KR20070026306A - Heterocyclic compounds and methods of making and using thereof - Google Patents

Abstract

Compounds of formula (I), and methods and/or compositions comprising compounds that are effective in modulating inflammatory responses, such as those resulting from AGE and glycated protein accumulation are provided. Methods and/or compositions comprising compounds that are effective in modulating smooth muscle cell proliferation and the diseases or conditions related thereto are also provided. ® KIPO & WIPO 2007

Description

Heterocyclyl Compounds and Methods for Making the Same and Uses thereof

The present invention relates to compounds, pharmaceutical compositions, and methods for their preparation and their use.

Glycated proteins and advanced end product (AGE) are involved in cell damage, such as diabetic tissue damage. This can occur by at least two major mechanisms: the regulation of cellular action through interaction with specific cell surface receptors, and the alteration of the extracellular matrix that causes protein crosslinking. Research suggests that the interaction of glycated proteins and AGEs with cells promotes inflammatory processes and oxidative cell damage. AGE increases lipoprotein oxidative and atherosclerosis. In addition, binding of AGE to matrix proteins induces the synthesis of IL-1, TNFα, VCAM-1, heme oxygenase, insulin-like growth factor, IL-6 and activates NF-κB. Diseases in which glycated proteins and AGE accumulation are suspected of major etiology include, but are not limited to, vascular complications of diabetes, microangiopathy, renal failure and Alzheimer's disease.

As observed in diabetic patients, the exact mechanism by which high plasma glucose causes microvascular damage is not fully understood. One possible mechanism by which hyperglycemia may be involved in microangiopathy is through a non-enzymatic glycation process of major proteins. Nonenzymatic glycation of major 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 glomerular disease, Proc. Natl. Acad. Sci. USA, 1994 (91) 9436-40; Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease, J. Am. Soc. Nephrol., 2000 (11) 1656-66; And Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis, Circ. Res., 1999 (84) 489-97.

Non-enzymatic glycation, ie, binding the protein with glucose results in glycated protein formation. The first step of this glycation pathway involves the non-enzymatic condensation of glucose with an amino group in the protein, mainly an epsilon-amino group of lysine residues, to form an Amadori adduct. These initial glycation products may undergo further reactions such as rearrangement, dehydration and condensation reactions to form irreversible late glycation products (AGE). These are a group of highly reactive molecules, and their interaction with certain receptors on the cell surface can lead to pathogenic consequences. Accumulation of glycated proteins occurs in the basement membrane of diabetic patients and is believed to be involved in the development of diabetic kidney disease and retinopathy. See: Immunohistochemical localization of glycated protein in diabetic rat kidney., Diabetes Res. Clin, Pract., 1990 (8) 215-9; And Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy., J. Am. Soc. Nephrol., 1996 (7) 183-90. Note: Inhibitors of AGE formation, such as aminoguanidine, have been shown to block the formation of AGEs and prevent the development of diabetic complications, including diabetic retinopathy (aminoguanidine prevents diabetes-induced arterial wall protein crosslinking, Science , 1986 (232) 1629-1632; Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine., Proc. Natl. Acad. Sci. USA., 1996 (93) 3902-7; and Potential benefit of inhibiors of advanced glycation end products in the progression of type II diabetes: a study with aminoguanidine in C57 / BLKsJ diabetic mice., Metabolism, 1998 (47) 1477-80.

One characteristic AGE receptor is RAGE, the receptor for AGE. See: Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis., Circ. Res. 1999 (84) 489-97; And Roles of the AGE-RAGE system in vascular injury in diabetes, Ann. NY Acad. Sci. 2000 (902) 163-70; discussion 170-2. Some in vitro and in vivo studies have shown that blocking RAGE by antibody or by adding soluble forms of receptors inhibits diabetic angiopathy, including diabetic atherosclerosis. See: Receptor-mediated ednothelial cell dysfunction in diabetic vasculopahy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats., J. Clin. Invest., 1996 (97) 238-43; Advanced glycation end products interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasulopathy of diabetes., J. Clin. Invest., 1995 (96) 1395-403; And Suppresion of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end products., Nat. Med. 1998 (4) 1025-31. In addition to AGE, RAGE appears to mediate the binding of several other ligands involved in physiology as well as normal physiology. See Blockade of RAGE-amphoterin signaling signaling suppresses tumor growth and metastases., Nature, 2000 (405) 354-60; RAGE mediates a novel proinflammatory axis: a central cell surface receptor for advanced glycation end product interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer diseases., Proc. Natl. Acad. Sci., USA., 1997 (94) 5296-301. Thus, blocking only RAGE can lead to other unexpected results. In addition, blockage of RAGE accumulates AGE in circulation, so long-term effects of RAGE blockage are unknown and may be more harmful than the disease to be treated.

One useful way to block AGE effects is to develop inhibitors that block AGE induced signals. See Activation of the receptor for advanced glycation end products triggers a p21 (ras) -dependent mitogen-activated protein kinase pathway regulated by oxidant stress., J. Biol. Chem., 1997 (272) 17810-4; And Cell activation by glycated proteins .; AGE receptors, receptor recognition factors and functional classification of AGEs, Cell. Mol. Biol. (Noisy-1e-grand), 1998 (44) 1013-23. However, the order of these signals causing inflammation is not clear. Thus, there is a need for compounds that can block AGE-induced activity, in particular AGE-induced inflammation or more particularly AGE-induced signals.

Another chronic condition in which no suitable and effective therapy exists is the treatment of antiproliferative diseases. Smooth muscle cell (SMC) hyperplasia is an important factor in the development of atherosclerosis and is also associated with the rate of failure after vascular surgery such as angioplasty and coronary artery bypass surgery. See: the comparative pathobiology of atherosclerosis and restenosis. Am. J. Cardiol. 86: 6H-11H (2000); And Restenosis: a challenge for pharmacology. Trends Pharmcaol Sci. 21: 274-9. In normal blood vessels, SMCs are stationary, but they proliferate when endothelial cell damage occurs. Naturally produced growth regulators, most of which are derived from endothelial cells, tightly control SMC proliferation in vivo.

Smooth muscle cell (VSMC) proliferation of abnormal vessels can act as a pathogenesis of vascular obstructive lesions, including atherosclerosis, vascular narrowing (restenosis) after successful angioplasty, and graft atherosclerosis after coronary artery transplantation. VSMC is The comparative pathobiology of atherosclerosis and restenosis. Am. J. Cardiol. 86: 6H-11H; And Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 100: discussed in S87-9. Many humans and animals are limited in life and lifestyle due to this condition. At present, no effective pharmacological treatment for controlling the obstructive pathogenesis, in particular restenosis, is known.

Transcutaneous vascular procedure (PTCA) is the most common procedure for inpatients in the United States. According to the American Heart Association, about one third of patients undergoing balloon angioplasty experience stenosis of the enlarged area within about six months. You may need to perform other angioplasty or coronary artery bypass surgery on the restenosis. The main feature of restenosis is an injury response, which leads to the activation of inflammatory cascades and the remodeling of internal and external cells of the carotid artery wall. This involves overgrowth of connective tissue and smooth muscle into the lumen of an artery known as neovascular endovascular hyperplasia. At present there is no effective pharmacological treatment for controlling the occlusion of blood vessels including but not limited to atherosclerosis, atherosclerosis, restenosis after coronary artery graft and graft atherosclerosis. The identification of effective therapies with minimal side effects will not require additional surgical procedures, such as coronary artery bypass surgery, which will restore quality of life.

Smooth muscle cell (SMC) hyperplasia is a major factor in the development of atherosclerosis and may also contribute to the rate of failure after vascular surgery such as angioplasty and coronary artery bypass surgery. In normal blood vessels, SMC is stationary but proliferates when the endothelial cells are damaged. Naturally produced growth regulators, most of which are derived from endothelial cells, tightly control SMC proliferation in vivo. Thus, there is a need for methods and compositions for altering gene expression in arteriovascular wall cells to inhibit thrombosis and SMC proliferation. In particular, what is needed are methods and compositions that inhibit SMC proliferation and related endovascular hyperplasia.

U.S. Patent 6,028,088 relates to certain thiazolidinedione compounds and is described as antiproliferative, anti-inflammatory and anti-infective agents. According to the literature, these specific compounds are used for the treatment of certain endocrine diseases, malignant and nonmalignant proliferative diseases and cardiovascular diseases.

Thus, there is a need to treat vascular obstructive onset conditions, in particular restenosis. Because of such frequent occurrences, currently available therapies are expensive and the condition is not suitable for many pharmacological therapies. The mechanisms involved in the control of vascular conditions related to SMC action are not clear and there are no therapies that prevent SMC activation. Thus, what is needed are methods and compositions for the treatment and prevention of hematologic obstruction. In particular, there is a need for methods and compositions for preventing and treating restenosis after treatment of vascular tissues. The present invention seeks to overcome the above and other drawbacks of the prior art.

Summary of the Invention

The present invention provides a composition comprising a compound of formula (I), a method effective for modulating an inflammatory response due to AGE and glycated protein accumulation and a compound effective for regulating an inflammatory response due to AGE and glycated protein accumulation It is about. The present invention also relates to a composition comprising a method effective for regulating smooth muscle cell proliferation and a disease or condition associated therewith and a compound comprising a compound effective for regulating smooth muscle cell proliferation and a disease or condition associated therewith.

The present invention provides compounds and compositions that specifically inhibit the inflammatory response due to AGE and glycated protein accumulation. The present invention also relates to pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, MCP-1, or by inducing the expression of perlecan, the heparin sulfate proteoglycan (HSPG). Provided are compounds and compositions that inhibit smooth muscle cell proliferation that may be mediated.

The present invention provides pharmaceutical compositions containing the novel compounds of formula (I), their pharmaceutically acceptable salts, and optionally one or more such compounds in combination with other active ingredients.

The present invention provides a process for preparing a compound of formula (I), a salt thereof, and a pharmaceutically acceptable composition thereof as defined above.

The invention also provides pharmaceutical compositions containing new compounds of formula (II), their pharmaceutically acceptable salts, and optionally one or more such compounds in combination with other active ingredients:

The present invention provides a process for the preparation of compounds of formula (II) as defined above, salts thereof, and pharmaceutically acceptable compositions thereof.

The present invention also provides pharmaceutical compositions of the formula (III) below, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing or admixing them or in combination with other active ingredients:

The present invention also provides a process for the preparation of compounds of formula III, salts thereof, and pharmaceutically acceptable compositions thereof.

The invention also provides pharmaceutical compositions of the formula (IV), pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing or mixtures thereof or in combination with other active ingredients:

The present invention also provides a process for the preparation of the compounds of formula (IV), their salts and their pharmaceutically acceptable compositions.

The present invention also provides pharmaceutical compositions of the formula (V), pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing or mixtures thereof or in combination with other active ingredients:

The invention also provides a process for the preparation of the compounds of formula (V), salts thereof and pharmaceutically acceptable compositions thereof.

According to one aspect of the invention, methods of using compounds of formula (I) include the treatment and / or prevention of inflammatory conditions such as mediated by AGE or glycated protein accumulation. Such inflammatory conditions include diabetic vascular complications including diabetic retinopathy, microangiopathy, 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 of the present invention. The invention also provides a method of inhibiting an inflammatory response, including an inflammatory response of endothelial cells, comprising administering an effective amount of a compound of the invention. The invention also provides a method of inhibiting thrombosis comprising administering an effective amount of a compound of the invention.

The present invention provides a method for treating or preventing organ transplantation angiopathy in a subject comprising administering a therapeutically effective amount of a compound of the invention. Implanted organs can include, but are not limited to, liver, kidney, heart, lung, pancreas, pancreatic islet, and skin. Such methods may further comprise administering a therapeutically effective amount of an immunosuppressive agent. Immunosuppressants include, but are not limited to, CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandandimmune , Thymoglobulins (Thymoglobulin) and Zenapax (Zenapax).

The invention also provides a method of treating or preventing restenosis in a subject comprising administering a therapeutically effective amount of a compound of the invention. The invention also provides a method of treating or preventing atherosclerosis in a subject comprising administering a therapeutically effective amount of a compound of the invention.

