeting, 1996), the compounds according to the invention can be employed for the treatment of osteoporosis. A', [0005] R is cycloalkyl having from 3 to 7 carbon [0017] The invention therefore furthermore relates to the car- atoms, alkylene-cycloalkyl having from 4 to 8 use of the compounds of the formula I and/or physiologi- bon atoms or alkenyl having from 2 to 8 carbon cally acceptable salts and solvates thereof for the preparation atoms, of a medicament for the treatment and prophylaxis of [0006] A' and A are each, independently of one diseases which are caused by an excessively low cAMP another, alkyl having from 1 to 12 carbon atoms, level and/or can be influenced by an increase in the cAMP which may be substituted by from 1 to 5 F and/or CI level. A' atoms or OH-groups, where and A together may [0018] In addition, the compounds exhibit an antagonistic alternatively be cycloalkyl or cycloalkylene having action to the production of TNF (tumour necrosis factor) and from 3 to 7 ring members, in which one or more CH~ are therefore suitable for the treatment of allergic and groups may be replaced by —S—, — 0—, — NH —, inflammatory illnesses, autoimmune diseases and transplant NA' — —,— NCOA' —or —NCOOA' —, rejection reactions. They can furthermore be employed for [0007] X is H or Hal, the treatment and prophylaxis of memory disorders, tumours, atherosclerosis, rheumatoid arthritis, multiple scle- [0008] Hal is F, CI, Br or I, and rosis, Crohn's disease, atopic dermatitis, diabetes mellitus, ulcerative colitis, cachexia, sepsis and AIDS. [0009] Q is alkyl or alkenyl having from 1 to 15 carbon atoms, in which from 1 to 5 —CH~ —groups [0019] The antiinflammatory action of the substances may be replaced by —0—, — S—, — SO~ —, according to the invention and their elficacy for the treat- US 2004/0067954 A1 Apr. 8, 2004

ment of, for example, autoimmune diseases, such as mul- and Th„and TH~ helper cells. This leukocyte response tiple sclerosis or rheumatoid arthritis, can be determined produces the characteristic cytokine pattern, involving TNF- analogously to the methods of N. Sommer et al. , Nature u, IL-I II, IL-2, and IL-6, as well as IL-10 and IL-13 (Pulkki Medicine 1, 244-248 (1995) or L. Sekut et al. , Clin. Exp. K J: Cytokines and cardiomyocyte death. Ann. Med. 1997 Immunol. 100, 126-132 (1995). 29: 339-343. Birks E J, Yacoub M H: The role of nitric oxide and cytokines in heart failure. Coron. Artery. Dis. 1997 8: [0020] The compounds can be employed for the treatment 389-402). of cachexia. The anti-cachectic action can be tested in TNF-dependent models of cachexia (P. Costelli et al. , J. [0030] The formation of these species has been demon- Clin. Invest. 95, 2367If. (1995); J. M. Argiles et al. , Med. strated in human patients with myocardial ischemia. Animal Res. Rev. 17, 477If. (1997)). models show that cytokine production correlates with the invasion of peripheral macrophages and neutrophils which PDE IV inhibitors can also inhibit the growth of [0021] can spread the damage into the still intact myocardium. tumour cells and are therefore suitable for tumour therapy (D. Marko et al. , Cell Biochem. Biophys. 28, 75If. (1998)). [0031] The main player in the cytokine response, however, The action of PDE IV inhibitors in the treatment of tumours is TNF-u, which integrates inflammatory and pro-apoptotic is described, for example, in WO 95/35281, WO 95/17399 responses and additionally has a direct negative ionotropic and WO 96/00215. elfect on cardiac myocytes (Ceconi C, Curello S, Bachetti T, Corti A, Ferrari R: Tumor necrosis factor in congestive heart invention therefore furthermore to the [0022] The relates failure: a mechanism of disease for the new millennium? use of the compounds of the formula I and/or physiologi- Prog. Cardiovasc. Dis. 1998 41: 25-30. cally acceptable salts and solvates thereof for the preparation of a medicament for the treatment and prophylaxis of [0032] Mann DL: The elfect of tumor necrosis factor- diseases which are caused by excessive production of alpha on cardiac structure and function: a tale of two tumour necrosis factor (TNF) and/or can be influenced by a cytokines. J.Card. Fail. 1996 2: S165-S172. Squadrito F, reduction in the production of TNF. Altavilla D, Zingarelli B, et al: Tumor necrosis factor involvement in myocardial ischaemia-reperfusion injury. [0023] PDE IV inhibitors can prevent mortality in models Eur. J.Pharmacol. 1993 237: 223-230). for sepsis and are therefore suitable for the therapy of sepsis (W. Fischer et al. , Biochem. Pharmacol. 45, 2399If. (1993)). [0033] It has been shown in animal models of myocardial infarction, that TNF-u is rapidly released during the reper- [0024] They can furthermore be employed for the treat- fusion phase (Herskowitz A, Choi S, Ansari AA, Wesselingh ment of memory disorders, atherosclerosis, atopic dermatitis S: Cytokine mRNA expression in postischemic/reperfused and AIDS. myocardium. Am. J.Pathol. 1995 146: 419-428) and that the [0025] The action of PDE IV inhibitors in the treatment of protective elfects of drugs such as dexamethasone (Arras M, asthma, inflammatory diseases, diabetes mellitus, atopic Strasser R, Mohri M, et al: Tumor necrosis factor-alpha is dermatitis, psoriasis, AIDS, cachexia, tumour growth or expressed by monocytes/macrophages following cardiac tumour metastases is described, for example, in EP 779 291. microembolization and is antagonized by cyclosporine. Basic. Res. Cardiol. 1998 93: 97-107), cyclosporin A (Arras [0026] The invention also relates to the use of the com- M, Strasser R, Mohri M, et al: Tumor necrosis factor-alpha pounds of fomula I for the preparation of a medicament to is expressed by monocytes/macrophages following cardiac treat myocardial diseases. microembolization and is antagonized by cyclosporine. Basic. Res. Cardiol. 1998 93: 97-107. [0027] Coronary artery disease is the most common cause of death in the western world. In the presence of a critical [0034] Squadrito F, Altavilla D, Squadrito G, et al: stenosed coronary artery, a decrease of blood flow may Cyclosporin-A reduces leukocyte accumulation and protects result in myocardial ischemia. Initiation of reperfusion against myocardial ischaemia reperfusion injury in rats. results, depending on the severity of the preceding ischemic Eur. J.Pharmacol. 1999 364: 159-168) or clorichromene period, in a reversibly or irreversibly injured myocardium, (Squadrito F, Altavilla D, Zingarelli B, et al: The elfect of which is characterized by a long-lasting depression or an cloricromene, a coumarine derivative, on leukocyte accu- irreversible loss of contractile function. Depending on the mulation, myocardial necrosis and TNF-alpha production in size of the alfected myocardial area, an acute or a chronic myocardial ischaemia-reperfusion injury. Life Sci. 1993 53: heart failure may develop. 341-355)correspond with a reduction of circulating TNF-u. [0028] A particular clinical problem in the above men- [0035] Preferred compounds of formula I are potent tioned scenario is the development of restenosis after a antagonists of macrophage and T-cell cytokine production. primarily successful reperfusion intervention by PTCA, They also inhibit the proliferation of T cells. Consequently, even after stent implantation, thrombolysis or coronary PDE IV inhibition may have a beneficial effect in those artery bypass grafting. myocardial diseases, which are causally linked to cytokine production and inflammatory processes. [0029] From experimental animal and clinical studies evi- dence exists, that in the dilferent above mentioned heart [0036] The invention also relates to the use of the com- diseases, i.e. coronary artery disease itself, reversible or pounds of the formula I and/or physiologically acceptable irreversible myocardial ischemia/reperfusion injury, acute or salts and solvates thereof for the preparation of a medica- chronic heart failure and restenosis, including instent-rest- ment for the treatment and prophylaxis of diseases which are enosis and stent-in-stent-restenosis, inflammatory processes caused by excessive production of macrophages and T-cells play a casual role. These inflammatory processes involve and/or can be influenced by a reduction in macrophage and resident and invading macrophages as well as neutrophils T-cell production. US 2004/0067954 A1 Apr. 8, 2004

[0037] The invention also relates to the use of the com- tis; infectious asthmatic bronchitis; productive bron- pounds of the formula I and physiologically acceptable salts chitis; staphylococcus or streptococcal bronchitis; and/or solvates thereof for the preparation of a medicament and vesicular bronchitis; for the treatment and prophylaxis of diseases which are [0045] bronchiectasis of whatever type, etiology, or caused by excessive proliferation of the T-cells and/or can be pathogenesis; or bronchiectasis that is a member influenced by an inhibition of the proliferation of the T-cells. selected from the group consisting of cylindric bron- [003II] As compared with PDE III inhibitors and the early chiectasis; sacculated bronchiectasis; fusiform bron- PDE IV inhibitor Rolipram, the compounds of the present chiectasis; capillary bronchiectasis; cystic bron- invention are devoid of hemodynamic side elfects, which chiectasis; dry. bronchiectasis; and follicular can be dose limiting for the treatment of most cardiovascular bronchiectasis; disorders. [0046] seasonal allergic rhinitis; or perennial allergic [0039] Preferably, the invention provides for the use of the rhinitis; or sinusitis of whatever type, etiology, or compounds of formula I for preparing a medicament in pathogenesis; or sinuisitis that is a member selected treating or preventing one or members selected from the from the group consisting of purulent or nonpurulent groups of diseases, disorders, and conditions consisting of: sinusitis; acute or chronic sinusitis; and ethmoid, frontal, maxillary, or sphenoid sinusitis, [0040] asthma of whatever type, etiology, or pathogenesis; or asthma that is a member selected from the [0047] rheumatoid arthritis of whatever type, etiol- group consisting of atopic asthma; non-atopic ogy, or pathogenesis; or rheumatoid arthritis that is a asthma; allergic asthma; atopic, bronchial, IgE-me- member selected from the group consisting of acute diated asthma; bronchial asthma; essential asthma; arthritis; acute gouty arthritis; chronic inflammatory true asthma; intrinsic asthma caused by pathophysi- arthritis; degenerative arthritis; infectious arthritis; ologic disturbances; extrinsic asthma caused by Lyme arthritis; proliferative arthritis; psoriatic arthri- environmental factors; essential asthma of unknown tis; and vertebral arthritis; or inapparent cause; non-atopic asthma; bronchitic and fever and associated with asthma; emphysematous asthma; exercise-induced [004II] gout, pain inflammation; asthma; occupational asthma; infective asthma caused by bacterial, fungal, protozoal, or viral infec- [0049] an eosinophil-related disorder of whatever tion; non-allergic asthma; incipient asthma; wheezy type, etiology, or pathogenesis; or an eosinophil- infant syndrome; related disorder that is a member selected from the group consisting of eosinophilia; pulmonary infiltra- [0041] chronic or acute bronchoconstriction; chronic tion eosinophilia; Lolfier's syndrome; chronic eosi- bronchitis; small airways obstruction; and emphy- nophilic pneumonia; tropical pulmonary eosino- sema; philia; bronchopneumonic aspergillosis; [0042] obstructive or inflammatory airways diseases aspergilloma; granulomas containing eosinophils; of whatever type, etiology, or pathogenesis; or an allergic granulornatous angijtis or Churg-Strauss obstructive or inflammatory airways disease that is a syndrome; polyarteritis nodosa (PAN); and systemic member selected from the group consisting of necrotizing vasculitis; asthma; pneumoconiosis; chronic eosinophilic pneu- [0050] atopic dermatitis; or allergic dermatitis; or monia; chronic obstructive pulmonary disease allergic or atopic eczema; (COPD); COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated there- [0051] urticaria of whatever type, etiology, or patho- with; COPD that is characterized by irreversible, genesis; or urticaria that is a member selected from progressive airways obstruction; adult respiratory the group consisting of immune-mediated urticaria; distress syndrome (ARDS), and exacerbation of air- complement-mediated urticaria; urticariogenic mate- ways hyper-reactivity consequent to other drug rial-induced urticaria; physical agent-induced urti- therapy; caria; stressinduced urticaria; idiopathic urticaria; acute urticaria; chronic urticaria; angioedema; cho- pneumoconiosis whatever or [0043] of type, etiology, linergic urticaria; cold urticaria in the autosomal pathogenesis; or pneumoconiosis that is a member dominant form or in the acquired form; contact selected from the consisting of aluminosis or group urticaria; giant urticaria; and papular urticaria; bauxite workers' disease; anthracosis or miners' asthma; asbestosis or steam-fifters' asthma; chalico- [0052] conjunctivitis of whatever type, etiology, or sis or flint disease; ptilosis caused by inhaling the pathogenesis; or conjunctivitis that is a member dust from ostrich feathers; siderosis caused by the selected from the group consisting of actinic con- inhalation of iron particles; silicosis or grinders' junctivitis; acute catarrhal conjunctivitis; acute con- disease; byssinosis or cotton-dust asthma; and talc tagious conjunctivitis; allergic conjunctivitis; atopic pneumoconiosis; conjunctivitis; chronic catarrhal conjunctivitis; purulent conjunctivitis; and vernal conjunctivitis; [0044] bronchitis of whatever type, etiology, or pathogenesis; or bronchitis that is a member selected [0053] uveitis of whatever type, etiology, or patho- from the group consisting of acute bronchitis; acute genesis; or uveitis that is a member selected from the laryngotracheal bronchitis; arachidic bronchitis; group consisting of inflammation of all or part of the catarrhal bronchitis; croupus bronchitis; dry bronchi- uvea; anterior uveitis; iritis; cyclitis; iridocyclitis; US 2004/0067954 A1 Apr. 8, 2004

granulornatous uveitis; nongranulornatous uveitis; [0063] central nervous system disorders of whatever phacoantigenic uveitis; posterior uveitis; choroiditis; type, etiology, or pathogenesis; or a central nervous and chorioretinitis; system disorder that is a member selected from the group consisting of depression; Parkinson's disease; psoriasis; [0054] learning and memory impairment; tardive dyskine- [0055] multiple sclerosis of whatever type, etiology, sia; drug. dependence; arteriosclerotic dementia; and or pathogenesis; or multiple sclerosis that is a mem- dementias that accompany Huntington's chorea, ber selected from the group consisting of primary Wilson's disease, paralysis agitans, and thalamic progressive multiple sclerosis; and relapsing remit- atrophies; sclerosis; ting multiple [0064] infection, especially infection by viruses [0056] autoimmune/inflammatory diseases of what- wherein such viruses increase the production of TNF-u ever type, etiology, or pathogenesis; or an autoim- in their host, or wherein such viruses are mune/inflammatory disease that is a member sensitive to upregulation of TNF-u in their host so selected from the group consisting of autoimmune that their replication or other vital activities are hematological disorders; hemolytic anemia; aplastic adversely impacted, including a virus which is a anemia; pure red cell anemia; idiopathic thrombocy- member selected from the group consisting of HIV- influ- topenic purpura; systemic lupus erythematosus; 1, HIV-2, and HIV-3; cytornegalovirus, CMV; polychondritis; scleroderma; Wegner's granuloma- enza; adenoviruses; and Herpes viruses, including tosis; dermatomyositis; chronic active hepatitis; Herpes zoster and Herpes simplex; myasthenia gravis; Stevens-Johnson syndrome; idio- [0065] yeast and fungus infections wherein said yeast pathic sprue; autoimmune inflammatory bowel dis- and fungi are sensitive to upregulation by TNF-u or Crohn's eases; ulcerative colitis; disease; endocrin elicit TNF-u production in their host, e. g. , fungal opthamopathy; Grave's disease; sarcoidosis; alveo- meningitis; particularly when administered in con- litis; chronic hypersensitivity pneumonitis; primary junction with other drugs of choice for the treatment biliary cirrhosis; juvenile diabetes or diabetes mel- of systemic yeast and fungus infections, including litus type 1; anterior uveitis; granulornatous or pos- but are not limited to, polymixins, e. g. , Polymycin B; terior uveitis; keratoconjunctivitis sicca; epidemic imidazoles, e.g. , clotrimazole, econazole, micona- keratoconjunctivitis; dilfuse interstitial pulmonary zole, and ketoconazole; triazoles, e.g. , fluconazole fibrosis or interstitial lung fibrosis; idiopathic pul- and itranazole; and amphotericins, e.g. , Amphoteri- monary fibrosis; cystic fibrosis; psoriatic arthritis; cin B and liposomal Amphotericin B; glomerulonephritis with and without nephrotic syndrome; acute glomerulonephritis; idiopathic neph- [0066] ischemia-reperfusion injury; autoimmune dia- rotic syndrome; minimal change nephropathy; betes; retinal autoimmunity; chronic lymphocytic inflammatory/hyperproliferative skin diseases; pso- leukemia; HIV infections; lupus erythematosus; kid- riasis; atopic dermatitis; contact dermatitis; allergic ney and ureter disease; urogenital and gastrointesti- contact dermatitis; benign familial pemphigus; pem- nal disorders; and prostate diseases. phigus erythematosus; pemphigus foliaceus; and [0067] In particular, compounds of formula I are useful in pemphigus vulgaris; the treatment of (I) inflammatory diseases and conditions [0057] prevention of allogeneic graft rejection fol- comprising: joint inflammation, rheumatoid arthritis, rheu- lowing organ transplantation; matoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, derma- [005II] inflammatory bowel disease (IBD) of what- titis, and Crohn's disease; (2) respiratory diseases and ever type, etiology, or pathogenesis; or inflammatory conditions comprising: asthma, acute respiratory distress bowel disease that is a member selected from the syndrome, chronic pulmonary inflammatory disease, bron- group consisting of ulerative colitis (UC); collag- chitis, chronic obstructive airway disease, and silicosis; (3) enous colitis; colitis polyposa; transmural colitis; infectious diseases and conditions comprising: sepsis, septic and Crohn's disease (CD); shock, endotoxic shock, gram negative, sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or [0059] septic shock of whatever type, etiology, or fungal infection, and influenza; (4) immune diseases and pathogenesis; or septic shock that is a member conditions comprising: autoimmune diabetes, systemic selected from the group consisting of renal failure; lupus erythematosis, graft vs. host reaction, allograft rejec- acute renal failure; cachexia; malarial cachexia; tions, multiple sclerosis, psoriasis, and allergic rhinitis; and hypophysial cachexia; uremic cachexia; cardiac (5) other diseases and conditions comprising: bone resorp- cachexia; cachexia suprarenalis or Addison's dis- tion diseases; reperfusion injury; cachexia secondary to ease; cancerous cachexia; and cachexia as a conse- infection or malignancy; cachexia secondary to human quence of infection by the human immunodeficiency acquired immune deficiency syndrome (AIDS), human virus (HI V); immuno-deficiency virus (HIV) infection, or AIDS related [0060] liver injury; complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia. [0061] pulmonary hypertension; and hypoxia-in- invention further the combi- duced pulmonary hypertension; [006II] The present relates to nation of a preferred compound of Formula I mentioned [0062] bone loss diseases; primary osteoporosis; and above together with one or more members selected from the secondary osteoporosis; group consisting of the following: (a) leukotriene biosyn- US 2004/0067954 A1 Apr. 8, 2004

