HK1092467B - N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses - Google Patents

Description

N-alkyl-hydroxamic acid-isoindolyl compounds and pharmaceutical uses thereof

The present invention is claimed at the benefit of U.S. provisional application No. 60/454,149, filed on 3/12/2003, which is incorporated herein by reference in its entirety.

1. Field of the invention

The present invention includes novel N-alkyl-hydroxamic acid-isoindolyl compounds, pharmaceutical compositions of these compounds, and methods of using these compounds and compositions in the treatment, prevention, and management of various diseases and disorders in mammals, such as diseases mediated by PDE4 inhibition, diseases associated with abnormal TNF- α levels, and/or diseases mediated by MMP inhibition.

2. Background of the invention

2.1.TNF-α

Tumor necrosis factor alpha (TNF- α) is a cytokine that is primarily released by inflammatory and mononuclear phagocytes in response to immune stimuli. TNF- α can enhance most cellular processes, such as differentiation, recruitment, proliferation, and protease degradation. At low levels, TNF- α confers protection against infectious agents, tumors, and cellular damage. However, TNF- α also plays a role in many diseases. When administered to a mammal such as a human, TNF- α causes or aggravates inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase reactions similar to those seen in acute infection and shock states. Increased or deregulated TNF- α production has been implicated in a number of diseases and medical conditions, such as cancers, e.g., solid and blood-borne tumors; heart disease, such as congestive heart failure; and viral, genetic, inflammatory, allergic and autoimmune diseases.

Cancer is a particularly devastating disease, and increased levels of TNF- α in the blood are associated with the risk and spread of cancer. Under normal conditions, in healthy individuals, cancer cells are unable to survive in the circulatory system, one of the reasons for which is that the vascular inner wall acts as a barrier to extravasation of tumor cells. However, it is known that in vitro, increased levels of cytokines can dramatically increase the adhesion of cancer cells to the endothelium. One explanation is that cytokines such as TNF- α stimulate the biosynthesis and expression of a cell surface receptor known as ELAM-1 (endothelial leukocyte adhesion molecule). ELAM-1 is a member of the family of calcium-dependent cell adhesion receptors known as LEC-CAM, which includes LECAM-1 and GMP-140. During the inflammatory response, ELAM-1 on endothelial cells acts as a "homing receptor" for leukocytes. ELAM-1 on endothelial cells has been shown to mediate enhanced adhesion of colon cancer cells to cytokine-treated endothelium (Rice et al, 1989, Science 246: 1303-.

Inflammatory diseases such as arthritis, related arthritis (e.g., osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, sepsis, psoriasis, chronic obstructive pulmonary disease, and chronic inflammatory pulmonary disease are also common and problematic conditions. TNF- α plays an important role in inflammatory responses, and administration of its antagonist blocks chronic and acute responses in animal models of inflammatory diseases.

Increased or deregulated TNF- α production is associated with the following diseases: viral diseases, genetic diseases, inflammatory diseases, allergic diseases and autoimmune diseases. Examples of such diseases include, but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic pulmonary inflammatory diseases; dermatitis; cystic fibrosis; septic shock; sepsis; (ii) endotoxic shock; hemodynamic shock; sepsis syndrome; reperfusion injury after ischemia; meningitis; psoriasis; fibrosis; cachexia; graft Versus Host Disease (GVHD); transplant rejection; autoimmune diseases; rheumatoid spondylitis; arthritis, such as rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis; osteoporosis; inflammatory bowel disease; crohn's disease; ulcerative colitis; multiple sclerosis; systemic lupus erythematosus; erythema nodosum leprosum (ENL in leprosy); radiation damage; asthma; and hyperoxic alveolar injury (hyperoxic alveolar injuryy). Tracey et al, 1987, Nature 330: 662-664 and Hinshaw et al, 1990, circ. shock 30: 279-292 (endotoxic shock); dezube et al, 1990, Lancet, 335: 662 (cachexia); millar et al, 1989, Lancet 2: 712-714 and Ferrai-Baliviera et al, 1989, Arch.Surg.124: 1400-1405 (adult respiratory distress syndrome); bertolini et al, 1986, Nature 319: 516-: 1424 + 1427, Holler et al 1990, Blood 75: 1011-: 1586-; pignet et al, 1990, Nature, 344: 245-247, Bissonnette et al, 1989, migration 13: 329- "Baughman et al, 1990, J.Lab.Clin.Med.115: 36-42 (chronic pulmonary inflammatory disease); elliot et al, 1995, int.J.Pharmac.17: 141-145 (rheumatoid arthritis); von Dullemen et al, 1995, Gastroenterology 109: 129-135 (Crohn's disease); duh et al, 1989, Proc.Nat.Acad.Sci.86: 5974-5978, Poll et al, 1990, Proc. Nat. Acad. Sci.87: 782 + 785, Monto et al, 1990, Blood 79: 2670, Clouse et al, 1989, J.Immunol.142, 431-: 782 + 784, Folks et al, 1989, Proc. Nat. Acad. Sci.86: 2365-.

2.2.PDE4

Cyclic adenosine monophosphate (cAMP) also plays a role in a number of diseases and disorders such as, but not limited to, asthma and inflammation (Lowe and Cheng, Drugs of the Future, 17(9), 799-. It has been shown that an increase in cAMP in inflammatory leukocytes inhibits their activation and subsequent release of inflammatory mediators including TNF-. alpha.and nuclear factor kappa B (NF-. kappa.B). Increased cAMP levels also lead to airway smooth muscle relaxation.

It is believed that the major cellular mechanism of cAMP inactivation is the breakdown of cAMP by a family of isozymes called cyclic nucleotide Phosphodiesterases (PDEs) (Beavo and Reitsnyder, Trends in pharm., 11, 150-155, 1990). There are 12 known members of the PDE family. It is known that inhibition of PDE type IV (PDE4) is particularly effective in inhibiting both inflammation-mediated release and airway smooth muscle relaxation (Verghese et al, Journal of pharmacological and experimental therapeutics, 272(3), 1313-1320, 1995). Thus, compounds that specifically inhibit PDE4 may inhibit inflammation and contribute to respiratory smooth muscle relaxation with minimal unwanted side effects, such as cardiovascular effects or antiplatelet effects.

The PDE4 family with specificity for cAMP is currently the largest family, consisting of at least 4 isozymes (a-d) and a variety of splice variants (Houslay, M.D. et al, Advances in Pharmacology 44, J.August et al, p.225, 1998). There are more than 20 isoforms of PDE4, which are expressed in a cell-specific manner regulated by many different promoters. Selective PDE4 inhibitors have been explored for disease states including: asthma, atopic dermatitis, depression, reperfusion injury, septic shock, toxic shock, endotoxic shock, adult respiratory distress syndrome, autoimmune diabetes, diabetic distress, multi-infarct dementia, AIDS, cancer, Crohn's disease, multiple sclerosis, cerebral ischemia, psoriasis, allograft rejection, restenosis, ulcerative colitis, cachexia, cerebral malaria, allergic rhinoconjunctivitis, osteoarthritis, rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), chronic bronchitis, eosinophilic granuloma (cosinophilic granuloma) and autoimmune encephalomyelitis (Houslay et al, 1998). PDE4 is present in the brain and in a number of inflammatory cells and has been found to be abnormally elevated in levels in a number of diseases including atopic dermatitis or eczema, asthma and hay fever (cf. OHSU flyer and J. of allergy and Clinical Immunology, 70: 452-457, 1982, Grewe et al). In individuals with atopic diseases, elevated PDE-4 activity is found in peripheral blood mononuclear leukocytes, T cells, mast cells, neutrophils, and basophils. Such increased PDE activity decreases cAMP levels and leads to disruption of cAMP control in these cells. This results in an increase in the immune response in the blood and tissues affected by it.

Some PDE4 inhibitors are reported to have broad spectrum anti-inflammatory activity, with high activity in models of asthma, Chronic Obstructive Pulmonary Disease (COPD) and other allergic diseases such as atopic dermatitis and hay fever. PDE4 inhibitors that have been used include theophylline, rolipram, denbufylline, ARIFLO, roflumilast, CDP 840 (triarylethane) and CP80633 (pyrimidinone). PDE4 inhibitors have been shown to affect eosinophilic responses, reduce basophilic histamine release, reduce IgE, PGE2, IL10 synthesis, and reduce I1-4 production against CD3 stimulation. Also, PDE4 inhibitors have been shown to block neutrophil function. Neutrophils play an important role in asthma, Chronic Obstructive Pulmonary Disease (COPD) and other allergic diseases. PDE4 inhibitors have been shown to inhibit the release of adhesion molecules, various reactive oxygen species, Interleukin (IL) -8, and neutrophil elastase, all of which are associated with neutrophils that disrupt lung architecture and thus airway function. PDE4 inhibitors affect a variety of functional pathways, acting on a variety of immune and inflammatory pathways, and thus affecting the synthesis or release of many immune mediators. (J.M.Handin and S.C.Chan, "Atomic Dermatities-Therapeutic Imperialization for New Phosphordiastris Inhibitors," Monocyte dyecorrelation of T Cells In AACI News, 7/2, 1995; J.M.Handin et al, "Type 4 Phosphordiastris Inhibitors Have closed In Vitro Effect Effects In Vitro Definitions," Journal of investigative Dermatology, 1996, 107, pp 51-56).

Some first generation PDE-4 inhibitors are effective at inhibiting PDE4 activity and alleviating many of the inflammatory problems caused by over-expression of this enzyme. However, their effectiveness is limited by side effects, particularly when used systemically, such as nausea and vomiting. Huang et al, cure. opin. in chem.biol., 2001, 5: 432-438. Indeed, all PDE4 inhibitors developed to date are small molecule compounds with the following central nervous system and gastrointestinal side effects: such as headache, nausea/vomiting and gastric fluid secretion.

2.3.MMP

Matrix Metalloproteinases (MMPs) are a family of proteases involved in connective tissue degradation and remodeling. Excessive degradation of extracellular matrix by MMPs has been implicated in the pathogenesis of a number of diseases including rheumatoid arthritis, osteoarthritis, cancer, multiple sclerosis, bone resorption diseases (e.g., osteoporosis), chronic obstructive pulmonary disease, restenosis, cerebral hemorrhage associated with stroke, periodontal disease, abnormal angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, skin ulceration, aneurysmal disease and diabetic complications. Thus, MMP inhibition is considered a good target for therapeutic intervention in such diseases. Numerous compounds have been reported to have MMP inhibitory activity (R.A. Nigel et al, Current Opinion on Therapeutic Patents, Vol.4, 7-16, (1994), R.P. Beckett et al, Drug Discovery Today, Vol.1, 16-26, (1996)). However, most are peptide derivatives based on the amino acid sequence of the enzyme cleavage site in the collagen molecule that constitutes the MMP substrate. There is a need for small molecule MMP inhibitors.

3. Summary of the invention

The present invention provides compounds useful for treating diseases mediated by PDE4 inhibition, as well as diseases mediated by TNF-a and MMPs. The invention also provides pharmaceutical compositions comprising these compounds and methods of using them in the treatment of various disorders.

One embodiment of the present invention encompasses compounds of formula (I) below and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof:

wherein:

y is-C (O) -, -CH₂-、-CH₂C (O) -or-SO₂-；

R₁And R₂Each independently is C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cycloalkyl or (C)_1-8-alkyl) cycloalkyl;

Z₁is H, C_1-6-alkyl, NH₂、NR₃R₄OR OR₅；

Z₂Is H or C (O) R₅；

X₁、X₂、X₃And X₄Each independently of the others being H, halogen, NO₂、OR₃、CF₃、C_{1- 6}Alkyl radicals, (C)_0-4-alkyl) - (C_3-6-cycloalkyl), (C)_0-4-alkyl) -N- (R)₈R₉)、(C_0-4-alkyl) -NHC (O) - (R)₈)、(C_0-4-alkyl) -NHC (O) CH (R)₈)(R₉)、(C_0-4-alkyl) -NHC (O) N (R)₈R₉)、(C_0-4-alkyl) -NHC (O) O (R)₈)、(C_0-4-alkyl) -O-R₈、(C_0-4-alkyl) -imidazolyl, (C)_0-4-alkyl) -pyrrolyl, (C)_0-4-alkyl) -oxadiazolyl, (C)_0-4-alkyl) -triazolyl or (C)_0-4-alkyl) -heterocycle;

R₃、R₄and R₅Each independently is H, C_1-6Alkyl, O-C_1-6-alkyl, phenyl, benzyl or aryl;

R₆and R₇Each independently is H or C_1-6-an alkyl group;

R₈and R₉Each independently is H, C_1-9Alkyl radical, C_3-6-cycloalkyl, (C)_1-6-alkyl) - (C_3-6-cycloalkyl), (C)_0-6-alkyl) -N (R)₄R₅)、(C_1-6-alkyl) -OR₅Phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrrolidinyl, morpholino or C_3-7-heterocycloalkyl.

Another embodiment of the invention encompasses methods of modulating (e.g., inhibiting) or reducing the level of PDE4 production in a mammal or in a mammalian cell, comprising administering to said mammal or mammalian cell an effective amount of a compound of the invention (e.g., a compound of formula I).

In another embodiment, the invention includes a method of modulating the production or reducing the level of TNF- α in a mammal or mammalian cells comprising administering to said mammal or mammalian cells an effective amount of a compound of the invention.

In yet another embodiment, the invention encompasses a method of modulating the production of MMPs, particularly inhibiting or reducing the levels thereof, in a mammal or mammalian cell, comprising administering to said mammal or mammalian cell an effective amount of a compound of the invention.

Other embodiments of the invention include methods of treating, preventing and managing various diseases or disorders, such as, but not limited to, Central Nervous System (CNS) diseases; myelodysplastic Syndrome (MDS) and related syndromes; complex Regional Pain Syndrome (CRPS) and related syndromes; cancer and related diseases; macular Degeneration (MD) and related syndromes; myeloproliferative disease (MPD) and related syndromes; and asbestos-related diseases and disorders.

Pharmaceutical compositions, modes of administration, formulations and methods of administration of the above compounds, alone or in combination, are described in more detail below.

3.1. Abbreviations and Definitions

Abbreviations used herein are conventional unless otherwise defined.

The term "treatment" as used herein refers to an action taken when a patient suffers from a particular disease or disorder to reduce the severity of the disease or disorder.

As used herein, unless otherwise indicated, the term "preventing" refers to an action taken to inhibit or reduce the severity of a particular disease or disorder before a patient begins to suffer from the disease or disorder.

As used herein, unless otherwise specified, the term "controlling" refers to preventing the recurrence of a particular disease or disorder in a patient already suffering from the disease or disorder, and/or prolonging the time that a patient already suffering from a particular disease or disorder is in remission. The term includes modulating the threshold (threshold), development and/or duration of a disease or disorder, or altering the manner in which a patient responds to a disease or disorder.

The term "therapeutically effective amount" means an amount of a compound administered sufficient to prevent or to alleviate to some extent the symptoms of one or more of the conditions or disorders being treated and to alleviate or eradicate the etiology of the disease.

The term "PDE 4-responsive condition or disease" or "condition or disease mediated by PDE4 inhibition" as used herein refers to a condition or disease that is responsive to modulation of PDE4 activity. Beneficial responses to PDE4 modulation include slowing or eliminating the disease and/or its attendant symptoms, inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms, and eliminating the disease or its clinical symptoms. PDE 4-reactive conditions or diseases may be fully or partially responsive to PDE4 modulation. PDE 4-reactive conditions or diseases may be associated with inappropriate, e.g., less than or greater than normal PDE4 activity. Inappropriate functional activity of PDE4 results because PDE4 is expressed in cells that do not normally express PDE4, which is a decrease in PDE4 expression (leading to, for example, lipid and metabolic disorders and diseases) or an increase in PDE4 expression. PDE 4-reactive conditions or diseases include PDE 4-mediated conditions or diseases.

Unless otherwise indicated, the term "alkyl", used alone or as part of another substituent group, refers to a straight or branched chain, acyclic or cyclic hydrocarbon group, or combinations thereof, which may be fully saturated, monounsaturated or polyunsaturated and may include divalent and polyvalent groups, having the indicated number of carbon atoms (e.g., C)_0-10Means 1-10 carbons, or is absent, i.e. C₀Meaning that the moiety is not present). Examples of the saturated hydrocarbon group include, for example, the following groups: methyl, ethylAlkyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl is a group having one or more double or triple bonds. Examples of unsaturated alkyl groups include ethenyl, 2-propenyl, butenyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers. Unless otherwise indicated, the term "alkyl" also includes alkyl derivatives defined in more detail below in "heteroalkyl," cycloalkyl, "and" alkylene. The term "alkylene" used alone or as part of another substituent refers to a divalent radical derived from an alkane, an example of which is-CH₂CH₂CH₂CH₂-. Generally, alkyl groups have 1 to 24 carbon atoms, and alkyl groups having 10 or less carbon atoms are preferred in the present invention. "lower alkyl" or "lower alkylene" is a short chain alkyl or alkylene group, typically having 8 or fewer carbon atoms.