The present invention provides a method of treating a disease mediated by inflammation in a subject comprising administering a therapeutically effective amount of a compound of the invention. More particularly, the disease mediated by inflammation may be an autoimmune disease. In this regard, autoimmune diseases include alopecia areata, ankylosing myelitis, antiphospholipid syndrome, autoimmune Addison disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous stools, cardiomyopathy, non-tropic spruce dermatitis, Chronic Fatigue Immune Disorder Syndrome (CFIDS), Chronic Inflammatory Debilitating Polyneuropathy, Chuck-Strauss Syndrome, Scar-like Crush, CREST Syndrome, Cold Aggregate Disease, Crohn's Disease, Discoid Lupus, Essential Mixed Cold Globulinemia, Fibromyalgia Fibromyalitis, Graves' disease, acute idiopathic neuritis, Hashimoto's respiratory tractitis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia (ITP), IgA kidney disease, insulin-dependent diabetes mellitus, juvenile arthritis, squamous cell, Meniere's disease, mixed combination Histosis, multiple sclerosis, myasthenia gravis, myofascial swelling, pernicious anemia, polyarteritis, polychondritis, polysecretory syndrome, rheumatoid polymyalgia, Polymyositis and dermatitis, primary angammagglobulinemia, primary cholangiosclerosis, psoriasis, Raynaud's syndrome, Reiter syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, muscular ankylosing syndrome, systemic lupus erythematosus, Takayasu Arteritis, transient arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo and Wegner's granulomatosis.

The invention also provides a method of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of a compound of the invention. The present invention also provides a method of treating or preventing metastasis in a subject comprising administering to the subject a therapeutically effective amount of a compound of the invention.

Another aspect of the invention is that of treating and / or preventing a proliferative condition, in particular inhibiting the proliferation of smooth muscle cells, comprising administering a composition comprising a compound of formula (I). It provides a method by using a compound. According to the present invention, the use of such compositions includes preventing and treating vascular occlusion conditions, including atherosclerosis and restenosis.

Another aspect of the invention provides a method of treating and / or preventing a disease mediated by an inflammatory state and a cell proliferative state by using a compound of formula (I).

Another aspect of the invention provides a method for treating and / or preventing a disease or disorder mediated by a cell adhesion molecule such as VCAM-1, wherein the disease is rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation Or an inflammatory disorder selected from allograft rejection, autoimmune diabetes or multiple sclerosis; Atherosclerosis, restenosis, coronary artery disease, angina pectoris, arterial disease, diabetes, diabetic kidney disease or diabetic retinopathy and one of the cell adhesion molecules are cardiovascular diseases selected from VCAM-1.

Another aspect of the invention provides a method of treating and / or preventing a disease by delivering a compound of formula (I) to a disease site by using a stent coated with a compound of formula (I).

The present invention also provides pharmaceutical compositions containing a compound of formula (I), salts thereof, or mixtures thereof in combination with a suitable carrier, solvent, diluent or medium commonly used in the manufacture of the composition.

The invention also provides oral, parenteral, subcutaneous, intramuscular, intravenous, intraarterial, bronchial, abdominal, arterial, cartilage, intraluminal, abdominal, cerebellar, intraventricular, intestinal, cervical, intraperitoneal, Intrahepatic, myocardial, drained, intrapelvic, intracardiac, intraperitoneal, pleural, prostate, intrapulmonary, intrarectal, kidney, intraretinal, spinal cord, intravaginal, intrathoracic, intrauterine, bladder It can be administered via the bolus, vaginal, rectal, buccal, sublingual, nasal or transdermal route.

The compositions of the present invention can be used orally, rectally, ophthalmically (including intravitreal or anterior), nasal, topical (including buccal and sublingual), vaginal or parenteral (subcutaneous, intramuscular, intravenous, intradermal, intratracheal cartilage and Formulations of the compounds of the invention which may be suitable for administration). Such formulations may be present in a single dosage form and may be prepared by conventional pharmaceutical techniques. This technique involves mixing together the active ingredient and a pharmaceutical carrier or excipient. Generally such formulations are prepared by mixing the active ingredient homogeneously and intimately with a liquid carrier or a finely divided solid carrier or both and then molding the product, if necessary.

Other examples of the present invention also provide the use of these intermediates, their salts and their pharmaceutically acceptable compositions in the novel intermediates, their preparation and the preparation of the compounds of formula (I).

Justice

 It is to be understood that the present invention may vary and is independent of the particular methods, sequences, cell lines, constructs and reagents described herein. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, but is only limited by the appended claims.

In this specification and the appended claims, the words used in the singular are to be understood to include the plural forms as well, unless the context clearly indicates otherwise. Thus, for example, "a compound" refers to one or more compounds and includes other equivalents known to those skilled in the art.

Unless defined otherwise, all technical and scientific terms described herein have the same meanings as known to those skilled in the art at the time the invention was practiced.

All documents and patents described herein are incorporated by reference for the purpose of disclosing and describing the structures and methods described in the documents that may be used in connection with the present invention. The documents discussed above and documents described throughout the following specification are presented in the prior art prior to the filing of the present invention. It does not mean that the inventors could have expected such contents from the prior invention.

As described herein, the term “compound” includes both single and multiple forms, and includes single or combined components having activity that can be determined by the assay of the present invention, combinations, fragments of such components And analogues or derivatives.

As used herein, the term “glycated protein” includes proteins that are enzymatically or non-enzymatically bound to glucose, and form an adduct adduct mainly by condensation of glucose with free epsilon-amino groups in the protein. In addition, the glycated proteins described herein are not only proteins containing these initial glycation products, but also glycation products resulting from other reactions such as rearrangements, dehydration and condensation reactions that form irreversible late glycation products (AGEs). Include. It should also be understood that materials which cause the cells or analytical components to react in a measurable manner can be used in the present invention. Increased formation and accumulation of glycated proteins and AGEs are believed to play a major role in the development of diabetic complications and atherosclerosis, leading to the development of various diabetic complications, including diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. can do. (1) preventing glycation of proteins, or (2) breaking crosslinks in the glycated protein (crosslinking destroyer, N-phenylacylthiazolium bromide, prevents the accumulation of late glycation products in blood vessels, Diabetologia , 2000 (43) 66-4) or (3) There is a great deal of in vivo evidence showing that diabetes-related complications can be reduced by blocking the interaction of glycated proteins with receptors. Despite the importance of AGEs in the development of diabetic microangiopathy, no medicament is known to block AGE formation.

The term "phenylamine" refers to a primary or secondary benzeneamine, more commonly known as aniline. The amino group on the aniline may be optionally substituted by hydrogen, alkyl (straight or branched C ₁ -C ₁₂ alkyl), cycloalkyl (C ₃ -C ₁₀ ), or optionally substituted aryl groups. The phenyl ring of the aniline derivative is alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl Amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, phosphate, It may be optionally substituted by one or more functional groups such as phosphonic acid or phosphonate or combinations of such functional groups. If possible, these groups may be present in the protected or unprotected form used in standard organic synthesis.

The term “naphthylamine” refers to primary or secondary α- or β-naphthylamine. Ring structures in naphthylamine are optionally alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, Amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl , Optionally one or more functional groups such as phosphate, phosphonic acid or phosphonate or combinations of these functional groups. If possible, these groups may be present in the protected or unprotected form used in standard organic synthesis.

The term “naphthylalkyl amine” refers to primary or secondary α- or β-naphthylalkyl amines (eg, 2-α-naphthylethylamine). The term "benzylalkyl amine" refers to a primary or secondary benzylalkyl amine (eg, phenylethyl amine). These aryl alkyl substituents or compounds may optionally be optically active or optically inactive. The aryl (ring) substituents of naphthylalkyl and benzalkyl amines are alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio , Arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pi It may be optionally substituted by one or more functional groups or combinations of such functional groups such as rollyl, pyrazolyl, phosphate, phosphonic acid or phosphonate. If possible, these groups may be present in the protected or unprotected form used in standard organic synthesis.

The term "quinolyl amine" refers to a primary or secondary quinolyl amine. These amines are in optically active or inactive forms. The aryl (ring) structure of the quinolyl amine is alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, Amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl , Optionally one or more functional groups such as phosphate, phosphonic acid or phosphonate or combinations of these functional groups. If possible, these groups may be present in the protected or unprotected form used in standard organic synthesis.

The term “heteroaryl amine” is pyrrole, pyrazole, imidazole, and indole. The aryl (ring) structures of heteroaryl amines are alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, Amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl , Optionally one or more functional groups such as phosphate, phosphonic acid or phosphonate or combinations of these functional groups. If possible, these groups may be present in the protected or unprotected form used in standard organic synthesis.

The term “polynucleotide” refers to a nucleotide of predetermined length in the form of a polymer, which is generally a ribonucleotide or a deoxynucleotide. Thus, the term includes, but is not limited to, single stranded, double stranded or multiple stranded DNA or RNA. Polynucleotides include genomic DNA, cDNA or DNA-RNA hybrids. In addition, the polynucleotides of the present invention can be produced synthetically.

Polynucleotides may include chemically modified, biochemically modified, or derived nucleotides. For example, polynucleotides may comprise partially modified nucleotides, such as methylated nucleotides or nucleotide analogs. Polynucleotides may include sugars, caps, nucleotide branches and linking groups such as fluororibose and thioate. The sequence of nucleotides can also be segmented by non-nucleotide components. Polynucleotides can also be polymerized and then modified to facilitate their attachment to other polynucleotides, proteins, metal ions, labeling components or solid supports.

The backbone of the polynucleotide may comprise sugar and / or phosphate groups that are modified or optionally substituted. Alternatively, the polynucleotide backbone may comprise polymers of synthetic subunits such as phosphoramidite and may be oligodeoxynucleoside phosphoramidates or mixed phosphoramidate-phosphodiester oligomers. See 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 the degree of complementarity. It may be partial homology or complete homology (ie, identical). Partially complementary sequences are those that at least partially inhibit the same sequence from hybridizing to the target polynucleotide; This also means using the functional term "practically homologous". Inhibition of hybridization of a complete complementary sequence to a target sequence can be investigated using hybridization assays (Southern or Northern blots, solution hybridization) under low stringency conditions. Substantially homologous sequences or probes will prevent or compete for the binding (hybridization) of the fully homologous sequence or probe to the target sequence under low stringency conditions. This does not mean that low stringency conditions should allow nonspecific binding; Low stringency conditions require that the two sequences bind to each other in a specific (ie selective) interaction. The absence of nonspecific binding can be tested by some complementarity deficient (eg less than about 30% identity) second target sequences; If no non-specific binding is present, the probe will not hybridize to the second non-complementary target sequence.

The term “gene” refers to a polynucleotide sequence comprising a coding sequence necessary for the production of a polypeptide or precursor, and may also include expression control sequences. Polypeptides may be encoded by full length coding sequences or by some sequences of coding sequences. Genes may be derived in whole or in part from sources known to those of skill in the art, including plant, fungal, animal, bacterial genomes or episomes, eukaryotes, nucleus or plasmid DNA, cDNA, viral DNA or chemically synthesized DNA. The gene may constitute an uninterrupted coding sequence or may comprise one or more introns bound by suitable junctions. The gene may also contain one or more variations of the form of a non-translated region, which may affect certain characteristics of the coding region or polynucleotide or polypeptide, such as the biological activity or chemical structure of the expression product, the rate of expression or the mode of expression control. . Such modifications include, but are not limited to, mutations, insertions, deletions and substitution of one or more nucleotides. In this regard, such modified genes are referred to as "variants" of native genes (discussed below).

"Gene expression" refers to the process by which nucleotide sequences are expressed to a degree that can be detected through successful transcription and translation.

The term “gene expression property” refers to a group of genes that represent a particular cell or tissue type in an activated state (eg, neurons, coronary endothelial cells, or diseased tissue). In one embodiment, gene expression properties are generated from cells exposed to a compound of the invention. This property can be compared with gene expression properties generated from cells of the same type prior to treatment with the compounds of the invention. A series of gene expression properties can also be generated from cells treated with the compounds of the invention at different doses or time routes to assess the effect of the compounds. Gene expression properties are known as gene expression signals.

The term "differential expression" refers to qualitative as well as qualitative differences in the eclipse and tissue expression patterns of a gene. For example, differentially expressed genes will have expression activated or fully inactivated under normal versus disease conditions. Such qualitatively regulated genes may exhibit expression patterns in tissue or cell types that may or may not be detected under control or disease conditions. As used herein, 'differentially expressed polynucleotide' refers to a gene that is differentially expressed such that detection of differentially expressed polynucleotides in a sample correlates a polynucleotide sequence that correlates with the presence of the differentially expressed gene in the sample. Refer.

Similarly, differentially expressed proteins can have expression activated or fully inactivated under normal versus disease conditions. Such qualitatively regulated proteins may exhibit expression patterns within certain tissues or cell types that may be detected under control or disease conditions or not at all. As used herein, “differentially expressed protein” refers to an amino acid sequence in which a differentially expressed protein is identified in a sample so that the differentially expressed protein in the sample correlates with the presence of the differentially expressed protein in the sample.

A "cell type" as described herein refers to a cell obtained from a given source (such as a tissue or an organ), a cell of a predetermined differentiation or a cell associated with a given pathogenesis or gene construct.