thesis inhibitors: 5-lipoxygenase (5-LO) inhibitors and 5-li- gold in the form of an aurothio group together with various poxygenase activating protein (FLAP) antagonists selected hydrophilic groups; (ii) immuno-suppressive agents, e. g. , from the group consisting of zileuton; fenleuton; tepoxalin; cyclosporine, azathioprine, and methotrexate; (jj) anti-gout Abbott-79175; Abbott-85761; N-(5-substituted) thiophene- agents, e. g. , colchicine; (kk) xanthine oxidase inhibitors, 2-alkylsulfonamides; 2, 6-di-tert-butylphenol hydrazones; e.g. , allopurinol; (H) uricosuric agents, e. g. , probenecid, the class of methoxytetrahydropyrans which includes Zen- sulfinpyrazone, and benzbromarone; (mm) antineoplastic eca ZD-2138; the compound SB-210661 and the class to agents, especially antimitotic drugs including the vinca which it belongs; the class of pyridinyl-substituted 2-cy- alkaloids such as vinblastine and vincristine; (nn) growth hormone secretagogues; inhibitors of matrix metallo- anonaphthafene compounds to which L 739,010 belongs; the (oo) proteases i. e. the stromelysins, the collagenases, class of 2-cyanoquinoline compounds to which L-746, 530 (MMPs), , and the gelatinases, as well as aggrecanase; especially belongs; the classes of indole and quinoline compounds to collagenase-1 (MMP-1), collagenase-2 (MMP-8), collage- which MK-591, MK-886, and BAY x 1005 belong; (b) nase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 receptor antagonists for leukotrienes LTB4, LTC4, LTD4, (MMP-10), and stromelysin-3 (MMP-11); (pp) transforming and LTE4 selected from the group consisting of the phe- growth factor (TGFP); (qq) platelet-derived growth factor nothiazin-3-one class of compounds to which L-651,392 (PDGF); (rr) fibroblast growth factor, e.g. , basic fibroblast belongs; the class of amidino compounds to which CGS- growth factor (bFGF); (ss) granulocyte macrophage colony 25019c belongs; the class of benzoxaolamines to which stimulating factor (GM-CSF); (tt) capsaicin; (uu) Tachyki- ontazolast belongs; the class of benzenecarboximidamides nin NK, and NK~ receptor antagonists selected from the to which BHL 284/260 belongs; and the classes of group consisting of NKP-608C; SB233412 (talnetant); and ompounds to which zafirlukast, ablukast, montelukast, pran- D-4418; and (vv) elastase inhibitors selected from the group lukast, verlukast (MK-679), RG-12525, Ro-245913, consisting of UT-77 and ZD-0892. iralukast (CGP 45715A), and BAY x 7195 belong; (c) PDE IV inhibitors; (d) 5-Lipoxygenase (5-1-0) inhibitors; or [0069] The present invention also relates to a combination 5-lipoxygenase activating protein (FLAP) antagonists; (e) of one or more compounds of formula I together with one or dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of more additional therapeutic agents to be co-administered to platelet activating factor (PAF); (f) leukotriene antagonists a patient to obtain some particularly desired therapeutic end (LTRAs) including antagonists of LTB4, LTC4, LTD4, and result. The second, etc. therapeutic agent may also be one or LTE4; (g) antihistaminic H, receptor antagonists including more compounds as described above or one or more PDE IV cetirizine, loratadine, desioratadine, fexofenadine, astemi- inhibitors known in the art and described in detail herein. zole, azelastine, and chlorpheniramine; (h) gastroprotective More typically, the second, etc. therapeutic agent will be H2 receptor antagonists; (i) u, - and u~-adrenoceptor agonist selected from a dilferent class of therapeutic agents. These vasoconstrictor sympatho mimetic agents administered selections are described in detail below. orally or topically for decongestant use, including propyl [0070] As used herein, the terms co-administration", "co- hexedrine, pseu- phenylephrine, phenylpropanolamine, administered", and "in combination with", referring to the doephedrine, naphazoline hydrochloride, oxymetazoline preferred compounds as mentioned above and one or more tetrahydrozoline xylometazo- hydrochloride, hydrochloride, other therapeutic agents, is intended to mean, and does refer line hydrochloride, and ethylnorepinephrine hydrochloride; to and include the following: j) u, - and u2-adrenoceptor agonists in combination with inhibitors of 5-lipoxygenase (5-LO); (k) anticholinergic [0071] (a) simultaneous administration of such com- agents including ipratropium bromide; tiotropiurn bromide; bination of compound(s) and therapeutic agent(s) to a patient in need of treatment, when such compo- oxitropium bromide; pirenzepine; and telenzepine; (I) IIy to I34 adrenoceptor agonists including etaproterenol, isoproter- nents are formulated together into a single dosage enol, isoprenaline, albuterol, salbutamol, formoterol, salme- form which releases said components at substantially terol, terbutaline, orciprenaline, bitolterol mesylate, and the same time to said patient; pirbuterol; (m) methylxanthanines including theophylline [0072] (b) substantially simultaneous administration and aminophylline; (n) sodium cromoglycate; (o) muscar- of such combination of compound(s) and therapeutic inic receptor (MI, M2, and M3) antagonists; (p) COX-1 agent(s) to a patient in need of treatment, when such inhibitors (NSAIDs); COX-2 selective inhibitors including components are formulated apart from each other rofecoxib; and nitric oxide NSAIDs; (q) insulin-like growth into separate dosage forms which are ingested at factor type I (IGF-I) mimetics; (r) ciclesonide; (s) inhaled substantially the same time by said patient, where- glucocorticoids with reduced systemic side elfects, includ- upon said components are released at substantially ing prednisone, prednisolone, flunisolide, triamcinolone the same time to said patient; acetonide, beclomethasone dipropionate, budesonide, fluti- [0073] sequential administration of such combi- casone propionate, and mometasone furoate; (t) tryptase (c) nation of compound(s) and therapeutic agent(s) to a inhibitors; (u) platelet activating factor (PAF) antagonists; patient in need of treatment, when such components (v) monoclonal antibodies active against endogenous are formulated apart from each other into separate inflammatory entities; (w) IPL 576; (x) antitumor necrosis dosage forms which are ingested at consecutive factor (TNFu) agents including Etanercept, Infliximab, and times by said patient with a significant time interval D2E7; (y) DMARDs including Leflunomide; (z) TCR pep- between each ingestion, whereupon said components tides; (aa) interleukin converting enzyme (ICE) inhibitors; are released at substantially dilferent times to said (bb) IMPDH inhibitors; (cc) adhesion molecule inhibitors patient; and including VLA-4 antagonists; (dd) cathepsins; (ee) MAP kinase Inhibitors; (fl) glucose-6 phosphate dehydrogenase [0074] (d) sequential administration of such combi- inhibitors; (gg) kinin-131- and B2-receptor antagonists; (hh) nation of compound(s) and therapeutic agent(s) to a US 2004/0067954 A1 Apr. 8, 2004

patient in need of treatment, when such components useful selective 5-lipoxygenase inhibitors such as the N-hy- are formulated together into a single dosage form droxyurea derivatives zileuton and Abbott-85761, repre- which releases said components in a controlled man- sented below: ner whereupon they are concurrently, consecutively, and/or overlappingly ingested at the same and/or dilferent times by said patient.

[0075] One or more of the compounds of fomula I can also be used in combination with leukotriene biosynthesis inhibitors, i. e. , 5-lipoxygenase inhibitors and/or 5-lipoxygenase activating protein antagonists, to form embodiments of the present invention. 5-Lipoxygenase (5-LO) is one of two Zileuton groups of enzymes that metabolize arachidonic acid, the F other group being the cyclooxygenases, COX-1 and COX-2.

[0076] The 5-lipoxygenase activating protein is an 18 kDa membrane-bound, arachido nate-binding protein which s stimulates the conversion of cellular arachidonic acid by 5-lipoxygenase. The arachidonic acid is converted into 5-hy- OH droperoxyeicosatetraenoic acid (5-HPETE), and this path- N NHn way eventually leads to the production of inflammatory leukotrienes; consequently, blocking the 5-lipoxygenase 0 activating protein or the 5-lipoxygenase enzyme itself pro- Abbott-85761 vides a desirable target for beneficially interfering with that pathway. One such 5-lipoxygenase inhibitor is zileuton. Among the classes of leukotriene synthesis inhibitors which [0081] Another N-hydroxyurea compound is fenleuton are useful for forming therapeutic combinations with the (Abbott-76745): compounds of formula I are the following:

[0077] (a) redox-active agents which include N-hydroxyureas; N-alkylhydroxamid acids; selenite; hydroxybenzofurans; hydroxylamines; and cat- echols; see Ford-Hutchinson et aL, "5-Lipoxyge- nase, " Ann. Rev. Biochem. 63, 383-417, 1994; Weit- N NH2. zel and Wendel, "Selenoenzymes regulate the activity of leukocyte 5-lipoxygenase via the peroxide 0 tone, " J. Biol. Chem. 268, 6288-92, 1993; Bjornstedt Fenleuton et al. "Selenite incubated with NADPH and mam- malian thioredoxin reductase yields selenide, which inhibits lipoxygenase and changes the electron spin [0082] Another N-hydroxyurea compound is Abbott- resonance spectrum of the active site iron, " Bio- 79175 chemistry 35, 8511-6, 1996; and Stewart et al. , "Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors, " J. Med. Chem. 40, 1955- 68, 1997;

[0078] (b) alkylating agents and compounds which 0 0 react with SH groups have been found to inhibit leukotriene synthesis in vitro; see Larsson et al. , "EIfects of 1-chloro-2, 4, 6trinitrobenzene on 5-lipoxygenase activity and cellular leukotriene synthe- Abbott-79175 sis, " Biochem. Pharmacol. 55, 863-71, 1998; and

[0079] (c) competitive inhibitors of 5-lipoxygenase, [0083] Abbott-79175 has a longer duration of action than based on thiopyranoindole and methoxyalkyl thiaz- zileuton; Brooks et al, J. Pharm. Exp. Therapeut 272 724, ole structures which may act as non-redox inhibitors 1995. of 5-lipoxygenase; see Ford-Hutchinson et al. , Ibid. ; [0084] Abbott-85761 is delivered to the lung by aerosol and Hamel et al. "Substituted (pyridylmethox- , administration of a homogeneous, physically stable and y)naphthalenes as potent and orally active 5-lipoxy- nearly monodispersed formulation; Gupta et al. , "Pulmonary genase inhibitors —synthesis, biological profile, and delivery of the 5-lipoxygenase inhibitor, Abbott-85761, in pharmacokinetics of L-739,01 "J.Med. Chem. 40, 0, beagle " International Journal of Pharmaceutics 147, 2866-75, 1997. dogs, 207-218, 1997. [0080] The observation that arachidonoyl hydroxyamate [0085] Fenleuton, Abbott-79175, Abbott-85761 or any of inhibits 5-lipoxygenase has led to the discovery of clinically the above-described derivatives thereof or of tepoxalin, are US 2004/0067954 A1 Apr. 8, 2004

combined with the preferred compounds described above to [0090] where "Het" is benzoxazol-2-yl; benzothiazol-2- form embodiments of the present invention. yl; pyridin-2-yl; pyrazin-2-yl; pyrimidin-2-yl; 4-phenylpy- [0086] Since the elucidation of the 5-LO biosynthetic rimidin-2-yl; 4, 6-diphenylpyrimidin-2-yl; 4-methyl-pyrimi- pathway, there has been an ongoing debate as to whether it din-2-yl; 4, 6-dimethylpyrimidin-2-yl; 4-butylpyrimidin-2- is more advantageous to inhibit the 5-lipoxygenase enzyme yl; 4, 6-dibutylpyrimidin-2-yl; and 4-methyl-6- or to antagonize peptido- or non-peptido leukotriene recep- phenylpyrimidin-2-yl. tors. Inhibitors of 5-lipoxygenase are deemed to be superior to LT-receptor antagonists, since 5-lipoxygenase inhibitors [0091] The N-(5-substituted)-thiophene-2-alkylsulfona- block the action of the full spectrum of 5-LO products, mides or the 2, 6-di-tert-butylphenol hydrazones or any of whereas LT-antagonists produce narrower elfects. Neverthe- the above-described derivatives thereof, are combined with combi- less, embodiments of the present invention include the preferrred compounds mentioned above to form embodi- nations of the preferred compounds with LT-antagonists as ments of the present invention. well as 5-LO inhibitors, as described below. Inhibitors of 5-lipoxygenase having chemical structures that dilfer from [0092] A further distinct class of 5-lipoxygenase inhibitors the classes of N-hydroxyureas and hydroxamic acids is that of methoxytetrahydropyrans to which Zeneca described above are also used in combination with the ZD-2138 belongs preferred compounds to form further embodiments of the present invention. An example of such a dilferent class is the N-(5-substituted)-thiophene-2-alkylsulfonamides of following formula

RX NHS02R' 0. 4 /

0 N [0087] where X is 0 or S; R' is methyl, iso-propyl, n-butyl, n-octyl, or phenyl; and R is n-pentyl, cyclohexyl, phenyl, ZD-2138 tetrahydro-l-naphthyl, 1- or 2-naphthyl, or phenyl mono- or di-substituted by CI, F, Br, CH~, OCH~, SCH~, SO~CH~, CF~, or iso-propyl. A preferred compound is

[0093] ZD-2138 is highly selective and highly active orally in a number of species and has been evaluated in the H N —S02 —CHg treatment of asthma and rheumatoid arthritis by oral admi- ninstration. Further details concerning ZD-2138 and derivatives thereof are disclosed in Crawley et al. , J. Med. Chem. , 0 35, 2600, 1992; and Crawley et al. , J. Med. Chem. 36, 295, 1993.

[0088] A further description of these compounds may be [0094] Another distinct class of 5-lipoxygenase inhibitors found in Beers et al. , "N-(5-substituted) thiophene-2-alkyl- is that to which the SmithKline Beecham compound sulfonamides as potent inhibitors of 5-lipoxygenase, SB-210661 belongs Bioorganic & Medicinal Chemistry 5(4), 779-786, 1997. [0089] Another distinct class of 5-lipoxygenase inhibitors is that of the 2, 6-di-tert-butylphenol hydrazones described in OH Cuadro et al. , "Synthesis and biological evaluation of 2, 6- ' di-tert. -butylphenol hydrazones as 5-lipoxygenase inhibi- '"Y tors, " Bioorganic & Medicinal Chemistry 6, 173-180, 1998. Compounds of this type are represented by 0 P F

[0095] Two further distinct and related classes of 5-lipoxygenase inhibitors comprise a series of pyridinyl-substituted 2-cyanonaphthalene compounds and a series of 2-cyanoquinoline compounds discovered by Merck Frosst. These two classes of 5-lipoxygenase inhibitors are exemplified by L-739, 010 and L-746, 530, respectively: US 2004/0067954 A1 Apr. 8, 2004

ionophore-challenged leukocytes, " J. Biol. Chem. 265, 1436-42, 1990; and Gorenne et al. , "1(R)-2-quinolin-2-yl- methoxy)phenyl)-2-cyclopentyl acetic acid) (BAY x1005), a potent leukotriene synthesis inhibitor: elfects on anti-IgE challenge in human airways, " J. Pharmacol. Exp. Ther. 268, 0 N 868-72, 1994. 0 [0100] MK-591, which has been designated quiflipon sodium, is represented below

S L-739,010 N

~N COONa N 0 0 0

Ct MK-591

[0101] The above-mentioned indole and quinoline classes of compounds and the specific compounds MK-591, IVIK- L-746, 530 886, and BAY x 1005 to which they belong, or any of the above-described derivatives of any of the above-mentioned classes, are combined with the preferred compounds men- Details concerning L-739,010 and L-746, 530 are [0096] tioned above to form embodiments of the present invention. disclosed in Dubeet al. , "Quinolines as potent 5-lipoxygenase inhibitors: synthesis and biological profile of L-746, [0102] One or more of the compounds of formula can also 530, " Bioorganic & Medicinal Chemistry 8, 1255-1260, be used in combination with receptor antagonists for leu- 1998; and in WO 95/03309 (Friesen et al. ). kotrienes LTB4, LTC4, LTD4, and LTE4. The most significant of these leukotrienes in terms of mediating inflamma- The class of methoxytetrahydropyrans including [0097] tory response, are LTB4 and LTD4. Classes of antagonists for Zeneca ZD-2138; or the lead SB-210661 and the compound the receptors of these leukotrienes are described in the class to which it or the series pyridinyl-substi- belongs; of paragraphs which follow. tuted 2-cyanonaphthalene compounds to which L 739,010 belongs, or the series of 2-cyanoquinoline compounds to [0103] 4-Bromo-2, 7-diemethoxy-3H-phenothiazin-3- which L-746, 530 belongs; or any of the above-described ones, including L-651,392, are potent receptor antagonists derivatives of any of the above-mentioned classes, are for LTB4 that are described in U. S. Pat. No. 4, 939,145 combined with the preferred compounds mentioned above to (Guindon et al. ) and U. S. Pat. No. 4, 845, 083 (Lau et al. ) form embodiments of the present invention.

[0098] In addition to the 5-lipoxygenase enzyme, the other Br endogenous agent which plays a significant role in the biosynthesis of the leukotrienes is the 5-lipoxygenase activating protein (FLAP). This role is an indirect one, in contrast to the direct role of the 5-lipoxygenase enzyme. Nevertheless, antagonists of the 5-lipoxygenase activating protein are employed to inhibit the cellular synthesis of leukotrienes, and as such are also used in combination with the preferred compounds mentioned above to form embodi- L-651,392 ments of the present invention. [0099] Compounds which bind to the 5-lipoxygenase activating protein and thereby block utilization of the endog- [0104] A class of amidino compounds that includes CGS- enous pool of archidonic acid which is present have been 25019c is described in U. S. Pat. No. 5,451, 700 (Morrissey synthesized from indole and quinoline structures; see Ford- and Suh); U. S. Pat. No. 5, 488, 160 (Morrissey); and U. S. Pat. Hutchinson et al. , Ibid. ; Rouzer et al. "WK-886, a potent and No. 5, 639,768 (Morrissey and Suh). These receptor antago- specific leukotriene biosynthesis inhibitor blocks and nists for LTB4 are typified by CGS-25019c, which is repre- reverses the membrane association of 5-lipoxygenase in sented below: US 2004/0067954 A1 Apr. 8, 2004

[0108] Ablukast is a receptor antagonist for LTD4 that is designated Ro 23-3544/001: NH

0 0 0H OH.

CGS-25019c

0 OH [0105] Ontazolast, a member of a class of benzoxaolamines that are receptor antagonists for LTB4, is described in Ablukast EP 535 521 (Anderskewitz et A):

[0109] Montelukast is a receptor antagonist for LTD4 0 which is sold commercially under the name Singulair and zP N is described in U. S. Pat. No. 5,565, 473: / S COO Na.

Ontozolast

Montekulast [0106] The same group of workers has also discovered a class of benzenecarboximidamides which are receptor antagonists for LTB4, described in WO 97/21670 (Ander- [0110] Other receptor antagonists for LTD4 include pran- skewitz et al. ); and WO 98/11119 (Anderskewitz et I.); and lukast, verlukast (MK-679), RG-12525, Ro-245913, which are typified by BIIL 284/260: iralukast (CGP 45715A), and BAY x 7195. [0111] The above-mentioned phenothiazin-3-one class of compounds, including L-651,392; the class of amidino compounds that includes CGS-25019c; the class of benzoxaola- HO 0 + 0 mines which includes Ontazolast; the class of benzenecarboximidamides which is typified by BHL 284/260; the hetero-cyclic amide derivatives including Zafirlukast; Ablukast and Montelukast and the classes of compounds to NHz which they belong; or any of the above-described deriva- BIIL 284/260 tives of any of the above-mentioned classes, are combined with the compounds of formula I to form embodiments of the present invention. [0107] Zafirlukast is a receptor antagonist for LTC4, LTD4, One or more of the compounds of formula I can and LTE4 which is sold commercially under the name [0112] also be used together with other therapeutic agents as well Accolate. It belongs to a class of heterocyclic amide as non-therapeutic agents to form combinations that are derivatives described in U. S. Pat. No. 4, 859, 692 (Bernstein further embodiments of the present invention and that are et al. ); U. S. Pat. No. 5,319, 097 (Holohan and Edwards); U. S. useful in the treatment of a significant number of dilferent Pat. No. 5, 294, 636 (Edwards and Sherwood); U. S. Pat. No. diseases, disorders, and conditions described herein. Said 5,482, 963; U. S. Pat. No. 5, 583, 152 (Bernstein et al. and ); embodiments comprise one or more preferred compounds U. S. Pat. No. 5, 612,367 (Timko et al. ): together with one or more of the following: 0— [0113] (a) PDE IV inhibitors; [0114] (b) 5-Lipoxygenase (5-LO) inhibitors; or 5-lipoxygenase activating protein (FLAP) antagonists; 0 [0115] (c) Dual inhibitors of 5-lipoxygenase (5-LO) N and antagonists of platelet activating factor (PAF); H / [0116] (d) Leukotriene antagonists (LTRAS) includ- 0 N ing antagonists of LTB4, LTC4, LTD4, and LTE4,' [0117] (e) Antihistaminic H, receptor antagonists Zafirlukast including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; US 2004/0067954 A1 Apr. 8, 2004 10

[011II] (f) Gastroprotective H~ receptor antagonists; [0142] (dd) Glucose-6 phosphate dehydrogenase inhibitors; [0119] (g) u, - and u~-adrenoceptor agonist vasoconstrictor sympathomimetic agents administered orally [0143] (ee) Kinin-B, - and B~-receptor antagonists; or topically for decongestant use, including propyl- [0144] (5) Gold in the form of an aurothio group hexedrine, phenylephrine, phenylpropanolamine, together with various hydrophilic groups; pseudoephedrine, nap hazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline [0145] (gg) Immunosuppressive agents, e. g. , hydrochloride, xylometazoline hydrochloride, and cyclosporine, azathioprine, and methotrexate; ethylnorepinephrine hydrochloride; [0146] (hh) Anti-gout agents, e.g. , colchicine; [0120] (h) u, - and u~-adrenoceptor agonists in com- [0147] (ii) Xanthine oxidase inhibitors, e.g. , allopu- bination with inhibitors of 5-lipoxygenase (5-LO); rinol; [0121] (i) Anticholinergic agents including ipratro- [014II] (jj) Uricosuric agents, e.g. , probenecid, sulfin- pium bromide; tiotropium bromide; oxitropium bro- pyrazone, and benzbromarone; mide; pirenzepine; and telenzepine; [0149] (kk) Antineoplastic agents, especially antimi- - to JI4-adrenoceptor agonists including [0122] (j) JI, totic drugs including the vinca alkaloids such as metaproterenol, isoproterenol, isoprenaline, vinblastine and vincristine; albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pir- [0150] (II) Growth hormone secretagogues; (mm) buterol; Inhibitors of matrix metalloproteases (MMPs), i.e. , the stromelysins, the collagenases, and the gelati- [0123] (k) Theophylline and aminophylline; nases, as well as aggrecanase; especially collage- [0124] (I) Sodium cromoglycate; nase-1 (MMP-1), collagenase-2 (MMP-S), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), [0125] (m) Muscarinic receptor (MI, M2, and M3) stromelysin-2 (MMP-10), and stromelysin-3 (MMP- antagonists; 11); [0126] (n) COX-1 inhibitors (NSAIDs); COX-2 [0151] (nn) Transforming growth factor (TGFJI); selective inhibitors including rofecoxib; and nitric oxide NSAIDs; [0152] (oo) Platelet-derived growth factor (PDGF); [0153] Fibroblast growth factor, e. g. basic fibro- [0127] (o) Insulin-like growth factor type I (IGF-I) (pp) , mimetics; blast growth factor (bFGF); [0154] Granulocyte macrophage colony stimu- [012II] Ciclesonide; (qq) (p) lating factor (GM-CSF); [0129] Inhaled glucocorticoids with reduced sys- (q) [0155] (rr) Capsaicin; temic side elfects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclom- [0156] (ss) Tachykinin NK, and NK~ receptor ethasone dipropion ate, budesonide, fluticasone antagonists selected from the group consisting of propionate, and mometasone furoate; NKP-60SC; SB-233412 (talnetant); and D4418; [0130] (r) Tryptase inhibitors; [0157] (tt) Elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; and [0131] (s) Platelet activating factor (PAF) antagonists; [015II] (uu) Adenosine A2a receptor agonists. [0132] (t) Monoclonal antibodies active against [0159] The invention was based on the object of discov- endogenous inflammatory entities; ering new uses of compounds having valuable properties, especially those which may be used to prepare medicaments. [0133] (u) IPL 576; [0160] It has been found that the compounds of formula I [0134] (v) Anti-tumor necrosis factor (TNFu) agents and their salts combine very valuable pharmacological prop- including Etanercept, Infliximab, and D2E7; erties with good tolerability for the treatment of myocardial diseases. [0135] (w) DMARDs including Leflunomide; [0161] The compounds of the formula I can be employed [0136] TCR peptides; (x) as medicament active ingredients in human and veterinary [0137] (y) Interleukin converting enzyme (ICE) medicine. They can furthermore be employed as intermedi- inhibitors; ates for the preparation of further medicament active ingredients. [013II] (z) IMPDH inhibitors;. [0162] Accordingly, the invention relates to the com- [0139] (aa) Adhesion molecule inhibitors including pounds of the formula I and to a process for the preparation VLA-4 antagonists; of compounds of the formula I according to Claim 1 and salts and solvates thereof, in particular physiologically tol- [0140] (bb) Cathepsins; erated salts and solvates thereof, characterised in that a [0141] (cc) MAP kinase inhibitors; compound of the formula H US 2004/0067954 A1 Apr. 8, 2004

[017II] Above and below, the radicals R', R, R, R, A', A, Hal, X, Q and L are as defined under the formulae I, II, IH, IV and V, unless expressly stated otherwise. R' [0179] A' and A together may be cycloalkyl or cycloalkylene in cases where A' and A are directly linked to a C- or a N-Atom in a CA'A —,NA'A —or CONA'A -group. Therefore, the C- or N-atom of said groups linked to A' and are members the resulting cycloalkyl- or cycloalk- H A ring of enyl-moiety. Additionally, one or more CH~-groups, preferably only one CH~-group, may be replaced by —S—, [0163] in which —0—, — NH —,— NA' —,— NCOA' —or —NCOOA' —. A' [0164] R' and R are as defined above, [01IIO] and A, independently of one another, are preferably alkyl, furthermore preferably alkyl which is substi- [0165] is reacted with a compound of the formula HI tuted by from 1 to 5 fluorine and/or chlorine atoms, furthermore preferably together alternatively cycloalkyl.

