JP2007509966A - Heterocyclic compounds and methods of making and using them - Google Patents

Abstract

Compositions and / or methods containing compounds of formula (I) and compounds effective in modulating inflammatory responses (eg, those resulting from AGE and glycated protein accumulation) are provided. Compositions and / or methods containing compounds that are effective in modulating smooth muscle cell proliferation and related diseases or conditions are also provided. The present invention relates to smooth muscle cell proliferation, which is expressed by pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, MCP-1 or perlecan, heparin sulfate proteoglycan (HSPG) Compounds and compositions that can be mediated by triggering are provided.

Description

(Field of Invention)
The present invention relates to compounds, pharmaceutical compositions, and methods of making and using them.

(Background of the Invention)
Glycated proteins and advanced glycation end products (AGE) contribute to cell damage (eg, diabetic tissue damage). This can occur by at least two major mechanisms: regulation of cell function through interaction with specific cell surface receptors, and changes in the extracellular matrix leading to the formation of protein bridges. Studies have shown that glycated proteins and AGE and cellular interactions promote inflammatory processes and oxidative cell damage. AGE increases the oxidizability and atherogenicity of lipoproteins. Furthermore, AGE that binds to the substrate protein induces the synthesis of IL-1, TNFa, VCAM-1, heme oxygenase, insulin-like growth factor, IL-6 and activates NF-B. Diseases in which glycated protein and AGE accumulation are suspected etiological factors include, but are not limited to, diabetic vascular complications, microangiopathy, renal failure, and Alzheimer's disease.

  As seen in diabetes, the actual mechanism by which high plasma glucose causes microangiopathy is not fully understood. One potential mechanism by which hyperglycemia can be linked to microangiopathy is by the process of non-enzymatic glycation of important proteins. Non-enzymatic glycation of important proteins is described in Nonenzymatic glycosylation and the pathogenesis of diabetic complications, Ann. Intern. Med. , 1984 (101) 527-537; Advanced glycation end products up-regulate gene expression found in diabetic globular diseases, Proc. Natl. Acad. Sci. USA. , 1994 (91) 9436-40; Expression of advanced end products and therial cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. Am. Soc. Nephrol. , 2000 (11) 1656-66; and Activation of receptor for advanced glide end products: a mechanism for chronic vascular function in diabetics. , Cirr. Res. 1999 (84) 489-97).

Non-enzymatic glycation (ie, glucose and protein linkage) leads to the formation of glycated proteins. The first step in this saccharification pathway involves the non-enzymatic condensation of glucose and free amino groups in the protein (mainly the ε-amino group of lysine residues), the formation of an Amadori adduct. These early glycation adducts can undergo further reactions such as transfer, dehydration, and condensation to form irreversible late terminal glycation products (AGE). These are highly reactive groups of molecules that interact with specific receptors on the cell surface that can lead to pathogenic consequences. Accumulation of glycated protein has been shown in the basement membrane of patients with diabetes and is thought to be related to the development of diabetic nephropathy and retinopathy. Immunohistochemical localization of glycated protein in diabetic rat kidney. Diabetes Res Clin. Pract. , 1990 (8) 215-9; and Role of Amadori-modified non-enzymatically glycated serum protein in the pathology of the diabetic nephropathy. , J .; Am. Soc. Nephrol. 1996 (7) 183-90. Inhibitors of AGE formation, such as aminoguanidine, have been shown to block the formation of AGE and prevent development of diabetes complications, including diabetic retinopathy (Aminoguanidine prevents diabetes-induced alterial wall protein cross-linking,
Science, 1986 (232) 1629-1632; Prevention of cardiovascular and real pathology of the advanced glycation inhibitor amine. , Proc. Natl. Acad. Soi. USA. , 1996 (93) 3902-7; and Potential benef of inhibitors of advanced glycation end products in the promotion of type II in the bios. , Metabolism, 1998 (47) 1477-80.

  One characterized AGE receptor is RAGE (a receptor for AGE). Activation of receptor for advanced glycation end products: a mechanism for chronic vascular function in diabetic vasopathology and athletics. Res. 1999 (84) 489-97; and Roles of the AGE-RAGE system in vasculatory in diabetics. , Ann. NY Acad. Sci. 2000 (902) 163-70; discussion 170-2. Several in vitro and in vivo studies show that blocking RAGE by either addition of soluble forms of antibodies or receptors inhibits vascular diseases including diabetic atherosclerosis. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hypermeability in diabetic rats. , J .; Clin. Invest. , 1996 (97) 238-43; Advanced glycation end products interacting with the human receptor inducible immunity of the -1 A potential mechanism for the accelerated vasculopathy of diabets. , J .; Clin. Invest. , 1995 (96) 1395-403; and Suppression of accelerated diabetic theerolysis by the soluble receptor for advanced glide end products, Nat. Med. 1998 (4) 1025-31. Besides AGE, RAGE appears to mediate the binding of several other ligands related to normal physiology as well as pathology. Blockade of RAGE-amphoterin signaling supresses tumour grow and metastases. , Nature, 2000 (405) 354-60; RAGE mediates a novel prolaminatory axis: a central cell surface receptor for S100 / calgranulin polypeptides. Cell. , 1999 (97) 889-901; and Amyloid-beta peptide-receptor for advanced glycation end production inductive effusion and macrophysical enhancement of macromolecules. , Proc. Natl. Acad. Sci. USA. . 1997 (94) 5296-301. Thus, simply blocking RAGE may have other unintended consequences. Furthermore, since the blockage of RAGE can lead to accumulation of AGEs in the circulation, the long-term effects of blockage of RAGE are unknown and may be more detrimental than the pathogenesis sought to be treated.

  One useful way to block the effects of AGE is to develop inhibitors that block AGE-induced signaling. Activation of the receptor for advanced glycation end products triggers a p21 (ras)-dependent mitogen-activated protein kinase b , J. et al. Biol. Chem. , 1997 (272) 17810-4; Obi Cell activation by glycated proteins; AGE receptors, receptor recognition factors and functional classification of AGEs. Cell. Mol. Biol. (Noise-le-grand), 1998 (44) 1013-23. However, the order of these signaling events leading to inflammation is not clear. Thus, what is needed is a compound that can block AGE-inducing activity, particularly AGE-induced inflammation, or more particularly AGE-induced signaling events.

  Another chronic condition for which no adequate and effective treatment exists is the treatment of antiproliferative injuries. Smooth muscle cell (SMC) hyperplasia is an important factor in the development of atherosclerosis and is responsible for a significant number of failure rates following vascular procedures such as angiogenesis and coronary artery bypass surgery . The competitive pathology of atherosclerosis and restenosis. Am. J. et al. Cardiol. 86: 6H-11H (2000); and Restenosis: a challenge for pharmacology. Trends Pharmacol Sci. 21: 274-9. In normal vessels, SMCs are quiescent but they proliferate when damage to the endothelium occurs. Naturally occurring growth factors, many of which are derived from the endothelium, closely control SMC proliferation in vivo.

  Abnormal vascular smooth muscle cell (VSMC) proliferation includes atherosclerosis, vascular restenosis after successful angiogenesis (restenosis), and graft atherosclerosis after coronary transplantation Can contribute to the pathogenesis of obstructive damage. VSMC is the Thecomparative-pathology of atherolysis and restenosis. Am. J. et al. Cardiol. 86: 6H-11H; and Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 100: discussed in S87-9. Many humans and animals have limited life spans and lifestyles due to these conditions. Currently, there are no known effective pharmaceutical treatments available that control these occlusive etiologies, particularly restenosis.

  The percutaneous coronary intervention (PTCA) procedure is the most common inpatient hospital procedure in the United States. According to the American Heart Association, about one third of patients undergoing balloon angioplasty have widened segment restenosis within about six months. Another angioplasty or coronary artery bypass procedure may need to be performed on the restenotic artery. An important feature of restenosis is the damage response that results in activation of the inflammatory cascade and remodeling of cells inside and outside the carotid wall. This includes excessive proliferation of connective tissue and smooth muscle into the lumen of the artery known as neointimal hyperplasia. Currently available to carry out the pathogenesis of vascular obstructive disorders such as, but not limited to, atherosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after coronary transplantation There is no effective pharmacological treatment. Identification of an effective treatment with minimal side effects restores quality of life without requiring additional surgical procedures such as coronary artery bypass surgery.

  Smooth muscle cell (SMC) hyperplasia is a major event in the development of atherosclerosis and may contribute to failure rates after vascular procedures such as angioplasty and coronary artery bypass surgery. In normal vessels, SMCs are at rest, but they proliferate when damage to the endothelium occurs. Naturally occurring growth regulators (many of these are derived from the endothelium) tightly control SMC proliferation in vivo. There is a need for methods and compositions in which altered gene expression in arterial wall cells inhibits thrombosis and SMC proliferation. In particular, what is needed are methods and compositions that inhibit SMC proliferation and associated intimal hyperplasia.

U.S. Patent No. 6,099,051 relates to certain thiazolidinedione compounds, which are described as antiproliferative, anti-inflammatory and anti-infective agents. In accordance with this disclosure, these particular compounds are used in the treatment of certain endocrine diseases, malignant diseases, and non-malignant proliferative diseases, and cardiovascular disorders.
US Pat. No. 6,028,088

  Therefore, there is a need for treatment of vaso-occlusive pathological conditions, particularly restenosis. Because of the frequent occurrence, currently available treatments are expensive and these conditions are refractory to many pharmacological therapies. The mechanisms associated with the control of vascular conditions associated with SMC function are not clear, and conventional preventive treatments for SMC activation are not available. Accordingly, there is a need for methods and compositions for the treatment and prevention of vaso-occlusive conditions. In particular, there is a need for methods and compositions for preventing and treating restenosis after treatment of vascular tissue. The present invention is directed to overcoming these and other deficiencies in the art.

(Summary of the Invention)
The present invention relates to compounds of formula (I) and to compositions and / or methods containing compounds that are effective in modulating inflammatory responses such as those resulting from AGE and glycated protein accumulation. The present invention also relates to compositions and / or methods containing compounds that are effective in modulating smooth muscle cell proliferation and related diseases or conditions.

  The present invention provides compounds and compositions that block inflammatory responses, particularly those resulting from AGE and glycated protein accumulation. In addition, the present invention relates to smooth muscle cell proliferation, which is due to pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, MCP-1, or perlecan, heparin sulfate proteoglycan (HSPG). Compounds and compositions that can be mediated by inducing expression of are provided.

本発明は、必要に応じて、他の活性成分と組み合わせて、式（Ｉ）の新規化合物、それらの薬学的に受容可能な塩、およびこのような化合物の１種またはそれ以上を含有する医薬組成物を提供する。

The present invention is directed to novel compounds of formula (I), pharmaceutically acceptable salts thereof, and medicaments containing one or more of such compounds, optionally in combination with other active ingredients. A composition is provided.

  The present invention also provides methods for preparing the compounds of formula (I) as defined above, their salts, and their pharmaceutically acceptable compositions.

  The present invention also contains novel compounds of formula (II), their pharmaceutically acceptable salts, and one or more of such compounds, optionally in combination with other active ingredients. A pharmaceutical composition is provided.

本発明はまた、上で定義した式（ＩＩ）の化合物、それらの塩、およびそれらの薬学的に受容可能な組成物を調製する方法を提供する。

The present invention also provides methods for preparing the compounds of formula (II) as defined above, their salts, and their pharmaceutically acceptable compositions.

  The present invention also includes novel compounds of formula (III), including but not limited to pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them in combination with other active ingredients provide.

本発明はまた、上で定義した式（ＩＩＩ）の化合物、それらの塩、およびそれらの薬学的に受容可能な組成物を調製する方法を提供する。

The present invention also provides a method for preparing the compounds of formula (III) as defined above, their salts, and their pharmaceutically acceptable compositions.

  The present invention also contains novel compounds of formula (IV), their pharmaceutically acceptable salts, and one or more of such compounds, optionally in combination with other active ingredients. A pharmaceutical composition is provided.

本発明はまた、上で定義した式（ＩＶ）の化合物、それらの塩、およびそれらの薬学的に受容可能な組成物を調製する方法を提供する。

The present invention also provides methods for preparing the compounds of formula (IV) as defined above, their salts, and their pharmaceutically acceptable compositions.

  The present invention relates to novel compounds of formula (V), pharmaceutically acceptable salts thereof, and medicaments containing one or more of such compounds, optionally in combination with other active ingredients A composition is provided.

本発明はまた、上で定義した式（Ｖ）の化合物、それらの薬学的に受容可能な塩、およびそれらの薬学的に受容可能な組成物を調製する方法を提供する。

The invention also provides methods of preparing the compounds of formula (V) as defined above, their pharmaceutically acceptable salts, and their pharmaceutically acceptable compositions.

  According to one aspect of the present invention, a method of using a compound of formula (I) includes treating and / or preventing an inflammatory condition (eg, mediated by AGE or glycated protein accumulation). Such inflammatory conditions include diabetic vascular complications (including retinopathy, microvascular disorders, renal failure and Alzheimer's disease).

  According to another aspect of the present invention, a method of inhibiting smooth muscle cell proliferation comprises administering an effective amount of a compound contemplated by the present invention. The invention also provides a method of blocking an inflammatory response (including an inflammatory response in endothelial cells), the method comprising administering an effective amount of a compound contemplated by the present invention. The present invention also provides a method of inhibiting thrombosis, the method comprising administering an effective amount of a compound contemplated by the present invention.

  The present invention also provides a method of treating or preventing organ transplant vascular disorders in a subject, the method comprising administering an effective amount of a compound contemplated by the present invention. Organs to be transplanted can include, but are not limited to, liver, kidney, heart, lung, pancreas, islet and skin. Such methods can further include administering a therapeutically or prophylactically effective amount of an immunosuppressive drug. This immunosuppressive drug may include, but is not limited to, CellCept, Gengraf, Microgam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, Zenapax.

  The present invention also provides a method of treating or preventing restenosis in a subject, the method comprising administering an effective amount of a compound contemplated by the present invention. The present invention also provides a method of treating or preventing atherosclerosis in a subject, the method comprising administering an effective amount of a compound contemplated by the present invention.

  The present invention also provides a method of treating a disease mediated by inflammation in a subject, the method comprising administering an effective amount of a compound contemplated by the present invention. More specifically, the disease mediated by inflammation may be an autoimmune disease. This autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune Addison disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, vesicular pemphigoid, cardiomyopathy , Celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scar pemphigoid, crest syndrome, cold agglutinin disease, Crohn's disease, circle Plate lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, Insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, meniere disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia Polyarteritis, polychondritis, polyglandular syndrome, rheumatic polymyalgia, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter syndrome, Rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, systemic stiffness syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, It can be vitiligo and Wegner granulomatosis.

  The present invention further provides a method of treating or preventing cancer in a subject, the method comprising administering an effective amount of a compound contemplated by the present invention. Furthermore, the present invention provides a method of treating or preventing metastasis in a subject, the method comprising administering to the subject an effective amount of a compound contemplated by the present invention.

  Yet another aspect of the present invention provides a method by using a compound of formula (I), which also treats and / or prevents a proliferative condition (in particular, inhibits smooth muscle cell proliferation). The method comprises administering a composition comprising a compound of formula (I). According to the present invention, the use of such compositions includes preventing and treating vascular occlusion conditions (including atherosclerosis and restenosis).

  Yet another aspect of the present invention provides methods for treating and / or preventing diseases mediated by inflammatory and cell proliferative conditions by using compounds of formula (I).

  Yet another aspect of the present invention provides for treating and / or preventing diseases or disorders mediated by cell adhesion molecules such as VCAM-1, wherein these diseases are rheumatoid arthritis, osteoarthritis Inflammatory disorders selected from asthma, dermatitis, psoriasis, organ transplant or allograft rejection, autoimmune diabetes or multiple sclerosis; atherosclerosis, autoimmune diabetes or multiple sclerosis; restenosis, coronary artery A cardiovascular disease selected from diseases, angina pectoris, dyslipidemia, small arterial disease, diabetes mellitus, diabetic nephropathy or diabetic retinopathy, one of these cell adhesion molecules is VCAM-1 It is.

  Yet another aspect of the invention treats and / or prevents the disease by delivering a compound of formula (I) at the site of the disease by using a stent coated with the compound of formula (I). To provide that.

  The present invention further provides pharmaceutical compositions, which are generally combined with a suitable carrier, solvent, diluent or vehicle typically used in preparing such compositions. Contains the compounds of formula (I), their salts or any mixtures thereof.

  The present invention further provides various compounds and compositions that can be administered by the following routes, respectively: oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral. Intracavity, intracavity, intracerebral membrane, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, pelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, lung Internal, rectal, intrarenal, intraretinal, intraspinal, synovial, intrathoracic, intrauterine, intravesical, vaginal, rectal, intraoral, sublingual, intranasal or transdermal.

  The compositions of the present invention may also contain formulations of the disclosed compounds, which may be oral, rectal, intraocular (including intravitreal or intracameral), topical (buccally and sublingually). Including), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal and epidural) administration may be suitable. These formulations may conveniently be presented in unit dosage form and prepared by convenient pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient with the pharmaceutical carrier or excipient. In general, these formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. .

  Yet another aspect of the present invention provides novel intermediates, methods for their preparation, and methods for preparing compounds of formula (I), their salts, and their pharmaceutically acceptable salts.

(Definition)
It should be understood that the present invention is limited to the particular methodologies, protocols, cell lines, constructs and reagents described herein, but can itself be varied. Also, the terminology used herein is monochromatic describing only a particular aspect and is not to be construed as limiting the scope of the invention (which is limited only by the appended claims). .

  As used herein and in the appended claims, the singular forms “a”, “an”, and “the”, unless the context clearly indicates that the plural is not included. Includes plural display. Thus, for example, reference to a compound (“a compound”) is a reference to one or more such compounds, and includes equivalents thereof known to those skilled in the art, and the like.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art at the time this invention was made.

  All publications and patents mentioned in this specification describe, for example, constructs and methodologies described in those publications that can be used in connection with the invention described herein. For the purposes of disclosure, it is incorporated herein by reference. Publications discussed above and throughout the headquarters are provided for their disclosure prior to the filing date of the present application. It should not be construed herein that there is an admission that the inventors are not entitled to preclude such disclosure based on the prior art.

  As used herein, the term “compound” includes any single element or combination of elements, including both singular and plural, and having activity that can be measured in the assays of the present invention. , Fragments, analogs or derivatives.

  As used herein, the term “glycated protein” is either enzymatic or non-enzymatic, mainly the condensation of free ε-amino groups and glucose (Amadori addition) in the protein. A protein linked to glucose. Furthermore, glycated proteins, as used herein, not only proteins containing these initial glycation products, but also additional reactions (eg, reconstitution, dehydration, and irreversibly advanced glycation) Also included are saccharification products obtained from condensation to form end products (AGE). It should be understood that any reagent that causes the cells or components of the assay to respond in a measurable manner is contemplated by the present invention. Improved formation and accumulation of glycated proteins and AGEs are believed to play an important role in the pathogenesis of diabetic complications and atherosclerosis, which is a range of diabetic complications (nephropathy, retinopathy). And the onset of neuropathy). Diabetes-related complications are due to (1) blocking glycation of the protein, (2) breaking the crosslinks in the glycated protein (crosslinking breaker N-phenacylthiazolium bromide is a late vascular glycation There is sufficient in vivo evidence to suggest that it can be reduced by blocking the interaction of the glycated protein with the receptor; Diabetologia., 2000 (43) 660-4), or (3) blocking the interaction of the glycated protein with the receptor Yes. Despite the importance of AGE in the pathogenesis of diabetic microangiopathy, there are no currently available pharmaceuticals known to block AGE formation.

The term “phenylamine” means a primary or secondary benzenamine, which is more commonly known as aniline. The amino group of the aniline can be optionally substituted with hydrogen, alkyl (C ₁ -C ₁₂ , linear or branched), cycloalkyl (C ₃ -C ₁₀ ), or aryl-substituted aryl group. The phenyl ring of the aniline derivative can be optionally substituted with one or more functional groups or combinations of functional groups (eg, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, Alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amide, sulfonamide, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyroyl, pyrazoyl, Phosphate, phosphonic acid or phosphonate). These groups can be represented in the protected or unprotected form used in standard organic synthesis, if applicable.

  The term “naphthylamine” means a primary or secondary α- or β-naphthylamine. The ring substructure of naphthylamine is optionally substituted with one functional group or combination of functional groups (eg, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, Haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amide, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyroyl, pyrazoyl, phosphate, Phosphonic acid or phosphonate). These groups can be represented in the protected or unprotected form used in standard organic synthesis.

  The term “naphthylalkylamine” means primary or secondary α- and β-naphthylalkylamines (eg, 2-α-naphthylethylamine). The term “benzalkylamine” means a primary or secondary benzylalkylamine (eg, phenylethylamine). These arylalkyl structures or compounds can be optically active or optically inactive. The aryl (ring) substructures of naphthylalkylamines and benzalkylamines can optionally be a single functional group or combination of functional groups (eg, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, Hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amide, sulfonamide, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl , Furanyl, pyroyl, pyrazoyl, phosphate, phosphonic acid or phosphonate). These groups can be represented in the protected or unprotected form used in standard organic synthesis.

  The term “quinolinylamine” means a primary or secondary quinolylamine. These amines can be optically active or optically inactive. The aryl (ring) substructure of the quinolylamine is optionally substituted with one functional group or combination of functional groups (eg, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, Aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amide, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyroloyl, pyrazoyl , Phosphate, phosphonic acid or phosphonate). These groups can be represented in the protected or unprotected form used in standard organic synthesis.

  The term “heteroarylamine” means pyrrole, pyrazole, imidazole and indole. The aryl (ring) substructure of the heteroarylamine is optionally substituted with one functional group or combination of functional groups (eg, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, Alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amide, sulfonamide, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, phosphate, phosphonic acid or phosphonate) Can be substituted. These groups can be represented in the protected or unprotected form used in standard organic synthesis.

  The term “polynucleotide” generally refers to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, the term includes, but is not limited to: single-stranded, double-stranded or multi-stranded DNA or RNA. The polynucleotide may further comprise genomic DNA, cDNA or DNA-DNA hybrid. Furthermore, the polynucleotides of the invention can be produced synthetically.

  A polynucleotide may comprise nucleotides that are chemically modified, biochemically modified, or derivatized. For example, a polynucleotide can include partially modified nucleotides (eg, methylated nucleotides) or nucleotide analogs. A polynucleotide may also contain sugars, caps, nucleotide branches, and linking groups such as fluororibose and thioate. Furthermore, the sequence of nucleotides can be interrupted by non-nucleotide components. In addition, the polynucleotide can be modified after polymerization to facilitate its binding to other polynucleotides, proteins, metal ions, labeling components or solid supports.

  The backbone of the polynucleotide may include modified and optionally substituted sugar and / or phosphate groups. Alternatively, the backbone of the polynucleotide can comprise a polymer of synthetic subunits (phosphoramidites) and can thus be an oligodeoxynucleoside phosphoramidite or a mixed phosphoramidite-phosphodiester oligomer. Peyrottes et al., NUCL. ACIDS RES. (1996) 24: 1841-1848, and Chaturvedi et al., NUCL. ACIDS RES. (1996) 24: 2318-2323.

  The term “homology” as used herein refers to a degree of complementarity. There may be partial homology or complete complementarity (ie identity). A partially complementary sequence is a sequence that at least partially inhibits the hybridization of the same sequence to a target polynucleotide; this is referred to using the functional term “substantially homologous”. . Inhibition of hybridization of a perfectly complementary sequence to a target sequence can be tested using hybridization assays (Southern or Northern blots, solution hybridization) under conditions of low stringency. A substantially homologous sequence or probe competes or inhibits binding of a fully homologous sequence or probe to a target sequence (ie, hybridization) under conditions of low stringency. This is, of course, a low stringency condition that allows non-specific binding; a low stringency condition is specific for binding of two sequences to each other (ie, selective). It needs to be an interaction. The absence of non-specific binding can be tested by the use of a second target sequence that lacks even a partial degree of complementarity (eg, less than about 30% identity); if there is no non-specific binding The probe does not hybridize to the second non-complementary target sequence.

  The term “gene” refers to a polynucleotide sequence that includes a coding sequence that is required for the production of a polypeptide or precursor, and may also include regulatory sequences. A polypeptide can be encoded by a full-length coding sequence or any portion of a coding sequence. A gene may be, in whole or in part, any source known to those skilled in the art (plant, fungus, animal, bacterial genome or episome, nuclear DNA or plasmid DNA, cDNA, viral DNA or chemically synthesized DNA. Derivatized). A gene can be composed of uninterrupted coding sequences or can include one or more introns joined by appropriate splice junctions. In addition, a gene may contain one or more modifications in either the coding region or the untranslated region, which may be a specific function of the polynucleotide or polypeptide (eg, biological activity or chemistry of the expression product). Structure, rate of expression, or mode of expression control). Such modifications include, but are not limited to, one or more nucleotide mutations, insertions, deletions and substitutions. In this regard, a modified gene can be referred to as a “variant” of a “native” gene (described below).

  “Gene expression” refers to the process by which a polynucleotide sequence undergoes successful transcription and translation such that a detectable level of the nucleotide sequence is expressed.

  The term “gene expression profile” refers to a group of genes that, in any activated state, represent a particular cell or tissue type (eg, neuron, coronary artery endothelium or diseased tissue). In one aspect, gene expression profiles are generated from cells exposed to the compounds of the invention. This profile can be compared with gene expression profiles made from the same type of cell type prior to treatment with the compounds of the invention. In addition, a series of gene expression profiles can be generated from cells treated with a compound of the invention, particularly at different doses or time courses, to assess the effect of the compound. A gene expression profile is also known as a gene expression signature.

  The term “differential expression” refers to both quantitative and qualitative differences in the temporal tissue expression pattern of a gene. For example, a differentially expressed gene can have its activated or fully inactivated expression in steady state versus disease state. Such qualitatively regulated genes can exhibit expression patterns that are detectable in a given tissue or cell type, either in a control or disease state, but not both. “Differentially expressed polynucleotide” as used herein refers to the detection of a differentially expressed polynucleotide in a sample resulting in a differentially expressed gene in the sample. Refers to a polynucleotide sequence that uniquely identifies a differentially expressed gene as correlated with the presence of.

  Similarly, a differentially expressed protein can have its activated or fully inactivated expression in steady state versus disease state. Such qualitatively regulated proteins can exhibit an expression pattern that is detectable in a given tissue or cell type, either in a control or disease state, but not both. “Differentially expressed protein” as used herein, the detection of a differentially expressed protein in a sample is the presence of a differentially expressed protein in the sample. Refers to an amino acid sequence that uniquely identifies differentially expressed proteins.

  As used herein, “cell type” refers to a cell from a given source (eg, tissue or organ), a cell in a given differentiation state, or a cell with a given pathology or genetic structure. Say.

  The term “polypeptide” refers to a polymeric form of amino acids of any length, which amino acids are translated amino acids, untranslated amino acids, chemically modified amino acids, biochemically modified amino acids, and It may contain derivatized amino acids. The polypeptide can be naturally occurring, a recombinant polypeptide, a synthetic polypeptide, or any combination thereof.

  Furthermore, as used herein, the term “polypeptide” refers to proteins, polypeptides, and peptides having any size, structure, or function. For example, a polypeptide can contain a series of amino acids linked by peptide bonds. Alternatively, a polypeptide may contain long chain amino acids joined by peptide bonds. In addition, a polypeptide may also contain fragments of naturally occurring proteins or peptides. A polypeptide may be a single molecule or a complex of multiple molecules. Furthermore, such polypeptides can have a modified peptide backbone.

  The term “polypeptide” further comprises immunologically tagged proteins and fusion proteins (fusion proteins with heterologous amino acid sequences, fusion proteins with heterologous leader sequences and homologous leader sequences, and an N-terminal methionine residue. Fusion proteins may or may not be included).

  The term “protein expression” refers to the process by which a polynucleotide sequence is successfully transcribed and translated so that a detectable level of amino acid sequence or protein is expressed.

  The term “protein expression profile” refers to a group of proteins that present a particular cell type or tissue type (eg, neuron, coronary artery endothelium, or diseased tissue). In one aspect, the protein expression profile is generated from cells that have been exposed to a compound of the invention. This profile can be compared to a protein expression profile generated from the same type of cells prior to treatment with a compound of the invention. In addition, a series of protein expression profiles can be generated from cells that have been treated with a compound of the invention (specifically at various doses or time courses to assess the effect of the compound). Protein expression profiles are also known as “protein expression signatures”.

  As used herein, “biomolecule” includes polynucleotides and polypeptides. Further, as used herein, “biomolecule sequence” is a term that refers to all or part of a polynucleotide sequence. A biomolecular sequence also refers to all or a portion of a polypeptide sequence.

  As used herein, a “host cell” is a microorganism, prokaryote, cultured as a unicellular body that can be used or used as a recipient for other transfer of recombinant vectors or polynucleotides. A cell, eukaryotic cell, or cell line, including the progeny of the original cell being transfected. It is understood that the unicellular progeny need not be completely identical in form or DNA complement or total DNA complement with the original parent due to natural, accidental or intentional mutations. The

  In the context of biomolecules (eg, perlecan), the term “functional equivalent” refers to a functional property that is substantially similar to all or a portion of a natural perlecan protein or a polynucleotide encoding a natural perlecan, or A protein or polynucleotide molecule having structural characteristics. A functional equivalent of a native perlecan protein can include modifications that depend on the need for such modifications for the performance of a particular structure or function. The term “functional equivalent” refers to a “fragment”, “variant”, “derivative”, “allele”, “hybrid”, “variant”, “analog”, or “chemical derivative” of natural perlecan. It is intended to include.

In the context of immunoglobulins, the term “functional equivalent” refers to an immunoglobulin molecule that exhibits immunological binding properties that are substantially similar to the parent immunoglobulin. As used herein, the term “immunological binding property” is a type of non-covalent interaction that occurs between an immunoglobulin molecule and an antigen specific for the immunoglobulin molecule. In practice, a functional equivalent of a monoclonal antibody immunoglobulin can, for example, inhibit the binding of a parent monoclonal antibody to its antigen. Functional equivalents are F (ab ′) ₂ fragments, F (ab) molecules, Fv fragments, signal chain fragments (scFv variably displayed on phage) as long as the immunoglobulin exhibits the properties of the parent immunoglobulin. ), Signal domain antibodies, chimeric antibodies and the like.

  As used herein, the term “isolated” refers to a polynucleotide, polypeptide, antibody, or polynucleotide, polypeptide, antibody that is in an environment different from the environment in which the host cell naturally occurs. Or a host cell. In general, an isolated polynucleotide, polypeptide, antibody, or host cell is substantially purified.

  As used herein, the term “substantially purified” is taken from its natural environment and is free of at least about 60% of other compounds with which the compound is naturally associated, At least about 65% free, at least about 70% free, at least about 75% free, at least about 80% free, at least about 83% free, at least about 85% free, or at least about 88% free, at least about 90% free, at least about 91% free, at least about 92% free, at least about 93% free, at least about 94% free, or at least about 95% free Free, at least about 96% free, at least about 97% free, at least about 98% free, or at least about 99% free Or, does not contain at least about 99.9%, it refers to a compound that does not contain at least about 99.99%. For example, a composition containing A is “substantially free” of B if at least 85% by weight of the total of A + B in the composition is A. Alternatively, A represents at least 90% by weight of the sum of A + B in the composition, and even more at least 95% or even 99% by weight.

  As used herein, “diagnosis” generally includes determining a subject's susceptibility to a disease or disorder, determining whether a subject is currently suffering from a disease or disorder, disease Or prognosis of a subject affected by a disorder (e.g., identifying pre-metastatic or metastatic cancer status, stage of cancer, or cancer responsiveness to treatment) and therapeutic (e.g., Subject status monitoring to provide information on therapeutic efficacy or efficacy.

  The term “biological sample” includes various sample types obtained or derived from organisms that can be used in diagnosis, monitoring, or other assays. This term refers to biological blood, serum, plasma, cells, proteins, carbohydrates, nucleic acids, urine, nasal discharge, mucosal secretions, cellular fluids, cellular exudates and other fluid samples, solid tissue samples (e.g. Biopsy specimen), or tissue culture or cells from tissue culture and their progeny. The term specifically includes clinical samples and further includes cells in cell cultures, cell supernatants, cell lysates, amniotic fluid, biological fluids, and tissue samples. The term also includes samples that have been manipulated in any way after acquisition (eg, treatment with reagents, solubilization, or enrichment for a particular component). The biological sample may be derived directly from an organism or collected from the environment.

  The terms “individual”, “subject”, “host” and “patient” mean any subject seeking diagnosis, treatment or therapy. The individual, subject, host or patient is a human, as appropriate. Other subjects include, but are not limited to, cows, horses, dogs, cats, guinea pigs, rabbits, rats, primates and mice.

  The terms “treatment”, “treating” and “treatment” are generally used herein to mean obtaining a desired pharmacological and / or physiological effect. This effect may be prophylactic in that the disease or its symptoms may be completely or partially prevented and / or partial or complete stabilization or healing of the disease and / or adverse effects attributable to the disease. It can be therapeutic in that it can. As used herein, “treatment” includes any treatment of a disease in a mammal (particularly a human), including the following: (a) Although susceptible to infection with a disease or condition Preventing the disease or symptom from developing in a subject who has not yet been diagnosed as suffering; (b) suppressing the symptom of the disease (ie, preventing its progression); or ( c) alleviating the symptoms of the disease (ie, causing regression of the disease or symptoms).

  The expression “therapeutically effective amount” refers to the amount of a compound that is effective in preventing, ameliorating, treating or delaying a sign of a disease or condition, for example, contemplated by the present invention.

  “Prophylactically effective amount” refers to an amount of a compound that is effective in preventing a disease or condition, eg, as contemplated by the present invention.

  “Liposomes” are small vesicles composed of various types of lipids, phospholipids, and / or surfactants useful for delivery of drugs to mammals. The compounds of the present invention can be delivered by liposomes. Liposome components are generally arranged in a bilayer configuration, similar to the lipid arrangement of biological membranes.

  Broadly "hybridization" refers to any process by which a polynucleotide sequence binds to a complementary sequence through base pairing. Hybridization conditions are defined by, for example, the prehybridization solution and the concentration of salt or formamide in the hybridization solution, or the hybridization temperature, which is well known in the art. Hybridization can occur under various stringency conditions. Hybridization can also mean binding of a protein capture agent to a target protein under certain conditions (eg, standard physiological conditions).

  As understood herein, the term “activation” refers to a signal pathway or biological response (eg, increased basal levels as described above, restored basal levels from an inhibitory state, and basal levels as described above). Any change in the path).

  The term “biological activity” refers to the biological behavior and effects of a protein or peptide. The biological activity of a protein can be affected at the cellular and molecular level. For example, the biological activity of a protein can be affected by changes at the molecular level. For example, antisense oligonucleotides can prevent translation of a particular mRNA, thereby inhibiting the biological activity of the protein encoded by that mRNA. Furthermore, an antibody can bind to a particular protein and inhibit the biological activity of that protein.

  As used herein, the term “oligonucleotide” refers to a polynucleotide sequence comprising, for example, from about 10 nucleotides (nt) to about 1000 nt. Oligonucleotides for use in the present invention are, for example, from about 15 nt to about 150 nt in length, or from about 150 nt to about 1000 nt. The oligonucleotide may be a naturally occurring oligonucleotide or a synthetic oligonucleotide. Oligonucleotides can be synthesized using the phosphoramidite method (Beaucage and Carruthers, Tetrahedron Lett. (1981) 22: 1859-1862) or the triester method (Mattuccii et al., J. Am. Chem. Soc. (1981) 103: 3185), Alternatively, it can be prepared by other chemical techniques known in the art.

  The term “microarray” generally refers to the type of gene or protein represented on the microarray by an oligonucleotide (polynucleotide sequence) or protein binding agent, where the type of gene or protein represented on the microarray is , Depending on the intended purpose of the microarray (eg, monitoring the expression of a human gene or protein). The oligonucleotides or protein binding agents in a given microarray can correspond to the same type, category, or group of genes or proteins. A gene or protein is a species of origin (eg, human, mouse, rat); disease state (eg, cancer); function (eg, protein kinase, tumor suppression); the same biological process (eg, apoptosis, signal It may be considered the same type if it shares some general properties such as introduction, cell cycle regulation, proliferation, differentiation). For example, one microarray type can be a “cancer microarray” in which each microarray oligonucleotide or protein binding agent corresponding to a gene or protein associated with cancer is present. An “epithelial microarray” can be a microarray of oligonucleotide or protein binding agents corresponding to a unique gene or protein. Similarly, a “cell cycle microarray” can be a microarray type in which the oligonucleotide or protein binding agent corresponds to a unique gene or protein associated with the cell cycle.

  The term “detectable” refers to standard techniques of polymerase chain reaction (PCR), reverse transcription (RT) -PCR (RT-PCR), differential display, and Northern analysis (these are known to those skilled in the art. Polynucleotide expression pattern detectable by (well-known). Similarly, polypeptide expression patterns can be “detected” by standard techniques, including immunoassays such as Western blots.

  “Target gene” refers to a polynucleotide (often a polynucleotide from a biological sample) designed to specifically hybridize with an oligonucleotide probe. It is either the presence or absence of the target polynucleotide to be detected, or the amount of target polynucleotide to be quantified. The target polynucleotide has a sequence that is complementary to the polynucleotide sequence of the corresponding probe directed to the target. A target polynucleotide can also mean a specific sequence of a larger polynucleotide from which the probe is directed, or the entire sequence (eg, gene or mRNA) for which it is desired to detect its expression level.

  "Target protein" refers to a polypeptide (often a polypeptide derived from a biological sample) to which a protein capture agent specifically hybridizes or binds. It is either the presence or absence of the target protein to be detected, or the amount of target protein to be quantified. The target protein has a structure that is recognized by the corresponding protein capture agent directed to the target. A target protein or amino acid can also refer to a larger protein-specific structure from which a protein capture agent is derived, or an overall structure (eg, a gene or mRNA) for which its expression level is desired to be detected.

  The term “complementary” refers to the topological compatibility or matching of the interaction surface between the probe molecule and its target. The target and its probe can be described as complementary, and furthermore, the contact surface properties are complementary to each other. For example, the hybridization or base pairing of nucleotides or nucleic acids is complementary, such as between two strands of a double-stranded DNA molecule, or between an oligonucleotide probe and a target.

  The term “background” refers to, for example, non-specific binding or other interaction between polynucleotides, between polypeptides, between small molecules and polypeptides, or between small molecules and polynucleotides. “Background” can also mean non-specific binding or other interactions in the context of assays (including immunoassays).

  In the microarray context, the term “background” refers to between a labeled target polynucleotide and a component of an oligonucleotide microarray (eg, oligonucleotide probe, control probe, microarray substrate) or between a target protein and a protein microarray protein. A hybridization signal resulting from non-specific binding or other interactions with a binding agent. A background signal can also be generated by the intrinsic fluorescence of the microarray component itself. A single background signal may be calculated for the entire microarray, or various backgrounds may be calculated for each target polynucleotide or target protein. The background may be calculated as the average hybridization signal intensity, or various background signals may be calculated for each target gene or target protein. Alternatively, the background may be a probe that is not complementary to any sequence found in the sample (eg, an opposite sense polynucleotide or a gene not found in the sample (eg, if the sample is a mammalian polynucleotide) Or the average hybridization signal intensity generated by hybridization to a probe) directed to a bacterial gene). The background can also be calculated as the average signal intensity generated by a region of the microarray that has no probe or protein binding agent at all.

  “Small molecule” refers to a complex of compounds or molecules consisting of carbon, hydrogen, oxygen, and nitrogen, either synthetically derived from nature or partially synthetic. These may also include other elements and are less than about 15,000, less than about 14,000, less than about 13,000, less than about 12,000, less than about 11,000, Less than 000 dalton, less than about 9,000 dalton, less than about 8,000 dalton, less than about 7,000 dalton, less than about 6,000 dalton, less than about 5,000 dalton, less than about 4,000 dalton, about 3,000 Less than Dalton, less than about 2,000 Dalton, less than about 1,000 Dalton, less than about 900 Dalton, less than about 800 Dalton, less than about 700 Dalton, less than about 600 Dalton, less than about 500 Dalton, less than about 400 Dalton, about 300 Dalton May have a molecular weight of less than, less than about 200 daltons, or less than about 100 daltons.

  The term “fusion protein” refers to a protein composed of two or more polypeptides, which are not typically linked in their native state, but their respective amino acids via peptide bonds. It is linked by a terminus and a carboxy terminus. The two or more polypeptide components are linked directly or indirectly via a peptide linker / peptide spacer.

  The term “normal physiological state” means a state that is unique within a living organism or cell. Some organs or organisms provide extreme conditions, but the organism's environment and intracellular environment usually changes and dominates around pH 7 (ie, pH 6.5-7.5). It contains water as a solvent and exists at a temperature above 0 ° C. and below 50 ° C. The concentration of the various salts depends on the referenced organ, organism, cell or cellular component.

  The term “cluster” is a group of clones or biomolecule sequences that are related to each other by sequence homology. In one example, clusters are formed based on specific stages of homology and / or overlap (eg, stringency). “Clustering” can be performed on sequence data. For example, a biomolecular sequence as being associated with a particular molecular or biological activity in a tissue is compared against another library or database of sequences. This type of search is useful for searching for homologous sequences in other tissues or samples or sequences that are considered functionally related, and this type of search can be performed on databases that have one or more clusterings. Used to streamline the present invention in that the biomolecule sequences can be clustered and then the method of the present invention can be performed. A sequence showing sufficient homology in its representative sequence is considered part of a “cluster”. Such “sufficient” homology can vary within the requirements of one skilled in the art.

  As used herein, the term “internal database” refers to a database maintained within a local computer network. This includes, for example, biomolecular sequences associated with the project. The database may include information related to the sequence (including but not limited to libraries in which a given sequence is found) and descriptive information about similar genes associated with the sequence. This internal database is maintained, if necessary, as a private database behind a barrier in the corporate network. However, the present invention contemplates an internal database available to the general public. This internal database may include sequences generated by the same company that maintains the database, and may also include sequences obtained from external sources.

  The term “external database” as understood herein refers to a database located outside of all internal databases. Typically, a corporate network that is different from a corporate network that maintains the internal database maintains the external database. This external database can be used, for example, to provide some descriptive information about the biomolecule sequences stored in the internal database. For example, its external database is maintained by Genbank and the National Center for Biotechnology Information (NCBI), which is part of the National Library of Medicine, a division of the National Library of Medicine. It is a related database.

(Detailed description of the invention)
The present invention relates to compounds of formula (I), analogs thereof, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. About. Furthermore, the present invention relates to compounds of formula (I), analogs thereof, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvents. The present invention relates to a pharmaceutical composition containing a Japanese product either individually or in any combination thereof. Furthermore, the present invention relates to compounds of formula (I), analogs thereof, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvents. It relates to a method of using Japanese products either individually or in any combination thereof. Furthermore, the present invention relates to compounds of formula (I), analogs thereof, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts thereof and pharmaceutically acceptable The present invention relates to a method for producing a solvate.

(Compound of general formula (I))
The present invention relates to compounds of formula (I) and to compositions and / or methods containing compounds that are effective in modulating inflammatory responses such as those resulting from AGE and glycated protein accumulation. The present invention also relates to compositions and / or methods containing compounds that are effective in modulating smooth muscle cell proliferation and related diseases or conditions.

  According to one aspect of the present invention, various compounds of general formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable Solvates are provided:

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According to this aspect,

は、

Is

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ここで、Ｌは、

It is. In this and other aspects,
Where L is

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And Q is

である。

It is.

R ¹ , R ² and R ³ are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy Group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, heterocyclyl group, Heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl Group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, carboxylic acid or derivatives thereof, Or a sulfonic acid or derivative thereof, wherein any ^{two of} R ¹ , R ² and R ³ are combined to form a 5- or 6-membered saturated cyclic ring, as appropriate, The saturated cyclic ring has 1 to 3 heteroatoms, where the heteroatom is O, S or N. The cyclic ring formed by any ^{two of} R ¹ , R ² or R ³ can be oxlanyl, 1,3-dioalanyl or 1,4-dioalanyl.

R ⁴ is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group, Alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclenyl group, Heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonate Group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, aryloxy An alkyl group, an aralkoxyalkyl group, a condensed heteroarylcycloalkyl group, a condensed heteroarylcycloalkenyl group, a condensed heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof.

Any of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halogen, nitro group, amino group, mono-substituted or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, if necessary , Cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl Group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio Group or heterocyclylsulfonyl group The group is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, wherein the heterocyclic group is optionally An optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group.

According to this and other aspects, A, B, D and J are independently O, S, N,> CH or — (CH ₂ ) _n —; “----” is optional E is O, S or —NR; K is N, C or CH; Y and Z are independently O, —NR, — (CH ₂ ) _u — or is S (= _{O) u;} G _{is, - (CH 2) s -} , - (CH 2) s -CH = CH- (CH 2) s - or - _{(CH 2)} s -C≡C- ₍ CH ₂ ) _s ; X, X ₁ , X ₂ , X ₃ and X ₄ are independently O, S or —NR; F is O, S or —NR; Y ¹ and Y ² is independently O or S; n, w, u are independently integers from 0 to 2; p, t, m, s, v are independently integers from 0 to 5. Yes; "Ar" is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group.

R and R ⁵ are each independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, An acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group;

The groups provided above are as follows:
A “halogen” group is fluorine, chlorine, bromine or iodine.

An “alkyl” group is a straight or branched (C ₁ -C ₁₀ ) alkyl group. Representative alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl.

A “cycloalkyl” group is a (C ₃ -C ₁₀ ) cycloalkyl group, which can be monocyclic or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

“Alkoxy” is (C ₁ -C ₁₀ ) alkyl-O—, wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy.