Unless otherwise indicated, the term "heteroalkyl," used alone or in combination with other terms, refers to a stable straight or branched chain, acyclic, or cyclic hydrocarbon radical, or combinations thereof, consisting of the indicated number of carbon atoms and 1-3 heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N and S can be located at any internal position of the heteroalkyl group. The heteroatom Si may be located at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH＝CH-O-CH₃、-Si(CH₃)₃、-CH₂-CH＝N-OCH₃and-CH ═ CH-N (CH)₃)-CH₃. Up to 2 heteroatoms may be adjacent, e.g. -CH₂-NH-OCH₃and-CH₂-O-Si(CH₃)₃. Also included in the term "heteroalkyl" are the groups described in more detail below in "heteroalkylene" and "heterocycloalkyl". The term "heteroalkylene", used alone or as part of another substituent, refers to a divalent radical derived from a heteroalkyl radical, an example being-CH₂-CH₂-S-CH₂CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms may also occupy one or both ends of the chain. For alkylene and heteroalkylene linking groups, no provision is made for the orientation of the linking group.

Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl", used alone or in combination with other terms, represent the cyclic forms of "alkyl" and "heteroalkyl", respectively. Thus, the terms "cycloalkyl" and "heterocycloalkyl" are included within the terms "alkyl" and "heteroalkyl," respectively. Furthermore, the term "C_3-18Cycloalkyl "refers to cycloalkyl groups having 3 to 18 carbon atoms. Furthermore, for heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the rest of its molecule. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- (1, 2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

Unless otherwise indicated, the terms "halo" or "halogen," used alone or as part of another substituent, refer to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Further, the term "haloalkyl" and the like is meant to include alkyl groups substituted with halogen atoms, which may be the same or different, in numbers from 1 to (2m '+ 1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "halo (C)₁-C₄) Alkyl "includes trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with 2 to (2m '+ 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group). Unless otherwise indicated, the term "perhaloalkyl" refers to an alkyl group substituted with (2m '+ 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "perhalo (C)₁-C₄) Alkyl "includes trifluoromethyl, pentachloroethyl, 1, 1, 1-trifluoro-2-bromo-2-chloroethyl, and the like.

Unless otherwise indicated, the term "aryl" used alone or in combination with other terms (e.g., aryloxy, arylsulfenoxy, arylalkyl) refers to an aromatic substituent that can be a ring or rings (up to three rings) which can be fused together or covalently attached. Each of these rings may contain 0-4 heteroatoms selected from N, O and S, where the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. An aryl group containing a heteroatom may be referred to as a "heteroaryl" group, and may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, triazolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for each of the above aromatic ring systems are selected from the following acceptable substituents.

The term "arylalkyl" includes such groups: wherein the aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, picolyl, etc.) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, etc.).

Each of the above terms (e.g., "alkyl", "heteroalkyl", and "aryl") includes both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

Substituents for alkyl and heteroalkyl groups (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: -OR ', - (O), - (NR '), - (N-OR ', - (NR ' R ',), - (SR ',), - (si ' R ' R ', - (oc) (O) R ', - (c) (O) R ', - (CO) CO₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)₂R′、-NH-C(NH₂)＝NH、-NR′C(NH₂)＝NH、-NH-C(NH₂)＝NR′、-S(O)R′、-S(O)₂R′、-S(O)₂NR' R ", -CN and-NO₂Ranging in value from 0 to (2N +1), wherein N is the total number of carbon atoms in the group, and wherein R ', R ", and R'" are each independently hydrogen, unsubstituted (C)₁-C₈) Alkyl and heteroalkyl radicals, unsubstituted aryl radicals, aryl radicals substituted by 1 to 3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy radicals or aryl radicals- (C)₁-C₄) An alkyl group. When R 'and R' are attached to the same nitrogen atom, they may be taken together with the carbon atom to which the nitrogen atom is attached to form a 5-, 6-or 7-membered ring containing 1 to 3 heteroatoms selected from N, O and S. For example, -NR' R "includes 1-pyrrolidinyl and 4-morpholinyl. From the substituents discussed above, those skilled in the art will appreciate that the term "alkyl" includes substituted alkyl groups, including haloalkyl groups (e.g., -CF)₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃and-C (O) CH₂OCH₃Etc.).

Likewise, the substituents for the aryl group may also vary and may be selected from: -halogen, -OR', -OC (O))R′、-NR′R″、-SR′、-R′、-CN、-NO₂、-CO₂R′、-CONR′R″、-C(O)R′、-OC(O)NR′R″、-NR″C(O)R′、-NR″C(O)₂R′、-NR′-C(O)NR″R″′、-NH-C(NH₂)＝NH、-NR′C(NH₂)＝NH、-NH-C(NH₂)＝NR′、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R″、-N₃、-CH(Ph)₂Fluoro (C)₁-C₄) Alkoxy and fluoro (C)₁-C₄) Alkyl groups ranging in number from 0 to the total number of ring opening valences (open valences) on the aromatic ring system; and wherein each of R ', R ' and R ' is hydrogen, (C)₁-C₈) Alkyl and heteroalkyl radicals, unsubstituted aryl radicals, (unsubstituted aryl radicals) - (C)₁-C₄) Alkyl or (unsubstituted aryl) oxy- (C)₁-C₄) An alkyl group.

The term "heteroatom" as used herein includes oxygen (O), nitrogen (N) and sulfur (S). In certain embodiments, the term also includes silicon (Si).

The term "pharmaceutically acceptable salts" includes salts prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine and magnesium salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, and phosphorous acid, as well as salts derived from relatively nontoxic organic acids; such as acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are amino acid salts (e.g., arginine salts) and organic acid salts (e.g., glucuronate and galacturonate). See, e.g., Berge et al (1977) j.pharm.sci.66: 1-19. Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into both base and acid addition salts.

Some salts of the compounds may be recovered in their neutral form by contacting with a base or acid, and the parent compound may be isolated by conventional means. The parent form of a compound may differ from its various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, a salt form is generally equivalent to the parent form of the compound.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are pharmacologically equivalent to unsolvated forms. Certain compounds of the invention may exist in polymorphic or amorphous forms. In general, all physical forms are equivalent for the uses given in this invention and are intended to be within the scope of the invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical or stereogenic centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers and mixtures thereof are all included in the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with, for example, the following radioisotopes: tritium (A)³H) Iodine-125 (¹²⁵I) And carbon-14 (¹⁴C) In that respect Radiolabeled compounds are useful as therapeutic agents (e.g., cancer therapeutics), research reagents (e.g., assays), and diagnostic agents (e.g., in vivo contrast agents).All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

4. Detailed description of the invention

The present invention includes novel compounds and compositions that are useful for treating, preventing, or managing diseases and disorders in a mammal (e.g., a human). Examples of such diseases or disorders include, but are not limited to, cancer; viral, genetic, inflammatory, allergic, and autoimmune diseases; and bacterial infections. The compounds of the invention are useful in the treatment, prevention or management of diseases which are caused or exacerbated by excessive, insufficient or unregulated levels of PDE4, TNF-alpha or MMP. More specific examples include, but are not limited to: central Nervous System (CNS) diseases; myelodysplastic syndrome (MDS) and related syndromes; complex Regional Pain Syndrome (CRPS) and related syndromes; cancer and related diseases; macular Degeneration (MD) and related syndromes; myeloproliferative disease (MPD) and related syndromes; and asbestos-related diseases or disorders.

The invention encompasses compounds of formula (I) and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof:

wherein:

y is-C (O) -, -CH₂-、-CH₂C (O) -or-SO₂-；

R₁And R₂Each independently is C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cycloalkyl or (C)_1-8-alkyl) cycloalkyl;

Z₁is H, C_1-6-alkyl, NH₂、NR₃R₄OR OR₅；

Z₂Is H or C (O) R₅；

X₁、X₂、X₃And X₄Each independently of the others being H, halogen, NO₂、OR₃、CF₃、C_{1- 6}Alkyl radicals, (C)_0-4-alkyl) - (C_3-6-cycloalkyl), (C)_0-4-alkyl) -N- (R)₈R₉)、(C_0-4-alkyl) -NHC (O) - (R)₈)、(C_0-4-alkyl) -NHC (O) CH (R)₈)(R₉)、(C_0-4-alkyl) -NHC (O) N (R)₈R₉)、(C_0-4-alkyl) -NHC (O) O (R)₈)、(C_0-4-alkyl) -O-R₈、(C_0-4-alkyl) -imidazolyl, (C)_0-4-alkyl) -pyrrolyl, (C)_0-4-alkyl) -oxadiazolyl, (C)_0-4-alkyl) -triazolyl or (C)_0-4-alkyl) -heterocycle;

R₃、R₄and R₅Each independently is H, C_1-6Alkyl, O-C_1-6-alkyl, phenyl, benzyl or aryl;

R₆and R₇Each independently is H or C_1-6-an alkyl group;

R₈and R₉Each independently is H, C_1-9Alkyl radical, C_3-6-cycloalkyl, (C)_1-6-alkyl) - (C_3-6-cycloalkyl), (C)_0-6-alkyl) -N (R)₄R₅)、(C_1-6-alkyl) -OR₅Phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrrolidinyl, morpholino or C_3-7-heterocycloalkyl.

In a preferred embodiment, Y is-CH₂-or-C (O) -.

In another preferred embodiment, Z₁Is H.

In another preferred embodiment, Z₁Is H, R₆Is C_1-6-alkyl, R₇Is H.

In another preferred embodiment, Z₂Is H, -C (O) CH₃or-C (O) CH₂CH₃。

In another preferred embodiment, Z₂Is H, -C (O) CH₃or-C (O) CH₂CH₃，X₄Is NHC (O) R₅。

In another preferred embodiment, Z₂Is H, -C (O) CH₃or-C (O) CH₂CH₃And R₁CH₃Or CHF₂，R₂Is C_1-8-an alkyl group.

In another preferred embodiment, Z₂Is H.

In yet another preferred embodiment, R₁Is CH₃Or CF₂H。

In yet another preferred embodiment, R₂Is CH₂CH₃、CH₃、CF₂H、CH₂-cyclopropyl or cyclopentyl.

In another preferred embodiment, R₆And R₇While being H, or R₆And R₇One of which is H and the other is CH₃。

In yet another preferred embodiment, X₄is-NHC (O) R₄，X₁Is H or halogen.

In yet another preferred embodiment, X₁、X₂、X₃And X₄Is NHCOCH₂N(CH₃)₂、NHCON(CH₃)₂、NHCONH₂、NHCOCH₃、NHCOCH(R₈)N(R₈R₉) Or OCH₃And the balance is H.

Exemplary compounds of the invention include, but are not limited to, the compounds listed in table 1 below:

TABLE 1

The compounds of the invention are generally present in solid form and can be recrystallized according to well-known methods to give crystals of high purity, preferably greater than 95% purity, more preferably greater than 98% purity. A narrow melting point range is generally an indication of purity. Thus, the compounds of the present invention preferably have a melting point in the range of 3 ℃ to 4 ℃, more preferably in the range of 2 ℃.

Different compounds of the invention contain one or more chiral centers and may exist as racemic or diastereomeric mixtures of enantiomers. The invention includes the use of stereomerically pure forms of the compounds, as well as the use of mixtures of these forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in the methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, e.g., Jacques, j, et al, eneriomers, Racemates and solutions (Wiley-Interscience, new york, 1981); wilen, s.h. et al, Tetrahedron 33: 2725 (1977); eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of solving Agents and Optical solutions, page 268 (eds. E.L.Eliel, Univ.of Notre Dame Press, Notre Dame, IN, 1972).

The compounds of the present invention may contain one or more chiral centers and/or double bonds and may therefore exist as stereoisomers and geometric isomers. The chemical structures and chemical moieties shown herein include all enantiomers and stereoisomers thereof, such as a mixture of stereoisomers in pure form of two stereoisomers.

As used herein, unless otherwise indicated, the term "stereomerically pure" or "enantiomerically pure" refers to a compound that contains one stereoisomer and is substantially free of its corresponding stereoisomer or enantiomer. For example, a compound is stereomerically or enantiomerically pure when it contains 80%, 90%, or 95% or more of one stereoisomer and 20%, 10%, or 5% or less of its corresponding stereoisomer. In certain instances, a compound of the invention is considered optically or enantiomerically pure (i.e., substantially R-form or substantially S-form) for a particular chiral neutral when the compound is about 80% ee (enantiomeric excess) or greater, preferably equal to or greater than 90% ee, and more preferably 95% ee for a particular chiral center.

As used herein, unless otherwise indicated, the term "stereoisomer mixture" includes racemic mixtures as well as stereoisomerically enriched mixtures (e.g., R/S ═ 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, and 70/30).

The compounds of formula I have at least one stereogenic center, represented as a:

in addition, when R is₆And R₇In a different case, the compounds of the formula I also have a stereogenic center, denoted by b. Furthermore, the compounds of formula I may have other steric substituents depending on the particular substituents at different positions in their structuresAnd (4) a heart. The present invention includes stereomerically pure compounds of formula I, as well as mixtures (e.g., racemic and stereomerically enriched mixtures) of these compounds.

In one embodiment, the present invention includes compounds of formula I wherein the configuration of the stereocenter a is (S).

In another embodiment, the present invention includes compounds of formula I wherein the configuration of the stereocenter a is (R).

In another embodiment, the invention includes compounds of formula I wherein R is₆And R₇In contrast, the configuration of the stereocenter b is (S).

In another embodiment, the invention includes compounds of formula I wherein R is₆And R₇In contrast, the configuration of the stereocenter b is (R).

When R is₆And R₇In contrast, the compounds of formula I have at least two chiral centers and can therefore exist in diastereomerically pure forms. As used herein, the two letter symbols representing diastereomeric configurations, the first letter refers to the configuration of chiral center a and the second letter refers to the configuration of chiral center b. For example, configuration RS, when used with a compound of formula I, refers to the configuration: wherein the chiral center a is in the R configuration and the chiral center b is in the S configuration.

In a related embodiment, the invention includes diastereomerically pure RR isomers of compounds of formula I, substantially free of other diastereomers.

In another embodiment, the invention encompasses diastereomerically pure RS isomers of the compounds of formula I, substantially free of other diastereomers.

In another related embodiment, the invention encompasses diastereomerically pure SR isomers of the compounds of formula I, substantially free of other diastereomers.

In yet another embodiment, the invention includes diastereomerically pure SS isomers of the compounds of formula I, substantially free of other diastereomers.

Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compounds as chiral salt complexes, or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomers or enantiomerically pure intermediates, reagents or catalysts by well-known asymmetric syntheses.

The invention also includes prodrugs of the compounds of formula I. The term "prodrug" as used herein, unless otherwise indicated, refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to yield the compound. Examples of prodrugs include, but are not limited to, derivatives of the compounds of the present invention that contain biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include derivatives of the compounds of the present invention, including-NO, -NO₂-ONO or-ONO₂And (4) partial. Prodrugs can generally be prepared by well known methods such as those described in the following references: burger's medicinal chemistry and Drug Discovery, 172-.

As used herein, unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate ester, respectively, of a compound having the following characteristics: 1) does not interfere with the biological activity of the compound, but may impart beneficial properties to the compound in vivo, such as uptake, duration of action, or onset of action; or 2) are biologically inactive per se, but are capable of being converted in vivo into biologically active compounds. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl ester, acetoxyethyl ester, aminocarbonyloxymethyl ester, pivaloyloxymethyl ester, and pivaloyloxyethyl ester), lactones (e.g., phthalidyl esters and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester, and isopropoxycarbonyloxyethyl ester), alkoxyalkyl esters, choline esters, and acylaminoalkyl esters (e.g., acetamidomethyl ester). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

The compounds of the present invention are defined herein by their chemical structure and/or chemical name. When a chemical compound refers to both its chemical structure and its chemical name but the chemical structure and the chemical name contradict each other, the chemical structure is taken as the standard.

The present invention provides pharmaceutical compositions comprising a therapeutically effective amount, or a prophylactically effective amount, of one or more compounds of the invention and a pharmaceutically acceptable vehicle or carrier. The pharmaceutically acceptable vehicle or carrier may include excipients, diluents, or mixtures thereof. The term "therapeutically effective amount" means the amount of a compound of the present invention that elicits the biological or medicinal response in a mammal being treated by a veterinarian or medical doctor. The term "prophylactically effective amount" refers to an amount of a compound of the present invention that prevents or inhibits pain or reduces pain in a mammal suffering from a medical condition for which a veterinarian or doctor is attempting to prevent, inhibit or reduce.