HI [01II1] In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, g, 9 or 10 carbon atoms, 1, 2, 3, 4, 5 or 6 carbon atoms, and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, furthermore preferably butyl, isobutyl, sec-butyl 0 —Q isopropyl, or tert-butyl, but also n-pentyl, isopentyl or 0 X neopentyl, R n-hexyl. Particular preference is given to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl. [0166] in which [01II2] Cycloalkyl preferably has 3-7 carbon atoms and is and are as defined and [0167] X, R Q above, preferably cyclopropyl or cyclobutyl, furthermore prefer- [016II] L is CI, Br, OH or a reactive esterified OH ably cyclopentyl or cyclohexyl, furthermore also cyclohep- group, or tyl, particularly preferably cyclopentyl. 2- [0169] in that a compound of the formula IV [01II3] Alkenyl is preferably allyl, or 3-butenyl, isobutenyl, sec-butenyl, further-more preferably 4-pentenyl, isopentenyl or 5-hexenyl. IV [01II4] Alkylene is preferably unbranched and is preferably methylene or ethylene, furthermore preferably propy- R' lene or butylene.

OH [01II5] Alkylenecycloalkyl preferably has 5-10 carbon atoms and is preferably methylenecyclopropyl, methyl- enecyclobutyl, furthermore preferably methylenecyclopen- tyl, methylenecyclohexyl or methylenecycloheptyl, furthermore alternatively ethylenecyclopropyl, ethylenecyclobutyl, [0170] in which ethylenecyclopentyl, ethylenecyclohexyl or ethylenecyclo- R' heptyl, propylenecyclopentyl, propylenecyclohexyl, butyle- [0171] and R are as defined above, necyclopentyl or butylenecyclohexyl. [0172] is reacted with a compound of the formula V [01II6] Hal is preferably F, CI or Br, but alternatively I, in L— Q — R particular F or CI. [0173] in which [01II7] The radicals R' and R may be identical or dilferent, where R' can be in the ortho- or meta-position to R . [0174] Q and R are as defined in Claim 1, and They are, independently of one another, for example [0175] L is CI, Br, OH or a reactive esterified OH hydroxyl, —S— CH~, —SO —CH~, —SO~CH~, F, CI, Br or I or are However, are pref- group, together methylenedioxy. they erably each methoxy, ethoxy, propoxy, cyclopentoxy, but [0176] and/or in that a basic compound of the for- also fluoro-, difluoro- or trifluoromethoxy or l-fluoro-, mula I is converted into one of its salts by treatment 2-fluoro-, 1,2-difluoro-, 2, 2-difluoro-, 1,2, 2-trifluoro- or 2, 2, with an acid. 2-trifluoroethoxy.

[0177] The term "solvates of the compounds of the [01IIII] R' is particularly preferably methoxy, ethoxy, formula I" is taken to mean adductions of inert cyclopentoxy or isopropoxy. solvent molecules onto the compounds of the for- [01II9] R' is particularly preferably in the ortho-position to mula I which form to their mutual attractive owing R force. Solvates are, for example, monohydrates or dihydrates or alcoholates. [0190] R is particularly preferably methoxy or ethoxy. US 2004/0067954 A1 Apr. 8, 2004 12

[0191] R is preferably A', F, CI, Br or I, hydroxyl, NH~, [0207] CH~ CHINA CH~ CHINA CH~CH~ O-alkyl, NO~, alkylamino, cyclo alkylamino or dialkylamino, where alkyl and cycloalkyl have one of the mean- [020II] CH~CH~CH~NA CH~CH~ ings indicated above, or [0209] CH~CH~CH~NA CH~ CHINA CH~CH~ [0210] CH~CH~CH~NA CH~CH~CH~NA CH~CH~ —N —N NH or [0211] in which A' is as defined above.

0 [0212] The phenyl ring substituted by the —0— Q — R group is preferably meta- or para-substituted, in particular para-substituted.

[0213] Throughout the invention, all radicals which occur more than once may be identical or ditferent, i.e. are independent of one another. Accordingly, the invention [0192] R is particularly preferably NH~, NO~, methoxy, relates, in particular, to the compounds of the formula I in ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy or which at least one of the said radicals has one of the decyloxy, CI or F, dimethylamino, diethylamino, methylamino, ethylamino, preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub- formulae Ia to Ih, which conform to the formula I and in which the radicals not designated in greater detail have the meaning indicated for the formula I, but in which

—N —N NH [0214] in Ia R' and R are each, independently of one or another, OA';

0 [0215] in Ib R' and R are each, independently of one another, OA',

[0216] A' and A are each, independently of one another, alkyl having 1-12 carbon atoms or cycloalkyl having 3-7 carbon atoms;

[0193] in which A is alkyl having from 1 to 12 carbon [0217] in Ic R' and R are each, independently of one atoms. A is preferably n-alkyl having 6, 7, g, 9, 10, 11 or 12 another, OA', carbon atoms, in particular n-alkyl having 7 or 11 carbon atoms. [021II] A' and A are each, independently of one another, alkyl having 1-12 carbon atoms or [0194] X is preferably H, F or CI, especially H. cycloalkyl having 3-7 carbon atoms, [0195] Q is preferably alkylene having from 1 to 10 carbon atoms, in which from 1 to 3 carbon atoms may be [0219] R is A', F, CI, hydroxyl, NH~, OA', NO~, replaced by —0—, — NH —or —NA' —,in particular alkylamino, cycloalkylamino, dialkylamino, methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene or n-heptylene, and the following groups: [01 96] CH~CH~OCH~CH~OCH~CH~ [01 97] CH~CH~OCH~CH~OCH~CH~ —N —N NH or [01 9 II] CH~CH~CH~O CH~CH~ [0199] CH~CH~CH~OCH~CH~OCH~CH~ 0 [0200] CH~CH~CH~OCH~CH~CH~OCH~CH~ [0201] CH~CH~NHCH~CH~NHCH~CH~ [0202] CH~CH~NHCH~CH~NHCH~CH~ [0203] CH~CH~CH~NHCH~CH~ [0220] in Id R' and R are each, independently of one [0204] CH~CH~CH~NHCH~CH~NHCH~CH~ another, OA', [0205] [0221] A' and A are each, independently of one CH~CH~CH~NHCH~CH~CH~NHCH~CH~ another, alkyl having 1-12 carbon atoms or [0206] CH~ CHINA CH~ CHINA CH~CH~ cycloalkyl having 3-7 carbon atoms, US 2004/0067954 A1 Apr. 8, 2004 13

[0222] R is A', F, CI, hydroxyl, NH~, OA', NO~, alkylamino, cycloalkylamino, dialkylamino,

—N —N NH or

—N —N NH 0 or

[0232] in which A is alkyl having from 1 to 12 carbon atoms,

[0233] Q is methylene, ethylene, n-propylene, is alkylene having from 1 to 10 carbon [0223] Q n-butylene, n-pentylene, n-hexylene or n-hepty- atoms, in which from 1 to 3 carbon atoms may be lene or the following groups: replaced by —0—; [0234] CH~CH~OCH~CH~OCH~CH~ [0224] in Ie R' and R are each, independently of one [0235] CH~CH~OCH~CH~OCH~CH~ another, OA', [0236] CH~CH~CH~OCH~CH~ [0225] A' and A are each, independently of one another, alkyl having 1-12 carbon atoms or [0237] CH~CH~CH~OCH~CH~OCH~CH~ cycloalkyl having 3-7 carbon atoms, [023II] CH~CH~CH~OCH~CH~CH~OCH~CH~ [0226] R is NH~, NO~, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy or decy- [0239] CH~CH~NHCH~CH~NHCH~CH~ loxy, CI or F, dimethylamino, diethylamino, [0240] CH~CH~NHCH~CH~NHCH~CH~ methylamino, ethylamino, [0241] CH~CH~CH~NHCH~CH~ [0242] CH~CH~CH~NHCH~CH~NHCH~CH~ [0243] —N —N NH or CH~CH~CH~NHCH~CH~CH~NHCH~CH~

0 [0244] CH~ CHINA CH~CH~NA CH~CH~ [0245] CH~ CHINA CH~CH~NA CH~CH~

[0246] CH~CH~CH~NA CH~CH~ [0247] [0227] in which A is alkyl having from 1 to 12 CH~CH~CH~NA CH~ CHINA CH~CH~ carbon atoms, [024II] [022II] Q is alkylene having from 1 to 10 carbon CH~CH~CH~NA CH~CH~CH~NA CH~CH~ atoms, in which from 1 to 3 carbon atoms may be [0249] in which A' is as defined above; replaced by —0—; [0250] in Ig R' is ethoxy in the ortho-position to R, [0229] in If R' and R are each, independently of one another, OA', [0251] R is methoxy; [0252] in Ih R' is ethoxy in the ortho-position to R, [0230] A' and A are each, independently of one another, alkyl having 1-12 carbon atoms or [0253] R is methoxy, cycloalkyl having 3-7 carbon atoms, [0254] A' and A are each, independently of one another, 1-12 carbon atoms or [0231] R is NH~, NO~, methoxy, ethoxy, propoxy, alkyl having cycloalkyl having 3-7 carbon atoms, isopropoxy, butoxy, pentoxy, hexyloxy or decyloxy, CI or F, dimethylamino, diethylamino, [0255] R is A', F, CI, hydroxyl, NH~, OA', NO~, methylamino, ethylamino, alkylamino, cycloalkylamino, dialkylamino, US 2004/0067954 A1 Apr. 8, 2004 14

[0261] A' and A are each, independently of one another, alkyl having 1-12 carbon atoms or cycloalkyl having 3-7 carbon atoms,

[0262] R is A', F, CI, hydroxyl, NH~, OA', NO~, —N —N NH alkylamino, cycloalkylamino, dialkylamino, or

—N —N NH or

0 [0256] Q is alkylene having from 1 to 10 carbon atoms, in which from 1 to 3 carbon atoms may be replaced by —0—; [0257] in Ii R' is cyclopentyloxy in the ortho-position to R, [0263] Q is alkylene having from 1 to 10 carbon [025II] R is methoxy; atoms, in which from 1 to 3 carbon atoms may be [0259] in Ij R' is cyclopentyloxy in the ortho-position replaced by —0—. to R, [0264] Particular preference is given, to the compounds of [0260] R is methoxy, the formulae I1 to I74:

~0 + N 0 0

I2 (.)

0 + N

~0 + N 0 0 US 2004/0067954 A1 Apr. 8, 2004 15

-continued ~NQ ~0 + N 0 0 0

~0 + N 0 0

~0 + N 0 0 ~n~ ~o~ ~0 + N 0 0

~0 + + &N 0 0 A~ ~N 0 + N

0 + N

0 US 2004/0067954 A1 Apr. 8, 2004 16

-continued

) X / A~ ~AH ~0 + N

A~ ~A ~0 + N 0 0 A~ ~A ~0 + N 0 0

0 + N + NH 0

~0 + N 0 0

~0 + N 0 0 US 2004/0067954 A1 Apr. 8, 2004 17

-continued ' ll ~0 + N 0 0

~0 + N 0 0

0 0

~O ~ + ~N + ~A~ ~Cl 0 0

~0 + N

0 Ct 0 US 2004/0067954 A1 Apr. 8, 2004 18

-continued

~0 + N

0 C1 0

~0 + N

0 C1 0

~0 + + N

0 C1 0 (.)

0 C1 0 A~ ~Cl ~0 + N

0 Ct 0

N N

0 C1 0 US 2004/0067954 A1 Apr. 8, 2004 19

-continued

N N

A~ ~AH ~0 + N

0 C1 0

~0 + + N ~NQ ~0 + + &N

0 C1 0 0 0

0 C1 0

~0 + N

0 C1 0 ~NQ

0 US 2004/0067954 A1 Apr. 8, 2004 20

-continued

NQ 0 + N

~N ~0 + N 0 0

0 ~NH ~0 + N 0 0

0 F ~H~ ~HH ~0 + N

0 F 0 0 ~HH ~0 + N

0 F 0 US 2004/0067954 A1 Apr. 8, 2004 21

-continued 0

~0 + N

0 F 0 O~ ~OH ~0 ~ N

0 F 0

N N

~0 + N

~0 + + N

A~ ~N i I 0 + N

0 US 2004/0067954 A1 Apr. 8, 2004 22

-continued

0 + N

~0 + + N

+ N ~0 + N 0 F 0

~0 ~ N

0 F 0 (.)

N N

0 O~ ~Cl + N ~0 N

0 F 0 US 2004/0067954 A1 Apr. 8, 2004 23

-continued

(.)

N N

~NQ ~0 + N +N~H~ 0 F 0 0

(.)

~N N

0 H~NH

~0 'NN, N

0 F 0 US 2004/0067954 A1 Apr. 8, 2004 24

-continued ' ll

0 Ct 0

~0 + + N 0 F 0

~0 + + &N 0 F 0

~0 + N 0 0 ~NQ

0 0 ~NQ N // S 0// QH 0 ~Cl

N N US 2004/0067954 A1 Apr. 8, 2004 25

-continued ~NQ 170 0 + N QN

0 ~NQ I71 0 + N

0 H~ ~H 172 0 + N

I73

0 + N

I74

0 + N Q NH

and salts and solvates thereof.

[0265] The compounds of the formula I and also the erably methylsulfonyloxy) or arylsulfonyloxy having 6-10 starting materials for their preparation are, prepared by carbon atoms (preferably phenyl- or p-tolylsulfonyloxy, methods known per se, as described in the literature (for furthermore also 2-naphthalenesulfonyloxy). Furthermore, example in the standard works, such as Houben-Weyl, the reactive esterified OH group L can also be obtained in Methoden der organischen Chemic [Methods of Organic situ, for example by reaction with polymeric or monomeric Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise triphenylphosphine or other phosphines and di-tert-butyl under reaction conditions which are known and suitable for azodicarboxylate or analogous azodicarboxylates. the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in [0267] If desired, the starting materials can also be formed greater detail. in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the com- [0266] If L is a reactive esterified OH group, this is pounds of the formula I. On the other hand, it is possible to preferably alkylsulfonyloxy having 1-6 carbon atoms (pref- carry out the reaction stepwise. US 2004/0067954 A1 Apr. 8, 2004 26

[0268] The compounds of the formula I can preferably be from the proportions of said enantiomers found in a racemic obtained by reacting compounds of the formula II with mixture. Where a compound of formula I comprises stere- compounds of the formula IH. oisomers that are diastereomers, there is included within the scope of said compound the individual diastereomers as well [0269] Some of the starting materials of the formula H and as mixtures of any two or more of said diastereomers in any HI are known. If they are not known, they can be prepared proportions thereof. by methods known per se. [0277] By way of illustration, in the case where there is a [0270] In detail, the reaction of the compounds of the single asymmetric carbon atom in a compound of formula I, formula H with the compounds of the formula HI is carried resulting in the ( —)(R) and (+)(S) enantiomers thereof, there out in the presence or absence of a solvent, preferably an is included within the scope of said compound all pharma- — inert solvent, at temperatures between about 20 and about ceutically acceptable salt forms, prodrugs and metabolites 150', preferably between 20 and 100'. thereof which are therapeutically active and useful in treat- or the diseases and conditions described [0271] Examples of suitable solvents are hydrocarbons, ing preventing such as hexane, petroleum ether, benzene, toluene or xylene; further herein. Where a compound of formula I exists in the form of — and enantiomers, there is also included chlorinated hydrocarbons, such as trichloroethylene, 1,2- ( )(R) (+)(S) dichloroethane, tetrachloromethane, chloroform or dichlo- within the scope of said compound the (+)(S) enantiomer — romethane; alcohols, such as methanol, ethanol, isopro- alone, or the ( )(R) enantiomer alone, in the case where all, panol, n-propanol, n-butanol or tert-butanol; ethers, such as substantially all, or a predominant share of the therapeutic activity resides in one of said enantiomers, and/or diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or only unwanted side elfects reside in one said enantiomers. dioxane; glycol ethers, such as ethylene glycol monomethyl only of or monoethyl ether or ethylene glycol dimethyl ether (dig- In the case where there is substantially no dilference between the biological activities of both enantiomers, there lyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide is further included within the scope of said compound of formula I the enantiomer and the — enantiomer (DMF); nitriles, such as acetonitrile; sulfoxides, such as (+)(S) ( )(R) non-racemic dimethyl sulfoxide (DMSO); nitro compounds, such as present together as a racemic mixture or as a mixture in amounts nitromethane or nitrobenzene; esters, such as ethyl acetate, any ratio of proportionate thereof. or mixtures of the said solvents. [0278] For example, the particular biological activities and/or physical and chemical properties of a pair or set of Compounds of the formula I can furthermore be [0272] enantiomers of a compound of formula I where such exist, obtained reacting compounds of the formula IV with by may suggest use of said enantiomers in certain ratios to compounds of the formula V. The starting compounds of the constitute a final therapeutic product. By way of illustration, formulae IV and V are generally known. If they are not in the case where there is a pair of enantiomers, they may be known, they can be prepared methods known per se. by employed in ratios such as 90% (R)-10% (S); 80% (R)-20% [0273] In the compounds of the formula III the radical (S); 70% (R)-30% (S); 60% (R)-40% (S); 50% (R)-50% (S); —CO —L is a pre-activated carboxylic acid, preferably a 40%o (R)-60%o (S); 30%o (R)-70%o (S); 20%o (R)-80%o (S); and carboxylic acid halide. 10% (R)-90% (S). After evaluating the properties of the various enantiomers of a compound of formula I where such [0274] The reaction of the compounds of the formula IV exist, the proportionate amount of one or more of said with compounds of the formula V is carried out under the enantiomers with certain desired properties that will consti- same conditions relating to the reaction time, temperature tute the final therapeutic product can be determined in a and solvent as have been described for the reaction of the straightforward manner. compounds of the formula II with compounds of the formula [0279] The invention therefor also relates to the optically HI. active forms (stereoisomers), the enantiomers, the race- [0275] A compound within the scope of formula I may be mates, the diastereomers and the salts and solvates of these such that its constituent atoms are capable of being arranged compounds. The term solvates of the compounds is taken to in space in two or more dilferent ways, despite having mean adductions of inert solvent molecules onto the com- identical connectivities. As a consequence, said compound pounds which form owing to their mutual attractive force. exists in the form of stereoisomers. Where the stereoisomers Solvates are, for example, monohydrates or dihydrates or are nonsuperimposable mirror images of each other, they are alcoholates. enantiomers which have chirality or handedness, because of [0280] The term pharmaceutically usable derivatives is the presence of one or more asymmetric carbon atoms in taken to mean, for example, the salts of the compounds their constituent structure. Enantiomers are optically active according to the invention and also so-called prodrug com- and therefore distinguishable because they rotate the plane pounds. polarized amounts, but in direc- of light by equal opposite [0281] The term prodrug derivatives is taken to mean, for tions. example, compounds of the formula I which have been [0276] All of these well known aspects of the stereochem- modified with, for example, alkyl or acyl groups, sugars or istry of the compounds of formula I are contemplated to be oligopeptides and which are rapidly cleaved in the organism a part of the present invention. Within the scope of the to give the elfective compounds according to the invention. present invention there is thus included compounds of These also include biodegradable polymer derivatives of the formula I that are stereoisomers, and where these are enan- compounds according to the invention, as described, for tiomers, the individual enantiomers, racemic mixtures of example, in Int. J. Pharm. 115, 61-67 (1995). said enantiomers, and artificial, i.e. , manufactured mixtures [0282] The invention also relates to mixtures of the com- containing proportions of said enantiomers that are dilferent pounds of the formula I according to the invention, for US 2004/0067954 A1 Apr. 8, 2004 27