“Cycloalkoxy” is a (C ₃ -C ₁₀ ) cycloalkoxy group. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.

“Alkenyl” is a (C ₂ -C ₆ ) alkenyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl.

“Cycloalkenyl” is a (C ₃ -C ₇ ) cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl.

“Alkoxyalkyl” is a (C ₁ -C ₆ ) alkoxy (C ₁ -C ₁₀ ) alkyl group, wherein the alkoxy and alkyl groups are as defined above. Representative alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl.

“Alkenyloxy” is (C ₂ -C ₆ ) alkenyl-O—, wherein the (C ₂ -C ₆ ) alkenyl group is as defined above. Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy.

“Cycloalkenyloxy” is (C ₃ -C ₇ ) cycloalkenyl-O—, wherein the (C ₃ -C ₇ ) cycloalkenyl group is as defined above. Exemplary cycloalkenyloxy groups include cycloethenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy.

“Acyl” is H—CO— or (C ₁ -C ₁₀ ) alkyl-CO—, wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Representative acyl groups include acetyl and propionyl.

“Acyloxy” is (C ₁ -C ₆ ) acyl-O—, wherein the acyl group is as defined above. Representative acyloxy groups include acetyloxy and propionyloxy.

  “Aryl” is a monocyclic or polycyclic ring system having about 5 to 14 carbon atoms. Representative groups include phenyl and naphthyl.

  “Aryloxy” is an aryl-O— group in which the aryl group is as defined above. Representative aryloxy groups include phenoxy, naphthyloxy, and the like.

  “Aroyl” is an aryl-CO— group in which the aryl group is as defined above. Representative aroyl groups include benzoyl and 1-naphthoyl.

  “Aroyloxy” is an aroyl-O— group in which the aroyl group is as defined above. Representative aroyloxy groups include benzoyloxy and 1-naphthoyloxy.

“Aralkyl” is an aryl- (C ₁ -C ₁₀ ) alkyl group, wherein the aryl group and (C ₁ -C ₁₀ ) alkyl group are as defined above. Representative aralkyl groups include benzyl and 2-phenylethyl.

“Aralkenyl” is an aryl- (C ₂ -C ₆ ) alkenyl group, wherein the aryl group and (C ₂ -C ₆ ) alkenyl group are as defined above.

“Aralkynyl” is an aryl- (C ₂ -C ₆ ) alkynyl group, wherein the aryl group is as defined above.

  “Aralkoxy” is an aralkyl-O— group in which the aralkyl group is as defined above. Representative aralkoxy groups include benzyloxy and 2-phenethyloxy.

  “Heterocyclyl” is a non-aromatic saturated monocyclic or polycyclic ring system having from about 5 to about 10 carbon atoms, which has at least one heteroatom and the heteroatom Is selected from O, S or N. Exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl.

  “Heterocyclenyl” is a non-aromatic mono- or polycyclic hydrocarbon ring system having from about 5 to 10 carbon atoms, which comprises at least one heteroatom and one double bond. And the heteroatom is selected from O, S or N. Exemplary heterocyclenyl groups include 1,2,3,4-tetrahydropyrimidine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5, Examples include 6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, and 2-pyrazolinyl.

  “Heteroaryl” is an aromatic monocyclic or polycyclic ring system having about 5 to about 10 carbon atoms, which has at least one heteroatom, which is , O, S or N. Exemplary heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxole, 1,3-benzoxiathiol, quinazolinyl, pyridyl, And thiophenyl.

“Heteroaralkyl” is a heteroaryl- (C ₁ -C ₁₀ ) alkyl group in which the heteroaryl and (C ₁ -C ₁₀ ) alkyl groups are as defined above. Representative heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl.

  “Heteroaryloxy” is heteroaryl-O—, wherein the heteroaryl group is as defined above. Exemplary heteroaryloxy groups include pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, phthalazinyloxy, indolyloxy, quinazolinyloxy, pyridyloxy, thienyloxy.

  “Heteroaralkoxy” is heteroaralkyl-O—, wherein the heteroaralkyl group is as defined above. Representative heteroaralkoxy groups include thienylmethyloxy and pyridylmethyloxy.

“Alkylcarbonyl” or “acyl” is (C ₁ -C ₁₀ ) alkyl-CO—, wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Representative alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl.

“Alkoxycarbonyl” is (C ₁ -C ₁₀ ) alkyl-O—CO—, wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl.

  “Arylcarbonyl” or “aroyl” is aryl-CO—, wherein the aryl group is as defined above. Representative arylcarbonyl groups include phenylcarbonyl and naphthylcarbonyl.

  “Aryloxycarbonyl” is aryl-O—CO—, wherein the aryl group is as defined above. Representative aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl.

“Aralkoxycarbonyl” is aryl- (C ₁ -C ₆ ) alkoxy-CO—, wherein aryl and (C ₁ -C ₆ ) alkoxy are as defined above. Representative aralkoxycarbonyl groups include benzyloxycarbonyl and 2-phenethyloxycarbonyl.

  “Heteroarylcarbonyl” is heteroaryl-CO—, wherein heteroaryl is as defined above. Exemplary heteroarylcarbonyl groups include pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl.

“Alkylsulfonyl” is (C ₁ -C ₁₀ ) alkylsulfonyl, wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Representative alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl.

“Arylsulfonyl” is aryl-SO ₂ —, wherein the aryl group is as defined above. Exemplary arylsulfonyl groups include benzenesulfonyl.

“Heteroarylsulfonyl” is heteroaryl-SO ₂ —, wherein heteroaryl is as defined above. Representative heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolylsulfonyl, pyrazolylsulfonyl, pyrrolylsulfonyl, pyridazinylsulfonyl, phthalazinylsulfonyl, quinazolinylsulfonyl, pyridylsulfonyl And thienylsulfonyl.

“Alkylsulfinyl” is (C ₁ -C ₁₀ ) alkylsulfinyl, wherein (C ₁ -C ₁₀ ) alkyl is as defined above. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl.

  “Arylsulfinyl” is aryl-SO—, wherein the aryl group is as defined above. Exemplary arylsulfonyl groups include phenylsulfinyl.

  “Heteroarylsulfinyl” is heteroaryl-SO—, wherein heteroaryl is as defined above. Representative heteroarylsulfinyl groups include pyrazinylsulfinyl, isothiazolylsulfinyl, oxazolylsulfinyl, pyrazolylsulfinyl, pyrrolylsulfinyl, pyridazinylsulfinyl, phthalazinylsulfinyl, quinazolinylsulfinyl, pyridylsulfinyl And thienylsulfinyl.

“Aralkylsulfinyl” is an aryl- (C ₁ -C ₁₀ ) alkyl-SO— group in which the aryl and (C ₁ -C ₁₀ ) alkyl groups are as defined above. Representative aralkylsulfinyl groups include benzylsulfinyl and 2-phenethylsulfinyl.

“Alkylthio” is (C ₁ -C ₁₀ ) alkyl-S—, wherein (C ₁ -C ₁₀ ) alkyl is as defined above. Exemplary alkylthio groups include methylthio, ethylthio and propylthio.

  “Arylthio” is aryl-S—, wherein the aryl group is as defined above. Representative arylthio groups include phenylthio groups.

  “Heteroarylthio” is heteroaryl-S—, wherein heteroaryl is as defined above. Exemplary heteroarylthio groups include pyrazinylthio, isothiazolylthio, oxazolylthio, pyrazolylthio, pyrrolylthio, pyridazinylthio, phthalazinylthio, quinazolinylthio, pyridylthio and thienylthio.

“Aralkylthio” is an aryl- (C ₁ -C ₁₀ ) alkyl-S— group in which the aryl and (C ₁ -C ₁₀ ) alkyl groups are as defined above. Exemplary aralkylthio groups include benzylthio and 2-phenethylthio.

“Aryloxyalkyl” is aryl-O— (C ₁ -C ₁₀ ) alkyl, wherein the aryl group and (C ₁ -C ₁₀ ) alkyl group are as defined above. Exemplary aryloxyalkyl groups include phenoxymethyl, phenoxyethyl, and phenoxypropyl.

“Aralkoxyalkyl” is aryl- (C ₁ -C ₁₀ ) alkyl-O— (C ₁ -C ₁₀ ) alkyl, wherein (C ₁ -C ₁₀ ) alkyl and aryl groups are As defined in. Exemplary aralkoxyalkyl groups include benzyloxymethyl, benzyloxyethyl and benzyloxypropyl.

“Fused heteroarylcycloalkyl” is fused heteroaryl and cyclo (C ₃ -C ₆ ) alkyl, where the heteroaryl group and cyclo (C ₃ -C ₆ ) alkyl group are as defined herein. Just as you did. Exemplary fused heteroarylcycloalkyl groups include 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl.

“Fused heteroarylcycloalkenyl” is fused heteroaryl and cyclo (C ₃ -C ₆ ) alkenyl, where the heteroaryl and cyclo (C ₃ -C ₆ ) alkenyl groups are defined herein. Just as you did. Exemplary fused heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxanyl.

  “Fused heteroarylheterocyclenyl” is fused heteroaryl and heterocyclenyl, wherein the heteroaryl and heterocyclenyl groups are as defined herein. Exemplary fused heteroarylheterocyclenyl groups include 7,8-dihydro [1,7] naphthyridinyl, 1,2-dihydro [2,7] naphthyridinyl.

A “carboxylic acid or derivative thereof” can be an amide or ester. Representative carboxylic acid _{groups, CONH 2, CONHMe, CONMe 2} , CONHEt, CONEt 2, CONHPh, COOCH 3, COOC 2 H 5 or COOC ₃ H ₇ and the like.

The “sulfonic acid or derivative thereof” can be an amide or ester. Exemplary sulfonic acid groups include SO ₂ NH ₂ , SONHMe, SO ₂ NMe ₂ , SO ₂ NHCF ₃ , COOCH ₃ , COOC ₂ H ₅ or COOC ₃ H ₇ .

As used herein:
R ^a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group;
R ^b is an alkyl group, an alkoxy group, an alkenyl group or an alkoxyalkyl group;
R ^c is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group;
R ^1a is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group , An alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group;
R ^1b is an acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group , An alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group;
R ^1c is an alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkyl A thio group, an aryloxyalkyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
R ^2a is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group , An alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group;
R ^2b is an acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group , An alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group;
R ^2c is an alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkyl A thio group, an aryloxyalkyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
R ^3a is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group , An alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group;
R ^3b is an acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group , An alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group;
R ^3c is an alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkyl A thio group, an aryloxyalkyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
R ^4a is hydrogen, hydroxy group, halogen, nitro group, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyl An oxy group or a cycloalkenyloxy group;
R ^4b is an acyl group, acyloxy group, aryl group, aryloxy group, aroyl group or aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclenyl group, heteroaryl group, heteroaralkyl group, hetero An aryloxy group or a heteroaralkoxy group;
R ^4c is an alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, or aralkylsulfinyl group, An alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof A derivative;
R ^5a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group;
R ^5b is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group;
R ^5c is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group;
^R′a is hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O═) group, or thio (S═) group. is there;
^R′b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl A group, a heterocyclyl group, or an aralkyl group;
^R′c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group;
R ^{″ a} is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O═) group, or thio (S═) group. is there;
R ^{″ b} is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl A group, a heterocyclyl group, or an aralkyl group;
R ^{″ c} is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl group;
R ^9a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^9b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group Or a heterocyclyl group or an aralkyl group;
R ^9c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^10a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^10b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group A heterocyclyl group or an aralkyl group;
R ^10c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^11a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^11b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group Or a heterocyclyl group or an aralkyl group;
R ^11c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^12a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^12b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group Or a heterocyclyl group or an aralkyl group;
R ^12c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^13a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^13b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group Or a heterocyclyl group or an aralkyl group;
R ^13c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^14a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^14b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group Or a heterocyclyl group or an aralkyl group;
R ^14c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^20a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^20b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group Or a heterocyclyl group or an aralkyl group;
R ^20c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group;
R ^21a is hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. ;
R ^21b is an alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group A heterocyclyl group or an aralkyl group;
R ^21c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group; Here, the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group.

G ^a is — (CH ₂ ) _s —, where s is an integer from 0 to 5;
G ^b _{is, - (CH 2) s -CH} = CH- (CH 2) s - a, where in, s is an integer from 0 to 5;
G ^c is — (CH ₂ ) _s —C≡C— (CH ₂ ) _s —, where s is an integer from 0 to 5;
Z ^a is O; Z ^b is NR; Z ^c is (—CH ₂ —) _u or S (═O) _u , where u is an integer from 0 to 2. ;
E ^a is O; E ^b is S; E ^c is NR;
p ^a is a 0 to 1; ^{p b} is a 2 to 3; ^{p c} is 4-5;
v ^a is 0 to 1; v ^b is 2 to 3; v ^c is 4 to 5;
w ^a is 0; w ^b is 1; w ^c is 2;
X ^a is O; X ^b is S; and X ^c is —NR.

  According to another aspect of the invention, various compounds of general formula (I) having general formula (II), tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts thereof And pharmaceutically acceptable solvates thereof are provided:

本明細書中で別に提供されている場合を除いて、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Except as otherwise provided herein, all symbols are as defined above in connection with formula (I).

  According to another aspect of the present invention, various compounds of general formula (I) having general formula (III), tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts thereof And pharmaceutically acceptable solvates thereof are provided:

別に提供されている場合を除いて、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Except where otherwise provided, all symbols are as defined above in connection with formula (I).

  R ′ and R ″ are independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O═) group, thio (S =) Group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group A heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group.

In one aspect of the invention, R ¹ , R ² , R ³ and R ⁵ are as defined above; R ⁴ is an optionally substituted aryl group, and in some cases, A phenyl group optionally substituted with a halogen, an alkoxy group or both; E is O or —NR, wherein R is as defined above; G is — (CH _{2) s} - or _{- (CH 2) s -CH =} CH- (CH 2) s - is; s is an integer from 1 to 3; and R 'and R "are as defined above Yes, in some cases, separately, hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, alkyl group, cycloalkyl group, alkoxy group, aryl group, or Acyl group.

  A large number of compounds having the general formula (III) are contemplated in the present invention. Various configurations of such compounds provided herein are also encompassed by the present invention, as provided below.

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。それゆえ、限定ではなく、例として、本発明は、以下の代表的な化合物を考慮している：

Here, all symbols are as defined above in relation to formula (I). Thus, by way of example and not limitation, the present invention contemplates the following representative compounds:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

  As yet another example, the present invention contemplates various compounds having the following general formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the present invention, R, R ⁵ , R ′, R ″ and E in formula (30) can be represented by the various formulas (30-1) to (30-243) as follows: Selected to produce a compound:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (30) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, or optionally substituted amino group; R ⁵ is hydrogen, hydroxy group, halogen, nitro group Are optionally substituted amino, alkyl, alkoxy, alkenyl, or alkoxyalkyl groups; R ′ and R ″ are independently hydrogen, halogen, nitro group, amino group, mono- or di- A substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; and E is O, S, or NH.

In other aspects of formula (30) of the present invention, R is hydrogen, an alkyl group, potassium or sodium; R ⁵ is hydrogen or an alkyl group; and all other symbols are represented by formula (I) As defined above in relation to
In other aspects of formula (30) of the present invention, E is O, S or NH; R ′ and R ″ are independently —H, —Cl, —Br or —CH ₃ ; R ⁵ is —H, —CH ₃ or —CH ₂ CH ₂ CH ₃ ; and R is —H, K or Na.

  Examples of compounds of formula (30) include, but are not limited to:

本発明はまた、次式を有する一般式（ＩＩＩ）の種々の化合物を考慮している：

The present invention also contemplates various compounds of general formula (III) having the formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the present invention, R ¹ , R ² , R ⁴ , E, R ′ and R ″ in formula (31) are represented by formulas (31-1) to (31-729) as follows: Is selected to produce a variety of compounds:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (31) of the present invention, R ¹ and R ² are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, or optionally substituted amino group, alkyl group , A cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R ⁴ represents hydrogen, a hydroxy group, a halogen, a nitro group, or An optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group; acyl group, acyloxy group , Aryl group, aryloxy group, aroyl group Or an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; R ′ and R ″ Are independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl Group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group, heterocyclyl group, or An aralkyl group; and other Symbol Te are as defined above in relation to formula (I).

In another aspect of the formula (31) of the present invention, R ¹ represents hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, alkyl group, cycloalkyl group, R ² is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group; R ⁴ is A substituted or unsubstituted aryl group, R ′ is a hydrogen, halogen, or alkyl group; and R ″ is a hydrogen, halogen, or alkyl group; and all other symbols are represented by the formula (I ) As defined above in relation to

In yet another aspect of formula (31) of the present invention, R ¹ is hydrogen or an alkoxy group; R ² is hydrogen or an alkoxy group; R ⁴ is a substituted or unsubstituted aryl group; 'Is hydrogen, halogen, or an alkyl group; R ″ is hydrogen, halogen, or an alkyl group; and E is O, S, or NH.

In yet another aspect of formula (31) of the present invention, R ¹ is —H or —OCH ₃ ; R ² is —H or —OCH ₃ ; R ⁴ is a substituted aryl group; R ′ is —H, —Cl, —Br, or —CH ₃ ; and R ″ is —H, —Cl, —Br, or —CH ₃ ; and E is O, S, or NH.

  The present invention further contemplates various compounds of general formula (III) having the general formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the invention, R ⁴ , R ′ and R ″ in formula (32) produce various compounds of formula (32-1) to formula (32-27) as follows: As selected:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of the invention, R ⁴ is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, or cycloalkoxy group; R ′ is , Hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl A group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; R ″ represents hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group Carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy Shi group, a cycloalkyl group, is an aryl group or a benzyl group; and all other symbols are as defined above in relation to formula (I).

In another aspect of the present invention, R ⁴ represents an alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group. , An aralkyl group, an aralkenyl group, an aralkynyl group, or an aralkoxy group; R ′ is hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, An oxo (O =) group, a thio (S =) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; R ″ is hydrogen, halogen, Nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy A group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, or benzyloxy group; And all other symbols are as defined above in connection with formula (I).

In one aspect of the invention, E is O or —NR; R ⁴ is

（これは、アルキル基またはアルコキシ基で置換されている）、

(Which is substituted with an alkyl or alkoxy group),

である；そしてＲ’およびＲ”は、上記のように定義される。このような化合物の例には、以下が挙げられるが、これらに限定されない：

And R ′ and R ″ are defined as above. Examples of such compounds include, but are not limited to:

本発明は、さらに、以下の一般式を有する種々の化合物を考慮している：

The present invention further contemplates various compounds having the following general formula:

ここで、Ｒ^４は、式（Ｉ）に関連して上で定義したとおりである。

Where R ⁴ is as defined above in relation to formula (I).

In one aspect of formula (33) of the present invention, R ⁴ is hydrogen, hydroxy group, halogen, nitro group, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, An alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group.

In another aspect of the formula (33) of the present invention, R ⁴ represents an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group or an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group. A heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group.

In still another aspect of the formula (33) of the present invention, R ⁴ represents an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group. , Alkylsulfinyl group, arylsulfinyl group, or aralkylated finyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, condensed heteroarylcycloalkyl group, condensed heteroarylcycloalkenyl group, condensed heteroarylheterocyclenyl Groups, carboxylic acids or their derivatives, or sulfonic acids or their derivatives.

In yet another aspect of formula (33) of the present invention, R ⁴ is

である。このような化合物の例には、以下が挙げられるが、これらに限定されない：

It is. Examples of such compounds include, but are not limited to:

本発明は、さらに、以下の一般式を有する種々の化合物を考慮している：

The present invention further contemplates various compounds having the following general formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

Here, R ²⁰ and R ²¹ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, Thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, A heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, ,If necessary, Substituted with a rhogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group Where the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and all other symbols are as defined above.

According to various aspects of the present invention, R, R ⁵ , R ²⁰ , R ²¹ , R ′ and R ″ in formula (34) can be represented by formula (34-1) to formula (34-729) as follows: ) Are selected to produce a variety of compounds:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (34) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group; R ⁵ is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group or alkoxyalkyl group; R ′ and R ″ are independently hydrogen , Halogen, nitro group, amino group, mono- or di-substituted amino group; hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group; alkyl group, cycloalkyl group, An alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; and R ²⁰ and R ²¹ are independently , Hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group; alkyl group, cycloalkyl Group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, heteroaryl group, heterocyclyl group, or aralkyl group .

In other aspects of formula (34) of the present invention, R is hydrogen or an alkyl group; R ⁵ is hydrogen or an alkyl group; R ′ and R ″ are independently hydrogen or halogen; R ²⁰ is hydrogen or halogen; and R ²¹ is hydrogen or halogen.

In yet another aspect of formula (34) of the present invention, R is —H, CH ₃ , or CH ₂ CH ₃ ; R ⁵ is —H or CH ₃ ; R ′ and R ″ are separately, -H, -F, or is ^{-Cl; R 20} is -H, -F, is -Cl or -Br,; and ^{R 21} is a -H, CH ₃ or -F, Representative compounds include, but are not limited to:

本発明は、さらに、以下の一般式を有する種々の化合物を考慮している：

The present invention further contemplates various compounds having the following general formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

Here, R ²⁰ and R ²¹ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, Thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, A heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, ,If necessary, Substituted with a rhogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group Wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and R ¹ is defined above.

According to various variations of the present invention, R ¹ , R ²⁰ and R ²¹ of formula (35) produce various compounds of formula (35-1) to formula (35-27) as follows: As selected:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of the formula (35) of the present invention, R ¹ represents hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group. , A cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R ²⁰ represents hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, A hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo (O =) group, or a thio (S =) group; and R ²¹ represents hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group. Group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group. .

In other aspects of formula (35) of the present invention, R ¹ is halogen, R ²⁰ is hydrogen or halogen, and R ²¹ is hydrogen or halogen.

In yet another aspect of formula (35) of the present invention, R ¹ is Cl or F, R ²⁰ is —H or —F, and R ²¹ is —F.

  Representative compounds of formula (35) include, but are not limited to:

そして、
本発明は、さらに、
本発明は、さらに、以下の一般式を有する種々の化合物を考慮している：

And
The present invention further provides:
The present invention further contemplates various compounds having the following general formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to some variations of the invention, R, R ⁴ , R ′ and R ″ in formula (36) produce compounds of formula (36-1) to formula (36-81) as follows: To be selected:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (36) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group; R ⁴ is an alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl A group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and R ′ and R ″ are independently hydrogen, halogen, nitro group Amino group, mono- or di-substituted Hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group; alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, Or a benzyloxy group.

In another aspect of the formula (36) of the present invention, R is hydrogen or an alkyl group; R ⁴ is a cycloalkenyl group, cycloalkenyloxy group, acyl group or acyloxy group, aryl group, aryloxy group, aroyl A group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and R ′ and R "Is independently hydrogen or halogen.

In yet another aspect of formula (36) of the present invention, R is —H or CH ₃ , R ⁴ is a halogen-substituted aryl group; and R ′ and R ″ are independently —H or -Cl; and all other symbols are as defined above in connection with formula (I).

  Examples of compounds of formula (36) include, but are not limited to:

そして、
本発明はまた、以下の一般式を有する種々の化合物を考慮している：

And
The present invention also contemplates various compounds having the following general formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to some variations of the invention, E, R ¹ and R ⁴ of formula (37) are selected to produce compounds of formula (37-1) to formula (37-27):

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of the formula (37) of the present invention, R ¹ represents hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, or an alkoxy group. , A cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R ⁴ represents an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group; Group, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclenyl group, heteroaryl group, heteroaralkyl group, heteroaryl Is aryloxy group or a heteroaralkoxy group; and all other symbols are as defined above in relation to formula (I).

In another aspect of formula (37) of the present invention, R ¹ is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, or alkyl group; R ⁴ Is a cycloalkenyl group, cycloalkenyloxy group, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclenyl group, heteroaryl A group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and all other symbols are as defined above in connection with Formula (I).

In yet another aspect of formula (37) of the present invention, R ¹ is hydrogen, halogen, or an alkoxy group; R ⁴ is a cycloalkenyl group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, An aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; And all other symbols are as defined above in connection with formula (I).

In another aspect of formula (37) of the present invention, R ¹ is hydrogen, halogen, or an alkoxy group; E is O or —NR; and R ⁴ is

であり、ここで、Ｒ^２２およびＲ^２３は、別個に、水素、ハロゲン、ニトロ基、アミノ基、一置換または二置換アミノ基、ヒドロキシ基、アルコキシ基、カルボキシ基、シアノ基、オキソ（Ｏ＝）基、チオ（Ｓ＝）基、アルキル基、シクロアルキル基、アルコキシ基、ハロアルコキシ基、シクロアルキル基、アリール基、ベンジルオキシ基、アシル基、アシルオキシ基、アロイル基、アルコキシカルボニル基、アリールオキシカルボニル基、ヘテロアリール基、ヘテロシクリル基、アラルキル基、アルキルスルホニル基、アルキルスルフィニル基、アリールスルホニル基、アリールスルフィニル基、アルキルチオ基、アリールチオ基、ヘテロアリールチオ基、アラルキルチオ基、またはヘテロシクリルスルホニル基であり、これは、必要に応じて、ハロゲン、ヒドロキシル基、ニトロ基、アミノ基、アルキルオキシ基、またはそれらの任意の組み合わせで置換されており、ここで、この複素環基は、必要に応じて置換したモルホリニル基、チオモルホリニル基またはピペリジニル基であり、ここで、このヘテロシクリル基上の置換基は、ハロゲン、ニトロ基、アミノ基、アルキル基、アルコキシ基またはアリール基である；そして他の全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Wherein R ²² and R ²³ are independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O = ) Group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxy A carbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl group This is necessary Substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl group, thiomorpholinyl group Or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and all other symbols in formula (I) As defined above in relation.

In yet another aspect of formula (37) of the present invention, R ¹ is hydrogen or halogen; E is O or NMe; R ⁴ is a substituted aryl group or a heterocyclic group; R ²² is R ²² is hydrogen or an alkoxy group; and all other symbols are as defined above in connection with formula (I).

In yet another aspect of formula (37) of the present invention, R ¹ is —H, —F, or MeO; E is O or NMe; R ⁴ is

であり、ここで、Ｒ^２２は、−ＨまたはＯＭｅである；そしてＲ^２３は、−ＦまたはＯＭｅである。

Where R ²² is —H or OMe; and R ²³ is —F or OMe.

  Representative compounds include, but are not limited to:

本発明の他の局面によれば、一般式（ＩＶ）を有する一般式（Ｉ）の種々の化合物、その互変異性型、その立体異性体、その多形、その薬学的に受容可能な塩、およびその薬学的に受容可能な溶媒和物が提供される：

According to another aspect of the invention, various compounds of general formula (I) having general formula (IV), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts And pharmaceutically acceptable solvates thereof are provided:

本明細書中で別に提供されている場合を除いて、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Except as otherwise provided herein, all symbols are as defined above in connection with formula (I).

  A large number of compounds having the general formula (IV) are contemplated in the present invention. Examples of such compounds include, but are not limited to:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

  Thus, for example, the present invention encompasses various compounds of general compound (IV) having the formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。本明細書中では、種々の立体配置が提供されているものの、他の立体配置は、本発明で考慮されることを理解すべきである。それゆえ、以下の一般式を有する化合物もまた、本発明で考慮される：

Here, all symbols are as defined above in relation to formula (I). While various configurations are provided herein, it should be understood that other configurations are contemplated by the present invention. Therefore, compounds having the following general formula are also contemplated in the present invention:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to some variations of the invention, R, R ¹ , R ⁴ , G and Z in formulas (88), (89), (90), (91), (92) are as follows: From formulas (88-1), (89-1), (90-1), (91-1) and (92-1), formulas (88-729), (89-729), (90-729) , (91-729) and (92-729) are selected to produce:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ and all other symbols are As defined above in relation to formula (I).

In other aspects of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is H or CH ₃ and R ⁵ is —H. , And all other symbols are as defined above in connection with formula (I).

In other aspects of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; R ⁵ is CH ₃ . And all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; G is — (CH ₂ ) _s , where s is an integer from 0 to 5; and all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or —CH ₃ ; R ⁵ is — is H; G is - _{(CH 2) s,} and wherein, s is an integer from 0 to 5; the and all other symbols, as defined above in relation to formula (I) It is as follows.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or —CH ₃ ; R ⁵ is CH is _3; G is - _{(CH 2) s,} and wherein, s is an integer from 0 to 5; the and all other symbols, as defined above in relation to formula (I) It is as follows.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ and Z is —NR. And all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ and R ⁵ is —H. Or CH ₃ ; Z is —NR; and all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ and G is — (CH ₂ ) s-, where s is an integer from 0 to 5; Z is -NR; and all other symbols are as defined above in connection with formula (I). It is.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H; G is — (CH ₂ ) s. Where s is an integer from 0 to 5; Z is —NR; and all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ and Z is O. And all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; R ⁵ is CH ₃ G is — (CH ₂ ) _s —, where s is an integer from 0 to 5; Z is —NR; and all other symbols are represented by formula (I) As defined above in relation to.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ and R ⁵ is —H. Or CH ₃ , Z is O, and all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; G is — (CH ₂ ) _s- , where s is an integer from 0 to 5; Z is O; and all other symbols are as defined above in connection with formula (I). is there.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; G is — (CH ₂ ) _s- , where s is an integer from 0 to 5; Z is O; and all other symbols are as defined above in connection with formula (I). is there.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; R ⁵ is H G is — (CH ₂ ) _s —, where s is an integer from 0 to 5; Z is O; and all other symbols are related to formula (I) And as defined above.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is —H or CH ₃ ; R ⁵ is CH ₃ G is — (CH ₂ ) _s —, where s is an integer from 0 to 5; Z is O; and all other symbols in formula (I) As defined above in relation.

In yet another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R ⁴ is a substituted or unsubstituted aryl group; and all others Is as defined above in connection with formula (I).

The present invention also encompasses various compounds of general formula (IV) having the formula:

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the present invention, R, R ⁴ , R ⁵ , G and Z of formula (93) produce compounds of formula (93-1) to (93-243) as follows: As selected:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (93) of the present invention, R is —H or CH ₃ and all other symbols are as defined above in connection with formula (I).

In another aspect of formula (93) of the present invention, R ⁴ is a substituted or unsubstituted aryl group; and all other symbols are as defined above in connection with formula (I).

In yet another aspect of formula (93) of the present invention, R ⁵ is —H or CH ₃ and all other symbols are as defined above in connection with formula (I).

In yet another aspect of formula (93) of the present invention, G is — (CH ₂ ) _s —, where s is an integer from 0 to 5; and all other symbols are represented by the formula As defined above in connection with (I).

In yet another aspect of formula (93) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group. R ⁴ represents an alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group , An aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; R ⁵ is hydrogen, a hydroxy group, a halogen, a nitro group, or An amino group substituted according to Alkyl group, alkoxy group, alkenyl group or alkoxyalkyl group; and all other symbols are as defined above in relation to formula (I).

In yet another aspect of formula (93) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, or an alkyl group; R ⁴ Is a cycloalkenyl group, cycloalkenyloxy group, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclenyl group, heteroaryl A group, heteroaralkyl group, heteroaryloxy group, or heteroaralkoxy group; R ⁵ is hydrogen, a hydroxy group, a halogen, an alkyl group, or an alkoxy group; and all other symbols are represented by the formula ( As defined above in connection with I).

In yet another aspect of formula (93) of the present invention, R is hydrogen or an alkyl group; R ⁴ is a substituted or unsubstituted aryl group; G is (—CH ₂ —) ₂ , (— CH ₂ —) ₃ or (—CH ₂ —) ₄ ; Z is O, S or NH; and R ⁵ is hydrogen or an alkyl group.

In yet another aspect of formula (93) of the present invention, R is —H or CH ₃ ; R ⁴ is a substituted or unsubstituted aryl group; G is (—CH ₂ —) ₂ , (—CH _2— ) ₃ or (—CH ₂ —) ₄ ; Z is O, S or NH; and R ⁵ is —H or CH ₃ .

  The present invention also encompasses various compounds of general formula (IV) as follows:

ここで、Ｒ^９およびＲ^１０は、別個に、水素、ハロゲン、ニトロ基、アミノ基、一置換または二置換アミノ基、ヒドロキシ基、アルコキシ基、カルボキシ基、シアノ基、オキソ（Ｏ＝）基、チオ（Ｓ＝）基、アルキル基、シクロアルキル基、アルコキシ基、ハロアルコキシ基、シクロアルキル基、アリール基、ベンジルオキシ基、アシル基、アシルオキシ基、アロイル基、アルコキシカルボニル基、アリールオキシカルボニル基、ヘテロアリール基、ヘテロシクリル基、アラルキル基、アルキルスルホニル基、アルキルスルフィニル基、アリールスルホニル基、アリールスルフィニル基、アルキルチオ基、アリールチオ基、ヘテロアリールチオ基、アラルキルチオ基、またはヘテロシクリルスルホニル基であり、これは、必要に応じて、ハロゲン、ヒドロキシル基、ニトロ基、アミノ基、アルキルオキシ基、またはそれらの任意の組み合わせで置換されており、ここで、この複素環基は、必要に応じて置換したモルホリニル基、チオモルホリニル基またはピペリジニル基であり、ここで、このヘテロシクリル基上の置換基は、ハロゲン、ニトロ基、アミノ基、アルキル基、アルコキシ基またはアリール基である；そして他の全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, R ⁹ and R ¹⁰ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, Thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, A heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, If necessary, ha Substituted with a gen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group Where the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and all other symbols are related to formula (I) As defined above.

According to various aspects of the invention, R, R ⁵ , G, Z, R ⁹ and R ¹⁰ of any of formulas (94), (95), (96) and (97) are as follows: From the formulas (94-1), (95-1), (96-1) and (97-1), the formulas (94-729), (95-729), (96-729) and (97-729) are obtained. ) Is selected to produce up to:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of any of formulas (94), (95), (96) and (97) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl A group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R ⁵ represents hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R ⁹ and R ¹⁰ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group or in certain thio (S =) group; G _{is, (- CH 2 -) 2} , (- CH 2 -) 3 or _(-CH 2 _-) is _4; and all other symbols Is as defined above in connection with formula (I).

In other aspects of any of formulas (94), (95), (96) and (97) of the invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, An alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R ⁵ represents hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxy group; R ⁹ and R ¹⁰ are each independently an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxy group; A carbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group. That; and G _{is, (- CH 2 -) 2} , (- CH 2 -) 3 or _(-CH 2 _-) is _4; and all other symbols above in relation to formula (I) As defined.

In yet another aspect of formulas (94), (95), (96) and (97) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, or an alkyl group. , An alkoxy group, an alkenyl group, or an alkoxyalkyl group; R ⁵ represents hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R ⁹ and R ¹⁰ are each independently an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group. This is because halogen, hydroxyl group, nitro group, amino group, Substituted with a killioxy group, or any combination thereof, wherein the heterocyclic group is an optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group, wherein the substitution on the heterocyclyl group The group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and G is (—CH ₂ —) ₂ , (—CH ₂ —) ₃ or (—CH ₂ —) ₄ . And all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulas (94), (95), (96) and (97) of the present invention, R is hydrogen or an alkyl group; R ⁵ is hydrogen or an alkyl group; R ⁹ is hydrogen, an alkoxy group, or

である；Ｒ^１０は、水素またはアルコキシ基である；そしてＧは、（−ＣＨ_２−）_２、（−ＣＨ_２−）_３または（−ＣＨ_２−）_４である。

R ¹⁰ is hydrogen or an alkoxy group; and G is (—CH ₂ —) ₂ , (—CH ₂ —) ₃ or (—CH ₂ —) ₄ .

In still other aspects of any of formulas (94), (95), (96) and (97) of the present invention, R is —H or Me; R ⁵ is —H or Me; R ⁹ is —H, —OMe, or

である；Ｒ^１０は、−Ｈ、ＯＭｅまたは−ＯＥｔである；そしてＧは、（−ＣＨ_２−）_２、（−ＣＨ_２−）_３または（−ＣＨ_２−）_４である。

R ¹⁰ is —H, OMe or —OEt; and G is (—CH ₂ —) ₂ , (—CH ₂ —) ₃ or (—CH ₂ —) ₄ .

  The present invention further encompasses various compounds of general formula (IV) as follows:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the present invention, R, R ¹ , R ⁵ , G and Z of any of formulas (98), (99), (100) and (101) can be represented by the formula ( 98-1), (99-1), (100-1) and (101-1) to formulas (98-243), (99-243), (100-243) and (101-243) Selected to produce a compound:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of any of formulas (98), (99), (100) and (101) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl A group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R ¹ represents hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, alkyl group, cycloalkyl group; Group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, or cycloalkenyloxy group; R ⁵ is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl Group, or optionally substituted amino group, alkyl group, cycloalkyl group An alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are defined above in connection with formula (I) It is as follows.

In other aspects of any of formulas (98), (99), (100), and (101) of the present invention, G is — (CH ₂ ) _s —, where s is 0-5. And all other symbols are as defined above in connection with formula (I).

In another aspect of any of formulas (98), (99), (100), and (101) of the present invention, G is — (CH ₂ ) _s —CH═CH— (CH ₂ ) _s —. Where s is an integer from 0 to 5; and all other symbols are as defined above in connection with formula (I).

In another aspect of any of formulas (98), (99), (100), and (101) of the present invention, G is — (CH ₂ ) _s —C≡C— (CH ₂ ) _s — Where s is an integer from 0 to 5; and all other symbols are as defined above in connection with formula (I).

  In other aspects of any of formulas (98), (99), (100), and (101) of the present invention, Z is O; and all other symbols are related to formula (I) As defined above.

  In other aspects of any of formulas (98), (99), (100), and (101) of the present invention, Z is NR; and all other symbols are related to formula (I) As defined above.

In other aspects of any of formulas (98), (99), (100) and (101) of the present invention, Z is (—CH ₂ —) _u or S (═O) _u , where , U is an integer from 0 to 2; and all other symbols are as defined above in connection with formula (I).

  In still other aspects of any of formulas (98), (99), (100) and (101) of the present invention, E is O, and all other symbols are related to formula (I) And as defined above.

  In yet another aspect of any of formulas (98), (99), (100) and (101) of the present invention, E is S, and all other symbols are related to formula (I) And as defined above.

  In still other aspects of any of formulas (98), (99), (100) and (101) of the present invention, E is NR and all other symbols are related to formula (I) And as defined above.

  Examples of compounds having general formula (IV) include, but are not limited to:

本発明の他の局面によれば、一般式（Ｖ）を有する一般式（Ｉ）の種々の化合物、その互変異性型、その立体異性体、その多形、その薬学的に受容可能な塩、およびその薬学的に受容可能な溶媒和物が提供される：

According to another aspect of the present invention, various compounds of general formula (I) having general formula (V), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts And pharmaceutically acceptable solvates thereof are provided:

本明細書中で別に提供されている場合を除いて、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Except as otherwise provided herein, all symbols are as defined above in connection with formula (I).

  Examples of compounds having general formula (V) contemplated by the present invention include, but are not limited to:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

  The present invention contemplates various compounds of general formula (V) having the formula:

ここで、Ｒ^１１、Ｒ^１２、Ｒ^１３およびＲ^１４は、別個に、水素、ハロゲン、ニトロ基、アミノ基、一置換または二置換アミノ基、ヒドロキシ基、アルコキシ基、カルボキシ基、シアノ基、オキソ（Ｏ＝）基、チオ（Ｓ＝）基、アルキル基、シクロアルキル基、アルコキシ基、ハロアルコキシ基、シクロアルキル基、アリール基、ベンジルオキシ基、アシル基、アシルオキシ基、アロイル基、アルコキシカルボニル基、アリールオキシカルボニル基、ヘテロアリール基、ヘテロシクリル基、アラルキル基、アルキルスルホニル基、アルキルスルフィニル基、アリールスルホニル基、アリールスルフィニル基、アルキルチオ基、アリールチオ基、ヘテロアリールチオ基、アラルキルチオ基、またはヘテロシクリルスルホニル基であり、これは、必要に応じて、ハロゲン、ヒドロキシル基、ニトロ基、アミノ基、アルキルオキシ基、またはそれらの任意の組み合わせで置換されており、ここで、この複素環基は、必要に応じて置換したモルホリニル基、チオモルホリニル基またはピペリジニル基であり、ここで、このヘテロシクリル基上の置換基は、ハロゲン、ニトロ基、アミノ基、アルキル基、アルコキシ基またはアリール基である；そして他の全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are independently hydrogen, halogen, nitro group, amino group, mono-substituted or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl This is the group Optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl group , A thiomorpholinyl group or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and all other symbols are represented by the formula ( As defined above in connection with I).

  In one aspect of formula (141) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group; and all other symbols in formula (I) As defined in relation.

  In another aspect of formula (141) of the present invention, R is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; and all other symbols are defined in relation to formula (I) It is as follows.

In another aspect of the formula (141) of the present invention, R ¹ represents hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, alkyl group, cycloalkyl group, An alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in connection with formula (I). is there.

In another aspect of the formula (141) of the present invention, R ² represents hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, alkyl group, cycloalkyl group, An alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in connection with formula (I). is there.

In still another aspect of the formula (141) of the present invention, R ¹¹ represents hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( An O =) group, or a thio (S =) group; and all other symbols are as defined in connection with formula (I).

In still another aspect of the formula (141) of the present invention, R ¹¹ represents an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or A heterocyclylsulfonyl group, optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is Optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and others All symbols of are defined in relation to formula (I) It is as follows.

In still another aspect of the formula (141) of the present invention, R ¹² represents hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( An O =) group, or a thio (S =) group; and all other symbols are as defined in connection with formula (I).

In still another aspect of the formula (141) of the present invention, R ¹² represents an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or A heterocyclylsulfonyl group, optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is Optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and others All symbols of are defined in relation to formula (I) It is as follows.

In still another aspect of the formula (141) of the present invention, R ¹³ represents hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( An O =) group, or a thio (S =) group; and all other symbols are as defined in connection with formula (I).

In another aspect of the formula (141) of the present invention, R ¹³ represents an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl group. A sulfonyl group, optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is required Optionally substituted morpholinyl, thiomorpholinyl or piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and other All symbols are as defined in connection with formula (I) It is.

In another aspect of the formula (141) of the present invention, R ¹⁴ represents hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) Group, or thio (S =) group; and all other symbols are as defined in connection with formula (I).

In still another aspect of the formula (141) of the present invention, R ¹⁴ represents an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or A heterocyclylsulfonyl group, optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group, or any combination thereof, wherein the heterocyclic group is Optionally substituted morpholinyl group, thiomorpholinyl group or piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; and others All symbols of are defined in relation to formula (I) It is as follows.

  In yet another aspect of formula (141) of the present invention, R is hydrogen or an alkyl group, and all other symbols are as defined in connection with formula (I).

In another aspect of formula (141) of the present invention, R, -H, CH ₃ or a _C 2 _{H 5,,} and all other symbols, as defined in relation to formula (I) is there.

In yet another aspect of formula (141) of the present invention, R ¹ is hydrogen or an alkyl group, and all other symbols are as defined in connection with formula (I).

In yet another aspect of formula (141) of the present invention, R ¹ is —H, CH ₃ , or C ₂ H ₅ and all other symbols are defined in relation to formula (I) It is as follows.

In another aspect of formula (141) of the present invention, R ² is hydrogen or an alkyl group, and all other symbols are as defined in relation to formula (I).

In other aspects of formula (141) of the present invention, R ² is —H, CH ₃ , or C ₂ H ₅ , and all other symbols are as defined in connection with formula (I). It is.

In yet another aspect of formula (141) of the present invention, R ¹¹ is hydrogen, halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in relation to formula (I) It is.

In other aspects of formula (141) of the present invention, R ¹¹ is —H, —Cl, —OCH ₃ , or —SCH ₃ , and all other symbols are related to formula (I) As defined.

In yet another aspect of formula (141) of the present invention, R ¹² is hydrogen, halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in connection with formula (I) It is.

In other aspects of formula (141) of the invention, R ¹² is H, Cl, —OCH ₃ , or —SCH ₃ , and all other symbols are defined in connection with formula (I) It is as follows.

In yet another aspect of formula (141) of the present invention, R ¹³ is hydrogen, halogen, or an alkyl group, and all other symbols are as defined in relation to formula (I).

In yet another aspect of formula (141) of the present invention, R ¹³ is —H, —F, or CH ₃ , and all other symbols are as defined in connection with formula (I). is there.

In yet another aspect of formula (141) of the present invention, R ¹⁴ is hydrogen, halogen, or an alkyl group, and all other symbols are as defined in relation to formula (I).

In yet another aspect of formula (141) of the present invention, R ¹⁴ is —H, —F, or —CH ₃ , and all other symbols are as defined in connection with formula (I). It is.

In another aspect of the formula (141) of the present invention, R ¹ and R ² are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group , A cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently , Hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or thio (S =) group, alkyl group, or A cycloalkyl group, an alkoxy group; and all other symbols are as defined above in connection with formula (I). That.

In another aspect of formula (141) of the present invention, R ¹ and R ² are independently hydrogen, hydroxy group, halogen, alkoxy group; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are independently Hydrogen, halogen, hydroxy group, alkoxy group; and all other symbols are as defined above in connection with formula (I).

In yet another aspect of formula (141) of the present invention, R ¹ and R ² are independently —H or —OCH ₃ ; R ¹¹ is —Cl, —OCH ₃ , or —SCH ₃ . R ¹² is —Cl, —OCH ₃ , or —H; R is —H, CH ₃ , or C ₂ H ₅ ; R ¹³ is F or CH ₃ ; R ¹⁴ is F or CH ₃ ; v is 0 or 1; and all other symbols are as defined above in connection with formula (I).

  The present invention also contemplates various compounds of general formula (V) as follows:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the present invention, R, R ¹ and R ² of formula (142) may produce various compounds of formula (142-1) to formula (142-27) as follows: To be selected:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (142) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group; R ¹ and R ² are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, An alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group.