In another embodiment, the invention includes a method of inhibiting PDE4 in a mammal, comprising administering to the mammal an effective amount of a compound of the invention.

In another embodiment, the invention includes a method of modulating TNF- α production or reducing TNF- α levels in a mammal comprising administering to said mammal an effective amount of a compound of the invention.

In yet another embodiment, the invention encompasses a method of inhibiting MMPs in a mammal, comprising administering to the mammal an effective amount of a compound of the invention.

In yet another embodiment, the invention encompasses a method of treating unwanted angiogenesis in a mammal, comprising administering to the mammal an effective amount of a compound of the invention. Angiogenesis-related diseases are well known in the art.

A separate embodiment of the invention encompasses methods of treating, preventing, or managing myelodysplastic syndrome (MDS), which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MDS refers to various hematopoietic stem cell disorders. MDS is characterized by impaired morphology and maturity of the cell marrow (aberrant bone marrow organization), peripheral cytopenia, and an uncertain risk of developing acute leukemia, all resulting from ineffective hematopoiesis. The Merck Manual 953 (17 th edition, 1999) and List et al, 1990, J.Clin.Oncol.8: 1424.

another independent embodiment of the invention encompasses methods of treating, preventing or managing Macular Degeneration (MD) comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MD refers to an eye disease that destroys central vision by damaging the macula.

A separate embodiment of the invention encompasses methods of treating, preventing or managing myeloproliferative disease (MPD) which comprise administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Myeloproliferative disease (MPD) refers to a group of disorders characterized by clonal abnormalities of hematopoietic stem cells. See, e.g., Current Medical diagnostics & Treatment, page 499 (37 th edition, Main edition by Tierney et al, Appleton & Lange, 1998).

The invention also encompasses methods of treating, preventing or managing Complex Regional Pain Syndrome (CRPS), which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during or after surgical treatment or physical therapy directed at reducing or avoiding symptoms of complex regional pain syndrome in the patient.

In another embodiment, the invention encompasses methods of treating, preventing or managing a Central Nervous System (CNS) disorder, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In another embodiment, the invention encompasses methods of treating, preventing or managing an asbestos-related disease or disorder, which comprise administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Asbestos-related diseases or disorders refer to diseases or disorders caused by exposure to asbestos.

The invention also encompasses methods of treating, preventing or managing Parkinson's disease or a related disorder, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In yet another embodiment, the invention encompasses methods of treating, preventing or managing cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention. The compounds of the invention are useful in the treatment, prevention or management of any cancer, for example, solid and blood-borne tumors. Specific examples of cancers that may be treated, prevented or controlled with the compounds of the present invention include, but are not limited to, skin cancers, such as melanoma; lymph node cancer; breast cancer; cervical cancer; uterine cancer; gastrointestinal cancer; lung cancer; ovarian cancer; prostate cancer; colon cancer; rectal cancer; oral cancer; brain cancer; head and neck cancer; throat cancer; testicular cancer; kidney cancer; pancreatic cancer; bone cancer; spleen cancer; liver cancer; bladder cancer; laryngeal cancer; nasal passage cancer; and AIDS-related cancers. The compounds are particularly useful in the treatment of, for example, the following blood and bone marrow cancers: multiple myeloma and acute and chronic leukemias, such as lymphoblastic, myeloblastic, lymphocytic, and myelogenous leukemias. The compounds of the invention are useful in the treatment, prevention or control of primary or metastatic tumors.

In yet another embodiment, the invention encompasses methods of treating, preventing or managing cancer in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention and an additional therapeutic agent.

In yet another embodiment, the invention encompasses methods of treating, preventing or managing an inflammatory disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention. The compounds of the present invention are particularly useful in the treatment, prevention or management of inflammatory diseases associated with TNF- α up-regulation, including but not limited to arthritis, such as rheumatoid arthritis and osteoarthritis; rheumatoid spondylitis; psoriasis; perfusion injury following ischemia; inflammatory bowel disease; and chronic inflammatory lung diseases.

In yet another embodiment, the invention encompasses methods of treating, preventing or managing an inflammatory disease in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention and an additional anti-inflammatory agent.

In another embodiment, the invention encompasses a method of treating, preventing or managing cardiac disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the invention. For example, the compounds of the invention are useful in the treatment, prevention or management of congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.

In one other embodiment, the invention encompasses a method of treating, preventing or managing osteoporosis in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention.

In another embodiment, the invention includes methods of treating, preventing or managing viral diseases, genetic diseases, allergic diseases, and autoimmune diseases. For example, the compounds may be used to treat, prevent or control diseases in mammals including, but not limited to: HIV, hepatitis, adult respiratory distress syndrome, bone resorption disease, chronic pulmonary inflammatory disease, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock (hemodynamic shock), sepsis syndrome, post-ischemic reperfusion injury, meningitis, psoriasis, fibrotic diseases, cachexia, graft versus host disease, transplant rejection, autoimmune diseases, rheumatoid spondylitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, leprosy erythema nodosum, radiation injury, cancer, asthma, or hyperoxic alveolar injury, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention.

In yet another embodiment, the invention encompasses a method of treating, preventing or controlling malaria, mycobacterial infection or opportunistic infection by HIV in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention.

In yet another embodiment, the invention relates to the treatment, prevention, or management of a mammal suffering from more than one condition that can be treated by a compound of the invention.

In the above embodiments, it is preferred that the mammal is in need of such treatment or prevention, i.e., that the mammal actually suffers from or is at risk of a medical condition, which condition is one that the compounds of the present invention can treat or prevent. However, the compounds of the invention may also be administered to a test animal in need of such treatment or prevention.

In another embodiment, the invention includes a method of modulating the production or reducing the level of PDE4 in a mammalian cell or tissue, comprising contacting the mammalian cell or tissue with an effective amount of a compound of the invention.

In another embodiment, the invention includes a method of modulating the production, preferably inhibiting or reducing the level of TNF- α in a mammalian cell or tissue, comprising contacting the mammalian cell or tissue with an effective amount of a compound of the invention.

In yet another embodiment, the invention includes a method of modulating the production or reducing the level of MMPs in a mammalian cell or tissue, comprising contacting the mammalian cell or tissue with an effective amount of a compound of the invention.

In these embodiments, the term "effective amount" refers to the amount of a compound that will elicit the biological response as determined by a researcher, veterinarian, medical doctor or clinician. It is understood that cells may be in cell culture or tissue culture (in vitro) or in organisms including humans (in vivo).

The invention may be understood by reference to the detailed description of the invention and the examples which are intended to illustrate non-limiting embodiments of the invention.

4.1. Preparation of the Compounds

The compounds can be prepared using known methods commonly used for the preparation of diimides and 2, 3-dihydro-1H-isoindolinones. However, the present invention also relates to improvements in the production of the final compounds, which are described in more detail below.

Reacting an N-alkoxycarbonyl diimide with an amine in the presence of a base such as sodium carbonate or sodium bicarbonate to give an N-substituted diimide substantially as described in the following references: sheary et al, Chem. & Ind., (1965) 1030-764 and Sheary et al, J.Pharm.Sci.57, 757-764 (1968). Alternatively, cyclic anhydrides can be reacted with suitable amines to form imides. Cyclic diimides can also be formed by refluxing a solution of an appropriately substituted dicarboxylic acid monoamide in anhydrous tetrahydrofuran with N, N' -carbonyldiimidazole. Alternatively, as shown below, 2-bromomethyl-benzoate can be reacted with a suitable amine to produce 2, 3-dihydro-1H-isoindolinone.

Other methods of formation are described in U.S. patent No. 5,605,914 and international publication No. WO01/34606a1, which are incorporated herein by reference in their entirety.

4.2. Pharmaceutical composition

The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, excipient or diluent and one or more compounds of the invention.

One embodiment provides the subject compounds together with pharmaceutically acceptable excipients, such as sterile saline, methylcellulose solutions, detergent solutions or other media, water, gelatin, oils and the like. The compounds or compositions may be used alone or in combination with any conventional carriers, diluents, and the like, and may be administered in single or multiple doses. The compositions are sterile, especially when used for parenteral administration. However, oral unit dosage forms need not be sterile. Useful carriers include water-soluble and water-insoluble solids, fatty acids, micelles, reverse micelles, liposomes, and semi-solid or liquid media, including aqueous solutions and non-toxic organic solvents. All of the above ingredients are processed by sonication, stirring, mixing, high shear mixing, heating, milling, grinding, aerosolization, pulverization, lyophilization, and the like to form a pharmaceutically acceptable composition.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is present in the mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparing" encompasses formulating an active compound with an encapsulating material as a carrier into a capsule wherein the active ingredient, with or without other carriers, is surrounded by a carrier, which is thus associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax (e.g., a mixture of fatty acid glycerides or cocoa butter) is first melted and the active ingredient is then homogeneously dispersed therein by stirring. The molten homogeneous mixture is then poured into a conventional size mold, allowed to cool and solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations may be formulated with aqueous solutions of polyethylene glycol.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water containing, for example, the following viscous materials: natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which may be converted shortly before use to liquid form preparations for oral administration. The liquid forms include solutions, suspensions, and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation may be subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing a plurality of discrete doses of the preparation, for example, a packaged tablet, capsule or powder in a vial or ampoule. Alternatively, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be in any suitable number in the form of a package.

The amount of active ingredient in a unit dose formulation may vary or may be adjusted between 0.1mg and 1000mg, preferably 1.0mg to 100mg, depending on the particular application and efficacy of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

As described herein, the pharmaceutical compositions and methods of the present invention may also include other therapeutically active compounds or other adjuvants useful in the treatment of metabolic disorders, cardiovascular diseases, inflammatory disorders or neoplastic diseases and pathologies associated therewith (e.g., diabetic neuropathy). In many cases, compositions comprising a compound of the invention and another drug have an additive or synergistic effect when administered.

4.3. Application method

According to the present invention, a compound or composition of the present invention is administered to a mammal (preferably a human) suffering from or at risk of a disease or medical condition, such as a cancer, for example, solid tumors and blood-borne tumors. Specific examples of cancers that can be treated, prevented or controlled by administration of the compounds of the present invention include, but are not limited to, skin cancers, such as melanoma; lymph node cancer; breast cancer; cervical cancer; uterine cancer; gastrointestinal cancer; lung cancer; ovarian cancer; prostate cancer; colon cancer; rectal cancer; oral cancer; brain cancer; head and neck cancer; throat cancer; testicular cancer; kidney cancer; pancreatic cancer; bone cancer; spleen cancer; liver cancer; bladder cancer; laryngeal cancer; nasal passage cancer; and AIDS-related cancers. The compounds are particularly useful in the treatment of, for example, the following blood and bone marrow cancers: multiple myeloma and acute and chronic leukemias, such as lymphoblastic, myeloblastic, lymphocytic, and myelogenous leukemias.

Other specific cancers include, but are not limited to, advanced malignancies, amyloidosis, neuroblastoma, meningioma, vascular involuntary tumor, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumors, glioblastoma, recurrent malignant glioma, astrocytoma multiforme (anaplastic astrocytoma), oligodendroma multiforme (anaplastic oligodendroglioma), neuroendocrine tumors, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, nuclear (karotype) acute myelogenous leukemia, hodgkin's lymphoma, non-hodgkin's lymphoma, cutaneous T cell lymphoma, diffuse cutaneous B cell lymphoma, large B cell lymphoma, low grade follicular lymphoma, metastatic melanoma (local melanoma, including but not limited to ocular melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal tumor, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma (scelroderma), cutaneous vasculitis, Langerhans' histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone refractory prostate cancer, resectable high risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and leiomyoma. In a specific embodiment, the cancer is a metastatic cancer. In another embodiment, the cancer is a refractory cancer or a cancer that is resistant to chemotherapy or radiation; in particular, it is refractory to thalidomide.

The compounds of the invention are also useful in the treatment, prevention or management of cardiac diseases such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.

The compounds of the present invention are also useful in the treatment, prevention or management of viral, genetic, inflammatory, allergic and autoimmune diseases. For example, the compounds may be used to treat, prevent or manage diseases including, but not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease; dermatitis; cystic fibrosis; septic shock; sepsis; (ii) endotoxic shock; hemodynamic shock; sepsis syndrome; reperfusion injury after ischemia; meningitis; psoriasis; fibrosis; cachexia; transplant rejection; autoimmune diseases; rheumatoid spondylitis; arthritis, such as rheumatoid arthritis and osteoarthritis; osteoporosis, crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; erythema nodosum leprosum; radiation damage; asthma; and hyperoxic alveolar injury.

The compounds of the present invention may also be used to treat, prevent or control bacterial infections, including but not limited to malaria, mycobacterial infection or opportunistic infections caused by HIV.

Another embodiment of the invention encompasses methods of treating, managing or preventing diseases and disorders associated with or characterized by unwanted angiogenesis, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Examples of diseases and disorders associated with or characterized by unwanted angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases, and rubeosis (neovascularization of the angle), which disease is mediated by unwanted or uncontrolled angiogenesis.

Other examples include, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic fossa, epidemic keratoconjunctivitis, atopic keratitis, superior eyelid keratitis (superior limbic keratitis), pterygium sarcoidosis, sjogrens disease (sjogrens), rosacea, phylectenulosis, syphilis, steatosis, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoan infections, kaposi's sarcoma, morren's ulcer, Terrien's marginal degeneration (Terrien's marginal degeneration), marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, wegener's sarcoidosis, scleritis, stevensis-Johnson's disease (stevens's disease), scleritis, scleroderma, stevensis-Johnson's disease, periphigoid radial keratotomy, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, paget's disease, venous embolism, arterial embolism, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme disease (Lyme's disease), elsholtzia disease (easlesse), behcet's disease, retinitis, choroiditis, presumed ocular histoplasmosis, congenital macular degeneration (Best's disease), Stargardt's disease, pars plana, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, rubeosis, sarcoidosis, sclerosis, soriatis, primary sclerosing, cholangitis, primary biliary strasis, idiopathic pulmonary fibrosis, endotoxemia, alcoholic shock syndrome, alcoholic intoxication, toxic shock syndrome, nephrotoxicity, and other diseases, Retroviral replication, wasting, meningitis, silicon-induced fibrosis, asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke, circulatory shock (circulatory shock), periodontitis, gingivitis, macrocytic anemia, refractory anemia, 5 q-syndrome, and veterinary disorders caused by: feline immunodeficiency virus, equine infectious anemia virus, caprine arthritis virus, visna virus, dyspnea virus (maedivirus), or lentivirus.

In one embodiment of the invention, the specific disease does not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, HIV, hepatitis, adult respiratory distress syndrome, bone resorption disease, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, meningitis, psoriasis, fibrosis, cachexia, transplant rejection, rheumatoid spondylitis, osteoporosis, crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, leprosy erythema nodosum, radiation injury, asthma, hyperoxic alveolar injury, malaria, and mycobacterial infection.

The compounds of the invention are also useful in the prevention of heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.

The compounds of the invention may also be used to treat, prevent or manage MDS and related syndromes, such as, but not limited to, Refractory Anemia (RA), refractory anemia with circulating sideroblasts (RARS), refractory anemia with primitive cytosis (RAEB), refractory anemia with primitive cytosis-transmutation (RAEB-T), chronic myelomonocytic leukemia (CMML) and symptoms such as anemia, thrombocytopenia, neutropenia, cytopenia, both types of cytopenia (two defective cell lines) and various types of cytopenia (three defective cell lines).

The compounds of the invention are also useful in the treatment, prevention or management of CRPS and related syndromes. As used herein, unless otherwise indicated, the term "CRPS" refers to a chronic pain disorder characterized by one or more of the following: pain, whether spontaneous or evoked, includes allodynia (pain felt by a stimulus that does not normally cause pain) and hyperalgesia (exaggerated response to a stimulus that normally causes only mild pain); pain that is inappropriate for a stimulating event (e.g., severe pain for many years following ankle sprain); localized pain not limited to a single peripheral nerve distribution; and spontaneous disorders associated with vegetative skin changes (abnormal hair and nail growth and skin ulcers) (e.g., edema, altered blood flow, and hyperhidrosis). Unless otherwise indicated, the terms "complex regional pain syndrome", "CRPS", and "CRPS and related syndromes" include: type I, including the condition known as Reflex Sympathetic Dystrophy (RSD), which occurs after an initial adverse event that is not a nerve injury; type II, including the condition known as causalgia, which occurs after nerve damage; acute phase (usually febrile phase 2-3 months); malnutrition period (showing vasomotor instability for months); the atrophic stage (usually the extremities are cold with atrophic changes); reflex neurovascular dystrophy; reflex malnutrition; sympathetically persistent pain syndrome; sudeck bone atrophy; hyperalgesic neurotrophism; shoulder-hand syndrome; post-traumatic malnutrition; trigeminal neuralgia; post-herpetic neuralgia; cancer-related pain; phantom limb pain; fibromyalgia; chronic fatigue syndrome; a radiculopathy; and other painful neuropathies such as diabetic neuropathy, syphilitic neuropathy or iatrogenic painful neuropathy caused by, for example, the following drugs: vincristine, velcade and thalidomide.