example mixtures of two diastereomers, for example in the [0291] Preferably, the invention provides for the use of the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100or 1:1000.These are compounds mentioned above for preparing a medicament particularly preferably mixtures of stereoisomeric com- for treating myocardial diseases, where said myocardial pounds. diseases show inflammatory and immunological characteristics. [02II3] A base of the formula I can be converted into the associated acid-addition salt using an acid, for example by [0292] Most preferably, the invention provides for the use reaction of equivalent amounts of the base and the acid in a of the compounds of formula I for preparing a medicament solvent, preferably an inert solvent such as ethanol, followed for treating coronary artery disease, reversible or irreversible by evaporation. Suitable acids for this reaction are, in myocardial ischemia/reperfusion injury, acute or chronic particular, those which give physiologically acceptable heart failure and restenosis, including instent-restenosis and acids. Thus, it is possible to use inorganic acids, for example stent-in-stent-restenosis. sulfuric acid, nitric acid, hydrohalic acids, such as hydro- [0293] Moreover, the invention provides for the use of the chloric acid or hydrobromic acid, phosphoric acids, such as compounds mentioned above for preparing a medicament orthophosphoric acid, or sulfamic acid, furthermore organic for treating ventricular remodeling after infarction or con- acids, in particular aliphatic, alicyclic, araliphatic, aromatic gestive heart failure of dilferent severity (according to or heterocyclic monobasic or polybasic carboxylic, sulfonic NYHA class I to IV). or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, [0294] The preparations for the treatment of the mentioned succinic acid, pimelic acid, fumaric acid, maleic acid, lactic diseases can be used as medicaments in human or veterinary acid, tartaric acid, malic acid, citric acid, gluconic acid, medicine. Suitable excipients are organic or inorganic sub- ascorbic acid, nicotinic acid, isonicotinic acid, methane- or stances which are suitable for enteral (for example oral), ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxy- parenteral, topical or nasal (for example in the form of nasal ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic spray) administration and do no react with the novel com- acid, naphthalenemono- and -disulfonic acids, or laurylsul- pounds, for example water, vegetable oils, benzyl alcohols, furic acid. Salts with physiologically unacceptable acids, for alkylene glycols, polyethylene glycols, glycerol triacetate, example picrates, can be used for the isolation and/or gelatine, carbohydrates, such as lactose or starch, magne- purification of the compounds of the formula I. sium stearates, talc or vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, cap- [02II4] On the other hand, if desired, the free bases of the sules, powders, granules, syrups, juices or drops, suitable for formula I can be liberated from their salts using bases (for rectal administration are suppositories, suitable for example sodium hydroxide, potassium hydroxide, sodium parenteral administration are solutions, preferably oil-based carbonate or potassium carbonate). or aqueous solutions, furthermore suspensions, emulsions or [02II5] The invention relates to compounds of the formula implants, and suitable for topical application are ointments, I and physiologically acceptable salts and solvates thereof as creams or powders. The novel compounds may also be medicaments. lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The prepara- [02II6] The invention also relates to the compounds of the tions indicated may be sterilised and/or comprise assistants, formula I and physiologically acceptable salts and solvates such as lubricants, preservatives, stabilisers and/or wetting thereof as phosphodiesterase IV inhibitors. agents, emulsifiers, salts for modifying the osmotic pressure, bulfer substances, colorants and flavours and/or one or more [02II7] The invention furthermore relates to the use of the further active ingredients, for example one or more vitamins. compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof for the preparation of [0295] The description which follows concerns the man- pharmaceutical preparations, in particular by non-chemical ner in which the preferred compounds as defined above, methods. In this case, they can be converted into a suitable together with other therapeutic agents or non-therapeutic dosage form together with at least one solid, liquid and/or agents where these are desired, are combined with what are semi-liquid excipient or assistant and, if desired, in combi- for the most part conventional pharmaceutically acceptable nation with one or more further active ingredients. carriers to form dosage forms suitable for the dilferent routes of administration which are utilized for any given patient, as [02IIII] The invention furthermore relates to pharmaceuti- well as appropriate to the disease, disorder, or condition for cal preparations comprising at least one compound of the which any given patient is being treated. formula I and/or one of its physiologically acceptable salts and/or solvates. [0296] The pharmaceutical compositions of the present invention comprise any one or more of the above-described [02II9] The preferred compounds of formula I show a inhibitory compounds of the present invention, or a phar- selective inhibition of phosphodiesterase IV, which is asso- maceutically acceptable salt thereof as also above-described, ciated with an intracellular increase in cAMP (N. Sommer et together with a pharmaceutically acceptable carrier in accor- al. , Nature Medicine, 1, 244-248 (1995)). dance with the properties and expected performance of such carriers which are well-known in the pertinent art. [0290] The inhibition of PDE IV can be demonstrated, for example, analogously to C. W. Davis in Biochim. Biophys. [0297] The amount of active ingredient that may be com- Acta 797, 354-362 (1984). The alfinity of the compounds of bined with the carrier materials to produce a single dosage the invention for phosphodiesterase IV is measured by form will vary depending upon the host treated, and the determining their IC5O values (the concentration of inhibitor particular mode of administration. It should be understood, required to achieve 50% inhibition of the enzyme activity). however, that a specific dosage and treatment regimen for US 2004/0067954 A1 Apr. 8, 2004 28

any particular patient will depend upon a variety of factors, [0301] Multiple salts forms are included within the scope including the activity of the specific compound employed, of the present invention where a preferred compound of the the age, body weight, general health, sex, diet, time of present invention contains more than one group capable of administration, rate of excretion, drug combination, and the forming such pharmaceutically acceptable salts. Examples judgment of the treating physician and the severity of the of typical multiple salt forms include, but are not limited to particular disease being treated. The amount of active ingre- bitartrate, diacetate, difumarate, dimeglumine, diphosphate, dient may also depend upon the therapeutic or prophylactic disodium, and trihydrochloride. agent, if any, with which the ingredient is co-administered. [0302] The pharmaceutical compositions of the present invention comprise any one or more of the above-described [029II] The preferred compounds may be utilized in the inhibitory compounds as defined in claims 1, 2 or 3, or a form of acids, esters, or other chemical classes of com- pharmaceutically acceptable salt thereof as also above- pounds to which the compounds described belong. It is also described, together with a pharmaceutically acceptable car- within the of the present invention to utilize those scope rier in accordance with the properties and expected perfor- compounds in the form of pharmaceutically acceptable salts mance of such carriers which are well-known in the derived from various and inorganic acids and bases. organic pertinent art. An active ingredient comprising a preferred compound is often utilized in the form of a salt thereof, especially where [0303] The term "carrier" as used herein includes accept- said salt form confers on said active ingredient improved able diluents, excipients, adjuvants, vehicles, solubilization pharmacokinetic properties as compared to the free form of aids, viscosity modifiers, preservatives and other agents well said active ingredient or some other salt form of said active known to the artisan for providing favorable properties in ingredient utilized previously. The pharmaceutically accept- the final pharmaceutical composition. In order to illustrate able salt form of said active ingredient may also initially such carriers, there follows a brief survey of pharmaceuti- confer a desirable pharmacokinetic property on said active cally acceptable carriers that may be used in the pharma- ingredient which it did not previously possess, and may even ceutical compositions of the present invention, and thereaf- positively alfect the pharmacodynamics of said active ingre- ter a more detailed description of the various types of dient with respect to its therapeutic activity in the body. ingredients. Typical carriers include but are by no means limited to, ion exchange compositions; alumina; aluminum The pharmacokinetic properties of said active [0299] stearate; lecithin; serum proteins, e.g. , human serum albu- ingredient which may be favorably alfected include, e.g. , the min; phosphates; glycine; sorbic acid; potassium sorbate; manner in which said active ingredient is transported across partial glyceride mixtures of saturated vegetable fatty acids; cell membranes, which in turn may directly and positively hydrogenated palm oils; water; salts or electrolytes, e. g. , alfect the absorption, distribution, biotransformation and prolamine sulfate, disodium hydrogen phosphate, potassium excretion of said active ingredient. While the route of hydrogen phosphate, sodium chloride, and zinc salts; col- administration of the pharmaceutical composition is impor- loidal silica; magnesium trisilicate; polyvinyl pyrrolidone; tant, and various anatomical, physiological and pathological cellulose-based substances; e.g. , sodium carboxy-methylcel- factors can critically alfect bioavailability, the solubility of lulose; polyethylene glycol; polyacrylates; waxes; polyeth- char- said active ingredient is usually dependent upon the ylenepolyoxypropylene-block polymers; and wool fat. acter of the particular salt form thereof which it utilized. Further, as the artisan understands, an aqueous solution of [0304] More particularly, the carriers used in the pharma- said active ingredient will provide the most rapid absorption ceutical compositions of the present invention comprise of said active ingredient into the body of a patient being various classes and species of additives which are members treated, while lipid solutions and suspensions, as well as independently selected from the groups consisting essen- solid dosage forms, will result in less rapid absorption of tially of those recited in the following paragraphs. said active ingredient. Oral ingestion of said active ingre- [0305] Acidifying and alkalizing agents are added to dient is the most preferred route of administration for obtain a desired or predetermined pH and comprise acidi- reasons of safety, convenience, and economy, but absorption fying agents, e.g. , acetic acid, glacial acetic acid, malic acid, of such an oral dosage form can be adversely alfected by and propionic acid. Stronger acids such as hydrochloric acid, physical characteristics such as polarity, emesis caused by nitric acid and sulfuric acid may be used but are less irritation of the gastrointestinal mucosa, destruction by preferred. Alkalizing agents include, e. g. , edetol, potassium digestive enzymes and low pH, irregular absorption or carbonate, potassium hydroxide, sodium borate, sodium propulsion in the presence of food or other drugs, and carbonate, and sodium hydroxide. Alkalizing agents which metabolism by enzymes of the mucosa, the intestinal flora, contain active amine groups, such as diethanolamine and or the liver. Formulation of said active ingredient into trolamine, may also be used. dilferent harmaceutically acceptable salt forms may be elfective in overcoming or alleviating one or more of the [0306] Aerosol propellants are required where the phar- above-recited problems encountered with absorption of oral maceutical composition is to be delivered as an aerosol dosage forms. under significant pressure. Such propellants include, e. g. , acceptable fluorochlorohydrocarbons such as dichlorodif- Among the pharmaceutical salts recited further [0300] luoromethane, dichlorotetrafluoroethane, and trichlo- above, those which are preferred include, but are not limited romonofluoromethane; nitrogen; or a volatile hydrocarbon to acetate, besylate, citrate, fumarate, gluconate, hemisuc- such as butane, propane, isobutane or mixtures thereof. cinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, piv- [0307] Antimicrobial agents including antibacterial, anti- alate, sodium phosphate, stearate, sulfate, sulfosalicylate, fungal and antiprotozoal agents are added where the phar- tartrate, thiomalate, tosylate, and tromethamine. maceutical composition is topically applied to areas of the US 2004/0067954 A1 Apr. 8, 2004 29

skin which are likely to have swered adverse conditions or valacyclovir; antihistamines for treating pruritis, atopic and sustained abrasions or cuts which expose the skin to infec- contact dermatitis, e.g. , diphenhydramine, terfenadine, tion by bacteria, fungi or protozoa. Antimicrobial agents asternizole, loratadine, cetirizi, ne, acrivastine, and temelas- include such compounds as benzyl alcohol, chlorobutanol, tine; topical anesthetics for relieving pain, irritation and phenylethyl alcohol, phenyl-mercuric acetate, potassium itching, e.g. , benzocaine, lidocaine, dibucaine, and pramox- sorbate, and sorbic acid. Antifungal agents include such ine hydrochloride; topical analgesics for relieving pain and compounds as benzoic acid, butylparaben, ethylparaben, inflammation, e. g. , methyl salicylate, camphor, menthol, and methylparaben, propylparaben, and sodium benzoate. resorcinol; topical antiseptics for preventing infection, e. g. , benzalkonium chloride and povidone-iodine; and vitamins [0308] Antimicrobial preservatives are added to the phar- and derivatives thereof such as tocopherol, tocopherol maceutical compositions of the present invention in order to acetate, retinoic acid and retinol. protect them against the growth of potentially harmful microorganisms, which usually invade the aqueous phase, [0313] Dispersing and suspending agents are used as aids but in some cases can also grow in the oil phase of a for the preparation of stable formulations and include, e. g. , composition. Thus, preservatives with both aqueous and poligeenan, povidone, and silicon dioxide. lipid solubility are desirable. Suitable antimicrobial preser- [0314] Emollients are agents, preferably non-oily and vatives include, e. g. , alkyl esters of p-hydroxybenzoic acid, water-soluble, which soften and soothe the skin, especially propionate salts, phenoxyethanol, methylparaben sodium, skin that has become dry because of excessive loss of water. propylparaben sodium, sodium dehydroacetate, benzalko- Such agents are used with pharmaceutical compositions of nium chloride, benzethonium chloride, benzyl alcohol, the present invention which are intended for topical appli- hydantoin derivatives, quaternary ammonium compounds cations, and include, e. hydrocarbon oils and waxes, and cationic polymers, imidazolidinyl urea, diazolidinyl g. , triglyceride esters, acetylated monoglycerides, methyl and urea, and trisodium ethylenediamine tetracetate (EDTA). other alkyl esters of fatty acids, o-C~o fatty acids, Preservatives, are preferably employed in amounts ranging Cyp Cpp C, Cyp Cpp fatty alcohols, lanolin and derivatives, polyhydric from about 0.01% to about 2.0% by weight of the total alcohol esters such as polyethylene glycol (200-600), poly- composition. oxyethylene sorbitan fatty acid esters, wax esters, phospho- [0309] Antioxidants are added to protect all of the ingre- lipids, and sterols; emulsifying agents used for preparing dients of the pharmaceutical composition from damage or oil-in-water emulsions; excipients, e.g. , laurocapram and degradation by oxidizing agents present in the composition polyethylene glycol monomethyl ether; humectants, e. g. , itself or the use environment, e. g. , anoxomer, ascorbyl sorbitol, glycerin and hyaluronic acid; ointment bases, e. g. , palmitate, butylated hydroxyanisole, butylated hydroxytolu- petrolatum, polyethylene glycol, lanolin, and poloxamer; ene, hypophosphorous acid, potassium metabisulfite, propyl penetration enhancers, e.g. , dimethyl isosorbide, diethyl- octyl and dodecyl gallate, sodium metabisulfite, sulfur diox- glycol monoethylether, 1-dodecylazacycloheptan-2-one, ide, and tocopherols. and dimethylsulfoxide (DMSO); preservatives, e.g. , benzalkonium chloride, benzethonium chloride, alkyl esters of [0310] agents are used to maintain a desired pH p Burring hydroxybenzoic acid, hydantoin derivatives, cetylpyri- of a composition once established, from the eKects of dinium chloride, propylparaben, quaternary ammonium outside agents and shifting equilibria of components of the compounds such as potassium benzoate, and thimerosal; composition. The may be selected from among burring sequestering agents comprising cyclodextrins; solvents, e. those familiar to the artisan skilled in the preparation of g. , acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, pharmaceutical compositions, e. g. , calcium, acetate, potas- cottonseed oil, ethyl acetate, glycerin, hexylene sium metaphosphate, potassium phosphate monobasic, and glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, meth- tartaric acid. ylene chloride, mineral oil, peanut oil, phosphoric acid, [0311] Chelating agents are used to help maintain the ionic polyethylene glycol, polyoxypropylene 15 stearyl ether, strength of the pharmaceutical composition and bind to and propylene glycol, propylene glycol diacetate, sesame oil, electively remove destructive compounds and metals, and and purified water; stabilizers, e. g. , calcium saccharate and include, e.g. , edetate dipotassium, edetate disodium, and thymol; surfactants, e. g. , lapyrium chloride; laureth 4, ie. , edetic acid. u-dodecyl-cu-hydroxy-poly(oxy-1, 2-ethanediyl) or polyethylene glycol monododecyl ether. [0312] Dermatologically active agents are added to the pharmaceutical compositions of the present invention where [0315] Emulsifying agents, including emulsifying and they are to be applied topically, and include, e. g. , wound stiffening agents and emulsion adjuncts, are used for pre- healing agents such as peptide derivatives, yeast, panthenol, paring oil-in-water emulsions when these form the basis of hexylresorcinol, phenol, tetracycline hydrochloride, lamin the pharmaceutical compositions of the present invention. and kinetin; retinoids for treating skin cancer, e.g. , retinol, Such emulsifying agents include, e. g. , non-ionic emulsifiers tretinoin, isotretinoin, etretinate, acitretin, and arotinoid; such as C, o-C~o fatty alcohols and said fatty alcohols con- mild antibacterial agents for treating skin infections, e.g. , densed with from 2 to 20 moles of ethylene oxide or resorcinol, salicylic acid, benzoyl peroxide, erythromycin- propylene oxide, (C~-C»)alkyl phenols condensed with benzoyl peroxide, erythromycin, and clindamycin; antifun- from 2 to 20 moles of ethylene oxide, mono- and di-C, o-C~o gal agents for treating tinea corporis, tinea pedis, candidiasis fatty acid esters of ethylene glycol, Cyp Cpp fatty acid and tinea versicolor, e.g. , griseofulvin, azoles such as monoglyceride, diethylene glycol, polyethylene glycols of miconazole, econazole, itraconazole, fluconazole, and keto- MW 200 6000, polypropylene glycols of MW 200-3000, and conazole, and allylamines such as naftifine and terfinafine; particularly sorbitol, sorbitan, polyoxyethylene sorbitol, antiviral agents for treating cutaneous herpes simplex, her- polyoxyethylene sorbitan, hydrophilic wax esters, ceto- pes zoster, and chickenpox, e.g. , acyclovir, famciclovir, and stearyl alcohol, oleyl alcohol, lanolin alcohols, cholesterol, US 2004/0067954 A1 Apr. 8, 2004 30

mono- and di-glycerides, glyceryl monostearate, polyethyl- hol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene ene glycol monostearate, mixed mono- and distearic esters glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, of ethylene glycol and polyoxyethylene glycol, propylene methylene chloride, mineral oil, peanut oil, phosphoric acid, glycol monostearate, and hydroxypropyl cellulose. Emulsi- polyethylene glycol, polyoxypropylene 15 stearyl ether, fying agents which contain active amine groups may also be propylene glycol, propylene glycol diacetate, sesame oil, used and typically include anionic emulsifiers such as fatty and purified water. acid soaps, e. g. , sodium, potassium and triethanolamine [0321] Stabilizers which are suitable for use include, e. g. soaps of fatty acids; alkali metal, ammonium or , Cyp Cpp calcium saccharate and thymol. substituted ammonium (Cyp Cgp)alkyl sulfates, (C, o- C3Q)alkyl sulfonates, and (Cyp C5p)alkyl ethoxy ether sul- [0322] Stiffening agents are typically used in formulations fonates. Other suitable emulsifying agents include castor oil for topical applications in order to provide desired viscosity and hydrogenated castor oil; lecithin; and polymers of and handling characteristics and include, e.g. , cetyl esters 2-propenoic acid together with polymers of acrylic acid, wax, myristyl alcohol, parafin, synthetic parafin, emulsify- both cross-linked with allyl ethers of sucrose and/or pen- ing wax, microcrystalline wax, white wax and yellow wax. taerythritol, having varying viscosities and identified by [0323] Sugars are often used to impart a variety of desired product names carbomer 910, 934, 934P, 940, 941, and characteristics to the pharmaceutical compositions of the 1342. Cationic emulsifiers having active amine groups may present invention and in order to improve the results also be used, including those based on quaternary ammo- obtained, and include, e.g. , monosaccharides, disaccharides nium, morpholinium and pyridinium compounds. Similarly, and polysaccharides such as glucose, xylose, fructose, reose, amphoteric emulsifiers having active amine groups, such as ribose, pentose, arabinose, allose, tallose, altrose, mannose, cocobetaines, lauryl dimethylamine oxide and cocoylimida- galactose, lactose, sucrose, erythrose, glyceraldehyde, or zoline, may be used. Useful emulsifying and stiffening any combination thereof. agents also include cetyl alcohol and sodium stearate; and emulsion adjuncts such as oleic acid, stearic acid, and stearyl [0324] Surfactants are employed to provide stability for alcohol. multi-component pharmaceutical compositions of the present invention, enhance existing properties of those com- [0316] Excipients include, e.g. , laurocapram and polyeth- positions, and bestow desirable new characteristics on said ylene glycol monomethyl ether. compositions. Surfactants are used as wetting agents, anti- [0317] Where the pharmaceutical composition of the foam agents, for reducing the surface tension of water, and present invention is to be applied topically, penetration as emulsifiers, dispersing agents and penetrants, and include, enhancers may be used, which include, e.g. , dimethyl isos- e.g. , lapyrium chloride; laureth 4, i.e. , u-dodecyl-cu-hy- orbide, diethyl-glycol-monoethylether, 1-dodecylazacyclo- droxy-poly(oxy-1, 2-ethanediyl) or polyethylene glycol heptan-2-one, and dimethylsulfoxide (DMSO). Such com- monododecyl ether; laureth 9, i.e. , a mixture of polyethylene positions will also typically include ointment bases, e.g. , glycol monododecyl ethers averaging about 9 ethylene oxide petrolatum, polyethylene glycol, lanolin, and poloxamer, groups per molecule; monoethanolamine; nonoxynol 4, 9 which is a block copolymer of polyoxyethylene and poly- and 10, i.e. , polyethylene glycol mono(p-nonylphenyl) oxypropylene, which may also serve as a surfactant or ether; nonoxynol 15, i. e. , u-(p-nonylphenyl)-cu-hydroxy- emulsifying agent. penta-deca(oxyethylene); nonoxynol 30, i. e. , u-(p-nonylphenyl)-cu-hydroxytriaconta(oxyethylene); poloxalene, [0318] Preservatives are used to protect pharmaceutical i. e. nonionic polymer of the polyethylenepolypropylene compositions of the present invention from degradative , glycol type, MW=approx. 3000; poloxamer, referred to in attack by ambient microorganisms, and include, e.g. , ben- the discussion of ointment bases further above; polyoxyl 8, zalkonium chloride, benzethonium chloride, alkyl esters of 40 and 50 stearate, i.e. poly(oxy-1, 2-ethanediyl), u-hydro- p-hydroxybenzoic acid, hydantoin derivatives, cetylpyri- , cu-hydroxy-; octadecanoate; polyoxyl 10 oleyl ether, i. e. dinium chloride, monothioglycerol, phenol, phenoxyetha- , poly(oxy-1, 2-ethanediyl), u-[(Z)-9-octadecenyl-cu-hy- nol, methylparagen, imidazolidinyl urea, sodium dehydroac- droxy-; polysorbate 20, i.e. sorbitan, monododecanoate, etate, propylparaben, quaternary ammonium compounds, , poly(oxy-1, 2-ethanediyl); polysorbate 40, i.e. sorbitan, especially polymers such as polixetonium chloride, potas- , monohexadecanoate, poly(oxy-1, 2-ethanediyl); polysorbate sium benzoate, sodium formaldehyde sulfoxylate, sodium 60, i. e. sorbitan, monooctadecanoate, poly(oxy-1, 2- propionate, and thimerosal. , ethanediyl); polysorbate 65, i.e. , sorbitan, trioctadecanoate, [0319] Sequestering agents are used to improve the sta- poly(oxy-1, 2-ethanediyl); polysorbate 80, i.e. , sorbitan, bility of the pharmaceutical compositions of the present mono-9-monodecenoate, poly(oxy-1, 2-ethanediyl); polysor- invention and include, e. g. , the cyclodextrins which are a bate 85, i.e. , sorbitan, tri-9-octadecenoate, poly(oxy-1, 2- family of natural cyclic oligosaccharides capable of forming ethanediyl); sodium lauryl sulfate; sorbitan monolaurate; inclusion complexes with a variety of materials, and are of sorbitan monooleate; sorbitan monopalmitate; sorbitan varying ring sizes, those having 6-, 7- and 8-glucose resi- monostearate; sorbitan sesquioleate; sorbitan trioleate; and dues in a ring being commonly referred to as u-cyclodex- sorbitan tristearate. trins, p-cyclodextrins, and 7-cyclodextrins, respectively. [0325] The pharmaceutical compositions of the present Suitable cyclodextrins include, e. g. , u-cyclodextrin, P-cy- invention may be prepared using very straightforward meth- clodextrin, 7-cyclodextrin, 6-cyclodextrin and cationized which is well understood the artisan of ordinary cyclodextrins. odology by skill. Where the pharmaceutical compositions of the present [0320] Solvents which may be used in preparing the invention are simple aqueous and/or other solvent solutions, pharmaceutical compositions of the present invention the various components of the overall composition are include, e.g. , acetone, alcohol, amylene hydrate, butyl alco- brought together in any practical order, which will be US 2004/0067954 A1 Apr. 8, 2004 31