The term “polypeptide” refers to an amino acid in the form of a polymer of any length, which may include translated, untranslated, chemically modified, biochemically modified and derived amino acids. Polypeptides may be naturally occurring, recombinant or synthetic or combinations thereof.

The term “polypeptide,” as used herein, also refers to proteins, polypeptides, and peptides of a predetermined size, structure, or function. For example, a polypeptide may comprise a sequence of amino acids linked to each other by peptide bonds. The polypeptide may alternatively comprise long chain amino acids linked by peptide bonds. Polypeptides can also include fragments of naturally occurring proteins or peptides. The polypeptide may be a single molecule or a multimolecular complex. Such polypeptides may also have modified peptide backbones.

The term “polypeptide” may include immunologically labeled proteins and fusion proteins, but may include, but is not limited to, fusion proteins with heterologous amino acid sequences, fusion proteins with heterologous and homologous leader sequences, and with or without N-terminal methionine residues. Fusion proteins.

The term “protein expression” refers to the successful transcription and translation of a polynucleotide sequence so that a detectable degree of amino acid sequence or protein is expressed.

The term “protein expression property” refers to a group of proteins that represent a particular cell or tissue type (eg, neurons, coronary endothelial cells, or diseased tissue). In one embodiment, protein expression properties are generated from cells exposed to the compounds of the invention. This property can be compared with protein expression properties generated from cells of the same type prior to treatment with the compounds of the present invention. A series of protein expression properties can also be generated from cells treated with the compounds of the invention at different doses or time routes to assess the effect of the compounds. Protein expression properties are known as protein expression signals.

As used herein, "biomolecule" includes polynucleotides and polypeptides. Also, as used herein, "biomolecule sequence" is a term that refers to all or part of a polynucleotide sequence. The biomolecule sequence can refer to all or part of a polypeptide sequence.

As used herein, “host cell” refers to a cell line cultured with a single cell component, which may or may be used as a receptor for recombinant vectors or other delivery of microorganisms, prokaryotic cells, eukaryotic cells or polynucleotides, It also includes the progeny of infected original cells. The progeny of a single cell are not necessarily identical to the original parent cell in terms of morphology or genome or overall DNA complementarity due to natural, accidental or intended mutation.

In the context of biomolecules such as perlecan, the term “functional equivalent” refers to a protein or polynucleotide molecule having functional or structural characteristics substantially similar to all or part of a natural perlecan protein or a natural perlecan-encoding polynucleotide. . Functional equivalents of natural perlecan protein may contain modifications depending on the need for such modifications for the exercise of a particular structure or specific function. The term "functional equivalent" is meant to encompass "fragments", "mutants", "derivatives", "alleles", "hybrids", "variants", "analogs" or "chemical derivatives" of natural perlecan.

In the case of immunoglobulins, the term “functional equivalent” refers to an immunoglobulin molecule that exhibits immunological binding properties substantially similar to parental immunoglobulins. As used herein, the term “immunological binding property” refers to a type of non-covalent interaction that occurs between an immunoglobulin molecule and an antigen that is immunoglobulin specific. Indeed, functional equivalents of monoclonal antibody immunoglobulins can inhibit, for example, binding of parental monoclonal antibodies to their antigens. Functional equivalents include F (ab) ₂ fragments, F (ab) molecules, Fv fragments, single-chain fragment variants (scFv) expressed on phage, single domain antibodies, chimeric antibodies, etc., as long as immunoglobulins characterize parent immunoglobulins. It may include.

As described herein, the term “isolated” refers to a polynucleotide, polypeptide, antibody or host cell in a different environment than when the polynucleotide, polypeptide, antibody or host cell is naturally produced. Isolated polynucleotides, polypeptides, antibodies, or host cells are substantially purified.

As used herein, the term "substantially purified" refers to a compound removed from the natural environment and at least about 60%, at least about 65%, at least about 70%, about 75% or more, about 80% or more, about 83% or more, about 85% or more, about 88% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about At least 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.9% or at least about 99.99%. For example, a composition containing A does not comprise "substantially B" if at least about 85% of the total A + B in the composition is A. Alternatively, A comprises at least about 90%, at least about 95%, or at least about 99% by weight of the total of A + B in the composition.

As used herein, "diagnosis" refers to the determination of a subject with a disease or disorder, to determine whether the sample is to be affected by the disease or disorder, the diagnosis of a sample affected by the disease or disorder (eg, pre-transition) Or metastatic cancer status, identification of cancer's responsiveness to the stage or treatment of the cancer) and therapy measurements (eg, monitoring the condition of the sample to provide information about the effectiveness or efficacy of the therapy).

The term "biological sample" includes various sample types obtained from an organism that can be used for diagnosis, monitoring or other assays. The term includes liquid samples of blood and other biological origin, solid tissue samples such as biopsy tissue, or tissue cultures or cells derived therefrom and progeny thereof. The term includes clinical samples and also includes cell culture, cell supernatants, cell lysates, serum, plasma, urine, amniotic fluid, biological fluids and tissue samples. The term also encompasses samples that are optionally manipulated after acquisition such as reagents, solubilization or concentration treatment of certain components.

The terms "individual", "sample", "host" and "patient" refer to a mammalian subject in need of diagnosis, treatment or therapy. The individual, sample, host or patient may optionally be a human. Other samples may include, but are not limited to, cows, horses, dogs, cats, guinea pigs, rabbits, mice, primates, and mice.

The terms “treatment”, “treating”, “treatment”, “treating” generally refer to obtaining the desired pharmacological and / or physiological effect. This effect may be prophylactic in that it can completely or partially prevent the disease or its manifestations and / or be therapeutic in terms of partially or completely stabilizing or treating the adverse effects attributable to the disease and / or disease. As used herein, “treatment” “treatment” includes the treatment of a disease in a mammal, particularly a human, such as (a) a disease or indication in a subject that is susceptible to the disease or indication but has not yet been diagnosed with the disease. Prevent the occurrence of; (b) inhibiting disease signs, ie inhibiting their occurrence; Or (c) alleviating disease signs, ie, inducing regression of the disease or signs.

The term "therapeutically effective amount" refers to an amount of a compound effective to prevent, alleviate, treat or delay the onset of a disease or condition.

A "prophylactically effective amount" means an amount of a compound for effective prevention of a disease or condition.

"Liposomes" are small vesicles composed of lipids, phospholipids and / or surfactants that are useful for throwing drugs into mammals. Compounds of the invention can be delivered by liposomes. The components of liposomes are often arranged in a two-layered form, similar to the lipid arrangement of biological membranes.

"Hybridization" broadly refers to the process by which a polynucleotide sequence is bound to a complementary sequence through base pairing. Hybridization conditions can be defined, for example, by the concentration of salt or formamide in the prehybridization and hybridization solution, or by the hybridization temperature, which is known in the art. Hybridization can occur under various stringency conditions. Hybridization refers to the binding of a protein-capturing agent to a target protein under certain conditions, such as normal physiological conditions.

As used herein, the term “activation” refers to altering signaling pathways or biological responses, including elevation above the base level, recovery from the inhibited state to the base state, and stimulation of the pathway above the base level.

The term "biological activity" refers to the biological properties 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 alterations at the molecular level. For example, antisense oligonucleotides can prevent translation of certain mRNAs, thereby inhibiting the biological activity of the protein encoded by the mRNA. Antibodies can also bind to specific proteins to inhibit the biological activity of the proteins.

The term “oligonucleotide” as described herein refers to a polynucleotide sequence comprising about 10 nucleotides (nt) to about 1000 nt. Oligonucleotides for use in the present invention are, for example, about 15 nt to about 150 nt, or about 150 nt to about 1000 nt in length. Oligonucleotides may be naturally occurring oligonucleotides or synthetic oligonucleotides. Oligonucleotides can be obtained by phosphoramidite (Beaucage and Carruthers, TERTRAHEDRON LETT. (1981) 22: 1859-1862) or by triester method (Matteucci et al. J. AM. CHEM. SOC. (1981) 103: 3185) or other chemical method known in the art.

The term “microarray” refers to the gene or protein type indicated on the microarray by oligonucleotide (polynucleotide sequence) or protein-binding agent, and the type of gene or protein indicated on the microarray is intended for the purpose of the microarray (eg , Monitoring the expression of human genes or proteins). Oligonucleotides or protein-binding agents on a given microarray may correspond to genes or proteins of the same type, class or group. The gene or protein may be the species from which they originate (eg, human, mouse, rat); Disease state (eg cancer); Function (eg protein kinases, tumor suppressors); The same type can be considered if they share some common features, such as the same biological processes (eg, apoptosis, signal induction, cell cycle regulation, proliferation, differentiation). For example, one microarray type may be a "cancer microarray" in which each microarray oligomeric nucleotide or protein binder corresponds to a gene or protein associated with cancer. An "epithelial microarray" can be a microarray of oligonucleotides or protein binders corresponding to unique epithelial cell genes or proteins. Similarly, a "cell cycle microarray" may be a microarray type in which an oligonucleotide or protein binder corresponds to a unique gene or protein associated with the cell cycle.

The term “detectable” refers to a polynucleotide expression pattern that can be detected through standard methods known to those skilled in the art, such as polymerase chain reaction (PCR), reverse transcriptase- (RT) PCR, fractional display, and northern analysis. Similarly, polypeptide expression patterns can be detected through standard techniques, including immunoassays such as western blots.

“Target gene” refers to a polynucleotide derived from a biological sample, designed to specifically hybridize an oligonucleotide probe. This is the presence or absence of the target polynucleotide to be detected or the amount of target polynucleotide to be quantified. The target polynucleotide is complementary to the polynucleotide sequence of the corresponding probe for the target. Target polynucleotide refers to the specific sequence of the large polynucleotide with which the probe is associated or the entire sequence (eg, gene or mRNA) of the expression level to be expressed.

A "target protein" is a polypeptide commonly derived from a biological sample to which a protein-capturing agent specifically hybridizes or binds. This is 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-capturing agent for the target. A target protein or amino acid refers to a specific substructure of a large protein with which the protein capture agent is associated or the entire structure (eg, gene or mRNA) of the expression level to be detected.

The term "complementary" refers to topological compatibility or suitability with the interaction surface of a probe molecule and its target. The target and its probes can be described complementarily, and the contact surface features are complementary to each other. Hybridization or base pairing is complementary between nucleotides or nucleic acids, 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, polynucleotides, polypeptides, small molecules and polypeptides or nonspecific binding or other interactions between small molecules and polynucleotides. "Background" may refer to nonspecific binding or other interactions in an assay including an immunoassay.

In the context of a microarray, the term “background” refers to a nonspecific binding between a component of an oligonucleotide microarray (eg, an oligonucleotide probe, a control probe, a microarray support) and a ringed target polynucleotide or between a protein binder of a protein microarray and a target protein. Or hybridization signals resulting from other interactions. The background signal may also be generated by intrinsic fluorescence of the microarray component itself. A single background signal can be calculated for the entire microarray, or different background signals can be generated for the target polynucleotide or target protein, respectively. Background can be calculated as the average hybridization signal intensity, or different background signals can be calculated for each target gene or target protein. Alternatively, the background is for probes that are not complementary to any sequence found in the sample (e.g., probes for polynucleotides or genes of opposite meaning that are not found in samples such as bacterial genes if the sample is a mammalian polynucleotide). It can be calculated as the average hybridized signal strength generated by hybridization. The background can also be calculated as the average signal intensity produced by the area of the microarray having no probes or protein binders at all.

“Small molecule” consists of carbon, hydrogen, oxygen and nitrogen and may contain other elements and has a molecular weight of 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 about 10,000, about 9,000 Less than about 8,000, less than about 7,000, less than about 6,000, less than about 5,000, less than about 4,000, less than about 3,000, less than about 2,000, less than about 1,000, less than about 900, less than about 800, less than about 700, less than about 600, It refers to a naturally occurring or partially synthesized compound or molecular complex that is less than about 500, less than about 400, less than about 300, less than about 200, less than about 100.

The term “fusion protein” refers to a protein consisting of two or more polypeptides that are not naturally bound in nature but are joined by each amino terminus and carboxy terminus through peptide bonds to form a single continuous polypeptide. It may be that two or more polypeptide elements are bound directly or indirectly through a peptide linker / spacer.

The term "normal physiological conditions" means typical conditions in living organisms or cells. Some organs or organisms provide extreme conditions, but the in vivo and intracellular environments are usually around pH 7 (ie pH 6.5 to pH 7.5), contain water as the main solvent and are present at temperatures between 0 ° C and 50 ° C. . The concentration of the various salts will vary depending on the organ, organism, cell or cell compartment used for reference.