The compounds of the invention are useful in the treatment, prevention or management of all types of CRPS and related syndromes, including but not limited to the conditions referred to as: CRPS type I, CRPS type II, Reflex Sympathetic Dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically sustained pain syndrome, causalgia, Sudeck bone atrophy, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post-herpetic neuralgia, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, post-operative pain, spinal cord injury pain, central pain after stroke, radiculopathy, and other painful neuropathies, such as diabetic neuropathy.

The compounds of the present invention are also useful in the treatment, prevention and management of MD and related syndromes such as, but not limited to, atrophic (dry) MD, exudative (wet) MD, age-related macular degeneration (ARM), Choroidal Neovascularization (CNVM), retinal Pigment Epithelial Detachment (PED), and retinal pigment epithelial atrophy (RPE).

The term Macular Degeneration (MD) as used herein includes all types of macular degenerative diseases regardless of the age of the patient, although some macular degenerative diseases are more common in certain age groups. These include, but are not limited to, congenital macular degeneration or vitelliform (most commonly in patients under the age of about 7 years); stagat's disease, juvenile macular dystrophy, or fundus macula (most common in patients from about 5 to about 20 years of age); behr's disease, Sorsby's disease, polynosic disease, or alveolar malnutrition (most common in patients from about 30 to about 50 years of age); and age-related macular degeneration (most commonly in patients about 60 years of age or older).

Symptoms associated with MD and related syndromes include, but are not limited to, drusen surrounding the macula lutea at the fundus, disc scar tissue under the macula, choroidal neovascularization, retinal pigment epithelium detachment, retinal pigment epithelium atrophy, abnormal blood vessels growing from the choroid (the blood vessel-rich tissue layer just below the retina), blurred or degenerated vision areas, central blind spots, pigment abnormalities, a continuous layer of particulate matter deposited inside the vitreous membrane, and increased and decreased vitreous membrane permeability.

Causes of MD include, but are not limited to, genetic, physical trauma, diseases such as diabetes, and infections, such as bacterial infections (e.g., leprosy, especially ENL). The compounds of the present invention are effective in treating, preventing or managing all types of MD and related syndromes or symptoms regardless of the cause.

The compounds of the invention may also be useful in the treatment, prevention or management of all types of MPD and associated syndromes or symptoms. Examples of MPDs that may be treated, prevented or managed by compounds of the invention include, but are not limited to, erythrocytosis (PRV), essential thrombocytosis (PT), Chronic Myelogenous Leukemia (CML), and Agnogenic Myeloid Metaplasia (AMM).

The term "myeloproliferative disease" or "MPD" as used herein refers to a disorder of hematopoietic stem cells characterized by one or more of the following: clonal expansion of a pluripotent hematopoietic progenitor cell with overproduction of one or more of the formed blood elements (e.g., elevated red blood cell count, elevated white blood cell count, and/or elevated platelet count), presence of philadelphia chromosome or bcr-abl gene, teardrop-shaped erythrocytic dysmorphism on peripheral blood smears, leukocytosis, giant abnormal platelets, abnormal increase in the number of bone marrow cells with reticulosis or collagen fibrosis, bone marrow series with low percentage of left-shift markers of promyelocytes and blasts, splenomegaly, thrombosis, risk of developing acute leukemia, or impaired cellular marrow morphology. Unless otherwise indicated, the term "myeloproliferative disease" or "MPD" includes: polycythemia (PRV), essential thrombocythemia (PT), Chronic Myelogenous Leukemia (CML) and Agnogenic Myeloid Metaplasia (AMM).

Symptoms associated with MPD include, but are not limited to, headache, dizziness, tinnitus, blurred vision, fatigue, night sweats, low grade fever, generalized pruritus, epistaxis, blurred vision, splenomegaly, abdominal distension, thrombosis, increased bleeding, anemia, spleen infarction, severe bone pain, hematopoiesis in the liver, ascites, esophageal varices, liver failure, respiratory distress, and priapism. The findings for MPD-related assays include, but are not limited to, clonal expansion of pluripotent hematopoietic progenitor cells with overproduction of one or more of the formed blood elements (e.g., elevated red blood cell count, elevated white blood cell count, and/or elevated platelet count), presence of philadelphia chromosome or bcr-abl gene, teardrop-shaped erythroid dysmorphism on peripheral blood smears, leukocytosis, giant abnormal platelets, abnormal increase in bone marrow cell number with reticulosis or collagen fibrosis, and bone marrow series with low percentage of marker left-shift of promyelocytes and blasts.

The compounds of the present invention are also useful in the treatment, prevention and management of all types of CNS disorders. Examples of CNS disorders include, but are not limited to, Parkinson's disease; alzheimer disease, mild cognitive impairment; depression; long-term memory impairment; amyotrophic Lateral Sclerosis (ALS); CNS trauma; hypokinesia disorder; the movement is too slow; bradykinesia; the movement is less; reduced dexterity; the sound is weak; the speech is monotonous; muscle stiffness; the mask is like a face; a reduction in blinking; bending the posture; the swing of the arm is reduced when walking; undersize word writing; parkinsonian tremor; a Parkinson's gait; the body position is unstable; a panicked gait; stiffness of the movement; cognitive disorders, mood disorders, sensory disorders, sleep or autonomic dysfunction; dementia; and sleep disorders.

In a particular embodiment, the central nervous system disorder to be prevented, treated and/or controlled is parkinson's disease, alzheimer's disease, mild cognitive impairment, dementia, depression, long-term memory impairment, Amyotrophic Lateral Sclerosis (ALS) or CNS trauma.

The invention includes methods of treating, preventing or managing a central nervous system disorder, preferably parkinson's disease or alzheimer's disease. In one embodiment, the methods of the invention are used to treat, prevent or control movement-related disorders, including but not limited to slow or bradykinesia, hypokinesia or akinesia, dyskinesia with lack of accurate motion control and finger dexterity, and other manifestations of bradykinesia, such as, but not limited to, weak voice and monotonous speech. In another embodiment, the methods of the invention are used to treat, prevent or manage myotonic related disorders, including but not limited to consistent increases in resistance to passive movement, interruption of passive movement, and combinations of spasticity and dystonia. In a particular embodiment, the methods of the invention are used to treat inflammation associated with parkinson's disease or a related disease. In yet another embodiment of the invention, parkinsonian tremor-like disorders treated, prevented or controlled by the methods of the invention include but are not limited to tremors of the face, chin, tongue, posture, and other tremors that exist at rest and reduced movement. In another embodiment, the methods of the invention are used to treat, prevent or control gait disorders including, but not limited to, the following disorders: like parkinson's gait, gliding, striding, tendency to turn around, and hungry gait. In another embodiment of the invention, non-motor symptoms treated, prevented or controlled using the methods of the invention include, but are not limited to, mood disorders, cognitive disorders, long-term memory impairment disorders, sensory disorders, sleep disorders, dementia and depression. In another embodiment of the invention, secondary forms of parkinson's disease treated, prevented or managed by the methods of the invention include, but are not limited to, drug-induced parkinson's disease, vascular parkinson's disease, multiple system atrophy, progressive supranuclear palsy, disorders with primary tau pathology, cortical basal sympathetic ganglionic degeneration, parkinson's disease with dementia, hyperkinetic disorders, chorea, Huntington's disease, dystonia, wilsondissasea, Tourette's syndrome, essential tremor, myoclonus, and tardive dyskinesia. In other embodiments of the invention, other central nervous system disorders treated, prevented or controlled by the methods of the invention include, but are not limited to, alzheimer's disease, mild cognitive impairment, Amyotrophic Lateral Sclerosis (ALS), and CNS trauma.

The compounds of the present invention are also useful in the treatment, prevention or management of asbestos-related diseases or disorders and related symptoms. Examples of asbestos-related diseases or disorders include, but are not limited to, malignant mesothelioma, asbestosis, malignant pleural effusion, benign pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, atelectasis, and bronchial carcinoma. The invention also includes methods of treating: the patient has previously received treatment for an asbestos-related disease or disorder but has poor or no therapeutic effect, and the patient has not previously received treatment for the disease or disorder. Because patients have different clinical manifestations and different clinical outcomes, the treatment given to a patient may be different, depending on his/her prognosis. The specific second agent and type of physical therapy that is effective for treating a single patient can be readily determined by the skilled practitioner without undue experimentation.

Symptoms of asbestos-related diseases or disorders include, but are not limited to, dyspnea, diaphragm obstruction, radiolucent sheet-like pleural casing, pleural effusion, pleural thickening, decreased chest circumference, chest discomfort, chest pain, fatigue, fever, perspiration, and weight loss. Examples of patients at risk for asbestos-related diseases or disorders include, but are not limited to, persons who have been exposed to asbestos at the workplace and family members thereof who have been exposed to asbestos adhering to the clothing of workers. Patients with a family history of asbestos-related diseases or disorders are also preferred candidates for prophylactic regimens.

4.4. Pharmaceutical preparation

The compounds of the present invention may be administered systemically or locally. In most cases, administration to a mammal will result in systemic release of the compounds of the invention (i.e., into the bloodstream). Methods of administration include enteral routes such as oral, buccal, sublingual and rectal; topical administration, such as transdermal administration; and parenteral administration. Suitable parenteral routes include injection through a hypodermic needle or catheter and non-injection routes such as intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intraventricular, intrathecal and intracameral injection; the latter being for example intravaginal, rectal or nasal administration. Preferably, the compounds and compositions of the present invention are administered orally. In particular embodiments, it is desirable to administer one or more compounds of the present invention topically to a site in need of treatment. This can be achieved by: local perfusion during surgery, topical application (e.g., in conjunction with wound dressings after surgery), by injection, by catheter, by suppository, or by implant; the implant is a porous, non-porous or gel-like material, including a membrane (e.g., a siliconized rubber membrane) or fiber.

The compounds of the present invention may be administered by typical delivery systems as well as by non-standard delivery systems, e.g., encapsulated in liposomes, microparticles, microcapsules, capsules, and the like. For example, the compounds and compositions of the present invention may be passed through a capsuleVesicle, particularly liposome administration (see Langer, 1990, Science)249: 1527 and 1533; treat et al, available from Liposomes in Therapy of infection Disease and Cancer, Lopez-Berestein and Fidler (main eds.), Liss, New York, pages 353-365 (1989); Lopez-Berestein, supra, page 317-; see generally above). In another example, the compounds and compositions of the present invention may be administered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. biomed. Eng.14: 201; buchwald et al, 1980, Surgery88: 507 Saudek et al, 1989, n.321: 574). In another example, polymeric materials may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press, Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J.Macromol.Sci.rev.Macromol.Chem.).23: 61; see also Levy et al, 1985, Science228: 190; during et al, 1989, ann.25: 351, a step of; howard et al, 1989, J.71: 105). In yet another example, a controlled Release system may be placed near the target area to be treated (e.g., liver), thus requiring only a small fraction of the systemic dose (see, e.g., Goodson, Medical Applications of controlled Release, supra, Vol.2, pp.115-138 (1984)). Other controlled release systems discussed in the following reviews may be used: langer, 1990, Science249：1527-1533。

When administered as a composition, the compounds of the present invention may be formulated together with a suitable amount of a pharmaceutically acceptable vehicle or carrier to provide a suitable form of administration for administration to a mammal. The term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound of the invention is formulated for administration to a mammal. Such pharmaceutically acceptable carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutically acceptable carrier may be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used. Preferably, the compounds and compositions of the present invention, and the pharmaceutically acceptable carriers, excipients, or diluents, are sterile when administered to a mammal. When the compounds of the present invention are administered intravenously, aqueous media are preferred carriers, such as water, saline solutions and aqueous dextrose and glycerol solutions.

The compounds and compositions can be in the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained release formulations thereof, or any other form suitable for administration to a mammal. In a preferred embodiment, the compounds and compositions of the present invention are formulated in accordance with conventional methods into pharmaceutical compositions suitable for oral or intravenous administration to humans. In one embodiment, the pharmaceutically acceptable carrier is a hard gelatin capsule. Examples of suitable pharmaceutical carriers and methods of formulating them are described in Remington: the Science and Practice of Pharmacy, Alfonsor.Gennaro eds, Mack Publishing Co.Easton, PA, 19 th edition, 1995, chapters 86, 87, 88, 91 and 92, which are incorporated herein by reference.

The compounds and compositions of the present invention formulated for oral administration are preferably in the form of capsules, tablets, pills, or any compressed pharmaceutical form. In addition, when in tablet or pill form, the compounds and compositions may be coated to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. Permselective membranes that encapsulate osmotically active driver compounds are also suitable for oral administration of the compounds and compositions of the present invention. In these latter platforms, liquid from the environment surrounding the capsule is inhaled, causing the compound to expand and expel the drug or pharmaceutical composition through the pores. These drug delivery platforms can provide the necessary zero order mode of administration that is different from the spike mode of immediate release formulations. Time delay materials such as glycerol monostearate or glycerol stearate may also be used. Oral compositions may include standard carriers, excipients, and diluents, such as magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, water, syrup, and methyl cellulose, and may also include lubricants, such as talc, magnesium stearate, mineral oil, wetting agents, emulsifying and suspending agents, and preservatives, such as methyl and propyl hydroxybenzoates. Such carriers are preferably of pharmaceutical grade. The compounds and compositions of the present invention for oral administration may optionally include one or more sweetening agents, such as fructose, aspartame or saccharin; one or more flavoring agents, such as peppermint, oil of wintergreen, or cherry; or one or more coloring agents to provide a palatable pharmaceutical preparation.

A therapeutically effective dosage regimen for the treatment of a particular disease or condition will depend on its nature and severity and can be determined by standard clinical techniques at the discretion of a physician. In addition, in vitro or in vivo assays may be employed to help identify the optimal dosage. Of course, the amount of a compound of the invention that constitutes a therapeutically effective dose will also depend on the route of administration. Generally, suitable dosages for oral administration are from about 0.001 mg to about 20mg, preferably from about 0.7 mg to about 6 mg, more preferably from about 1.5 mg to about 4.5 mg, of a compound of the invention per kg of body weight per day. In a preferred embodiment, a single dose or divided doses of about 0.01mg to about 1000mg of a compound of the invention is administered orally to a mammal (preferably a human) per day, more preferably about 0.1mg to about 300mg, or about 1mg to about 100mg per day. The dosages referred to herein refer to the total dose administered, that is, if the compound of the invention is administered more than once, the preferred dosage corresponds to the total dose of the compound of the invention administered. Oral compositions preferably contain 10% to 95% by weight of a compound of the invention. Preferred unit oral-dosage forms include pills, tablets and capsules, more preferably capsules. Typically such unit dosage forms may contain about 0.01mg, 0.1mg, 1mg, 5mg, 10mg, 15mg, 20mg, 50mg, 100mg, 250mg or 500mg of a compound of the invention, preferably from about 5mg to about 200mg of a compound per unit dose.

In another embodiment, the compounds and compositions of the present invention may be administered parenterally (e.g., by intramuscular, intrathecal, intravenous, and intraarterial routes), preferably intravenously. Typically, the compounds and compositions of the present invention for intravenous administration are solutions in sterile isotonic aqueous carriers such as water, saline, ringer's solution or dextrose solution. If necessary, the composition may further comprise a solubilizer. The intravenous drug composition may optionally include a local anesthetic (e.g., lidocaine) to reduce pain at the injection site. For intravenous administration, the compounds and compositions of the present invention may be provided in the form of a sterile lyophilized powder or an anhydrous concentrate in a sealed container, such as an ampoule or sachet, with the amount of active agent indicated on the container. Such powder injections or concentrates may be diluted with a suitable aqueous medium prior to intravenous administration. Prior to use, ampoules containing sterile water, saline solution or other suitable aqueous medium may be provided for dilution of the powder for injection or concentrate. Or the composition may be provided ready for use in a pre-mixed form. When the compound or composition of the invention is administered by intravenous infusion, it may be dispersed in an infusion bottle containing sterile pharmaceutical grade water, saline or other suitable medium.

Rectal administration may be accomplished by the use of suppositories prepared from conventional carriers such as cocoa butter, modified vegetable oils and other fatty bases. Suppositories can be prepared by well-known methods using well-known formulations, see for example Remington: the Science and practice of Pharmacy, Alfonso R.Gennaro eds, Mack Publishing Co.Easton, PA, 19 th edition, 1995, p.1591-1597, which is incorporated herein by reference.