dictated largely by considerations of convenience. Those sweetening, flavoring or coloring agents may also be added. components having reduced water solubility, but sulficient Alternatively, the pharmaceutical compositions of this solubility in the same co-solvent with water, may all be invention may be administered in the form of suppositories dissolved in said co-solvent, after which the co-solvent for rectal administration. These can be prepared by mixing solution will be added to the water portion of the carrier the agent with a suitable non-irritating excipient which is whereupon the solutes therein will become dissolved in the solid at room temperature but liquid at the rectal temperature water. To aid in this dispersion/solution process, a surfactant and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and may be employed. polyethylene glycols. [0326] Where the pharmaceutical compositions of the present invention are to be in the form of emulsions, the [0329] The pharmaceutical compositions of the present components of the pharmaceutical composition will be invention may also be administered topically, especially brought together in accordance with the following general when the target of treatment includes areas or organs readily procedures. The continuous water phase is first heated to a accessible by topical application, including diseases of the temperature in the range of from about 60' to about 95' C. , eye, the skin, or the lower intestinal tract. Suitable topical preferably from about 70' to about 85' C. , the choice of formulations are readily prepared for each of these areas or which temperature to use being dependent upon the physical organs. and chemical properties of the components which make up Topical application for the lower intestinal tract can the oil-in-water emulsion. Once the continuous water phase [0330] be elfected in a rectal suppository formulation, as described has reached its selected temperature, the components of the above, or in a suitable enema formulation. Topically active final composition to be added at this stage are admixed with transdermal patches may also be used. the water and dispersed therein under high-speed agitation. Next, the temperature of the water is restored to approxi- [0331] For topical applications, the pharmaceutical com- mately its original level, after which the components of the positions may be formulated in a suitable ointment contain- composition which comprise the next stage are added to the ing the active component suspended or dissolved in one or composition mixture under moderate agitation and mixing more carriers. Carriers for topical administration of the continues for from about 5 to about 60 minutes, preferably compounds of this invention include, but are not limited to, about 10 to about 30 minutes, depending on the components mineral oil, liquid petrolatum, white petrolatum, propylene of the first two stages. Thereafter, the composition mixture glycol, polyoxyethylene, polyoxypropylene compound, is passively or actively cooled to from about 20' to about 55' emulsifying wax and water. Alternatively, the pharmaceuti- C. for addition of any components in the remaining stages, cal compositions can be formulated in a suitable lotion or after which water is added in sulficient quantity to reach its cream containing the active components suspended or dis- original predetermined concentration in the overall compo- solved in one or more pharmaceutically acceptable carriers. sition. Suitable carriers include, but are not limited to, mineral oil, [0327] According to the present invention, the pharma- sorbitan monostearate, polysorbate, cetyl esters wax, cet- ceutical compositions may be in the form of a sterile earyl alcohol, 2-octyldodecanol, benzyl alcohol and water. injectable preparation, for example a sterile injectable aque- [0332] Pharmaceutical compositions within the scope of ous or oleaginous suspension. This suspension may be the present invention include those wherein the therapeuti- formulated according to techniques known in the art using cally elfective amount of an active ingredient comprising a suitable dispersing or wetting agents and suspending agents. preferred compound required for treating or preventing The sterile injectable preparation may also be a sterile diseases, disorders, and conditions mediated by or associ- injectable solution or suspension in a non-toxic parenterally ated with modulation of PDE IV activity as described herein, acceptable diluent or solvent, for example as a solution in is provided in a dosage form suitable for systemic admin- 3-butanediol. Among the acceptable vehicles and solvents 1, istration. Such a pharmaceutical composition will contain that may be employed are water, Ringer's solution and said active ingredient in suitable liquid form for delivery by: isotonic sodium chloride solution. In addition, sterile, fixed injection or infusion which is intraarterial, intra- or oils are conventionally employed as a solvent or suspending (I) transdermal, subcutaneous, intramuscular, intraspinal, medium. For this bland fixed oil be purpose, any may intrathecal, or intravenous, wherein said active ingredient: employed including synthetic mono- or di-glycerides. Fatty is contained in solution as a solute; is contained in the acids, such as oleic acid and its glyceride derivatives are (a) (b) discontinuous phase of an emulsion, or the discontinuous useful in the preparation of injectables, as do natural phar- phase of an inverse emulsion which inverts upon injection or maceutically acceptable oils, such as olive oil or castor oil, infusion, said emulsions containing suitable emulsifying especially in their polyoxyethylated versions. These oil agents; or is contained in a suspension as a suspended solutions or suspensions may also contain a long-chain (c) solid in colloidal or microparticulate form, said suspension alcohol diluent or dispersant, such as Rh, HCIX or similar containing suitable suspending agents; injection or infu- alcohol. (2) sion into suitable body tissues or cavities as a depot, wherein [032II] The pharmaceutical compositions of the present said composition provides storage of said active ingredient invention may be orally administered in any orally accept- and thereafter delayed-, sustained-, and/or controlled-release able dosage form including, but not limited to, capsules, of said active ingredient for systemic distribution; (3) instil- tablets, aqueous suspensions or solutions. In the case of lation, inhalation or insufflation into suitable body tissues or tablets for oral use, carriers which are commonly used cavities of said pharmaceutical composition in suitable solid include lactose and corn starch. Lubricating agents, such as form, where said active ingredient: (a) is contained in a solid magnesium stearate, are also typically added. For oral implant composition providing delayed-, sustained-, and/or administration in a capsule form, useful diluents include controlled-release of said active ingredient; (b) is contained lactose and dried corn starch. When aqueous suspensions are in a particulate composition to be inhaled into the lungs; or required for oral use, the active ingredient is combined with (c) is contained in a particulate composition to be blown into emulsifying and suspending agents. If desired, certain suitable body tissues or cavities, where said composition US 2004/0067954 A1 Apr. 8, 2004 32

optionally provides delayed-, sustained-, and/or controlled- ally providing delayed-, sustained-, and/or controlled-re- release of said active ingredient; or (4) ingestion of said lease of said active ingredient to said local site; (b) in a pharmaceutical composition in suitable solid or liquid form particulate composition which is inhaled into a local site for peroral delivery of said active ingredient, where said comprising the lungs; or (c) in a particulate composition active ingredient is contained in a solid dosage form; or (b) which is blown into a local site, where said composition is contained in a liquid dosage form. includes components which will ensure that said active ingredient has predominantly local activity, with insignifi- [0333] Particular dosage forms of the above-described cant sys temic carryover activity, and optionally provides pharmaceutical compositions include suppositories as a (I) delayed-, sustained-, and/or controlled release of said active special type of implant, comprising bases which are solid at ingredient to said local site. For ophthalmic use, the phar- room temperature but melt at body temperature, slowly maceutical compositions may be formulated as micronized releasing the active ingredient with which they are impreg- suspension in isotonic, pH adjusted sterile saline, or, pref- nated into the surrounding tissue of the body, where the erably, as solutions in isotonic, adjusted sterile saline, active ingredient becomes absorbed and transported to elfect pH either with our without a preservative such as benzylalko- systemic administration; solid peroral dosage forms (2) nium chloride. Alternatively, for ophthalmic uses, the phar- selected from the group consisting of (a) delayed-release maceutical compositions may be formulated in an ointment oral tablets, capsules, caplets, lozenges, troches, and multi- such as petrolatum. particulates; (b) enteric-coated tablets and capsules which prevent release and absorption in the stomach to facilitate [0335] The pharmaceutical compositions of the present delivery distal to the stomach of the patient being treated; (c) invention may also be administered by nasal aerosol or sustained-release oral tablets, capsules and microparticu- inhalation through the use of a nebulizer, a dry powder lates which provide systemic delivery of the active ingredi- inhaler or a metered dose inhaler. Such compositions are ent in a controlled manner up to a 24-hour period; (d) prepared according to techniques well-known in the art of fast-dissolving tablets; (e) encapsulated solutions; (f) an oral pharmaceutical formulation and may be prepared as solu- paste; (g) a granular form incorporated in or to be incorpo- tions in saline, employing benzyl alcohol or other suitable rated in the food of a patient being treated; and (h) liquid preservatives, absorption promoters to enhance bioavailabil- peroral dosage forms selected from the group consisting of ity, hydrofluorocarbons, and/or other conventional solubi- solutions, suspensions, emulsions, inverse emulsions, elix- lizing or dispersing agents. irs, extracts, tinctures, and concentrates. [0336] As already mentioned, the preferred compounds of [0334] Pharmaceutical compositions within the scope of the present invention may be administered systemically to a the present invention include those wherein the therapeuti- patient to be treated as a pharmaceutical composition in amount an ingredient a cally elfective of active comprising suitable liquid form by injection or infusion. There are a compound of the present invention required for treating or number of sites and organ systems in the body of the patient preventing diseases, disorders, and conditions mediated by which will allow the properly formulated pharmaceutical or associated with modulation of PDE IV activity as composition, once injected or infused, to permeate the entire described herein is provided in a dosage form suitable for body and all of the organ system of the patient being treated. local administration to a patient being treated, wherein said An injection is a single dose of the pharmaceutical compo- pharmaceutical composition contains said active ingredient sition forced, usually by a syringe, into the tissue involved. in suitable liquid form for delivering said active ingredient The most common types of injections are intramuscular, by: (I) injection or infusion into a local site which is intravenous, and subcutaneous. By contrast, an infusion is intra- intraarterial, intraarticular, intrachondrial, intracostal, the gradual introduction of the pharmaceutical composition intra- transdermal, intrafasicular, intraligamentous, cystic, or into the tissue involved. The most common type of infusion intramedulary, intramuscular, intranasal, intraneural, is intravenous. Other types of injection or infusion comprise intraocular, i.e. , opthalmic administration, intraosteal, intraarterial, intra- or transdermal (including subcutaneous), intra- intrapelvic, intrapericardial, intraspinal, intrasternal, or intraspinal especially intrathecal. In these liquid pharma- synovial, intratarsal, or intrathecal; including components ceutical compositions, the active ingredient may be con- which provide delayed-release, controlled-release, and/or tained in solution as the solute. This is the most common and sustained-release said ingredient into of active said local most preferred type of such composition, but requires an site; where said active ingredient is contained: (a) in solution active ingredient in a salt form that has reasonably good as a solute; (b) in the discontinuous phase of an emulsion, or aqueous solubility. Water (or saline) is by far the most the discontinuous phase of an inverse emulsion which preferred solvent for such compositions. Occasionally inverts upon injection or infusion, said emulsions containing supersaturated solutions may be utilized, but these present suitable emulsifying agents; or (c) in a suspension as a stability problems that make them impractical for use on an suspended solid in colloidal or microparticulate form, said everyday basis. suspension containing suitable suspending agents; or (2) injection or infusion as a depot for delivering said active [0337] If it is not possible to obtain a form of some ingredient to said local site; wherein said composition preferred compound that has the requisite degree of aqueous provides storage of said active ingredient and thereafter solubility, as may sometimes occur, it is, within the skill of delayed-, sustained-, and/or controlled-release of said active the artisan to prepare an emulsion, which is a dispersion of ingredient into said local site, and wherein said composition small globules of one liquid, the discontinuous or internal also includes components which ensure that said active phase, throughout a second liquid, the continuous or external ingredient has predominantly local activity, with little sys- phase, with which it is immiscible. The two liquids are temic carryover activity; or wherein said pharmaceutical maintained in an emulsified state by the use of emulsifiers composition contains said active ingredient in suitable solid which are pharmaceutically acceptable. Thus, if the active form for delivering said inhibitor by: (3) instillation, inha- ingredient is a water-insoluble oil, it can be administered in, lation or insulflation to said local site, where said active an emulsion of which it is the discontinuous phase. Also ingredient is contained: (a) in a solid implant composition where the active ingredient is water-insoluble but can be which is installed in said local site, said composition option- dissolved in a solvent which is immiscible with water, an US 2004/0067954 A1 Apr. 8, 2004 33

emulsion can be used. While the active ingredient would solizing particulate formulations. These particulate compo- most commonly be used as the discontinuous or internal sitions may also be formulated to provide delayed-, sus- phase of what is referred to as an oil-in-water emulsion, it tained-, and/or controlled-release of the active ingredient in could also be used as the discontinuous or internal phase of accordance with well understood principles and known an inverse emulsion, which is commonly referred to as a materials. water-in-oil emulsion. Here the active ingredient is soluble in water and could be administered as a simple aqueous [0341] Other means of systemic administration which may solution. However, inverse emulsions invert upon injection utilize the active ingredients of the present invention in or infusion into an aqueous medium such as the blood, and either liquid or solid form include transdermal, intranasal, oKer the advantage of providing a more rapid and eKIcient and opthalmic routes. In particular, transdermal patches dispersion of the active ingredient into that aqueous medium prepared in accordance with well known drug delivery than can be obtained using an aqueous solution. Inverse technology may be prepared and applied to the skin of a emulsions are prepared by using suitable, pharmaceutically patient to be treated, whereafter the active-agent by reason acceptable emulsifying agents well known in the art. Where of its formulated solubility characteristics migrates across the active ingredient has limited water solubility, it also may the epidermis and info the dermal layers of the patient's skin be administered as a suspended solid in colloidal or micro- where it is taken up as part of the general circulation of the particulate form in a suspension prepared using suitable, patient, ultimately providing systemic distribution of the pharmaceutically acceptable suspending agents. The sus- active ingredient over a desired, extended period of time. pended solids containing the active ingredient may also be are are formulated as delayed-, sustained-, and/or controlled-release Also included implants which placed beneath the compositions. epidermal layer of the skin, i. e. between the epidermis and the dermis of the skin of the patient being treated. Such an [033II] While systemic administration will most frequently implant will be formulated in accordance with well known be carried out by injection or infusion of a liquid, there are principles and materials commonly used in this delivery many situations in which it will be advantageous or even technology, and may be prepared in such a way as to provide necessary to deliver the active ingredient as a solid. Sys- controlled-, sustained-, and/or delayed-release of the active temic administration of solids is carried out by instillation, ingredient into the systemic circulation of the patient. Such inhalation or insuKIation of a pharmaceutical composition in subepidermal (subcuticular) implants provide the same suitable solid form containing the active ingredient. Instil- facility of installation and delivery eKiciency as transdermal lation of the active ingredient may entail installing a solid patches, but without the limitation of being subject to implant composition into suitable body tissues or cavities. degradation, damage or accidental removal as a conse- The implant may comprise a matrix of bio-compatible and quence of being exposed on the top layer of the patient' s bio-erodible materials in which particles of a solid active skin. ingredient are dispersed, or in which, possibly, globules or isolated cells of a liquid active ingredient are entrapped. [0342] In the above description of pharmaceutical com- Desirably, the matrix will be broken down and completely positions containing a preferred compound, the equivalent absorbed by the body. The composition of the matrix is also expressions: "administration", "administration of', "admin- preferably selected to provide controlled-, sustained-, and/or istering", and "administering a" have been used with respect delayed release of the active ingredient over extended peri- to said pharmaceutical compositions. As thus employed, ods of time, even as much as several months. these expressions are intended to mean providing to a patient in need of treatment a pharmaceutical composition of the [0339] The term "implant" most often denotes a solid present invention by any of the routes of administration pharmaceutical composition containing the active ingredi- herein described, wherein the active ingredient is a preferred ent, while the term "depot' usually implies a liquid pharma- compound or a prodrug, derivative, or metabolite thereof ceutical composition containing the active ingredient, which which is useful in treating a disease, disorder, or condition is deposited in any suitable body tissues or cavities to form mediated by or associated with modulation of PDE IV a reservoir or pool which slowly migrates to surrounding activity in said patient. Accordingly, there is included within tissues and organs and eventually becomes systemically the scope of the present invention any other compound distributed. However, these distinctions are not always rig- which, upon administration to a patient, is capable of idly adhered to in the art, and consequently, it is contem- directly or indirectly providing a preferred compound. Such plated that there is included within the scope of the present compounds are recognized as prodrugs, and a number of invention liquid implants and solid depots, and even mixed established procedures are available for preparing such solid and liquid forms for each. Suppositories may be prodrug forms of the preferred compounds. regarded as a type of implant, since they comprise bases which are solid at room temperature but melt at a patient' s [0343] The dosage and dose rate of the compounds eKec- body temperature, slowly releasing the active ingredient tive for treating or preventing, a disease, disorder, or condi- with which they are impregnated into the surrounding tissue tion mediated by or associated with modulation of PDE IV of the patient's body, where the active ingredient becomes activity, will depend on a variety of factors, such as the absorbed and transported to eKect systemic administration. nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the [0340] Systemic administration can also be accomplished specific pharmaceutical composition used, and the observa- by inhalation or insuKIation of a powder, i.e. , particulate tions and conclusions of the treating physician. composition containing the active ingredient. For example, the active ingredient in powder form may be inhaled into the [0344] For example, where the dosage form is oral, e.g. , a lungs using conventional devices for aerosolizing particulate tablet or capsule, suitable dosage levels of the preferred formulations. The active ingredient as a particulate formu- compounds will be between about 0. 1 pg/kg and about 50.0 lation may also be administered by insufflation, i. e. , blown mg/kg of body weight per day, preferably between about 5.0 or otherwise dispersed into suitable body tissues or cavities pg/kg and about 5.0 mg/kg of body weight per day, more by simple dusting or using conventional devices for aero- preferably between about 10.0 pg/kg and about 1.0 mg/kg of US 2004/0067954 A1 Apr. 8, 2004 34

body weight per day, and most preferably between about phosphate) level and/or can be influenced by an increase in 20.0 pg/kg and about 0.5 mg/kg of body weight per day of the cAMP level. The increased cAMP level causes inhibition the active ingredient. or prevention of inflammation and causes muscle relaxation. In particular, the PDE IV inhibitors according to the inven- [0345] Where the dosage form is topically administered to tion can be used in the treatment of allergic diseases, asthma, the bronchia and lungs, e. by means of a powder inhaler g. , chronic bronchitis, atopic dermatitis, psoriasis and other skin or nebulizer, suitable dosage levels of the compounds will be diseases, inflammatory disorders, autoimmune diseases, between about 0.001 and about 10.0 mg/kg of body pg/kg such as, for example, rheumatoid arthritis, multiple sclero- weight per preferably between about 0.5 and day, pg/kg sis, Crohn's disease, diabetes mellitus or ulcerative colitis, about 0.5 mg/kg of body weight per day, more preferably osteoporosis, transplant rejection reactions, cachexia, between about 1.0 and about 0.1 mg/kg of body pg/kg tumour growth or tumour metastases, sepsis, memory dis- weight per day, and most preferably between about 2. 0 pg/kg orders, atherosclerosis and AIDS. and about 0.05 mg/kg of body weight per day of the active ingredient. [0353] In general, the substances according to the invention are preferably administered in doses corresponding to [0346] Using representative body weights of 10 kg and the compound rolipram of between 1 and 500 mg, in 100 kg in order to illustrate the range of daily oral dosages particular between 5 and 100 mg per dosage unit. The daily which might be used as described above, suitable dosage dose is preferably between about 0.02 and 10 mg/kg of body levels of the preferred compounds will be between about weight. However, the specific dose for each patient depends 1.0-10. 0 and 500.0-5000. 0 per preferably pg mg day, on a wide variety of factors, for example on the efficacy of between about 50.0-500. 0 and 50.0-500. 0 mg per day, pg the specific compound employed, on the age, body weight, more preferably between about 100.0-1000. 0 and 10.0- pg general state of health, sex, on the diet, on the time and 100.0 per day, and most preferably between about mg method of administration, on the excretion rate, medicament 200. 0-2000.0 and about 5.0-50. 0 per day of the active pg mg combination and severity of the particular illness to which ingredient comprising a preferred compound. These ranges the therapy applies. Oral administration is preferred. of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient. The number of EXAMPLE I times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the T-Cell half-life of the active ingredient, which reflects its rate of EIfect of the Compounds of Formula I on catabolism and clearance, as well as the minimal and opti- Proliferation mal blood plasma or other body fluid levels of said active [0354] Peripheral blood mononuclear cells (PBMC) are ingredient attained in the patient which are required for isolated from the blood of healthy donors by the Lymphop- therapeutic efficacy. rep gradient method. 200000 PBMC/well are cultured in [0347] Numerous other factors must also be considered in RPMI1640 culture medium containing 5% heat inactivated deciding upon the number of doses per day and the amount human serum (AB pool) for 5 days at 37' C. and 10% CO~ of active ingredient per dose that will be administered. Not in 96 well flat bottom microtiter plates. The T cells within the least important of such other factors is the individual the PBMC preparation are selectively stimulated with an respsonse of the patient being treated. Thus, for example, monoclonal antibody to CD3. Cultures are set up as tripli- where the active ingredient is used to treat or prevent cates including a control group receiving no treatment. The asthma, and is administered topically via aerosol inhalation compounds of formula I are dissolved in DMSO at 10 M into the lungs, from one to four doses consisting of acuations and diluted in culture medium. Control cultures are treated of a dispensing device, i.e. , "pulfs" of an inhaler, will be with DMSO equivalent to the inhibitor concentration. 18 hrs administered. each day, each dose containing from about before the end of the assay, H-thymidine is added to the 50.0 pg to about 10.0 mg of active ingredient. cultures. The incorporation of radioactivity into the cells is then measured in a beta-counter. [034II] The invention also relates to a set (kit) consisting of separate packs of [0355] The data of at least three independent experiments are calculated as percent inhibition of the control [0349] (a) an elfective amount of a compound of the (mean~SEM) without inhibitor. From this data the IC-50 formula I and/or its pharmaceutically usable deriva- value is determined. tives, solvates and stereoisomers, including mixtures Results: thereof in all ratios, and [0356] [0357] The compounds of formula I alford a marked [0350] (b) an elfective amount of a further medica- reduction of T-cell proliferation. ment active ingredient. [0351] The set comprises suitable containers, such as EXAMPLE H boxes, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules each containing an EIfect of the Compounds of Formula I on Cytokine elfective amount of a compound of the formula I and/or its Production in Human Peripheral Blood Monocytic pharmaceutically usable derivatives, solvates and stereoiso- Cells mers, including mixtures thereof in all ratios, and an elfec- Peripheral blood mononuclear cells are tive amount of a further medicament active ingredient in [035II] (PBMC) isolated from the blood of healthy donors the dissolved or lyophilised form. by Lymphop- rep gradient method. 200000 PBMC/well are cultured in [0352] The compounds of the formula I and the physi- RPMI1640 culture medium containing 5% heat inactivated ologically acceptable salts and solvates thereof can be human serum (AB pool). at 37' C. and 10% CO~ in 96 well employed preferably for combating diseases which are flat bottom microtiter plates. Cultures are set up as triplicates caused by an excessively low cAMP (cycloadenosine mono- including a control group. Solutions of the compounds of US 2004/0067954 A1 Apr. 8, 2004 35