In other aspects of formula (142) of the present invention, R ¹ and R ² are independently a halogen or an alkyl group; and R is hydrogen, an alkyl group,

である。

It is.

In yet another aspect of formula (142) of the present invention, R ¹ is —OCH ₃ or —F; R ² is —OCH ₃ or —Cl; R is —H or C ₂ H _5. ,

である。

It is.

  The present invention also contemplates various compounds of general formula (V) as follows:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

In one aspect of formula (143) of the present invention, R ¹ and R ² are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, A cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R ¹³ and R ¹⁴ are independently hydrogen, halogen, nitro group; , Amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy Group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group , An alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; and all other symbols are as defined in connection with formula (I).

In another aspect of the formula (143) of the present invention, R ¹ and R ² independently represent an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group; a heterocyclyl group , A heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group; R ¹³ and R ¹⁴ are each independently hydrogen, halogen, Nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group Haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, A sil group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; and all other symbols are as defined in connection with formula (I) It is.

In another aspect of formula (143) of the present invention, R ¹ and R ² are independently hydrogen, an alkyl group, or an alkoxy group; R ¹³ and R ¹⁴ are independently hydrogen, halogen, an alkyl group Or an alkoxy group; and all other symbols are as defined in connection with formula (I).

In yet another aspect of formula (143) of the present invention, R ¹ and R ² are —H or —OCH ₃ ; R ¹³ is CH ₃ or —F; R ¹⁴ is —H or — F; and all other symbols are as defined in connection with formula (I).

  The present invention also contemplates various compounds of general formula (V) having the following formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

  According to various aspects of the invention, R, R1, R2, v, and p of formula (144) produce various compounds of formulas (144-1) to (144-243) as follows: To be selected:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (144) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group; R ¹ and R ² are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl A group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in connection with formula (I).

In another aspect of formula (144) of the present invention, R ¹ and R ² are independently hydrogen, an alkyl group, or an alkoxy group; and all other symbols are all represented by formula (I ) As defined above in relation to

In yet another aspect of formula (144) of the present invention, R ¹ and R ² are —OCH ₃ ; and all other symbols are as defined in relation to formula (I).

  The present invention further contemplates various compounds of general formula (V) having the following formula:

ここで、全ての記号は、式（Ｉ）に関連して上で定義したとおりである。

Here, all symbols are as defined above in relation to formula (I).

According to various aspects of the present invention, R, R ¹ , R ² , R ^11, and R ¹² of formula (145) can be represented by the following formulas (145-1) to (145-243): Is selected to produce a compound of:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

In one aspect of formula (145) of the present invention, R is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group; R ¹ and R ² are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl A group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and R ¹¹ and R ¹² are each independently hydrogen, halogen, nitro group, amino group, mono-substituted or di-substituted amino group , Hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, or A thio (S =) group, an alkyl group, a cycloalkyl group or an alkoxy group;

In other aspects of formula (145) of the present invention, R is hydrogen or an alkyl group; R ¹ and R ² are independently hydrogen, a hydroxy group, a halogen, an alkoxy group; and R ¹¹ and R ¹² is independently hydrogen, halogen, hydroxy group, or alkoxy group.

In yet another aspect of formula (145) of the present invention, R is —H or C ₂ H ₅ ; R ¹ and R ² are —OCH ₃ ; and R ¹¹ and R ¹² are independently , -H, it is -F or CH _3,.

  The present invention further contemplates various compounds of general formula (V) having the following formula:

ここで、Ｒは、式（Ｉ）に関連して上で定義したとおりである。

Where R is as defined above in relation to formula (I).

  In one aspect of formula (146) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group.

  In another aspect of the formula (146) of the present invention, R is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group.

  In still another aspect of the formula (146) of the present invention, R is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group.

  In yet another aspect of formula (146) of the present invention, R is —H or an alkyl group.

In yet another aspect of the compounds of formula (146), R is -H or _C 2 _{H 5.}

  Additional examples of compounds having general formula (V) include, but are not limited to:

本明細書中で図示または記述した任意の化合物（上で図示または記述した種々の式の化合物を含めて）は、薬学的に受容可能な塩として、提供され得る。

Any compound illustrated or described herein (including compounds of various formulas illustrated or described above) can be provided as pharmaceutically acceptable salts.

  Pharmaceutically acceptable salts that form part of the present invention include salts derived from: Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; N, N′— Diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, Piperidine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N, N′-diphenylethylenediamine, N, N′-dibenzylethylenediamine, -Benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, or spermidine; alkylphenylamine, glycinol or phenyl group Chiral bases such as ricinol; natural amino acid salts (eg glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine , Phenylalanine); an unnatural amino acid (eg, D-isomer or substituted amino acid); guanidine, substituted guanidine, The substituents, nitro, amino, alkyl, selected from alkenyl or alkynyl; ammonium or substituted ammonium salts and aluminum salts. Salts may include, where appropriate, acid addition salts which are: sulfate, nitrate, phosphate, perchlorate, borate, hydrohalide, acetate, tartrate, maleate. Citrate, succinate, pamoate, methanesulfonate, benzoic acid, salicylate, hydroxynaphthoate, benzenesulfonate, ascorbic acid, glycerophosphoric acid, ketoglutaric acid. Pharmaceutically acceptable solvates can be hydrated or can contain other crystallization solvents (eg, alcohols).

(Methods for preparing these compounds)
The compounds of the present invention can be prepared according to the following methods. However, other methods with other process conditions can be used to form the compounds of the present invention.

(Method I)
According to one aspect of the present invention, there is provided a method for preparing a compound of general formula (II):

ここで、Ｒ^１は、Ｂに結合されている；Ｒ^２は、Ｊに結合されている；Ｒ^３は、−Ｈである；Ａ、Ｂ、ＤおよびＪは、別個に、−ＣＨである；Ｒ^１およびＲ^２は、別個に、アルコキシ基またはアラルコキシ基である；Ｒ^４は、３位置および／または４位置でそれぞれアルコキシ基またはアラルコキシ基で必要に応じて置換されたフェニル基である；ＸおよびＥは、それぞれ、Ｏであり、Ｇは、−（ＣＨ_２）_ｓ−、（ＣＨ_２）_ｓ−ＣＨ＝ＣＨ−（ＣＨ_２）_ｓ−、または（ＣＨ_２）_ｓ−ＣＨ＝ＣＨ−（ＣＨ_２）_ｓ−であり、ここで、ｓは、０〜５の整数である；Ｆは、Ｏ、Ｓまたは−ＮＲである；ＹおよびＺは、別個に、Ｏ、−ＮＲ、（ＣＨ２）ｎまたはＳ（＝Ｏ）ｎであり、ここで、ｎは、０〜２の整数である；Ｙ^１およびＹ^２は、別個に、ＯまたはＳである；ＲおよびＲ^５は、別個に、水素、ヒドロキシ基、ハロゲン、ニトロ基、必要に応じて置換したアミノ基、アルキル基、アルコキシ基、アルケニル基、アルコキシアルキル基、シクロアルケニルオキシ基、アシル基、アリール基、アラルキル基、ヘテロシクリル基またはヘテロアリール基である；そして「Ａｒ」は、必要に応じて置換したフェニル基または必要に応じて置換したナフチル基である。

Where R ¹ is bound to B; R ² is bound to J; R ³ is —H; A, B, D and J are independently —CH. R ¹ and R ² are independently an alkoxy group or an aralkoxy group; R ⁴ is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the 3 and / or 4 positions, respectively; X and E are each a O, G _{is, - (CH 2) s -} , (CH 2) s -CH = CH- (CH 2) s - or _{(CH 2), s -CH =} CH- _{(CH 2) s} - a, where in, s is an integer of 0 to 5; F is, O, is S or -NR; Y and Z are, independently, O, -NR, (CH2 ) n or S (= O) n, where, n is an integer of 0 to 2; ^{Y 1} and ² is independently O or S; R and R ⁵ are, independently, hydrogen, hydroxy group, a halogen, a nitro group, an amino group optionally substituted alkyl group, an alkoxy group, an alkenyl group, an alkoxy An alkyl group, a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; and “Ar” is an optionally substituted phenyl group or an optionally substituted naphthyl group. is there.

This method first involves rutin hydrate of formula (IIa) wherein “Rut” is rutinose; R ¹ is bound to B; R ² is bound to J; R ³ is H; A, B, D and J are independently —CH, R ¹ and R ² are independently hydroxy groups; R ⁴ is in the 3 position and / or 4 A phenyl group optionally substituted at the position with a hydroxy group; X, Y and E are O; and "----" is any chemical bond) is represented by formula (IIa) Wherein R ¹ is bound to B; R ² is bound to J; R ³ is H; A, B, D and J are each independently —CH in a; ^{R 1} and ^{R 2} are, independently, is an alkoxy group or an aryloxy group; ^{R 4} is 3 position and 4 position Alkylating to a phenyl group optionally substituted with an alkoxy or aralkoxy group; X, Y and E are O; and all other symbols are as defined above) Includes:

このアルキル化は、ハロゲン化アルキルアルキル化剤またはアラルキル化剤を使用して、実行される。適当であり得る試薬の例には、ＭｅＩ、ＥｔＩ、ＥｔＢｒ、ｎ−ＰｒＩ、ｎ−ＰｒＢｒ、ｉ−ＰｒＢｒ、ｉ−ＰｒＩ、ｎ−ＢｕＣｌまたはｓ−ＢｕＢｒ；硫酸ジアルキル（例えば、硫酸ジメチルまたは硫酸ジエチル）；またはハロゲン化アラルキル（例えば、ハロゲン化ベンジル）が挙げられる。この反応は、例えば、以下のアルカリの存在下にて、実行され得る：水素化ナトリウム（ＮａＨ）、水素化カリウム（ＫＨ）、カリウム第三級ブトキシド（ｔ−ＢｕＯＫ）、酢酸カリウム（ＫＯＡｃ）、酢酸ナトリウム（ＮａＯＡｃ）、ｎ−ブチルリチウム（ｎ−ＢｕＬｉ）、ｓｅｃ−ブチルリチウム（ｓ−ＢｕＬｉ）、第三級ブチルリチウム（ｔ−ＢｕＬｉ）、リチウムジイソプロピルアミド（ＬＤＡ）、炭酸ナトリウム（Ｎａ_２ＣＯ_３）、炭酸カリウム（Ｋ_２ＣＯ_３）、炭酸水素ナトリウム（ＮａＨ_３）、炭酸水素カリウム（ＫＨＣＯ_３）、水酸化ナトリウム（ＮａＯＨ）、水酸化カリウム（ＫＯＨ）、またはそれらの任意の混合物。使用される溶媒は、例えば、ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）、ヘキサメチリン酸（ＨＭＰＡ）、１，４−ジオキサン、アセトン、ジメチルエーテル、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、またはそれらの任意の混合物である。

This alkylation is carried out using a halogenated alkyl alkylating agent or an aralkylating agent. Examples of reagents that may be suitable include MeI, EtI, EtBr, n-PrI, n-PrBr, i-PrBr, i-PrI, n-BuCl or s-BuBr; dialkyl sulfates (eg dimethyl sulfate or diethyl sulfate Or halogenated aralkyl (eg, benzyl halide). This reaction can be performed, for example, in the presence of the following alkalis: sodium hydride (NaH), potassium hydride (KH), potassium tertiary butoxide (t-BuOK), potassium acetate (KOAc), Sodium acetate (NaOAc), n-butyl lithium (n-BuLi), sec-butyl lithium (s-BuLi), tertiary butyl lithium (t-BuLi), lithium diisopropylamide (LDA), sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), sodium bicarbonate (NaH ₃ ), potassium bicarbonate (KHCO ₃ ), sodium hydroxide (NaOH), potassium hydroxide (KOH), or any mixture thereof. Solvents used are, for example, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylic acid (HMPA), 1,4-dioxane, acetone, dimethyl ether, diethyl ether, tetrahydrofuran (THF), or any mixture thereof It is.

According to one aspect of the invention, the reaction temperature can be about −30 ° C. to about 250 ° C., such as about 30 ° C. to about 100 ° C. The duration of this reaction can be from about 0.5 hours to about 100 hours, such as from about 20 hours to about 80 hours. This reaction may be performed under an inert atmosphere (eg, nitrogen (N ₂ ), argon (Ar), or helium (He)).

  The compound of formula (IIa) is then hydrolyzed to the compound of formula (IIb):

ここで、Ｒ^１は、Ｂに結合されている；Ｒ^２は、Ｊに結合されている；Ｒ^３は、Ｈである；Ａ、Ｂ、ＤおよびＪは、別個に、−ＣＨである；Ｒ^１およびＲ^２は、別個に、アルコキシ基またはアリールオキシ基である；Ｒ^４は、３位置および４位置で必要に応じてアルコキシ基またはアラルコキシ基で置換されたフェニル基である；Ｘ、ＹおよびＥは、Ｏである；そして他の全ての記号は、上で定義したとおりである。

Where R ¹ is bound to B; R ² is bound to J; R ³ is H; A, B, D and J are independently —CH; R ¹ and R ² are independently an alkoxy group or an aryloxy group; R ⁴ is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the 3 and 4 positions; X, Y And E is O; and all other symbols are as defined above.

  This hydrolysis is carried out using an inorganic acid (for example, hydrochloric acid (HCl), sulfuric acid (H 2 SO 4) or a mixture thereof) and water as required. The reaction temperature may be maintained at about −30 ° C. to about 250 ° C., such as about 50 ° C. to about 150 ° C. The duration of this reaction can be from about 0.5 hours to about 100 hours, such as from about 1 hour to about 50 hours.

  The compound of formula (IIb) is then reacted with the compound of formula (IIc) to give the compound of formula (IId):

ここで、「Ｈａｌ」は、ハロゲンである；「Ａｒ」、Ｇ、ＺおよびＲ^５は、上で定義したとおりである；そして「−−−−」は、任意の化学結合である：

Where “Hal” is a halogen; “Ar”, G, Z and R ⁵ are as defined above; and “----” is any chemical bond:

ここで、Ｒ^１は、Ｂに結合されている；Ｒ^２は、Ｊに結合されている；Ｒ^３は、Ｈである；Ａ、Ｂ、ＤおよびＪは、別個に、−ＣＨである；Ｒ^１およびＲ^２は、別個に、アルコキシ基またはアリールオキシ基である；Ｒ^４は、３位置および４位置で必要に応じてアルコキシ基またはアラルコキシ基で置換されたフェニル基である；そして他の全ての記号は、上で定義したとおりである。

Where R ¹ is bound to B; R ² is bound to J; R ³ is H; A, B, D and J are independently —CH; R ¹ and R ² are independently an alkoxy group or an aryloxy group; R ⁴ is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the 3 and 4 positions; and other All symbols are as defined above.

This reaction, a base (e.g., NaH, KH, KOtBu, KOAc , NaOAc, NaOEt, KOEt, n-BuLi, s-BuLi, t-BuLi, LDA, Na 2 CO 3, K 2 CO 3, NaHCO 3, KHCO ₃ , NaOH or KOH). This reaction is optionally carried out in the presence of a solvent (eg, DMF, DMSO, HMPA, 1,4-dioxane, acetone, dimethyl ether, diethyl ether, THF, or mixtures thereof). The reaction temperature can be maintained at about −30 ° C. to 150 ° C., such as about 30 ° C. to about 100 ° C. The duration of this reaction can be from about 1 hour to about 50 hours, such as from about 2 hours to about 25 hours. The reaction _is under an inert atmosphere of N 2, Ar or He, may be performed.

  Finally, the compound of formula (IId) is condensed with the compound of formula (IIe) to give the compound of formula (II).

ここで、Ｆ、ＹおよびＹは、上で定義したとおりである：

Where F, Y and Y are as defined above:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

This condensation can be carried out using a base such as Et ₃ N, diethylamine, diisopropylethylamine, diisopropylamine, DBU, piperidine, or any mixture thereof. The reaction can be carried out in the presence of an acid (eg, benzoic acid, formic acid, acetic acid, or any mixture thereof). This reaction can be carried out in the presence of a solvent such as benzene, toluene, xylene, ethanol, i-propanol, butanol, DMF, DMSO, 1,4-dioxane, or any mixture thereof. The reaction can be maintained at a temperature of about 30 ° C to about 300 ° C, such as about 50 ° C to about 200 ° C. The duration of this reaction can be from about 10 hours to about 150 hours, such as from about 20 hours to about 80 hours. The reaction _is under an inert atmosphere of N 2, Ar or He, may be performed.

(Method 2)
According to another aspect of the invention, a method for preparing a compound of formula (II) is provided. All symbols are as defined above except that X and E are O.

まず最初に、式（ＩＩｆ）の化合物は、式（ＩＩｇ）の化合物にアシル化される：

First, a compound of formula (IIf) is acylated to a compound of formula (IIg):

ここで、ＸおよびＥは、Ｏである；そして他の全ての記号は、上で定義したとおりである：

Where X and E are O; and all other symbols are as defined above:

このアシル化は、アシル化剤（例えば、無水酢酸）を使用して、実行され得る。この反応は、必要に応じて、塩基（例えば、Ｎａ_２ＣＯ_３、Ｋ_２ＣＯ_３、ＮａＨＣＯ_３、ＫＨＣＯ_３、ＮａＯＨ、ＫＯＨ、またはそれらの任意の混合物）の存在下にて、実行される。この反応は、約−３０℃〜約１５０℃、例えば、約１０℃〜約５０℃の温度で、維持され得る。この反応の持続時間は、約１０分間〜約５時間、例えば、約２０分間〜約２時間であり得る。

This acylation can be carried out using an acylating agent such as acetic anhydride. This reaction is optionally performed in the presence of a base (eg, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, or any mixture thereof). The reaction can be maintained at a temperature of about −30 ° C. to about 150 ° C., such as about 10 ° C. to about 50 ° C. The duration of this reaction can be from about 10 minutes to about 5 hours, such as from about 20 minutes to about 2 hours.

  The compound of formula (IIg) can then be rearranged to the compound of formula (IIh):

ここで、ＸおよびＥは、Ｏである；そして他の全ての記号は、上で定義したとおりである。こり反応は、必要に応じて、溶媒（例えば、ＤＣＭ、ＣＨＣｌ_３、１，２−ジクロロエタン、四塩化炭素、二硫化炭素、ニトロベンゼン、１，２−ジクロロベンゼン、またはそれらの任意の混合物）の存在下にて、実行される。この反応は、ルイス酸（例えば、塩化アルミニウム（ＡｌＣｌ_３）、塩化亜鉛（ＺｎＣｌ_２）または塩化スズ（ＳｎＣｌ_４））の存在下にて、またはＵＶ光の存在下にて、実行され得る。その反応温度は、約５０℃〜約３００℃、例えば、約８０℃〜約２００℃で維持され得る。この反応の持続時間は、約１０分間〜約５０時間、例えば、約２０分間〜約１０時間であり得る。この反応は、無水反応条件下にて、実行され得る。

Where X and E are O; and all other symbols are as defined above. The scraping reaction is optionally carried out in the presence of a solvent (eg DCM, CHCl ₃ , 1,2-dichloroethane, carbon tetrachloride, carbon disulfide, nitrobenzene, 1,2-dichlorobenzene, or any mixture thereof). Below is executed. This reaction can be carried out in the presence of a Lewis acid (eg, aluminum chloride (AlCl ₃ ), zinc chloride (ZnCl ₂ ) or tin chloride (SnCl ₄ )) or in the presence of UV light. The reaction temperature may be maintained at about 50 ° C. to about 300 ° C., such as about 80 ° C. to about 200 ° C. The duration of this reaction can be from about 10 minutes to about 50 hours, such as from about 20 minutes to about 10 hours. This reaction can be carried out under anhydrous reaction conditions.

  The compound of formula (IIh) is then condensed to the compound of formula (IIi):

ここで、ＸおよびＥは、Ｏを表わし、そして他の全ての記号は、上で定義したとおりである。その反応は、塩基（例えば、Ｎａ_２ＣＯ_３、Ｋ_２ＣＯ_３、ＮａＨＣＯ_３、ＫＨＣＯ_３、ＮａＯＨ、ＫＯＨ、またはそれらの任意の混合物）の存在下にて、実行される。その反応温度は、約−３０℃〜約５０℃、例えば、約０℃〜約２０℃で維持され得る。この反応の持続時間は、約２時間〜約５０時間、例えば、約５時間〜約２０時間であり得る。

Where X and E represent O, and all other symbols are as defined above. The reaction is performed in the presence of a base (eg, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, or any mixture thereof). The reaction temperature can be maintained at about −30 ° C. to about 50 ° C., such as about 0 ° C. to about 20 ° C. The duration of this reaction can be from about 2 hours to about 50 hours, such as from about 5 hours to about 20 hours.

  The compound of formula (IIi) then undergoes a cyclization reaction to form the compound of formula (IIb):

ここで、全ての記号は、上で定義したとおりである。この反応は、塩基（例えば、Ｎａ_２ＣＯ_３、ＫＣＯ_３、ＮａＨＣＯ_３、ＫＨＣＯ_３、ＮａＯＨ、ＫＯＨ、またはそれらの任意の混合物）を使用して、実行される。その反応温度は、約−３０℃〜約５０℃、例えば、約−５℃〜約３０℃で維持され得る。この反応の持続時間は、約０．５時間〜約１０時間、例えば、約０．２時間〜約５時間であり得る。

Here, all symbols are as defined above. This reaction is performed using a base (eg, Na ₂ CO ₃ , KCO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, or any mixture thereof). The reaction temperature can be maintained at about −30 ° C. to about 50 ° C., such as about −5 ° C. to about 30 ° C. The duration of this reaction can be from about 0.5 hours to about 10 hours, such as from about 0.2 hours to about 5 hours.

  The compound of formula (IIb) is then reacted with the compound of formula (IIc) to give the compound of formula (IId):

ここで、「Ｈａｌ」は、ハロゲンである；そして他の全ての記号は、上で定義したとおりである：

Where “Hal” is halogen; and all other symbols are as defined above:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

  The compound of formula (IId) is then reacted with the compound of formula (IIe) to give the compound of formula (II):

ここで、Ｆは、Ｏ、Ｓまたは−ＮＲである；Ｙ^１およびＹ^２は、別個に、ＯまたはＳである：

Where F is O, S or —NR; Y ¹ and Y ² are independently O or S:

ここで、ＥおよびＸは、Ｏである；そして他の全ての記号は、上で定義したとおりである。

Where E and X are O; and all other symbols are as defined above.

  Conversion of the compound of formula (lib) to the compound of formula (II) is carried out as provided in Method 1.

(Method 3)
According to another aspect of the present invention, a method for preparing a compound of formula (II) is provided:

ここで、Ｘは、Ｏであり、Ｅは、−ＮＲであり、そして他の全ての記号は、上で定義したとおりである。

Where X is O, E is —NR, and all other symbols are as defined above.

  First of all, the compound of formula (IIj) is converted to the compound of formula (IIk):

ここで、全ての記号は、上で定義したとおりである：

Where all symbols are as defined above:

ここで、全ての記号は、上で定義したとおりである。この反応は、塩基（例えば、Ｎａ_２ＣＯ_３、Ｋ_２ＣＯ_３、ＮａＨＣＯ_３、ＫＨＣＯ_３、ＮａＯＨ、ＫＯＨ、またはそれらの任意の混合物）を使用して、実行され得る。この反応は、溶媒（例えば、ベンゼン、トルエン、キシレン、メタノール、エタノール、ｉ−プロパノール、ブタノール、ＤＭＦ、ＤＭＳＯ、１，４−ジオキサン、またはそれらの任意の混合物）の存在下にて、実行され得る。その反応温度は、約−３０℃〜約１５０℃、例えば、約２０℃〜約８０℃で維持され得る。この反応の持続時間は、約０．５時間〜約２０時間、例えば、約２時間〜約１０時間であり得る。

Here, all symbols are as defined above. This reaction can be carried out using a base, such as Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, or any mixture thereof. This reaction can be carried out in the presence of a solvent such as benzene, toluene, xylene, methanol, ethanol, i-propanol, butanol, DMF, DMSO, 1,4-dioxane, or any mixture thereof. . The reaction temperature can be maintained at about −30 ° C. to about 150 ° C., such as about 20 ° C. to about 80 ° C. The duration of this reaction can be from about 0.5 hours to about 20 hours, such as from about 2 hours to about 10 hours.

  The compound of formula (Ilk) is then reacted with the compound of formula (IIm) to give the compound of formula (IIn):

ここで、「Ｈａｌ」は、ハロゲンであり、そしてＲ^４は、上で定義したとおりである：

Where “Hal” is halogen and R ⁴ is as defined above:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

This reaction can occur in the presence of a brominating agent such as bromine, aqueous bromine, N-bromosuccinimide, copper bromide, or any mixture thereof. The solvent is acetic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, dichloromethane (DCM), chloroform (CHCl ₃ ), 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, or those Any mixture. This reaction can be carried out in the presence of a catalytic amount of hydrobromic acid. The reaction temperature can be about −10 ° C. to about 150 ° C., such as about 0 ° C. to about 40 ° C. The duration of this reaction can be from about 1 hour to about 72 hours, such as from about 1 hour to about 20 hours.

Alternatively, this reaction can be carried out using a solvent (eg acetonitrile, DMF, DMSO, DCM, CHCl ₃ , 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, HMPA, 1,4-dioxane, acetone, dimethyl ether. , Diethyl ether, THF, water, or any mixture thereof). This reaction, a base (e.g., NaH, KH, KOtBu, KOAc , NaOAc, n-BuLi, s-BuLi, t-BuLi, LDA, Na 2 CO 3, K 2 CO 3, NaHCO 3, KHCO 3, NaOH, Can be carried out in the presence of KOH, an amine (eg, Et ₃ N, diethylamine, diisopropylethylamine, diisopropylamine), DBU, or any mixture thereof). The reaction temperature can be about −78 ° C. to about 150 ° C., such as about −30 ° C. to 40 ° C. The duration of this reaction can vary from about 10 minutes to about 72 hours, such as from about 30 minutes to about 15 hours. This reaction can be carried out under an inert atmosphere maintained with N ₂ , Ar or He.

  The compound of formula (IIn) is then converted to the compound of formula (IIb):

ここで、Ｘは、Ｏであり、Ｅは、−ＮＲであり、そして他の全ての記号は、上で定義したとおりである。この反応は、ポリリン酸を使用して、実行され得る。必要に応じて、この反応は、溶媒（例えば、アセトニトリル、ＤＭＳＯ、１，４−ジオキサン、ＴＨＦ、水、またはそれらの任意の混合物）の存在下にて、実行され得る。その反応温度は、約０℃〜３００℃、例えば、約５０℃〜約１８０℃であり得る。この反応の持続時間は、約１０分間〜約７２時間、例えば、約２〜１５時間であり得る。この反応は、Ｎ_２、ＡｒまたはＨｅで維持される不活性雰囲気下にて、実行され得る。

Where X is O, E is —NR, and all other symbols are as defined above. This reaction can be carried out using polyphosphoric acid. If necessary, this reaction can be carried out in the presence of a solvent such as acetonitrile, DMSO, 1,4-dioxane, THF, water, or any mixture thereof. The reaction temperature can be from about 0 ° C to 300 ° C, such as from about 50 ° C to about 180 ° C. The duration of this reaction can be about 10 minutes to about 72 hours, such as about 2 to 15 hours. This reaction can be carried out under an inert atmosphere maintained with N ₂ , Ar or He.

  The compound of formula (IIb) is then reacted with the compound of formula (IIc) to give the compound of formula (IId):

ここで、全ての記号は、上で定義したとおりである：

Where all symbols are as defined above:

ここで、Ｅは、−ＮＲであり、そして他の全ての記号は、上で定義したとおりである。

Where E is -NR, and all other symbols are as defined above.

  The compound of formula (IId) is then reacted with the compound of formula (IIe) to give the compound of formula (II):

ここで、全ての記号は、上で定義したとおりである：

Where all symbols are as defined above:

ここで、Ｘは、Ｏであり、Ｅは、−ＮＲであり、そして他の全ての記号は、上で定義したとおりである。

Where X is O, E is —NR, and all other symbols are as defined above.

(Method 4)
According to another aspect of the present invention, a method for preparing a compound of formula (IV) is provided. This method includes the following steps:

ここで、全ての記号は、上で定義したとおりである。

Here, all symbols are as defined above.

Conversion of a compound of formula (IVa) to a compound of formula (IVc) can be accomplished using a suitable acyl chloride of formula IVb using a base (eg, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, triethylamine, diisopropylethylamine, or any mixture thereof). The reaction is carried out in the presence of a solvent (eg, benzene, toluene, xylene, DMF, DMSO, 1,4-dioxane, dichloromethane, CHCl ₃ , 1,2-dichloroethane, carbon tetrachloride, or any mixture thereof). Can be executed. The reaction temperature can be maintained at about −30 ° C. to about 150 ° C., such as about 20 ° C. to about 80 ° C. The duration of this reaction can be from about 6 hours to about 72 hours, such as from about 2 hours to about 24 hours. The reaction _is under an inert atmosphere of N 2, Ar or He, may be performed.

Conversion of a compound of formula (IVc) to a compound of (IVd) can be accomplished by using a base (eg, NaH, KH, KOtBu, KOAc, NaOAc, NaOEt, KOET, n-BULi, s-BULi, t-BULi, LDA, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, or any mixture thereof). The reaction can be carried out in a solvent such as benzene, toluene, xylene, methanol, ethanol, i-propanol, t-butanol, or any mixture thereof. The reaction temperature may be maintained at about −70 ° C. to about 250 ° C., such as about −10 ° C. to about 150 ° C. The duration of the reaction can be from about 5 hours to about 150 hours, such as from about 20 to about 100 hours. The reaction _is under an inert atmosphere of N 2, Ar or He, may be performed.

  Conversion of the compound of formula (IVd) to the compound of formula (IV) may be carried out as provided in Method 1.

(Method 5)
According to another aspect of the present invention, a method for preparing a compound of formula (Va) is provided. This method includes the following steps:

式（ＩＩｂ）の化合物の式（ＩＩｄ）の化合物への変換は、方法１で提供したとおりに実行され得る。式（ＩＩｄ）の化合物の式（Ｖａ）の化合物への変換は、試薬（例えば、ＥＤＣＩまたはＣＤＩ）および溶媒（例えば、ＤＭＦ、クロロホルム、ジクロロメタン、ジメチルアセトアミド、テトラヒドロフラン、ジオキサン、エーテル、またはそれらの任意の混合物）の存在下にて、式（ＩＩｄ）の化合物と式（ＩＩｐ）の化合物とを反応させることにより、実行され得る。その反応の温度は、約１０℃〜約６０℃、例えば、約２０℃〜約３５℃で維持され得る。この反応の持続時間は、約５時間〜約１２時間、例えば、約１０時間〜約１２時間であり得る。この反応は、窒素雰囲気下にて、実行され得る。

Conversion of the compound of formula (IIb) to the compound of formula (IId) may be carried out as provided in Method 1. Conversion of a compound of formula (IId) to a compound of formula (Va) can be accomplished by reagent (eg, EDCI or CDI) and solvent (eg, DMF, chloroform, dichloromethane, dimethylacetamide, tetrahydrofuran, dioxane, ether, or any of them Can be carried out by reacting the compound of formula (IId) with the compound of formula (IIp) in the presence of a mixture of The temperature of the reaction can be maintained at about 10 ° C to about 60 ° C, such as about 20 ° C to about 35 ° C. The duration of this reaction can be from about 5 hours to about 12 hours, such as from about 10 hours to about 12 hours. This reaction can be carried out under a nitrogen atmosphere.

(Method 6)
According to another aspect of the invention, a method for preparing a compound of formula (Vb) is provided.

この方法は、以下の工程を包含する：

This method includes the following steps:

式（ＶＩａ）の化合物の式（ＶＩｂ）の化合物への変換は、ホルムアミドの存在下にて、窒素雰囲気で、実行される。その反応の温度は、約１０℃〜約７０℃、例えば、２５℃〜約４５℃で維持され得る。この反応の持続時間は、約１時間〜約９時間、例えば、約２〜約４時間であり得る。

The conversion of the compound of formula (VIa) to the compound of formula (VIb) is carried out in the presence of formamide in a nitrogen atmosphere. The temperature of the reaction can be maintained at about 10 ° C to about 70 ° C, such as 25 ° C to about 45 ° C. The duration of this reaction can be from about 1 hour to about 9 hours, such as from about 2 to about 4 hours.

  Conversion of the compound of formula (VIb) to the compound of formula (Vb) is carried out as provided in Method 5.

  It should be understood that in any of the reactions presented here, any reactive group in the substrate molecule can be protected according to conventional chemical methods. Suitable protecting groups include, for example, tertiary butyldimethylsilyl, methoxymethyl, triphenylmethyl, benzyloxycarbonyl, tetrahydropyran (THP); amino or anilino groups to protect hydroxyl groups or phenolic hydroxyl groups. N-tert-butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenylmethoxycarbonyl (-N-FMOC), benzophenone imine, propargyloxycarbonyl ( POC); aldehydes include acetal protection and ketones include ketal protection. Methods for forming and removing such protecting groups include conventional methods appropriate for the molecule to be protected.

  Enantiomers of compounds of formula (II) can be obtained by using their single enantiomeric form of the reactants in the appropriate method or by reacting the reaction in the presence of a reagent or catalyst. It can be prepared by performing in enantiomeric form. These single enantiomers can be prepared by resolving the racemic mixture by conventional methods.

  Stereoisomers of the compounds of the invention can be reacted in their single enantiomeric form in the presence of a reagent or catalyst by using the reactants in their single enantiomeric form in this way. Or by resolving a mixture of stereoisomers in the usual manner. Some of these methods include the use of microbial resolution, diastereomeric salts formed wherever chiral acids (eg, mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid) or chiral bases (eg, brucine, Cinchona alkaloids and their derivatives). Commonly used methods are compiled in JAQUES, ENANTIOMERS, and RACEMATES AND RESOLUTION (1981). Where appropriate, compounds of formula (I) can be resolved by: treatment with chiral amines, amino acids, amino alcohols derived from amino acids; converting acids to amides using normal reaction conditions; Separating the diastereomers by fractional crystallization or chromatography; and preparing the stereoisomers of the compound of formula (I) by hydrolyzing the pure diastereomeric amides.

  The stereoisomers of the present invention may also include E and Z isomers or mixtures thereof in various proportions.

(Prescription and pharmaceutical composition)
The present invention relates to pharmaceutical compositions containing one or more compounds of general formula (I), their salts, in combination with a compound of general formula (I), pharmaceutically acceptable carriers and diluents, Or a pharmaceutically acceptable composition thereof.

  The pharmaceutical compositions of the present invention can be used to treat bacterial infections. They can also be used to treat bacterial infections associated with multidrug resistance. The pharmaceutical compositions of the invention can also be used to modulate inflammatory responses, particularly those resulting from AGE and glycated protein accumulation. The pharmaceutical compositions of the invention can also be used to modulate smooth muscle cell proliferation and related diseases or conditions. The compositions provided herein also include vascular occlusion conditions (eg, stenosis, restenosis and atherosclerosis); diseases mediated by inflammation (eg, autoimmune diseases); and hyperproliferative diseases ( For example, it can be used to treat cancer).

(A. Pharmaceutically acceptable salt)
The compositions of the present invention optionally include one or more salts of the compounds of the present invention contained therein. Such salts are commonly referred to as non-toxic “pharmaceutically acceptable salts”. However, in preparing the compounds of the invention or their pharmaceutically acceptable salts, other salts may be useful. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts (eg, solutions of the compound such as pharmaceutically acceptable acids (eg, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid). , Succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, or any mixture thereof). In addition, when the compounds of the present invention comprise an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts (eg, sodium or potassium salts); alkaline earth salts (eg, calcium salts or A magnesium salt); a salt formed with a suitable organic ligand (eg a quaternary ammonium salt); or any mixture thereof.

  Examples of pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bicarbonate, bitartrate, borate, bromide, calcium edetate, camsylate , Carbonate, chloride, clavulanic acid, citrate, dihydrochloride, edetate, edesylate, estolate, esylate, fumarate, glucoceptate, glucone Acid, glutamic acid, glycolylarsanylate, hexyl resorinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobion Acid salt, laurin Salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitride, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamo Acid salt (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, basic acetate, succinate, tannin Acid salts, tartrate salts, teocrate, tosylate, triethiodide and valerate are included, but are not limited to these.

(B. Alternative shape compounds)
If the compounds of the invention have at least one chiral center, they can therefore exist as enantiomers accordingly. These compounds can exist as diastereomers if they have two or more chiral centers. If the invention has geometric isomers, it should be understood that all such isomers and mixtures thereof are included within the scope of the invention. Furthermore, some of the crystal forms of these compounds may exist as polymorphs and can be considered in the present invention. In addition, some of these compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also intended to be encompassed by the present invention. Is done. If the process for preparing the compounds according to the invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques (eg preparative chromatography).

  In addition, the compounds of the invention can be prepared in racemic form. Alternatively, individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. These compounds are salts using standard techniques such as optically active acids such as (+) di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-1-tartaric acid. Subsequent to formation, the free base can be separated into their component enantiomers by fractional crystallization and regeneration). These compounds can also be resolved by forming diastereomeric esters followed by chromatographic separation and removal of chiral auxiliary. Alternatively, these compounds can be resolved using a chiral HPLC column.

  The compounds of the invention are formulated and administered as prodrugs as appropriate. In general, prodrugs contain functional derivatives of the claimed compounds, which can be enzymatically activated or converted into more active parent forms. Therefore, in the methods of treatment of the present invention, the term “administering” refers to a specifically disclosed compound or a compound that is not specifically disclosed but that is converted to a specific compound in vivo after administration to a patient. Including treating various disorders. The usual procedure for selecting and preparing suitable prodrug derivatives is described, for example, in DESIGN OF PRODRUGS (1985); Wihnan, 14 BIOCHEM. Soc. TRANS. 375-82 (1986); STELLA et al., Prodrugs: A Chemical Approach to Targeted Drug Delivery in DIRECTED DRUG DELIVERY 247-67 (1985), each of which is incorporated herein by reference. Yes.

  The prodrugs of the present invention include phosphate-containing prodrugs, thiophosphate-containing prodrugs, and sulfate-containing prodrugs. Peptide-containing prodrugs, D-amino acid-containing prodrugs, glycated prodrugs, β-lactam-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorouridine prodrugs, and other 5-fluorouridine prodrugs Drugs, which can be converted into more active prodrugs.

  Enzymes that can be used in the methods and compositions of the present invention include, but are not limited to: alkaline phosphatase for converting phosphate-containing prodrugs to free drugs; converting sulfate-containing prodrugs to free drugs An arylsulfatase to convert; a cytosine deaminase to convert non-toxic 5-fluorocytosine to an anticancer agent; a proteolytic enzyme to convert a peptide-containing prodrug to a free drug (eg, serratia proteolytic enzyme, Thermolysin, subtilisin, carboxypeptidase, and cathepsins (eg, cathepsins B and L)); D-alanyl carboxypeptidases for converting prodrugs containing D-amino acid substituents; Hydrocarbon-cleaving enzymes for conversion (eg, β-galactosidase and neuraminidase); β-lactamases for converting drugs derivatized with β-lactams to free drugs; and phenoxyacetyl groups at their amine nitrogens or Penicillin amidase (eg, penicillin V amidase or penicillin G amidase) for converting each drug derivatized with a phenylacetyl group into a free drug.

  Alternatively, antibodies with enzymatic activity (also known in the art as “abzymes”) can be used to convert the prodrugs of the invention into free active agents. See, for example, Massey, 328 NATURE 457-48 (1987).

(C. Pharmaceutical adjuvant)
In addition to the compounds contemplated by the present invention, the pharmaceutical compositions of the present invention may further comprise at least one suitable adjuvant or carrier (eg, diluent, binder, stabilizer, buffer, salt, lipophilicity). Solvent, preservatives, adjuvants, or any combination thereof). Examples and methods for preparing such sterile solutions are described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)), the contents of which are described in their entirety. Incorporated herein by reference. In general, a pharmaceutically acceptable carrier suitable for the mode of administration, solubility and / or stability of the compound can be selected.

  Pharmaceutical excipients and additives useful in the present invention include proteins, amino acids and carbohydrates (eg, saccharides (monosaccharides, disaccharides, trisaccharides, tetrasaccharides and oligosaccharides); derivatized saccharides (eg, alditol, Aldonic acids, esterified sugars); and polysaccharides)), but are not limited to these, they are present one at a time or in combination, alone or in combination, of 1-99. It is contained in the range of 99%. Exemplary protein excipients include serum albumin (eg, human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, or any combination thereof). Typical amino acid components (which can also function in buffer capacity) include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame Can be mentioned.

  Suitable carbohydrate excipients for use in the present invention include, for example, monosaccharides (eg, fructose, maltose, galactose, glucose, D-mannose, sorbose); disaccharides (eg, lactose, sucrose, trehalose, Cellobiose); polysaccharides (eg raffinose, meletitol, maltodextrin, dextran, starch); and alditols (eg mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myo-inositol).

  The pharmaceutical composition containing the compound of the present invention also contains a buffer or a pH adjusting agent. Typically, this buffer is a salt prepared from an organic acid or organic base. Exemplary buffers include salts of organic acids (eg, citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid salts); Tris, tromethamine hydrochloride or phosphate buffer Or any combination thereof.

  Furthermore, the pharmaceutical composition of the present invention can be prepared by using a polymer excipient / additive (eg, polyvinylpyrrolidone, ficoll (polymer sugar), dextrate (eg, cyclodextrin (eg, 2-hydroxypropyl), as necessary. -Β-cyclodextrin)), polyethylene glycol), flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (eg polysorbates (eg “TWEEN 20” and “TWEEN 80”)) , Lipids (eg, phospholipids, fatty acids), steroids (eg, cholesterol) and chelating agents (eg, EDTA), and any combination thereof. Representative pharmaceutical excipients and / or additives include, for example, REMINGTON: THE SCIENCE & PRACTICE OF PHARMACY (1995), Williams & Williams (1995)) and PHYSICIAN'S DESK REFERence (1998)), the contents of each of which are incorporated herein by reference.

(1. Pharmaceutical composition for oral administration)
For oral administration in the form of a tablet or capsule, the compound is combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, or any combination thereof. obtain. In addition, suitable binders, lubricants, disintegrants and colorants can also be incorporated into the mixture. Suitable binders include, but are not limited to: starch; gelatin; natural sugars (eg glucose or β-lactose); corn sweeteners; natural and synthetic gums (eg acacia, tragacanth or Sodium alginate, carboxymethylcellulose); polyethylene glycol; wax; or any combination thereof. Lubricants used in these dosage forms include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or any combination thereof. . Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, or any combination thereof.

  Formulations of the present invention suitable for oral administration are as individual units (eg, cachets or tablets, each containing a predetermined amount of active ingredient); as powders or granules; aqueous or non-aqueous liquids As a solution or suspension in; or as an oil-in-water liquid emulsion or water-in-oil emulsion and as a bolus.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are typically prepared by compressing the active ingredient in a free-flowing form (eg, a powder or granules) with a suitable machine, optionally with a binder, lubricant, inert diluent, Mixed with preservatives, surfactants or dispersants. Molded tablets are typically made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. These tablets may be coated or cut as needed and formulated to give a delayed or controlled release of the active ingredient therein.

  The compositions of the present invention are optionally incorporated into biodegradable polymers, thereby permitting sustained release of the compound. These polymers can be used where drug release is desired (eg, restenosis). Transplanted near the site. Such biodegradable polymers and their uses are described, for example, in Brem et al., 74 J. MoI. NEUROSURG. 441-46 (1991). Suitable examples of sustained release compositions include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the present invention, and these matrices are formed into molded articles (eg, films or microcapsules). The Examples of sustained release matrices include polyesters, hydrogels (eg, poly (2-hydroxyethyl) methacrylate or poly (vinyl alcohol)), polylactic acid (US Pat. No. 3,773,919); L-glutamic acid and ethyl-L-glutamic acid copolymer, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer (e.g. LUPRON), which is incorporated herein by reference in its entirety. DEPOT® (Tap Pharmaceuticals, Inc., Chicago, IL) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3- Hydroxybutyric acid is mentioned.

(2. Pharmaceutical composition for parenteral administration)
“Parenteral” as used herein includes subcutaneous injections, intravenous, intramuscular, intraperitoneal injection, or infusion techniques. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which make the antioxidant, buffer, bacteriostatic and its formulation isotonic with the blood of the intended recipient. Solutes); and aqueous and non-aqueous sterile suspensions, which optionally contain suspending agents and thickeners. These formulations can be presented in unit dose or multi-dose containers (eg, sealed ampoules and vials) and stored in a lyophilized state, which contains a sterile liquid carrier (eg, for injection) just prior to use. It is only necessary to add water). Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets (eg, those described above).

  For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. These pharmaceutical compositions can be administered parenterally by injecting a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Acceptable liquid carriers include, for example, but are not limited to, vegetable oils (eg, peanut oil, cottonseed oil, sesame oil) and organic solvents (eg, solketal, glycerol formal). These formulations are prepared by dissolving or suspending the active ingredient in a liquid carrier such that the final formulation contains from about 0.005% to 30% by weight of the active ingredient (ie, a compound of the invention). Can be prepared.

(3. Pharmaceutical compositions for other routes of administration)
Formulations suitable for topical administration in the mouth include medicinal drops containing the ingredients in seasoned bases or vehicles (eg, sucrose and acacia or tragacanth); inert bases or vehicles (eg, gelatin and glycerin) Or sucrose and acacia), and gargles, which contain compounds to be administered in a suitable liquid carrier. These liquid forms may include suitably flavored suspending or dispersing agents such as synthetic and natural gums, tragacanth, acacia, and methylcellulose.

  Formulations for rectal administration may be presented as suppositories with appropriate bases, which contain, for example, cocoa butter or a salicylate.