The term “cluster” refers to a group of clones or biomolecule sequences that are related to each other by sequence homology. As one example, clusters are formed based on a certain degree of homology and / or overlap (eg stringency). "Clustering" can be performed according to sequence data. For example, biomolecular sequences that are considered to be related to specific molecules or biological activities in one tissue will be compared to other libraries or sequence databases of sequences. This type of study is useful for finding homologous and functionally related sequences in other tissues or samples, and the methods of the invention in that clustering is used in one or more databases to cluster the biomolecule sequences prior to practicing the methods of the invention. Can be simplified. Sequences exhibiting sufficient homology with representative sequences are considered part of the "cluster". Such "sufficient" homology will vary depending on the needs of those skilled in the art.

As used herein, the term "internal database" refers to a database within a local computer network. It contains, for example, biomolecule sequences associated with the project. It may also contain, but is not limited to, information related to the sequence including the library in which the desired sequence was found and detailed information about the gene associated with the sequence. The internal database can sometimes exist as a private database protected by a firewall within the enterprise network. However, the present invention contemplates internal databases available to the public. The internal database may include sequence data generated by the same company having that database and may include sequence data obtained from outside.

As used herein, the term "external database" refers to a database that exists outside of all internal databases. Typically, a corporate network other than an enterprise network with an internal database will have an external database. An external database can be used to provide some detailed information about the biomolecule sequences stored in the internal database. For example, the external database may be a GenBank and related database stored by the National Center for Biotechnology Information (NCB), which is part of the National Library of Medicine.

Detailed description of the invention

The present invention relates to compounds of formula (I), analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. The invention also encompasses compounds of formula (I), analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, individually or in combination It relates to a pharmaceutical composition. The invention also provides the use of the compounds of formula (I), analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, individually or in combination It is about a method. The invention also relates to methods of preparing compounds of formula (I), analogs thereof, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates.

Compound of formula (I)

The present invention relates to a composition comprising a compound of formula (I) and a compound useful for modulating the inflammatory response resulting from the accumulation of AGEs and glycated proteins and a method of modulating the inflammatory response using the compound. The present invention also relates to a composition comprising a compound effective for modulating smooth muscle cell proliferation and associated diseases or conditions and a method for controlling said disease or condition.

According to a first aspect of the present invention there is provided a compound of formula (I), a tautomeric form thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof. :

According to this point,

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R ¹ , R ² and R ³ are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cyclo Alkoxy groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, Aralkyl group, aralkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkyl Sulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group , Heteroarylthio group, aralkylthio group, aryl Oxyalkyl groups, carboxylic acids or derivatives thereof, sulfonic acids or derivatives thereof, R ¹ , R ² And two of R ³ in combination optionally form a 5- or 6-membered saturated cyclic ring having 1 to 3 heteroatoms, wherein said heteroatom is O, S or N. R ¹ , R ² And the cyclic ring formed by two of R ³ may be oxalanyl, 1,3-dioalanyl, or 1,4-dioxalanyl.

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, cycloal Kenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, aralkyl groups, aralkenyl groups, Aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, Aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, Aralkylsulfinyl groups, alkylthio groups, sub Thio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, aralkoxyalkyl group, fused heteroarylcycloalkyl group, fused heteroarylcycloalkenyl group, fused heteroarylheterocyclyl group, Carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof.

R ¹ , R ² , R ³ And R ⁴ is optionally 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 Carbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, Substituted by an aralkylthio group or, optionally, a heterocyclyl sulfonyl group substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally Substituted morpholinyl groups, thiomorpholinyl groups, It is a substituent on the blood and possess FER group, a heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group.

According to the above and other aspects, A, B, D and J are independently O, S, N,> CH or (-CH _2- ) _n ; '----' is any chemical bond; E is O, S or -NR; K is N, C or CH; Y and Z are independently O, —NR, (—CH ₂ —) _u or 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 an integer from 0 to 2; p, t, m, s, v are independently integers from 0 to 5; 'Ar' is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group.

R and R ⁵ are independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, Acyl group, aryl group, aralkyl group, heterocyclyl group, or heteroaryl group.

The groups indicated above are as follows:

'Halogen' is fluorine, chlorine, bromine or iodine.

An 'alkyl' group is a straight or branched (C ₁ -C ₁₀ ) alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl.

A 'cycloalkyl' group may be monocyclic or polycyclic as a (C ₃ -C ₇ ) cycloalkyl group. Examples of 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. Examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, isopropoxy.

'Cycloalkoxy' is a (C ₃ -C ₆ ) cycloalkoxy group. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.

'Alkenyl' is a (C ₂ -C ₆ ) alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl.

'Cycloalkenyl' is a (C ₃ -C ₇ ) cycloalkenyl group. Examples of 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. Examples of 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. Examples of alkenyloxy 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. Examples of 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. Examples of acyl groups include acetyl, propionyl.

'Acyloxy' is (C ₁ -C ₆ ) acyl-O—, wherein the acyl group is as defined above. Examples of acyloxy include acetyloxy, propionyloxy.

'Aryl' is a monocyclic or polycyclic ring system of about 5 to 14 carbon atoms. Examples include phenyl, naphthyl.

'Aryloxy' is an aryl-O- group wherein the aryl group is as defined above. Examples of aryloxy groups include phenoxy, naphthyloxy.

'Aroyl' is an aryl-CO- group wherein the aryl group is as defined above. Examples of aroyl groups include benzoyl, 1-naphthoyl.

'Aroyloxy' is an aroyl-O- group wherein the aroyl group is as defined above. Examples of aroyloxy groups include benzoyloxy, 1-naphthoyloxy.

"Aralkyl" is an aryl - (C ₁ -C ₁₀₎ alkyl group, wherein the aryl and (C ₁ -C ₁₀₎ alkyl group as defined above. Examples of aralkyl include benzyl, 2-phenylethyl.

'Aralkenyl' is an aryl- (C ₂ -C ₆ ) alkenyl group, where the aryl and (C ₂ -C ₆ ) alkenyl groups are as defined above.

'Aralkynyl' is an aryl- (C ₂ -C ₆ ) alkynyl group, where aryl and alkynyl are as defined above.

'Aralkoxy' is an aralkyl-O- group wherein the aralkyl group is as defined above. Examples of aralkoxy groups include benzoyloxy, 2-phenethyloxy.

'Heterocyclyl' is a nonaromatic saturated monocyclic or monocyclic ring system having from about 5 to about 10 carbon atoms and having at least one hetero atom selected from O, S or N. Examples of heterocyclyl groups are aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,, 3-dioxolanyl, 1,4-dioxolanyl It includes.

'Heterocyclinyl' is a non-aromatic saturated monocyclic or monocyclic hydrocarbon ring system having from about 5 to about 10 carbon atoms and having at least one hetero atom selected from O, S or N. Examples of heterocyclinyl groups include 1,2,3,4-tetrahydropyrimidine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine , 1,4,5,6-tetrahydropyrimidine, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 2-pyrazolinyl.

'Heteroaryl' is a non-aromatic saturated monocyclic or monocyclic ring system having from about 5 to about 10 carbon atoms and having at least one hetero atom selected from O, S or N. Examples of heteroaryl groups are pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidinyl, furyl, indolyl, isoindoleyl, 1,3-benzodioxol, 1 , 3-benzooxathiol, quinazolinyl, pyridyl, thiophenyl.

"Heteroaralkyl" is heteroaryl-, and (C ₁ -C ₁₀₎ alkyl group, where heteroaryl and (C ₁ -C ₁₀₎ alkyl group as defined above. Examples of heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl.

'Heteroaryloxy' is heteroaryl-O-, wherein the heteroaryl group is as defined above. Examples of heteroaryloxy groups include pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, phthalazinyloxy, indolyloxy, quinazolinyloxy, pyridyloxy, thienyloxy.

'Heteroaralkoxy' is heteroaralkyl-O-, wherein the heteroaralkyl group is as defined above. Examples of heteroaralkoxy groups include thienylmethyloxy, pyridylmethyloxy.

'Alkylcarbonyl' or 'acyl' is (C ₁ -C ₁₀ ) alkyl-CO-, wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Examples of 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. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl.

'Arylcarbonyl' or 'aroyl' is aryl-CO-, wherein the aryl group is as defined above. Examples of arylcarbonyl groups include phenylcarbonyl, naphthylcarbonyl.

'Aryloxycarbonyl' is aryl-O-CO-, wherein the aryl group is as defined above. Examples of aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl.

'Aralkoxycarbonyl' is aryl- (C ₁ -C ₆ ) alkoxy-CO-, wherein aryl and (C ₁ -C ₆ ) alkoxy are as defined above. Examples of aralkoxycarbonyl groups include benzyloxycarbonyl, 2-phenethyloxycarbonyl.

'Heteroarylcarbonyl' is heteroaryl-CO-, wherein heteroaryl is as defined above. Examples of heteroarylcarbonyl groups include pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl.

'Alkylsulfonyl' is (C ₁ -C ₁₀ ) alkyl-SO _2- , wherein the (C ₁ -C ₁₀ ) alkyl group is as defined above. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl.

'Arylsulfonyl' is aryl-SO _2- , where the aryl group is as defined above. Examples of arylsulfonyl groups include benzenesulfonyl.

'Heteroarylsulfonyl' is heteroaryl-SO _2- , wherein heteroaryl is as defined above. Examples of heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolylsulfonyl, pyrazolylsulfonyl, pyrrolylsulfonyl, pyridazinylsulfonyl, phthalazinylsulfonyl, quinazolinylsulfonyl, Pyridylsulfonyl, thienylsulfonyl.

'Alkylsulfinyl' is (C ₁ -C ₁₀ ) alkyl-SO-, wherein (C ₁ -C ₁₀ ) alkyl is as defined above. Examples of alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl.

'Arylsulfinyl' is aryl-SO, wherein the aryl group is as defined above. Examples of arylsulfinyl groups include phenylsulfinyl.

'Heteroarylsulfinyl' is heteroaryl-SO-, wherein heteroaryl is as defined above. Examples of heteroarylsulfinyl include pyrazinylsulfinyl, isothiazolylsulfinyl, oxazolylsulfinyl, pyrazolylsulfinyl, pyrrolylsulfinyl, pyridazinylsulfinyl, phthalazinylsulfinyl, quinazolinylsulfinyl, pyri Dilsulfinyl and thienylsulfinyl.

'Aralkylsulfinyl' is an aryl- (C ₁ -C ₁₀ ) alkyl-SO- group wherein the aryl and (C ₁ -C ₁₀ ) alkyl groups are as defined above. Examples of aralkylsulfinyl groups include benzylsulfinyl, 2-phenethylsulfinyl.

'Alkylthio' is (C ₁ -C ₁₀ ) alkyl-S-, wherein (C ₁ -C ₁₀ ) alkyl is as defined above. Examples of alkylthio include methylthio, ethylthio and propylthio.

'Arylthio' is aryl-S-, wherein aryl is as defined above. Examples of arylthio include phenylthio groups.

'Heteroarylthio' is heteroaryl-S-, wherein heteroaryl is as defined above. Examples of heteroarylthio include pyrazinylthio, isothiazolylthio, oxazolylthio, pyrazolylthio, pyrrolylthio, pyridazinylthio, phthalazinylthio, quinazolinylthio, pyridylthio and thienylthio Include.

'Aralkylthio' is an aryl- (C ₁ -C ₁₀ ) alkyl-S- group wherein the aryl and (C ₁ -C ₁₀ ) alkyl groups are as defined above. Examples of aralkylthio groups include benzylthio and 2-phenethylthio.

'Aryloxyalkyl' is aryl- (C ₁ -C ₁₀ ) alkyl wherein the aryl and (C ₁ -C ₁₀ ) alkyl groups are as defined above. Examples of aryloxyalkyl groups include phenoxymethyl, phenoxyethyl and phenoxypropyl.

'Aralkoxyalkyl' is aryl- (C ₁ -C ₁₀ ) alkyl-O- (C ₁ -C ₁₀ ) alkyl, wherein the (C ₁ -C ₁₀ ) alkyl and aryl groups are as defined above. Examples of aralkoxyalkyl groups include benzyloxymethyl, benzyloxyethyl and benzyloxypropyl.

'Fused heteroarylcycloalkyl' is fused heteroaryl and cyclo (C ₃ -C ₆ ) alkyl, wherein the heteroaryl and cyclo (C ₃ -C ₆ ) alkyl groups are as defined above. Examples of fused heteroarylcycloalkyl groups include 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolyl.

'Fused heteroarylcycloalkenyl' is fused heteroaryl and cyclo (C ₃ -C ₆ ) alkenyl, wherein the heteroaryl and cyclo (C ₃ -C ₆ ) alkenyl groups are as defined above. Examples of fused heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl.