For the formulation and administration of Topical dosage forms, well known transdermal and intradermal delivery vehicles (e.g., lotions, creams, and ointments) and transdermal delivery devices (e.g., patches) can be used (Ghosh, T.K.; Pfister, W.R.; Yum, S.I. Transdermal and Topical drug delivery Systems, Interpharm Press, Inc. page 249-297, which is incorporated herein by reference). For example, a reservoir patch design may include an adhesive coated backing sheet and a reservoir containing a compound or composition of the present invention separated from the skin by a semi-permeable membrane (e.g., U.S. Pat. No. 4,615,699, incorporated herein by reference). The adhesive coated bottom layer extends beyond the boundary of the reservoir so as to provide a concentric seal with the skin and to maintain the reservoir in close proximity to the skin.

The mucoadhesive forms of the present invention include, but are not limited to, ophthalmic solutions, sprays and aerosols or other forms known to those skilled in the art. See, e.g., Remington's pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4 th edition, Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity may be formulated as mouthwashes or oral gels. In one embodiment, the aerosol comprises a carrier. In another embodiment, the aerosol does not comprise a carrier.

The compounds of the invention may also be administered directly to the lungs by inhalation. For administration by inhalation, the compounds of the invention may be conveniently administered to the lungs by a variety of different devices. For example, a metered dose inhaler ("MDI") using a canister charged with a suitable low boiling propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, may be used to administer the compound of formula I directly to the lungs. MDI devices are available from various suppliers, such as 3M Corporation, Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome, Schering Plough, and Vectra.

Alternatively, the compounds of the invention may be administered to the lungs using a Dry Powder Inhaler (DPI) device (see, e.g., Raleigh et al, proc. amer. assoc. cancer Research annual meeting, 1999, 40, 397, which are incorporated herein by reference). DPI devices typically use a mechanism such as gas explosion to cause the dry powder in the container to produce an aerosol that is then inhaled by the patient. DPI devices are also well known in the art and are available from various vendors including, for example, Fisons, Glaxo-Wellcome, inlae Therapeutic Systems, ML Laboratories, Qdose, and Vectra. A common class of devices is multi-dose DPI ("MDDPI") systems, which can administer more than one therapeutic dose. MDDPI devices are available from various companies, such as AstraZeneca, GlaxoWellcome, IVAX, ScheringPlough, SkyePharma, and Vectura. For example, gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a powder base (e.g., lactose or starch) suitable for use in these systems.

Another type of device that can administer the compounds of the present invention to the lungs is a liquid spray device, which is available from companies such as Aradigm Corporation. Liquid spray systems aerosolize liquid drug formulations with very small nozzle orifices, which can then be inhaled directly into the lungs.

In a preferred embodiment, the compounds of the invention are administered to the lungs using a nebulizer device. Nebulizers produce aerosols from liquid pharmaceutical formulations by using, for example, ultrasonic energy to form particles that are easily inhaled (see, for example, Verschoyle et al, British J Cancer, 1999, 80, supplement 2, 96, incorporated herein by reference). Examples of nebulizers include devices provided by the following companies: sheffield/systematic Pulmonary DeliveryLtd. (see Armer et al, U.S. Pat. No. 5,954,047; van der Linden et al, U.S. Pat. No. 5,950,619; van der Linden et al, U.S. Pat. No. 5,970,974, incorporated herein by reference), Aventis and Batelle Pulmonary therapeutics.

In a particularly preferred embodiment, the compounds of the present invention are administered to the lungs using an electrohydrodynamic ("EHD") aerosol device. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see, e.g., Noakes et al, U.S. Pat. No. 4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, PCT application, WO 94/12285; Coffee, PCT application, WO 94/14543; Coffee, PCT application, WO95/26234, Coffee, PCT application, WO 95/26235, Coffee, PCT application, WO95/32807, which are incorporated herein by reference). When using an EHD aerosol device to administer a formulation containing a compound of formula I to the lungs, the electrochemical properties of the pharmaceutical formulation are important parameters to be optimized, and such optimization can be routinely performed by those skilled in the art. EHD aerosol devices are more effective in delivering drugs to the lungs than existing pulmonary delivery techniques. Other methods of intrapulmonary administration are known to the skilled artisan and are within the scope of the invention.

Liquid drug formulations suitable for use in nebulizers and liquid spray devices and EHD aerosol devices typically contain a pharmaceutically acceptable carrier. Preferably the pharmaceutically acceptable carrier is a liquid, such as ethanol, water, polyethylene glycol or a perfluorocarbon. Other materials may optionally be added to modify the aerosol characteristics of a solution or suspension of a compound of the invention. Preferably the material is a liquid, such as ethanol, ethylene glycol, polyethylene glycol or a fatty acid. Other methods of formulating liquid pharmaceutical solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611, which is incorporated herein by reference). The compounds of formula I may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds of the present invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or with ion exchange resins, or as sparingly soluble derivatives, e.g. as a sparingly soluble salt.

Alternatively, other delivery systems may be used. Liposomes and emulsions are well known examples of delivery vehicles which may be used to administer the compounds of the present invention. Certain organic solvents, such as dimethylsulfoxide, may also be used, although generally more toxic. The compounds of the present invention may also be administered in a controlled release system. In one embodiment, a pump (Sefton, CRCCrit. Ref Biomed Eng., 1987, 14, 201; Buchwald et al, Surgery, 1980, 88, 507; Saudek et al, N.Engl. J. Med, 1989, 321, 574) may be used. In another embodiment, polymeric materials may be used (see Medical Applications of controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla (1974); controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol.Sci.Rev.Macromol.Chem., 1983, 23, 61; see also Levy et al, Science 1985, 228, 190; During et al, Ann. Neurol., 1989, 25, 351; Howard et al, 1989, J. Neurosurg.71, 105). In yet another embodiment, a Controlled Release system can be placed near the target of the compounds of the invention (e.g., the lung), thus, only a small fraction of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, supra, Vol.2, p.115 (1984)). Other controlled release systems can be used (see, e.g., Langer, Science, 1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the mucosal dosage forms encompassed by the invention are well known to those skilled in the art of pharmacy and depend on the particular site or method of administration of a given pharmaceutical composition or dosage form. Bearing this in mind, typical excipients include, but are not limited to, water, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, which are non-toxic and pharmaceutically acceptable. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

The pH of the pharmaceutical composition or dosage form, or the pH of the tissue to which the pharmaceutical composition or dosage form is applied, may be adjusted to improve delivery of one or more active ingredients. Likewise, the polarity of the solvent carrier, its ionic strength or tonicity may also be adjusted to improve drug delivery. Stearates and like compounds can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to improve drug delivery. Based on this, stearates can serve as lipid carriers for formulations, as emulsifiers or surfactants, and as delivery or permeation enhancers. Different salts, hydrates or solvates of the active ingredient may be used to further adjust the properties of the resulting composition.

The invention also provides a pharmaceutical package or kit comprising one or more containers containing one or more compounds of the invention. The container is optionally accompanied by instructions, which must be in a format consistent with governmental regulatory agencies regulations for the manufacture, use or sale of pharmaceuticals or biological products, and which must indicate approval documents for the manufacture, use or sale of pharmaceuticals for human consumption by the governmental regulatory agencies. In one embodiment, the kit comprises more than one compound of the invention. In another embodiment, the kit comprises a compound of the invention and another biologically active agent.

The compounds of the invention are preferably tested in vitro and in vivo prior to use in humans to determine their desired therapeutic or prophylactic activity. For example, in vitro assays may be used to determine whether administration of a particular compound or combination of compounds of the invention is preferred. Animal model systems may also be used to demonstrate that the compounds and compositions of the invention are safe and effective. Other methods are known to the skilled person and are included within the scope of the invention.

4.5. Combination therapy

In certain embodiments, one compound of the present invention is administered to a mammal, preferably a human, concurrently with one or more other therapeutic agents, or one or more compounds of the present invention are administered to a mammal, preferably a human, concurrently with one or more other therapeutic agents. By "simultaneously" is meant that the compound of the present invention and the other agent are administered to the mammal sequentially and at spaced intervals such that the compound of the present invention acts in concert with the other agent to provide an increased or synergistic benefit over other modes of administration. For example, the ingredients may be administered simultaneously or sequentially at different time points, in any order; however, if not simultaneously, they should be administered in a sufficiently short time to provide the desired therapeutic effect. Preferably all of the ingredients are administered simultaneously, and if not simultaneously, preferably they are all administered within about 6 hours to about 12 hours of each other.

When used in combination with other therapeutic agents, the compounds of the present invention and the therapeutic agents may act additively, or more preferably synergistically. In one embodiment, a compound or composition of the invention is administered simultaneously with other therapeutic agents in the same pharmaceutical composition. In another embodiment, the compound or composition of the invention is administered simultaneously with the other therapeutic agent in separate pharmaceutical compositions. In yet another embodiment, the compounds or compositions of the present invention are administered before or after the administration of the other therapeutic agent. Because many of the diseases that can be treated with the compounds and compositions of the present invention are chronic, in one embodiment, combination therapy involves the alternating administration of a compound or composition of the present invention and a pharmaceutical composition containing another therapeutic agent, e.g., to minimize the toxicity associated with the particular agent. In certain embodiments, when the compositions of the present invention are administered concurrently with other therapeutic agents that potentially produce toxic side effects (including but not limited to toxicity), the therapeutic agents are preferably administered at a dose below the threshold that induces toxic side effects. Other therapeutic agents include, but are not limited to, hematopoietic growth factors, cytokines, anti-cancer agents, antibiotics, immunosuppressive agents, steroids, antihistamines, leukotriene (lukatriene) inhibitors, and other therapeutic agents described herein.

Preferred additional therapeutic agents include, but are not limited to, infliximab (Remicade TM), docetaxel, celecoxib (TM), melphalan, dexamethasone (dexamethasone), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, carmustine wafer capsule, tamoxifen, topotecan, methotrexate, and mixtures thereof,Paclitaxel TM, taxotere, fluorouracil, leucovorin, irinotecan, adatA, CPT-11, interferon alphA, pegylated interferon alphA, capecitabine, cisplatin, thiotepA, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel (paclitaxel), vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, clarithromycin formulation, busulfan, prednisone, bisphosphonate, arsenic trioxide, PEG INTRON-A, doxorubicin hydrochloride liposome, vincristine, dexamethasone (decadron), doxorubicin, paclitaxel, ganciclovir, doxorubicin, estramustine, Emcyt, sulindac, and etoposide.

The invention also includes mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit at least some pharmacological activity in vivo based on the protein. Examples of mutants include, but are not limited to, proteins in which one or more amino acid residues differ from the corresponding amino acid residue in the naturally occurring form of the protein. The term "mutant" also includes proteins that lack the sugar moiety normally found in their naturally occurring form (e.g., non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to a protein of interest or an active portion thereof. See, e.g., penechet, m.l. and Morrison, s.l., j.immunol.methods 248: 91-101(2001).

Recombinant and mutant forms of G-CSF can be prepared according to the following references: U.S. patent nos. 4,810,643, 4,999,291, 5,528,823 and 5,580,755;all of these documents are incorporated herein by reference. Recombinant and mutant forms of GM-CSF can be prepared according to the following references: U.S. patent nos. 5,391,485, 5,393,870 and 5,229,496; all of these documents are incorporated herein by reference. Indeed, recombinant forms of G-CSF and GM-CSF are currently marketed in the United states for the treatment of certain chemotherapy-related conditions. The recombinant form of G-CSF, known as filgrastim, has been marketed in the United states under the trade name ofIs useful for reducing the incidence of infections manifested as febrile neutropenia in patients with non-myeloid malignancies and receiving myelosuppressive anticancer drugs associated with a high incidence of severe neutropenia with fever. Physicians' Desk Reference, 587-. Recombinant forms of GM-CSF, known as sargramostim, have also been marketed in the United states under the trade name GM-CSFIs suitable for use in elderly patients with Acute Myelogenous Leukemia (AML) after induction of chemotherapy to shorten the time to neutrophil recovery. Physicians' Desk Reference, 1755-. The recombinant form of EPO is designated alfa-lipstatin, sold in the United states under the trade name EPOFor stimulating erythropoiesis by stimulating division and maturation of committed erythrocyte precursor cells. Physicians' desk reference, 582-.

Growth factors or cytokines such as G-CSF, GM-CSF, EPO, etc. may also be administered in the form of vaccines. For example, vaccines that secrete or cause secretion of cytokines such as G-CSF and GM-CSF can be used in the methods, pharmaceutical compositions, and kits of the invention. See, e.g., emers, l.a., et al, curr. opinion mol.ther: 3(1): 77-84(2001).

Examples of anticancer agents that may be used in various embodiments of the invention (including the methods, dosing regimens, mixtures, pharmaceutical compositions and dosage forms and kits of the invention) include, but are not limited to: acivicin; aclarubicin; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; altretamine; an apramycin; amenthraquinone acetate; amsacrine; anastrozole; an atramycin; an asparaginase enzyme; a triptyline; azacitidine; azatepa; (ii) azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; bisnefaede dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib; chlorambucil; a sirolimus; cisplatin; cladribine; cllinaltol mesylate; cyclophosphamide; cytarabine; dacarbazine; actinomycin D; daunorubicin hydrochloride; decitabine; (ii) dexomaplatin; 2, dizagutanin; 1, dizagutinine mesylate; diazaquinone; dacarbazine; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotandrosterone propionate; daptomycin; edatrexae; eflornithine hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; (iii) flucitabine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; ifosfamide; ilofovir dipivoxil; interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2 a; interferon alpha-2 b; interferon alpha-n 1; interferenceAlpha-n 3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liazole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; (ii) maxolone; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; metoclopramide; mitodomide; mitokacin; mitorubin; mitoxantrone; mitomacin; mitomycin; mitospirane culturing; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noramycin; ormaplatin; oshuzuren; paclitaxel; a pemetrexed; a pelithromycin; nemadectin; pellomycin sulfate; cultivating phosphoramide; pipobroman; piposulfan; piroxantrone hydrochloride; (ii) a plicamycin; pramipexole; porfimer sodium; a podomycin; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazolofuran; (ii) lybodenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium phosphono-aspartate; a sparamycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; streptomycin; a streptozocin; a sulfochlorophenylurea; a talithromycin; sodium tegafur; taxotere; tegafur; tiloxanthraquinone hydrochloride; temoporfin; (ii) teniposide; a tiroxiron; a testosterone ester; thiamiprine; thioguanine; thiotepa; thiazolfurin; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; tritrazol glucuronic acid; triptorelin; tobramzole hydrochloride; uramustine; uretipi; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinblastine sulfate; vinorelbine tartrate; vinblastine sulfate; vinzolidine sulfate; (ii) vorozole; zeniplatin; 1, neat setastine; and zorubicin hydrochloride. Other anti-cancer agents include, but are not limited to: 20-epi-1, 25-dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenosylpentanol; (ii) Alexanox; aldesleukin; ALL-TK antagonist; altretamine; amifostine; (ii) amidox; amifostine; 5-aminoketonesValeric acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; an angiogenesis inhibitor; an antagonist D; an antagonist G; antarelix; anti-dorsal developmental morphogenetic protein-1; anti-androgens, prostate cancer; anti-estrogen agents; an antineoplastic ketone; an antisense oligonucleotide; aphidicolin; an apoptosis gene modulating agent; an apoptosis modulating agent; (ii) an allopurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; amoxicillin; axinatatin 1; axinatatin 2; axinatatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; a BCR/ABL antagonist; benzochlor; benzoyl staurosporine; a beta-lactam derivative; beta-alethine; aclacinomycin B; betulinic acid; a bFGF inhibitor; bicalutamide; a bisantrene group; dinitropyridinylpiperazine (bisazidinylsphermine); (ii) bisnefarde; bistetralene A; bizelesin; brefflate; briprimine; titanium is distributed; buthionine sulfoximine; calcipotriol; inhibin C; a camptothecin derivative; canaryox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; a cartilage derived inhibitor; folding to get new; casein kinase Inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; (ii) chlorolins; chloroquinoxaline sulfonamide; (ii) cicaprost; a cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin a 4; combretastatin analogs; a concanagen; crambescidin 816; clinatot; depsipeptide (cryptophycin) 8; depsipeptide a derivatives; curve A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; a cytolytic factor; a cytostatin; daclizumab; decitabine; dehydrogenatedmin B; deslorelin; dexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; diazaquinone; didemnin B; diethylnorpermine; dihydro-5-azacytidine; a dihydrotaxol; a dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; etokomustine; edifulin; epirubicin; etafluoroOrnithine; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine analogue; an estrogen agonist; an estrogen antagonist; idazoxan; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavonoid antineoplastic agents (flavopiridol); fluorineStatin; a flashterone; fludarabine; fluoroaurourigenin hydrochloride; fowler; 2, fulvestrant; fostrexed; fotemustine; gadoteridine; gallium nitrate; galocitabine; ganirelix; (ii) a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; iloperidone; ilofovir dipivoxil; ilomastat; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; doxorubicin iodoxide; 4-epothilones; iprop; isradine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; leguminous kiosks; sulfuric acid lentinan; leptin statin; letrozole; leukemia inhibitory factor; leukocyte interferon-alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liazole; linear polyamine analogs; a lipophilic glycopeptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; earthworm phosphatide; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; a lytic peptide; maytansine; preparing glycitin A; marimastat; (ii) maxolone; mammary silk arrestin; matrilysin inhibitors; a matrix metalloproteinase inhibitor; (ii) a melanoril; merbarone; 1, meperiline; methioninase; metoclopramide; an inhibitor of MIF; mifepristone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofagotine; moraxel booth(ii) a Erbitux, human chorionic gonadotropin; mopidanol; mustard anticancer drugs; mycaperoxide B; a mycobacterial cell wall extract; myriaporone; n-acetyldinaline; an N-substituted benzamide; nafarelin; naretide (nagestip); naloxone + pentazocine; napavin; naphterpin; a nartostim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; a nitric oxide modulator; a nitroxide antioxidant; nitrulyn; o is⁶-benzylguanine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; an oral cytokine inducer; ormaplatin; an oxateclone; oxaliplatin; oxanonomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; palauamine; palmitoyl rhizomycin; pamidronic acid; panaxatriol; panomifen; a parabencin; pazeliptin; a pemetrexed; pedunculing; pentosan sodium polysulfate; pentostatin; (ii) pentazole; perfluorobromoalkane; cultivating phosphoramide; perillyl alcohol; a phenylazeocin; phenyl acetate; a phosphatase inhibitor; a hemolytic streptococcus preparation; pilocarpine hydrochloride; pirarubicin; pirtroxine; placetin A; placetin B; a plasminogen activator inhibitor; a platinum complex; a platinum compound; a platinum-triamine complex; porfimer sodium; a podomycin; prednisone; propylbisacridone; prostaglandin H2; a proteasome inhibitor; protein a-based immunomodulators; inhibitors of protein kinase C; microalgae protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoline acridine; pyridoxylated hemoglobin polyethylene glycol conjugates; a raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated reteplatin; rhenium (Re) 186 etidronate; rhizomycin; a ribozyme; RIIretinamide; rohitukine; romurtide; loquimex; rubiginone B1; ruboxyl; safrog; saintopin; SarCNU; sarcophylol A; sargrastim; a Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium boron carbonate; sodium phenylacetate; solverol; growth regulator binding eggWhite; sonaming; phosphono-winteric acid; spicamycin D; spiromustine; spleenetin; spongistatin 1; squalamine; stiiamide; a matrix-dissolving protease inhibitor; sulfinosine; a superactive vasoactive intestinal peptide antagonist; (ii) surfasta; suramin; swainsonine triol octahydro; tamustine; tamoxifen methyl iodide; taulomustine; tazarotene; sodium tegafur; tegafur; telluropyrylium; a telomerase inhibitor; temoporfin; (ii) teniposide; tetrachlorodecaoxide; tetrazomine; (ii) a thioablistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thymotreonam; thyroid stimulating hormone; tin ethyl iopurpururin; tirapazamine; titanocenebichloride; topstein; toremifene; a translation inhibitor; tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; a tyrosine phosphorylation inhibitor; an UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; a urokinase receptor antagonist; vapreotide; variolin B; vilareol; vermine; verdins; verteporfin; vinorelbine; vinxaline; vitexin; (ii) vorozole; zanoteron; zeniplatin; benzal vitamin C; and neat stastatin ester.