  Formulations suitable for intravaginal administration can be presented as pessaries, tampons, gels, pastes, foams or spray formulations containing the active ingredient and a suitable carrier.

  These compounds can also be incorporated into microcapsules, for example in colloidal drug delivery systems (eg liposomes, albumin globules, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. In coacervation technology or interfacial polymerization (hydroxymethylcellulose or gelatin-microcapsules and poly (methyl methacrylate) microcapsules, respectively). REMINGTON'S PHARMACEUTICAL SCIENCES (A. Osol, 16th edition, (1980)), the contents of which are hereby incorporated by reference in their entirety.

  The compounds considered in the present invention are formulated as liposomes as needed. Liposomes can be obtained by any suitable method (eg, US Pat. Nos. 5,013,556; 4,485,045; 4,544,545; WO 97/38731; Epstein et al., 82 PROC. NATL. ACAD.SCI.USA 3688 (1985); and Hwang et al., 77 PROC.NATL.ACAD.SCI.USA 4030 (1980), each of which is incorporated herein by reference in its entirety. As described). The compounds of the present invention can also be administered in the form of liposome delivery systems (eg, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles). Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  The compounds of the invention can also be delivered by using monoclonal antibodies as individual carriers for coupling the compound molecules. The compounds of the invention can also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol or polyethylene oxide polylysine (which is optionally substituted with palmitoyl residues) Can be mentioned.

(D. Pharmaceutically acceptable preservatives)
The present invention provides stable formulations, preservative solutions and formulations containing preservatives, and multipurpose preservative formulations suitable for pharmaceutical or veterinary applications, which are in a pharmaceutically acceptable formulation. Contains at least one compound considered in the present invention. The preservative formulation contains at least one known preservative, including at least one of the following: phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercury nitrite, phenoxyethanol, Formaldehyde, chlorobutanol, magnesium chloride (eg hexahydrate), alkylparabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or those in aqueous diluent Any mixture of. Any suitable concentration (eg, 0.001-5%) or mixture, any range or value therein can be used, including 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4. 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1 .7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4 .5, 4.6, 4.7, 4.8, 4.9, but is not limited thereto. Non-limiting examples include no preservative, 0.1-2% m-cresol (eg, 0.1, 0.2, 0.3.0.4, 0.5, 0.9, 1 0.0%), 0.1-3% benzyl alcohol (eg, 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001 -0.5% thimerosal (eg 0.005, 0.01), 0.001-2.0% phenol (eg 0.05, 0.25, 0.28, 0.5,. 9, 1.0%), and 0.0005 to 1.0% alkyl parabens (eg, 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009). 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%) Mentioned That.

  If necessary, other excipients (for example, isotonic agents, buffers, antioxidants, antiseptics) can be added to the diluent. Isotonic agents (eg, glycerin) are typically used at known concentrations. A physiologically acceptable buffer is typically added to increase pH control. These formulations can include a wide range of pH (eg, from about pH 4 to about pH 10, specifically in the range of about pH 5 to about pH 9, more specifically in the range of about 6.0 to about 8.0). According to one aspect of the present invention, the formulations of the present invention have a pH between about 6.8 and about 7.8. Suitable buffers include phosphate buffers (eg, sodium phosphate and phosphate buffered saline (PBS)).

  These pharmaceutical compositions include other additives (eg, solubilizers (eg, Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40) as needed to reduce aggregation. (Polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene-polyoxypropylene block copolymer) and PEG (polyethylene glycol)) Or a non-ionic surfactant (eg, polysorbate 20 or 80, or poloxamer 184 or 188, Pluronic® polyol, other block copolymers), and chelating agents (eg, EDTA and EGTA) These additives are particularly useful if a pump or plastic container is used to administer the pharmaceutical composition.The presence of a pharmaceutically acceptable surfactant indicates that the composition is Reduce the tendency to agglomerate.

During any process of preparing the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is a common protecting group (eg PROTECTIVE GROUPS IN ORGANIC CHEMISTRY (1973); and GREEN AND
WUTS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991), each of which is incorporated by reference herein in its entirety. These protecting groups can be removed at a subsequent convenient stage using methods known in the art.

(E. Combination therapy)
In addition, the compounds of the present invention and other therapeutic agents that exist naturally or can be made by recombinant methods (eg, chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, nucleolytic compounds, radioisotopes, Simultaneous or sequential administration of the receptor, prodrug activating enzyme) may be desired. Combination administration includes simultaneous administration using separate formulations or a single pharmaceutical formulation, as well as sequential administration in either order, where both (or all) active therapeutic agents are biologically active. There is a period in which activity is exerted simultaneously.

  The compounds of the present invention are optionally administered in combination with at least one selected from the group consisting of: an anti-rheumatic drug (eg, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept) ), Sodium gold thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), muscle relaxant, hypnotic, non-steroidal anti-inflammatory (NSAID), antiallergic agent, anesthetic, sedative, Local anesthetics, neuromuscular blocking agents, anticancer agents, antibacterial agents (eg, aminoglycosides, antifungal agents, anthelmintic agents, antiviral agents, carbapenem, cephalosporin, fluoroquinolone ), Macrolide, penicillin, sulfonamide, tetracycline, another antibacterial agent), anti-psoriatic agent, corticosteroid, anabolic steroid, diabetes-related agent, mineral, thyroid agent, vitamin, Calcium-related hormones, diarrhea, cough, antiemetics, antiulcers, laxatives, anticoagulants, erythropoietin (eg, epotin alpha), filgrastim (eg, G-CSF, Neupogen, sargramostim (GM-CSF, Leukine), immunization, immunoglobulins, immunosuppressive agents (eg, basiliximab, cyclosporine) , Daclizumab), growth hormone, hormone replacement agent, estrogen receptor module, mydriatic agent, ciliary muscle modulator, alkylating agent, antimetabolite, mitotic inhibitor, radiopharmaceutical, antidepressant, antidepressant , Antipsychotics, anxiolytics, hypnotics, sympathomimetics, stimulants, donepezil, tacrine, asthma drugs, beta agonists, steroid inhalation, leucotelin inhibitors, methylxanthine, cromolyn, epinephrine or Its analog, Dornase α (Pulmozyme), cytokine, or any combination thereof.

  Such anti-cancer or anti-bacterial compounds can also include toxin molecules that are co-administered with at least one compound of the present invention or sequentially administered in either order. The term “toxin” also includes both endotoxins and exotoxins produced by any naturally occurring, mutated or recombinant bacterium or virus, which can be any pathological in humans and other animals. Conditions (including toxin shock that can cause death) can be caused. Toxins can act to selectively kill diseased cells or tissues as needed. The pathological cell can be a cancer or other cell. Such toxins may be purified or recombinant, toxins or toxin fragments containing at least one functional cytotoxic domain of toxins (eg, ricin, diphtheria toxin, venom toxin, or bacterial toxins). Possible but not limited to. This pathological condition includes toxin shock and can lead to death. Such toxins include, but are not limited to: Enterotoxin producing E. coli. E. coli heat labile enterotoxin (LT), thermostable enterotoxin (ST), Shigella cytotoxin, Aeromonas enterotoxin, toxin shock syndrome toxin-1 (TSST-1), type A staphylococcal enterotoxin (SEA), type B staphylococcal enterotoxin (SEA) SEB), C-type staphylococcal enterotoxin (SEC), Streptococcal enterotoxin, and the like. Such bacteria include, but are not limited to: Enterotoxin producing E. coli. E. coli (ETEC) seed line, enterohemorrhagic E. coli E. coli strains (e.g., serotype 0157: H7 strain), Staphylococcus species (e.g., Staphylococcus aureus, Staphylococcus pyogenes), Shigella species (e.g. For example, Salmonella typhi, Salmonella cholera-suis, Salmonella enteritidis), Clostridium species (eg, Clostridium perfringens, Clostridium difficile, Clostridium) botulinum), Camphlobacter species (e.g., Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species (e.g., Heliobacter pylori), Aeromonas species (e.g., Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae), Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (e.g., Vibrios cholera, Vibrios parahemolyticus), Klebsiella species, Pseudomonas aeruginosa, and Streptococci. For example, Stein, INTERNAL MEDICINE, pages 1-13 (3rd edition, Little, Brown and Co., Boston) (1990); EVANS et al., BACTERIAL INFECTIONS OF HUMANS: EPIDEMOLOGY AND CONTROL, pages 239-254 (version 239-254). Medical Book Co., New York) (1991); MANDELL et al., PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES (3rd edition, Churchill Livingstone (1990); ); Wood et al., 76 FE. S MICROBIOLOGY IMMUNOLOGY 121-134 (1991); Marrack et al, 248 SCIENCE 705-711 (1990) (the contents of which is incorporated by reference is herein in its entirety) by reference.

  The compounds of the present invention can be administered in combination with at least one immunosuppressive agent for use, for example, in the treatment or prevention of vaso-occlusive conditions such as transplant vascular disorders. Suitable immunosuppressive drugs include, but are not limited to: CellCept (Roche Labs.), Gengraf (Abbott Labs., Inc.), Microgam (Ortho-Clinical), Neoral (Novatislo, Netho), Ortho. OKT3 (Ortho-Biotech), Prograf (Fujisawa), Rapamune (Wyeth-Ayerst), Sandimmune (Novartis), Thymoglobulin (SangStat), Zenapax (Roche), or any combination thereof.

  The therapeutic agent is administered with the compounds of the invention, including chemotherapeutic agents, in any order, simultaneously or sequentially at various times. A “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include: alkylating agents (eg, thiotepa and cyclophosphamide); alkyl sulfonates (eg, bubufan, improsulfan and pipersulfan); aziridine (eg, Benzodopa, carbocon, metredopa and uredopa); ethyleneimine and methylelamelamine (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaolamide and trimethylolomelamine); nitrogen mustard (eg chlorambucil, chlornafazine) , Chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembihin, phenesterine, prednisotin, trofosf Nitrourea (eg, cannustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine); antibiotics (eg, aclacinomycin, actinomycin, ausuramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, Carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, esorubicin, idamubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olivomycin, peplomycin, podophylomycin, puromycin, queramycin, rorubicin, streptonigrin , Streptozocin, tubercidine, ubenimex, dinostatin, zorubicin); Agents (eg, methotrexate and 5-fluorouracil (5-FU)); folic acid analogs (eg, denopterin, methotrexate, pteropterin, trimethrexate); purine analogs (tatoeva, fludarabine, 6-mercaptopurine, thiapurine, thioguanine); pyridine Analogs (eg, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine, 5-FU); androgens (eg, carsterone, drmostanolone propionate, test lactone); anti-adrenal (eg, , Aminoglutethimide, mitotane, trilostane); folic acid fillers (eg folic acid); acegraton; aldophosphamide glycosides; Acids; amsacrine; vestlabcil; bisantrene; edatralxate; defefamide; demecorcin; Pirarubicin; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK®; razoxan; schizofuran; spirogermanium; tenuazonic acid; triazone; 2,2 ', 2 "-trichlorotriethylamine; urethane; vindesine; dacarbazine; Mitobronitol; mitractol; pipobroman; gasitocin; arabinoside ("Ara-C"); cyclophosphine Thiotepa; taxoids (e.g., paclitaxel (TAXOL <(R)>, Bristol-Myers Squibb Oncology, Princeton, NJ) and doxetaxel (TAXOTERE <(R)>, Rhone-Cine); Rhone-Poulenc; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues (eg cisplatin and carboplatin); vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; Aminopterin; xeloda; ibandron CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; and any of the pharmaceutically acceptable salts, acids or derivatives described above. Also within this definition are anti-hormonal agents that function to modulate or inhibit the action of hormones on tumors (eg, antiestrogens (tamoxifen, raloxifene, aromatase inhibition 4 (5) -imidazole, 4-hydroxy tamoxifen, trixifene) And anti-androgens (eg, flutamide, nilutamide, bicalutamide, leuprolide and goserelin); and any of the pharmaceutically acceptable salts, acids above Or a derivative).

  The therapeutic agent includes a cytokine. The term “cytokine” is a general term for a protein released by one cell population that acts on another cell as an intracellular mediator. As used herein, the term “cytokine” refers to a biologically active equivalent of a protein from a natural source or from a recombinant cell culture, and a native sequence cytokine. including. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among cytokines are growth hormones (eg, human growth hormone, N-methionyl human growth hormone, and bovine growth hormone); thyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormone (eg, , Follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and luteinizing hormone (LH); liver growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-α and -β; Mouse gonadotropin-related peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factor (eg, NGF-β); platelet growth factor; transforming growth factor (TGF) (eg , TGF-α and TGF-β); insulin-like growth factor-I and -II-II; erythropoietin (EPO); osteoinductive factor; interferon (eg, interferon-α, -β and -γ); colony stimulating factor ( CSF) (eg, macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (GCSF)); interleukin (IL) (eg, IL-1, IL- 1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15); tumor necrosis factor (Eg, TNF-α or TNF-β); and other polypeptide factors (including LIF and kit ligand (KL)).

  The compounds of the present invention include anti-inflammatory agents (including but not limited to: corticosteroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone, and doxamethasone), Non-steroidal drugs (salicylic acid derivatives, ie aspirin; para-aminophenol derivatives, ie acetaminophen; indole and indene acetate (indomethacin, sulindac and etodolac), heteroaryl acetate (tolmethine, diclofenac and ketorolac), aryl propionate (Ibuprofen and its derivatives), anthranilic acid (mefenamic acid and meclofenamic acid), enolic acid (piroxicam, tenoxicam, Nylbutazone and oxyphetatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate)), commercially available non-steroidal anti-inflammatory drugs include: Examples include, but are not limited to: Anaprox (Roche Labs.), Arthrotec (Seale), Cataflam (Novartis), Celeblex (Pfizer), Clinoril (Merck), Dolobid (Merck), Feldene (Pc) , Lodine (Wyeth-Ayerst), Mobic (Boehringer Ingelheim), Motrin (McNeil Co.) nsummer), Naprosyn (Roche Labs.), Orudis (Wyeth-Ayerst), Oruvail (Wyeth-Ayerst), Ponsel (First Horizon), Relafen (GlaxoSmithKline), Tolectin (T). ), Vioxx (Merck), Voltaren (Novartis), Advair (GlaxoSmithKline), Flovent (GlaxoSmithKline), Pulmicort (AstraZeneca), terc (Schering) ), Dipentum (Pharmacia & Upjohn), and Rowasa (Solvay).

  In yet another embodiment, the compounds of the invention can be administered in combination with an anti-rheumatic agent. Commercially available anti-rheumatic agents include, but are not limited to: Anaprox (Roche Labs.), Arava (Aventic), Arthrotec (Searle), Azulfidine (Pharmacia & Upjohn), Cataflam (Cataflam) Pfizer), Celestone (Schering), Cuprimine (Merck), Enbrel (Immunex), Feldene (Pfizer), Gengraf (Abbott), Indocin (Merck), Lodine (Wyeth-r ), Pediapred (Celltech , Prednisone (Roxanne), Remicade (Centocor), Solu-Medrol (Pharmacia & Upjohn), Triliate (Purdue Frederick) and Voltaren (Novartis).

  In addition, the compounds of the present invention may be any cardiovascular agent, including but not limited to: adrenergic blockers (eg, Cardura (Pfizer), Dibenzyline (WellSpring), Hytrin (Abbott), Minipress (Pfizer) ) And Minizide (Pfizer)); Adrenergic stimulators (eg, Aldoclor (Merck), Aldomet (Merck), Aldoril (Merck), Catapres (Boehringer Ingelheim), Clorpres (Tex)) β-adrenergic blockers (eg, Coreg (GlaxoSmithKline) and Normodyne ( angiotensin converting enzyme inhibitors (eg, Accupri (Parke-Davis), Aceon (Solvay), Altace (Monarch), Captopril (Mylan), Enalapriat (Baxter Anesthesia), Lotte (Bristol-Myers Squibb), Priviril (Merck), Univasc (Schwarz), Vaotec (Merck) and Zestril (AstraZeneca)); angiotensin converting enzyme inhibitors (eg, Lexel (AstraZent), AstraZentec) Abbott), Accurate (Parke-Davis), Lotensin (Novartis), Prinzide (Merck), Uniretic (Schwarz), Vaeretic (Merck) and Zestoretic (AstraZeneca), Receptor (AstraZeneca) Briston-Myers Squibb), Cozaar (Merck), Diovan (Novartis), Micadis (Boehringer Ingelheim) and Teveten (Unimed)); antiarrhythmic drugs (groups I-IV), antihyperlipidemic drugs (e.g. antihyperlipidemic drugs) Sequestering agent, fibric acid derivative, H G-CoA reductase inhibitors and nicotinic acid); β-adrenergic blockers; calcium channel blockers; cardiotonic drugs; vasodilators (coronary dilators, natriuretic peptides and peripheral vasodilators); Can be used in combination.

  According to one aspect of the present invention, the therapeutic agents include small molecule toxins, including maytansine, calicheamicin, trichothene and CC 1065. According to another aspect of the invention, the therapeutic agent comprises one or more calicheamicin branches. Members of the calicheamicin family of antibiotics can produce double-strand DNA breaks below picomolar concentrations. Structured analogs of calicheamicin are also known. See Hinman et al., 53 CANCER RESEARCH 3336-42 (1993); Rode et al., 58 CANCER RESEARCH 2925-28 (1998), the contents of which are hereby incorporated by reference in their entirety. .

  In yet another aspect of the invention, the therapeutic agent can include one or more enzymatically active toxins and fragments thereof. Examples of such toxins include diphtheria toxin, diphtheria A chain, exotoxin A chain (derived from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modesin A chain, α-sarcin, dianthine protein, Phytolaca americana protein (PAP, PAPAII and PAP-S), momordica charantia inhibitor, calcin, crotin saponaaria officinalis inhibitor, gelonin, retogellin, mitogencline Enomycin and Nonbinding active fragments of trichothecenes (tricothecenes) and the like. See, for example, WO 93/21232, the contents of which are hereby incorporated by reference in their entirety.

The present invention further contemplates therapeutic agents having nucleolytic activity, such as ribonucleases and deoxyribonucleases. In addition, various radioisotopes are available for the production of radioconjugated binding partners. Examples include the radioisotopes of Y ⁹⁰ , At ²²² , Ret ⁸⁶ , Re ¹⁸⁶ , Sm ¹⁵³ , Bi ²¹² , P ³² and Lu.

  The compounds of the invention can be conjugated to receptors (eg, streptavidin) for use in tumor pretargeting. Briefly, the compound-receptor conjugate is administered to the patient and unbound conjugate is removed from the circulation along with the chelator. A ligand (eg, biotin) conjugated to a cytotoxic agent is then administered.

(1. Timing of administration)
According to one aspect of the invention, the compounds described herein are administered prior to administration of the second therapeutic agent. Administration of the compound can occur anytime minutes to hours before administration of the second therapeutic agent. The compound may alternatively be administered at any time from hours to days before the second therapeutic agent, possibly weeks and months.

  More specifically, the compound of the present invention is at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes before the second therapeutic agent. Min, at least about 7 min, at least about 8 min, at least about 9 min, at least about 10 min, at least about 11 min, at least about 12 min, at least about 13 min, at least about 14 min At least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, at least about 21 minutes, at least about 22 minutes, at least About 23 minutes, at least about 24 minutes, at least about 25 minutes, at least about 26 minutes, at least about 27 minutes, at least about 28 minutes, at least about 29 minutes At least about 30 minutes, at least about 31 minutes, at least about 32 minutes, at least about 33 minutes, at least about 34 minutes, at least about 35 minutes, at least about 36 minutes, at least about 37 minutes, at least about 38 minutes, at least about 39 minutes, at least about 40 minutes, at least about 41 minutes, at least about 42 minutes, at least about 43 minutes, at least about 44 minutes, at least about 45 minutes, at least about 46 minutes Before, at least about 47 minutes, at least about 48 minutes, at least about 49 minutes, at least about 50 minutes, at least about 51 minutes, at least about 52 minutes, at least about 53 minutes, at least about 54 minutes, At least about 55 minutes, at least about 56 minutes, at least about 57 minutes, at least about 58 minutes, at least about 59 minutes, and also Of at least about 60 minutes, may be administered.

  Further, the compound of the present invention may be at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 2 hours before the second therapeutic agent. About 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 At least about 16 hours ago, at least about 17 hours ago, at least about 18 hours ago, at least about 19 hours ago, at least about 20 hours ago, at least about 21 hours ago, at least about 22 hours ago, at least about 23 hours ago Or at least about 24 hours prior to administration.

  Further, the compounds of the present invention can be used at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 1 day before the second therapeutic agent. 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days ago, at least about 19 days ago, at least about 20 days ago, at least about 21 days ago, at least about 22 days ago, at least about 23 days ago, at least about 24 days ago, at least about 25 days ago, at least about 26 days ago, at least about 27 days ago, at least about 28 days ago, at least about 29 days ago, at least About 30 days ago, or at least about 31 days ago, it may be administered.

  The compound of the invention is at least about 1 week before, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks before the second therapeutic agent. At least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks At least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks.

  Further, the compounds of the present invention can be used at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 2 months before the second therapeutic agent. Administration may be about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

  According to another aspect of the invention, the compound of the invention is administered after the therapeutic agent. Administration of the compound can occur anytime from minutes to hours after administration of the therapeutic agent. The compound may alternatively be administered at any time, from hours to days after the second therapeutic agent, possibly even weeks and months.

  More specifically, the compound of the present invention is at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes after the second therapeutic agent. After minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes At least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, at least about 21 minutes, at least about 22 minutes, at least After about 23 minutes, at least about 24 minutes, at least about 25 minutes, at least about 26 minutes, at least about 27 minutes, at least about 28 minutes, at least about 29 minutes After at least about 30 minutes, at least about 31 minutes, at least about 32 minutes, at least about 33 minutes, at least about 34 minutes, at least about 35 minutes, at least about 36 minutes, at least about 37 minutes, at least about After 38 minutes, at least about 39 minutes, at least about 40 minutes, at least about 41 minutes, at least about 42 minutes, at least about 43 minutes, at least about 44 minutes, at least about 45 minutes, at least about 46 minutes After, at least about 47 minutes, at least about 48 minutes, at least about 49 minutes, at least about 50 minutes, at least about 51 minutes, at least about 52 minutes, at least about 53 minutes, at least about 54 minutes, After at least about 55 minutes, at least about 56 minutes, at least about 57 minutes, at least about 58 minutes, at least about 59 minutes, and After at least about 60 minutes, it may be administered.

  More specifically, the compound of the invention is at least about 6 hours after at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours after the second therapeutic agent. After time, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours At least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least Administration can be after about 23 hours, or at least about 24 hours.

  Further, the compounds of the present invention can be used at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 7 days after the second therapeutic agent. After 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about After 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days later, at least about 29 days later, at least After about 30 days, or at least about 31 days later, it may be administered.

  The compound of the invention is at least about 7 weeks after at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks after the second therapeutic agent. After week, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks At least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks.

  Further, the compounds of the present invention can be used at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 6 months after the second therapeutic agent. Administration may be after about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

  The compounds of formula (I) can also be administered in combination with other medicaments used in treating cardiovascular disease, which include platelet aggregation inhibitors (eg, aspirin), anti Thrombotic drugs (eg, coumadin), calcium channel antagonists (eg, diltiazem and nefidipine, angiotensin converting enzyme (ACE) inhibitors (eg, captopril and enanopril) and beta blockers (eg, propanalol). The compound can also be administered in combination with a non-steroidal anti-inflammatory drug (eg, ibuprofen, indomethacin, sulindac) or a COX II inhibitor (eg, rofecoxib or celecoxib) The therapeutic amount of the compound of formula (I) is Also used with corticosteroids They can also be administered in combination with a TNF-a modulator (eg, etanercept or infliximab) The therapeutic amount of a compound of formula (I) can also be an HMGCoA reductase inhibitor, a PPAR-? Can be administered with HDL elevator or retinoid.

(Method of administration)
The compounds of the present invention can be administered by any suitable means, including oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intrathecal, intrachondral. Intraluminal, intracerebral, intraventricular, large intestine, cervical canal, intragastric, intrahepatic, intramyocardial, intraosseous, pelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal , Intrarenal, intraretinal, intrathecal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, oral, sublingual, intranasal or transdermal means. Not.

(A. Pulmonary / nasal administration)
An inhalation device for administering a compound of the present invention has several desirable features. For example, delivery by this inhalation device is advantageously reliable, reproducible and accurate. For pulmonary administration, at least one pharmaceutical composition is delivered in a particle size effective to reach the lower respiratory tract of the lung or sinus. The inhalation device delivers dry small particles (typically less than about 10 μm, for example about 1-5 μm) as needed to obtain good respiratory compatibility.

  The pharmaceutical compositions of the present invention can be delivered by any suitable inhalation or nasal device. Devices that can deposit the aerosolized formulation in the patient's sinus cavity or alveoli include, but are not limited to, metered dose inhalers, nebulizers, dry powder generators and sprays. Other devices suitable for pulmonary or intranasal administration are also known in the art.

  All such devices can be used to administer a pharmaceutical composition by aerosol. Such aerosols can contain either a solution (both aqueous or non-aqueous) or solid particles. Metered dose inhalers, such as the Ventolin® metered dose inhaler, typically use a propellant gas and need to be activated during inspiration. See, for example, WO 98/35888; WO 94/16970. Turbohaler® (Astra), Rotahaler® (Glaxo), Diskus® (Glaxo), Spiros® inhaler (Dura), devices sold by Inhale Therapeutics, and Spinhaler (registered) Dry powder inhalers, such as the trademark) powder inhalers (Fisons), use expiratory activation of mixed powders. See, eg, US Pat. Nos. 5,458,135; 4,668,218; WO 97/25086; WO 94/08552; WO 94/06498; and EP 0 237 507, each of which is Generally incorporated herein by reference). Nebulizers such as AERx®, Aradigm, the Ultravent® nebulizer (Malllinkrodt) and the Acorn II® nebulizer (Marquest Medical Products) produce aerosols from solution. Inhalers, dry powder inhalers generate small particle aerosols. These specific examples of commercially available inhalation devices are to be construed as representative of specific devices suitable for carrying out the invention and are not to be construed as limiting the scope of the invention.

  When the carrier is a solid, suitable formulations for intranasal administration include, for example, coarse powders having a particle size of about 20 to 500 microns, in the manner in which olfactory agents are administered (ie, Administered by rapid inhalation from a container of powder held closed, through the route to the nose). When the carrier is a liquid, for example, formulations suitable for administration as a nasal spray or nasal spray include aqueous or oily solutions of the active ingredient.

(1. Administration as a spray)
Sprays containing the pharmaceutical compositions of the invention can be made by forcing a suspension or solution of the compounds contemplated by the invention through a nozzle under pressure. The size and configuration of the nozzle, the pressure applied, and the liquid feed rate are selected to achieve the desired discharge and particle size. An electrospray can be created, for example, by an electric field in communication with a capillary tube or nozzle feed. Typically, particles of at least one compound delivered by spray are less than about 20 μm, less than about 19 μm, less than about 18 μm, less than about 17 μm, less than about 16 μm, less than about 15 μm, less than about 14 μm, less than about 13 μm. Less than about 12 μm, less than about 11 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm Has a diameter.

  A pharmaceutical composition according to the present invention suitable for use in combination with a spray is typically from about 0.1 mg to about 100 mg (or mg / gm) per ml of solution or any of them in an aqueous solution. A compound contemplated by the present invention in a range or value concentration, including, but not limited to, the following: 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80 90 or 100 mg / ml or mg / gm. The pharmaceutical composition can contain excipients, buffers, isotonic agents, preservatives, surfactants or, for example, zinc. The pharmaceutical composition can also contain excipients or reagents that stabilize the compound (eg, buffers, reducing agents, bulk proteins or carbohydrates). Bulk proteins useful in pharmaceutical compositions and suitable for use in sprays include albumin, protamine and the like. Typical carbohydrates useful in pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose and the like. The pharmaceutical composition can also contain a surfactant, which can prevent or reduce surface-induced aggregation of the pharmaceutical composition caused by atomizing the solution when forming an aerosol. A variety of conventional surfactants (eg, polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters) can be used. The amount is generally in the range between 0.001% and 10% by weight of the formulation. Suitable surfactants include, but are not limited to, polyoxyethylene, sorbitan monooleate, polysorbate 80, polysorbate 20, and the like. Additional reagents known in the art can also be included in the pharmaceutical composition.

(2. Administration by nebulizer)
The pharmaceutical compositions of the invention can be administered with a nebulizer (eg, a jet nebulizer or an ultrasonic nebulizer). Typically, in a jet nebulizer, a source of compressed air is used to create a high velocity air jet through the orifice. As the gas expands beyond the nozzle, a low pressure region is created that draws a solution of the composition protein through a capillary tube connected to a liquid reservoir. The liquid stream from the capillary tube is sheared into unstable filaments and droplets as it exits, creating an aerosol. A range of configurations, flow rates and baffle types can be used to achieve the desired performance characteristics from a given jet nebulizer. In ultrasonic nebulizers, high frequency electrical energy is typically used to create vibratory mechanical energy using piezoelectric transducers. This energy is transferred directly or through a coupling fluid to the formulation of the composition protein, creating an aerosol containing the composition protein. Advantageously, the particles of the pharmaceutical composition delivered by the nebulizer are less than about 20 μm, less than about 19 μm, less than about 18 μm, less than about 17 μm, less than about 16 μm, less than about 15 μm, less than about 14 μm, less than about 13 μm, about 12 μm. Less than, less than about 11 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 mM, less than about 2 μm, less than about 1 μm .

  A pharmaceutical composition containing a compound of the present invention suitable for use with a nebulizer (either jet or ultrasound) typically has from about 0.1 mg to about 100 mg (or mg / gm) per ml of solution. Or any concentration or value within it in the concentration of a compound contemplated by this invention, including but not limited to: 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80 90 or 100 mg / ml or mg / gm. The pharmaceutical composition can contain excipients, buffers, isotonic agents, preservatives, surfactants or, for example, zinc. The pharmaceutical composition can also contain excipients or reagents that stabilize the compound (eg, buffers, reducing agents, bulk proteins or carbohydrates). Bulk proteins useful in pharmaceutical compositions and suitable for use in sprays include albumin, protamine and the like. Exemplary carbohydrates useful in pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose, or any combination thereof. The pharmaceutical composition can also contain a surfactant, which can prevent or reduce surface-induced aggregation of the pharmaceutical composition caused by atomizing the solution when forming an aerosol. A variety of conventional surfactants (eg, polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters) can be used. The amount is generally in the range between 0.001% and 10% by weight of the formulation. Suitable surfactants for the purposes of the present invention include polyoxyethylene, sorbitan monooleate, polysorbate 80, polysorbate 20, and the like. Additional reagents known in the art can also be included in the pharmaceutical composition.

(3. Administration by metered dose inhaler)
In a metered dose inhaler (MDI), the propellant, the compound of the invention, and any excipients or other additives are contained in the canister as a mixture containing a liquefied compressed gas. Upon activation of the throttle valve, the mixture is released as an aerosol, which is typically less than about 20 μm, less than about 19 μm, less than about 18 μm, less than about 17 μm, less than about 16 μm, less than about 15 μm, Less than about 14 μm, less than about 13 μm, less than about 12 μm, less than about 11 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, about 2 μm Less than about 1 μm in size range.

  The desired aerosol particle size can be determined by formulating the compounds of the present invention produced by various methods known to those skilled in the art, including but not limited to jet milling, spray drying, critical point condensation. Can be obtained. Suitable metered dose inhalers include those manufactured by 3M or Glaxo, which use hydrofluorocarbon propellants.

  Pharmaceutical compositions for use with metered dose inhalers are generally divided into finely divided powders (which are suspended in a propellant with the aid of a surfactant, for example). Containing the compounds considered in the present invention). This propellant may be any conventional material used for this purpose (eg, chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons or hydrocarbons (including trichlorofluorocarbons, dichlorofluoromethane, dichlorotetrafluoroethanol and 1, 1,1,2-tetrafluoroethane, HFA-134a (hydrofluoroalkane-134a), HFA-227 (hydrofluoroalkane-227) and the like). The surfactant can be selected to stabilize the compound of the invention as a suspension of the propellant to protect the active ingredient against chemical degradation and the like. Suitable surfactants include sorbitan trioleate, soy lecithin, oleic acid and the like. In some cases, solution aerosols are formed using a solvent such as ethanol. Those skilled in the art will appreciate that the methods of the present invention can be achieved by pulmonary administration of the compounds contemplated by the present invention by devices not described herein.

(B. Mucosal administration)
The compositions and methods of the present invention for administering a compound contemplated by the present invention for absorption through the mucosal surface comprise a plurality of submicron particles, a mucoadhesive polymer, a bioactive peptide and an aqueous continuous phase (this is , Which promotes absorption through the mucosal surface by achieving mucoadhesion of the emulsion particles). See, for example, US Pat. No. 5,514,670. Suitable mucosal surfaces for applying the compositions of the present invention can include the cornea, conjunctiva, buccal, sublingual, intranasal, intravaginal, pulmonary, abdominal, intestinal and rectal routes of administration. Pharmaceutical compositions (eg, suppositories) for vaginal or rectal administration can contain excipients (eg, polyalkylene glycols, petrolatum, cocoa butter). Pharmaceutical compositions for intranasal administration can be solid and can contain excipients (eg, lactose) or can be aqueous or oily solutions of nasal drops. Excipients for buccal administration include sugar, calcium stearate, magnesium stearate, pregelatinized starch. See, for example, US Pat. No. 5,849,695.

(C. Dermal administration)
The pharmaceutical compositions of the invention can be administered by the transdermal route using the form of transdermal patches well known to those skilled in the art. For transdermal administration, the compounds of the invention can be administered in a delivery device (eg, liposomes or polymeric nanoparticles, microparticles, microcapsules or microspheres (collectively referred to as microparticles unless otherwise specified)). Encapsulated. Any suitable device can be used, such as synthetic polymers (eg, polyhydroxy acids (eg, polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyanhydrides and polyphosphazenes)) and There are natural macromolecules (eg, collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides), and any combination thereof. See, for example, US Pat. No. 5,814,599, the contents of which are hereby incorporated by reference in their entirety. To be administered in the form of a transdermal delivery system, the dosage administration can be, for example, continuous rather than intermittent throughout the dosage regimen.

  Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes containing the ingredients to be administered in a pharmaceutically acceptable carrier. According to one aspect of the present invention, a transdermal patch is used as a topical delivery system.

  The topical composition can be mixed with various carrier materials to form alcohol-containing solutions, topical cleansers, face-wash creams, skin gels, skin lotions and shampoos in cream or gel formulations, including alcohol, Aloe gel, allantoin, glycerin, vitamin A and E oil, mineral oil, PPG2 myristyl propionate, or any mixture thereof. Examples of such carriers and formulation methods can be found in Remington's Pharmaceutical Sciences (1990), the contents of which are hereby incorporated by reference in their entirety. The pharmaceutical formulation may contain from about 0.005% to about 10% by weight of the active ingredient, for example from about 0.01% to 5% by weight of the active ingredient.

(D. Long-term administration)
For a single administration, it may be desirable to deliver the compound of the invention to the subject over an extended period of time (eg, 1 week to 1 year). Certain medical devices can be used to provide continuous dosing, intermittent dosing, or dosing according to patient requirements. These devices may include pumps or diffusion devices, or other devices, including a drug reservoir and, optionally, a diagnostic or monitoring component that regulates the delivery of the drug. Various sustained-release forms, depot forms or transplant dosage forms are available. For example, a dosage form can contain a pharmaceutically acceptable non-toxic salt of a compound contemplated by the present invention, which has low solubility in body fluids, including, for example, (a) multiple Basic acids (eg, phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acid, polygalacturonic acid, or any mixture thereof); (b) many A valent metal cation (eg, zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, or any mixture thereof) or an organic cation (eg, N, N′-dibenzyl- Ethylenediamine or a salt with ethylenediamine); or (c) a combination of (a) and (b) (eg tan Zinc nitrate). In addition, the compounds of the invention, or relatively insoluble salts (eg, those described immediately above) can be obtained in gels (eg, aluminum monostearate gel) using, for example, sesame oil suitable for injection. Can be prescribed. Exemplary salts include, but are not limited to, zinc salts, zinc tannates, pamoates, and any mixtures thereof. Other types of delayed release depot formulations for infusion are non-toxic, non-antigenic polymers that degrade slowly (eg, as described in US Pat. No. 3,773,919, for example, polylactic acid / A compound or salt dispersed or encapsulated in a polyglycolic acid polymer). These compounds or their relatively insoluble salts can also be formulated, especially in cholesterol matrix silastic pellets for use in animals. Additional sustained-release depots or transplant formulations (eg, gas or liquid liposomes) are described, for example, in US Pat. No. 5,770,222; SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS (1978), which is hereby incorporated by reference in its entirety. (Incorporated as a reference in the book).

(Determination of dosage)
In general, the compounds contemplated by the present invention are used at an appropriate dosage, alone or in combination with other therapeutic agents, to obtain optimal efficacy while minimizing any possible toxicity. obtain. The dosing regimen utilizing the compounds of the present invention will vary according to factors such as the patient's species, age, weight, sex, disease; severity of the disease being treated; route of administration; patient renal and liver function; Can be selected according to the specific compound used). A physician or veterinarian having ordinary skill can easily determine the effective amount of drug required to prevent, counteract or block disease progression.

  Optimal accuracy in achieving drug concentrations within the range that yields maximum efficacy with minimal toxicity requires a regimen based on the kinetics of the compound's availability to the target site (s) It can be. When determining the optimal concentration for a treatment regimen, drug distribution, equilibrium and excretion can be considered. The dosage of the compounds contemplated by this invention can be adjusted when combined to achieve the desired effect. On the other hand, the dosages of these various drugs can be separately optimized and combined to achieve synergistic effects, where the symptoms can be obtained if any drug is used alone. It is alleviated more than it would be.

In particular, the toxicity and therapeutic efficacy of the compounds considered in the present invention has been shown to be therapeutic in cell cultures or experimental animals, for example LD ₅₀ (dose that kills 50% of the population) and ED ₅₀ (50% of the population). It can be determined by standard pharmaceutical procedures to determine (effective dose). The dose ratio between toxic and therapeutic effects is the therapeutic index and may be expressed as _the ratio _LD 50 / _{ED 50.} Typically, compounds that exhibit a high therapeutic index are used. While compounds that exhibit toxic side effects can be used, delivery that allows such compounds to be targeted to affected tissue sites to minimize possible damage to uninfected cells, thereby reducing side effects Care should be taken to design the system. In general, the compounds of the invention can be administered in a manner that maximizes efficacy and minimizes toxicity.

Data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies generally within a range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. The dose can be formulated in animal models with an IC ₅₀ (concentration of test compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

  Furthermore, dosage administration of the pharmaceutical composition of the invention can be optimized using a pharmacokinetic / pharmacodynamic modeling system. For example, one or more dosage regimens can be selected and pharmacokinetic / pharmacodynamics can be used to determine the pharmacokinetic / pharmacodynamic profile of one or more dosage regimens. Next, a dosing regimen of administration that achieves the desired pharmacokinetic / pharmacodynamic response can be selected based on the particular pharmacokinetic / pharmacodynamic profile. See WO 00/67776, the contents of which are hereby incorporated by reference in their entirety.

  Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes of a disclosed pharmaceutical composition or disclosed pharmaceutical combination (whether or not formulated in the same composition). For therapeutic purposes, the term “jointly effective amount” as used herein refers to biological or biological in a tissue system, animal or human being sought by a researcher, veterinarian, physician or other clinician. The amount of each active compound or agent (alone or in combination) that exhibits a medical response, including alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (ie, preventing the onset or progression of a disorder), the term “jointly effective amount” refers to the onset of a disorder in a subject sought by a researcher, veterinarian, physician or other clinician The amount of each active compound or drug (alone or in combination) that inhibits progression is meant. Thus, the present invention provides a combination of two or more therapeutic agents, where, for example, (a) each therapeutic agent is administered separately in a therapeutically or prophylactically effective amount. (B) at least one therapeutic agent of this formulation, if administered alone, is a sub-therapeutic or sub-prophylactic amount, but in combination with a second or additional therapeutic agent according to the present invention; Administered in a therapeutically or prophylactically effective amount; or (c) both therapeutic agents, if administered alone, are in sub-therapeutic or sub-prophylactic amounts, but together When administered, it is administered in a therapeutically or prophylactically effective amount. Combinations of three or more therapeutic agents are possible as well. Combination therapy includes simultaneous administration of a single formulation containing all active agents; substantially simultaneous administration of more than one formulation; and administration of two or more active agents that are separately formulated.

(Dosage)
The pharmaceutical composition of the invention can be administered in a single daily dose, or the entire daily dose can be administered in daily, twice, three or four divided doses. For oral administration, the daily dosage of these compositions can vary over a wide range from about 0.0001 to about 1,000 mg per patient per day. This range is more specifically about 0.001 mg / kg body weight / day to 10 mg / kg body weight / day, about 0.1-100 mg / day, about 1.0-50 mg / day for adults (about 60 kg). Or about 1.0 to 20 mg / day.

  For oral administration, these pharmaceutical compositions are preferably provided in the form of tablets with or without nicks, which is about 0. 01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, Contains 300, 350, 400, 450, 500, 550, 600, 650 or 700 mg of active ingredient.

  In the case of injection, it is usually convenient to carry out by intravenous route in an amount of about 0.01-30 mg, about 0.1-20 mg or about 0.1-10 mg per day for an adult (about 60 kg). It is. For other animals, the dose calculated for 60 kg can be administered as well.

  The daily dosage of these pharmaceutical compositions can vary over a wide range from about 0.01 to about 1000 mg per adult per day. For oral administration, these pharmaceutical compositions are optionally provided in tablet form for 5.0, 10.0, 15 for symptomatic adjustment of dosage to the patient being treated. 0.0, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650 or 700 milligrams of active ingredient. An effective amount of the agent is typically provided at a dosage level of about 0.1 mg / kg body weight / day to about 20 mg / kg body weight / day. According to one aspect of the invention, this dosage level is from about 0.2 mg / kg body weight / day to about 10 mg / kg body weight / day. According to another aspect of the invention, the dosage level is from about 0.5 mg / kg body weight / day to about 10 mg / kg body weight / day. These compounds can be administered on a regimen of about 1 to about 10 times per day.

  Dosages for the compounds of the present invention may include, as appropriate, the following: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0 .8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 3, 94, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / dose, or any range, value or portion thereof, or 0.1, 0.5, 0.9, 1. 0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8. 9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13. 5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5. 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9 .9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 500 and / or 5000 [mu] g / ml in an amount to achieve a serum concentration serum concentration / single or multiple administration or any range thereof, the value or portion.

  By way of non-limiting example, human or animal treatment can be performed using 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 using single infusion or repeated doses. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 at least one day of the 38th, 39th or 40th day 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or at least one week or In at least one year of 20 years, or in any combination thereof, 0.1-100 mg / kg of a compound of the invention (eg 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg / day).

  Specifically, the pharmaceutical composition of the present invention may be administered at least once a week for several weeks. According to one aspect of the present invention, these pharmaceutical compositions are administered at least once a week over a period of weeks to months. According to another aspect of the invention, these pharmaceutical compositions are administered at least once a week for 4-9 weeks. According to yet another aspect of the invention, these pharmaceutical compositions are administered once a week for 4 weeks.

  More specifically, these pharmaceutical compositions are applied for about 2 days, at least once a day, about 3 days, at least once a day, about 4 days, at least once a day, about 5 days. At least once a day for about 6 days at least once a day for about 7 days at least once a day for about 8 days at least once a day for at least about 9 days at least once a day About 10 days, at least once a day, about 11 days, at least once a day, about 12 days, at least once a day, about 13 days, at least once a day, about 14 days, At least once a day for about 15 days, at least once a day for about 16 days, at least once a day for about 17 days Therefore, at least once a day for about 18 days, at least once a day, about 19 days, at least once a day, about 20 days, at least once a day, about 21 days, at least 1 day 1 At least once a day for about 23 days at least once a day for at least about 24 days at least once a day for about 25 days at least once a day for about 26 days At least once a day for about 27 days at least once a day for about 28 days at least once a day for about 29 days at least once a day for at least about 30 days at least once a day Or at least once daily for about 31 days.

  Alternatively, these pharmaceutical compositions are at least about once every day, at least about every 2 days, at least about every 3 days, at least about every 4 days, at least about every 5 days, at least about 6 times. Once a day, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days Once, at least about every 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days At least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least About once every 25 days Administration at least once every 26 days, at least once every 27 days, at least once every 28 days, at least once every 29 days, at least once every 30 days, or at least once every 31 days Can be done.

  The pharmaceutical composition of the present invention may alternatively be about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, About once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, Administered once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks obtain.

  Alternatively, the pharmaceutical composition of the present invention is about once a month, about once every two months, about once every three months, about once every four months, about once every five months, about once every six months, It can be administered about once every 7 months, about once every 8 months, about once every 9 months, about once every 10 months, about once every 11 months, or about once every 12 months.

  Alternatively, these pharmaceutical compositions may be administered at least once a week, at least about 3 weeks, at least once a week, about 4 weeks, at least once a week, about 5 weeks, at least a week for about 2 weeks. Once, about 6 weeks, at least once a week, about 7 weeks, at least once a week, about 8 weeks, at least once a week, about 9 weeks, at least once a week, about 10 weeks At least once a week, for about 11 weeks, at least once a week, for about 12 weeks, at least once a week, for about 13 weeks, at least once a week, for about 14 weeks, at least one week Over about 15 weeks, at least once a week, about 16 weeks, at least once a week, about 17 weeks At least once a week for about 18 weeks, at least once a week, once for about 19 weeks, or at least weekly, for about 20 weeks, at least once a week, it can be administered.