formula I are prepared in DMSO at 10 M and diluted in culture medium. Control cultures are treated with concen- -continued trations of DMSO equivalent to the inhibitor concentrations. 0 The culture supernatants of three independent experiments are pooled and cytokine activity in the supernatant is measured with commercially available ELISA test kits. [0359] The data are calculated as percent inhibition/stimulation of the control without the compound and the IC5O value or EC5O value in case of stimulation is determined thereof. [0360] Result [0361] The compounds of formula I alford a marked [0366] Asolution of 2. 10 I of iodoethane in 6.0 I of diethyl reduction in the release of IL-2, IFN-y, TNF-u and IL-12. ether was added dropwise to a mixture of 4. 00 kg of The immunosuppressant cytokine IL-10, however, is stimu- isovanilin and 10.50 kg of potassium carbonate in 32.5 I of lated. acetonitrile. The mixture was stirred overnight and subjected to conventional work-up, giving 3. EXAMPLE IH [0367] Step B: EIfect of the Compounds of Formula I on Experimental Myocardial Infarction in Rats [0362] The compounds of formula I, administered intrap- eritoneally with 1, 3, and 10 mg/kg, 1 hour before reversible occlusion of the left coronary artery in rats cause a significant dose dependent reduction of infarct size. In correspon- . dence with this protection, a reduction of plasma TNF-u ) levels is observed, as measured by ELISA. (.

EXAMPLE IV

EIfect of the Compounds of Formula I on Experimental Myocardial Infarction in Rabbits

[0363] There is a cardioprotective elfect by PDE IV inhibition in anaesthetised rabbits subjected to 30 minutes of coronary artery occlusion (side branch of the ramus circum- flexus of the left coronary artery) followed by 120 minutes Na —N of reperfusion. Compounds of formula I applied prior to the coronary occlusion, reduce infarct size as compared with Q placebo treatment. The areas at risk are comparable between 6 verum and placebo groups. The cardioprotective elfect can- not be attributed to favorable hemodynamic elfects, since heart rate and mean aortic pressure remain constant through- [036II] 1.10 kg of sodium cyanide are introduced into a out the experimental protocol. solution of 3.00 kg of 3, 3.15 I of morpholine and 3.42 kg [0364] Above and below, all temperatures are given in ' C. of toluene-4-sulfonic acid in 18 I of THF. The mixture was In the following examples, "conventional work-up" means stirred overnight and subjected to conventional work-up, that water is added if necessary, the pH is adjusted, if giving 6. necessary, to between 2 and 10, depending on the constitu- tion of the end product, the mixture is extracted with ethyl [0369] Step C: acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation.

Example 1 [0365] Step A:

+ I 0 US 2004/0067954 A1 Apr. 8, 2004 36

subsided, 250.00 g of 10 in 2 I of THF are added dropwise -continued with stirring and ice-cooling at 0-5' C. The mixture was N stirred for 18 hours at RT, and 100 ml of water are added dropwise with stirring and cooling. When the hydrolysis was complete, a solution of 500 g of sodium carbonate decahy- drate and 200 ml of water at 80' C. was allowed to run in rapidly. After brief stirring, the batch was filtered with suction, and the filtrate was subjected to conventional work- up, giving 11 (m. p: 101-103' C.).

[0375] Step F:

[0370] A solution of 0.064 kg of sodium in 1.30 I of methanol was added to 3.840 kg of 6. A mixture of 1.385 I of methyl acrylate in 13.0 I of tetrahydro-furan was subsequently added dropwise, and the mixture was stirred over- ~0 + NH night. Conventional work-up gave 8.

[0371] Step D:

12 Y N 0

13 NH9+OH H3N [0376] 165.00 g of 11 and 80.71 ml of pyridine are 10 dissolved in dichloromethane. 156.90 g of 12, dissolved in 100 ml of dichloromethane, are added dropwise at 10-15' C. and the batch was stirred overnight at 15-20' C. Con- [0372] 4.80 kg of 8 are dissolved in 14.0 I of ethanol, and , 850.0 ml of hydrazinium hydroxide are added. The mixture ventional work-up gave 13 in crystalline form. was stirred overnight and subjected to conventional work- [0377] Step G up, giving 10. [0373] Step E: ~ N ~0 NaOH 0 0 Li X1H4 13 OH

10 ~0 + N 0 ~0 + + &NH 0 14

[0378] 195.00 g of 13 are introduced into 1.2 I of ethanol 19' [0374] 2 I of THF are allowed to reaction into a suspension at C. , and 1.2 I of a 2M sodium hydroxide solution are of 40. 00 g of lithium aluminium hydride in 100 ml of toluene added. The mixture was stirred overnight at RT. Conven- over the course of 10 minutes. When the exothermicity had tional work-up gave 14 as a crystalline solid. US 2004/0067954 A1 Apr. 8, 2004 37

[0379] Step H:

~0 + + N 0 0 14 15

~0 + + &N 0 0 16

[0380] 106.00 mg of 14, 0.055 ml of triethylene glycol monomethyl ether and 250.00 mg of triphenylphosphine -continued (polymeric) are introduced into CHzClz, and 141.00 mg of ~OH di-tert-butyl azodicarboxylate are introduced at RT with + N stirring. The mixture was stirred overnight at RT and sub- ~0 + jected to conventional work-up, giving 16. 0 0 Example 2 17 [0381] [0382] 17.70 g of 14, 4.00 ml of 2-chloroethanol, 20.00 g of potassium carbonate and 20.00 ml of dimethylformamide OH are combined and stirred overnight at 120' C. Water was HOCH OH O1 added to the mixture, and precipitated material was filtered ~0 N N oK with suction. Crystallisation of the residue from ethanol gave 17. 0 0 [0383] The following compounds are obtained analo- the precursors: 14 gously using corresponding Examples 3-110 [0384]

0 —Q

R + N

R R Q R

l3) OCzHs OCHH —CH, CH, — OH l4) OCzHs OCHH —CHzCHzOCHzCHz— OH lm. p. : 139' C.) l5) OCzHs OCHH —CHzCHzOCHzCHzOCHzCHz- OH l6) OCzHs OCHH —CH, CH, — OCHH l7) OCzHs OCHH —CHzCHzOCHzCHz— OCHH ls) OCzHs OCHH —CHzCHzOCHzCHzOCHzCHz- OCHH l9) OCzHs OCHH —CH, CH, — NHz l10) OCzHs OCHH —CHzCHzOCHzCHz— NHz ill) OCzHs OCHH —CHzCHzOCHzCHzOCHzCHz— NHz US 2004/0067954 A1 Apr. 8, 2004 38

-continued

0 —Q

R + N

R R Q R

(12) OCzHs OCHs —CHzCHz- Cl (13) OCzHs OCHs —CHzCHzOCHzCHz— Cl (14) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- Cl (m. p. : 53' C.) (15) OCzHs OCHs —CHzCHz— N(CHs)z (m. p. : 95' C.) (16) OCzHs OCHs —CHzCHzOCHzCHz- N(CHs)z (17) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (18) OCzHs OCHs —CHz- COOH (19) OCzHs OCHs —CHzCHzOCHz— COOH (20) OCzHs OCHs z z z z z COOH (21) OCzHs OCHs —CHz- COOCzHs (22) OCzHs OCHs —CHzCHzOCHz— COOCzHs (23) OCzHs OCHs —CHzCHzOCHzCHzOCHz- COOCzHs (24) OCzHs OCHs —CH, CH, — OCO(CHz)sCHs (25) OCzHs OCHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (26) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (27) OCzHs OCHs —CHzCHz— OCO(CHz)~OCHs (28) OCzHs OCHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (29) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(30) OCzHs OCHs ~HzCHz

(31) OCzHs OCHs —CHzCHzOCHzCHz—

(32) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- —N NH

(33) OCzHs OCHs ~HzCHz

(34) OCzHs OCHs ~HzCHzOCHzCHz

(35) OCzHs OCHs ~HzCHzOCHzCHzOCHzCHz ~ OCzHs

(36) OCzHs OCHs ~HzCHz 0

0 US 2004/0067954 A1 Apr. 8, 2004 39

-continued

N N 0

R R Q R

OCzHs OCHs ~HzCHzOCHzCHz 0

OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz — 0

0 (») OCzHs OCHs —CHzCHz- OH (40) OCzHs OCHs —CHzCHzOCHzCHz— OH (41) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OH (42) OCzHs OCHs —CHzCHz— OCHs (45) OCzHs OCHs —CHzCHzOCHzCHz- OCHs (44) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCHs (45) OCzHs OCHs —CHzCHz- NHz (46) OCzHs OCHs —CHzCHzOCHzCHz— NHz (47) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- NHz (48) OCzHs OCHs —CH, CH, — C1 (49) OCzHs OCHs —CHzCHzOCHzCHz— C1 (5o) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- C1 (») OCzHs OCHs —CHzCHz— N(CHs)z (52) OCzHs OCHs —CHzCHzOCHzCHz- N(CHs)z (») OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (54) OCzHs OCHs —CHz- COOH (55) OCzHs OCHs —CHzCHzOCHz— COOH (56) OCzHs OCHs z z z z z COOH (57) OCzHs OCHs —CHz- COOCzHs (58) OCzHs OCHs —CHzCHzOCHz— COOCzHs (59) OCzHs OCHs —CHzCHzOCHzCHzOCHz- COOCzHs (60) OCzHs OCHs —CH, CH, — OCO(CHz)sCHs (61) OCzHs OCHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (62) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (65) OCzHs OCHs —CHzCHz— OCO(CHz)~OCHs (64) OCzHs OCHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (65) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(66) OCzHs OCHs ~HzCHz

(67) OCHs OCHs ~HzCHzOCHzCHz

(68) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz

(69) OCHs OCHs ~HzCHz US 2004/0067954 A1 Apr. 8, 2004 40

-continued

N N 0

R R Q R

(70) OCHs OCHs ~HzCHzOCHzCHz

OCHs OCHs — (71) ~HzCHzOCHzCHzOCHzCHz ~ OCgHs

(72) OCHs OCHs ~HzCHz

(73) OCHs OCHs ~HzCHzOCHzCHz 0

(74) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz 0

(75) OCzHs OCzHs —CHzCHz- OH (76) OCzHs OCzHs —CHzCHzOCHzCHz— OH (77) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- OH (78) OCzHs OCzHs —CHzCHz— OCHs (79) OCzHs OCzHs —CHzCHzOCHzCHz- OCHs (80) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCHs (81) OCzHs OCzHs —CHzCHz- NHz (82) OCzHs OCzHs —CHzCHzOCHzCHz— NHz (83) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- NHz (84) OCzHs OCzHs —CHzCHz— Ct (85) OCzHs OCzHs —CHzCHzOCHzCHz- Ct (86) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— Ct (87) OCzHs OCzHs —CHzCHz- N(CHs)z (88) OCzHs OCzHs —CHzCHzOCHzCHz— N(CHs)z (89) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- N(CHs)z (90) OCzHs OCzHs —CHz— COOH (91) OCzHs OCzHs —CHzCHzOCHz- COOH (92) OCzHs OCzHs —CHzCHzOCHzCHzOCHz— (93) OCzHs OCzHs —CHz- COOCzHs (94) OCzHs OCzHs —CHzCHzOCHz— COOCzHs (95) OCzHs OCzHs —CHzCHzOCHzCHzOCHz- COOCzHs (96) OCzHs OCzHs —CHzCHz— OCO(CHz)sCHs (97) OCzHs OCzHs —CHzCHzOCHzCHz- OCO(CHz)sCHs (98) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)sCHs (99) OCzHs OCzHs —CHzCHz- OCO(CHz)~OCHs (100) OCzHs OCzHs —CHzCHzOCHzCHz— OCO(CHz)~OCHs (101) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs US 2004/0067954 A1 Apr. 8, 2004 41

-continued

N N

R R Q R

i102) OCzHs OCzHs CHzCHz

i103) OCzHs OCzHs CHzCHzOCHzCHz—

i104) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz- —N NH

i105) OCzHs OCzHs CHzCHz

i106) OCzHs OCzHs CHzCHzOCHzCHz—

— i107) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz ~ OCzHs

i108) OCzHs OCzHs CHzCHz

i109) OCzHs OCzHs CHzCHzOCHzCHz—

i110) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz — O US 2004/0067954 A1 Apr. 8, 2004 42

Examples 111-146 -continued [0385] 0 —Q~

N 0 —Q~

(141) —CHzCHz—

(111) —CHzCHz— OH (112) —CHzCHzOCHzCHz— OH (113) —CHzCHzOCHzCHzOCHzCHz— OH (114) —CHzCHz— OCHs (115) —CHzCHzOCHzCHz— OCHs (142) —CHzCHzOCHzCHz— (116) —CHzCHzOCHzCHzOCHzCHz— OCHs (117) —CHzCHz— NHz (118) —CHzCHzOCHzCHz— NHz (119) —CHzCHzOCHzCHzOCHzCHz— NHz (120) —CHzCHz— Ct (121) —CHzCHzOCHzCHz— Ct (122) —CHzCHzOCHzCHzOCHzCHz— Ct (123) —CHzCHz— N(CHs)z (124) —CHzCHzOCHzCHz— N(CHs)z (125) —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (143) ~HzCHzOCHzCHzOCHzCHz 0( 2Hs (126) CHz COOH (127) —CHzCHzOCHz— COOH ~ (128) —CHzCHzOCHzCHzOCHz— COOH (129) CHz COOCzHs (130) —CHzCHzOCHz— COOCzHs (131) —CHzCHzOCHzCHzOCHz— COOCzHs (132) —CHzCHz— OCO(CHz)sCHs (133) —CHzCHzOCHzCHz— OCO(CHz)sCHs (134) —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)sCHs (135) CHzCHz OCO(CHz)~OCHs (144) —CHzCHz— (136) —CHzCHzOCHzCHz— OCO(CHz)~OCHs 0 (137) —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(138) —CHzCHz—

(145) —CHzCHzOCHzCHz— 0

(139) —CHzCHzOCHzCHz—

(146) —CHzCHzOCHzCHzOCHzCHz — 0

(140) —CHzCHzOCHzCHzOCHzCHz- —N NH 0 US 2004/0067954 A1 Apr. 8, 2004 43

Examples 147-254 [0386]

0 —Q R' ~R,

R R Q R

(147) OCzHs OCHs —CHzCHz- OH (148) OCzHs OCHs —CHzCHzOCHzCHz— OH (149) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OH (150) OCzHs OCHs —CHzCHz— OCHs (151) OCzHs OCHs —CHzCHzOCHzCHz- OCHs (152) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCHs (153) OCzHs OCHs —CH, CH, — NHz (154) OCzHs OCHs —CHzCHzOCHzCHz— NHz (155) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- NHz (156) OCzHs OCHs —CHzCHz— C1 (157) OCzHs OCHs —CHzCHzOCHzCHz- C1 (158) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— C1 (159) OCzHs OCHs —CHzCHz- N(CHs)z (160) OCzHs OCHs —CHzCHzOCHzCHz— N(CHs)z (161) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- N(CHs)z (162) OCzHs OCHs —CHzCHz— COOH (163) OCzHs OCHs —CHzCHzOCHzCHz- COOH (164) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— COOH (165) OCzHs OCHs —CHz- COOCzHs (166) OCzHs OCHs —CHzCHzOCHz— COOCzHs (167) OCzHs OCHs —CHzCHzOCHzCHzOCHz- COOCzHs (168) OCzHs OCHs —CHz— OCO(CHz)sCHs (169) OCzHs OCHs —CHzCHzOCHz- OCO(CHz)sCHs (170) OCzHs OCHs —CHzCHzOCHzCHzOCHz— OCO(CHz)sCHs (171) OCzHs OCHs —CHzCHz- OCO(CHz)~OCHs (172) OCzHs OCHs —CHzCHzOCHzCHz— OCO(CHz)~OCHs (173) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(174) OCzHs OCHs ~HzCHz

(175) OCzHs OCHs ~HzCHzOCHzCHz

(176) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- —N NH

(177) OCzHs OCHs ~HzCHz

(178) OCzHs OCHs —CHzCHzOCHzCHz—

OCHs — (179) OCzHs ~HzCHzOCHzCHzOCHzCHz ~ OCgHs US 2004/0067954 A1 Apr. 8, 2004 44

-continued

R R Q R

(180) OCzHs OCHs ~HzCHz 0

(181) OCzHs OCHs —CHzCHzOCHzCHz— 0

(182) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz — O

(183) OCHs OCHs —CHzCHz- OH (184) OCHs OCHs —CHzCHzOCHzCHz— OH (185) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OH (186) OCHs OCHs —CH, CH, — OCHs (187) OCHs OCHs —CHzCHzOCHzCHz— OCHs (188) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCHs (189) OCHs OCHs —CHzCHz— NHz (190) OCHs OCHs —CHzCHzOCHzCHz- NHz (191) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— NHz (192) OCHs OCHs —CHzCHz- Ct (193) OCHs OCHs —CHzCHzOCHzCHz— Ct (194) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- Ct (195) OCHs OCHs —CHzCHz— N(CHs)z (196) OCHs OCHs —CHzCHzOCHzCHz- N(CHs)z (197) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (198) OCHs OCHs —CHz- COOH (199) OCHs OCHs —CHzCHzOCHz— COOH (200) OCHs OCHs —CHzCHzOCHzCHzOCHz- COOH (201) OCHs OCHs —CHz— COOCzHs (202) OCHs OCHs —CHzCHzOCHz- COOCzHs (203) OCHs OCHs —CHzCHzOCHzCHzOCHz— COOCzHs (204) OCHs OCHs —CHzCHz- OCO(CHz)sCHs (205) OCHs OCHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (206) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (207) OCHs OCHs —CHzCHz— OCO(CHz)~OCHs (208) OCHs OCHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (209) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(210) OCHs OCHs ~HzcHz

(211) OCHs OCHs ~HzcHzOCHzcHz US 2004/0067954 A1 Apr. 8, 2004 45

-continued

0 —Q R' ~R,

R R Q R

(212) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- —N NH

(213) OCHs OCHs ~HzcHz

(214) OCHs OCHs ~HzcHzOCHzcHz

(215) OCH, OCH, ~HzCHzOCHzCHzOCHzCHz ~ OC2Hs

(21 6) OCHs OCHs ~HzcHz 0

0 (217) OCHs OCHs ~HzCHzOCHzCHz 0

0 (218) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz — 0

(219) OCzHs OCzHs —CH, CH, — OH (220) OCzHs OCzHs —CHzCHzOCHzCHz— OH (221) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- OH (222) OCzHs OCzHs —CHzCHz— OCHs (223) OCzHs OCzHs —CHzCHzOCHzCHz- OCHs (224) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCHs (225) OCzHs OCzHs —CHzCHz- NHz (226) OCzHs OCzHs —CHzCHzOCHzCHz— NHz (227) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- NHz (228) OCzHs OCzHs —CHzCHz— C1 (229) OCzHs OCzHs —CHzCHzOCHzCHz- C1 (230) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— C1 (231) OCzHs OCzHs —CH, CH, — N(CHs)z (232) OCzHs OCzHs —CHzCHzOCHzCHz— N(CHs)z (233) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- N(CHs)z (234) OCzHs OCzHs —CHz— COOH (235) OCzHs OCzHs —CHzCHzOCHz— COOH US 2004/0067954 A1 Apr. 8, 2004 46

-continued

0 —Q R' ~R,

R R Q R

(236) OCzHs OCzHs —CHzCHzOCHzCHzOCHz- COOH (237) OCzHs OCzHs —CHz— COOCzHs (238) OCzHs OCzHs —CHzCHzOCHz- COOCzHs (239) OCzHs OCzHs —CHzCHzOCHzCHzOCHz— COOCzHs (240) OCzHs OCzHs —CHzCHz- OCO(CHz)sCHs (241) OCzHs OCzHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (242) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (243) OCzHs OCzHs —CHzCHz— OCO(CHz)~OCHs (244) OCzHs OCzHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (245) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(246) OCzHs OCzHs CHzCHz