'Fused heteroarylheterocyclyl' is a fused heteroaryl and heterocyclinyl, wherein the heteroaryl and heterocyclinyl groups are as defined above. Examples of fused heteroarylheterocyclylyl include 7,8-dihydro [1,7] naphthyridinyl, 1,2-dihydro [2,7] naphthyridinyl.

'Carboxylic acid or derivative thereof' may be an amide or ester. Examples of carboxylic acid groups include CONH ₂ , CONMe, CONMe ₂ , CONHEt, CONEt ₂ , CONHPh, COOCH ₃ , COOC ₂ H ₅ or COOC ₃ H ₇ .

'Sulfonic acid or derivative thereof' may be an amide or ester. Examples of sulfonic acid groups include SO ₂ NH ₂ , SO ₂ NHMe, SO ₂ NMe ₂ , SO ₂ NHCF ₃ , COOCH ₃ , COOC ₂ H ₅ , or COOC ₃ H ₇ It includes.

In this specification:

R ^a is hydrogen, hydroxy group, halogen, nitro group, 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, acyl group, aryl group, aralkyl group, heterocyclyl group, or 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, cyclo Alkenyl group, alkoxyalkyl group, alkenyloxy group, or 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, heteroaryl Oxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, or 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, aralkylthio group, aryloxyalkyl group, carboxylic acid or derivative thereof, or sulfonic acid or 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, cyclo Alkenyl group, alkoxyalkyl group, alkenyloxy group, or 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, heteroaryl Oxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, or 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, aralkylthio group, aryloxyalkyl group, carboxylic acid or derivative thereof, or sulfonic acid or 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, cyclo Alkenyl group, alkoxyalkyl group, alkenyloxy group, or 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, heteroaryl Oxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, or 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, aralkylthio group, aryloxyalkyl group, carboxylic acid or derivative thereof, or sulfonic acid or derivative thereof;

R ^4a 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, cyclo Alkenyl groups, alkoxyalkyl groups, alkenyloxy groups, or cycloalkenyloxy groups;

R ^4b is an acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, hetero Cylyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, or heteroaralkoxy group;

R ^4c is an alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl Groups, aralkylsulfinyl groups, alkylthio groups, arylthio groups, heteroarylthio groups, aralkylthio groups, fused heteroarylcycloalkyl groups, fused heteroarylcycloalkenyl groups, fused heteroarylheterocyclo Nil groups, carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof;

R ^5a is hydrogen, hydroxy group, halogen, nitro group or 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, acyl group, aryl group, aralkyl group, heterocyclyl group, or heteroaryl group;

R ^'a is hydrogen, halogen, a nitro group, an amino group, a 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;

R ^'b is 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 alkoxycarbonyl group, an aryloxycarbonyl group , Heteroaryl group, heterocyclyl group, or aralkyl group;

^R'c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group or heterocyclyl sulfonyl 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;

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 group, heterocyclyl group, or aralkyl group;

R ^"c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group or heterocyclyl sulfonyl 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, heterocyclyl group, or aralkyl group;

R ^9c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or optionally halogen, hydroxyl A heterocyclyl sulfonyl group substituted by a group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclyl group is optionally substituted morpholinyl group, thiomorpholinyl group or piper And a 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, aryl oxycarbonyl group, Heteroaryl group, heterocyclyl group, or aralkyl group;

R ^10c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a 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, heterocyclyl group, or aralkyl group;

R ^11c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a 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, heterocyclyl group, or aralkyl group;

R ^12c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a 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 =) It is a 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, heterocyclyl group, or aralkyl group;

R ^13c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a 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, heterocyclyl group, or aralkyl group;

R ^14c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a 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, heterocyclyl group, or aralkyl group;

R ^20c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a 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, heterocyclyl group, or aralkyl group;

R ^21c is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, or halogen, hydroxyl group, nitro Heterocyclyl sulfonyl groups optionally substituted by groups, amino groups, alkyloxy groups or combinations thereof, wherein the heterocyclyl groups are optionally substituted morpholinyl groups, thiomorpholinyl groups or pipers And a substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group, or aryl group.

G ^a is-(CH ₂ ) _s -wherein s is an integer from 0 to 5;

G ^b is-(CH ₂ ) _s -CH = CH- (CH ₂ ) _s- , where 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 , wherein u is an integer from 0 to 2;

E ^a is O; E ^b is S; E ^c is NR;

p ^a is 0-1; p ^b is 2-3; p ^c is 4-5;

V ^a is 0-1; V ^b is 2-3; V ^c is 4-5;

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 present invention, the general formula (II)

(II)

(II)

There are provided various compounds of formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. Unless defined otherwise, all symbols are as defined in connection with Formula (I) above.

According to another aspect of the present invention, the general formula (III)

(III)

(III)

There are provided various compounds of formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. Unless defined otherwise, all symbols are as defined in connection with Formula (I) above.

R ′ and R ″ independently of one another are 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 Carbonyl group, heteroaryl group, heterocyclyl group, or aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group , Aralkylthio group, or heterocyclyl sulfonyl group

In one aspect of the invention, R ¹ , R ² , R ³ and R ⁴ are as defined above; R ⁴ is an optionally substituted aryl group, in some cases a phenyl group optionally substituted by halogen, 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) 2 - and; s is an integer of 1-3; And R ′ and R ″ are as defined above and in some cases independently hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxyl group, alkoxy group, alkyl group, cyclo Alkyl group, alkoxy group, aryl group, or acyl group.

Many compounds having formula (III) are included in the present invention. Various structures of such compounds described herein are also included in the present invention as described below:

Wherein all symbols are as defined in relation to formula (I). Thus, by way of non-limiting example, the invention may include the following exemplary compounds:

Wherein all symbols are as defined in relation to formula (I).

As another example, the present invention may include various compounds having the formula (30):

Wherein all symbols are as defined in relation to formula (I).

According to various embodiments of the invention, R, R ⁵ , R ', R "and E of formula (30) are selected to produce various compounds of formulas (30-1) to (30-243) do:

In the above, all symbols are as defined above.

In one aspect of the 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, 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, alkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, aryl group or benzyl Oxy group and E is O, S or NH.

In another aspect of formula (30) of the present invention, R is hydrogen, an alkyl group, potassium or sodium; R ⁵ is hydrogen or an alkyl group; All other symbols are as defined above in connection with formula (I).

In another aspect 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:

The invention also encompasses various compounds of formula (III) having the formula (31)

Wherein all symbols are as defined above in connection with formula (I).

According to various aspects of the invention, R ¹ , R ² , R ⁴ , E, R ′, and R ″ in formula (31) are modified to produce various compounds of formulas (31-1) to (31-729) Is selected:

Wherein all symbols are as defined above.

In one aspect of the 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 Groups, cycloalkyl groups, alkoxy groups, cycloalkoxy groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups or cycloalkenyloxy groups; R ⁴ 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, Alkenyloxy groups, cycloalkenyloxy groups; Acyl group, acyloxy group, aryl group, aryloxy group, aroyl group or aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclyl Groups, heteroaryl groups, heteroaralkyl groups, heteroaryloxy groups or heteroaralkoxy groups; 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, aryloxycar A carbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group, and all other symbols are as defined above in connection with formula (I).

As another aspect of the above formula (31) of the present invention, R ¹ is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, or optionally substituted amino group, alkyl group, cycloalkyl group , An alkoxy 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 and R 'is a hydrogen, halogen or alkyl group; And R ″ is hydrogen, halogen, or an alkyl group; and all other symbols are as defined above in connection with formula (I).

In another aspect of the above 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 and R 'is a hydrogen, halogen or alkyl group; And R ″ is hydrogen, halogen, or an alkyl group; and E is O, S or NH.

In another aspect of the 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 and 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 invention also encompasses various compounds of formula (III) having the formula (32)

Wherein all symbols are as defined above in connection with formula (I).

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

In the formula, 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 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, or benzyloxy group; R ″ is 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, or benzyloxy group; all other symbols are as defined above in connection with formula (I).

In one embodiment of the invention, R ⁴ is an alkenyl, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, cycloalkenyloxy group, acyl group, acyloxy group, aryl group, aryloxy group, aroyl Groups, aroyloxy groups, aralkyl groups, aralkenyl groups, aralkynyl groups, or aralkoxy groups; R 'is 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, or benzyloxy group; R ″ is 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, or benzyloxy group; all other symbols are as defined above in connection with formula (I).

;

이며; 또 R' 및 R"는 상기 정의한 바와 같다. 이러한 화합물의 예는 다음과 같으며, 이하에 한정되지 않는다: In one embodiment of the invention, E is O or -NR; R ⁴ is optionally substituted with an alkyl group or an alkoxy group

;

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

The present invention also encompasses various compounds having the general formula (33)

Wherein R ⁴ is as defined above in connection with formula (I).

As 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, or cycloalkoxy group, Alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group, or cycloalkenyloxy group.

As another aspect of formula (33) of the present invention, R ⁴ is an acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl Group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, or heteroaralkoxy group.

As another aspect of formula (33) of the present invention, R ⁴ is an alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroaryl Sulfonyl group, alkylsulfinyl group, arylsulfinyl group, or aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group, fused heteroarylcycloalkyl group, fused hetero Arylcycloalkenyl groups, fused heteroarylheterocyclyl groups, carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof.

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

이다. 이러한 화합물 의 예는 다음을 포함하며, 이들에 한정되지 않는다:

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

The present invention also encompasses various compounds having the general formula (34)

Wherein all symbols are as defined above in connection with formula (I).

R ²⁰ And R ²¹ is 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, aralkyl Or a heterocyclyl sulfonyl group optionally substituted by a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclyl group is optionally substituted Polyyl group, thiomorpholinyl group, or piperazinyl , And 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.

According to various examples of the invention, R, R ⁵ , R ²⁰ , R ²¹ , R 'and R "of formula (34) are modified to produce various compounds of formulas (34-1) to (34-729) Is selected:

Wherein all symbols are as defined above.

In one aspect of formula (34) of the 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 =) groups; alkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, aryl groups or benzyloxy groups; and R ²⁰ and R ²¹ are independently hydrogen, halogen, nitro groups, amino groups , Mono- or di-substituted amino groups, hydroxy groups, alkoxy groups, carboxy groups, cyano groups, oxo (O =) groups, thio (S =) groups; alkyl groups, cycloalkyl groups, alkoxy groups, halo Alkoxy groups, cycloalkyl groups, aryl groups, benzyloxy groups, acyl groups, acyloxy groups, aroyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, heteroaryl groups, heterocyclyl groups or aralkyl groups.

In another aspect 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 hydrogen or halogen; R ²⁰ is hydrogen or halogen; and R ²¹ is hydrogen or halogen.

In another aspect of formula (34) of the invention, R is —H, CH ₃ or CH ₂ CH ₃ ; R ⁵ is -H or CH ₃ Is; R 'and R "are -H, -F or -Cl; R ²⁰ is -H, -F, -Cl or -Br; and R ²¹ is -H, CH ₃ or -F. Exemplary compounds Including, but not limited to:

The present invention also encompasses various compounds having the formula (35):

Wherein all symbols are as defined above in connection with formula (I).

R ²⁰ And R ²¹ is 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 Or a heterocyclyl sulfonyl group optionally substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally substituted morpholi Neyl group, thiomorpholinyl group, or piperazinyl group And the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; And R ¹ is as defined above.

According to some variations of the invention, R ¹ , R ²⁰ and R ²¹ of formula (35) are selected to produce various compounds of formula (35-1) to formula (34-27):

In the formula, all symbols are as defined above.

As one aspect of formula (35) of the present invention, R ¹ 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; R ²⁰ 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; R ²¹ represents a 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 to be

In another aspect of formula (35) of the invention, R ¹ is halogen, R ²⁰ is hydrogen or halogen, and R ²¹ is hydrogen or halogen.

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

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

The present invention also encompasses various compounds having the following formula (36):

Wherein all symbols are as defined above in connection with formula (I).

According to some variations of the invention, R, R ⁴ , R 'and R "of formula (36) are selected to produce compounds of formula (36-1) to (36-81) as follows:

Wherein all symbols are as defined above.

In one aspect of formula (36) of the 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, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, Aralkyl group, aralkenyl group, aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group or heteroaralkoxy group; And 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 =) groups: alkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, aryl groups or benzyloxy groups.

In another aspect of formula (36) of the 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 group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group , An alkoxy group, a heterocyclyl group, a heterocyclinyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; And R 'and R "are independently hydrogen or halogen.

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

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

The present invention also encompasses various compounds having the following general formula (37):

Wherein all symbols are as defined above in connection with 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 (37-27):

Wherein all symbols are as defined above.