  Alternatively, these pharmaceutical compositions can be about 1 month, at least once a week, about 2 months, at least once a week, about 3 months, at least once a week, about 4 months, at least a week. Once, about 5 months, at least once a week, about 6 months, at least once a week, about 7 months, at least once a week, about 8 months, at least once a week, about 9 months At least once a week, for about 10 months, at least once a week, for about 11 months, or at least once a week, for about 12 months, at least once a week.

(Method of using compound)
(A. Heparance sulfate proteoglycan regulation)
The present invention includes methods and compositions comprising the identification of compounds for the treatment and prevention of vascular diseases, particularly cardiovascular diseases. More particularly, the present invention relates to methods and compositions for the treatment and prevention of smooth muscle cell proliferation, such as “antiproliferative” compounds that result in the synthesis of proteoglycans. Methods for screening compounds or molecules that induce HSPG synthesis include the addition of such compounds to the assay and measurement of HSPG synthesis, including but not limited to the production of Syndecan, Glypican, and Perlecan. To do. Methods for measuring the induction of Perlecan synthesis are also contemplated herein. Although some aspects of the invention have been described with respect to Perlecan, the compositions, methods and assays described herein are equally applicable in the context of other HSPGs, including Syndecan and Glypican. It is important to note that. HSPG production is important in the regulation of SMC proliferation, and the methods and compositions described herein provide high throughput screening for molecules that induce HSPG production and modulate SMC proliferation.

  Furthermore, the present invention includes methods and compositions for gene therapy comprising administering a composition comprising a nucleic acid that results in the synthesis or expression of HSPG (particularly Perlecan). For example, a vector comprising a nucleic acid encoding Perlecan or an active fragment of Perlecan is provided for cells such as circulating tissue cells such as endothelial cells. Such vectors are known to those skilled in the art and can be administered in a formulation that enhances uptake of the vector by the cells.

  The present invention also includes methods and compositions for inducing synthesis or expression of HSPG, including but not limited to HSPGs such as Syndecan, Glypican and Perlecan, including active fragments of HSPG (eg, active fragments of Perlecan) Induction and synthesis of As used herein, when HSPG is referenced, the entire molecule or fragment is included therein. For example, Perlecan refers to the entire Perlecan molecule or fragment. Perlecan fragments can have the same or different effects on cells. All of these fragments and activities are contemplated in the present invention.

  The primary extracellular HSPG in the vascular matrix is Perlecan (a protein originally identified in the basement membrane). This interacts with extracellular matrix proteins, growth factors and receptors. Perlecan is also present in non-vascular basement membranes and other extracellular matrix structures. It consists of a core protein of about 450,000 kDa Mr, with three HS chains of about 70 kDa Mr attached to one end of the molecule. The Perlecan core protein has a complex functional organization consisting of five consecutive domains with homology to molecules involved in the control of cell proliferation, lipoprotein binding and cell adhesion. N-terminal domain I (amino acids about 1-195) contains the binding site for the HS chain. Domain II contains four repeats homologous to the ligand binding protein of the LDL receptor. Domain III has homology to laminin domains IVa and IVb and is thought to mediate cell adhesion.

  SMC hyperplasia is a major event in the development of atherosclerosis and is responsible for a significant number of failure rates (especially restenosis) after vascular procedures such as angioplasty and coronary artery bypass surgery. Proliferation of the arterial wall SMC in response to local injury is a major feature of many vascular proliferative disorders. While not wishing to be limited by theory, it is generally considered to control the proliferation of SMCs that are based on endothelium. In normal blood vessels, SMCs are stationary, but they proliferate when damage to the endothelium occurs. Naturally occurring growth regulators (many of these are derived from the endothelium) tightly regulate SMC proliferation in vivo.

  While not wishing to be limited by any particular mechanism, it is believed that extracellular HSPG mediates quiescence in SMC. Perlecan synthesis is induced in serum-depleted resting SMC. For example, Perlecan inhibits DNA synthesis and SMC growth, and Perlecan blockage results in stimulation of DNA synthesis, even in the absence of serum and growth factors. Induction of Perlecan and other HSPGs is an important issue for inhibition of SMC proliferation. Known antiproliferative factors do not inhibit SMC proliferation when the effects of Perlecan are blocked. Thus, the present invention includes methods and compositions for mediating the synthesis of Perlecan and other HSPGs, where expression and amount teach the maintenance of SMC in a quiescent state. Such methods and compositions of the present invention also include the treatment and prevention of vascular diseases, and more particularly pathologies associated with SMC proliferation. Specifically, such pathologies include atherosclerosis and restenosis.

  The invention also includes vaso-occlusive conditions (neovascular intimal hyperplasia, restenosis, graft vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis) Include, but are not limited to, methods and compositions for treatment and prevention. Such methods and compositions include methods for inhibition of smooth muscle cell (SMC) growth and proliferation, and methods for induction of quiescence in smooth muscle cells. The invention further includes methods and compositions for inducing HSPG synthesis and expression (including but not limited to induction of HSPGs such as Syndecan, Glypicans and Perlecan) (eg, Perlecan synthesis and gene expression). .

  Neointimal hyperplasia is commonly seen after various forms of major components of vascular injury and venous graft response to harvesting and surgical implantation into high-pressure arterial circulation. In neointimal hyperplasia, smooth muscle cells in the middle layer of the vascular wall are activated, divided, proliferated, and migrated into the inner layer. The resulting abnormal neointimal cells contain pro-inflammatory molecules (including cytokines, chemokines, and adhesion molecules that further induce a cascade of events that lead to obstructive neovascular disease, resulting in transplant failure) To express.

  Proliferation of SMC in response to local injury is a major feature of vascular proliferative disorders such as atherosclerosis and restenosis after angiogenesis. While not wishing to be bound by any particular theory, it is generally considered that the endothelium controls the growth of the underlying SMC. In normal vessels, SMCs are at rest, but they proliferate when damage to the endothelium occurs. In addition to producing various growth factors, the endothelium also produces important growth inhibitors. HSPG acts as a barrier to cationic molecules and macromolecules, protects the basement membrane, major structural components of type IV collagen from proteolytic attack, cytokines and growth factors (basal fibroblast growth factor (bFGF) , Including, but not limited to, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and transforming growth factor β (TGF-β) Functioning to conserve these cytokines, regulating mesoderm cell fates, positioning the heart, acting in angiogenesis and angiogenesis after ischemic injury, Inducing the interaction of cells with adhesive proteins and blood vessels, inducing smooth muscle cell proliferation during atherogenesis Control various vascular functions, including acting to increase cell spreading, inhibiting chemotaxis, and providing non-thrombogenic characteristics of lipoprotein metabolism and endothelial cells Possible vascular cell membrane and extracellular matrix components. Furthermore, it is considered that HSPG has different functions at different positions. For example, cell surface HSPG functions as a co-receptor for growth factors and supports cell growth, whereas extracellular HSPG can inhibit cell growth.

  It is currently thought that endothelial HSPG inhibits SMC proliferation, but it is not known whether SMCs synthesize antiproliferative HSPGs that act as autocrine inhibitors. While not wishing to be bound by any particular theory, HSPG inhibits DNA synthesis and SMC growth, and HSPG blockade results in stimulation of DNA synthesis, even in the absence of serum and growth factors. Currently considered. Indeed, known anti-proliferative factors do not inhibit SMC proliferation when the effect of HSPG is blocked.

  Examples of HSPGs include Syndecan, Glypican, and Perlecan, which occur within the cardiovascular system. Vascular SMC expresses Syndecan 1, 2, and 4, Glypican-1 and Perlecan. However, the regulation of HSPG expression in these cells is not known. Cell growth stimulating factors such as platelet-derived growth factor (PDGF), thrombin, serum, oxidized low density lipoprotein (LDL) and lysolecithin have been shown to reduce HSPG, in particular Perlecan. In contrast, cellular antiproliferative factors, TGF-β, apolipoprotein E, and heparin stimulate HSPG.

  The present invention includes methods and compositions for the treatment and prevention of smooth muscle cell proliferation (including vaso-occlusive pathology). Such methods include the step of administering a composition comprising a therapeutic agent that can inhibit SMC proliferation. Administration of such therapeutic agents (eg, thiazolidinedione compositions as described above) that are effective in SMC growth, for example, humans and animals suspected of having vasculopathy, or other angiogenesis or endothelium damage Is administered to humans and animals undergoing the above procedure. An effective amount is administered to such humans and animals at dosages that are safe and effective. Routes of administration include, but are not limited to, intravenous therapy, subcutaneous therapy, transdermal therapy, nasal therapy, and aspiration therapy. Such therapeutic agents may be used in conjunction with other therapeutic agents or altered patient activity (eg, exercise or dietary changes).

  The compounds of the present invention are also useful in the treatment or prevention of at least one cardiovascular disease in a cell, tissue, organ, animal or patient. These cardiovascular diseases include cardiac stunn syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, bleeding, arteriosclerosis, atherosclerosis, restenosis, diabetic atherosclerotic disease, Hypertension, arterial hypertension, renovascular hypertension, syncope, shock, cardiovascular syphilis, heart failure, pulmonary heart, primary pulmonary hypertension, cardiac arrhythmia, atrial ectopic beat, atrial flutter, atrial fibrillation (Persistent or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammatory response, disordered or multifocal atrial tachycardia, regular narrow QRS tachycardia, certain arrhythmias , Ventricular fibrillation, His bundle arrhythmia, atrioventricular block, leg block, myocardial ischemia Disease, coronary artery disease, angina, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial diverticulum, heart tumor, aortic aneurysms or Peripheral aneurysm, aortic dissection, inflammation of the aorta, occlusion of the abdominal aorta and its bifurcation, peripheral vascular disorder, occlusive arterial disorder, peripheral atherosclerotic disease, occlusive thromboangiitis, peripheral artery dysfunction , Raynaud's phenomenon and disease, advanced cyanosis, advanced erythema, venous disease, venous thrombosis, dilated serpentine vein, arteriovenous fistula, lymphedema, lipemia, unstable angina, reperfusion injury, postpump Examples include, but are not limited to, post pump syndrome, ischemic reperfusion injury, and the like. Such methods optionally involve the effective amount of a composition or pharmaceutical composition containing at least one compound, cell, tissue, organ, animal or animal in need of such modulation, treatment or therapy. Administering to the patient.

(1. Evaluation of HSPG activity)
The present invention includes methods and compositions for determining therapeutic factors that can result in SMC proliferation. Such assays are taught herein and can be used as assays to determine factors that affect the amount or activity of HSPG (eg, Perlecan) in such assays. For example, in one assay, Perlecan is induced in cells by a specific inducer and the response is measured. Potential therapeutic agents are then added to the replication assay to determine the effect on Perlecan induction. When using such methods and compositions, therapeutic agents are determined that inhibit Perlecan, increase Perlecan induction, or have no effect. Such therapeutic agents can then be used in animals with SMC proliferative pathologies.

  The invention also includes a composition comprising a compound identified by this method as having the desired activity. These compositions are useful in the treatment of cells, tissues, or whole organisms. Such compositions may be used in biological conditions (vascular occlusion including atherosclerosis, transplant vasculopathy, cardiac allograft vasculopathy, restenosis and graft atherosclerosis after coronary transplantation. In an effective amount for the treatment of conditions such as, but not limited to, sexual injury) and is formulated for use in a method of administration. These compositions may include other compounds, including compounds having activity and pharmaceutical additives (required for administration of compounds having the desired activity). The composition can also be administered exclusively or with other pharmaceutical compositions, and surgical methods for treating smooth muscle cell proliferation and vaso-occlusive disease include before, during and after the PTCA procedure. However, it is not limited to these.

  In the assays of the invention, the compound initially has an unknown activity or effect. The activity of the compound is unknown in that the effect of the compound in the assay of the present invention has not yet been determined. The compound can have many other known activities and can be a compound with other therapeutic uses. Any factor to which the cells or components of the assay respond in a measurable manner is contemplated by the present invention.

  The present invention includes methods and compositions for measuring the activity of unknown compounds. Such methods include assays for specific activities of biological compounds involved in known cellular responses. The assay provides a measurable response that determines the activity of the unknown compound. This response can be measured by methods known to those skilled in the art (eg, ELISA). One aspect of the invention involves measuring the effect of a compound on SMC proliferation in response to an HSPG inducer.

  In accordance with one aspect of the present invention, a compound presumed to cause HSPG synthesis is added to the cells in the assay. The cellular response can be measured by measuring the level of HSPG synthesis measured by methods known to those skilled in the art and comparing it to the amount of HSPG synthesis in untreated cells. The compound may have a stimulating effect, an inhibitory effect, a stabilizing effect, or no effect.

  According to another aspect of the present invention, a composition presumed to cause SMC proliferation is added to smooth muscle cells in growth medium or serum-free medium. Changes in cell proliferation can be measured by methods known to those skilled in the art and can be compared to the proliferation of cells not treated with this compound. The composition may have a stimulating effect, an inhibitory effect, a stabilizing effect, or no effect.

  Compositions having an HSPG stimulating effect (especially a Perlecan stimulating effect) are useful as anti-proliferative therapeutic agents, particularly for inhibiting SMC proliferation and thus treating vaso-occlusive conditions. For example, these selective activators of Perlecan include small organic molecules, peptides, peptoids that act directly on Perlecan that modulate biological activity or increase the biological stability of the protein. Or a polynucleotide. In addition, Perlecan selective activators can increase Perlecan biology by increasing transcription of the Perlecan gene, increasing the biological stability of the Perlecan mRNA, or increasing the translation of the Perlecan mRNA into a protein. Stability can be increased. In addition, Perlecan selective activators may block or reduce the effects of factors or proteins that inhibit Perlecan activity.

  The invention also includes methods and compositions for assays that can be used to identify such selective activators or inhibitors of Perlecan. These assays readily determine the amount of Perlecan and activators that upregulate its biological activity and inhibitors that downregulate. In general, such assays include promoter-based assays for identifying compounds that affect Perlecan, and recombinant, partial generation from cells that express Perlecan in the presence or absence of the compound of interest. Perlecan biological activity assays in proteins, or lysates. Perlecan measurements include Perlecan protein biological activity assay and quantification using ELISA or Western blot determination, or Perlecan RNA quantification using RT-PCR, or Northern blot.

  Both indirect and direct methods of measuring changes in Perlecan are contemplated by the present invention. The assay method contemplated by this specification relies on indirect measurement of Perlecan by measuring determinants of Perlecan activity or expression.

  Furthermore, a direct determination of the change in the amount of Perlecan protein can be made using other immunological methods (eg Western blot), densitometry or ELISA methods. Alternatively, direct determination of changes in the amount of Perlecan mRNA can be accomplished using RT-PCR or Northern blots known to those skilled in the art. Measurements are also made directly using purified or partially purified Perlecan proteins, which are either cell lysates, and recombinant or native forms of proteins. Means for measuring biological activity are known to those skilled in the art.

  Another method of identifying and determining compounds that affect Perlecan is a compound that interacts with or interacts with a promoter region of the Perlecan gene or interacts with a protein that interacts with the promoter region, and the Perlecan protein's Identifying a compound that is important for transcriptional regulation of expression. In general, the method includes a vector comprising within the promoter-reporter construct a regulatory sequence of the Perlecan gene and an indicator region controlled by the regulatory sequence. The protein product of the indicator region is referred to herein as a reporter enzyme or reporter protein. The regulatory region of the Perlecan sequence comprises nucleotides in the range of about −4000 to +2000, the transcription start site is +1, for example, −2500 to +1200 relative to the transcription start site, for example −1500 ~ + 800.

  Cells are transfected with the vector and then treated with the compound of interest. For example, transfected cells are treated with a compound suspected of affecting Perlecan transcription, and the level of activity of the Perlecan regulatory sequence is compared to the level of activity in cells not treated with the compound. The level of activity of the Perlecan regulatory sequence is determined by measuring the reporter protein or measuring the activity of the reporter enzyme controlled by the regulatory sequence. An increase in the amount of reporter protein or reporter enzyme activity indicates a stimulating effect on Perlecan by a positive acting promoter, while a decrease in the amount of reporter protein or reporter enzyme activity indicates a negative effect on the promoter, and thus Perlecan Indicates a negative impact on

  Furthermore, the present invention includes methods and compositions for identifying Perlecan proteins or selective inhibitors of biological activity. These selective inhibitors of Perlecan are small organic molecules, peptides, peptoids or polynucleotides that act directly on the Perlecan or Perlecan promoter region and modulate the expression of the protein or reduce its biological stability. It is. In addition, Perlecan selective inhibitors reduce Perlecan biosynthesis by reducing the transcription of the Perlecan gene, reducing the biological stability of the Perlecan mRNA, or reducing the translation of the Perlecan mRNA into a protein. Can be reduced. Furthermore, selective inhibitors of Perlecan may block or reduce the effects of factors or proteins that increase the activity of Perlecan.

（Ｂ．ヘパラナーゼ調節）
ＨＳＰＧは、上皮下細胞外マトリックスおよび血管の基底膜の重要な構成要素である。Ｒｏｓｅｎｂｅｒｇら，９９ Ｊ．Ｃｌｉｎ．Ｉｎｖｅｓｔ．２０６２−７０（１９９７）。基底膜は、コラーゲンおよび非コラーゲンタンパク質、ならびに実質を裏側の間質結合組織から分離するプロテオグリカンからなる、細胞外マトリックスの連続したシートである。これらは、透過性の特徴を有し、そして細胞構造を維持する役割を果たす。

(B. Heparanase regulation)
HSPG is an important component of the subepithelial extracellular matrix and the vascular basement membrane. Rosenberg et al., 99 J. MoI. Clin. Invest. 2062-70 (1997). The basement membrane is a continuous sheet of extracellular matrix consisting of collagen and non-collagen proteins and proteoglycans that separate the parenchyma from the backside stromal connective tissue. They have permeability characteristics and play a role in maintaining cellular structure.

  In addition to HSPG, the basal lamina consists of a complex network of fibronectin, laminin, collagen and vitronectin, which are mainly adhesion proteins. Wight et al., 6 Curr. Opin. Lipidol. 326-334 (1995). Heparan sulfate (HS) is an important structural component of the basal lamina. Each of the adhesion proteins interacts with the HS side chain of HSPG in the matrix. Thus, HSPG acts as a barrier to the extravasation of metastatic and inflammatory cells. Cleavage of HS to endoglycosidase by paranase is produced by metastatic tumor cells and inflammatory cells, destroying the laminar filtering features. In addition, HS degradation may support extracellular matrix degradation, thereby facilitating cell migration by allowing blood-borne cells to escape into the bloodstream. Vlodavsky et al., 12 Invasion Metastasis 112-127 (1992).

  Heparanase activity has been described in many tissue and cell types, including liver, placenta, platelets, fibroblasts, neutrophils, activated T lymphocytes and activated B lymphocytes, monocytes. And epithelial cells (7-16). Nakajima et al., (31) Cancer Lett. 277-283 (1986); Nakajima et al., 36 J. MoI. Cell. Biochem. 157-167 (1988); Ricoveri et al., 46 Cancer Res. 3855-3861 (1986); Gallagher et al., 250 Biochem. J. et al. 719-726 (1988); Dempsey et al., 10 Glycobiology 467 (2000); Goshen et al., 2 Mol. Hum. Reprod. 679 (1996); Paris et al., 76 Immunol Cell Biol. 104-113 (1998); Gilat et al., 181 J. MoI. Exp. Med. 1929-1934 (1995); Graham et al., 39 Biochem. Mol. Biol. Int. 56371 (1996); Pilarisetti et al., 270 J. et al. Biol. Chem. 29760-29765 (1995).

  There is increasing interest in heparan sulfate compounds and their related enzymes due to the potential relationship between normal activity and tumor invasiveness and tumor metastasis activity. An important process in tissue invasion by tumor cells and leukocytes carried by blood is its passage through the vascular endothelial cell layer and subsequent backside basal lamina or basement membrane and extracellular with a series of secreted proteins and glycosidases Includes matrix decomposition. Nakajinia et al., 220 Science 611-613 (1983); Vlodavsky et al., 12 Invasion Metastasis 112-127 (1992).

  Heparanase activity has been shown to correlate with the metastatic potential of animal and human tumor cell lines. Nakajima et al., 31 Cancer Lett. 277-283 (1986); Nakajima et al., 212 Prog Clin Biol Res. 113-122 (1986); Freeman et al., 325 Biochem. J. et al. 229-237 (1997); Vlodavsky et al., 5 Nat. Med. 793-802 (1999); Hulet et al., 5 Nat Med. 803-809 (1999). This is also known to modulate growth factor activity. Many growth factors remain bound to heparan sulfate in a storage form and are degraded by heparanase during angiogenesis, improving cancer cell viability.

  Serum heparanase levels in rats were higher than intensity after injection of highly metastatic mammalian adenocarcinoma cells into rats. Furthermore, heparanase activity in the serum of rats with MTLn3 tumors correlates well with the extent of metastasis. In addition, serum / urine heparanase activity in cancer patients has been shown to increase 2-4 fold, especially in the presence of tissue metastases. Since cleavage of HS appears to be essential for the passage of metastatic cancer cells and leukocytes through the basement membrane, the study of heparanase inhibitors has led to novel and highly selective species of anti-metastatic drugs and anti-inflammatory Provides the potential for the development of sex drugs.

  Accordingly, the present invention further relates to compounds that modulate heparanase activity. Such compounds include cancer (malignant and non-malignant cell proliferation, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B cell, T cell or FAB ALL, acute myeloid leukemia (AML), chronic Myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodysplastic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, multiple myeloma, capage Sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome / malignant hypercalcemia, solid tumor, adenocarcinoma, sarcoma, malignant myeloma, hemangioma, metastatic disease, cancer Examples include, but are not limited to, related bone resorption, cancer-related bone pain.

  In accordance with another aspect of the present invention, the compounds contemplated by the present invention are useful in modulating heparanase activity as a means for the treatment and prevention of autoimmune diseases.

  By way of background, in the normal course of disease resolution in an infected tissue, local quiescent immune effector cells in the body are activated after recognizing the antigen of the infected organism as foreign. Upon activation, these effector cells in the body synthesize and secrete signaling molecules (chemokines, lymphokines, and cytokines) that attract additional immune effector cells to the site of infection, and this infection At the site they are also activated. Once activated, these immune effector cells can exit the vasculature and enter the infected tissue where they begin to be attracted to and destroyed by infectious agents and infected tissue . This process continues until the infection is eradicated.

  However, sometimes the immune system does not function well or overreacts to the initial injury, leading to the onset of chronic and acute diseases that are debilitating and endangering life. This is because (1) the immune system mistakenly recognizes normal tissue cell surface molecules as foreign molecules, (2) chemokines, cytokines and lymphokines synthesis and secretion are not blocked after eradication of the disease, or ( 3) can occur when the immune system overreacts to overt infection and destroys a significant amount of the surrounding normal tissue.

  In normal activity, activated effector cells attract other effector cells to blood vessels near the infection. To be “effective”, these activated cells must leave the blood vessel and enter the infected tissue. The process of exiting the circulation and entering the inflamed tissue involves two different steps. Initially, immune effector cells must bind to the lumen / tip surface of the vessel wall. This is achieved through the interaction of immune effector cell adhesion molecules with their recognition receptors locally upregulated on epithelial cells lining the vasculature near the site of infection.

  Second, after binding to the apical surface and before invading the inflamed tissue, the immune effector cells surround the basement membrane (BM) and the basal portion of the blood vessel, and the extracellular matrix that gives the blood vessel its shape and strength ( ECM) must be broken. BM and ECM consist of structural proteins incorporated within a fiber meshwork, which meshwork consists mainly of structures containing complex carbohydrates (glycosaminoglycans), the main components of which are Heparin sulfate proteoglycan (HSPG). To break this barrier, immune effector cells must weaken or destroy it, which is achieved by local secretion of proteases and heparinase.

  Accordingly, inhibition of heparanase using the compounds of the present invention finds use in arthritis and other autoimmune diseases. More particularly, the compounds of the invention are useful in treatment or prevention in at least one autoimmune related disease in a cell, tissue, organ, animal or patient. Such autoimmune related diseases include, but are not limited to: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis , Gastric ulcer, seronegative arthropathy, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis / uveitis / optic neuritis, idiopathic pulmonary fibrosis Systemic vasculitis / Wegener's granulomatosis, sarcoidosis, orchiditis / vasectomy reversal procedure, allergy / atopic disease, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonia, transplantation Fragment, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, Gramyang Sepsis, Gram-negative sepsis, culture-negative sepsis, fungal sepsis, neutropenic fever, urinary sepsis, meningococcal blood, trauma / bleeding, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome Rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathology, clonal pathology, sickle cell anemia, diabetes, nephrosis, atopic disease, hypersensitivity reaction, allergic rhinitis, hay fever, perennial plant rhinitis, conjunctivitis, endometriosis , Asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic disease, thrombocytopenia, transplant rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplantation Rejection, pancreas graft rejection, lung graft rejection, bone marrow graft (BMT) rejection, skin allograft rejection, cartilage graft rejection, bone graft Rejection, small intestine graft rejection, fetal thymus graft rejection, parathyroid graft rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reaction, Graves' disease, Raynaud's disease ), Type B insulin resistant diabetes, asthma, myasthenia gravis, -mediated cytotoxicity, type III hypersensitivity reaction, POEMS syndrome (polyneuropathy, organomegaly, endocrine disorder, monoclonal hypergammaglobulinemia, and Skin change syndrome), polyneuropathy, organomegaly, endocrine disorder, monoclonal hypergammaglobulinemia, skin change syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison disease, self Immunohemolytic anemia, autoimmune hepatitis, idiopathic pulmonary fibrosis, scleroderma, diabetes mellitus, chronic active hepatitis , Vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonia, allograft rejection, granulomas caused by intracellular organisms, drug sensitivity , Metabolic / idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis , Thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial familial hemophagocytic lymphohistiocytosis, skin disease state, psoriasis, hair loss Disease, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, hemodialysis, uremia, toxicity, pre-eclampsia, ankylosing spondylitis, Behcet's disease, bullous celestial Acne, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigus, CREST syndrome, cold agglutinin disease, disc Lupus, essential mixed cold globulinemia, fibromyalgia-fibromyositis, Graves' disease, Giant-Barre, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus , Juvenile arthritis, lichen planus, Meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Kogan syndrome, polychondritis, polyglandular syndrome, polymyalgia rheumatica, multiple Myositis and dermatomyositis, primary agammaglobulinemia, Raynaud's phenomenon, Reiter syndrome, rheumatic fever, Sjogren's syndrome, stiff man syndrome Takayasu arteritis, temporal arteritis / giant cell arteritis, Wegener's granulomatosis; okt3 treatment, anti-cd3 treatment, cytokine treatment, chemotherapy, radiotherapy (eg, asthenia, anemia, cachexia, etc.) But not limited to), chronic salicylic acid poisoning and the like.

(1. Heparanase assay)
The invention further relates to a method for assaying heparanase activity. In this regard, the effectiveness of the compounds of the present invention can be assessed using such assays. Future candidate compounds are also useful in the output methods of the invention and can be evaluated using the assays discussed herein. Furthermore, the present invention also provides for any glycosidase pseudo (glycosaminoglycan degradation activity, chondroitinase, heparan sulfate endoglycosidase, heparan sulfate exoglycosidase, polysaccharide lyase, keratanase, hyaluronidase, glucanase, amylase, and other glycosidases and Compositions and methods for assays that measure (including but not limited to enzymes) are contemplated.

  Accordingly, in one aspect, the present invention includes compositions and methods for measuring cellular activity and enzyme activity. Such assays can be used to measure such activity, both qualitatively and quantitatively. Furthermore, the assays described herein for determining the presence of such activity can be used in methods for the diagnosis of metastasis, metastatic potential and inflammatory conditions. Furthermore, the assays of the invention can be used to screen for compounds that alter, stimulate or inhibit such cellular and enzymatic activities.

Existing heparanase assays require preparation of radiolabeled substrate and separation of degradation products from uncleaved substrate. Goshen et al., 2 MOL. HUM. REPROD. 679-84 (1996); Nakajima et al., 31 CANCER LETT. 277-83 (1986). Other heparanase assays require biosynthetic radiolabeling of matrix-related HSPG and detection of HS chain degradation by gel filtration analysis of radiolabeled material released from the matrix. Vlodsky et al., 12 INVASION METASTASIS 112-27 (1992)
A solid phase heparanase assay has also been developed, where chemically and biosynthetically radiolabeled heparin and HS chains are bound to a solid support, and release of the radiolabel from the solid support is: A measure of enzyme activity. An assay using such a procedure is taught in US Pat. No. 4,859,581. U.S. Pat. No. 4,859,581 is obviously hereby incorporated by reference in its entirety.

  Previous work has also radiolabeled both heparin and HS with iodinated or partially de-N-sulfated substrates of naturally occurring glucosamine residues. Such a procedure requires the use of radiolabeled iodine, which is a powerful emitter and is therefore undesirably harmful. For example, one sensitive radioactive assay for heparanase requires affinity chromatography of the heparanase cleavage product on a column of histidine-rich glycoprotein sepharose. Freeman and Parish, 325 BIOCHEM. J. et al. 229-37 (1997).

  There are several non-radioactive assays available for heparanase. One assay for heparanase involves measuring the optical density (230 nm) of unsaturated uronic acid formed during heparin degradation. Color-based assays for measuring heparanase activity take advantage of the ability of heparin to prevent color development during the interaction of protein and the dye Coomassie brilliant blue. Kahn and Newman, 196 ANAL. BIOCHEM. 373-76 (1991).

  In another heparanase assay, a composition comprising biotin-HS is mixed with a biological sample (eg, a tumor sample, body fluid, or other fluid suspected of having heparanase activity) to form a reaction mixture. The sample can be pretreated to remove contaminants or reactive materials (eg, endogenous biotin). After incubation, an aliquot or portion of the reaction mixture portion is removed and placed in a biotin-binding plate. Reagents for the enzyme are added to form a detectable color product. For example, a decrease in color formation from a known standard indicates the presence of heparanase activity in the sample. The biotin binding plate comprises any means for binding biotin (preferably to a solid surface). See WO 02/23197, which is expressly incorporated herein by reference in its entirety.

  In general, a method for measuring heparanase activity involves binding one of the binding partners to a substrate for the enzyme to be measured. Incubation with the sample containing the enzyme to be measured allows the enzymatic activity to be measured in the reaction mixture. Some or all of the reaction mixture is then mixed with a complementary binding partner, depending on the amount required, so that the binding partners are ligated together. This is the first binding reaction. After incubation to allow binding, washing is performed. A complementary binding partner complementary to the first binding partner bound to the substrate is added. This complementary binding partner may or may not be the same as the first complementary binding partner. This is a second binding reaction. The complementary binding partner in the second binding reaction is labeled in a manner that is detectable. For example, the complementary binding partner is labeled with an enzyme that produces a detectable color change when appropriate reaction conditions are present.

  Some methods involve the use of binding partners including but not limited to biotin and streptavidin. One method of binding one of the binding partners (eg, biotin) can be used either in a biotin binding step, binding biotin to the plate, or detecting available biotin. The number of biotin or other binding partner (available for secondary binding) is the quantitative result of the assay. “Complementary binding partner” means one of a pair of binding partners (eg, biotin and streptavidin, or an antibody and its antigen). Biotin is a complementary binding partner for streptavidin; streptavidin is a complementary binding partner for biotin. Antibodies that specifically bind to biotin are also complementary binding partners of biotin.

  In the above methods, the labeled binding partner (ie, enzyme labeled streptavidin) is any detectable marker (including but not limited to enzymes, dyes, chemiluminescence, and other methods known in the art). It can be labeled with. One such method involves labeling with an enzyme that produces a color change in the detectable substrate. This method is safe, easy and effective and can be used in both qualitative and quantitative methods.

  Using the above method, the amount of enzyme activity in the sample can be determined. The above methods can also be used to determine compounds that can inhibit enzyme activity. For example, a composition comprising a candidate compound is added to a known amount of heparanase either before or during incubation of heparanase and its substrate binding partner. If this compound alters the activity of heparanase, the assay method of the invention will show a change in the amount of detectable label. Such assays are used for high-throughput determination of compound activity. See WO 02/23197, which is expressly incorporated herein by reference in its entirety.

(C. Inflammation regulation)
The present invention relates to methods and compositions comprising compounds or molecules that have specific biological effects and are useful as therapeutic agents. In particular, the present invention relates to methods and compositions comprising compounds or molecules effective to cause inflammation. More particularly, the invention relates to methods and compositions comprising compounds or molecules that are effective in inhibiting inflammation caused by the accumulation or presence of glycated proteins or AGEs. The invention also includes biological conditions (type I and type II diabetes-induced vasculopathy, other vasculopathy, microangiopathy, renal dysfunction, Alzheimer's syndrome and pro-inflammatory diseases (eg, atheromatous arteries). Compositions and methods for the treatment of (including but not limited to sclerosis) are provided.

  The present invention has utility in inhibiting inflammation or cell activation by glycated proteins or AGEs. Pharmacological inhibition of AGE-induced cell activation provides the basis for therapeutic intervention in many diseases, particularly diabetic complications and Alzheimer's disease. Therapeutic approaches for the inhibition of AGE-induced inflammation include blocking protein glycation, blocking AGE interactions with receptors, and blocking AGE-induced signaling or signaling-related inflammatory responses. Examples include, but are not limited to:

  For example, the method of the present invention is to block the AGE effect by inhibiting AGE-induced signaling. The order of these signaling events that lead to inflammation is not clear, but inhibition of these signaling events results in a diminished or absent inflammatory outcome. Compounds that block AGE-induced upregulation of inflammatory molecules were determined using screening assays. The invention encompasses methods and compositions comprising a compound or molecule such as the tizolidinedione provided herein.

  Other aspects of the invention include methods of blocking glycated protein-induced inflammation and compositions comprising compounds that block glycated protein-induced inflammation. A further aspect of the invention includes tizolidinedione compounds that can inhibit the AGE effect. A still further aspect of the invention utilizes a composition comprising a compound of the formula contemplated by the invention that blocks glycated protein-induced inflammation.

  Enhanced formation and accumulation of glycated proteins and AGE play a major role in the pathogenesis of diabetic complications and atherosclerosis, leading to the development of nephropathy, retinopathy, and neurosis. There is a great deal of in vivo evidence that suggests that diabetes-related complications can be reduced by: 1) preventing protein glycation, 2) disrupting crosslinks in glycated proteins, or 3) receptors Blocking the interaction of glycated proteins with. Despite the importance of AGEs in the pathogenesis of diabetic microangiopathy, there are no currently available medications known to block AGE formation.

  Aminoguanidine (which prevents AGE formation) is being actively followed as a treatment for diabetic vasculopathy. Furthermore, some studies have shown that aminoguanidine reduces AGE formation, but did not inhibit glomerular basement membrane thickness or improved endothelial function in diabetic rats. For example, Birrel et al., 43 DIABETLOGIA 110-16 (2000); Wada et al., 42 DIABETLOGIA 743-47 (1999); Soulis et al., 50 KIDNEY INT. 627-34 (1996).

  In addition to inhibiting AGE formation, AGE cross-linking disruptors are also being actively followed as a treatment for vasculopathy. N-phenacylthiazolium bromide (PTB) is a prototype AGE crosslinker that reacts with and cleaves AGE-induced protein crosslinks. PTB reduced AGE accumulation but did not interfere with vascular permeability. Cooper et al., 43 DIABETOLOGIA 660-64 (2000).

  Inhibiting the reaction with the AGE receptor is an alternative approach to the treatment of related pathologies. RAGE (a known receptor for AGE) is a potential therapeutic target. Blockage of RAGE inhibited AGE-induced inflammation. However, due to the multiple functions of RAGE and possible long-term side effects of accumulated AGE in plasma, this method is not currently being followed in humans. Using the methods and compositions of the present invention, more specific inhibitory compounds can be used for treatment.

  Endothelial cells are the target organ in diabetes. Laight et al., 15 DIABETES METAB. REV. 274-82 (1999); Stehouwer et al., 34 CARDIOVASC. 55-68 (1997). Up-regulation of molecules involved in endothelial cell inflammation, such as IL-6 and monocyte chemoattractant protein-1 (MCP-1), leads to endothelial dysfunction and vasculopathy. Stehouwer et al., 34 CARDIOVASC. 55-68 (1997); Libby, 247 J. et al. INTERN. MED. 349-58 (2000); Van Lente, 293 CLINICA. CHIMICA. ACTA. 31-52 (2000).

  The overall approach to understanding and treating diabetes and its complications is to interfere with gene regulation (eg, leading to cytokine production) and inhibit AGE-induced inflammation.

  The effectiveness of the compounds of the invention in inhibiting glycated protein-induced inflammation and AGE-induced inflammation is described herein and in US Provisional Application No. 60 / 259,306, which is incorporated herein in its entirety. Are incorporated by reference). Such assays involve the measurement of specific activities of biological components involved in known cellular responses. These assays provide a measurable response in which the activity of the compound is determined. One aspect of the invention involves measuring the effect of a compound on the inflammatory response by a cell to the presence of a stimulatory factor. Yet another aspect of the invention includes endothelial cells that are stimulated by the addition of a glycated protein, a stimulatory factor. Endothelial cells respond by producing specific cytokines. The amount of cytokine produced is determined by measurement protocols known to those skilled in the art. The compounds of the invention are then added to the assay and the production of cytokines is measured. From a comparison of an assay without compound to an assay with compound, the biological effects of this compound can be determined. This compound may have an inhibitory effect, a stimulating effect, or no effect at all. Compounds for the treatment of inflammation include those that have an inhibitory effect.

  The assay involves endothelial cells that are stimulated in an inflammatory response due to the presence of the glycated protein, glycated human serum albumin. Such endothelial cells produce cytokines. The method according to the present invention includes measuring the amount of cytokine IL-6, and another aspect of the present invention includes measuring the amount of cytokine MCP-1. Preferably, although not required, the amount of cytokine produced is determined using an immunological method (eg, an ELISA assay). The methods of the present invention are not limited by the type of assay used to measure the amount of cytokines produced, and any method known to those of skill in the art, as well as any method developed later, may include stimulators and It can be used to measure the amount of cytokine produced in response to a compound having an unknown activity.

  IL-6 is a pro-inflammatory cytokine that is known to play an important role in the pathogenesis of diabetes and atherosclerosis. Horii et al., 39 KIDNEY INT. SUPPL. 71-5 (1993); Huber et al., 19 ARTERIOSCLER THROMB. VASC. BIOL. 2364-67 (1999); Shikano et al., 85 NEPHRON 81-5 (2000); Pickup et al., 8 (67) LIFE SCI. 291-300 (2000). IL-6 also promotes the proliferation of kidney mesangial cells and thus contributes to kidney damage. Kado et al., 36 ACTA. DIABETOL. 67-72 (1999). Serum IL-6 levels in diabetic subjects were significantly higher than normal healthy controls (3.48 ± 3.29 pg / ml vs. 0.784 ± 0.90 pg / ml, mean ± / SD). In addition to urine, IL-6 levels are a good indicator of diabetic nephropathy. Serum IL-6 is useful in the assessment of atherosclerosis and kidney damage.

  Another pro-inflammatory cytokine, MCP-1, is found to be highly expressed in human atherosclerotic injury and is hypothesized to play a central role in monocyte recruitment into the arterial wall and diseased area. . Libby, 247 J.M. INTERN. MED. 349-58 (2000). Recent studies indicate that MCP-1 is also a key etiological factor in diabetic nephropathy. Eitner et al., 51 KIDNEY INT. 69-78 (1997); Banba et al., 58 KIDNEY INT. See 684-90 (2000).

  Glycated albumin stimulates endothelial cell production of IL-6 and MCP-1. The effect of glycated albumin on IL-6 production is comparable to that of TNFα, a known inducer of IL-6. These cytokines are known to be factors in vascular disease. Due to the well-established role of these cytokines in vascular disease, screening for compounds that block these cytokines AGE induction is a new approach to identify therapeutic factors that block AGE-induced inflammation I will provide a.

  Once a baseline response to a stimulatory factor for production of cytokines by endothelial cells (and thus including a control level for this screening assay) is established, these methods can be used for compounds with unknown activity. Includes addition. The effect of this compound on the baseline response is determined by comparing the amount of cytokine produced in the presence of the stimulatory factor and the amount of cytokine produced in the presence of the stimulatory factor and the compound of the invention. The In one method, compounds that have an inhibitory effect on cellular inflammation in the presence of glycated albumin are then used as therapeutic agents. One or more compounds can be added to the screening assay. Combinations or mixtures of compounds can be added. Different amounts and formulations of the compound are added to determine the effect in the screening assay. This screening assay can also be used to determine the stimulatory compound (s) that have no effect in the assay.

  Table 2 provides examples that inhibited the pro-inflammatory cytokines IL-6 and MCP-1.

本発明はまた、所望の活性を有するとして、この方法によって同定された化合物を含む組成物を含む。これらの組成物は、細胞、組織、または生物全体の処置において有用である。このような組成物は、生物学的状態（Ｉ型およびＩＩ型の糖尿病誘発性脈管症、他の脈管症、微小血管症、腎臓機能不全、アルツハイマー症候群および炎症誘発性疾患（例えば、アテローム性動脈硬化症）が挙げられるがこれらに限定されない）の処置のための有効量で投与のために処方される。この組成物は、所望の活性を有する化合物の投与のために必要な薬学的補助剤を含み得る。

The present invention also includes compositions comprising a compound identified by this method as having the desired activity. These compositions are useful in the treatment of cells, tissues, or whole organisms. Such compositions may be used in biological conditions (type I and type II diabetes-induced vasculopathy, other vasculopathy, microangiopathy, renal dysfunction, Alzheimer's syndrome and pro-inflammatory diseases (eg, atheroma Formulated for administration in an effective amount for the treatment of (including but not limited to atherosclerosis). The composition may contain pharmaceutical auxiliaries necessary for the administration of the compound having the desired activity.

  Furthermore, the compounds of the invention are useful in treatment or prevention in at least one autoimmune related disease in a cell, tissue, organ, animal or patient. Such autoimmune related diseases include, but are not limited to: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis , Gastric ulcer, seronegative arthropathy, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis / uveitis / optic neuritis, idiopathic pulmonary fibrosis Systemic vasculitis / Wegener's granulomatosis, sarcoidosis, orchiditis / vasectomy reversal procedure, allergy / atopic disease, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonia, transplantation Fragment, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, Gramyang Sepsis, Gram-negative sepsis, culture-negative sepsis, fungal sepsis, neutropenic fever, urinary sepsis, meningococcal blood, trauma / bleeding, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome Rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathology, clonal pathology, sickle cell anemia, diabetes, nephrosis, atopic disease, hypersensitivity reaction, allergic rhinitis, hay fever, perennial plant rhinitis, conjunctivitis, endometriosis , Asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic disease, thrombocytopenia, transplant rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplantation Rejection, pancreas graft rejection, lung graft rejection, bone marrow graft (BMT) rejection, skin allograft rejection, cartilage graft rejection, bone graft Rejection, small intestine graft rejection, fetal thymus graft rejection, parathyroid graft rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reaction, Graves' disease, Raynaud's disease ), Type B insulin resistant diabetes, asthma, myasthenia gravis, -mediated cytotoxicity, type III hypersensitivity reaction, POEMS syndrome (polyneuropathy, organomegaly, endocrine disorder, monoclonal hypergammaglobulinemia, and Skin change syndrome), polyneuropathy, organomegaly, endocrine disorder, monoclonal hypergammaglobulinemia, skin change syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison disease, self Immunohemolytic anemia, autoimmune hepatitis, idiopathic pulmonary fibrosis, scleroderma, diabetes mellitus, chronic active hepatitis , Vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonia, allograft rejection, granulomas caused by intracellular organisms, drug sensitivity , Metabolic / idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis , Thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial familial hemophagocytic lymphohistiocytosis, skin disease state, psoriasis, hair loss Disease, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, hemodialysis, uremia, toxicity, pre-eclampsia, ankylosing spondylitis, Behcet's disease, bullous celestial Acne, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigus, CREST syndrome, cold agglutinin disease, disc Lupus, essential mixed cold globulinemia, fibromyalgia-fibromyositis, Graves' disease, Giant-Barre, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus , Juvenile arthritis, lichen planus, Meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Kogan syndrome, polychondritis, polyglandular syndrome, polymyalgia rheumatica, multiple Myositis and dermatomyositis, primary agammaglobulinemia, Raynaud's phenomenon, Reiter syndrome, rheumatic fever, Sjogren's syndrome, stiff man syndrome Takayasu arteritis, temporal arteritis / giant cell arteritis, Wegener's granulomatosis; okt3 treatment, anti-cd3 treatment, cytokine treatment, chemotherapy, radiotherapy (eg, asthenia, anemia, cachexia, etc.) But not limited to), chronic salicylic acid poisoning and the like. For example, The Merck Manual, 12th-17th Editions, Merck & Company, Rahway, NJ (1972, 1977, 1982, 1987, 1992, 1999); Pharmacoedo Handbook, Well et al., Second Aid. (1998, 2000).

(D. Hyperproliferative disease)
Some compounds of the invention have cytotoxic activity and are therefore also useful in the treatment or prevention of at least one hyperproliferative disease in a cell, tissue, organism or patient. These hyperproliferative diseases include, but are not limited to: malignant and non-malignant cell proliferation, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B cell, T cell or FAB. ALL, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodysplastic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-Hodgkin lymphoma , Burkitt's lymphoma, multiple myeloma, capage sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome / malignant hypercalcemia, solid tumor, adenocarcinoma, sarcoma, malignant Myeloma, hemangioma, metastatic disease, cancer-related bone resorption, cancer-related bone pain, or any combination thereof.