(247) OCzHs OCzHs CHzCHzOCHzCHz—

(248) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz- —N NH

(249) OCzHs OCzHs CHzCHz

(250) OCzHs OCzHs CHzCHzOCHzCHz—

(251) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz ~ OCzHs

(252) OCzHs OCzHs CHzCHz 0

0 (253) OCzHs OCzHs CHzCHzOCHzCHz— 0

0 US 2004/0067954 A1 Apr. 8, 2004 47

-continued

0 —Q~

R R Q R

(254) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz — 0

Examples 255-362 [0387]

R + N 0 —Q ~R, 0

R R Q R

(255) OCzHs OCHs —CHzCHz- OH (256) OCzHs OCHs —CHzCHzOCHzCHz— OH (m. p. : 139' C.) (257) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OH (258) OCzHs OCHs —CH, CH, — OCHs (259) OCzHs OCHs —CHzCHzOCHzCHz— OCHs (260) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCHs (261) OCzHs OCHs —CHzCHz— NHz (262) OCzHs OCHs —CHzCHzOCHzCHz- NHz (263) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— NHz (264) OCzHs OCHs —CHzCHz- Cl (265) OCzHs OCHs —CHzCHzOCHzCHz— Cl (266) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- Cl (m. p. : 53' C.) (267) OCzHs OCHs —CHzCHz— N(CHs)z (m. p. : 95' C.) (268) OCzHs OCHs —CHzCHzOCHzCHz- N(CHs)z (269) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (270) OCzHs OCHs —CHz- COOH (271) OCzHs OCHs —CHzCHzOCHz— COOH (272) OCzHs OCHs —CHzCHzOCHzCHzOCHz- COOH (273) OCzHs OCHs —CHz— COOCzHs (274) OCzHs OCHs —CHzCHzOCHz- COOCzHs (275) OCzHs OCHs —CHzCHzOCHzCHzOCHz— COOCzHs (276) OCzHs OCHs —CHzCHz- OCO(CHz)sCHs (277) OCzHs OCHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (278) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (279) OCzHs OCHs —CHzCHz— OCO(CHz)~OCHs (280) OCzHs OCHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (281) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(282) OCzHs OCHs ~HzcHz US 2004/0067954 A1 Apr. 8, 2004 48

-continued

R + N 0 —Q Rs

R R Q R

(283) OCzHs OCHs —CHzCHzOCHzCHz

(284) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- —N NH

(285) OCzHs OCHs ~HzCHz

(286) OCzHs OCHs —CHzCHzOCHzCHz—

OCHs — (287) OCzHs ~HzCHzOCHzCHzOCHzCHz ~ OCzHs

(288) OCzHs OCHs ~HzcHz

(289) OCzHs OCHs —CHzCHzOCHzCHz—

(290) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz — O

(291) OCHs OCHs ~HzcHz OH

(292) OCHs OCHs —CHzCHzOCHzCHz- OH (293) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— OH (294) OCHs OCHs —CH, CH, — OCHs (295) OCHs OCHs —CHzCHzOCHzCHz— OCHs (296) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCHs (297) OCHs OCHs —CH, CH, — NHz (298) OCHs OCHs —CHzCHzOCHzCHz— NHz (299) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- NHz (300) OCHs OCHs —CH, CH, — C1 (301) OCHs OCHs —CHzCHzOCHzCHz— C1 US 2004/0067954 A1 Apr. 8, 2004 49

-continued

R + N 0 —Q Rs

R R Q R

(302) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- Ct (303) OCHs OCHs —CHzCHz— N(CHs)z (304) OCHs OCHs —CHzCHzOCHzCHz- N(CHs)z (305) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (306) OCHs OCHs —CHz- COOH (307) OCHs OCHs —CHzCHzOCHz— COOH (308) OCHs OCHs —CHzCHzOCHzCHzOCHz- COOH (309) OCHs OCHs —CHz— COOCzHs (310) OCHs OCHs —CHzCHzOCHz- COOCzHs (311) OCHs OCHs —CHzCHzOCHzCHzOCHz— COOCzHs (312) OCHs OCHs —CHzCHz- OCO(CHz)sCHs (313) OCHs OCHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (314) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (315) OCHs OCHs —CHzCHz— OCO(CHz)~OCHs (316) OCHs OCHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (317) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(318) OCHs OCHs ~HzCHz

(319) OCHs OCHs ~HzCHzOCHzCHz

(320) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz

(321) OCHs OCHs ~HzCHz

(322) OCHs OCHs ~HzCHzOCHzCHz

(323) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz ~ OCzHs

(324) OCHs OCHs ~HzCHz 0

0 (325) OCHs OCHs ~HzCHzOCHzCHz 0

0 US 2004/0067954 A1 Apr. 8, 2004 50

-continued

R + N 0 —Q Rg

R R Q R

(326) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz — 0

(327) OCzHs OCzHs —CHzCHz- OH (328) OCzHs OCzHs —CHzCHzOCHzCHz— OH (329) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- OH (330) OCzHs OCzHs —CHzCHz— OCHs (331) OCzHs OCzHs —CHzCHzOCHzCHz- OCHs (332) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCHs (333) OCzHs OCzHs —CHzCHz- NHz (334) OCzHs OCzHs —CHzCHzOCHzCHz— NHz (335) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- NHz (336) OCzHs OCzHs —CHzCHz— C1 (337) OCzHs OCzHs —CHzCHzOCHzCHz- C1 (338) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— C1 (339) OCzHs OCzHs —CH, CH, — N(CHs)z (340) OCzHs OCzHs —CHzCHzOCHzCHz— N(CHs)z (341) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- N(CHs)z (342) OCzHs OCzHs —CHz— COOH (343) OCzHs OCzHs —CHzCHzOCHz- COOH (344) OCzHs OCzHs —CHzCHzOCHzCHzOCHz— COOH (345) OCzHs OCzHs CHz- COOCzHs (346) OCzHs OCzHs CHzCHzOCHz— COOCzHs (347) OCzHs OCzHs CHzCHzOCHzCHzOCHz- COOCzHs (348) OCzHs OCzHs —CHzCHz— OCO(CHz)sCHs (349) OCzHs OCzHs —CHzCHzOCHzCHz- OCO(CHz)sCHs (350) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)sCHs (351) OCzHs OCzHs —CH, CH, — OCO(CHz)~OCHs (352) OCzHs OCzHs —CHzCHzOCHzCHz— OCO(CHz)~OCHs (353) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(354) OCzHs OCzHs CHzCHz

(355) OCzHs OCzHs —CHzCHzOCHzCHz

(356) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz —N NH

(357) OCzHs OCzHs CHzCHz

(358) OCzHs OCzHs CHzCHzOCHzCHz— US 2004/0067954 A1 Apr. 8, 2004 51

-continued

R + N 0 —Q Rs

R R Q R (359) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz ~ OCzHs

(360) OCzHs OCzHs CHQCHz 0

0 (361) OCzHs OCzHs CHQCHQOCHQCHz— 0

(362) OCzHs OCzHs CHQCHQOCHQCHQOCHQCHz — 0

Examples 363-398 -continued [0388]

N N Q QW N (0 N Q QW (0 R

(377) —CHzCHzOCHzCHzOCHzCHz— N(CHQ)z R (378) CHz COOH (363) —CHzCHz— OH (379) —CHzCHzOCHz— COOH (364) —CHzCHzOCHzCHz— OH (380) —CHzCHzOCHzCHzOCHz— COOH (365) —CHzCHzOCHzCHzOCHzCHz— OH (381) CHz COOCzHs (366) —CHzCHz— OCHQ (382) —CHzCHzOCHz— COOCzHs (367) —CHzCHzOCHzCHz— OCHQ (368) —CHzCHzOCHzCHzOCHzCHz— OCHQ (383) —CHzCHzOCHzCHzOCHz— COOCzHs (369) —CHzCHz— NHz (384) —CHzCHz— OCO(CHz)QCHQ (370) —CHzCHzOCHzCHz— NHz (385) —CHzCHzOCHzCHz— OCO(CHz)QCHQ (371) —CHzCHzOCHzCHzOCHzCHz— NHz (386) —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)QCHQ (372) —CHzCHz— Ct (387) —CHzCHz— OCO(CHz)iQCHQ (373) —CHzCHzOCHzCHz— Ct — (374) —CHzCHzOCHzCHzOCHzCHz— Ct (388) CHzCHzOCHzCHz— OCO(CHz)iQCHQ (375) CHzCHz N(CHQ)z (389) —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)iQCHQ (376) —CHzCHzOCHzCHz— N(CHQ)z US 2004/0067954 A1 Apr. 8, 2004 52

-continued -continued

0 N N Q QM N Q QW (0 (0

R R (390) —CHzCHz— (396) —CHzCHz—

(391) —CHzCHzOCHzCHz—

(392) —CHzCHzOCHzCHzOCHzCHz- (397) —CHzCHzOCHzCHz— —N NH

(393) —CHzCHz—

(398) —CHzCHzOCHzCHzOCHzCHz — 0

(394) —CHzCHzOCHzCHz—

—CHzCHzOCHzCHzOCHzCHz (395) ~ OCzHs Examples 399-506 [0389]

N 0 —Q ~R,

R R Q R

(399) OCzHs OCHQ —CH, CH, — OH (400) OCzHs OCHQ —CHzCHzOCHzCHz— OH (401) OCzHs OCHQ —CHzCHzOCHzCHzOCHzCHz- OH (402) OCzHs OCHQ —CHzCHz— OCHQ (403) OCzHs OCHQ —CHzCHzOCHzCHz- OCHQ (404) OCzHs OCHQ —CHzCHzOCHzCHzOCHzCHz— OCHQ (405) OCzHs OCHQ —CHzCHz- NHz (406) OCzHs OCHQ —CHzCHzOCHzCHz— NHz (407) OCzHs OCHQ —CHzCHzOCHzCHzOCHzCHz- NHz (408) OCzHs OCHQ —CHzCHz— C1 (409) OCzHs OCHQ —CHzCHzOCHzCHz- C1 (410) OCzHs OCHQ —CHzCHzOCHzCHzOCHzCHz— C1 (411) OCzHs OCHQ —CHzCHz- N(CHQ)z (412) OCzHs OCHQ —CHzCHzOCHzCHz— N(CHQ)z (413) OCzHs OCHQ —CHzCHzOCHzCHzOCHzCHz- N(CHQ)z (414) OCzHs OCHQ —CHz— COOH US 2004/0067954 A1 Apr. 8, 2004 53

-continued

N 0 —Q ~R,

R R Q R

(415) OCzHs OCHs —CHzCHzOCHz- COOH (416) OCzHs OCHs —CHzCHzOCHzCHzOCHz— COOH (417) OCzHs OCHs —CHz- COOCzHs (418) OCzHs OCHs —CHzCHzOCHz— COOCzHs (419) OCzHs OCHs —CHzCHzOCHzCHzOCHz- COOCzHs (420) OCzHs OCHs —CHzCHz— OCO(CHz)sCHs (421) OCzHs OCHs —CHzCHzOCHzCHz- OCO(CHz)sCHs (422) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)sCHs (423) OCzHs OCHs —CHzCHz- OCO(CHz)~OCHs (424) OCzHs OCHs —CHzCHzOCHzCHz— OCO(CHz)~OCHs (425) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(426) OCzHs OCHs ~HzCHz

(427) OCzHs OCHs ~HzCHzOCHzCHz

(428) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz- —N NH

(429) OCzHs OCHs ~HzCHz

(430) OCzHs OCHs ~HzCHzOCHzCHz

(431) OCzHs OCHs ~HzCHzOCHzCHzOCHzCHz ~ OCzHs

(432) OCzHs OCHs ~HzCHz 0

(433) OCzHs OCHs —CHzCHzOCHzCHz 0

0 US 2004/0067954 A1 Apr. 8, 2004 54

-continued

N 0 —Q ~R,

R R Q R

(434) OCzHs OCHs —CHzCHzOCHzCHzOCHzCHz — 0

(435) OCHs OCHs —CHzCHz- OH (436) OCHs OCHs —CHzCHzOCHzCHz— OH (437) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OH (438) OCHs OCHs —CHzCHz— OCHs (439) OCHs OCHs —CHzCHzOCHzCHz- OCHs (440) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCHs (441) OCHs OCHs —CHzCHz- NHz (442) OCHs OCHs —CHzCHzOCHzCHz— NHz (443) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- NHz (444) OCHs OCHs —CH, CH, — C1 (445) OCHs OCHs —CHzCHzOCHzCHz— C1 (446) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- C1 (447) OCHs OCHs —CHzCHz— N(CHs)z (448) OCHs OCHs —CHzCHzOCHzCHz- N(CHs)z (449) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— N(CHs)z (450) OCHs OCHs —CHz- COOH (451) OCHs OCHs —CHzCHzOCHz— COOH (452) OCHs OCHs —CHzCHzOCHzCHzOCHz- COOH (453) OCHs OCHs —CHz— COOCzHs (454) OCHs OCHs —CHzCHzOCHz- COOCzHs (455) OCHs OCHs z z z z z COOCzHs (456) OCHs OCHs —CHzCHz- OCO(CHz)sCHs (457) OCHs OCHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (458) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (459) OCHs OCHs —CH, CH, — OCO(CHz)~OCHs (460) OCHs OCHs —CHzCHzOCHzCHz— OCO(CHz)~OCHs (461) OCHs OCHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(462) OCHs OCHs ~HzCHz

(463) OCHs OCHs ~HzCHzOCHzCHz

(464) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz- —N NH

(465) OCHs OCHs ~HzCHz

(466) OCHs OCHs ~HzCHzOCHzCHz US 2004/0067954 A1 Apr. 8, 2004 55

-continued

N 0 —Q ~R,

R R Q R (467) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz ~ OC2Hs

(468) OCHs OCHs ~HzcHz 0

0 (469) OCHs OCHs ~HzCHzOCHzCHz 0

0 (470) OCHs OCHs ~HzCHzOCHzCHzOCHzCHz — 0

(471) OCzHs OCzHs —CH, CH, — OH (472) OCzHs OCzHs —CHzCHzOCHzCHz— OH (473) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- OH (474) OCzHs OCzHs —CHzCHz— OCHs (475) OCzHs OCzHs —CHzCHzOCHzCHz- OCHs (476) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCHs (477) OCzHs OCzHs —CHzCHz- NHz (478) OCzHs OCzHs —CHzCHzOCHzCHz— NHz (479) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- NHz (480) OCzHs OCzHs —CHzCHz— C1 (481) OCzHs OCzHs —CHzCHzOCHzCHz- C1 (482) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— C1 (483) OCzHs OCzHs —CH, CH, — N(CHs)z (484) OCzHs OCzHs —CHzCHzOCHzCHz— N(CHs)z (485) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- N(CHs)z (486) OCzHs OCzHs —CHz— COOH (487) OCzHs OCzHs —CHzCHzOCHz- COOH (488) OCzHs OCzHs —CHzCHzOCHzCHzOCHz— COOH (489) OCzHs OCzHs —CHz- COOCzHs (490) OCzHs OCzHs —CHzCHzOCHz— COOCzHs (491) OCzHs OCzHs z z z z z COOCzHs (492) OCzHs OCzHs —CHzCHz- OCO(CHz)sCHs (493) OCzHs OCzHs —CHzCHzOCHzCHz— OCO(CHz)sCHs (494) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz- OCO(CHz)sCHs (495) OCzHs OCzHs —CHzCHz— OCO(CHz)~OCHs (496) OCzHs OCzHs —CHzCHzOCHzCHz- OCO(CHz)~OCHs (497) OCzHs OCzHs —CHzCHzOCHzCHzOCHzCHz— OCO(CHz)~OCHs

(498) OCzHs OCzHs CHzCHz US 2004/0067954 A1 Apr. 8, 2004 56

-continued

R R Q R

l499) OCzHs OCzHs CHzCHzOCHzCHz

l500) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz —N NH

l501) OCzHs OCzHs CHzCHz

l502) OCzHs OCzHs CHzCHzOCHzCHz—

— i503) OCzHs OCzHs ~HzCHzOCHzCHzOCHzCHz ~ O( zHs

l504) OCzHs OCzHs CHzCHz

l505) OCzHs OCzHs CHzCHzOCHzCHz

l506) OCzHs OCzHs CHzCHzOCHzCHzOCHzCHz — O

[0390] The examples below relate to pharmaceutical acid, sterile filtered, transferred into injection vials, lyophi- preparations: lised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingre- EXAMPLE A dient.

Injection Vials EXAMPLE B Suppositories [0391] A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 I of [0392] A mixture of 20 g of an active ingredient of the bidistilled water is adjusted to pH 6.5 using 2N hydrochloric formula I is melted with 100 g of soya lecithin and 1400 g US 2004/0067954 A1 Apr. 8, 2004 57

of cocoa butter, poured into moulds and allowed to cool. 1. Compounds of the formula I Each suppository contains 20 mg of active ingredient.

EXAMPLE C

Solution R' N [0393] A solution is prepared from 1 g of an active 0 —Q ingredient of the formula I, 9.38 g of NaH2P04. 2H20, 28. 48 0 X g of Na2HP04. 12H20 and 0.1 g of benzalkonium chloride in R 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This solution can be used in the form of eye drops. in which R' and EXAMPLE D R are each, independently of one another, H, OH, OR, Ointment SR, SOR, S02R or Hal, where R' and R together may alternatively be —0— CH2 —0—, [0394] 500 mg of an active ingredient of the formula I are R is Hal, NHA', NA'A, mixed with 99.5 g of Vaseline under aseptic conditions. OH, OA, N02, NH2, CN, COOH, COOA', CONH2, CONHA', CONA'A, EXAMPLE E NHCOA', NHS02A', NHCOOA',

Tablets

[0395] A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a —N —N NH conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F

Coated Tablets [0396] Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G

—N N —SOPH, Capsules

[0397] 2 kg of active ingredient of the formula I are introduced in a conventional manner into hard gelatine capsules in such a way that each capsule contains 20 mg of R is A', cycloalkyl having from 3 to 7 carbon atoms, the active ingredient. alkylene-cycloalkyl having from 4 to 8 carbon atoms or alkenyl having from 2 to 8 carbon atoms, EXAMPLE H A' and A are independently one another, alkyl having Amp oules each, of from 1 to 12 carbon atoms, which may be substituted [0398] A solution of 1 kg of active ingredient of the by from 1 to 5 F and/or CI atoms or OH-groups, where formula I in 60 I of bidistilled water is sterile filtered, A' and A together may alternatively be cycloalkyl or transferred into ampoules, lyophilised under sterile condi- cycloalkylene having from 3 to 7 ring members, in tions and sealed under sterile conditions. Each ampoule which one or more CH2 groups may be replaced by contains 10 mg of active ingredient. —S—, — 0—, — NH —,— NA' —,— NCOA' —or —NCOOA' —, EXAMPLE I x is H or Hal,

Inhalation Spray Hal is F, CI, Br or I and Q is alkyl or alkenyl having from 1 to 15 carbon atoms, [0399] 14 g of active ingredient of the formula I are in which from to be dissolved in 10 I of isotonic NaCI solution, and the solution 1 5 —CH2 —groups may replaced — —S — — is transferred into commercially available spray containers by 0—, —, S02—, CH(Hal) —, NH with mechanism. The solution can be into the —C(Hal)2 —,— CHA —,— CA A —,— —or pump sprayed —NA' mouth or nose. One spray shot (about 0. 1 ml) corresponds to —, a dose of about 0.14 mg. and salts and solvates thereof. US 2004/0067954 A1 Apr. 8, 2004 58

2. Compounds of the formula I according to claim 1, cycloalkylamino, dialkylamino, or characterised in that R' and R are each, independently of one another, methoxy, ethoxy, propoxy, cyclopentoxy, fluoro-, difluoro- or trifluoromethoxy, or l-fluoro-, 2-fluoro-, 1,2-difluoro-, 2, 2-difluoro-, 1,2, 2-trifluoro- or 2, 2, 2-trifluoroethoxy.

3. Compounds of the formula I according to one or more or of the preceding claims, characterised in that A' and A are each, independently of one another, alkyl having from 1 to 0 12 carbon atoms, alkyl having from 1 to 10 carbon atoms which is substituted by from 1 to 5 fluorine and/or chlorine atoms, or together are alternatively cycloalkyl having from 3 to 7 carbon atoms. 4. Compounds of the formula I according to one or more of the preceding claims, characterised in that Q is alkylene from 1 to carbon in which from 1 to having 10 atoms, 3 where alkyl has from 1 to 10 carbon atoms and cycloalkyl carbon atoms may be replaced by —0 —NH —or —, has from 3 to 7 carbon atoms, and A' is as defined in claim —NA' and A' is as defined in claim 1. —, 1. 5. Compounds of the formula I according to one or more of the preceding claims, characterised in that R is preferably 6. Compounds of the formula I1 to I74 according to claim A', F, CI, Br or I, hydroxyl, NH~, O-alkyl, NO~, alkylamino, 1:

~0 + N 0 0 12 (.)

0 + N

N N

~0 ~ N ~ N 0~ 0 0 0 US 2004/0067954 A1 Apr. 8, 2004 59

-continued

N ~0 + N 0 0

~0 + + &N 0 0 ~n~ ~o~ ~0 + N 0 0

~0 + + &N 0 0 A~ ~N 0 + N

N US 2004/0067954 A1 Apr. 8, 2004 60

-continued A~ ~AH ~0 + N 0 0

A~ ~A ~0 + N 0 0 A~ ~A ~0 + N 0 0 ~NQ 0 + N

~0 ~ N 0 0

~0 + N 0 0 US 2004/0067954 A1 Apr. 8, 2004 61

-continued

~O ~ + N ~ ~A~ 0 0

0 0

~O ~ + N ~ ~A~ ~Cl 0 0

~0 + N

~0 + + N

0 C1 ~n~ ~o~ ~0 + N

0 C1 0 US 2004/0067954 A1 Apr. 8, 2004 62

-continued

~0 + N

0 C1 0

N N

0 C1

(.)