In one embodiment of the invention, the compounds of the invention may also be used not only to directly treat diseases, but also to reduce the dose or toxicity of other chemotherapeutic agents. For example, the compounds of the present invention may be administered to reduce gastrointestinal toxicity associated with topoisomerase inhibitors (e.g., irinotecan).

4.6. Biological assay

Compounds having PDE4, TNF- α and MMP inhibitory activity may be determined using methods well known in the art, including, but not limited to, enzyme immunoassays, radioimmunoassays, immunoelectrophoreses and affinity labels. Other assays that may be used include LPS-induced TNF and PDE4 enzymatic assays and methods given in the following references: international patent publication Nos. WO01/90076A1, WO01/34606A1, each of which is incorporated herein by reference in its entirety.

PBMC were obtained from normal donors by Ficoll-Hypaque density gradient centrifugation. Cells were cultured in RPMI supplemented with 10% AB + serum, 2mM L-glutamine, 100U/ml penicillin and 100mg/ml streptomycin.

Test compounds were dissolved in dimethyl sulfoxide (Sigma Chemical) and further diluted in supplemented RPMI. The final concentration of dimethyl sulfoxide in the PBMC suspension in the presence or absence of drug was 0.25% by weight. Test compounds were assayed starting at 50mg/ml in a half log dilution. Test compounds were added to PBMC (10) in 96-well plates 1 hour before LPS addition⁶Individual cells/ml).

PBMC (10) were stimulated by treatment with 1mg/ml LPS (List Biological Labs, Campbell, Calif.) from Salmonella minnesota R595 in the presence or absence of test compounds⁶Individual cells/ml). The cells were then cultured at 37 ℃ for 18-20 hours. Supernatants were harvested and TNF α levels were measured immediately or refrigerated at-70 ℃ (no more than 4 days) until measured.

The concentration of TNF α in the supernatant was determined using a human TNF α ELISA kit (ENDOGEN, Boston, MA) according to the manufacturer's instructions.

Phosphodiesterase can be determined using conventional models. For example, human pre-monocytic cell line U937 cells were grown to 1X10 using the method of Hill and Mitchell⁶Individual cells/ml, then collected by centrifugation. Will be 1x10⁹The cell pellet of individual cells was washed in phosphate buffered saline and then frozen at-70 ℃ for later purification, or immediately lysed in cold homogenization buffer (20mM Tris-HCl, pH 7.1, 3mM 2-mercaptoethanol, 1mM magnesium chloride, 0.1mM ethylene glycol-bis- (. beta. -aminoethyl ether) -N, N, N ', N' -tetraacetic acid (EGTA), 1. mu.M phenyl-methylsulfonyl fluoride (PMSF) and 1. mu.g/ml leupeptin). The cells were homogenized in a Dounce homogenizer for 20 strokes and centrifuged to obtain a supernatant containing the cytoplasmic fraction. The supernatant was then applied to a Sephacryl S-200 column equilibrated with homogenization buffer. By usingThe buffer was homogenized, phosphodiesterase was eluted at a rate of about 0.5ml/min, and phosphodiesterase activity-/+ rolipram was measured in each fraction. Fractions containing phosphodiesterase activity (rolipram sensitive) were pooled and divided into aliquots for later use.

Phosphodiesterase assay was performed in a total volume of 100 μ l containing: varying concentrations of test compound, 50mM Tris-HCl (pH 7.5), 5mM magnesium chloride and 1 μ McAMP (of which 1% is³H cAMP). The reaction was incubated at 30 ℃ for 30 minutes and then stopped by boiling for 2 minutes. The extracts used for these experiments were pre-determined for phosphodiesterase IV content such that the reaction was in the linear range and less than 15% of the total substrate was consumed. After the reaction was terminated, the sample was cooled at 4 ℃ and then treated with 10. mu.l of 10mg/ml snake venom at 30 ℃ for 15 min. Then, 200. mu.l of a quaternary ammonium type ion exchange resin (AG1-X8, BioRad) was added for 15 minutes, and the unused substrate was removed. The sample was then centrifuged at 3000rpm for 5min and 50. mu.l of the aqueous phase was removed and counted. The assay was repeated 2 times per data point and activity was expressed as a percentage of the control. The IC of the compound was then determined from the dose-response curve of the minimum of three independent experiments₅₀。

The following examples are provided for illustrative purposes and are not to be construed as limiting the scope of the invention.

5.Examples

The reagents and solvents used below are available from commercial sources, such as Aldrich chemical Co. (Milwaukee, Wisconsin, USA).¹H-NMR and¹³C-NMR spectra were recorded on a Bruker AC250MHz NMR spectrometer. The characteristic peaks were characterized in the following order: chemical shift, number of peak splits (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant (hertz (Hz)), and number of protons.

5.1. Example 1

(1R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxy-propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide

A solution of (3R) -3-amino-3- (3-ethoxy-4-methoxy-phenyl) -propan-1-ol (1.1g, 4.9mmol), methyl 2-bromomethyl-6- (cyclopropanecarbonyl-amino) -benzoate (1.5g, 4.8mmol) and triethylamine (0.75ml, 5.4mmol) in DMF (10ml) was heated at 100 ℃ for 18 h. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50ml) and water (50 ml). The organic layer was washed with HCl (1N, 50ml), brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give an oil. The oil was stirred in diethyl ether (5ml) and hexane (5ml) to give a suspension. The suspension was filtered to give (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxy-propyl]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (1.3g, yield 64%, white solid):

mp，103-105℃；¹H NMR(CDCl₃)δ0.86-0.93(m，2H，CH₂)，1.08-1.12(m，2H，CH₂)，1.44(t，J＝7Hz，3H，CH₃)，1.64-1.73(m，1H，CH)，2.11-2.32(m，2H，CH₂)，3.37(dd，J＝4，9Hz，1H，OH)，3.50-3.59(m，1H，CHH)，3.74-3.79(m，2H，NCHH，CHH)，3.80(s，3H，CH₃)，4.06(q，J＝7Hz，2H，CH₂)，4.16(d，J＝18Hz，1H，NCHH)，6.65(dd，J＝4，11Hz，1H，NCH)，6.83-6.99(m，4H，Ar)，7.44(t，J＝8Hz，1H，Ar)，8.45(d，J＝8Hz，1H，Ar)，10.52(s，1H，NH)；¹³C NMR(CDCl₃)8.35，14.77，16.22，33.85，46.23，50.52，55.98，58.59，64.55，111.36，112.99，116.77，116.99，117.83，119.77，130.73，133.37，138.05，141.49，148.62，149.25，170.33，172.76；

C₂₄H₂₈N₂O₅analytical calculation of (a): c, 67.91; h, 6.65; and N, 6.60. Measured value: c, 67.92; h, 6.67; n, 6.37.

5.2. Example 2

(1R) -2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxy-propyl ] -7-nitro-2, 3-dihydro-isoindol-1-one

Following the procedure of example 1, (1R) -2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxy-propyl ] -7-nitro-2, 3-dihydro-isoindol-1-one was prepared from (3R) -3-amino-3- (3-ethoxy-4-methoxy-phenyl) -propan-1-ol (3.0g, 13mmol), methyl 2-bromomethyl-6-nitro-benzoate (3.6g, 13mmol), and triethylamine (2ml, 14mmol) in DMF (40ml) to give a yellow solid (4.1g, 81%) as:

¹H NMR(CDCl₃)δ1.44(t，J＝7Hz，3H，CH₃)，2.13-2.31(m，2H，CH₂)，3.54-3.59(m，1H，CHH)，3.71-3.77(m，1H，NCHH)，3.87(s，3H，CH₃)，3.94(d，J＝16Hz，1H，NCHH)，4.06(q，J＝7Hz，2H，CH₂)，4.26(d，J＝16Hz，1H，NCHH)，5.70(dd，J＝4，11Hz，1H，NCH)，6.85-6.99(m，3H，Ar)，7.55-7.77(m，3H，Ar)；¹³C NMR(CDCl₃)δ14.76，33.92，45.80，51.30，55.98，58.65，64.63，65.84，111.39，113.22，119.75，122.91，124.13，126.74，130.66，132.11，143.84，146.66，148.68，149.33，164.22.

5.3. example 3

(3R) - (tert-butoxy) -N- {3- (3-ethoxy-4-methoxyphenyl) -3- [ 7-nitro-1-oxoisoindolin-2-yl ] -propyl } carbonylamino (tert-butoxy) formate

To a solution of (1R) -2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxy-propyl ] -7-nitro-2, 3-dihydro-isoindol-1-one (4.1g, 11mmol), (tert-butoxy) carbonylamino (tert-butoxy) formate (3.0g, 13mmol) and triphenylphosphine in THF (40ml) at room temperature was added diisopropyl azodicarboxylate (2.6ml, 13 mmol). After 30min, the solvent was removed in vacuo. The residue was purified by chromatography (silica gel) to give (3R) - (tert-butoxy) -N- {3- (3-ethoxy-4-methoxyphenyl) -3- [ 7-nitro-1-oxoisoindolin-2-yl ] -propyl } carbonylamino (tert-butoxy) formate (5g, yield 78%):

¹H NMR(CDCl₃)δ1.41(s，9H，3CH₃)，1.42(t，J＝7Hz，3H，CH₃)，1.51(s，9H，3CH₃)，2.39-2.52(m，2H，CH₂)，3.59-3.69(m，2H，CH₂)，3.84(s，3H，CH₃)，4.06(q，J＝7Hz，2H，CH₂)，4.11(d，J＝16Hz，1H，NCHH)，4.43(d，J＝16Hz，1H，NCHH)，5.4.7(dd，J＝7，9Hz，1H，NCH)，6.81(d，J＝8Hz，1H，Ar)，6.94-6.99(m，2H，Ar)，7.55-7.77(m，3H，Ar).

5.4. example 4

(3R) - (tert-butoxy) -N- {3- [7- (cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) propyl } carbonylamino (tert-butoxy) formate

Reacting (3R) -N- [3- (7-amino-1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propyl](tert-butoxy) carbonylamino (tert-butoxy) formate (4.1g, 7.2mmol), cyclopropanecarbonyl chloride (0.8 mmol)0ml, 8.8mmol) and triethylamine (1.3ml, 9.3mmol) in THF (20ml) was heated at reflux for 2 hours. The solution was extracted with ethyl acetate (100ml) and sodium bicarbonate (saturated, 50 ml). The organic layer was washed with sodium bicarbonate (saturated, 50ml), brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give (3R) - (tert-butoxy) -N- {3- [7- (cyclopropylcarbonylamino) -1-oxodihydroisoindol-2-yl]-3- (3-ethoxy-4-methoxyphenyl) propyl } carbonylamino (tert-butoxy) formate (4.4g, yield 95%, white solid):

mp，153-155℃；¹H NMR(CDCl₃)δ0.84-0.92(m，2H，CH₂)，1.06-1.13(m，2H，CH₂)，1.42(s，9H，3CH₃)，1.43(t，J＝7Hz，3H，CH₃)，1.50(s，9H，3CH₃)，1.65-1.73(m，1H，CH)，2.38-2.48(m，2H，CH₂)，3.61-3.73(m，2H，CH₂)，3.85(s，3H，CH₃)，4.03(d，J＝18Hz，1H，NCHH)，4.04(q，J＝7Hz，2H，CH₂)，4.33(d，J＝18Hz，1H，NCHH)，5.47(t，J＝7Hz，1H，NCH)，6.81-7.00(m，4H，Ar)，7.42(t，J＝8Hz，1H，Ar)，8.42(d，J＝8Hz，1H，Ar)，10.61(s，1H，NH)；¹³C NMR(CDCl₃)8.21，14.76，16.16，27.58，28.03，29.14，46.21，47.93，52.21，55.96，58.45，64.54，82.57，85.01，111.45，112.58，116.73，117.54，117.67，119.37，131.36，133.08，138.02，141.39，148.59，149.12，152.21，154.61，169.50，172.70；

C₃₄H₄₅N₃O₉analytical calculation of (a): c, 63.83; h, 7.09; and N, 6.57. Measured value: c, 63.84; h, 7.03; n, 6.44.

5.5. Example 5

N- [3- (7-amino-1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propyl ] (tert-butoxy) carbonylamino (tert-butoxy) formate

A mixture of (tert-butoxy) -N- {3- [ 7-nitro-1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) propyl } carbonylamino (tert-butoxy) formate (5.0g, 8.3mmol) and Pd/C (500mg) in ethyl acetate (60ml) was shaken under hydrogen for 24 hours. The suspension was filtered through a pad of celite. The solvent was removed in vacuo to give N- [3- (7-amino-1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propyl ] (tert-butoxy) carbonylamino (tert-butoxy) formate (4.4g, yield 93%, yellow solid):

mp，85-87℃；¹H NMR(CDCl₃)δ1.42(s，9H，3CH₃)，1.43(t，J＝7Hz，3H，CH₃)，1.49(s，9H，3CH₃)，2.34-2.44(m，2H，CH₂)，3.59-3.70(m，2H，CH₂)，3.82(s，3H，CH₃)，3.94(d，J＝16Hz，1H，NCHH)，4.02(q，J＝7Hz，2H，CH₂)，4.24(d，J＝16Hz，1H，NCHH)，5.23(brs，2H，NH₂)，5.39(t，J＝8Hz，1H，NCH)，5.52(d，J＝8Hz，1H，Ar)，5.58(d，J＝8Hz，1H，Ar)，6.80(d，J＝8Hz，1H，Ar)，6.89-6.92(m，2H，Ar)，7.16(t，J＝8Hz，1H，Ar)；¹³C NMR(CDCl₃)δ14.74，27.58，28.05，28.99，45.99，48.18，51.58，55.93，64.46，82.44，84.87，110.99，111.37，112.70，113.31，115.29，119.32，131.93，132.59，142.54，146.00，148.48，148.89，152.20，154.60，170.00；

C₃₀H₄₁N₃O₈analytical calculation of (a): c, 63.03; h, 7.23; and N, 7.35. Measured value: c, 63.07; h, 7.27; and N, 7.08.