(Drug-coated medical devices)
The compounds of the present invention, alone or in combination with other agents, together with delivery devices to effectively prevent and treat vascular diseases, particularly vascular diseases caused by injury and / or transplantation Can be used. Various medical treatment devices used to treat vascular diseases can ultimately induce further complications. For example, balloon angioplasty is a procedure used to increase blood flow through arteries and is an excellent treatment for coronary stenosis. However, as noted above, this procedure typically causes some damage to the vessel wall, thereby exacerbating the problem at a later point in time. Although other procedures and diseases can cause similar damage, exemplary compounds of the invention have been described for the treatment of restenosis, complications after percutaneous, transluminal coronary angioplasty, And other similar arterial / venous procedures (including arterial junctions), blood vessels and other fluids of other organs or parts of the body (eg liver, lungs, bladder, kidney, brain, prostate, neck and feet) Related to the conduit to be transported.

  Local delivery of the compounds of the present invention, and optionally other therapeutic agents from the stent, prevents vascular recoil and remodeling via actuation of the stent scaffold. Drug-coated stents can prevent multiple components of neointimal hyperplasia or restenosis and can reduce inflammation and thrombosis. Topical administration of the compounds of the present invention and other therapeutic agents to the stented coronary artery may have additional therapeutic benefits. For example, higher tissue concentrations of the compounds of the present invention and other therapeutic agents can be achieved using local delivery rather than systemic administration. Furthermore, reduction of systemic toxicity can be achieved using local delivery rather than systemic administration while maintaining higher tissue concentrations. When using local delivery from a stent rather than systemic administration, a single procedure may be sufficient for better patient adaptation. A further benefit of the combination with therapeutic agents and / or compounds is that the dose of each therapeutic agent can be reduced, thereby limiting their toxicity, but nevertheless restenosis, inflammation and Reduction of thrombosis can be achieved. Thus, local stent-based therapy is a means of improving the treatable ratio (efficacy / toxicity) of anti-restenosis therapeutic agents, anti-inflammatory therapeutic agents and anti-thrombotic therapeutic agents.

  Exemplary compounds of the invention are described herein with respect to the treatment of restenosis and other related complications, but the compounds of the invention alone, or topical as part of a combination of therapeutic agents. It is important to note that mechanical delivery can be used to treat a wide variety of conditions using any number of medical devices or to improve the function and / or lifetime of the device. For example, after a cataract surgery, an artificial lens placed to restore vision is often folded by the formation of a subsequent cataract. The latter is often the result of cell hyperplasia on the lens surface and could be minimized by combining the drug with the device. Often due to tissue growth or accumulation of proteinaceous material inside, surfaces, and surroundings of equipment (eg, shunts for hydrocephalus, dialysis grafts, colon fistula bag attachment equipment, ear drainage tubes) Other medical devices that lead to non-functional pacemakers and implantable defibrillators may also benefit from this device-drug combination approach. Other surgical instruments, sutures, clasps, anastomosis devices, vertebral discs, bone pins, suture anchors, hemostats, barriers, forceps, screws, Plates, chips, vascular grafts, tissue adhesives and sealants, tissue skeletons, various types of bandages, bone substitutes, intraluminal devices, and vascular supports also use this drug-device combination approach. Can provide increased patient benefit. Any type of medical device can be coated in some manner with only the compounds of the invention, or part of a therapeutic agent combination that improves treatment over the use of this device or therapeutic agent alone. Can be coated.

  In addition to various medical devices, these coatings can be used in combination with other therapeutic agents to deliver the compounds of the present invention, and these other therapeutic agents include: Antimitotics (natural products such as vinca alkaloids (eg, vinplastin, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (eg, etoposide, teniposide), antibiotics (dactinomycin ( Actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracycline, mitoxantrone, bleomycin, plicamycin (mitromycin) and mitomycin, the ability to systematically metabolize the enzyme (L-asparagine and synthesize its own asparagine L-asparagina without Antiplatelet agents (eg, G (GP) IIb / IIIa inhibitors and vitronectin receptor antagonists); antiproliferative / antimitotic alkylating agents (eg, nitrogen mustard (mechloretamine, cyclophosphamide and Analogs, melphalan, chlorambucil), ethyleneimine and methylmelamine (hexamethylmelamine and thiotepa), alkylsulfonate-busulfan, nitrosourea (carmustine (BCNU) and analog, streptozocin), trazen-dacarbazinine (DTIC)); antiproliferation / Anti-mitotic antimetabolites (eg folic acid analogues (methotrexate), pyridine analogues (fluorouracil, floxuridine, and cytarabine), purine analogues and related Inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (Cladribine))); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotan, aminoglutethimide; hormones (eg, estrogen); Anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (eg tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab); Anti- chemotactic agents; antisecretory agents (brebeldine); anti-inflammatory agents (eg, adrenocortic steroids (cortisol, cortisone, Fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone, and dexamethasone)); non-steroidal agents (salicylic acid derivatives, ie, aspirin); para-aminophenol derivatives (ie, acetomiphene); indole and indenacetic acid ( Indomethacin, sulindac, and etodalac), heteroaryl acetic acid (tolmethine, diclofenac, and ketorolac), arylpropionic acid (ibuprofen and derivatives), anthranilic acid (mefenamic acid, and meclofenamic acid), enolic acid (piroxicam, tenoxicam, phenylbutazone) , And oxyfentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, and Sodium thiomalate); immunosuppressant, (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mefetil); angiogenic agent: vascular endothelial growth factor (VEGF), fiber Blast growth factor (FGF); angiotensin receptor blocker; nitric oxide donor; antisense oligonucleotide and combinations thereof; cell cycle inhibitor, mTOR inhibitor, and growth factor signaling kinase inhibitor.

  Although many stents may be utilized in accordance with the present invention, for purposes of simplicity, a limited number of stents are described herein. Those skilled in the art will recognize that any stent can be utilized in connection with the present invention. Further, as described above, other medical devices can be utilized.

  Stents are commonly used as tubular structures that are placed within the lumen of a tube to reduce occlusion. Typically, the stent is inserted into the lumen in an unexpanded configuration and then expands spontaneously or expands in situ with the aid of a second device. A general method of dilation is a catheter that is inflated within a stented vessel or body passage to shear and break occlusions associated with vessel wall components and to obtain an enlarged lumen. By the use of an angioplasty balloon attached to.

  Stents can resemble expandable cylinders to open and hold blood vessels, tubes, or lumens (more specifically, to protect arterial segments from restenosis after angioplasty) May include a windowed structure for placement within a blood vessel, tube, or lumen. The stent can expand in the circumferential direction and can be maintained in an expanded structure that is rigid in the circumferential or radial direction. The stent can be axially flexible, for example, when secured to a band, the stent avoids any outwardly protruding component parts.

  Stents can be made using any number of methods. For example, a stent can be made from a hollow or formed stainless steel that can be machined using laser, electrical discharge grinding, chemical etching or other means. The stent is inserted into the body and placed at the desired site in an unexpanded form. Expansion can be effected on the blood vessel by a balloon catheter, where the final diameter of the stent is a function of the diameter of the balloon catheter used. A stent according to the present invention may be embodied in a shape memory material (eg, including a suitable alloy of nickel and titanium or stainless steel).

  Structures formed from stainless steel can be self-expanding by constructing the stainless steel in a predetermined manner (eg, by twisting into a knitted configuration). After the stent is formed, it can be compressed to show a space small enough to allow its insertion in a blood vessel or other tissue by the insertion means, where the insertion means is a suitable catheter, Or a flexible rod is provided. As it emerges from the catheter, the stent can be configured to expand to the desired configuration, where this expansion is triggered automatically or by changes in pressure, temperature or electrical stimulation.

  Further, the stent can be modified to include one or more reservoirs. Each of the reservoirs can be opened or closed as desired. These reservoirs can be specifically designed to retain the delivered compound or therapeutic / therapeutic combination.

  Regardless of the design of the stent, it is preferred to have a therapeutic / therapeutic agent combination dosage applied with sufficient specificity and concentration to provide an effective dosage within the affected area. In this regard, the reservoir size within the band is sized to adequately apply the dosage of the therapeutic / therapeutic agent combination at the desired location and in the desired amount.

  Alternatively, the entire inner and outer surfaces of the stent can be coated with a therapeutic dose, with a therapeutic agent / therapeutic agent combination. This coating technique can vary depending on the therapeutic / therapeutic agent combination. Also, the coating technique can vary depending on the material comprising the stent or other intraluminal medical device.

  One or more compounds of the present invention, and in some embodiments, other therapeutic agents in combination can be incorporated onto or attached to the stent in a number of ways. For example, the compound can be incorporated into a polymer matrix and sprayed onto the outer surface of the stent. This compound elutes from the polymer matrix over time and enters the surrounding tissue. This compound typically remains on the stent for at least 3 days to about 6 months, such as between 7 and 30 days.

  Many non-corrosive polymers are utilized in connection with this compound. According to one aspect of the invention, the polymer matrix comprises two layers. The base layer comprises a solution of poly (ethylene-covinyl acetate) and polybutyl methacrylate. This compound is incorporated into the base layer. The outer layer contains only polybutyl methacrylate and acts as a nucleic acid barrier that prevents the compound from elution too fast. The thickness of the outer layer or top coat determines the rate at which the compound elutes from the matrix. Basically, the compound elutes from the matrix by diffusion through the polymer matrix. The polymer is permeable so that solids, liquids and gases can escape from it. The overall thickness of the polymer matrix is from about 1 micron to about 20 microns or more. A primer layer and metal surface treatment may be utilized before the polymer matrix is attached to the medical device. For example, acid cleaning, alkali (base) cleaning, sanitization, and parylene deposition can be used as part of the overall process described above.

  Poly (ethylene-co-vinyl acetate), polybutyl methacrylate and compound solutions can be incorporated into or on the stent in a number of ways. For example, the solution can be sprayed onto the stent or the stent can be immersed in the solution. This solution can be sprayed onto the stent and then dried. In another embodiment, the solution can be charged to one polarity and the stent is charged to the opposite polarity. In this manner, the solution and stent are attracted to each other. When using this type of spraying process, waste can be reduced and more precise control over the thickness of the coating can be achieved. Other methods include spin coating and plasma polymerization.

  Drug-coated stents are available from Johnson & Johnson, Inc. (New Brunswick, NJ), Guidant Corp. (Santa Clara, CA), Medtronic, Inc. (Minneapolis, MN), Cook Group Incorporated (Bloomington, IN), Abbott Labs. , Inc. (Abbott Park, IL), and Boston Scientific Corp. Manufactured by many companies including (Natick, MA). See, for example, US Pat. No. 6,273,913; US Patent Application No. 20020051730; WO 02/26271; and WO 02/26139. Each is incorporated herein by reference in its entirety.

(Expression profile and microarray usage method)
The present invention contemplates a variety of microarrays, which can be used to study and monitor gene expression in response to treatment with the inventive compound. For example, the microarrays of the present invention can include, for example, specific organisms or cell types (human microarrays, vascular microarrays, inflammation microarrays, cancer microarrays, apoptosis microarrays, oncogene and tumor suppressor microarrays, cell-cell interaction microarrays, cytokines and cytokines. Including, or representative of, receptor microarrays, blood microarrays, cell cycle microarrays, neuroarrays, mouse microarrays, and rat microarrays, or combinations thereof. In further embodiments, the microarray comprises cardiovascular disease, vascular disorder condition, inflammatory disease, autoimmune disease, neurological disease, immunological disease, various cancers, infectious diseases, endocrine disorders, and genetic diseases. It may represent a disease comprising.

  Alternatively, microarrays useful in assessing the efficacy of the compounds of the present invention may represent specific tissue types including, but not limited to: heart, liver, prostate, tissue, nerve, muscle, or connective tissue; For example, coronary endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, skin microvascular endothelium, pulmonary arterial endothelium, uterine muscle microvascular endothelium, keratinocyte epithelium, tracheal epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, near kidney Tubule epithelium, small airway epithelium, kidney epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cell, skeletal muscle, astrocyte, aortic smooth muscle, mesangial cell, Coronary smooth muscle, tracheal branch smooth muscle, uterine smooth muscle, lung fibroblast, osteoblast, prostate stromal cell, or a combination thereof.

  The present invention further contemplates a microarray comprising a gene expression profile comprising one or more polynucleotide sequences comprising complementary and homologous sequences, wherein the gene expression profile is a cell treated with a compound of the invention. Coronary endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, cutaneous microvascular endothelium, pulmonary arterial endothelium, uterine muscle microvascular endothelium, keratinocyte epithelium, tracheal epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium , Renal proximal tubule epithelium, small airway epithelium, kidney epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural precursor cell, skeletal muscle, astrocyte, aortic smooth muscle, Selected from the group comprising mesangial cells, coronary artery smooth muscle, tracheal branch smooth muscle, uterine smooth muscle, lung fibroblasts, osteoblasts, prostate stromal cells

  The present invention contemplates a microarray comprising one or more protein binding agents, wherein a protein expression profile is generated from a cell type treated with a compound of the present invention and coronary endothelium, umbilical artery endothelium, umbilical vein Endothelium, aortic endothelium, cutaneous microvascular endothelium, pulmonary arterial endothelium, uterine muscle microvascular endothelium, keratinocyte epithelium, tracheal epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, kidney epithelium, umbilical cord Arterial smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cell, skeletal muscle, astrocyte, aortic smooth muscle, mesangial cell, coronary smooth muscle, tracheal branch smooth muscle, uterine smooth Selected from the group consisting of muscle, lung fibroblasts, osteoblasts, prostate stromal cells.

  More particularly, the present invention contemplates methods for reproducible measurement and evaluation of, for example, the expression of specific mRNAs or proteins in a specific set of cells. One method involves laser capture microdissection techniques, T7-based RNA amplification, production of cDNA from amplified RNA, and various methods to create gene expression analysis profiles for very few specific cells. Combine and utilize DNA microarrays containing DNA molecules immobilized against specific genes (including HSPGs such as perlecan). Desired cells are individually identified, attached to the substrate by laser capture techniques, and the captured cells are then separated from the remaining cells. RNA can then be extracted from the captured cells and amplified about 1 million times using T7-based amplification techniques, and cDNA can be prepared from the amplified RNA. A wide variety of specific DNA molecules that hybridize with specific polynucleotides of the microarray are prepared and the DNA molecules are immobilized on a suitable substrate. CDNA made from the captured cells is applied to the microarray under conditions that allow hybridization of the cDNA to immobilized DNA on the microarray. Captured cell expression profiles are derived from analysis of hybridization results using amplified RNA or cDNA made from captured cell amplified RNA and specific immobilized DNA molecules on the microarray It is done. The result of the hybridization indicates, for example, which genes of those shown on the microarray as probes are hybridized to the cDNA from the cells to be captured and / or the amount of a particular gene. The result of the hybridization represents the gene expression profile of the captured cells. The gene expression profiles of the captured cells can be used to compare the gene expression profiles of different sets of captured cells. For example, gene expression profiles can be generated from cells (and untreated cells) that have been treated with the compounds of the present invention. Similarities and differences provide useful information for determining differences between the same cell type under different conditions, and more particularly, changes in gene expression in response to treatment with a compound of the invention.

  The techniques used for gene expression analysis are equally applicable in the context of protein expression profiles. The entire protein can be isolated from a cell sample and hybridized to a microarray containing multiple protein binding agents, which can include antibodies, receptor proteins, small molecules. Using any of several assays known in the art, hybridization can be detected and analyzed as described above. In the case of fluorescence detection, an algorithm can be used to extract a protein expression profile representative of a particular cell type. In this regard, changes in protein expression in response to treatment of cells with the compounds of the invention can be assessed.

  Accordingly, in one aspect, the present invention is a specific used for detecting changes in gene transcription levels resulting from exposing selected tissues or cells to a candidate agent (eg, a compound of the present invention). Includes at least one microarray corresponding to a population of genes isolated from a tissue type or cell type. Biological samples from organisms or established cell lines can be exposed to the candidate agent in vivo or ex vivo. Accordingly, tissue or cellular gene transcripts (mainly mRNA) are isolated by methods well known in the art. SAMBROOK et al., MOLECULAR CLONING: A LAB. MANUAL (2001). The isolated transcript is then contacted with the microarray under conditions where the transcript hybridizes with the corresponding probe to form a hybridization pair. Thus, the microarray provides a model of transcription reactivity and is exposed to specific drug candidates. A hybridization signal is then detected in each hybridization pair to obtain a gene expression profile.

  Gene and / or protein expression profiles and microarrays can also be used to identify active or inactive compounds of a particular gene (eg, perlecan or other HSPG). Compounds that increase transcription rate or stimulation or stabilize protein activity are considered activated, and compounds that decrease rate or inhibit protein activity are considered not activated . Furthermore, the biological effect of the compound can be influenced by the biological state of the cell. This condition is characterized by cell constructs. One aspect of the biological state of the cell is the transcriptional state of the cell. The transcriptional state of a cell includes the identity and amount of construct RNA species (particularly mRNA) in the cell under certain conditions. Thus, the gene expression profiles, microarrays, and algorithms discussed herein analyze and characterize the transcriptional state of a given cell or tissue exposed to active or inactive compounds, particularly the compounds of the present invention. Can be used for.

  Microarray technology and methods of analyzing results are well known in the art. U.S. Patent Nos. 6,263,287; 6,239,209; 6,218,122; 6,197,599; 6,156,501; No. 5,837,832; No. 5,700,637; No. 5,445,934; US Patent Application Nos. 2001/0014461 Al; 2001/0039016 Al; 2001/0034023 Al WO 01/94946; and WO 01/77668. See also Haab et al., 2 GENOME BIOLOGY 1-12 (2001); Brown et al., 97 PROC. NATL. ACAD. SCI. USA 262-7 (2000); Getz et al., 97 PROC. NATL. ACAD. Scl. USA 12079-84 (2000); Harrington et al., 3 CURRENT OPINION MICROBIOL 285-91 (2000); Holter et al., 97 PROC. NATL. ACAD. SCI. USA 8409-14 (2000); MacBeath et al., 289 SCIENCE 1760-63 (2000); Duggan et al., 21 NATURE GENET 10-14 (1999); Lipshutz et al., 21 NATURE GENET 5-9 (1999); Eisen et al., 95 PROC. . NATL. ACAD. Sci. USA 14863-68 (1998); Ermoleva et al., 20 NATURE GENET. 19-23 (1998); Hacia et al., 26 NUCLEICA AcIDs REs. 3865-66 (1998); Lockhart et al., NUCLEIC ACIDS SYMP. SER. 11-12 (1998); Schena et al., 16 TRENDS BIOTECHNOL. 301-6 (1998); Shalon, 46 PATHOL. BIOL. 107-9 (1998); Welford et al., 26 NUCLEIC ACIDRES. 3059-65 (1998); Blanchard et al., 11 BIOSENSORS BIOELECTRONICS 687-90 (1996); Lockhart et al., 14 NATURE BIOTECHNOL. 1675-80 (1996); Schena et al., 93 PROC. NATL. ACAD. SCI. USA 10614-19 (1996); Tomayo et al., 96 PROC. NATL. ACAD. SCI. USA 2907-12 (1996); Schena et al., 270 SCIENCE 467-70 (1995).

(Database creation, database access and related usage)
The present invention encompasses various methods, including methods that provide diagnostic agents and predictors for biomolecules (including HSPGS, particularly perlecan). The present invention further includes methods for providing diagnostic agents and predictors for the effectiveness of the compounds of the present invention. The present invention further contemplates a method for providing an expression profile database for normal and diseased tissues, and a method for generating such a database.

  The expression profile database may be an internal database designed to contain expression profiles generated to assess the effects of the compounds of the present invention as well as commentary information about other sources and methods. Such information may include, for example: the database found in a given biomolecule, patient information related to the expression profile (including age, cancer or tumor type or progression), of the present invention Information related to the compound (eg, dosing and administration information), detailed information about this sequence, relevant cDNAs related to tissue or cell sources, sequence data obtained from external sources, expression for a given gene Profile and associated disease state or course (eg, whether an expression profile is associated with or indicates a particular disease state) and methods of preparation. Expression profiles can be based on protein and / or polynucleotide microarray data obtained from commercial or enterprise sources. This database can be categorized into two sections: one storing sequences and associated expression profiles, and the other storing related information. This database may be maintained as a personal database using a firewall within the central computer facility. However, the present invention is not limited at all, and the expression profile database is publicly available.

  This database may be a network system that connects a client and a network server. The network can be any of many conventional network systems. These networks include a local area network (LAN) or a wide area network (WAN) as is known in the art (eg, Ethernet (registered trademark)). The server may include software that accesses database information to process user requests, and software that provides an interface for communicating information to client devices. The server may support World Wide Web and maintain a website and web browser for client use. Client / server environments, database servers, and networks are well documented in the technology, trading, and patent literature.

  Through a web browser, the client can configure a survey request to retrieve data from, for example, a microarray database and an expression profile database. For example, a user may “point and click” user interface elements (eg, buttons, pull-down menus, and scroll bars). The client's request can be communicated to the web application that formats it, more information from the system database, such as information based on microarrays or expression data obtained by the client, and / or other representations or genotypes Generate queries that can be used for information. In particular, the client can submit expression data based on a microarray expression profile obtained from a patient treated with a compound of the invention, and using the system, the client's expression data and the expression data contained in the database can be Get a diagnosis based on the comparison by this system. As an example, the system compares the expression profile submitted by the client with the expression profile contained in the database and then provides the client with diagnostic information based on the best match between the client expression profile and the database profile. Thus, in one aspect, comparison of expression profiles assists the clinician in determining the effects of treatment with the compounds of the present invention. Based on such comparison, the clinician may change or adjust the treatment regimen.

  In addition, the website provides hyperlinks to public databases (eg, related databases maintained by the National Center for Biotechnology Information (NCBI), which is part of GenBank and the National Library of Medicine), as well as gene expression analysis, genetic disease Any link that provides relevant information about the scientific literature may be provided. Information (identifiers, identifier types, biomolecular sequences, common cluster identifiers (such as GenBank, Unigene, Incyte template identifiers) and species names associated with each gene are contemplated).

  The present invention also provides a system for accessing and comparing biological information, particularly information useful in relation to expression profiles and the compositions and methods of the present invention. The computer system includes a computer processor, a suitable memory operably connected to the computer processor, and a computer processor stored in memory executing on the computer processor, and the system includes an expression profile of a patient-derived biomolecule sequence And means for matching the biomolecule expression profile and sequence identification information in the database. More particularly, the computer system is used to match expression profiles generated from biological samples treated with compounds of the present invention with expression profiles and other information in the database.

  Further, a system for accessing and comparing information contained in a biomolecule database comprises a computer program including computer code, for example, an expression profile generated from a patient treated with a compound of the present invention, An algorithm is provided for matching biomolecular sequence expression profiles and sequence identification information.

  The present invention contemplates the use of a graphical user interface (“GUI”), for example, for accessing expression profile information stored in a biomolecule database. The GUI can be composed of two frames. The first frame may include a selectable list of biomolecule databases accessible by the user. If a biomolecule is selected in the first frame, then the second frame, along with any other phenotype or genotype information, is from a pair comparison of the expression profile database and the expression profile supplied by the client The resulting information can be displayed.

  The second frame of the GUI may include sequence expression information and profiles contained in the selected database. Further, the second frame may allow the user to select a subset (including all of the biomolecule sequences) and perform operations on the enumeration of biomolecule sequences. A user may select a subset of biomolecule sequences by selecting a selection box associated with the biomolecule sequence. Operations that can be performed include, but are not limited to: downloading all enumerated biomolecule sequences to a database spreadsheet with classification information, and a selected subset of biomolecule sequences in the user's file. , Download all enumerated biomolecules to database spreadsheet software without classification information, and display classification information about a selected subset of biomolecule sequences.

  If the user chooses to display classification information about the selected subset of biomolecule sequences, the second GUI. Can be presented to the user. The second GUI may include an enumeration of one or more external databases that are used to create an expression profile database as described above. Further, for external databases, the GUI may display an enumeration of one or more fields associated with each external database. The GUI may allow the user to select or exclude each of the one or more fields displayed on the second GUI. In yet another embodiment, the GUI may also allow the user to select or exclude each of one or more external databases.

The methods of the present invention further relate to commercial and other uses of the compositions and methodologies of the present invention. In one aspect, methods include the following: expression profiles database for consumers (ie, patients, physicians, medical service providers, researchers, and pharmaceutical distributors and manufacturers). Marketing, sales or licensing of the compositions and methodologies of the present invention in the context of providing (especially a database generated by the use of the compounds of the present invention) This includes establishing a delivery system for delivering goods, and optionally establishing a sales group for marketing the pharmaceutical composition.

  The present invention further performs target discovery (including identification) with one or more drug discovery methods described above, as described above, with test compounds that modulate gene expression profiles or gene product activity (eg, perlecan). A method of performing therapeutic profiling of the identified agents or their further analogs for efficacy and toxicity in animals; and, optionally, one of the agents identified as having an accessible therapeutic profile A method of formulating a pharmaceutical composition comprising the above; as well as a method of licensing or selling the right to further drug development of the identified agent, as appropriate, is provided.

  The invention is further illustrated by the following preparations and examples, which are not to be construed as limiting the scope of the invention in any way. It will be apparent to those skilled in the art that various other modifications, embodiments, and equivalents exist without departing from the spirit of the invention and / or the scope of the appended claims.

(Preparation 1)
(1- [4- (2-Bromoethoxy) phenyl] -1-ethanone)

４−ヒドロキシアセトフェノン（２０ｇ、１４７ｍｍｏｌ）および炭酸カリウム（８１ｇ、５８８ｍｍｏｌ）の混合物を２Ｌ丸底フラスコに入れ、そしてアセトン（１Ｌ）を加えた。この反応混合物に、ジブロモエタン（３８ｍＬ）を一度に加え、次いで、その反応混合物を、窒素雰囲気下にて、３６時間還流させた。この反応混合物を室温まで冷却し、そして濾過し、残渣をアセトン（２×１００ｍＬ）で洗浄し、その濾液を合わせ、そして減圧下にて濃縮した。その粗製物を、１０〜１５％酢酸エチル／石油エーテル（２Ｌ）を使用することにより、シリカゲルでクロマトグラフィーにかけて、白色固形物として、表題化合物７ｇ（２０％）を得た。融点５８〜６１℃。

A mixture of 4-hydroxyacetophenone (20 g, 147 mmol) and potassium carbonate (81 g, 588 mmol) was placed in a 2 L round bottom flask and acetone (1 L) was added. To this reaction mixture was added dibromoethane (38 mL) in one portion and then the reaction mixture was refluxed for 36 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered, the residue washed with acetone (2 × 100 mL), the filtrates combined and concentrated under reduced pressure. The crude was chromatographed on silica gel using 10-15% ethyl acetate / petroleum ether (2 L) to give 7 g (20%) of the title compound as a white solid. Mp 58-61 ° C.

（調製２）
（２−（３，４−ジメトキシフェニル）−３−ヒドロキシ−５，７−ジメトキシ−４Ｈ−４−クロメノン）

(Preparation 2)
(2- (3,4-Dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone)

工程（ｉ）：
３−［（６−０−（デオキシ−ａ−Ｌ−マンノピラノシル）−β−グルコピラノシル）オキシ］−２−（３，４−ジメトキシフェニル）−５，７−ジメトキシ−４Ｈ−１−ベンゾピラン−４−オン

Step (i):
3-[(6-0- (Deoxy-aL-mannopyranosyl) -β-glucopyranosyl) oxy] -2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4- on

ルチン水和物（１）（８０ｇ、１２０．５ｍｍｏｌ）および炭酸カリウム（３２０ｇ、２３１９ｍｍｏｌ）の混合物を２Ｌ三ッ口丸底フラスコ（これには、窒素雰囲気付きの還流冷却器および滴下漏斗を取り付けた）に入れ、そしてアセトン（１．５Ｌ）を加えた。この反応混合物に、硫酸ジメチル（１６０ｍＬ）を滴下した。その反応混合物を、６０℃で、６８時間還流した。次いで、この反応混合物を２５℃まで冷却し、分離した固形物を濾過した。その残渣をアセトン（１Ｌ）で洗浄し、続いて、メタノール（５００ｍＬ）で洗浄し、濾液を合わせ、そして減圧下にて濃縮して、黄色粘着性固形物として、表題化合物（８０ｇ、９１％）を得た。

A mixture of rutin hydrate (1) (80 g, 120.5 mmol) and potassium carbonate (320 g, 2319 mmol) was added to a 2 L three-necked round bottom flask (to which was attached a reflux condenser and dropping funnel with a nitrogen atmosphere). ) And acetone (1.5 L) was added. To this reaction mixture, dimethyl sulfate (160 mL) was added dropwise. The reaction mixture was refluxed at 60 ° C. for 68 hours. The reaction mixture was then cooled to 25 ° C. and the separated solid was filtered. The residue was washed with acetone (1 L) followed by methanol (500 mL), the filtrates combined and concentrated under reduced pressure to give the title compound (80 g, 91%) as a yellow sticky solid. Got.

Step (ii): 2- (3,4-dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone The compound obtained in step (i) (80 g, 110 mmol) was 2 L single-necked round bottom. Into a flask and at 25 ° C. hydrochloric acid (20%, 1 L) was added. The reaction mixture was refluxed at 100 ° C. for 2 hours and then cooled to 25 ° C. The separated solid was filtered, washed with isopropanol (200 mL) and dried in vacuo to give the title compound (27.5 g, 70%) as a pale yellow solid. Mp 192-194 ° C.

（調製３）
（１−（４−｛２−［２−（３，４−ジメトキシフェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−３−クロメニルオキシ］エトキシ｝フェニル）−１−エタノン）

(Preparation 3)
(1- (4- {2- [2- (3,4-Dimethoxyphenyl) -5,7-dimethoxy-4-oxo-4H-3-chromenyloxy] ethoxy} phenyl) -1-ethanone)

調製２で得た化合物（２５ｇ、６９．６ｍｍｏｌ）、調製１で得た化合物（２１．５ｇ、８８．４ｍｍｏｌ）および炭酸カリウム（７７ｇ、５５７ｍｍｏｌ）の混合物を１Ｌ丸底フラスコに入れ、その反応混合物に、ＤＭＦ（４００ｍＬ）を加えた。この反応混合物を窒素雰囲気下にて３時間撹拌しつつ、８０℃まで加熱した。この反応混合物を２５℃まで冷却し、そして氷冷水（１Ｌ）にゆっくりと注いだ。分離した固形物を濾過し、そして水（２×５００ｍＬ）で洗浄した。それをメタノールで倍散し、そして濾過して、真空下にて乾燥した後、淡褐色固形物として、表題化合物（３１．５ｇ、８７％）を得た。融点１４３〜１４４℃。

A mixture of the compound obtained in Preparation 2 (25 g, 69.6 mmol), the compound obtained in Preparation 1 (21.5 g, 88.4 mmol) and potassium carbonate (77 g, 557 mmol) was placed in a 1 L round bottom flask and the reaction mixture Was added DMF (400 mL). The reaction mixture was heated to 80 ° C. with stirring for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and slowly poured into ice cold water (1 L). The separated solid was filtered and washed with water (2 × 500 mL). After triturating with methanol and filtering and drying under vacuum, the title compound (31.5 g, 87%) was obtained as a light brown solid. Mp 143-144 ° C.

（調製４）
（酢酸４−フルオロフェニル）

(Preparation 4)
(4-fluorophenyl acetate)

４−フルオロフェノール（２０ｇ、１７８．５ｍｍｏｌ）を単口１Ｌ丸底フラスコに入れ、そこに、水酸化ナトリウム溶液（水１００ｍＬ中で１２ｇ）を加えた。その反応混合物を、２５℃で、５〜１０分間撹拌し、そして砕氷（５０ｇ）を加え、続いて、無水酢酸（３０ｍＬ）を加えた。この反応混合物を、同じ温度で、１５分間撹拌し、そこに、水（３００ｍＬ）を加え、続いて、塩酸（６Ｎ、６０ｍＬ）を加えた。その混合物をクロロホルム（３×１００ｍＬ）で抽出し、合わせた抽出物を硫酸ナトリウムで乾燥し、そして減圧下にて濃縮して、白色固形物として、表題化合物（２６ｇ、９５％）を得た。

4-Fluorophenol (20 g, 178.5 mmol) was placed in a single neck 1 L round bottom flask to which was added sodium hydroxide solution (12 g in 100 mL water). The reaction mixture was stirred at 25 ° C. for 5-10 minutes and crushed ice (50 g) was added followed by acetic anhydride (30 mL). The reaction mixture was stirred for 15 minutes at the same temperature, to which water (300 mL) was added followed by hydrochloric acid (6N, 60 mL). The mixture was extracted with chloroform (3 × 100 mL) and the combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (26 g, 95%) as a white solid.

（調製５）
（（２−ヒドロキシ−４−フルオロフェニル）−１−エタノン）

(Preparation 5)
((2-hydroxy-4-fluorophenyl) -1-ethanone)

調製４で得た酢酸４−フルオロフェニル（２５ｇ、２２３ｍｍｏｌ）、塩化アルミニウム（８９ｇ、６７０ｍｍｏｌ）の混合物を１Ｌ単口丸底フラスコ（これには、空気冷却器および塩化カルシウムガードチューブを取り付けた）に入れた。その反応混合物を、３０分間にわたって、１２０〜１２５℃までゆっくりと加熱し、次いで、１６５℃まで加熱した（ＨＣｌガスの発生が認められた）。この混合物を、同じ温度で、３０分間撹拌し、次いで、室温まで冷却した。そこに、水（５００ｍＬ）を加え、続いて、６Ｎ ＨＣｌ（１５０ｍＬ）を加えた。この混合物をクロロホルム（３×２００ｍＬ）で抽出し、合わせた有機層を硫酸ナトリウムで乾燥し、そして減圧下にて濃縮して、白色固形物として、表題化合物（２１ｇ、８４％）を得た。

A mixture of 4-fluorophenyl acetate (25 g, 223 mmol) and aluminum chloride (89 g, 670 mmol) obtained in Preparation 4 was placed in a 1 L single neck round bottom flask (which was equipped with an air cooler and a calcium chloride guard tube). I put it in. The reaction mixture was slowly heated to 120-125 ° C. over 30 minutes, then heated to 165 ° C. (HCl gas evolution was observed). The mixture was stirred at the same temperature for 30 minutes and then cooled to room temperature. Thereto was added water (500 mL), followed by 6N HCl (150 mL). The mixture was extracted with chloroform (3 × 200 mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (21 g, 84%) as a white solid.

（調製６）
（１−（５−フルオロ−２−ヒドロキシフェニル）−３−（４−メトキシフェニル）−２−プロペン−１−オン）

(Preparation 6)
(1- (5-Fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) -2-propen-1-one)

メタノール中の（２−ヒドロキシ−４−フルオロフェニル）−１−エタノン（これは、調製５で得た）（３ｇ、１９．７ｍｍｏｌ）および４−フルオロベンズアルデヒド（４．３７ｇ、１９．７ｍｍｏｌ）の混合物に、０℃で、Ｎ_２雰囲気下にて、水酸化ナトリウム溶液をゆっくりと加えた。その反応混合物を、０〜１０℃で、１０時間撹拌した。そこに、水（１００ｍＬ）を加え、続いて、６Ｎ ＨＣｌ（１５ｍＬ）を加えた。分離した固形物を濾過により除き、そして真空乾燥して、黄色固形物として、３ｇ（４１％）の表題化合物を得た。

Mixture of (2-hydroxy-4-fluorophenyl) -1-ethanone (obtained in Preparation 5) (3 g, 19.7 mmol) and 4-fluorobenzaldehyde (4.37 g, 19.7 mmol) in methanol Was slowly added sodium hydroxide solution at 0 ° C. under N ₂ atmosphere. The reaction mixture was stirred at 0-10 ° C. for 10 hours. Thereto was added water (100 mL), followed by 6N HCl (15 mL). The separated solid was removed by filtration and dried in vacuo to give 3 g (41%) of the title compound as a yellow solid.

（調製７）
（６−フルオロ−２−（４−メトキシフェニル）−３−ヒドロキシ−４Ｈ−４−クロメノン）

(Preparation 7)
(6-Fluoro-2- (4-methoxyphenyl) -3-hydroxy-4H-4-chromenone)

調製６で得たカルコン生成物（３．０ｇ、１１ｍｍｏｌ）をメタノール（３０ｍＬ）に溶解し、そして０℃まで冷却した。この混合物に水酸化ナトリウム溶液（２０ｍＬ、２０％）を加え、次いで、その反応混合物を、同じ温度で、５〜１０分間撹拌した。この混合物に過酸化水素を加え、そして撹拌を、０〜１０℃で、１時間継続した。そこに、水（１００ｍＬ）を加え、続いて、６Ｎ ＨＣｌ（３０ｍＬ）を加えた。分離した固形物を濾過により除き、そして真空乾燥して、黄色固形物として、１．０ｇ（３２％）の表題化合物を得た。

The chalcone product obtained in Preparation 6 (3.0 g, 11 mmol) was dissolved in methanol (30 mL) and cooled to 0 ° C. To this mixture was added sodium hydroxide solution (20 mL, 20%) and then the reaction mixture was stirred at the same temperature for 5-10 minutes. Hydrogen peroxide was added to the mixture and stirring was continued at 0-10 ° C. for 1 hour. Thereto was added water (100 mL), followed by 6N HCl (30 mL). The separated solid was removed by filtration and dried in vacuo to give 1.0 g (32%) of the title compound as a yellow solid.

（調製８）
（１−（４−｛２−［６−フルオロ−２−（４−メトキシフェニル）−４−オキソ−４Ｈ−３−クロメニルオキシ｝フェニル）−１−エタノン）

(Preparation 8)
(1- (4- {2- [6-Fluoro-2- (4-methoxyphenyl) -4-oxo-4H-3-chromenyloxy} phenyl) -1-ethanone)

調製７で得た生成物（０．３ｇ、１．０４ｍｍｏｌ）、調製１で得た化合物（０．２５ｇ、１．０４ｍｍｏｌ）および炭酸カリウム（０．８６ｇ、６．２ｍｍｏｌ）の混合物を１Ｌ丸底フラスコに入れ、その混合物に、ＤＭＦ（１５ｍＬ）を加えた。この混合物を、窒素雰囲気下にて３時間撹拌しつつ、８０℃まで加熱した。その反応混合物を２５℃まで冷却し、そして氷冷水（１Ｌ）にゆっくりと注いだ。分離した固形物を濾過し、そして水（２×５００ｍＬ）で洗浄した。それをメタノールで倍散し、そして濾過して、真空下に乾燥した後、淡褐色固形物として、表題化合物（０．４ｇ、８５％）を得た。

A mixture of the product obtained in Preparation 7 (0.3 g, 1.04 mmol), the compound obtained in Preparation 1 (0.25 g, 1.04 mmol) and potassium carbonate (0.86 g, 6.2 mmol) was added to a 1 L round bottom. Place in a flask and add DMF (15 mL) to the mixture. The mixture was heated to 80 ° C. with stirring for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and slowly poured into ice cold water (1 L). The separated solid was filtered and washed with water (2 × 500 mL). After triturating with methanol and filtering and drying under vacuum, the title compound (0.4 g, 85%) was obtained as a light brown solid.

(Preparation 9)
(N-methylanthranilic acid)

アントラニル酸メチル−Ｎ−メチル（２０ｇ、１２１ｍｍｏｌ）のメタノール（１００ｍＬ）溶液（これは、２５０ｍＬ単口丸底フラスコに入れた）に、０〜１０℃で、ＮａＯＨ（９．６９ｇ、２４２ｍｍｏｌ）の水２５ｍＬ溶液を加えた。その反応混合物を、６時間にわたって、５０℃まで加熱し、次いで、室温まで冷却した。この反応混合物からメタノールを完全に除去し、そこに、水（１００ｍＬ）を加えた。この混合物をエーテル（３×５０ｍＬ）で洗浄し、そして水層を氷冷２Ｎ ＨＣｌで酸性化した（ｐＨ約５〜６）。分離した固形物を濾過し、水（２×５０ｍＬ）で洗浄し、そして真空乾燥して、白色固形物として、表題化合物１７．０ｇ（９３％）を得た。融点１７８〜１８０℃。

A solution of methyl anthranilate-N-methyl (20 g, 121 mmol) in methanol (100 mL) in a 250 mL single neck round bottom flask at 0-10 ° C. with NaOH (9.69 g, 242 mmol) in water. A 25 mL solution was added. The reaction mixture was heated to 50 ° C. over 6 hours and then cooled to room temperature. Methanol was completely removed from the reaction mixture, and water (100 mL) was added thereto. The mixture was washed with ether (3 × 50 mL) and the aqueous layer was acidified with ice cold 2N HCl (pH˜5-6). The separated solid was filtered, washed with water (2 × 50 mL), and dried in vacuo to give 17.0 g (93%) of the title compound as a white solid. Mp 178-180 ° C.

（調製１０）
（２−ブロモ−１−（４−メチルフェニル）−１−エタノン）

(Preparation 10)
(2-Bromo-1- (4-methylphenyl) -1-ethanone)

４−メチルアセトフェノン２０ｇ（１５０ｍｍｏｌ）の氷酢酸１００ｍＬ撹拌溶液に、１０〜１５℃で、触媒量のＨＢｒ（０．５ｍＬ）を滴下し、続いて、２１．４０ｇ（１３４ｍｍｏｌ）の臭素（これは、酢酸（３０ｍＬ）に溶解した）を滴下した。その反応混合物を、２５〜３５℃で、５時間撹拌し、次いで、水（１００ｍＬ）に注いだ。分離した固形物を濾過して、必要な生成物（２０ｇ、６５％）を得た。

To a stirred solution of 20 g (150 mmol) of 4-methylacetophenone in 100 mL of glacial acetic acid, a catalytic amount of HBr (0.5 mL) was added dropwise at 10-15 ° C., followed by 21.40 g (134 mmol) of bromine (this was Acetic acid (30 mL) was added dropwise. The reaction mixture was stirred at 25-35 ° C. for 5 hours and then poured into water (100 mL). The separated solid was filtered to give the required product (20 g, 65%).

（調製１１）
（エチル−２−メチルアミノアミノ安息香酸２−（４−メチルフェニル）−２−オキソ）

(Preparation 11)
(Ethyl-2-methylaminoaminobenzoic acid 2- (4-methylphenyl) -2-oxo)

調製９で得たＮ−メチルアントラニル酸（１０．０ｇ、６６ｍｍｏｌ）のジメチルホルムアミド１００ｍＬ溶液（これは、２５０ｍＬ単口丸底フラスコに入れた）に、ＫＯＨ（３．８９ｇ、６９ｍｍｏｌ）に水１０ｍＬ溶液を加え、その混合物を、２５〜３５℃で、４５分間撹拌した。この混合物を１０℃まで冷却し、そこに、調製１０で得たブロモケトン（１６．９ｇ、７９ｍｍｏｌ）を加えた。この反応混合物を、室温で、１０時間撹拌し、次いで、氷水（５００ｍＬ）に注いだ。分離した固形物を濾過し、水（２×１００ｍＬ）で洗浄し、そして真空乾燥して、白色固形物として、表題化合物（１１．０ｇ、５８％）を得た。融点：９６〜９８℃。

A solution of N-methylanthranilic acid (10.0 g, 66 mmol) obtained in Preparation 9 in 100 mL of dimethylformamide (which was placed in a 250 mL single-necked round bottom flask), KOH (3.89 g, 69 mmol) in 10 mL of water And the mixture was stirred at 25-35 ° C. for 45 minutes. The mixture was cooled to 10 ° C., and the bromoketone obtained in Preparation 10 (16.9 g, 79 mmol) was added thereto. The reaction mixture was stirred at room temperature for 10 hours and then poured into ice water (500 mL). The separated solid was filtered, washed with water (2 × 100 mL) and dried in vacuo to give the title compound (11.0 g, 58%) as a white solid. Melting point: 96-98 ° C.

（調製１２）
（３−ヒドロキシ−１−メチル−２−（４−メチルフェニル）−１，４−ジヒドロ−４−キノリノン）

(Preparation 12)
(3-hydroxy-1-methyl-2- (4-methylphenyl) -1,4-dihydro-4-quinolinone)

ポリリン酸（ＰＰＡ、８０ｇ）を、２５０ｍＬ単口丸底フラスコ中で、窒素雰囲気下にて、１４０℃まで加熱した。調製１１で得たエチル−２−メチルアミノ安息香酸２−（４−メチルフェニル）−２−オキソ（１０ｇ、３５ｍｍｏｌ）を少しずつ加え、その混合物を、１４０℃で、６時間撹拌した。この混合物を２５〜３５℃まで冷却し、その混合物に氷冷水を加え、そして３０分間撹拌した。．分離した固形物を濾過し、水で洗浄し、そして真空乾燥して、褐色固形物として、表題化合物（６．０ｇ、７３％）を得た。融点２１６〜２１８℃。

Polyphosphoric acid (PPA, 80 g) was heated to 140 ° C. in a 250 mL single neck round bottom flask under a nitrogen atmosphere. Ethyl-2-methylaminobenzoic acid 2- (4-methylphenyl) -2-oxo (10 g, 35 mmol) obtained in Preparation 11 was added in portions and the mixture was stirred at 140 ° C. for 6 hours. The mixture was cooled to 25-35 ° C, ice cold water was added to the mixture and stirred for 30 minutes. . The separated solid was filtered, washed with water, and dried in vacuo to give the title compound (6.0 g, 73%) as a brown solid. Melting point 216-218 ° C.