In one aspect of formula (37) of the invention, R ¹ is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy Groups, cycloalkoxy groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups or cycloalkenyloxy groups; 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 group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, or heteroaralkoxy group ; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (37), 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 , An alkoxy group, a heterocyclyl group, a heterocyclinyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (37) of the invention, R ¹ is a hydrogen, halogen or alkoxy 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 , An alkoxy group, a heterocyclyl group, a heterocyclinyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; All other symbols are as defined above in connection with formula (I).

이고, 이때 R²² 및 R²³ 은 독립적으로 수소, 할로겐, 니트로 기, 아미노 기, 일- 또는 이-치환된 아미노 기, 히드록시 기, 알콕시 기, 카르복시 기, 시아노 기, 옥소(O=) 기, 티오(S=) 기; 알킬 기, 시클로알킬 기, 알콕시 기, 할로알콕시 기, 시클로알킬 기, 아릴 기, 벤질옥시 기, 아실 기, 아실옥시 기, 아로일 기, 알콕시카르보닐 기, 아릴옥시카르보닐 기, 헤테로아릴 기, 헤테로시클릴 기, 아르알킬 기, 알킬술포닐 기, 알킬술피닐 기, 아릴술포닐 기, 아릴술피닐 기, 알킬티오 기, 아릴티오 기, 헤테로아릴티오 기, 아르알킬티오 기이거나, 또는 경우에 따라 할로겐, 히드록실 기, 니트로 기, 아미노 기, 알킬옥시 기 또는 이들의 조합에 의해 치환된 헤테로시클릴 술포닐 기 이며, 상기 헤테로시클릴 기는 경우에 따라 치환된 모르폴리닐 기, 티오모르폴리닐 기, 또는 피페르지닐 기이고, 헤테로시클릴 기 상의 치환기는 할로겐, 니트로기, 아미노 기, 알킬 기, 알콕시 기 또는 아릴 기이고; 또 기타 모든 기호는 화학식(I)과 관련하여 상기 정의한 바와 같다. In another aspect of formula (37) of the invention, R ¹ is a hydrogen, halogen or alkoxy group; E is O or -NR; R ⁴ is

Where R ²² And R ²³ is 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 Optionally a heterocyclyl sulfonyl group substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally substituted morpholinyl group, thio Morpholinyl group, or piperazinyl group, 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 in connection with formula (I).

In 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 heterocyclyl group; R ²² is hydrogen or alkoxy group; R ²³ is hydrogen or alkoxy group; And all other symbols are as defined above in connection with formula (I).

이며; 이때 R²² 는 -H 또는 OMe 이며; 또 R²³ 은 -F 또는 OMe 이다. In another aspect of formula (37) of the present invention, R ¹ is -H, -F or MeO; E is O or NMe; R ⁴ is

Is; Then R ²² is -H or OMe; And R ²³ is -F or OMe.

Exemplary compounds include, but are not limited to:

According to another embodiment of the present invention, the formula (IV)

를 갖는 다양한 화학식(I)의 화합물, 그의 토오토머 형태, 그의 입체이성질체, 그의 다형체, 그의 약제학적으로 허용가능한 염 및 그의 약제학적으로 허용가능한 용매화물이 제공된다. 다르게 언급하지 않는 한, 모든 기호는 화학식(I)과 관련하여 상기 정의된 바와 같다.

Various compounds of formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates are provided. Unless stated otherwise, all symbols are as defined above in connection with formula (I).

Many compounds having formula (IV) can be included in the present invention. Examples of such compounds include, but are not limited to:

Wherein all symbols are as defined in relation to formula (I).

Accordingly, the present invention includes various compounds of the compound (V) having the formula (87):

Wherein all symbols are as defined above in connection with formula (I). It should be noted that various structures are described herein and that other structures are included in the present invention. Accordingly, compounds of the following formula are also included in the present invention:

Wherein all symbols are as defined above in connection with formula (I).

According to the present invention, R, R ¹ , R ⁴ , G and Z of the formulas (88), (89), (90), (91) and (92) are represented by the following formulas (88-1), (89-1) ), (90-1), (91-1) and (92-1) to formulas (88-729), (89-729), (90-729), (91-729) and (92-729) It is chosen to produce a compound of:

In the formula, all symbols are as defined above.

In one aspect of the formulas (88), (89), (90), (91), and (92) of the present invention, R is -H or CH _3, and all other symbols are described above in relation to formula (I). As defined.

As another aspect of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH ₃ , R ⁵ is -H and all other symbols are represented by the formula ( As defined above in connection with I).

As another aspect of the 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 represented by the formula ( As defined above in connection with I).

As another aspect of formulas (88), (89), (90), (91), and (92) of the present invention, R is -H or CH ₃ , and G is-(CH ₂ ) _s- , wherein s Is 0 to 5; And all other symbols are as defined above in connection with formula (I).

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

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

In another aspect of formulas (88), (89), (90), (91), and (92) of the present invention, R is -H or CH ₃ ; G is-(CH ₂ ) _s -wherein 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 another aspect 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 -wherein 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 another aspect of formulas (88), (89), (90), (91), and (92) of the present invention, R is -H or CH ₃ ; Z is O; And all other symbols are as defined above in connection with formula (I).

In another aspect 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 -wherein s is an integer from 0 to 5; Z is -N; And all other symbols are as defined above in connection with formula (I).

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

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

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

In another aspect 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 -wherein s is an integer from 0 to 5; Z is O; And all other symbols are as defined above in connection with formula (I).

In another aspect 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 -wherein s is an integer from 0 to 5; Z is O; And all other symbols are as defined above in connection with formula (I).

In another aspect of formulas (88), (89), (90), (91), and (92) 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).

The present invention also encompasses various compounds of formula (IV) having the formula (93)

Wherein all symbols are as defined in relation to formula (I).

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

In the formula, 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 with respect to formula (I).

In another aspect of formula (93) of the invention, R ⁴ is a substituted or unsubstituted aryl group; All other symbols are as defined with respect to formula (I).

In another aspect of formula (93) of the present invention, R ⁵ is -H or CH ₃ ego; All other symbols are as defined with respect to formula (I).

In another aspect of formula (93) of the present invention, G is-(CH ₂ ) _s -wherein s is an integer from 0 to 5; All other symbols are as defined with respect to formula (I).

In another aspect of formula (93) of the 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, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl Groups, aralkenyl groups, aralkynyl groups, aralkoxy groups, heterocyclyl groups, heterocyclinyl groups, heteroaryl groups, heteroaralkyl groups, heteroaryloxy groups, or heteroaralkoxy groups; R ⁵ is hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, or alkoxyalkyl group; All other symbols are as defined with respect to formula (I).

In 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 is a cycloalkenyl group, cycloalkenyloxy, acyl group or acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkenyl group, aralkynyl group, An alkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, or heteroaralkoxy group; R ⁵ is hydrogen, hydroxy group, halogen, alkyl group, or alkoxy group; All other symbols are as defined with respect to formula (I).

In 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 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 invention also encompasses various compounds of formula (IV)

Wherein R ⁹ and R ¹⁰ independently of one another are hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O = ) Groups, thio (S =) groups, alkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, aryl groups, benzyloxy groups, acyl groups, acyloxy groups, aroyl groups, alkoxycarbonyl groups , Aryloxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroaryl Thio group, aralkylthio group, or optionally a heterocyclyl sulfonyl group substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein said heterocyclyl group Morpholinyl groups, thiomorpholinyl groups, substituted according to The blood and possess FER group, 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; And all other symbols are as defined above in connection with formula (I).

According to various aspects of the present invention, R, R ⁵ , G, Z, R ⁹ and R ¹⁰ in formulas (94), (95), (96) and (97) are represented by the following formulas (94-1), (95) -1), (96-1) and (97-1) to (94-729), (95-729), (96-729) and (97-729) to produce compounds of:

In the formula, all symbols are as defined above.

As another aspect of formulas (94), (95), (96) and (97) 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 ⁹ and R ¹⁰ independently of one another are hydrogen, halogen, nitro group, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, Or a thio (S =) group; G is-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -or-(CH ₂ ) _4- ; And all other symbols are as defined in relation to formula (I).

As another aspect of formulas (94), (95), (96) and (97) b 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 ⁹ and R ¹⁰ are each independently of the 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; G is-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -or-(CH ₂ ) _4- ; And all other symbols are as defined in relation to formula (I).

As another aspect of formulas (94), (95), (96) and (97) 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 ⁹ and R ¹⁰ are independently of each other an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group Is a heterocyclyl sulfonyl group optionally substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally substituted morpholinyl group, thio Morpholinyl group, or piperazinyl group, the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; G is-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -or-(CH ₂ ) _4- ; And all other symbols are as defined in relation to formula (I).

이고; R¹⁰ 은 수소 또는 알콕시 기이며; 또 G는 -(CH₂)₂-, -(CH₂)₃- 또는 -(CH₂)₄- 이다. In another aspect 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

ego; R ¹⁰ is hydrogen or alkoxy group; And G is-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -or-(CH ₂ ) _4- .

이고; R¹⁰ 은 -H, -OMe 또는 -OEt 이며; 또 G는 -(CH₂)₂-, -(CH₂)₃- 또는 -(CH₂)₄- 이다. In another aspect of formulas (94), (95), (96), and (97) of the present invention, R is -H or Me; R ⁵ is -H, -OMe or

ego; R ¹⁰ is -H, -OMe or -OEt; And G is-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -or-(CH ₂ ) _4- .

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

Wherein all symbols are as defined above in connection with formula (I).

According to various aspects of the present invention, R, R ¹ , R ⁵ , G and Z in Formulas (98), (99), (100) and (101) are represented by the following Formulas (98-1), (99-1) , To generate compounds of (100-1) and (101-1) to (98-243), (99-243), (100-243) and (101-243):

In the formula, all symbols are as defined above.

As one aspect of formulas (98), (99), (100) and (101) 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 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, cycloal A kenyl group, an alkoxyalkyl group, an alkenyloxy group or a cycloalkenyloxy group; R ⁵ 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, cyclo Alkenyl group, alkoxyalkyl group, alkenyloxy group or cycloalkenyloxy group; All other symbols are as defined above in connection with formula (I).

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

As another aspect of formulas (98), (99), (100) and (101) of the present invention, G is-(CH ₂ ) _s -CH = CH (CH ₂ ) _s -wherein s is 0 to 5 An integer; And all other symbols are as defined above in connection with formula (I).

As another aspect of formulas (98), (99), (100) and (101) of the present invention, G is-(CH ₂ ) _s -C = C- (CH ₂ ) _s -wherein s is 0 to 5 Is an integer of; And all other symbols are as defined above in connection with formula (I).

In another aspect of Formulas (98), (99), (100) and (101) of the present invention, Z is O; And all other symbols are as defined above in connection with formula (I).

In another aspect of Formulas (98), (99), (100) and (101) of the present invention, Z is NR; And all other symbols are as defined above in connection with formula (I).

As another aspect of the formulas (98), (99), (100) and (101) of the present invention, Z is-(CH _2- ) _u -or S (= 0) _u , wherein u is 0 to 2 An integer; And all other symbols are as defined above in connection with formula (I).

In another aspect of Formulas (98), (99), (100) and (101) of the present invention, E is O; And all other symbols are as defined above in connection with formula (I).

In another aspect of Formulas (98), (99), (100) and (101) of the present invention, E is S; And all other symbols are as defined above in connection with formula (I).

Examples of compounds having formula (IV) are as follows, but are not limited to:

According to another aspect of the present invention, the general formula (V)

를 갖는 화학식(I)의 다양한 화합물, 그의 토오토머 형태, 그의 입체이성질체, 그의 다형체, 그의 약제학적으로 허용가능한 염, 및 그의 약제학적으로 허용가능한 용매화물이 제공된다. 다르게 정의하지 않는 한, 모든 기호는 화학식(I)과 관련하여 상기 정의한 바와 같다.

There are provided various compounds of formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. Unless defined otherwise, all symbols are as defined above in connection with formula (I).

Examples of compounds of formula (V) included in the present invention include, but are not limited to:

Wherein all symbols are as defined above in connection with formula (I).

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

In the food,

R ¹¹ , R ¹² , R ¹³ And R ¹⁴ is independently hydrogen, halogen, nitro, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo (O =) group, thio (S = ) Groups, alkyl groups, cycloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, aryl groups, benzyloxy groups, acyl groups, acyloxy groups, aroyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, Heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkylthio group Or a heterocyclyl sulfonyl group optionally substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally substituted morpholinyl Groups, thiomorpholinyl groups, or piperazinyl groups And, the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group or aryl group; All other symbols are as defined above in connection with formula (I).

In one aspect of formula (141) of the invention, R is hydrogen, hydroxy group, halogen, nitro group, or optionally substituted amino group; All other symbols are as defined above in connection with formula (I).