5.6. Example 6

(3R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide

(3R) - (tert-butoxy) -N- {3- [7- (cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl ester at room temperature]A solution of (E) -3- (3-ethoxy-4-methoxyphenyl) propyl } carbonylamino (tert-butoxy) formate (4.1g, 6.4mmol) in dichloromethane (20ml) and trifluoroacetic acid (9ml) was stirred for 1.5 hours. The solvent was removed in vacuo to give a yellow oil. The resulting oil was extracted with ethyl acetate (50ml) and sodium bicarbonate (saturated, 50 ml). The organic layer was washed with brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give an oil. The oil was stirred in diethyl ether (15ml) to give a suspension. The suspension was filtered to give (3R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (2.1g, yield 75%, white solid):

mp，136-138℃；¹H NMR(CDCl₃)δ0.84-0.91(m，2H，CH₂)，1.06-1.14(m，2H，CH₂)，1.43(t，J＝7Hz，3H，CH₃)，1.64-1.71(m，1H，CH)，2.23-2.45(m，2H，CH₂)，2.99(t，J＝7Hz，2H，CH₂)，3.85(s，3H，CH₃)，3.95(d，J＝16Hz，1H，NCHH)，4.06(q，J＝7Hz，2H，CH₂)，4.26(d，J＝16Hz，1H，NCHH)，5.57(dd，J＝6，10Hz，1H，NCH)，6.81-6.99(m，4H，Ar)，7.41(t，J＝8Hz，1H，Ar)，8.42(d，J＝8Hz，1H，Ar)，10.57(s，1H，NH)；¹³C NMR(CDCl₃)8.27，14.77，16.19，28.83，45.79，50.40，51.49，55.96，64.57，111.44，112.84，116.73，117.39，117.73，119.52，131.27，133.13，137.99，141.36，148.62，149.18，169.55，172.72；

C₂₄H₂₉N₃O₅analytical calculation of (a): c, 65.59; h, 6.65; n, 9.56. Measured value: c, 65.30; h, 6.63; and N, 9.21.

5.7. Example 7

(1R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide

(3R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl]A solution of-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (340mg, 0.77mmol) and 2, 2, 2-trifluoroethyl formate (1g) in THF (4ml) was heated to reflux for 3 hours. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50ml) and sodium hydrogencarbonate (saturated, 50 ml). The organic layer was washed with brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give a solid. The resulting solid was purified by preparative HPLC to give (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (220mg, yield 61%, white solid):

mp，102-104℃；¹H NMR(DMSO-d6)δ0.87-0.89(m，4H，2CH₂)，1.31(t，J＝7Hz，3H，CH₃)，1.73-1.80(m，1H，CH)，2.31-2.38(m，2H，CH₂)，3.43-3.53(m，2H，CH₂)，3.73(s，3H，CH₃)，3.98-4.07(m，2H，CH₂)，4.14(d，J＝18Hz，1H，NCHH)，4.54(d，J＝18Hz，1H，NCHH)，5.26-5.29(m，1H，NCH)，6.93-6.96(m，3H，Ar)，7.18(d，J＝8Hz，1H，Ar)，7.49(t，J＝8Hz，1H，Ar)，7.85(s，0.6H，CH)，8.22(d，J＝8Hz，1H，Ar)，8.24(s，0.4H，CH)，9.64(s，0.5H，NH)，10.07(s，0.5H，NH)，10.57(s，1H，NH)；¹³C NMR(DMSO-d6)7.45，14.65，15.51，28.77，46.31，52.13，55.91，64.38，112.99，113.74，116.93，117.35，117.54，120.02，132.03，132.60，137.18，142.23，148.35，149.17，168.60，171.59；

C₂₅H₂₉N₃O₆+0.3H₂analytical calculation of O: c, 63.49; h, 6.31; n, 8.89, H₂O, 1.14. Measured value: c, 63.11; h, 6.16; n, 8.73, H₂O，0.77。

5.8. Example 8

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide

Following the procedure of example 7, (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide (0.7g, 1.7mmol) and 2, 2, 2-trifluoroethyl formate (2.2g, 17mmol) in THF (10ml) was prepared, a white solid was obtained (480mg, yield 64%):

mp：79-81℃ ¹H NMR(DMSO-d6)δ1.31(t，J＝7Hz，3H，CH₃)，1.99(s，3H，CH₃)，2.32-2.42(m，2H，CH₂)，3.40-3.52(m，2H，CH₂)，3.73(s，3H，CH₃)，3.98-4.02(m，2H，CH₂)，4.14(d，J＝17Hz，1H，NCHH)，4.54(d，J＝17Hz，1H，NCHH)，5.23-5.28(m，1H，NCH)，6.92-6.96(m，3H，Ar)，7.18(d，J＝8Hz，1H，Ar)，7.50(t，J＝8Hz，1H，Ar)，7.83(s，0.5H，CH)，8.24-8.27(m，1.5H，Ar，CH)，9.64(s，0.5H，OH)，10.07(s，0.5H，OH)，10.30(s，1H，NH)；¹³C NMR(DMSO-d6)δ14.70，24.50，28.34，28.52，43.39，45.81，46.19，46.74，51.14，51.92，55.45，63.81，111.97，112.39，116.63，117.39，119.66，131.60，132.70，137.02，142.21，142.30，147.96，148.54，157.35，168.21，168.38，168.51；

C₂₃H₂₇N₃O₆+0.4H₂analytical calculation of O: c, 61.57; h, 6.25; n, 9.36; h₂O, 1.61. Measured value: c, 61.77; h, 6.18; n, 8.97; h₂O，0.55。

5.9. Example 9

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide (1.6g, 3.6mmol) and 2, 2, 2-trifluoroethyl formate (5g, 39mmol) in THF (20ml) was prepared according to the procedure of example 7 from N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide, a white solid was obtained (0.7g, yield 41%):

mp：81-83℃ ¹H NMR(DMSO-d6)δ1.18(d，J＝7Hz，6H，2CH₃)，1.31(t，J＝7Hz，3H，CH₃)，2.34-2.38(m，2H，CH₂)，2.56-2.65(m，1H，CH)，3.39-3.51(m，2H，CH₂)，3.73(s，3H，CH₃)，3.96-4.05(m，2H，CH₂)，4.16(d，J＝17Hz，1H，NCHH)，4.55(d，J＝17Hz，1H，NCHH)，5.25-5.29(m，1H，NCH)，6.93-6.97(m，3H，Ar)，7.18(d，J＝8Hz，1H，Ar)，7.50(t，J＝8Hz，1H，Ar)，7.83(s，0.5H，CH)，8.25(s，0.5H，CH)，8.28(d，J＝8Hz，1H，Ar)，9.63(s，0.5H，OH)，10.07(s，0.5H，OH)，10.47(s，1H，NH)；¹³C NMR(DMSO-d6)δ14.69，19.16，19.21，28.39，28.60，35.94，43.35，45.92，46.26，46.73，51.17，51.92，55.44，63.78，111.97，112.34，116.55，117.54，117.58，119.68，131.54，132.16，151.12，142.28，147.94，148.53，157.36，161.80，168.37，168.53，174.93；

C₂₅H₃₁N₃O₆+0.4H₂analytical calculation of O: c, 62.98; h, 6.72; n, 8.81; h₂O, 1.51. Measured value: c, 62.96; h, 6.80; n, 8.84; h₂O，1.48。

5.10. Example 10

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide

To (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl at 0 deg.C]-1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide (350mg, 0.82mmol) in dichloromethane (3ml) and acetyl formate (84mg) in dichloromethane (1ml) were added. After 1 hour, the resulting mixture was extracted with ethyl acetate (25ml) and water (25 ml). The organic layer was washed with brine (20ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl esterBase of]-1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide (90mg, yield 24%, white solid):

mp：96-98℃；¹H NMR(CDCl₃)δ1.46(t，J＝7Hz，3H，CH₃)，2.26(s，3H，CH₃)，2.81-2.83(m，2H，CH₂)，3.56(t，J＝6Hz，2H，CH₂)，3.85(s，3H，CH₃)，4.10(q，J＝7Hz，2H，CH₂)，5.25(t，J＝8Hz，1H，NCH)，6.82(d，J＝8Hz，1H，Ar)，7.06-7.09(m，2H，Ar)，7.45(d，J＝8Hz，1H，Ar)，7.64(t，J＝8Hz，1H，Ar)，7.72(s，1H，CH)，8.75(d，J＝8Hz，1H，Ar)，9.49(s，1H，NH)；¹³C NMR(CDCl₃)δ14.73，24.95，28.35，46.61，51.92，55.93，64.46，111.37，112.79，115.21，118.05，120.63，124.90，130.33，131.09，136.02，137.47，148.48，149.40，155.73，167.72，169.27，170.07；

C₂₃H₂₅N₃O₇+0.3H₂analytical calculation of O: c, 59.95; h, 5.60; n, 9.12; h₂O, 1.17. Measured value: c, 59.94; h, 5.59; n, 8.98; h₂O，1.22。

5.11. Example 11

(1R) -N- {2- [3- (N-acetoxy-N-formyl-amino) -1- (3-ethoxy-4-methoxy-phenyl) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide

To a solution of (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide (300mg, 0.64mmol) in acetonitrile (6ml) at room temperature was added acetic anhydride (0.1ml, 1 mmol). After 4 hours, the solvent was removed in vacuo and the residue was purified by chromatography (silica gel) to give (1R) -N- {2- [3- (N-acetoxy-N-formyl-amino) -1- (3-ethoxy-4-methoxy-phenyl) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide (0.21g, yield 64%, white solid):

mp：72-74℃ ¹H NMR(DMSO-d6)δ1.17(d，J＝7Hz，6H，2CH₃)，1.31(t，J＝7Hz，3H，CH₃)，2.19(s，3H，CH₃)，2.32-2.50(m，2H，CH₂)，2.59-2.68(m，1H，CH)，3.60-3.67(m，2H，CH₂)，3.73(s，3H，CH₃)，3.99-4.09(m，3H，NCHH，CH₂)，4.56(d，J＝17Hz，1H，NCHH)，5.30-5.38(m，1H，NCH)，6.88-6.93(m，3H，Ar)，7.18(d，J＝8Hz，1H，Ar)，7.50(t，J＝8Hz，1H，Ar)，8.11(s，1H，CH)，8.29(d，J＝8Hz，1H，Ar)，10.47(8，1H，NH)；¹³C NMR(DMSO-d6)δ14.69，18.01，19.16，28.87，35.94，45.87，46.13，51.18，55.45，63.80，111.96，112.32，116.55，117.55，119.76，131.30，132.79，137.14，142.32，147.99，148.59，157.50，163.00，167.31，168.57，174.94；

C₂₇H₃₃N₃O₇+0.2H₂analytical calculation of O: c, 62.95; h, 6.53; n, 8.16; h₂O, 0.70. Measured value: c, 62.81; h, 6.63; n, 7.92; h₂O，0.59。

5.12. Example 12

(1R) -N- {2- [3- (N-aminocarbonyl-N-hydroxy-amino) -1- (3-ethoxy-4-methoxy-phenyl) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide

To (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl at room temperature]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide (1.3g, 2.6mmol)To a solution of potassium cyanate (442mg, 5.5g) in water (10ml) was added. After 1 hour, the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with HCl (1N, 25ml), brine (25ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give (1R) -N- {2- [3- (N-aminocarbonyl-N-hydroxy-amino) -1- (3-ethoxy-4-methoxy-phenyl) -propyl]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide (0.70g, yield 55%, white solid):

mp：137-139℃ ¹H NMR(DMSO-d6)δ1.18(d，J＝7Hz，6H，2CH₃)，1.31(t，J＝7Hz，3H，CH₃)，2.25-2.34(m，2H，CH₂)，2.51-2.66(m，1H，CH)，3.22-3.40(m，2H，CH₂)，3.73(s，3H，CH₃)，3.95-4.06(m，2H，CH₂)，4.10(d，J＝18Hz，1H，NCHH)，4.55(d，J＝18Hz，1H，NCHH)，5.26(t，J＝8Hz，1H，NCH)，6.34(s，2H，NH₂)，6.92-6.98(m，3H，Ar)，7.18(d，J＝8Hz，1H，Ar)，7.50(t，J＝8Hz，1H，Ar)，8.29(d，J＝8Hz，1H，Ar)，9.34(s，1H，CH)，10.48(s，1H，NH)；¹³C NMR(DMSO-d6)δ14.70，19.18，28.73，35.94，46.25，47.22，52.04，55.43，63.76，111.94，112.40，116.55，117.52，117.60，119.58，131.99，132.73，137.12，142.20，147.89，148.43，161.57，168.34，174.93；

C₂₅H₃₂N₄O₆+0.9H₂analytical calculation of O: c, 59.96; h, 6.80; n, 11.19; h₂And O, 3.24. Measured value: c, 60.16; h, 6.58; n, 10.81; h₂O，3.24。

5.13. Example 13

(1R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide

(1R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ester at room temperature]A solution of-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (460mg, 1mmol) and acetic anhydride (0.2ml) in acetonitrile (6ml) was stirred for 16H. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50ml) and sodium hydrogencarbonate (saturated, 50 ml). The organic layer was washed with brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ester]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (370mg, yield 72%, white solid):

mp，106-108℃；¹H NMR(DMSO-d6)δ0.87-0.89(m，4H，2CH₂)，1.31(t，J＝7Hz，3H，CH₃)，1.76-1.80(m，1H，CH)，2.19(s，3H，CH₃)，2.27-2.40(m，2H，CH₂)，3.65-3.68(m，2H，CH₂)，3.73(s，3H，CH₃)，3.97-4.08(m，3H，NCHH，CH₂)，4.56(d，J＝18Hz，1H，NCHH)，5.20-5.39(m，1H，NCH)，6.89-6.93(m，3H，Ar)，7.17(d，J＝8Hz，1H，Ar)，7.49(t，J＝8Hz，1H，Ar)，8.12(s，1H，CH)，8.23(d，J＝8Hz，1H，Ar)，10.57(s，1H，NH)；

C₂₇H₃₁N₃O₇+0.3H₂analytical calculation of O: c, 62.97; h, 6.19; n, 8.16, H₂O, 1.05. Measured value: c, 63.03; h, 6.12; n, 7.98, H₂O，0.81。

5.14. Example 14

(N- {3- [7- (cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) propyl } acetylamino) acetate

A solution of cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyamino-propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (0.3g, 0.7mmol) and acetic anhydride (68. mu.L, 0.7mmol) in dichloromethane (2ml) was stirred at room temperature for 1 hour. The resulting mixture was extracted with dichloromethane (20ml) and sodium bicarbonate (saturated, 20 ml). The organic layer was concentrated in vacuo to give an oil. This oil was purified by preparative HPLC to give (N- {3- [7- (cyclopropylcarbonylamino) -1-oxodihydroisoindol-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) propyl } acetylamino) acetate (25mg, yield 7%, white solid):

mp，123-125℃；¹H NMR(CDCl₃)δ0.87-0.91(m，2H，CH₂)，1.08-1.39(m，2H，CH₂)，1.45(t，J＝7Hz，3H，CH₃)，1.63-1.71(m，1H，CH)，1.98(s，3H，CH₃)，2.20(s，3H，CH₃)，2.39-2.48(m，2H，CH₂)，3.73(t，J＝7Hz，2H，CH₂)，3.86(s，3H，CH₃)，4.02(d，J＝16Hz，1H，NCHH)，4.08(q，J＝7Hz，2H，CH₂)，4.34(d，J＝16Hz，1H，NCHH)，5.41(t，J＝8Hz，1H，NCH)，6.82-6.95(m，3H，Ar)，7.00(d，J＝8Hz，1H，Ar)，7.43(t，J＝8Hz，1H，Ar)，8.43(d，J＝8Hz，1H，Ar)，10.58(s，1H，NH)；¹³CNMR(CDCl₃)8.26，14.78，16.19，18.46，20.26，29.09，46.04，46.69，52.12，55.97，64.56，111.42，112.47，116.82，117.41，117.71，119.45，130.92，133.21，138.00，141040，148.64，149.21，168.47，169.54，172.67；

C₂₈H₃₃N₃O₇analytical calculation of (a): c, 64.23; h, 6.35; and N, 8.03. Measured value: c, 63.87; h, 6.37; and N, 7.95.