（調製１３）
（４−（２−ブロモエトキシ）ベンズアルデヒド）

(Preparation 13)
(4- (2-bromoethoxy) benzaldehyde)

４−ヒドロキシベンズアルデヒド（１０．０ｇ、８２ｍｍｏｌ）および炭酸カリウム（４６ｇ、３２６ｍｍｏｌ）の混合物を２Ｌ丸底フラスコに入れ、そしてＤＭＦ（１５０ｍＬ）を加えた。この混合物を４５分間撹拌し、そしてジブロモエタン（４６ｇ）を一度に加え、次いで、その反応混合物を、２５〜３５℃で、窒素雰囲気下にて、９６時間撹拌した。この反応混合物を２５〜３５℃まで冷却し、次いで、水（５００ｍＬ）に注いだ。その混合物をＥｔＯＡｃ（３×１００ｍＬ）で抽出し、合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥し、そして減圧下にて濃縮した。その粗生成物を、１０〜１５％酢酸エチル／石油エーテルを使用することにより、シリカゲルカラムクロマトグラフィーで精製して、白色固形物として、表題化合物（８．５０ｇ、４５％）を得た。

A mixture of 4-hydroxybenzaldehyde (10.0 g, 82 mmol) and potassium carbonate (46 g, 326 mmol) was placed in a 2 L round bottom flask and DMF (150 mL) was added. The mixture was stirred for 45 minutes and dibromoethane (46 g) was added in one portion, then the reaction mixture was stirred at 25-35 ° C. under a nitrogen atmosphere for 96 hours. The reaction mixture was cooled to 25-35 ° C. and then poured into water (500 mL). The mixture was extracted with EtOAc (3 × 100 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10-15% ethyl acetate / petroleum ether to give the title compound (8.50 g, 45%) as a white solid.

（調製１４）
（１−（３−｛２−［１−メチル−２−（４−メチルフェニル）−４−オキソ−１，４−ジヒドロ−３−キノリニルオキシ］エトキシ｝フェニル）−１−エタノン）

(Preparation 14)
(1- (3- {2- [1-Methyl-2- (4-methylphenyl) -4-oxo-1,4-dihydro-3-quinolinyloxy] ethoxy} phenyl) -1-ethanone)

調製１２で得たヒドロキシ化合物（３．０ｇ、１１ｍｍｏｌ）、調製１で得たブロモケト化合物（２．４３ｇ、１０ｍｍｏｌ）および炭酸カリウム（６．２４ｇ、４５ｍｍｏｌ）の混合物を１Ｌ丸底フラスコに入れ、そしてＤＭＦ（３０ｍＬ）を加えた。その混合物を、撹拌しつつ、８０℃まで加熱し、この温度で、窒素雰囲気下にて、１２時間保持した。、この混合物を２５℃まで冷却し、そして氷冷水（１Ｌ）にゆっくりと注いだ。分離した固形物を濾過し、そして水（２×５００ｍＬ）で洗浄した。それをメタノールで倍散し、そして濾過して、真空下に乾燥した後、淡褐色固形物として、表題化合物（２．８ｇ、６４％）を得た。

A mixture of the hydroxy compound obtained in Preparation 12 (3.0 g, 11 mmol), the bromoketo compound obtained in Preparation 1 (2.43 g, 10 mmol) and potassium carbonate (6.24 g, 45 mmol) was placed in a 1 L round bottom flask, and DMF (30 mL) was added. The mixture was heated to 80 ° C. with stirring and held at this temperature for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25 ° C. and slowly poured into ice cold water (1 L). The separated solid was filtered and washed with water (2 × 500 mL). After triturating with methanol and filtering and drying under vacuum, the title compound (2.8 g, 64%) was obtained as a light brown solid.

（調製１５）
（４−（２−ブロモ−エトキシ）−安息香酸エチルエステル）

(Preparation 15)
(4- (2-Bromo-ethoxy) -benzoic acid ethyl ester)

工程（ｉ）
４−ヒドロキシ安息香酸（１５ｇ、１０８．６ｍｍｏｌ）のエタノール（２００ｍＬ）溶液に、０℃で、無水条件下にて、ＳＯＣｌ_２（１６ｍＬ、２１７．４ｍｍｏｌ）を加えた。その混合物を、撹拌しつつ、７時間にわたって、還流状態まで加熱した。その反応が完結した後、この混合物を真空下にて濃縮し、その残渣を、ｐＨが７．０に達するまで、ＮａＨＣＯ_３水溶液を使用して中和した。分離した固形物を濾過し、水（２×５０ｍＬ）で洗浄し、そして真空乾燥して、収率８９％（１６ｇ）で、所望化合物を得た。

Step (i)
To a solution of 4-hydroxybenzoic acid (15 g, 108.6 mmol) in ethanol (200 mL) at 0 ° C. under anhydrous conditions was added SOCl ₂ (16 mL, 217.4 mmol). The mixture was heated to reflux with stirring for 7 hours. After the reaction was complete, the mixture was concentrated in vacuo and the residue was neutralized using aqueous NaHCO ₃ until the pH reached 7.0. The separated solid was filtered, washed with water (2 × 50 mL) and dried in vacuo to give the desired compound in 89% yield (16 g).

Step (ii)
A mixture of 4-hydroxybenzoic acid ester (5 g, 30.12 mmol) and anhydrous K ₂ CO ₃ (4.62 g, 33.51 mmol) in acetone (50 mL) was stirred at 50 ° C. for 30 minutes under a nitrogen atmosphere. Stir. To this mixture was added 1,2-dibromoethane (34 g, 180.7 mmol) at the same temperature and stirring was continued for 6 hours. The mixture was filtered and the residue was washed with acetone (2 × 25 mL). The filtrates were collected, combined and concentrated. The residue was purified by crystallization from hexanes to give the desired product in 96% yield (6.0 g).

(Preparation 16)
(4- {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic acid ethyl ester)

ＤＭＦ（２０ｍＬ）中の２−（３，４−ジメトキシフェニル）−３−ヒドロキシ−５，７−ジメトキシ−４Ｈ−４−クロメノン（これは、調製２で得た）（４ｇ、１１．１７ｍｍｏｌ）、４−（２−ブロモ−エトキシ）−安息香酸エチルエステル（これは、調製１５で得た）（３．６６ｇ、１３．４０ｍｍｏｌ）およびＫ_２ＣＯ_３（４．６２ｇ、３３．５１ｍｍｏｌ）の混合物を、８０℃で、窒素雰囲気下にて、９時間撹拌した。この混合物を水（６０ｍＬ）に注ぎ、そして３０分間撹拌した。分離した固形物を濾過し、水（２×２０ｍＬ）で洗浄し、そして真空乾燥して、収率６８％（４．２ｇ）で、所望生成物を得た。

2- (3,4-Dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone (which was obtained in Preparation 2) (4 g, 11.17 mmol) in DMF (20 mL), A mixture of 4- (2-bromo-ethoxy) -benzoic acid ethyl ester (obtained in Preparation 15) (3.66 g, 13.40 mmol) and K ₂ CO ₃ (4.62 g, 33.51 mmol) The mixture was stirred at 80 ° C. for 9 hours under a nitrogen atmosphere. The mixture was poured into water (60 mL) and stirred for 30 minutes. The separated solid was filtered, washed with water (2 × 20 mL) and dried in vacuo to give the desired product in 68% yield (4.2 g).

(Preparation 17)
(4- {2- [2- (3,4-dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic acid)

調製１６で得た４−｛２−［２−（３，４−ジメトキシ−フェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−エトキシ｝−安息香酸エチルエステル（４ｇ、７．２７ｍｍｏｌ）のメタノール（４０ｍＬ）およびジオキサン（４０ｍＬ）混合物溶液に、２５〜３５℃で、ＫＯＨ（２．０ｇ、３６．３６ｍｍｏｌ）の水（１０ｍＬ）溶液を加え、その混合物を、６０℃で、６時間撹拌した。次いで、真空下にて、この混合物から溶媒を除去し、その残渣を例ＨＣｌで酸性化した。分離した固形物を濾過し、冷水（２×３ｍＬ）で洗浄し、そして真空乾燥した。その粗生成物を、エタノールから結晶化することにより精製して、収率８４％（３．２ｇ）で、所望の酸を得た。

4- {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic acid ethyl ester obtained in Preparation 16 ( To a solution of 4 g, 7.27 mmol) in methanol (40 mL) and dioxane (40 mL) at 25-35 ° C. was added a solution of KOH (2.0 g, 36.36 mmol) in water (10 mL) and the mixture was added to 60 Stir at 6 ° C. for 6 hours. The solvent was then removed from the mixture under vacuum and the residue was acidified with Example HCl. The separated solid was filtered, washed with cold water (2 × 3 mL) and dried in vacuo. The crude product was purified by crystallization from ethanol to give the desired acid in 84% yield (3.2 g).

(Preparation 18)
(2- (Toluene-4-sulfonylamino) -succinamic acid)

水（７５ｍＬ）およびジオキサン（７５ｍＬ）の混合物中のＬ−アスパラギン（Ａｓｐｅｒｇｉｎｅ）（１５ｇ、１００ｍｍｏｌ）、ＮａＯＨ（４．４ｇ、１１０ｍｍｏｌ）の撹拌溶液に、０℃で、塩化ｐ−トルエンスルホニル（２０．９ｇ、１１０ｍｍｏｌ）を加えた。１分間撹拌した後、その反応混合物に、同じ温度で、水（７５ｍＬ）中の追加量のＮａＯＨ（４．４ｇ、１１０ｍｍｏｌ）を加えた。撹拌を１時間継続し、次いで、低真空下にて、この混合物からジオキサンを除去した。その残渣を酢酸エチル（２×３０ｍＬ）で洗浄し、水層を集め、合わせ、そして０℃で撹拌しつつ、濃ＨＣｌで非常にゆっくりと酸性化した。分離した固形物を濾過し、そして冷水（２×３０ｍＬ）で洗浄して、収率５９％（１７ｇ）で、所望生成物を得た。融点：１９８〜２００℃。

To a stirred solution of L-Asparagine (15 g, 100 mmol), NaOH (4.4 g, 110 mmol) in a mixture of water (75 mL) and dioxane (75 mL) at 0 ° C., p-toluenesulfonyl chloride (20. 9 g, 110 mmol) was added. After stirring for 1 minute, an additional amount of NaOH (4.4 g, 110 mmol) in water (75 mL) was added to the reaction mixture at the same temperature. Stirring was continued for 1 hour and then dioxane was removed from the mixture under low vacuum. The residue was washed with ethyl acetate (2 × 30 mL), the aqueous layers were collected, combined and acidified very slowly with concentrated HCl while stirring at 0 ° C. The separated solid was filtered and washed with cold water (2 × 30 mL) to give the desired product in 59% yield (17 g). Melting point: 198-200 ° C.

(Preparation 19)
(3-Amino-2- (toluene-4-sulfonylamino) propionic acid ethyl ester)
Step (i):
3-Amino-2- (toluene-4-sulfonylamino) -propionic acid

ＮａＯＨ（１．９５ｇ、４８．９５ｍｍｏｌ）の冷（０℃）撹拌水（８．７ｍＬ）溶液に、臭素（０．３６ｍＬ、６．９９ｍｍｏｌ）をゆっくりと滴下した。５分間後、調製１８（２．０ｇ、６．９９ｍｍｏｌ）およびＮａＯＨ（０．５５ｇ）の冷水（６．４ｍＬ）溶液を一度に加えた。この溶液を、０℃で、２０分間、次いで、９０℃で、３０分間撹拌した。その混合物を０℃まで冷却し、そのｐＨを、濃ＨＣｌをゆっくりと加えることにより、７．０に調整した。分離した固形物を濾過し、冷ＥｔＯＡｃ（２×２５ｍＬ）で洗浄し、そして真空乾燥して、収率６１％（１．１ｇ）で、所望化合物を得た。融点２２５〜２２６℃。

Bromine (0.36 mL, 6.99 mmol) was slowly added dropwise to a cold (0 ° C.) stirred water (8.7 mL) solution of NaOH (1.95 g, 48.95 mmol). After 5 minutes, a solution of preparation 18 (2.0 g, 6.99 mmol) and NaOH (0.55 g) in cold water (6.4 mL) was added in one portion. The solution was stirred at 0 ° C. for 20 minutes and then at 90 ° C. for 30 minutes. The mixture was cooled to 0 ° C. and the pH was adjusted to 7.0 by slowly adding concentrated HCl. The separated solid was filtered, washed with cold EtOAc (2 × 25 mL) and dried in vacuo to give the desired compound in 61% yield (1.1 g). Melting point 225-226 [deg.] C.

Step (ii)
3-Amino-2- (toluene-4-sulfonylamino) -propionic acid ethyl ester

工程（ｉ）で得た化合物（２ｇ、７．７５ｍｍｏｌ）のエタノール（２０ｍＬ）冷（０℃）撹拌溶液に、無水条件下にて、ＳＯＣｌ_２（１．２５ｍＬ、１７．０５ｍｍｏｌ）を加えた、その混合物を、撹拌しつつ、１２時間にわたって、還流状態まで加熱した。その反応が完結した後、この混合物を真空下にて濃縮して、収率９０％（２．０ｇ）で、表題化合物の塩酸塩を得た。これを、さらに精製することなく、次の工程に使用した。

To an ethanol (20 mL) cold (0 ° C.) stirred solution of the compound obtained in step (i) (2 g, 7.75 mmol) under anhydrous conditions was added SOCl ₂ (1.25 mL, 17.05 mmol). The mixture was heated to reflux with stirring for 12 hours. After the reaction was complete, the mixture was concentrated in vacuo to give the hydrochloride salt of the title compound in 90% yield (2.0 g). This was used in the next step without further purification.

(Preparation 20)
(4- (3,4-Dimethoxyphenylcarboxamide) -1-methyl-3-propyl-1H-5-pyrazolecarboxamide)

ジクロロメタン（３００ｍＬ）中の４−アミノ−１−メチル−３−プロピル−１Ｈ−５−ピラゾールカルボキサミド（１９．５７ｇ、１０７．５ｍｍｏｌ）およびトリエチルアミン（５４．４ｇ、１３４．３８ｍｍｏｌ）の混合物を１リットルの三ッ口丸底フラスコ（これには、窒素バルーン、圧力均等滴下漏斗および隔壁を取り付けた）に入れた。その混合物に、０℃で、圧力均等滴下漏斗を経由して、窒素雰囲気下にて、０．５時間にわたって、塩化３，４−ジメトキシ−１−ベンゼンカルボニル（２１．５ｇ、１０７．５ｍｍｏｌ）のジクロロメタン（１００ｍＬ）溶液を加えた。添加後、反応温度を２５℃まで上げ、そして内容物をさらに１２時間撹拌した。この反応混合物から、減圧下にて、ジクロロメタンを除去し、得られた固形物を冷水（２×１５０ｍＬ）で洗浄し、濾過し、そして真空乾燥して、白色固形物として、表題化合物３３ｇ（８９％）を得た。融点：１７６〜１７８℃。

A mixture of 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxamide (19.57 g, 107.5 mmol) and triethylamine (54.4 g, 134.38 mmol) in dichloromethane (300 mL) was added to one liter. Placed in a three-necked round bottom flask equipped with a nitrogen balloon, pressure equalizing dropping funnel and septum. To the mixture was added 3,4-dimethoxy-1-benzenecarbonyl chloride (21.5 g, 107.5 mmol) at 0 ° C. via a pressure equalizing dropping funnel under nitrogen atmosphere for 0.5 h. Dichloromethane (100 mL) solution was added. After the addition, the reaction temperature was raised to 25 ° C. and the contents were stirred for an additional 12 hours. From the reaction mixture, dichloromethane was removed under reduced pressure and the resulting solid was washed with cold water (2 × 150 mL), filtered and dried in vacuo to give 33 g (89 of title compound as a white solid). %). Melting point: 176-178 ° C.

（調製２１）
（５−（３，４−ジメトキシフェニル）−１−メチル−３−プロピル−６，７−ジヒドロ−１Ｈ−ピラゾロ［４，３−ｄ］ピリミジン−７−オン）

(Preparation 21)
(5- (3,4-Dimethoxyphenyl) -1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-7-one)

第三級ブタノール（３５０ｍＬ）中の４−（３，４−ジメトキシフェニルカルボキサミド）−１−メチル−３−プロピル−１Ｈ−５−ピラゾールカルボキサミド（これは、調製２０で得た）（１７ｇ、４９．１３ｍｍｏｌ）を１リットル単口丸底フラスコ（これには、還流冷却器を取り付けた）に入れ、そこに、カリウム第三級ブトキシド（１６．５５ｇ、１４７．３８ｍｍｏｌ）を慎重に加え、そして内容物を、窒素雰囲気下にて、６３時間還流した。その反応混合物を２５〜３５℃まで冷却し、そして真空下にて、第三級ブタノールを完全に除去した。その残渣に冷水（２００ｍＬ）を加え、続いて、撹拌下にて、そのｐＨが７で一定となるまで、希塩酸（３Ｎ）を加えた。形成された固形物を濾過により除き、そして真空乾燥して、白色固形物として、表題化合物１３ｇ（８１％）を得た。融点：２１０〜２１２℃。

4- (3,4-Dimethoxyphenylcarboxamide) -1-methyl-3-propyl-1H-5-pyrazolecarboxamide (which was obtained in Preparation 20) in tertiary butanol (350 mL) (17 g, 49. 13 mmol) into a 1 liter single neck round bottom flask (which was fitted with a reflux condenser) to which potassium tert-butoxide (16.55 g, 147.38 mmol) was carefully added and the contents Was refluxed for 63 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25-35 ° C. and tertiary butanol was completely removed under vacuum. Cold water (200 mL) was added to the residue, followed by dilute hydrochloric acid (3N) until the pH was constant at 7 under stirring. The formed solid was removed by filtration and dried in vacuo to give 13 g (81%) of the title compound as a white solid. Melting point: 210-212 ° C.

（調製２２）
（１−［４−（２−ブロモエチルアミノ）フェニル］−１−エタノン）

(Preparation 22)
(1- [4- (2-Bromoethylamino) phenyl] -1-ethanone)

１リットルの二ッ口丸底フラスコ（これには、 圧力均等滴下漏斗および隔壁を取り付けた）に入れた６０％ＮａＨ（５．９３ｇ、２４７．０８ｍｍｏｌ）のＤＭＦ（８０ｍＬ）懸濁液に、圧力均等滴下漏斗を経由して、窒素雰囲気下にて、０℃で、ｐ−アミノアセトフェノン（２０ｇ、１４８．１ｍｍｏｌ）のＤＭＦ（６０ｍＬ）を滴下し、そして内容物を、２５℃で、２時間撹拌した。次いで、撹拌した溶液に、１，２−ジブロモエタン（９７．４８ｇ、５１８．５ｍｍｏｌ）を滴下し、そして内容物を、９０℃で、さらに１８時間撹拌した。その反応混合物を２５〜３５℃まで冷却し、そして撹拌しつつ、冷水（６５０ｍＬ）に慎重に加えた。有機物を酢酸エチル（３×２００ｍＬ）で抽出し、合わせた有機物を水（２×１００ｍＬ）で洗浄し、続いて、ブライン洗浄した。分離した有機物をＮａ_２ＳＯ_４で乾燥し、そして減圧下にて濃縮した。その粗製物を、１５〜２０％酢酸エチル／石油エーテル（３リットル）を使用することにより、シリカゲルでクロマトグラフィーにかけて、淡黄色固形物として、表題化合物５．１ｇ（１４％）を得た。

To a suspension of 60% NaH (5.93 g, 247.08 mmol) in DMF (80 mL) in a 1 liter two-necked round bottom flask equipped with a pressure equalizing dropping funnel and septum was Via an equal dropping funnel, at 0 ° C. under nitrogen atmosphere, p-aminoacetophenone (20 g, 148.1 mmol) in DMF (60 mL) was added dropwise and the contents were stirred at 25 ° C. for 2 h. did. To the stirred solution was then added 1,2-dibromoethane (97.48 g, 518.5 mmol) dropwise and the contents were stirred at 90 ° C. for an additional 18 hours. The reaction mixture was cooled to 25-35 ° C. and carefully added to cold water (650 mL) with stirring. The organics were extracted with ethyl acetate (3 × 200 mL) and the combined organics were washed with water (2 × 100 mL) followed by brine. The separated organic was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude was chromatographed on silica gel using 15-20% ethyl acetate / petroleum ether (3 liters) to give 5.1 g (14%) of the title compound as a pale yellow solid.

（調製２３）
（１−（４−｛２−［５−（３，４−ジメトキシフェニル）−１−メチル−７−オキソ−３−プロピル−６，７−ジヒドロ−１Ｈ−ピラゾロ［４，３−ｄ］ピリミジン−６−イル］エチルアミノ｝フェニル）−１−エタノン）

(Preparation 23)
(1- (4- {2- [5- (3,4-Dimethoxyphenyl) -1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidine -6-yl] ethylamino} phenyl) -1-ethanone)

調製２１で得た５−（３，４−ジメトキシフェニル）−１−メチル−３−プロピル−６，７−ジヒドロ−１Ｈ−ピラゾロ［４，３−ｄ］ピリミジン−７−オン（２ｇ、６．０９ｍｍｏｌ）、調製２２で得た１−［４−（２−ブロモエチルアミノ）フェニル］−１−エタノン（１．５５ｇ、６．４０５ｍｍｏｌ）および炭酸カリウム（４．２１３ｇ、３．５ｍｍｏｌ）の混合物を１００ｍＬ丸底フラスコに入れ、これに、ＤＭＦ（２０ｍＬ）を加えた。その反応混合物を、２５℃で、窒素雰囲気下にて、１６時間撹拌した。この反応混合物を氷冷水（１００ｍＬ）にゆっくりと注いだ。分離した固形物を濾過し、水（２×５ｍＬ）で洗浄し、そして真空乾燥して、淡黄色固形物として、表題化合物２．６ｇ（８７％）を得た。融点：１８２〜１８４℃。

5- (3,4-Dimethoxyphenyl) -1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-7-one obtained in Preparation 21 (2 g, 6. 09 mmol), a mixture of 1- [4- (2-bromoethylamino) phenyl] -1-ethanone (1.55 g, 6.405 mmol) and potassium carbonate (4.213 g, 3.5 mmol) obtained in Preparation 22. DMF (20 mL) was added to a 100 mL round bottom flask. The reaction mixture was stirred at 25 ° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was slowly poured into ice cold water (100 mL). The separated solid was filtered, washed with water (2 × 5 mL) and dried in vacuo to give 2.6 g (87%) of the title compound as a pale yellow solid. Melting point: 182-184 ° C.

（調製２４）
（６，７−ジメトキシキナゾリン−４（３Ｈ）−オン）

(Preparation 24)
(6,7-dimethoxyquinazolin-4 (3H) -one)

２−アミノ−４，５−ジメトキシ安息香酸（２９．６ｇ、０．１５ｍｏｌ）およびホルムアミド（０．６ｍｏｌ、２４ｍＬ）の混合物を、窒素雰囲気下にて、激しく攪拌した。この混合物を、４時間にわたって、１４５℃まで加熱した。完結後、その反応混合物を冷却し、そして水（１２０ｍＬ）を加えた。固形物を濾過し、冷水（２×２０ｍＬ）で洗浄し、続いて、ヘキサン（２×２０ｍＬ）で洗浄して、収率４０％で、１２．５ｇの所望生成物を得た。融点２９５〜２９６℃（ｌｉｔ ２９６〜２９７℃）。

A mixture of 2-amino-4,5-dimethoxybenzoic acid (29.6 g, 0.15 mol) and formamide (0.6 mol, 24 mL) was stirred vigorously under a nitrogen atmosphere. The mixture was heated to 145 ° C. for 4 hours. After completion, the reaction mixture was cooled and water (120 mL) was added. The solid was filtered and washed with cold water (2 × 20 mL) followed by hexane (2 × 20 mL) to give 12.5 g of the desired product in 40% yield. Melting point 295-296 ° C (lit 296-297 ° C).

（実施例１）
（５−［−１−（４−｛２−［２−（３，４−ジメトキシフェニル）−５，７−ジメトキシ−４−オキソ−４ｈ−３−クロメニルオキシ］エトキシ｝フェニル）エチリデン］−１，３−チアゾラン−２，４−ジオン）

Example 1
(5-[-1- (4- {2- [2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4-oxo-4h-3-chromenyloxy] ethoxy} phenyl) ethylidene]- 1,3-thiazolane-2,4-dione)

調製３で得た化合物（３１ｇ、５９．６ｍｍｏｌ）、チアゾリデン−１，３−ジオン（４０ｇ、３４１ｍｍｏｌ）、安息香酸（１４．５ｇ、１１８．８ｍｍｏｌ）およびピペリジン（１０．１ｇ、１１８．８ｍｍｏｌ）の混合物を１Ｌ単口丸底フラスコに入れ、これに、トルエン（６００ｍＬ）を加えた。この丸底フラスコにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そしてシリカゲルカラムに通した。その生成物を、０．５〜１％ＭｅＯＨ／ＣＨＣｌ_３（５Ｌ）を使用することにより溶出して、白色固形物として、表題化合物２２ｇ（６０％）を得た。融点：２０５〜２０６℃。

Of the compound obtained in Preparation 3 (31 g, 59.6 mmol), thiazolidene-1,3-dione (40 g, 341 mmol), benzoic acid (14.5 g, 118.8 mmol) and piperidine (10.1 g, 118.8 mmol). The mixture was placed in a 1 L single neck round bottom flask and to this was added toluene (600 mL). The round bottom flask was equipped with a Dean-Stark apparatus (connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and passed through a silica gel column. The product was eluted by using 0.5-1% MeOH / CHCl ₃ (5 L) to give 22 g (60%) of the title compound as a white solid. Melting point: 205-206 ° C.

（実施例２）
実施例２は、実施例１で提供した方法に従って、調製した。

(Example 2)
Example 2 was prepared according to the method provided in Example 1.

（実施例３）
実施例３は、実施例１で提供した方法に従って、調製した。

(Example 3)
Example 3 was prepared according to the method provided in Example 1.

（実施例４）
実施例４は、実施例１で提供した方法に従って、調製した。

Example 4
Example 4 was prepared according to the method provided in Example 1.

（実施例５）
実施例５は、実施例１で提供した方法に従って、調製した。

(Example 5)
Example 5 was prepared according to the method provided in Example 1.

（実施例６）
実施例６は、実施例１で提供した方法に従って、調製した。

(Example 6)
Example 6 was prepared according to the method provided in Example 1.

（実施例７）
実施例７は、実施例１で提供した方法に従って、調製した。

(Example 7)
Example 7 was prepared according to the method provided in Example 1.

（実施例８）
実施例８は、実施例１で提供した方法に従って、調製した。

(Example 8)
Example 8 was prepared according to the method provided in Example 1.

（実施例９）
実施例９は、実施例１で提供した方法に従って、調製した。

Example 9
Example 9 was prepared according to the method provided in Example 1.

（実施例１０）
実施例１０は、実施例１で提供した方法に従って、調製した。

(Example 10)
Example 10 was prepared according to the method provided in Example 1.

（実施例１１）
実施例１１は、実施例１で提供した方法に従って、調製した。

(Example 11)
Example 11 was prepared according to the method provided in Example 1.

（実施例１２）
実施例１２は、実施例１で提供した方法に従って、調製した。

(Example 12)
Example 12 was prepared according to the method provided in Example 1.

（実施例１３）
（５−［−１−（４−｛２−［６−フルオロ−２−（４−メトキシフェニル）−４−オキソ−４Ｈ−３−クロメニルオキシ］エトキシ｝フェニル）エチリデン］−１，３−チアゾラン−２，４−ジオン）

(Example 13)
(5-[-1- (4- {2- [6-Fluoro-2- (4-methoxyphenyl) -4-oxo-4H-3-chromenyloxy] ethoxy} phenyl) ethylidene] -1,3- Thiazolane-2,4-dione)

調製８で得た化合物（０．３５ｇ、０．７２ｍｍｏｌ）、チアゾリデン−１，３−ジオン（０．５４ｇ、４．６８ｍｍｏｌ）、安息香酸（０．１９ｇ、１．５６ｍｍｏｌ）およびピペリジン（０．１３ｇ、１．５６ｍｏｌ）の混合物を１Ｌ単口丸底フラスコに入れ、これに、トルエン（１５ｍＬ）を加えた。この丸底フラスコにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そしてシリカゲルカラムに通した。その生成物を、０．５〜１％ＭｅＯＨ／ＣＨＣｌ_３（５Ｌ）を使用することにより溶出して、灰白色固形物として、表題化合物０．３２ｇ（７５％）を得た。融点：２１０〜２１２℃。

The compound obtained in Preparation 8 (0.35 g, 0.72 mmol), thiazolidene-1,3-dione (0.54 g, 4.68 mmol), benzoic acid (0.19 g, 1.56 mmol) and piperidine (0.13 g) , 1.56 mol) was placed in a 1 L single neck round bottom flask, and toluene (15 mL) was added thereto. The round bottom flask was equipped with a Dean-Stark apparatus (connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and passed through a silica gel column. The product was eluted by using 0.5-1% MeOH / CHCl ₃ (5 L) to give 0.32 g (75%) of the title compound as an off-white solid. Melting point: 210-212 ° C.

（実施例１４）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 14)
This compound was prepared according to the procedure provided in Example 13.

（実施例１５）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 15)
This compound was prepared according to the procedure provided in Example 13.

（実施例１６）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 16)
This compound was prepared according to the procedure provided in Example 13.

（実施例１７）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 17)
This compound was prepared according to the procedure provided in Example 13.

（実施例１８）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 18)
This compound was prepared according to the procedure provided in Example 13.

（実施例１９）
この化合物は、実施例１３で提供した手順に従って、調製した。

Example 19
This compound was prepared according to the procedure provided in Example 13.

（実施例２０）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 20)
This compound was prepared according to the procedure provided in Example 13.

（実施例２１）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 21)
This compound was prepared according to the procedure provided in Example 13.

（実施例２２）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 22)
This compound was prepared according to the procedure provided in Example 13.

（実施例２３）
この化合物は、実施例１３で提供した手順に従って、調製した。

(Example 23)
This compound was prepared according to the procedure provided in Example 13.

（実施例２４）
（５−［１−（４−｛２−［１−メチル−４−オキソ−２−（４−メチルフェニル）−１，４−ジヒドロ−３−キノリニルオキシ］エトキシ）フェニル｝メチリデン］−１，３−チアゾラン−２，４−ジオン）

(Example 24)
(5- [1- (4- {2- [1-Methyl-4-oxo-2- (4-methylphenyl) -1,4-dihydro-3-quinolinyloxy] ethoxy) phenyl} methylidene] -1,3 -Thiazolane-2,4-dione)

調製１４で得た化合物（１５０ｍｇ、０．３６ｍｍｏｌ）、チアゾリデン−１，３−ジオン（６４ｍｇ、０．５４ｍｍｏｌ）、安息香酸（８８ｍｇ、０．７２ｍｍｏｌ）およびピペリジン（６１ｍｇ、０．７２ｍｍｏｌ）の混合物を１Ｌ単口丸底フラスコに入れ、これに、トルエン（６００ｍＬ）を加えた。この丸底フラスコにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そしてシリカゲルカラムに通した。その生成物を、０．５〜１％ＭｅＯＨ／ＣＨＣｌ_３（５Ｌ）を使用することにより溶出して、褐色固形物として、表題化合物１００ｍｇ（５４％）を得た。融点：２５０〜２５２℃。

A mixture of the compound obtained in Preparation 14 (150 mg, 0.36 mmol), thiazolidene-1,3-dione (64 mg, 0.54 mmol), benzoic acid (88 mg, 0.72 mmol) and piperidine (61 mg, 0.72 mmol) Into a 1 L single neck round bottom flask, toluene (600 mL) was added. The round bottom flask was equipped with a Dean-Stark apparatus (connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and passed through a silica gel column. The product was eluted by using 0.5-1% MeOH / CHCl ₃ (5 L) to give 100 mg (54%) of the title compound as a brown solid. Melting point: 250-252 ° C.

（実施例２５）
この化合物は、実施例２４で提供した手順に従って、調製した。

(Example 25)
This compound was prepared according to the procedure provided in Example 24.

（実施例２６）
この化合物は、実施例２４で提供した手順に従って、調製した。

(Example 26)
This compound was prepared according to the procedure provided in Example 24.

（実施例２７）
この化合物は、実施例２４で提供した手順に従って、調製した。

(Example 27)
This compound was prepared according to the procedure provided in Example 24.

（実施例２９）
この化合物は、実施例２４で提供した手順に従って、調製した。

(Example 29)
This compound was prepared according to the procedure provided in Example 24.

（実施例２９）
（３−（４−｛２−［２−（３，４−ジメトキシ−フェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−エトキシ｝−ベンゾイルアミノ）−２−（トルエン−４−スルホニルアミノ）−プロピオン酸エチルエステル）

(Example 29)
(3- (4- {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoylamino) -2- (Toluene-4-sulfonylamino) -propionic acid ethyl ester)

調製１７で得た４−｛２−［２−（３，４−ジメトキシ−フェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−エトキシ｝−安息香酸（３ｇ、５．７４ｍｍｏｌ）、調製１９で得た３−アミノ−２−（トルエン−４−スルホニルアミノ）−プロピオン酸エチルエステル（２．２２ｇ、６．８９ｍｍｏｌ）のＤＭＦ（２０ｍＬ）溶液に、２５〜３５℃で、窒素雰囲気下にて、ＥＤＣＩ（１．６４ｇ、８．６１ｍｍｏｌ）、ＨＯＢｔ（１ｇ、７．４６ｍｍｏｌ）およびＮ−メチルモルホリン（２．０ｇ、２０．０９ｍｍｏｌ）を加えた。その混合物を、同じ温度で、１２時間撹拌した。反応が完結した後、この混合物を水（６０ｍＬ）に注ぎ、そして３０分間撹拌した。分離した固形物を濾過し、水（２×２０ｍＬ）で洗浄し、そして真空乾燥した。その粗生成物をエタノールから再結晶することにより精製して、収率５１％（２．３ｇ）で、所望生成物を得た。

4- {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic acid (3 g, obtained in Preparation 17 5.74 mmol), 3-amino-2- (toluene-4-sulfonylamino) -propionic acid ethyl ester obtained in Preparation 19 (2.22 g, 6.89 mmol) in DMF (20 mL) solution at 25-35 ° C. In a nitrogen atmosphere, EDCI (1.64 g, 8.61 mmol), HOBt (1 g, 7.46 mmol) and N-methylmorpholine (2.0 g, 20.09 mmol) were added. The mixture was stirred at the same temperature for 12 hours. After the reaction was complete, the mixture was poured into water (60 mL) and stirred for 30 minutes. The separated solid was filtered, washed with water (2 × 20 mL) and dried in vacuo. The crude product was purified by recrystallization from ethanol to give the desired product in 51% yield (2.3 g).

（実施例３０）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 30)
This compound was prepared according to the procedure provided in Example 29.

（実施例３１）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 31)
This compound was prepared according to the procedure provided in Example 29.

（実施例３２）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 32)
This compound was prepared according to the procedure provided in Example 29.

（実施例３３）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 33)
This compound was prepared according to the procedure provided in Example 29.

（実施例３４）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 34)
This compound was prepared according to the procedure provided in Example 29.

（実施例３５）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 35)
This compound was prepared according to the procedure provided in Example 29.

（実施例３６）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 36)
This compound was prepared according to the procedure provided in Example 29.

（実施例３７）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 37)
This compound was prepared according to the procedure provided in Example 29.

（実施例３８）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 38)
This compound was prepared according to the procedure provided in Example 29.

（実施例３９）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 39)
This compound was prepared according to the procedure provided in Example 29.

（実施例４０）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 40)
This compound was prepared according to the procedure provided in Example 29.

（実施例４１）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 41)
This compound was prepared according to the procedure provided in Example 29.

（実施例４２）
この化合物は、実施例２９で提供した手順に従って、調製した。

(Example 42)
This compound was prepared according to the procedure provided in Example 29.

（実施例４３）
（３−（４−｛２−［２−（３，４−ジメトキシ−フェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−エトキシ｝−ベンゾイルアミノ）−２−（トルエン−４−スルホニルアミノ）−プロピオン酸）

(Example 43)
(3- (4- {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoylamino) -2- (Toluene-4-sulfonylamino) -propionic acid)

実施例２９で得た３−（４−｛２−［２−（３，４−ジメトキシ−フェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−エトキシ｝−ベンゾイルアミノ）−２−（トルエン−４−スルホニルアミノ）−プロピオン酸（５００ｍｇ、０．７３ｍｍｏｌ）のエチルエステルのエタノール（１０ｍＬ）およびジオキサン（１０ｍＬ）の混合物溶液に、２５〜３５℃で、Ｋ_２ＣＯ_３（３００ｍｇ、２．１９ｍｍｏｌ）の水（５ｍＬ）溶液を加え、その混合物を、同じ温度で、２４時間撹拌した。次いで、真空下にて、この混合物から溶媒を除去し、その残渣を冷ＨＣｌで酸性化した。分離した固形物を濾過し、冷水（２×５ｍＬ）で洗浄し、そして真空乾燥して、収率５２％（２５０ｍｇ）で、所望の酸を得た。

3- (4- {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoyl obtained in Example 29 A mixture of ethyl ester of amino) -2- (toluene-4-sulfonylamino) -propionic acid (500 mg, 0.73 mmol) in ethanol (10 mL) and dioxane (10 mL) at 25-35 ° C., K ₂ CO _{2. 3} (300 mg, 2.19 mmol) in water (5 mL) was added and the mixture was stirred at the same temperature for 24 h. The solvent was then removed from the mixture under vacuum and the residue was acidified with cold HCl. The separated solid was filtered, washed with cold water (2 × 5 mL) and dried in vacuo to give the desired acid in 52% yield (250 mg).

（実施例４４）
この化合物は、実施例４３で提供した手順に従って、調製した。

(Example 44)
This compound was prepared according to the procedure provided in Example 43.

（実施例４５）
この化合物は、実施例４３で提供した手順に従って、調製した。

(Example 45)
This compound was prepared according to the procedure provided in Example 43.

（実施例４６）
（５−［（Ｅ，Ｚ）−１−（４−｛２−［５−（３，４−ジメトキシフェニル）−１−メチル−７−オキソ−３−プロピル−６，７−ジヒドロ−１Ｈ−ピラゾロ［４，３−ｄ］ピリミジン−６−イル］エチルアミノ｝フェニル）エチリデン］１，３−チアゾラン−２，４−ジオン）

(Example 46)
(5-[(E, Z) -1- (4- {2- [5- (3,4-dimethoxyphenyl) -1-methyl-7-oxo-3-propyl-6,7-dihydro-1H- Pyrazolo [4,3-d] pyrimidin-6-yl] ethylamino} phenyl) ethylidene] 1,3-thiazolane-2,4-dione)

調製２３で得た１−（４−｛２−［５−（３，４−ジメトキシフェニル）−１−メチル−７−オキソ−３−プロピル−６，７−ジヒドロ−１Ｈ−ピラゾロ［４，３−ｄ］ピリミジン−６−イル］エチルアミノ｝フェニル）−１−エタノン（２．４ｇ、４．９１ｍｍｏｌ）、チアゾリデン−２，４−ジオン（２．８７ｇ、２４．５４ｍｍｏｌ）、安息香酸（１．２０ｇ、９．８１ｍｍｏｌ）およびピペリジン（０．８４ｇ、９．８１ｍｍｏｌ）の混合物を１００ｍＬ単口丸底フラスコに入れ、これに、トルエン（６０ｍＬ）を加えた。この丸底フラスコ（ＲＢＦ）にディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、３５時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして１時間撹拌した。形成された固形生成物を濾過により除いた。この固形物をイソプロパノール（５ｍＬ）で倍散することにより純粋な生成物を得、これを、濾過により除き、そして真空乾燥して、淡緑色固形物（１．５１ｇ、２．５６ｍｍｏｌ）として、表題化合物を得た。融点：２１５〜２１８℃。

1- (4- {2- [5- (3,4-Dimethoxyphenyl) -1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3] obtained in Preparation 23. -D] pyrimidin-6-yl] ethylamino} phenyl) -1-ethanone (2.4 g, 4.91 mmol), thiazolidene-2,4-dione (2.87 g, 24.54 mmol), benzoic acid (1. A mixture of 20 g, 9.81 mmol) and piperidine (0.84 g, 9.81 mmol) was placed in a 100 mL single neck round bottom flask, to which toluene (60 mL) was added. The round bottom flask (RBF) was fitted with a Dean-Stark apparatus (connected to a reflux condenser). The reaction mixture was heated to reflux under a nitrogen atmosphere for 35 hours. The reaction mixture was cooled to 25 ° C. and stirred for 1 hour. The formed solid product was removed by filtration. Trituration of the solid with isopropanol (5 mL) gave the pure product, which was removed by filtration and dried in vacuo to give the title as a pale green solid (1.51 g, 2.56 mmol). A compound was obtained. Melting point: 215-218 ° C.

（実施例４７）
この化合物は、実施例４３で提供した手順に従って、調製した。

(Example 47)
This compound was prepared according to the procedure provided in Example 43.

（実施例４８）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 48)
This compound was prepared according to the procedure provided in Example 46.

（実施例４９）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 49)
This compound was prepared according to the procedure provided in Example 46.

（実施例５０）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 50)
This compound was prepared according to the procedure provided in Example 46.

（実施例５１）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 51)
This compound was prepared according to the procedure provided in Example 46.

（実施例５２）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 52)
This compound was prepared according to the procedure provided in Example 46.

（実施例５３）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 53)
This compound was prepared according to the procedure provided in Example 46.

（実施例５４）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 54)
This compound was prepared according to the procedure provided in Example 46.

（実施例５５）
この化合物は、実施例４６で提供した手順に従って、調製した。

(Example 55)
This compound was prepared according to the procedure provided in Example 46.

（実施例５６）
（５−［１−（３−フルオロ−４−｛２−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 56)
(5- [1- (3-Fluoro-4- {2- [2- (4-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−２−フルオロ−フェノキシ）−エトキシ］−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４５ｇ、１．０ｍｍｏｌ）、２，４−チアゾリデンジオン（０．７０３ｇ、６．０１ｍｍｏｌ）、安息香酸（２２５ｍｇ、１．８４ｍｍｏｌ）およびピペリジン（１５０ｍｇ、１．７６ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、１％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、白色固形物として、表題化合物２０９ｍｇ（３８％）を得た。

Compound 3- [2- (4-acetyl-2-fluoro-phenoxy) -ethoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.45 g, 1.0 mmol) ), 2,4-thiazolidenedione (0.703 g, 6.01 mmol), benzoic acid (225 mg, 1.84 mmol) and piperidine (150 mg, 1.76 mmol) were placed in a single necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 1% MeOH—CHCl ₃ ) to give 209 mg (38%) of the title compound as a white solid.

（実施例５７）
（５−［１−（３−クロロ−４−｛２−［２−（２−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 57)
(5- [1- (3-Chloro-4- {2- [2- (2-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−２−クロロ−フェノキシ）−エトキシ］−２−（２−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（４００ｍｇ、０．８６ｍｍｏｌ）、２，４−チアゾリデンジオン（５０４ｍｇ、４．３ｍｍｏｌ）、安息香酸（２５０ｍｇ、２．０４ｍｍｏｌ）およびピペリジン（１６０ｍｇ、１．８８ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして真空下にて濃縮した。その残渣をカラムクロマトグラフィーで精製し、続いて、エーテルで洗浄して、灰白色固形物として、表題化合物２００ｍｇ（４１％）を得た。

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (2-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (400 mg, 0.86 mmol), A mixture of 2,4-thiazolidenedione (504 mg, 4.3 mmol), benzoic acid (250 mg, 2.04 mmol) and piperidine (160 mg, 1.88 mmol) was placed in a single-necked round bottom flask with toluene ( 50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated under vacuum. The residue was purified by column chromatography followed by washing with ether to give 200 mg (41%) of the title compound as an off-white solid.

（実施例５８）
（５−［１−（４−｛２−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 58)
(5- [1- (4- {2- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -phenyl)- Ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（３９ｇ、９ｍｍｏｌ）、２，４−チアゾリデンジオン（６３．５ｇ、５４ｍｍｏｌ）、安息香酸（２２．２ｇ、１８．１ｍｍｏｌ）およびピペリジン（１６ｇ、１８．７９ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５００ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして真空下にて濃縮した。その残渣をカラムクロマトグラフィー（これは、０〜１％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物２４ｇ（５０％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (39 g, 9 mmol), 2,4-thiazoli A mixture of dendione (63.5 g, 54 mmol), benzoic acid (22.2 g, 18.1 mmol) and piperidine (16 g, 18.79 mmol) was placed in a single neck round bottom flask, to which toluene (500 mL) was added. It was. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated under vacuum. The residue was purified by column chromatography (using 0-1% MeOH—CHCl ₃ ) to give 24 g (50%) of the title compound as a light brown solid.

（実施例５９）
（５−［１−（３−｛２−［２−（３，４−ジメトキシ−フェニル）−６−フルオロ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 59)
(5- [1- (3- {2- [2- (3,4-Dimethoxy-phenyl) -6-fluoro-4-oxo-4H-chromen-3-yloxy] -ethoxy} -phenyl) -ethylidene] -Thiazolidine-2,4-dione)

化合物３−［２−（３−アセチル−フェノキシ）−エトキシ］−２−（３，４−ジメトキシ−フェニル）−６−フルオロ−クロメン−４−オン（０．５ｇ、１．０４ｍｍｏｌ）、２，４−チアゾリデンジオン（０．７９ｇ、６．６ｍｍｏｌ）、安息香酸（０．２７ｇ、２．２ｍｍｏｌ）およびピペリジン（０．１９ｇ、２．２３ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３５ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濾過した。その固形物をｉ−ＰｒＯＨ（２０ｍＬ）で倍散し、そして濾過して、灰白色固形物として、表題化合物０．３８ｇ（６３％）を得た。

Compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (3,4-dimethoxy-phenyl) -6-fluoro-chromen-4-one (0.5 g, 1.04 mmol), 2, A mixture of 4-thiazolidenedione (0.79 g, 6.6 mmol), benzoic acid (0.27 g, 2.2 mmol) and piperidine (0.19 g, 2.23 mmol) was placed in a single-necked round bottom flask. Toluene (35 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and filtered. The solid was triturated with i-PrOH (20 mL) and filtered to give 0.38 g (63%) of the title compound as an off-white solid.