In one aspect of formula (141) of the present invention, R is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹ is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy Groups, cycloalkoxy groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups, or cycloalkenyloxy groups; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ² is hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy Groups, cycloalkoxy groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups, or cycloalkenyloxy groups; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹¹ is hydrogen, halogen, nitro, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( O =) group or thio (S =) group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹¹ is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkyl Or a heterocyclyl sulfonyl group optionally substituted by a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or a combination thereof, and these heterocyclyl groups are optionally substituted A polyyl group, a thiomorpholinyl group or a piperazinyl group, and the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group, or aryl group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹² is hydrogen, halogen, nitro, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( O =) group or thio (S =) group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹² is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkyl Or a heterocyclyl sulfonyl group optionally substituted by a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclyl group is optionally substituted A polyyl group, a thiomorpholinyl group or a piperazinyl group, and the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group, or aryl group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹³ is hydrogen, halogen, nitro, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( O =) group or thio (S =) group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ¹³ is an alkyl sulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an aryl sulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkyl Or a heterocyclyl sulfonyl group optionally substituted by a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or a combination thereof, wherein the heterocyclyl group is optionally substituted A polyyl group, a thiomorpholinyl group or a piperazinyl group, and the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group, or aryl group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹⁴ is hydrogen, halogen, nitro, amino group, mono- or di-substituted amino group, hydroxy group, alkoxy group, carboxy group, cyano group, oxo ( O =) group or thio (S =) group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹⁴ is an alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, aralkyl Or a heterocyclyl sulfonyl group optionally substituted by a thio group or optionally a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or a combination thereof, wherein the heterocyclyl group is optionally A substituted morpholinyl group, thiomorpholinyl group or piperazinyl group, and the substituent on the heterocyclyl group is a halogen, nitro group, amino group, alkyl group, alkoxy group, or aryl group; All other symbols are as defined above in connection with formula (I).

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

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

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

In 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 as defined above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ² is hydrogen or an alkyl group; All other symbols are as defined above in connection with formula (I).

In another aspect 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 above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ¹¹ is hydrogen, halogen, alkoxy group, or alkylthio group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ¹¹ is -H, -Cl, -OCH ₃ or -SCH ₃ And all other symbols are as defined above in connection with formula (I).

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

In another aspect of formula (141) of the present invention, R ¹² is H, Cl, -OCH ₃ or -SCH ₃ And all other symbols are as defined above in connection with formula (I).

In another aspect of formula (141) of the invention, R ¹³ is a hydrogen, halogen or alkyl group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ¹³ is -H, -F or CH ₃ ; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ¹⁴ is hydrogen, halogen or an alkyl group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (141) of the present invention, R ¹⁴ is -H, -F or -CH ₃ ; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹ And R ² Is 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, cycloal A kenyl group, an alkoxyalkyl group, an alkenyloxy group or a cycloalkenyloxy group; R ¹¹ , R ¹² , 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 =) groups, thio (S =) groups, alkyl groups, cycloalkyl groups, alkoxy groups; All other symbols are as defined above in connection with formula (I).

As 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 is independently hydrogen, halogen, hydroxy group, alkoxy group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (141) of the present invention, R ¹ And R ² Is independently -H or -OCH ₃ ; R ¹¹ is -Cl, -OCH ₃ or -SCH _3, and; 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; All other symbols are as defined above in connection with formula (I).

The invention also encompasses various compounds of formula (V) having the formula:

Wherein all symbols are as defined above in connection with formula (I).

According to various aspects of the present invention, R, R ¹ and R ² of formula (142) are selected to produce various compounds of formula (142-1) to (142-27):

In the formula, 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; And R ¹ and R ² are independently hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkenyl group, cycloalkenyl Group, alkoxyalkyl group, alkenyloxy group, or cycloalkenyloxy group.

이다. In another aspect of formula (142) of the present invention, R ¹ and R ² are independently halogen or alkyl groups; And R is hydrogen, an alkyl group,

to be.

이다. In 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 ,

to be.

The invention also encompasses various compounds of formula (V) having the formula:

Wherein all symbols are as defined above in connection with formula (I).

In one aspect of formula (143) of the invention, 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, alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group or 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, alkoxycarbonyl group, aryloxycar A carbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group; All other symbols are as defined above in connection with formula (I).

As another aspect of formula (143) of the present invention, R ¹ and R ² are independently acyl group, acyloxy group, aryl group, aryloxy group, aroyl group, aroyloxy group, aralkyl group, aralkoxy group ; Heterocyclyl, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, or heteroarylcarbonyl 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, alkoxycarbonyl group, aryloxycar A carbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group; All other symbols are as defined above in connection with formula (I).

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

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

The invention also encompasses various compounds of formula (V) having the formula:

Wherein all symbols are as defined above in connection with formula (I).

According to various aspects of the present invention, R, R ¹ , R ² , v and p of Formula (144) are selected to produce various compounds of Formulas (144-1) to (144-243):

In the formula, all symbols are as defined above.

In one aspect of formula (144) of the 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, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, Alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group or cycloalkenyloxy group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (144) of the invention, R ¹ and R ² are independently hydrogen, an alkyl group, or an alkoxy group; All other symbols are as defined above in connection with formula (I).

In another aspect of formula (144) of the invention, R ¹ and R ² are independently -OCH ₃ ; All other symbols are as defined above in connection with formula (I).

The present invention may include various compounds of formula (V) having the formula:

Wherein all symbols are as defined above in connection with formula (I).

According to various aspects of the present invention, R, R ¹ , R ² , R ¹¹ and R ¹² in formula (145) are selected to produce various compounds of formula (145-1) to (145-243):

In the formula, all symbols are as defined above.

In one aspect of formula (145) of the 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, or optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy group , Alkenyl group, cycloalkenyl group, alkoxyalkyl group, alkenyloxy group or cycloalkenyloxy group; R ¹¹ and R ¹² 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 =) groups, alkyl groups, cycloalkyl groups, alkoxy groups.

In another aspect of formula (145) of the invention, R is hydrogen or an alkyl group; R ¹ and R ² are independently hydrogen, hydroxy groups, halogens, alkoxy groups; And R ¹¹ and R ¹² are independently hydrogen, halogen, hydroxy group, or alkoxy group.

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

The invention also encompasses various compounds of formula (V) having the formula:

Wherein R is as defined above in connection with formula (I).

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

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

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

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

In another aspect of formula (146) of the present invention, R is -H or C ₂ H ₅ .

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

It is to be understood that the compounds described above, including those of the various formulas described above, may be provided as pharmaceutically acceptable salts. Pharmaceutically acceptable salts that form part of the invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; N, N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydramine, iso Propylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N, N'-diphenylethylenediamine, N, N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkyl Salts of organic bases such as amines, trialkylamines, thiamines, aminopyrimidines, aminopyridine, purines or spermidines; Salts of chiral bases such as alkylphenylamine, glycinol, or phenylglycinol; Salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; Non-natural amino acids such as D-isomers or substituted amino acids; Guanidine, substituted guanidine, wherein the substituent is selected from nitro, amino, alkyl, alkenyl or alkynyl; Ammonium or substituted ammonium salts and aluminum salts. Salts include sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartarate, maleates, citrate, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates Suitable acid addition salts which are, benzenesulfonate, ascorbate, glycerophosphate, ketoglutarate. Pharmaceutically acceptable solvates may be hydrates or may include other solvents for crystallization such as alcohols.

Process of Preparation of the Compound

 The compound of this invention can be manufactured according to the following process. However, it should be understood that other methods with other process conditions may be used to prepare the compounds of the present invention.

Process 1

According to a first aspect of the present invention there is provided a process for preparing a compound of formula (II):

In the food,

R ¹ is attached to B;

R ² is attached to J;

R ³ is -H;

A, B, D and J are independently -CH;

R ¹ and R ² are independently alkoxy groups or aralkoxy groups;

R ⁴ is a phenyl group which may optionally be substituted by an alkoxy group or an alkoxy group optionally in the third position and / or the fourth position;

X and E are each O;

G is-(CH ₂ ) _s -,-(CH ₂ ) _s -CH = CH- (CH ₂ ) _s -or (CH ₂ ) _s -C = C- (CH ₂ ) _s- , where s is 0 An integer from to 5; F is O, S or -NR;

Y and Z are independently O, —NR, — (CH ₂ ) _n or S (═O) _n , where n is an integer from 0 to 2;

Y ¹ and Y ² are independently O or S;

R and R ⁵ are independently hydrogen, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, acyl group, aryl Groups, aralkyl groups, heterocyclyl groups or heteroaryl groups; In addition

'Ar' is optionally substituted phenyl group or optionally substituted naphthyl group.

The process first follows the formula (IIa)

(Wherein 'Rut' is Lutinose; R ¹ is attached to B; R ² is attached to J; R ³ is H; A, B, D and J are independently -CH and R ¹ and R ² are independently an alkoxy group or an alkoxy group; R ⁴ is a phenyl group optionally optionally substituted by an alkoxy group or an alkoxy group in the third position and / or the fourth position; X, Y and E are O; and '---' is any chemical bond, alkylating the routine hydrate, wherein R ¹ is attached to B; R ² is attached to J; R ³ is H; A, B, D and J are independently -CH; R ¹ and R ² are independently alkoxy groups or aryloxy groups; R ⁴ is a phenyl group which may optionally be substituted by an alkoxy group or an alkoxy group in the third position and / or the fourth position; X, Y and E are O; And all other symbols include producing compounds of formula IIa as defined above.

The alkylation is carried out using alkyl halide alkylating agents or aralkylating agents. Examples of suitable alkylating agents include MeI, EtI, EtBr, n-PrI, n-PrBr, i-PrBr, i-PrI, n-BuCl, or s-BuBr; Dialkyl sulfates such as dimethylsulfate or diethylsulfate; Or aralkyl halides such as benzyl halides. The reaction is in the presence of alkalis, such as sodium hydride (NaH), potassium hydride (KH), potassium t-butoxide (t-BuOK), potassium acetate (KOAc), sodium acetate (NaOAc), n-butyl lithium (n- BuLi), sec-butyl lithium (s-BuLi), t-butyllithium (t-BuLi), lithium diisopropyl amide (LDA), sodium carbonate (Na ₂ CO ₃ ), sodium hydroxide (NaOH), sodium bicarbonate (NaHCO ₃ ), potassium bicarbonate (KHCO ₃ ), sodium hydroxide (NaOH), potassium hydroxide (KOH), or mixtures thereof. Solvents used are, for example, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethic acid (HMPA), 1,4-dioxane, acetone, dimethyl ether, diethyl ether, tetrahydrofuran (THF), or Mixtures thereof.

According to one aspect of the invention, the reaction temperature is about -30 ° C to about 250 ° C, such as about 30 ° C to about 100 ° C. The reaction duration is from about 0.5 hours to about 100 hours, such as from about 20 hours to about 80 hours. This reaction can be carried out in an inert atmosphere, for example under nitrogen (N ₂ ), argon (Ar) or helium (He).

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

In which R ¹ is attached to B; R ² is attached to J; R ³ is H; A, B, D and J are independently -CH; R ¹ and R ² are independently alkoxy groups or aralkoxy groups; R ⁴ is a phenyl group which may optionally be substituted by an alkoxy group or an alkoxy group in the third position and / or the fourth position; X, Y and E are O; And all other symbols as defined above.

The hydrolysis reaction can be carried out using an inorganic acid such as hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ) or a mixture of these and water. The reaction temperature is about -30 ° C to about 250 ° C, such as about 50 ° C to about 150 ° C. The reaction duration is 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 a compound of formula (IIc) to produce a compound of formula (IId):

In the food,

'Hal' is halogen; 'Ar', G, Z and R ⁵ are as defined above; '---' is any chemical bond.

In the food,

R ¹ is attached to B; R ² is attached to J; R ³ is H; A, B, D and J are independently -CH; R ¹ and R ² are independently alkoxy groups or aralkoxy groups; R ⁴ is a phenyl group which may optionally be substituted by an alkoxy group or an alkoxy group in the third position and / or the fourth position; And all other symbols as defined above.

The reaction is carried out with a base such as NaH, KH, KOtBu, KOAc, NaOAc, NaOEt, KOEt, n-BuLi, s-BuLi, t-BuLi, LDA, Na ₂ CO, K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH Or in the presence of KOH. This reaction is carried out in the presence of a solvent such as DMF, DMSO, HMPA, 1,4-dioxane, acetone, dimethyl ether, multiethyl ether, THF or mixtures thereof. The reaction temperature is about -30 ° C to about 150 ° C, such as about 30 ° C to about 100 ° C. The reaction duration is from about 1 hour to about 50 hours, such as from about 2 hours to about 25 hours. This reaction is carried out under an inert atmosphere such as N ₂ , Ar or He.