5.15. Example 15

(1R) -Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (formyl-hydroxy-amino) -butyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide

To (1R) - [1- (3-ethoxy-4-methoxy-phenyl) -3-oxo-butyl]To a solution of tert-butyl carbamate (1.0g, 3.1mol) in ethanol (10ml) and pyridine (1ml) was added hydroxylamine (1g, 14 mmol). The resulting solution was heated to reflux for 10 min. The solvent was removed in vacuo. The residue was extracted with dichloromethane (50ml) and HCl (0.1N, 25 ml). The organic layer was washed with brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give (1R) - [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyimino-butyl]Tert-butyl carbamate cyclopropanecarboxylic acid (1g, white solid), which was used in the next step without further purification. The crude (1R) - [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyimino-butyl is reacted at room temperature]A solution of tert-butyl carbamate cyclopropanecarboxylic acid (1g) in trifluoroacetic acid (3ml) and dichloromethane (3ml) was stirred for 30 min. The solvent was removed in vacuo to give an oil. The crude oil, methyl 2-bromomethyl-6- (cyclopropanecarbonyl-amino) -benzoate (1.0g, 3.2mmol) and triethylamine (1.0ml, 7.2mmol) in DMF (10ml) was heated at 100 ℃ for 19 hours. The solvent was removed in vacuo. The residue was extracted with dichloromethane (50ml) and water (25 ml). The organic layer was washed with brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo. The residue was purified by chromatography (silica gel) to give (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyimino-butyl]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (540mg, white solid). To (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3-hydroxyimino-butyl-at room temperature]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (540mg, 1.2mmol) in THF (5ml) and ethanol (5ml) borane-pyridine (0.5ml, 4mmol) was added and the mixture was allowed to standFor 2 hours. The resulting mixture was poured into sodium bicarbonate (saturated, 25 ml). The mixture was extracted with dichloromethane (2X 30 ml). The organic layer was washed with brine (25ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo to give an oil. The crude oil and a solution of 2, 2, 2-trifluoroethyl formate (1.5g, 12mmol) in THF (10ml) were heated to reflux for 2 h. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50ml) and HCl (1N, 50 ml). The organic layer was washed with brine (50ml) and over MgSO₄And (5) drying. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (formyl-hydroxy-amino) -butyl]Diastereomer mixture of 3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide (ratio 1: 2) (370mg, yield 64%, white solid):

mp，142-144℃；¹H NMR (DMSO-d6)δ0.87-0.89(m，4H，2CH₂)，1.14-1.33(m，6H，2CH₃)，1.72-1.79(m，1H，CH)，2.22-2.32(m，2H，CH₂)，3.72(s，3H，CH₃)，3.60-3.80(m，1H，CH)，4.00-4.21(m，3H，CH₂，NCHH)，4.50-4.57(m，1H，NCHH)，5.19-5.24(m，1H，NCH)，6.85-6.97(m，3H，Ar)，7.16(d，J＝8Hz，1H，Ar)，7.48(t，J＝8Hz，1H，Ar)，[7.67(s，OCH)]，7.89(s，1H，OCH)，8.20-8.27(m，1H，Ar)，9.43-[9.47(brs，OH)]，9.83(brs，1H，OH)，10.56-10.58(m，1H，NH)；¹³C NMR(DMSO-d6)δ7.41，14.69，15.54，34.50，35.09，46.49，51.79，55.99，64.52，113.21，113.96，116.90，117.25，117.74，119.97，132.09，132.64，137.22，142.23，178.39，149.21，168.45，168.79，171.56；

C₂₆H₃₁N₃O₆+0.5H₂analytical calculation of O: c, 63.66; h, 6.58; n, 8.57; h₂O, 1.84. Measured value: c, 63.46; h, 6.51; n, 8.47; h₂O，1.07。

5.16. Example 16: 50mg solid tablet

Tablets may be prepared in the following manner, each tablet containing 50mg of (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide:

composition of(for 1000 tablets)

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide 50.0g

Lactose 50.7g

Wheat starch 7.5g

Polyethylene glycol 60005.0 g

Talcum powder 5.0g

Magnesium stearate 1.8g

Proper amount of deionized water

First, the solid furnish is passed through a 0.6mm mesh wide screen. The active ingredient, lactose, talc, magnesium stearate and half starch are then mixed. The other half of the starch was suspended in 40ml of water and the suspension was added to 100ml of boiling aqueous polyethylene glycol solution. The paste obtained is added to the pulverulent material and the mixture is granulated, if necessary with addition of water. The granules were dried at 35 ℃ overnight, passed through a 1.2mm mesh wide sieve and compressed into tablets of approximately 6mm diameter, which were concave on both sides.

5.17. Example 17: 100mg solid tablet

Tablets may be prepared in the following manner, each containing 100mg of (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide:

composition of(for 1000 tablets)

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide 100.0g

Lactose 100.0g

Wheat starch 47.0g

Magnesium stearate 3.0g

First, all solid ingredients were passed through a 0.6mm mesh wide screen. The active ingredient, lactose, magnesium stearate and half starch are then mixed. The other half of the starch was suspended in 40ml of water and the suspension was added to 100ml of boiling water. The paste obtained is added to the pulverulent material and the mixture is granulated, if necessary with addition of water. The granules were dried at 35 ℃ overnight, passed through a 1.2mm mesh wide sieve and compressed into tablets of approximately 6mm diameter, which were concave on both sides.

5.18. Example 18: 75mg chewable tablet

Chewable tablets may be prepared in the following manner, each tablet containing 75mg of (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide:

composition of(for 1000 tablets)

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide 75.0g

Mannitol 230.0g

Lactose 150.0g

Talcum powder 21.0g

Glycine 12.5g

Stearic acid 10.0g

Saccharin 1.5g

Appropriate amount of 5% gelatin solution

First, all solid ingredients were passed through a 0.25mm mesh wide screen. Mannitol and lactose were mixed, a gelatin solution was added and granulated, passed through a 2mm mesh wide sieve, dried at 50 ℃, then passed through a 1.7mm mesh wide sieve, (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide, glycine and saccharin were carefully mixed, mannitol, lactose granules, stearic acid and talc were added, all mixed well and compressed into tablets of about 10mm diameter, with concave sides and nicks on the top.

5.19. Example 19: 10mg tablet

Tablets may be prepared in the following manner, each containing 10mg of (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide.

Composition of(for 1000 tablets)

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide 10.0g

Lactose 328.5g

Corn starch 17.5g

Polyethylene glycol 60005.0 g

Talcum powder 25.0g

Magnesium stearate 4.0g

Proper amount of deionized water

First, the solid furnish is passed through a 0.6mm mesh wide screen. Then, the active amide ingredient, lactose, talc, magnesium stearate and half of the starch are mixed well. The other half of the starch was suspended in 65ml and the suspension was added to 260ml of boiling polyethylene glycol water. The paste obtained is added to the pulverulent material, and the entire mixture is then mixed and granulated, if necessary with addition of water. The granules were dried at 35 ℃ overnight, passed through a 1.2mm mesh wide sieve and compressed into tablets of approximately 10mm diameter, which were concave on both sides and had nicks on the top.

5.20. Example 20: 100mg gelatin capsule

Gelatin dry-filled capsules may be prepared in the following manner, each capsule containing 100mg of (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide:

composition of(for 1000 granules)

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide 100.0g

Microcrystalline cellulose 30.0g

Sodium dodecyl sulfate 2.0g

Magnesium stearate 8.0g

Sodium lauryl sulfate was added to (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide through a 0.2mm mesh wide sieve and the two components were mixed thoroughly for 10 minutes. Then, microcrystalline cellulose was added thereto through a 0.9mm mesh wide sieve, and all the components were further mixed for 10 minutes. Finally, magnesium stearate was added thereto through a 0.8mm wide sieve, and after mixing for 3 minutes, the mixture was filled into size 0 (long) gelatin dry-filled capsules each filled with 140 mg.

5.21. Example 21: injection solution

For example, a 0.2% injection or infusion solution can be prepared as follows:

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide 5.0g

22.5g of sodium chloride

Phosphate buffer pH 7.4300.0 g

Deionized water to 2500.0ml

(1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide was dissolved in 1000ml of water and then filtered through a microfilter. Buffer was added and then water was added to bring the total volume to 2500 ml. To prepare the unit dosage form, 1.0ml or 2.5ml (2.0 mg or 5.0mg of amide per ampoule) is filled into each glass ampoule.

All publications and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application were individually incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of presentation, it will be readily apparent to those of ordinary skill in the art in light of the present disclosure that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims.

Claims (53)

1. A compound of the following formula (I):

wherein:

y is-C (O) -, -CH₂-、-CH₂C (O) -or-SO₂-；

R₁And R₂Each independently is C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C)_1-8-alkyl) cycloalkyl;

Z₁is H, C_1-6Alkyl, NR₃R₄OR OR₅Wherein R is₃、R₄And R₅Each independently is H or C_1-6-an alkyl group;

Z₂is H or C (O) R₅Wherein R is₅Is H, C_1-6-alkyl, or O-C_1-6-an alkyl group;

X₁、X₂、X₃is H;

X₄is NO₂、(C_0-4-alkyl) -N- (R)₈R₉)、(C_0-4-alkyl) -NHC (O) - (R)₈) Or (C)_0-4-alkyl) -NHC (O) CH (R)₈)(R₉)；

R₆And R₇Each independently is H or C_1-6-an alkyl group; and

R₈and R₉Each independently is H, C_1-9-alkyl, or C_3-6-a cycloalkyl group.

2. The compound of claim 1, wherein Y is-CH₂-or-C (O) -.

3. The compound of claim 1, wherein Z₁Is H.

4. The compound of claim 3, wherein R₆Is C_1-6-alkyl, R₇Is H.

5. The compound of claim 1, wherein Z₂Is H, -C (O) CH₃or-C (O) CH₂CH₃。

6. The compound of claim 5, wherein X₄Is NHC (O) R₈Wherein R is₈Is H, C_1-9-alkyl, or C_3-6-a cycloalkyl group.

7. The compound of claim 5, wherein R₁Is CH₃Or CF₂H，R₂Is C_1-8-an alkyl group.

8. The compound of claim 5, wherein Z₂Is H.

9. The compound of claim 1, wherein R₁Is CH₃Or CF₂H。

10. The compound of claim 1, wherein R₂Is CH₂CH₃、CH₃、CF₂H、CH₂-cyclopropyl or cyclopentyl.

11. The compound of claim 1, wherein R₆And R₇While being H, or R₆And R₇One of which is H and the other is CH₃。

12. The compound of claim 1, wherein X₄is-NHC (O) R₈Wherein R is₈Is H, C_1-9-alkyl, or C_3-6-a cycloalkyl group.

13. The compound of claim 1, wherein the configuration of the stereocenter a is (S).

14. The compound of claim 1, wherein the configuration of the stereocenter a is (R).

15. The compound of claim 1, wherein R₆And R₇In contrast, the configuration of the stereocenter b is (S).

16. The compound of claim 1, wherein R₆And R₇In contrast, the configuration of the stereocenter b is (R).

17. A diastereomerically pure SS isomer of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. A diastereomerically pure RS isomer of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A diastereomerically pure SR isomer of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A diastereomerically pure RR isomer of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. A compound, wherein the compound is:

1) (3R) - (tert-butoxy) -N- {3- [7- (cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) propyl } carbonylamino (tert-butoxy) formate;

2) n- [3- (7-amino-1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propyl ] (tert-butoxy) carbonylamino (tert-butoxy) formate;

3) (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide;

4) (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide;

5) (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide;

6) (1R) -N- {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide;

7) (1R) -N- {2- [3- (N-acetoxy-N-formyl-amino) -1- (3-ethoxy-4-methoxy-phenyl) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide;

8) (1R) -N- {2- [3- (N-aminocarbonyl-N-hydroxy-amino) -1- (3-ethoxy-4-methoxy-phenyl) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -isobutyramide;

9) (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (N-formyl-N-hydroxy-amino) -propyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide;

10) (N- {3- [7- (cyclopropylcarbonylamino) -1-oxoisoindol-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) propyl } acetylamino) acetate; or

11) (1R) -cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -3- (formyl-hydroxy-amino) -butyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a compound of formula (I):

wherein:

y is-C (O) -, -CH₂-、-CH₂C (O) -or-SO₂-；

R₁And R₂Each independently is C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C)_1-8-alkyl) cycloalkyl;

Z₁is H, C_1-6Alkyl, NR₃R₄OR OR₅Wherein R is₃、R₄And R₅Each independently is H or C_1-6-an alkyl group;

Z₂is H or C (O) R₅Wherein R is₅Is H, C_1-6-alkyl, or O-C_1-6-an alkyl group;

X₁、X₂、X₃is H;

X₄is NO₂、(C_0-4-alkyl) -N- (R)₈R₉)、(C_0-4-alkyl) -NHC (O) - (R)₈) Or (C)_0-4-alkyl) -NHC (O) CH (R)₈)(R₉)；

R₆And R₇Each independently is H or C_1-6-an alkyl group; and

R₈and R₉Each independently is H, C_1-9-alkyl, or C_3-6-a cycloalkyl group.

23. Use of a compound of claim 1 for the preparation of a medicament useful for inhibiting phosphodiesterase type 4 (PDE4) in a mammal.

24. The use of a compound of claim 1 for the manufacture of a medicament for modulating tumor necrosis factor α (TNF- α) production in a mammal.

25. Use of a compound of claim 1 for the manufacture of a medicament for inhibiting Matrix Metalloproteases (MMPs) in a mammal.

26. The use of a compound according to claim 1 in the manufacture of a medicament for the treatment, prevention or management of myelodysplastic syndrome.

27. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment, prevention or management of a myeloproliferative disease.

28. The use of a compound of claim 1 in the manufacture of a medicament for the treatment, prevention or management of parkinson's disease.

29. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment, prevention or management of complex regional pain syndrome.

30. The use of claim 27, wherein the medicament is administered before, during or after surgical or physical therapy to reduce or avoid symptoms of complex regional pain syndrome in a patient.

31. Use of a compound of claim 1 for the manufacture of a medicament for the treatment, prevention or management of unwanted angiogenesis.

32. Use of a compound of claim 1 for the manufacture of a medicament for the treatment, prevention or management of cancer.

33. The use of claim 32, wherein the cancer is a solid tumor or a blood-borne tumor.

34. The use of claim 33, wherein the cancer is skin cancer; lymph node cancer; breast cancer; cervical cancer; uterine cancer; gastrointestinal cancer; lung cancer; ovarian cancer; prostate cancer; colon cancer; rectal cancer; oral cancer; brain cancer; head and neck cancer; throat cancer; testicular cancer; kidney cancer; pancreatic cancer; bone cancer; spleen cancer; liver cancer; bladder cancer; laryngeal cancer; or nasal passage cancer.

35. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment, prevention or management of inflammatory diseases, autoimmune diseases, arthritis, rheumatoid arthritis, inflammatory bowel disease, crohn's disease, aphthous ulcers, cachexia, graft-versus-host disease, asthma, adult respiratory distress syndrome, or acquired immunodeficiency syndrome.

36. The use of a compound of claim 1 for the preparation of a medicament for the treatment, prevention or management of pulmonary inflammation.

37. The use of a compound as claimed in claim 1 in the manufacture of a medicament for the treatment, prevention or management of depression.

38. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment, prevention or management of chronic obstructive pulmonary disease.

39. The use of claim 38, wherein the compound is administered by means of an inhaler.

40. Use of a compound of claim 1 for the manufacture of a medicament for the treatment, prevention or management of inflammatory bowel disease.

41. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment, prevention or management of atopic dermatitis.

42. The use of a compound according to claim 1 in the manufacture of a medicament for the treatment, prevention or management of psoriasis.

43. The use of claim 42, wherein the compound is administered topically.

44. The use of a compound according to claim 1 in the manufacture of a medicament for the treatment, prevention or management of crohn's disease.

45. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment, prevention or management of rheumatoid arthritis.

46. The use of a compound of claim 1 for the preparation of a medicament for the treatment, prevention or management of asthma.

47. The use of claim 46, wherein the compound is administered by an inhaler.

48. Use of a compound according to claim 1 for the preparation of a medicament for the treatment, prevention or management of multiple sclerosis.

49. The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment, prevention or management of heart disease.

50. Use of a compound of claim 1 in the manufacture of a medicament for the treatment, prevention or management of macular degeneration.

51. The use of a compound according to claim 1 for the preparation of a medicament for the treatment, prevention or management of a central nervous system disorder.

52. Use of a compound of claim 1 for the manufacture of a medicament for the treatment, prevention or management of asbestos-related diseases.

53. The use of any one of claims 23-52, wherein the patient or mammal is a human