0 + N

0 C1 0 A~ ~Cl ~0 + N

0 C1 0

~0 + N

O Ct ~o~ ~0 + N

O Ct 0 US 2004/0067954 A1 Apr. 8, 2004 63

-continued O~ ~OH ~0 + + N

0 C1 0 ~N

N N

~NQ ~0 + N + N 0~

0 C1 0 0 0

~0 + + &N

0 C1 0

~0 + N

0 C1 0 ~NQ 0 + N

0 US 2004/0067954 A1 Apr. 8, 2004 64

-continued

~0 + + &N 0 0

~0 + + &N

0 ~NH ~0 + N

~0 + N

0 F 0 ~H~ ~HH ~0 + + &N 0 F 0 ~HH I45 ~0 + N

~0 + N

0 F 0 US 2004/0067954 A1 Apr. 8, 2004 65

-continued O~ ~OH ~0 + N

0 F 0

~N N

~0 + N

A~ ~N i I

N N

0 US 2004/0067954 A1 Apr. 8, 2004 66

-continued

~0 + N

N N

~0 + + N 0 F 0 (.)

0 A~ ~Cl ~0 + N

~0 + N

0 F 0 US 2004/0067954 A1 Apr. 8, 2004 67

-continued (.)

0 + N

0 ~NQ ~0 ~ N ~ N 0~

0 F 0 0 (.)

~0 + N

0 F 0 ' ll ~0 + N

0 Ct 0 ' ll ~0 + N

0 F 0 US 2004/0067954 A1 Apr. 8, 2004 68

-continued

~0 + N

0 F 0

~0 + N 0 0

~NQ N N //

// QH 0 0 ~a N N ~NQ 0 + N QN

0 ~NQ 0 + N US 2004/0067954 A1 Apr. 8, 2004 69

-continued ~N+ I72 0 + N

I73

0 ~ + N

I74

0 + N

0 and salts and solvates thereof.

7. Process for the preparation of compounds of the in that a compound of the formula IV formula I and salts and solvates thereof, characterised in that a compound of the formula H IV

R' N OH 0 X

in which X, R' and R are as defined in claim 1, is reacted H with a compound of the formula V in which L— Q — R v in which R' and R are as defined in claim 1, is reacted with a Q and R are as defined in claim 1, and compound of the formula HI L is CI, Br, OH or a reactive esterified OH group, and/or in that a basic compound of the formula I is HI converted into one of its salts by treatment with an acid. II. Compounds of the formula II

0 —Q R' 0 X R

in which

R and Q are as defined in claim 1, and H

L is CI, Br, OH or a reactive esterified OH group, or in which R' and R are as defined in claim 1. US 2004/0067954 A1 Apr. 8, 2004 70

9. Compounds of the formula IV able salts and/or solvates thereof for the preparation of a medicament for the treatment and prophylaxis of myocardial diseases. Iv 19. Use of the compounds of the formula I according to one or more of claims 1 to 6 and/or physiologically accept- R' able salts and/or solvates thereof for the preparation of a N medicament for the treatment and prophylaxis of myocardial OH diseases which have inflammatory and/or immunological 0 characteristics. 20. Use of the compounds of the formula I according to one or more of claims 1 to 6 and/or physiologically accept- in which X, R' and R are as defined in claim 1. able salts and/or solvates thereof for the preparation of a 10. Use of the compounds of the formula I according to medicament for the treatment and prophylaxis of coronary one or more of claims 1 to 6 and/or physiologically accept- artery disease, reversible or irreversible myocardial able salts and/or solvates thereof for the preparation of a ischemia/reperfusion injury, acute or chronic heart failure medicament. and restenosis, including instent-restenosis and stent-in- 11. Compounds of the formula I according to one or more stent-restenosis. of claims 1 to 6 and/or physiologically acceptable salts 21. Use of the compounds of the formula I according to and/or solvates thereof as phosphodiesterase IV inhibitors. one or more of claims 1 to 6 and/or physiologically accept- 12. Use of the compounds of the formula I according to able salts and/or solvates thereof for the preparation of a one or more of claims 1 to 6 and/or physiologically accept- medicament for the treatment and prophylaxis of ventricular able salts and/or solvates thereof for the preparation of a remodeling after infarction or congestive heart failure of medicament the treatment and prophylaxis of diseases which diflerent severity. are caused by an excessively low cAMP level and/or can be 22. Use of the compounds of the formula I according to influenced by an increase in the cAMP level. one or more of claims 1 to 6 and/or physiologically accept- 13. Use of the compounds of the formula I according to able salts and/or solvates thereof for the preparation of a one or more of claims 1 to 6 and/or physiologically accept- medicament for treating a subject suflering from a disease or able salts and/or solvates thereof for the preparation of a condition mediated by the PDE IV isozyme in its role or medicament for the treatment and prophylaxis of diseases regulating the activation and degranulation of human eosio- which can be influenced by a reduction in the production of phils. tumour necrosis factor (TNF). 23. Use of the compounds of the formula I according to 14. Pharmaceutical preparation, characterised by a con- one or more of claims 1 to 6 and/or physiologically accept- tent of at least one compound of the formula I according to able salts and/or solvates thereof for the preparation of a one or more of claims 1 to 6 and/or one of its physiologically medicament for the treatment and prophylaxis of diseases acceptable salts and/or one of its solvates. which are caused by excessive production of macrophages 15. Process for the preparation of pharmaceutical prepa- and T-cells and/or can be influenced by a reduction in rations, characterised in that at least one compound of the macrophage and T-cell production. formula I according to one or more of claims 1 to 6 and/or 24. Use of the compounds of the formula I according to one of its physiologically acceptable salts and/or one of its one or more of claims 1 to 6 and/or physiologically accept- solvates is brought into a suitable dosage form together with able salts and/or solvates thereof for the preparation of a at least one solid, liquid or semi-liquid excipient or assistant. medicament for the treatment and prophylaxis of diseases 16. Compounds of the formula I according to one or more which are caused by excessive proliferation of the T-cells of claims 1 to 6 and physiologically acceptable salts and/or and/or can be influenced by an inhibition of the proliferation solvates thereof for combating allergic diseases, asthma, of the T-cells. chronic bronchitis, atopic dermatitis, psoriasis and other skin 25. Use of compounds of the formula I according to at diseases, inflammatory disorders, autoimmune diseases, least one of claims 1 to 6 and/or physiologically acceptable such as, for example, rheumatoid arthritis, multiple sclero- salts and/or solvates thereof for combating diseases. sis, Crohn's disease, diabetes mellitus or ulcerative colitis, 26. Use of compounds of the formula I according to at osteoporosis, transplant rejection reactions, cachexia, least one of claims 1 to 6 and/or physiologically acceptable tumour growth or tumour metastases, sepsis, memory dis- salts and/or solvates thereof for preparing a medicament in orders, atherosclerosis and AIDS. treating or preventing one or members selected from the 17. Use of compounds of the formula I according to one groups of diseases, disorders, and conditions consisting of: or more of claims 1 to 6 and physiologically acceptable salts and/or solvates thereof for the preparation of a medicament asthma of whatever type, etiology, or pathogenesis; or for the treatment and prophylaxis of allergic diseases, asthma that is a member selected from the group asthma, chronic bronchitis, atopic dermatitis, psoriasis and consisting of atopic asthma; non-atopic asthma; aller- other skin diseases, inflammatory disorders, autoimmune gic asthma; atopic, bronchial, IgE-mediated asthma; diseases, such as, for example, rheumatoid arthritis, multiple bronchial asthma; essential asthma; true asthma; intrin- sclerosis, Crohn's disease, diabetes mellitus or ulcerative sic asthma caused by pathophysiologic disturbances; colitis, osteoporosis, transplant rejection reactions, cachexia, extrinsic asthma caused by environmental factors; tumour growth or tumour metastases, sepsis, memory dis- essential asthma of unknown or inapparent cause; non- orders, atherosclerosis and AIDS. atopic asthma; bronchitic asthma; emphysematous 1II. Use of the compounds of the formula I according to asthma; exercise-induced asthma; occupational one or more of claims 1 to 6 and/or physiologically accept- asthma; infective asthma caused by bacterial, fungal, US 2004/0067954 A1 Apr. 8, 2004 71

protozoal, or viral infection; non-allergic asthma; eosinophils; allergic granulornatous angijtis' or Churg- incipient asthma; wheezy infant syndrome; Strauss syndrome; polyarteritis nodosa (PAN); and systemic necrotizing vasculitis; chronic or acute bronchoconstriction; chronic bronchitis; small airways obstruction; and emphysema; atopic dermatitis; or allergic dermatitis; or allergic or atopic eczema; obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis; or an obstructive or urticaria of whatever type, etiology, or pathogenesis; or inflammatory airways disease that is a member selected urticaria that is a member selected from the group from the group consisting of asthma; pneumoconiosis; consisting of immune-mediated urticaria; complement- chronic eosinophilic pneumonia; chronic obstructive mediated urticaria; urticariogenic material-induced pulmonary disease (COPD); COPD that includes urticaria; physical agent-induced urticaria; stressin- chronic bronchitis, pulmonary emphysema or dyspnea duced urticaria; idiopathic urticaria; acute urticaria; associated therewith; COPD that is chronic urticaria; angioedema; cholinergic urticaria; cold urticaria in the autosomal dominant form or in the characterized by irreversible, progressive airways acquired form; contact urticaria; giant urticaria; and obstruction; adult respiratory distress syndrome papular urticaria; (ARDS), and exacerbation of airways hyper-reactivity consequent to other drug therapy; conjunctivitis of whatever type, etiology, or pathogenesis; or conjunctivitis that is a member selected from the pneumoconiosis whatever or of type, etiology, pathogen- group consisting of actinic conjunctivitis; acute esis; or pneumoconiosis that is a member selected from catarrhal conjunctivitis; acute contagious conjunctivi- the group consisting of aluminosis or bauxite workers' tis; allergic conjunctivitis; atopic conjunctivitis; miners' disease; anthracosis or asthma; asbestosis or chronic catarrhal conjunctivitis; purulent conjunctivi- steam-fifters' asthma; chalicosis or flint disease; ptilo- tis; and vernal conjunctivitis; sis caused by inhaling the dust from ostrich feathers; siderosis caused by the inhalation of iron particles; uveitis of whatever type, etiology, or pathogenesis; or silicosis or grinders' disease; byssinosis or cotton-dust uveitis that is a member selected from the group asthma; and talc pneumoconiosis; consisting of inflammation of all or part of the uvea; anterior uveitis; iritis; cyclitis; iridocyclitis; granulor- bronchitis of whatever type, etiology, or pathogenesis; or natous uveitis; nongranulornatous uveitis; phacoanti- bronchitis that is a member selected from the group genic uveitis; posterior uveitis; choroiditis; and chori- consisting of acute bronchitis; acute laryngotracheal oretinitis; bronchitis; arachidic bronchitis; catarrhal bronchitis; croupus bronchitis; dry bronchitis; infectious asthmatic psoriasis; bronchitis; productive bronchitis; or staphylococcus multiple sclerosis of whatever type, etiology, or patho- streptococcal bronchitis; and vesicular bronchitis; genesis; or multiple sclerosis that is a member selected bronchiectasis of whatever type, etiology, or pathogen- from the group consisting of primary progressive mul- esis; or bronchiectasis that is a member selected from tiple sclerosis; and relapsing remitting multiple sclero- the group consisting of cylindric bronchiectasis; sac- Slsj culated bronchiectasis; fusiform bronchiectasis; capil- autoimmune/inflammatory diseases of whatever type, eti- bron- lary bronchiectasis; cystic bronchiectasis; dry ology, or pathogenesis; or an autoimmune/inflamma- and follicular chiectasis; bronchiectasis; tory disease that is a member selected from the group seasonal allergic rhinitis; or perennial allergic rhinitis; or consisting of autoimmune hematological disorders; sinusitis of whatever type, etiology, or pathogenesis; or hemolytic anemia; aplastic anemia; pure red cell ane- sinuisitis that is a member selected from the group mia; idiopathic thrombocytopenic purpura; systemic consisting of purulent or nonpurulent sinusitis; acute or lupus erythematosus; polychondritis; scleroderma; chronic sinusitis; and ethmoid, frontal, maxillary, or Wegner's granulomatosis; dermatomyositis; chronic sphenoid sinusitis, active hepatitis; myasthenia gravis; Stevens-Johnson syndrome; idiopathic sprue; autoimmune inflammatory rheumatoid arthritis of whatever type, etiology, or patho- bowel diseases; ulcerative colitis; Crohn's disease; genesis; or rheumatoid arthritis that is a member endocrin opthamopathy; Grave's disease; sarcoidosis; selected from the group consisting of acute arthritis; alveolitis; chronic hypersensitivity pneumonitis; pri- acute gouty arthritis; chronic inflammatory arthritis; mary biliary cirrhosis; juvenile diabetes or diabetes degenerative arthritis; infectious arthritis; Lyme arthri- mellitus type I; anterior uveitis; granulomatous or tis; proliferative arthritis; psoriatic arthritis; and verte- posterior uveitis; keratoconjunctivitis sicca; epidemic bral arthritis; keratoconjunctivitis; dilfuse interstitial pulmonary fibrosis or interstitial lung fibrosis; idiopathic pulmo- gout, and fever and pain associated with inflammation; nary fibrosis; cystic fibrosis; psoriatic arthritis; glom- an eosinophil-related disorder of whatever type, etiology, erulonephritis with and without nephrotic syndrome; or pathogenesis; or an eosinophil-related disorder that acute glomerulonephritis; idiopathic nephrotic syn- is a member selected from the group consisting of drome; minimal change nephropathy; Inflammatory/ eosinophilia; pulmonary infiltration eosinophilia; hyperproliferative skin diseases; psoriasis; atopic der- Loffier's syndrome; chronic eosinophilic pneumonia; matitis; contact dermatitis; allergic contact dermatitis; tropical pulmonary eosinophilia; bronchopneumonic benign familial pemphigus; pemphigus erythematosus; aspergillosis; aspergilloma; granulomas containing pemphigus foliaceus; and pemphigus vulgaris; US 2004/0067954 A1 Apr. 8, 2004 72

prevention of allogeneic graft rejection following organ and/or solvates thereof together with one or more members transplantation; selected from the group consisting of the following:

inflammatory bowel disease (IBD) of whatever type, (a) Leukotriene biosynthesis inhibitors, 5-lipoxygenase etiology, or pathogenesis; or inflammatory bowel dis- (5-LO) inhibitors, and 5-lipoxygenase activating pro- ease that is a member selected from the group consist- tein (FLAP) antagonists selected from the group con- ing of ulerative colitis (UC); collagenous colitis; colitis sisting of zileuton; fenleuton; tepoxalin; Abbott-79175; polyposa; transmural colitis; and Crohn's disease (CD); Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2, 6-di-tert. -butylphenol hydrazones; Zen- septic shock of whatever type, etiology, or pathogenesis; eca ZD-2138; SB-210661; pyridinyl-substituted 2-cy- or shock that is a member selected from the septic anonaphthalene compound L-739, 010; group consisting of renal failure; acute renal failure; 2-cyanoquinoline compound L-746, 530; indole and cachexia; malarial cachexia; hypophysial cachexia; quinoline compounds MK-591, MK-886, and BAY x uremic cachexia; cardiac cachexia; cachexia suprarena- 1005; lis or Addison's disease; cancerous cachexia; and cachexia as a consequence of infection by the human (b) Receptor antagonists for leukotrines LTB4, LTC4, immunodeficiency virus (HIV); LTD4, and LTE4 selected from the group consisting of phenothiazin-3-one compound L-651,392; amidino liver injury; compound CGS-25019c; benzoxazolamine compound benzene-carboximidamide pulmonary hypertension; and hypoxia-induced pulmo- ontazolast; compound BIIL compounds zafirlukast, ablukast, mon- nary hypertension; 284/260; telukast, pranlukast, verlukast (MK-679), RG-12525, bone loss diseases; primary osteoporosis; and secondary Ro-245913, iralukast (CGP 45715A), and BAYx7195; osteoporosis; (c) PDE IV inhibitors; central nervous system disorders of whatever type, etiol- 5-Lipoxygenase (5-LO) inhibitors; and 5-lipoxyge- ogy, or pathogenesis; or a central nervous system (d) nase activating protein antagonists; disorder that is a member selected from the group (FLAP) consisting of depression; Parkinson's disease; learning (e) Dual inhibitors of 5-lipoxygenase (5-LO) and antago- and memory impairment; tardive dyskinesia; drug. nists of platelet activating factor (PAF); dependence; arteriosclerotic dementia; and dementias that accompany Huntington's chorea, Wilson's disease, (f) Leukotriene antagonists (LTRAs) of LTB4, LTC4, paralysis agitans, and thalamic atrophies; LTD4, LTE4,

infection, especially infection by viruses wherein such (g) Antihistaminic H, receptor antagonist cetirizine, lora- viruses increase the production of TNF-u in their host, tadine, desloratadine, fexofenadine, astemizole, azelas- or wherein such viruses are sensitive to upregulation of tine, and chlorpheniramine; TNF-u in their host so that their replication or other Gastroprotective receptor antagonists; vital activities are adversely impacted, including a virus (h) H~ which is a member selected from the group consisting (i) u, - and u~-adrenoceptor agonist vasoconstrictor sym- of HIV-1, HIV-2, and HIV-3; cytomegalovirus, CMV; pathomimetic agents administered orally or topically influenza; adenoviruses; and Herpes viruses, including for decongestant use, selected from the group consist- Herpes zoster and Herpes simplex; ing of propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline, hydro- yeast and fungus infections wherein said yeast and fungi chloride, oxymetazoline hydrochloride, are sensitive to upregulation by TNF-u or elicit TNF-u tetrahydrozoline hydrochloride, xylometazoline hydro- production in their host, e.g. , fungal meningitis; par- chloride, and ethylnorepinephrine hydrochloride; ticularly when administered in conjunction with other drugs of choice for the treatment of systemic yeast and (j) one or more u, - and u~-adrenoceptor agonists as fungus infections, including but are not limited to, recited in (i) above in combination with one or more polymixins, e.g. , Polymycin B; imidazoles, e. g. , clot- inhibitors of 5-lipoygenase (5-LO) as recited in (a) rimazole, econazole, miconazole, and ketoconazole; above; triazoles, e.g. , fluconazole and itranazole; and amphotericins, e. g. , Amphotericin B and liposomal Amphot- (k) Anticholinergic agents ipratropium bromide; tiotro- ericin B; pium bromide, oxitropium bromide; pirenzepine; and telenzepine; ischemia-reperfusion injury; autoimmune diabetes; retinal autoimmunity; chronic lymphocytic leukemia; HIV (I) II, - to II~-adrenoceptor agonists selected from the infections; lupus erythematosus; kidney and ureter dis- group consisting of metaproterenol, isoproterenol, iso- ease; urogenital and gastrointestinal disorders; and prenaline, albuterol, salbutamol, formoterol, salme- prostate diseases. terol, terbutaline, orciprenaline, bitolterol, and pirbuterol; Use of compounds of the formula I according to at least one of claims 1 to 6 and/or physiologically acceptable (m) Theophylline and aminophylline; salts and/or solvates thereof for combating diseases (n) Sodium cromoglycate; 27. The combination of a compound as defined in one or more of claims 1 to 6 and/or physiologically acceptable salts (o) Muscarinic receptor (M1, M2, and M3) antagonists; US 2004/0067954 A1 Apr. 8, 2004 73

(p) COX-1 inhibitors (NSAIDs); and nitric oxide (II) Xanthine oxidase selected from the group consisting NSAIDs; of allopurinol;

(q) COX-2 selective inhibitor rofecoxib; (mm)Uricosuric agents selected from the group consisting of probenecid, sulfinpyrazone, and benzbromarone; (r) Insulin-like growth factor type I (IGF-I) mimetics; (s) Ciclesonide; (nn) Antineoplastic agents that are antimitotic drugs selected from the group consisting of vinblastine and (t) Inhaled glucocorticoids with reduced systemic side vincristine; elfects selected from the group consisting of prednisone, prednisolone, flunisolide, triamcinolone (oo) Growth hormone secretagogues; acetonide, beclomethasone dipropionate, budesonide, Inhibitors of matrix metalloproteases that fluticasone propionate, and mometasone furoate; (pp) (MMPs) are selected from the group consisting of the stromel- (u) Tryptase inhibitors; ysins, the collagenases, the gelatinises, aggrecanase, collagenase-1 (MMP-1), collagenase-2 (MMP-S), col- (v) Platelet activating factor (PAF) antagonists; lagenase-3 (MMP-13), stromelysin-1 (MMP-3), (w) Monoclonal antibodies active against endogenous stromelysin-2 (MMP-10), and stromelysin-3 (MMP- inflammatory entities; 11); IPL (x) 576; (qq) Transforming growth factor (TGFII); Anti-tumor necrosis factor (TNFu) agents selected (y) (rr) Platelet-derived growth factor (PDGF); from the group consisting of etanercept, infliximab, and D2E7; (ss)Fibroblast growth factor selected from the group consisting of basic fibroblast growth factor (bFGF); (z) DMARDs selected from the group consisting of leflunomide; (tt) Granulocyte macrophage colony stimulating factor (aa) TCR peptides; (GM-CSF); (bb) Interleukin converting enzyme (ICE) inhibitors; (uu) Capsaicin; (cc) IMPDH inhibitors; (vv)Tachykinin NK, and NK~ receptor antagonists selected from the group consisting of NKP-60SC; (dd) Adhesion molecule inhibitors including VLA-4 SB-233412 (talnetant); and D-4418; antagonists; inhibitors selected from the consist- (ee) Cathepsins; (ww)EIastase group ing of UT-77 and ZD-0892; and (5) MAP kinase inhibitors; (xx)Adenosine A2a receptor agonists. Glucose-6 phosphate dehydrogenase inhibitors; (gg) 2II. Set (kit) consisting of separate packs of (hh) Kinin-B, - and B~-receptor antagonists; (a) an elfective amount of a compound of the formula I (ii) Gold in the form of an aurothio group in combination according to one or more of claims 1 to 6 and/or its with hydrophilic groups; pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and (jj) Immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotr- (b) an elfective amount of a further medicament active exate; ingredient. (kk) Anti-gout agents selected from the group consisting of colchicines;