（実施例６０）
（５−［１−（４−｛２−［２−（４−クロロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 60)
(5- [1- (4- {2- [2- (4-Chloro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -phenyl)- Ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−２−（４−クロロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（１．１９ｇ、２．４５ｍｍｏｌ）、２，４−チアゾリデンジオン（１．７２ｇ、１４．７０ｍｍｏｌ）、安息香酸（０．５９ｇ、４．８３ｍｍｏｌ）およびピペリジン（０．４１５ｇ、４．８２ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（１００ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして真空下にて濃縮した。その残渣をカラムクロマトグラフィー（これは、６％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物０．７３ｇ（３０％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (4-chloro-phenyl) -1-methyl-1H-quinolin-4-one (1.19 g, 2.45 mmol), 2, A mixture of 4-thiazolidenedione (1.72 g, 14.70 mmol), benzoic acid (0.59 g, 4.83 mmol) and piperidine (0.415 g, 4.82 mmol) was placed in a single necked round bottom flask. Toluene (100 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated under vacuum. The residue was purified by column chromatography (using 6% MeOH—CHCl ₃ ) to give 0.73 g (30%) of the title compound as a light brown solid.

（実施例６１）
（５−［１−（３−｛２−［２−（３，４−ジフルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 61)
(5- [1- (3- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -phenyl ) -Ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（３−アセチル−フェノキシ）−エトキシ］−２−（３，４−ジフルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（１．０ｇ、２．２２ｍｍｏｌ）、２，４−チアゾリデンジオン（１．５６ｇ、１３．３６ｍｍｏｌ）、安息香酸（３２５ｍｇ、２．６７ｍｍｏｌ）およびピペリジン（３２５ｍｇ、３．８２ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィーで精製して、淡褐色固形物として、表題化合物４８８ｍｇ（４０％）を得た。

Compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4-one (1.0 g, 2.22 mmol), A mixture of 2,4-thiazolidenedione (1.56 g, 13.36 mmol), benzoic acid (325 mg, 2.67 mmol) and piperidine (325 mg, 3.82 mmol) was placed in a single neck round bottom flask, Toluene (30 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography to give 488 mg (40%) of the title compound as a light brown solid.

（実施例６２）
（５−［１−（４−｛２−［１−エチル−２−（４−フルオロ−フェニル）−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 62)
(5- [1- (4- {2- [1-Ethyl-2- (4-fluoro-phenyl) -4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -phenyl)- Ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−１−エチル−２−（４−フルオロ−フェニル）−１Ｈ−キノリン−４−オン（０．６ｇ、１．３５ｍｍｏｌ）、２，４−チアゾリデンジオン（０．９４６ｇ、８．０８ｍｍｏｌ）、安息香酸（２００ｍｇ、１．６４ｍｍｏｌ）およびピペリジン（２００ｍｇ、２．３５ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物３３３ｍｇ（４５％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -1-ethyl-2- (4-fluoro-phenyl) -1H-quinolin-4-one (0.6 g, 1.35 mmol), 2, A mixture of 4-thiazolidenedione (0.946 g, 8.08 mmol), benzoic acid (200 mg, 1.64 mmol) and piperidine (200 mg, 2.35 mmol) was placed in a single-necked round bottom flask with toluene ( 30 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using MeOH-CHCl ₃ ) to give 333 mg (45%) of the title compound as a light brown solid.

（実施例６３）
（５−［１−（４−｛２−［２−（３，４−ジフルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 63)
(5- [1- (4- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -phenyl ) -Ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−２−（３，４−ジフルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（１．７５ｇ、３．８９ｍｍｏｌ）、２，４−チアゾリデンジオン（２．７４ｇ、２３．３８ｍｍｏｌ）、安息香酸（４７５ｍｇ、３．８９ｍｍｏｌ）およびピペリジン（３３１ｍｇ、３．８９ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物８３０ｍｇ（３９％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4-one (1.75 g, 3.89 mmol), A mixture of 2,4-thiazolidenedione (2.74 g, 23.38 mmol), benzoic acid (475 mg, 3.89 mmol) and piperidine (331 mg, 3.89 mmol) was placed in a single neck round bottom flask, Toluene (30 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (which uses MeOH-CHCl ₃ ) to give 830 mg (39%) of the title compound as a light brown solid.

（実施例６４）
（５−［１−（４−｛２−［７−クロロ−２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリン−２，４−ジオン）

(Example 64)
(5- [1- (4- {2- [7-Chloro-2- (4-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazoline-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−７−クロロ−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４ｇ、０．８５ｍｍｏｌ）、２，４−チアゾリデンジオン（０．５０２ｇ、４．２９ｍｍｏｌ）、安息香酸（１９０ｍｇ、１．５５ｍｍｏｌ）およびピペリジン（１４５ｍｇ、１．７０ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濾過した。その固形物を還流下にて、２時間にわたって、ｉ−ＰｒＯＨで処理し、次いで、濾過した。その固形物をヘキサンで洗浄し、そしてカラムクロマトグラフィーで精製して、白色固形物として、表題化合物２００ｍｇ（４１％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-chloro-2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.4 g, 0.85 mmol) ), 2,4-thiazolidenedione (0.502 g, 4.29 mmol), benzoic acid (190 mg, 1.55 mmol) and piperidine (145 mg, 1.70 mmol) were placed in a single necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and filtered. The solid was treated with i-PrOH at reflux for 2 hours and then filtered. The solid was washed with hexane and purified by column chromatography to give 200 mg (41%) of the title compound as a white solid.

（実施例６５）
（５−［１−（４−｛２−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エチルアミノ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 65)
(5- [1- (4- {2- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethylamino} -phenyl) -Ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェニルアミノ）−エトキシ］−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４ｇ、０．９３ｍｍｏｌ）、２，４−チアゾリデンジオン（０．６５ｇ、５．６ｍｍｏｌ）、安息香酸（２２５ｍｇ、１．８４ｍｍｏｌ）およびピペリジン（１８０ｍｇ、２．１１ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（１００ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、０〜２％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、黄色固形物として、表題化合物２００ｍｇ（４１％）を得た。

Compound 3- [2- (4-acetyl-phenylamino) -ethoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.4 g, 0.93 mmol), 2 , 4-thiazolidenedione (0.65 g, 5.6 mmol), benzoic acid (225 mg, 1.84 mmol) and piperidine (180 mg, 2.11 mmol) were placed in a single-necked round bottom flask with toluene. (100 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 0-2% MeOH—CHCl ₃ ) to give 200 mg (41%) of the title compound as a yellow solid.

（実施例６６）
（５−｛２−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−ベンジリデン）−チアゾリジン−２，４−ジオン）

Example 66
(5- {2- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzylidene) -thiazolidine-2,4- Zeon)

化合物４−｛２−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−ベンズアルデヒド（０．３ｇ、０．７１９ｍｍｏｌ）、２，４−チアゾリデンジオン（０．１６８ｇ、１．４３ｍｍｏｌ）、安息香酸（３０ｍｇ、０．２４ｍｍｏｌ）およびピペリジン（３０ｍｇ、０．３５ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、１２時間にわたって、還流状態まで加熱した。この反応混合物を５０℃まで冷却し、そして濾過した。その残渣を熱ＭｅＯＨで洗浄し、そして真空乾燥して、褐色固形物として、表題化合物２００ｍｇ（５４％）を得た。

Compound 4- {2- [2- (4-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzaldehyde (0.3 g, 0.719 mmol ), 2,4-thiazolidenedione (0.168 g, 1.43 mmol), benzoic acid (30 mg, 0.24 mmol) and piperidine (30 mg, 0.35 mmol) were placed in a single-necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 50 ° C. and filtered. The residue was washed with hot MeOH and dried in vacuo to give 200 mg (54%) of the title compound as a brown solid.

（実施例６７）
（５−｛２−［２−（４−ブロモ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−ベンジリデン）−チアゾリジン−２，４−ジオン）

(Example 67)
(5- {2- [2- (4-Bromo-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzylidene) -thiazolidine-2,4- Zeon)

化合物４−｛２−［２−（４−ブロモ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−ベンズアルデヒド（０．１２５ｇ、０．２５ｍｍｏｌ）、２，４−チアゾリデンジオン（０．１７８ｇ、１．５ｍｍｏｌ）、安息香酸（６３ｍｇ、０．５１ｍｍｏｌ）およびピペリジン（４５ｍｇ、０．５２ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、１２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。分離した固形物を濾過し、ジエチルエーテルで洗浄し、そして真空乾燥して、淡褐色固形物として、表題化合物８０ｍｇ（５３％）を得た。

Compound 4- {2- [2- (4-Bromo-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzaldehyde (0.125 g, 0.25 mmol) ), 2,4-thiazolidenedione (0.178 g, 1.5 mmol), benzoic acid (63 mg, 0.51 mmol) and piperidine (45 mg, 0.52 mmol) were placed in a single-necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The separated solid was filtered, washed with diethyl ether and dried in vacuo to give 80 mg (53%) of the title compound as a light brown solid.

（実施例６８）
（５−［１−（４−｛２−［２−（５−フルオロ−２−メチル−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 68)
(5- [1- (4- {2- [2- (5-Fluoro-2-methyl-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−２−（５−フルオロ−２−メチル−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．２５ｇ、０．５６ｍｍｏｌ）、２，４−チアゾリデンジオン（０．３９４ｇ、３．３７ｍｍｏｌ）、安息香酸（１４２ｍｇ、１．１６ｍｍｏｌ）およびピペリジン（１００ｍｇ、１．１７ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、３〜２０％ＥｔＯＡｃ−ＣＨＣｌ_３を使用する）で精製して、褐色固形物として、表題化合物８０ｍｇ（２６％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (5-fluoro-2-methyl-phenyl) -1-methyl-1H-quinolin-4-one (0.25 g, 0.56 mmol) ), 2,4-thiazolidenedione (0.394 g, 3.37 mmol), benzoic acid (142 mg, 1.16 mmol) and piperidine (100 mg, 1.17 mmol) were placed in a single neck round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 3-20% EtOAc-CHCl ₃ ) to give 80 mg (26%) of the title compound as a brown solid.

（実施例６９）
（５−［１−（３−｛２−［２−（４−フルオロ−２−メチル−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 69)
(5- [1- (3- {2- [2- (4-Fluoro-2-methyl-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（３−アセチル−フェノキシ）−エトキシ］−２−（４−フルオロ−２−メチル−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．２５ｇ、０．５６ｍｍｏｌ）、２，４−チアゾリデンジオン（０．３９４ｇ、３．３７ｍｍｏｌ）、安息香酸（１５０ｍｇ、１．２２ｍｍｏｌ）およびピペリジン（１００ｍｇ、１．１７ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、３〜２０％ＥｔＯＡｃ−ＣＨＣｌ_３を使用する）で精製して、褐色固形物として、表題化合物１２０ｍｇ（３９％）を得た。

Compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (4-fluoro-2-methyl-phenyl) -1-methyl-1H-quinolin-4-one (0.25 g, 0.56 mmol) ), 2,4-thiazolidenedione (0.394 g, 3.37 mmol), benzoic acid (150 mg, 1.22 mmol) and piperidine (100 mg, 1.17 mmol) were placed in a single-necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 3-20% EtOAc-CHCl ₃ ) to give 120 mg (39%) of the title compound as a brown solid.

（実施例７０）
（５−［１−（４−｛３−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−プロポキシｌ−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 70)
(5- [1- (4- {3- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -propoxyl-phenyl)- Ethylidene] -thiazolidine-2,4-dione)

化合物３−［３−（４−アセチル−フェノキシ）−プロポキシ］−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４０ｇ、０．８９８ｍｍｏｌ）、２，４−チアゾリデンジオン（０．６３１ｇ、５．３９ｍｍｏｌ）、安息香酸（２２５ｍｇ、１．８２ｍｍｏｌ）およびピペリジン（１７５ｍｇ、２．０５ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、１％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、白色固形物として、表題化合物１３０ｍｇ（２７％）を得た。

Compound 3- [3- (4-acetyl-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.40 g, 0.898 mmol), 2, A mixture of 4-thiazolidenedione (0.631 g, 5.39 mmol), benzoic acid (225 mg, 1.82 mmol) and piperidine (175 mg, 2.05 mmol) was placed in a single-necked round bottom flask with toluene ( 30 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 1% MeOH—CHCl ₃ ) to give 130 mg (27%) of the title compound as a white solid.

（実施例７１）
（５−［１−（３−｛３−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−プロポキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 71)
(5- [1- (3- {3- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -propoxy} -phenyl)- Ethylidene] -thiazolidine-2,4-dione)

化合物３−［３−（３−アセチル−フェノキシ）−プロポキシ］−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４５ｇ、１．０１１ｍｍｏｌ）、２，４−チアゾリデンジオン（０．７１０ｇ、６．０６ｍｍｏｌ）、安息香酸（３００ｍｇ、２．４６ｍｍｏｌ）およびピペリジン（３００ｍｇ、３．５２ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、０．３％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物１８７ｍｇ（３４％）を得た。

Compound 3- [3- (3-acetyl-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.45 g, 1.011 mmol), 2, A mixture of 4-thiazolidenedione (0.710 g, 6.06 mmol), benzoic acid (300 mg, 2.46 mmol) and piperidine (300 mg, 3.52 mmol) was placed in a single-necked round bottom flask with toluene ( 50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 0.3% MeOH—CHCl ₃ ) to give 187 mg (34%) of the title compound as a light brown solid.

（実施例７２）
（５−［１−（３−クロロ−４−｛３−［２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ）−プロポキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 72)
(5- [1- (3-Chloro-4- {3- [2- (4-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy) -propoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［３−（４−アセチル−２−クロロ−フェノキシ）−プロポキシ］−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４０ｇ、０．８６ｍｍｏｌ）、２，４−チアゾリデンジオン（０．６０３ｇ、５．１６ｍｍｏｌ）、安息香酸（１５０ｍｇ、１．２３ｍｍｏｌ）およびピペリジン（３００ｍｇ、３．５２ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、２％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物１４０ｍｇ（３０％）を得た。

Compound 3- [3- (4-acetyl-2-chloro-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.40 g, 0.86 mmol) ), 2,4-thiazolidenedione (0.603 g, 5.16 mmol), benzoic acid (150 mg, 1.23 mmol) and piperidine (300 mg, 3.52 mmol) were placed in a single necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 2% MeOH—CHCl ₃ ) to give 140 mg (30%) of the title compound as a light brown solid.

（実施例７３）
（５−［１−（４−｛２−［７−フルオロ−２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 73)
(5- [1- (4- {2- [7-Fluoro-2- (4-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−７−フルオロ−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４０ｇ、０．８９ｍｍｏｌ）、２，４−チアゾリデンジオン（０．５２１ｇ、４．４５ｍｍｏｌ）、安息香酸（２００ｍｇ、１．６３ｍｍｏｌ）およびピペリジン（１５０ｍｇ、１．７６ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、０．５〜１％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、褐色固形物として、表題化合物１００ｍｇ（２１％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-fluoro-2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.40 g, 0.89 mmol) ), 2,4-thiazolidenedione (0.521 g, 4.45 mmol), benzoic acid (200 mg, 1.63 mmol) and piperidine (150 mg, 1.76 mmol) were placed in a single necked round bottom flask. Toluene (50 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (which uses 0.5-1% MeOH—CHCl ₃ ) to give 100 mg (21%) of the title compound as a brown solid.

（実施例７４）
（５−［１−（４−｛２−［２−（３，４−ジフルオロ−フェニル）−７−フルオロ−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 74)
(5- [1- (4- {2- [2- (3,4-Difluoro-phenyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−２−（３，４−ジフルオロ−フェニル）−７−フルオロ−１−メチル−１Ｈ−キノリン−４−オン（０．４０ｇ、０．８５ｍｍｏｌ）、２，４−チアゾリデンジオン（０．５０ｇ、４．２８ｍｍｏｌ）、安息香酸（１９０ｍｇ、１．５５ｍｍｏｌ）およびピペリジン（１４５ｍｇ、１．７０ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（５０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を５０℃まで冷却し、濾過し、そして熱トルエンで洗浄した。その固形物を、還流下にて、１０時間にわたって、トルエンで処理し、濾過し、熱ＭｅＯＨで洗浄し、そして乾燥して、白色固形物として、表題化合物１２５ｍｇ（２６％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -7-fluoro-1-methyl-1H-quinolin-4-one (0.40 g, 0 .85 mmol), 2,4-thiazolidenedione (0.50 g, 4.28 mmol), benzoic acid (190 mg, 1.55 mmol) and piperidine (145 mg, 1.70 mmol) were placed in a single neck round bottom flask. To this was added toluene (50 mL). The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 50 ° C., filtered and washed with hot toluene. The solid was treated with toluene at reflux for 10 hours, filtered, washed with hot MeOH and dried to give 125 mg (26%) of the title compound as a white solid.

（実施例７５）
（５−［１−（４−｛２−［２−（３，４−ジフルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−３−フルオロ−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 75)
(5- [1- (4- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -3 -Fluoro-phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−２−フルオロ−フェノキシ）−エトキシ］−２−（３，４−ジフルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４０ｇ、０．８５６ｍｍｏｌ）、２，４−チアゾリデンジオン（０．７０１ｇ、５．９９ｍｍｏｌ）、安息香酸（２００ｍｇ、１．６４ｍｍｏｌ）およびピペリジン（２００ｍｇ、２．３５ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、１〜２％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物１７０ｍｇ（３５％）を得た。

Compound 3- [2- (4-acetyl-2-fluoro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.40 g, 0 .856 mmol), 2,4-thiazolidenedione (0.701 g, 5.99 mmol), benzoic acid (200 mg, 1.64 mmol) and piperidine (200 mg, 2.35 mmol) were placed in a single neck round bottom flask. To this was added toluene (30 mL). The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (which uses 1-2% MeOH—CHCl ₃ ) to give 170 mg (35%) of the title compound as a light brown solid.

（実施例７６）
（５−［１−（４−｛２−［７−クロロ−２−（３，４−ジフルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 76)
(5- [1- (4- {2- [7-chloro-2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−７−クロロ−２−（３，４−ジフルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．６０ｇ、１．２ｍｍｏｌ）、２，４−チアゾリデンジオン（０．８７２ｇ、７．０ｍｍｏｌ）、安息香酸（１５１ｍｇ、１．２ｍｍｏｌ）およびピペリジン（１０５ｍｇ、１．２ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（２０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、白色固形物として、表題化合物１５０ｍｇ（２１％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-chloro-2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.60 g, 1 .2 mmol), 2,4-thiazolidenedione (0.872 g, 7.0 mmol), benzoic acid (151 mg, 1.2 mmol) and piperidine (105 mg, 1.2 mmol) in a single neck round bottom flask. To this was added toluene (20 mL). The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using MeOH-CHCl ₃ ) to give 150 mg (21%) of the title compound as a white solid.

（実施例７７）
（５−［１−（３−クロロ−４−｛２−［７−クロロ−２−（３，４−ジフルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 77)
(5- [1- (3-Chloro-4- {2- [7-chloro-2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinoline-3 -Yloxy] -ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−２−クロロ−フェノキシ）−エトキシ］−７−クロロ−２−（３，４−ジフルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．５０ｇ、０．９６ｍｍｏｌ）、２，４−チアゾリデンジオン（０．６７７ｇ、５．０ｍｍｏｌ）、安息香酸（１１７ｍｇ、０．９６ｍｍｏｌ）およびピペリジン（９５ｍｇ、０．９６ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（２０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、白色固形物として、表題化合物１２０ｍｇ（２０％）を得た。

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -7-chloro-2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4-one (0 .50 g, 0.96 mmol), 2,4-thiazolidenedione (0.677 g, 5.0 mmol), benzoic acid (117 mg, 0.96 mmol) and piperidine (95 mg, 0.96 mmol) Toluene (20 mL) was added to the bottom flask. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (which uses MeOH-CHCl ₃ ) to give 120 mg (20%) of the title compound as a white solid.

（実施例７８）
（５−［１−（４−｛２−［６−フルオロ−２−（４−フルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 78)
(5- [1- (4- {2- [6-Fluoro-2- (4-fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -Phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−フェノキシ）−エトキシ］−６−フルオロ−２−（４−フルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（０．４ｇ、０．８２ｍｍｏｌ）、２，４−チアゾリデンジオン（０．５８１ｇ、４．９６ｍｍｏｌ）、安息香酸（６５０ｍｇ、５．３２ｍｍｏｌ）およびピペリジン（５００ｍｇ、５．８７ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、０．５〜１％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物８０ｍｇ（１６％）を得た。

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -6-fluoro-2- (4-fluoro-phenyl) -1-methyl-1H-quinolin-4-one (0.4 g, 0.82 mmol) ), 2,4-thiazolidenedione (0.581 g, 4.96 mmol), benzoic acid (650 mg, 5.32 mmol) and piperidine (500 mg, 5.87 mmol) were placed in a single necked round bottom flask. Toluene (30 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (which uses 0.5-1% MeOH—CHCl ₃ ) to give 80 mg (16%) of the title compound as a light brown solid.

（実施例７９）
（５−［１−（３−クロロ−４−｛２−［２−（３，４−ジフルオロ−フェニル）−６−フルオロ−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 79)
(5- [1- (3-Chloro-4- {2- [2- (3,4-difluoro-phenyl) -6-fluoro-1-methyl-4-oxo-1,4-dihydro-quinoline-3 -Yloxy] -ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−２−クロロ−フェノキシ）−エトキシ］−２−（３，４−ジフルオロ−フェニル）−６−フルオロ−１−メチル−１Ｈ−キノリン−４−オン（１．４ｇ、２．７０ｍｍｏｌ）、２，４−チアゾリデンジオン（１．９６ｇ、１６．７ｍｍｏｌ）、安息香酸（６００ｍｇ、４．９１ｍｍｏｌ）およびピペリジン（４７０ｍｇ、５．５１ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（３０ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、７２時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濃縮した。その残渣をカラムクロマトグラフィー（これは、０．５〜１％ＭｅＯＨ−ＣＨＣｌ_３を使用する）で精製して、淡褐色固形物として、表題化合物４０ｍｇ（８％）を得た。

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -6-fluoro-1-methyl-1H-quinolin-4-one (1 .4 g, 2.70 mmol), 2,4-thiazolidenedione (1.96 g, 16.7 mmol), benzoic acid (600 mg, 4.91 mmol) and piperidine (470 mg, 5.51 mmol) Toluene (30 mL) was added to the bottom flask. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated. The residue was purified by column chromatography (using 0.5-1% MeOH—CHCl ₃ ) to give 40 mg (8%) of the title compound as a light brown solid.

（実施例８０）
（５−［１−（３−クロロ−４−｛２−［２−（３，４−ジフルオロ−フェニル）−１−メチル−４−オキソ−１，４−ジヒドロ−キノリン−３−イルオキシ］−エトキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 80)
(5- [1- (3-Chloro-4- {2- [2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione)

化合物３−［２−（４−アセチル−２−クロロ−フェノキシ）−エトキシ］−２−（３，４−ジフルオロ−フェニル）−１−メチル−１Ｈ−キノリン−４−オン（９７ｇ、２００ｍｍｏｌ）、チアゾリジン−２，４−ジオン（１４１ｇ、１２００ｍｍｏｌ）、安息香酸（４４ｇ、３６１ｍｍｏｌ）およびピペリジン（３５ｇ、４１１．７ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（１０００ｍＬ）を加えた。この丸底フラスコにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そしてシリカゲルカラムに通した。その生成物を、０．３〜０．９％ＭｅＯＨ／ＣＨＣｌ_３を使用することにより溶出して、灰白色固形物として、表題化合物３７ｇ（３２％）を得た。

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4-one (97 g, 200 mmol), A mixture of thiazolidine-2,4-dione (141 g, 1200 mmol), benzoic acid (44 g, 361 mmol) and piperidine (35 g, 411.7 mmol) was placed in a single-necked round bottom flask to which toluene (1000 mL) was added. . The round bottom flask was equipped with a Dean-Stark apparatus (connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and passed through a silica gel column. The product was eluted by using 0.3-0.9% MeOH / CHCl ₃ to give 37 g (32%) of the title compound as an off-white solid.

（実施例８１）
（５−［１−（４−｛３−［２−（３，４−ジメトキシ−フェニル）−５，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−３−イルオキシ］−プロポキシ｝−フェニル）−エチリデン］−チアゾリジン−２，４−ジオン）

(Example 81)
(5- [1- (4- {3- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -propoxy} -phenyl)- Ethylidene] -thiazolidine-2,4-dione)

化合物３−［３−（４−アセチル−フェノキシ）−プロポキシ］−２−（３，４−ジメトキシ−フェニル）−７−エチル−５−メトキシ−クロメン−４−オン（０．３０ｇ、０．５６２ｍｍｏｌ）、２，４−チアゾリデンジオン（３３０ｍｇ、２．８２ｍｍｏｌ）、安息香酸（１３２ｍｇ、１．０８ｍｍｏｌ）およびピペリジン（９６ｍｇ、１．１３ｍｍｏｌ）の混合物を単口丸底フラスコに入れ、これに、トルエン（１５ｍＬ）を加えた。このＲＢＦにディーン−スターク装置（これは、還流冷却器に連結した）を取り付けた。その反応混合物を、窒素雰囲気下にて、４８時間にわたって、還流状態まで加熱した。この反応混合物を２５℃まで冷却し、そして濾過した。その固形物を乾燥して、白色固形物として、表題化合物１８９ｍｇ（３４％）を得た。

Compound 3- [3- (4-acetyl-phenoxy) -propoxy] -2- (3,4-dimethoxy-phenyl) -7-ethyl-5-methoxy-chromen-4-one (0.30 g, 0.562 mmol) ), 2,4-thiazolidenedione (330 mg, 2.82 mmol), benzoic acid (132 mg, 1.08 mmol) and piperidine (96 mg, 1.13 mmol) were placed in a single neck round bottom flask, Toluene (15 mL) was added. The RBF was fitted with a Dean-Stark device (which was connected to a reflux condenser). The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and filtered. The solid was dried to give 189 mg (34%) of the title compound as a white solid.

（実施例８２〜９１）
以下の化合物は、上で述べた方法を使用して、当業者により容易に調製される：

(Examples 82 to 91)
The following compounds are readily prepared by those skilled in the art using the methods described above:

同様に、他の出発物質および中間体は、公知方法（例えば、参考例またはそれらの明らかな化学等価物で記載された方法）を適用または適応することにより、調製される（参考文献：（ｉ）Ｊ．ＨＥＴ．ＣＨＥＭ．，１９９９（３６）１４１；（ｉｉ）ブロモケトンの調製については、以下を参照のこと（ａ）Ｊ．ＭＥＤ．ＣＨＥＭ．１９９６（３９），２９３９−２９５２；（ｂ）Ｊ．ＨＥＴ．ＣＨＥＭ．，１９７２（９）８８７；（ｂ）ＩＮＤＩＡＮ Ｊ．ＣＨＥＭ．ＳＥＣＴ．，１９９０（２９）７７；（ｃ）ＴＥＴＲＡＨＥＤＲＯＮ ＬＥＴＴ．，１９９７（３８）３５８１；（ｄ）ＣＨＥＭ．ＰＨＡＲＭ．ＢＵＬＬ．１９９２（４０）１１７０）。

Similarly, other starting materials and intermediates are prepared by applying or adapting known methods (eg, those described in the Reference Examples or their obvious chemical equivalents) (Ref: (i ) J. HET. CHEM., 1999 (36) 141; (ii) For the preparation of bromoketone, see: (a) J. MED.CHEM. 1996 (39), 2939-2952; (B) INDIAN J. CHEM. SECT., 1990 (29) 77; (c) TETRAHEDRON LETT., 1997 (38) 3581; (d) CHEM. PHARM. 1992 (40) 1170).

  These pharmaceutically acceptable salts are compounds of formula (I) in the presence of a solvent such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, or any mixture thereof. (When applicable) and 1 to 4 equivalents of base (e.g., sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide, or any mixture thereof) It is prepared by reacting with Organic bases such as lysine, arginine, diethanolamine, choline, tromethamine, guanidine, or any derivative or mixture thereof can also be used. Alternatively, the acid addition salt may be acid (eg, hydrochloric acid, bromide, etc.) in the presence of a solvent (eg, ethyl acetate, ether, alcohol, acetone, THF, dioxane, or any mixture thereof) where applicable. Hydrogen, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid Or any mixture thereof). Amino acid salt salts may be prepared by reacting a compound of formula (I) with the respective group in the presence of a solvent, such as an alcohol and a ketone, or any mixture thereof.

  Various polymorphs of the compounds of general formula (I) according to the invention can be obtained by crystallizing the compounds of formula (I) under different conditions (for example of different solvents for recrystallization or of those By using a mixture); by performing crystallization at different temperatures; or by using various cooling modes (ranging from very fast cooling to very slow cooling) during crystallization, Can be prepared. Polymorphs may also be obtained when this compound is heated or melted, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other such techniques.

  Pharmaceutically acceptable solvates of the compound of formula (I), which form part of the invention, are prepared by conventional methods, for example, compound of formula (I) and solvent (eg water, By dissolving in methanol, ethanol, etc. (eg water)) and by recrystallization using different crystallization techniques.

  The regioisomers of the compounds of formula (I) can be prepared, for example, by changing the reaction conditions using reagents (eg acid to base, or base to acid) or the free base hydrazine with diketone instead of its salt. It can be prepared by reacting. The molar ratio can also change this regioisomer formation.

Claims (59)

Compounds of general formula (I), tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof:

here,

Is

Is
Where L is

Is
Where Q is

Is
Here, R ¹ , R ² and R ³ are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group , Cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, Heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroaryls Sulfonyl, aralkylsulfinyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxyalkyl, carboxylic acid or derivatives thereof Or any sulfonic acid or derivative thereof, wherein any ^{two of} R ¹ , R ² and R ³ are combined to form a 5- or 6-membered saturated cyclic ring, as appropriate. The saturated cyclic ring has 1 to 3 heteroatoms, wherein the heteroatom is O, S or N;
Here, R ⁴ represents hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cyclo Alkenyl, alkoxyalkyl, alkenyloxy, cycloalkenyloxy, acyl, acyloxy, aryl, aryloxy, aroyl, aroyloxy, aralkyl, aralkenyl, aralkynyl, aralkoxy, heterocyclyl, Heterocyclenyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxy An alkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
Where A, B, D and J are independently O, S, N,> CH or — (CH ₂ ) _n —;
Where "----" is any chemical bond;
Where E is O, S or —NR;
Where K is N, C or CH;
Where Y and Z are independently O, —NR, — (CH ₂ ) _u — or S (═O) _u ;
Here, G _{is, - (CH 2) s -} , - (CH 2) s -CH = CH- (CH 2) s - or - is _{(CH 2) s -C≡C- (CH} 2) s ;
Where X, X ₁ , X ₂ , X ₃ and X ₄ are independently O, S or —NR;
Where F is O, S or —NR;
Where Y ¹ and Y ² are independently O or S;
Here, n, w and u are each independently an integer of 0 to 2;
Where p, t, m, s, v are independently integers from 0 to 5;
Here, R and R ⁵ are each independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyl group An oxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; and
Where “Ar” is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group,
Compound. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl Substituted with a group, A group is optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl The compound according to claim 1, which is a group, a thiomorpholinyl group or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group. Compounds of general formula (II), tautomeric forms thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof:

Here, R ¹ , R ² and R ³ are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group , Cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, Heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroaryls Sulfonyl, aralkylsulfinyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxyalkyl, carboxylic acid or derivatives thereof Or any sulfonic acid or derivative thereof, wherein any ^{two of} R ¹ , R ² and R ³ are combined to form a 5- or 6-membered saturated cyclic ring, as appropriate. The saturated cyclic ring has 1 to 3 heteroatoms, wherein the heteroatom is O, S or N;
Here, R ⁴ represents hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cyclo Alkenyl, alkoxyalkyl, alkenyloxy, cycloalkenyloxy, acyl, acyloxy, aryl, aryloxy, aroyl, aroyloxy, aralkyl, aralkenyl, aralkynyl, aralkoxy, heterocyclyl, Heterocyclenyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxy An alkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
Where A, B, D and J are independently O, S, N,> CH or — (CH ₂ ) _n —;
Where "----" is any chemical bond;
Where E is O, S or —NR;
Where Y and Z are independently O, —NR, — (CH ₂ ) _u — or S (═O) _u ;
Here, G _{is, - (CH 2) s -} , - (CH 2) s -CH = CH- (CH 2) s - or - is _{(CH 2) s -C≡C- (CH} 2) s ;
Where X is O, S or —NR;
Where F is O, S or —NR;
Where Y ¹ and Y ² are independently O or S;
Where n and u are each independently an integer from 0 to 2;
Where s is an integer from 0 to 5;
Here, R and R ⁵ are each independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyl group An oxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; and
Where “Ar” is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group,
Compound. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl Substituted with a group, A group is optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl 4. The compound according to claim 3, which is a group, a thiomorpholinyl group or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group. Compounds of general formula (III), tautomeric forms thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof:

Here, R ¹ , R ² and R ³ are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group , Cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, Heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroaryls Sulfonyl, aralkylsulfinyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxyalkyl, carboxylic acid or derivatives thereof Or any sulfonic acid or derivative thereof, wherein any ^{two of} R ¹ , R ² and R ³ are combined to form a 5- or 6-membered saturated cyclic ring, as appropriate. The saturated cyclic ring has 1 to 3 heteroatoms, wherein the heteroatom is O, S or N;
Here, R ⁴ represents hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cyclo Alkenyl, alkoxyalkyl, alkenyloxy, cycloalkenyloxy, acyl, acyloxy, aryl, aryloxy, aroyl, aroyloxy, aralkyl, aralkenyl, aralkynyl, aralkoxy, heterocyclyl, Heterocyclenyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxy An alkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
Where "----" is any chemical bond;
Where E is O, S or —NR;
Where Z is O, —NR, — (CH ₂ ) _u — or S (═O) _u ;
Here, G _{is, - (CH 2) s -} , - (CH 2) s -CH = CH- (CH 2) s - or - is _{(CH 2) s -C≡C- (CH} 2) s ;
Where u is an integer from 0 to 2;
Where s is an integer from 0 to 5;
Here, R and R ⁵ are each independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyl group An oxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; and
Here, R ′ and R ″ are each independently hydrogen, halogen, nitro group, amino group, mono- or disubstituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O═) group, Thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group, aryloxycarbonyl group, A heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group,
Compound. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl Substituted with a group, A group is optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl 6. A compound according to claim 5, which is a group, a thiomorpholinyl group or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group. 6. A compound according to claim 5, wherein one or both of R 'and R "are independently substituted with a halogen, hydroxyl group, nitro group, amino group or alkyloxy group. 6. A compound according to claim 5, wherein one or both of R 'and R "are independently substituted with a heterocyclyl group, said heterocyclyl group comprising a morpholinyl group, thiomorpholine or piperidine. 6. The compound of formula (III) according to claim 5, wherein the compound is:

Compounds of general formula (IV), tautomeric forms thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof:

Here, R ¹ and R ² are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy Group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, heterocyclyl group, Heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl Group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, carboxylic acid or derivatives thereof, Or a sulfonic acid or derivative thereof, wherein any ^{two of} R ¹ , R ² and R ³ are combined to form a 5- or 6-membered saturated cyclic ring, as appropriate, The saturated cyclic ring has 1 to 3 heteroatoms, where the heteroatoms are O, S or N;
Here, R ⁴ represents hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cyclo Alkenyl, alkoxyalkyl, alkenyloxy, cycloalkenyloxy, acyl, acyloxy, aryl, aryloxy, aroyl, aroyloxy, aralkyl, aralkenyl, aralkynyl, aralkoxy, heterocyclyl, Heterocyclenyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxy An alkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
Where D and J are independently O, S, N,> CH or CH ₂ ;
Where "----" is any chemical bond;
Where E is O, S or —NR;
Where K is N, C or CH;
Where Z is O, —NR, — (CH ₂ ) _u — or S (═O) _u ;
Here, G _{is, - (CH 2) s -} , - (CH 2) s -CH = CH- (CH 2) s - or - is _{(CH 2) s -C≡C- (CH} 2) s ;
Where X is O, S or —NR;
Where F is O, S or —NR;
Where Y ¹ and Y ² are independently O or S;
Where u is an integer from 0 to 2;
Where s is an integer from 0 to 5;
Here, R and R ⁵ are each independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyl group An oxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; and
Where “Ar” is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group,
Compound. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl Substituted with a group, A group is optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl The compound according to claim 10, which is a group, a thiomorpholinyl group or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group. 11. A compound of formula (IV) according to claim 10, wherein the compound is:

Compound of general formula (V), its tautomeric form, its stereoisomer, its polymorph, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate:

Here, R ¹ , R ² and R ³ are each independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group , Cycloalkoxy group, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group, Heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroaryls Sulfonyl, aralkylsulfinyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxyalkyl, carboxylic acid or derivatives thereof Or any sulfonic acid or derivative thereof, wherein any ^{two of} R ¹ , R ² and R ³ are combined to form a 5- or 6-membered saturated cyclic ring, as appropriate. The saturated cyclic ring has 1 to 3 heteroatoms, wherein the heteroatom is O, S or N;
Here, R ⁴ represents hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cyclo Alkenyl, alkoxyalkyl, alkenyloxy, cycloalkenyloxy, acyl, acyloxy, aryl, aryloxy, aroyl, aroyloxy, aralkyl, aralkenyl, aralkynyl, aralkoxy, heterocyclyl, Heterocyclenyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, aryloxy An alkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof;
Where A, B, D and J are independently O, S, N,> CH or — (CH ₂ ) _n —;
Where E is O, S or —NR;
Where K is N, C or CH;
Where L is

Is
Where Y and Z are independently O, —NR, — (CH ₂ ) _u — or S (═O) _u ;
Here, G _{is, - (CH 2) s -} , - (CH 2) s -CH = CH- (CH 2) s - or - is _{(CH 2) s -C≡C- (CH} 2) s ;
Where X ₁ , X ₂ , X ₃ and X ₄ are independently O, S or —NR;
Where X is O, S or —NR;
Where n and w are independently integers from 0 to 2;
Where p, t and v are each independently an integer from 0 to 5;
Here, R is hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, acyl group, An aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; and
Where “Ar” is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group,
Compound. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S =) group, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group, benzyloxy group, acyl group, acyloxy group, aroyl group, alkoxycarbonyl group , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or heterocyclylsulfonyl Substituted with a group, A group is optionally substituted with a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or any combination thereof, wherein the heterocyclic group is optionally substituted morpholinyl 14. A compound according to claim 13, which is a group, a thiomorpholinyl group or a piperidinyl group, wherein the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group. 14. A compound of formula (V) according to claim 13, wherein the compound is:

A method of treating or preventing a disease mediated by an inflammatory response or smooth muscle cell proliferation in a human or animal comprising a therapeutic or prophylactically effective amount of the compound of claim 1 in the human or animal. Comprising the step of administering. 17. The method of claim 16, wherein the inflammatory response comprises diabetic vascular complications, wherein the diabetic vascular complications include diabetic retinopathy, microvascular disorder, renal failure or Alzheimer's disease. 17. The method of claim 16, wherein the inflammatory response results from glycated protein or late terminal glycation product accumulation. 19. The method of claim 18, wherein the glycated protein or the late terminal glycated product accumulation is mediated by pro-inflammatory cytokines. 21. The method of claim 19, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-a or MCP-1. 17. The method of claim 16, wherein the smooth muscle cell proliferation is inhibited by inducing perlecan expression. 17. The method of claim 16, wherein the smooth muscle cell proliferation is mediated by proinflammatory cytokines. 23. The method of claim 22, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-a or MCP-1. A method of treating or preventing unwanted inflammation in a human or animal, wherein a composition containing the compound of claim 1 in a therapeutically or prophylactically effective amount is administered to said human or animal having said undesirable inflammation. A method comprising the steps. A method of treating or preventing undesired smooth muscle cell proliferation in a human or animal, wherein said human or animal having said undesired smooth muscle cell proliferation contains a therapeutic or prophylactically effective amount of the compound of claim 1. Administering a composition to be administered. A method of treating or preventing a disease or disorder mediated by a cell adhesion molecule, comprising administering to a patient in need thereof a composition comprising a compound of claim 1 in a therapeutic or prophylactically effective amount. Including the method. 27. The method of claim 26, wherein the disease or disorder mediated by the cell adhesion molecule is an inflammatory disorder or a cardiovascular disease. 28. The method of claim 27, wherein the inflammatory disorder is rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplant or allograft rejection, autoimmune diabetes or multiple sclerosis. 28. The method of claim 27, wherein the cardiovascular disease is restenosis, coronary artery disease, angina pectoris, dyslipidemia, small artery disease, diabetes mellitus, diabetic nephropathy or diabetic retinopathy. 27. The method of claim 26, wherein the cell adhesion molecule is VCAM-1. And further comprising administering a therapeutically or prophylactically effective amount of at least one other agent, wherein the at least one other agent comprises a platelet aggregation inhibitor, an antithrombotic agent, a calcium channel antagonist, an angiotensin converting enzyme. Inhibitors, beta blockers, non-steroidal anti-inflammatory drugs, COX II inhibitors, corticosteroids, TNF-a modulators, HMGCoA reductase inhibitors, PPAR-? 27. The method of claim 26, comprising an agonist, HDL elevator or retinoid. 32. The method of claim 31, wherein the at least one other agent is aspirin, diltiazem, nefidipine, captopril, enaropril, propanalol, ibuprofen, indomethacin, sulindac, rofecoxib, celecoxib, etanercept or infliximab. A method of treating or preventing cancer in a human or animal comprising administering to said human or animal a therapeutic or prophylactically effective composition containing a compound of claim 1. 34. The method of claim 33, wherein the cancer comprises melanoma, prostate cancer, leukemia, lymphoma, non-small cell lung cancer, central nervous system cancer, breast cancer, colon cancer, ovarian cancer, or kidney cancer. A method of inhibiting smooth muscle cell proliferation in a human or animal comprising administering to said human or animal a therapeutic or prophylactically effective composition containing a compound of claim 1. A method of blocking an inflammatory response in an endothelial cell of a human or animal comprising the step of administering to said human or animal a composition containing a compound as claimed in claim 1 in a therapeutic or prophylactically effective amount. . A method of treating or preventing organ transplant vasculopathy in a human or animal comprising the step of administering to said human or animal a composition containing the compound of claim 1 in a therapeutically or prophylactically effective amount. ,Method. 38. The method of claim 37, wherein the organ is liver, kidney, heart, lung, pancreas, islet and skin. 38. The method of claim 37, further comprising administering a therapeutically or prophylactically effective amount of an immunosuppressive drug. 40. The method of claim 39, wherein the immunosuppressive drug is CellCept, Gengraf, Microgam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, Zenapax. The administration is oral, parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraperitoneal, intracapsular, intrachondral, intracavity, intracavitary, intraventricular, intracolonic, intracolonic, intracervical Intragastric, intrahepatic, intramyocardial, intraosseous, pelvic, intrapericardial, intraperitoneal, intrapleural, prostate, intrapulmonary, rectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic 40. The method of claim 39, wherein the method is intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal or transdermal. 40. The method of claim 39, wherein the immunosuppressive drug is administered prior to the composition. 40. The method of claim 39, wherein the immunosuppressive drug is administered after the composition. 40. The method of claim 39, wherein the immunosuppressive drug is administered concurrently with the composition. A method of treating or preventing restenosis in a human or animal comprising administering to said human or animal a composition containing a compound of claim 1 in a therapeutically or prophylactically effective amount. A method of treating or preventing atherosclerosis in a human or animal comprising the step of administering to said human or animal a composition containing a compound as claimed in claim 1 in a therapeutically or prophylactically effective amount. ,Method. A method of treating a disease mediated by inflammation in a human or animal comprising administering to said human or animal a composition comprising a therapeutic or prophylactically effective amount of a compound of claim 1. Method. 48. The method of claim 47, wherein the inflammation mediated disease is an autoimmune disease. The autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune Addison disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, vesicular pemphigoid, cardiomyopathy , Celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scar pemphigoid, crest syndrome, cold agglutinin disease, Crohn's disease, circle Plate lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, Insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, meniere disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia Polyarteritis, polychondritis, polyglandular syndrome, rheumatic polymyalgia, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter syndrome, Rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, systemic stiffness syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, 49. The method according to claim 48, wherein the method is vitiligo or Wegner granulomatosis. A method of treating or preventing metastasis in a human or animal comprising administering to said human or animal a therapeutic or prophylactically effective amount of a composition containing a compound of claim 1. A method of modulating Perlecan activity in a human or animal comprising administering to said human or animal a therapeutically effective amount of a composition containing a compound according to claim 1. A method of modulating heparanase in a human or animal comprising administering to said human or animal a composition containing a therapeutically effective amount of the compound of claim 1. A stent coated with a composition comprising the compound of claim 1. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 55. The pharmaceutical composition according to claim 54, which is in the form of a tablet, capsule, powder, syrup, solution, suspension. A medical device coated with a composition comprising the compound of claim 1. The medical device is a shunt, colostomy bag mounting device, ear drainage tube, pacemaker and implantable defibrillator lead, suture, staple, anastomosis device, vertebral disc, bone pin, suture anchor, hemostatic 57. The medical device of claim 56, wherein the medical device is a barrier, clamp, screw, plate, clip, vascular graft, tissue adhesive or sealant, tissue scaffold, bone substitute, intraluminal device, and vascular support. A method of treating or preventing cardiovascular disease in a human or animal comprising administering to said human or animal a composition containing a therapeutically effective amount of the compound of claim 1. 59. The cardiovascular disease is atherosclerosis, restenosis, coronary artery disease, angina pectoris, dyslipidemia, small artery disease, diabetes mellitus, diabetic nephropathy or diabetic retinopathy The method described.