Finally, the compound of formula (IId) is condensed together with the compound of formula (IIe) to form a compound of formula (II):

In the food,

F, Y ¹ , Y ² are as defined above.

In the formula, all symbols are as defined above.

The condensation reaction can be carried out using a base such as Et ₃ N, diethylamine, diisopropylethylamine, diisopropyl amine, DBU, piperidine or mixtures thereof. This reaction can be carried out in the presence of an acid, such as in the presence of benzoic acid, formic acid, acetic acid or mixtures 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 mixtures thereof. This reaction is maintained at a temperature of about 30 ° C to about 300 ° C, such as about 50 ° C to about 200 ° C. The reaction duration is about 10 hours to about 150 hours, such as about 20 hours to about 80 hours. This reaction can be carried out under an inert atmosphere of N ₂ , Ar or He.

Process 2

According to another aspect of the present invention, a process for preparing a compound of formula (II) is provided. Except X and E are O, all symbols are as defined above.

First, formula (IIf)

Wherein X and E are O; and the other symbols are as defined above, acylating the compound gives the compound of formula (IIg):

The acylation can be carried out using an acylating agent such as acetic anhydride. This reaction can optionally be carried out in the presence of a base such as for example Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, or mixtures thereof. This reaction can be carried out 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 is from about 10 minutes to about 5 hours, such as from about 20 minutes to about 2 hours.

Compounds of formula (IIg) are rearranged to yield compounds of formula (IIh):

Wherein X and E are O; All other symbols are as defined above. This reaction can be carried out in the presence of a solvent such as DCM, CHCl ₃ , 1,2-dichloroethane, carbon tetrachloride, carbon disulfide, nitrobenzene, 1,2-dichlorobenzene, or mixtures thereof. This reaction can be carried out in the presence of Lewis acid such as, for example, aluminum chloride (AlCl ₃ ), zinc chloride (ZnCl ₂ ), or tin chloride (SnCl ₄ ) or in the presence of UV light. And maintained at about 300 ° C, such as about 80 ° C to about 200 ° C. The duration of this reaction is 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.

Compounds of formula (IIh) are condensed to yield compounds of formula (IIi):

In the food,

X and E are O; All other symbols are as defined above. This reaction is carried out in the presence of a base, for example Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH or mixtures thereof. This reaction temperature is maintained at about −30 ° C. to about 50 ° C., such as about 0 ° C. to about 20 ° C. The duration of this reaction is from about 2 hours to about 50 hours, such as from about 5 hours to about 20 hours.

Compounds of formula (IIi) are subjected to cyclization to form compounds of formula (IIb):

In the formula, all symbols are as defined above. This reaction is carried out in the presence of a base, for example Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH or mixtures thereof. This reaction temperature is maintained at about -30 ° C to about 50 ° C, such as about -5 ° C to about 30 ° C. The duration of this reaction is from about 0.5 hours to about 10 hours, such as from about 0.2 hours to about 5 hours.

Compounds of formula (IIb) react with compounds of formula (IIc) to form compounds of formula (IId)

In which 'Hal' is halogen; And all other symbols as defined above.

Wherein all symbols are as defined above.

The compound of formula (IId) is reacted with a compound of formula (IIe) to form a compound of formula (II):

Wherein F is O, S or -NR; Y ¹ and Y ² are independently O or S.

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

The conversion of the compound of formula (IIb) to the compound of formula (II) is carried out as in step 1.

Process 3

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

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

First, a compound of formula IIj is converted to a compound of formula IIk:

Wherein all symbols are as defined above.

Wherein all symbols are as defined above.

The reaction is carried out in the presence of a base, for example Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH or mixtures thereof. This reaction can also be carried out in the presence of a solvent such as, for example, benzene, toluene, xylene, methanol, ethanol, isopropanol, butanol, DMF, DMSO, 1,4-dioxane, or mixtures thereof. This reaction temperature is maintained at about -30 ° C to about 150 ° C, such as about 20 ° C to about 80 ° C. The duration of this reaction is from about 0.5 hours to about 20 hours, such as from about 2 hours to about 10 hours.

Compounds of formula (IIk) react with compounds of formula (IIm) to form compounds of formula (IIn)

In which 'Hal' is halogen and R ⁴ is as defined above.

Wherein all symbols are as defined above.

The reaction can be carried out in the presence of a brominating agent such as, for example, bromine, bromine water, N-bromosuccinamide, copper bromide, or mixtures thereof. This solvent is acetic acid, propionic acid, butanoic acid, pentanic acid, hexanoic acid, dichloromethane (DCM), chloroform (CHCl ₃ ), 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol or mixtures thereof. The reaction can be carried out in the presence of a catalytic amount of hydrobromic acid. The reaction temperature may be about −10 ° C. to about 150 ° C., such as about 0 ° C. to about 40 ° C. The reaction duration may be about 1 hour to about 72 hours, such as about 1 hour to about 20 hours.

Alternatively, the reaction can be, for example, acetonitrile, DMF, DMSO, DCM, CHCl ₃ , 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, HMPA, 1,4-dioxane, acetone, dimethyl ether, It may be carried out in the presence of a solvent such as diethyl ether, THF, water, or a mixture thereof. This reaction is for example a base such as 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, KOH , Et ₃ N, diethyl amine, diisopropylethyl amine, diisopropyl amine, an amine base such as DBU, or a mixture thereof. The reaction temperature may 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 in an inert atmosphere such as N ₂ , Ar or He.

Compounds of formula (IIn) are converted to compounds of formula (IIb):

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

Compounds of formula (IIb) are then reacted with compounds of formula (IIc) to produce compounds of formula (IId):

Wherein all symbols are as defined above.

Wherein E is -NR; And all other symbols as defined above.

Compounds of formula (IId) are then reacted with compounds of formula (IIe) to produce compounds of formula (II):

Wherein all symbols are as defined above.

Wherein X is O and E is -NR; All other symbols are as defined above.

Process 4

According to another aspect of the present invention, a process for preparing a compound of formula (IV) is provided. This process includes:

Wherein all symbols are as defined above.

Conversion of a compound of formula (IVa) to a compound of formula (IVc) is for example Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , NaOH, KOH, triethyl amine, diisopropylethylamine, or these It can be carried out using a suitable acylchloride of formula (IVb) in the presence of a base such as a mixture of. This reaction can be carried out, for example, in a solvent such as benzene, toluene, xylene, DMF, DMSO, 1,4-dioxane, dichloromethane, CHCl ₃ , 1,2-dichloroethane, carbon tetrachloride or mixtures thereof. This reaction temperature is maintained at a temperature of about -30 ° C to about 150 ° C, such as about 20 ° C to about 80 ° C. The duration of this reaction is from about 6 hours to about 72 hours, such as from about 2 hours to about 24 hours. This reaction can be carried out under an inert atmosphere of N ₂ , Ar or He.

Conversion of a compound of formula (IVc) to a compound of formula (IVd) is for example 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 mixtures thereof. This reaction can be carried out, for example, in a solvent such as benzene, toluene, xylene, methanol, ethanol, isopropanol, t-butanol, or mixtures thereof. The reaction temperature is about -70 ° C to about 250 ° C, such as about -10 ° C to about 150 ° C. The duration of the reaction is from about 5 hours to about 150 hours, such as from about 20 hours to about 100 hours. This reaction is carried out under an inert atmosphere such as N ₂ , Ar or He.

The conversion of the compound of formula (IVd) to the compound of formula (IV) can be carried out as in step 1.

Process 5

According to another aspect of the present invention, there is provided a process for preparing a compound of formula Va. This process includes:

The conversion of the compound of formula (IIb) to the compound of formula (IId) can be carried out as in step 1. Converting a compound of formula (IId) to a compound of formula (Va) converts the compound of formula (IId) in the presence of a reagent such as EDCI or CDI and for example DMF, chloroform, dichloromethane, dimethylacetamide, tetrahydrofuran , By reacting with a compound of formula (IIp) in the presence of a solvent such as dioxane, ether or a mixture thereof. The temperature of this reaction can be carried out at about 10 ° C to about 60 ° C, such as about 20 ° C to about 35 ° C. The duration of this reaction is from about 5 hours to about 12 hours, such as from about 10 hours to about 12 hours. This reaction can be carried out in a nitrogen atmosphere.

Process 6

According to another aspect of the present invention, a process for preparing a compound of formula (Vb) is provided.

The process includes:

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 this reaction can be carried out at about 10 ° C to about 70 ° C, such as about 25 ° C to about 45 ° C. The duration of this reaction is from about 1 hour to about 9 hours, such as from about 2 hours to about 4 hours.

The conversion of the compound of formula (VIb) to the compound of formula (Vb) is carried out as in step 5.

It should be understood that any reactive group on the substrate molecule may be protected according to conventional chemical techniques. Suitable protecting groups include, for example, butyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, or tetrahydropyran (THP) to protect hydroxyl or phenolic hydroxy groups; Nt-butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenyl methoxy carbonyl (-N-FMOC), to protect amino or anilino groups, Benzophenoneimine or propargyloxy carbonyl (POC); Acetal protecting groups for protecting aldehydes; And ketal protecting groups for protecting ketones. Methods of forming and removing such protecting groups are conventional methods suitable for the molecules to be protected.

Enantiomers of the compounds of formula (II) can be prepared by using reactants in the form of a single enantiomer in the process or by carrying out the reaction in the presence of a reagent or catalyst in the form of a single enantiomer.

Stereoisomers of the compounds of the present invention can be prepared using reactants in the form of a single enantiomer by carrying out the reaction in the presence of a reactant or catalyst in the form of a single enantiomer or by dissolving a mixture of stereoisomers by conventional methods. . Some methods involve the use of microbial resolutions that dissolve diastereomeric salts formed of chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid or lactic acid, or chiral bases such as brucin, ginafi alkaloids and derivatives thereof. Include. Commonly used methods follow JAQUES, ENANTIOMERS, RACEMATES AND RESOLUTION (1981). Where appropriate, the compound of formula (I) may be dissolved by the following steps: treating with chiral amine, amino acid, aminoalcohol derived from amino acid; Carrying out the usual reaction conditions for converting the acid to an amide; Separating diastereomers by fractional crystallization or chromatography; And preparing stereoisomers of the compound of formula (I) by hydrolyzing the pure diastereomeric amides.

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

Formulations and Pharmaceutical Compositions

The present invention provides a pharmaceutical composition comprising a compound of formula (I), at least one compound of formula (I) and salts thereof, or a pharmaceutically acceptable composition in combination with a pharmaceutically acceptable carrier and diluent .

The pharmaceutical compositions of the present invention can be used to treat bacterial infections. It can also be used to treat bacterial infections associated with multi-drug resistance. The pharmaceutical compositions of the present invention can also be used to modulate inflammatory responses, particularly those resulting from AGE and glycated protein accumulation. The pharmaceutical compositions of the present invention can also be used to modulate smooth muscle cell proliferation and associated disease or symptom relief. The composition provided in the present invention may include vascular occlusion conditions such as stenosis, restenosis and atherosclerosis; Diseases caused by inflammation such as autoimmune diseases; And hyperproliferative diseases such as cancer.

A. Pharmaceutically Acceptable Salts

The composition of the present invention optionally comprises one or more salts of the compound of the present invention contained therein. Such salts are commonly referred to as non-toxic "pharmaceutically acceptable salts". However, other salts may be useful for the preparation of the compounds of the present invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the present invention are pharmaceutically acceptable acids of such compound solutions and, for example, hydrochloric acid, sulfuric acid, fumaric acid, malic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or mixtures thereof. Acid addition salts formed by mixing the solution. In addition, when a compound of the present invention has an acid moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; Salts formed with suitable organic ligands such as quaternary ammonium salts; Or mixtures thereof.

Examples of pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clathrate Culaulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluco Nate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, Methylniate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothe Nates, Phosphates / Diphosphates, Polygalactronates, Salicylates, Stearates, Sulfates, Subacetates, Succinates, Tannates, Tartrates, TeOCates, Tosylates, Triethiodide And valerates.

B. Other Forms of Compound

If the compounds of the invention have at least one chiral center, they may therefore exist as enantiomers. If the compound has two or more chiral centers, it may exist as diastereomers. Where the compounds of the present invention have geometric isomers, it is understood that all such isomers and mixtures thereof are included within the scope of the present invention. In addition, some crystalline forms for the compounds may exist as polymorphs and are included in the present invention. In addition, some compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of the present invention. When the process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography.

In addition, the compounds of the present invention may be prepared in racemic form. Alternatively, individual enantiomers can be prepared by enantiospecific synthesis or resolution. The compound is fractionally crystallized after forming a salt with an optically active acid such as (+) di-p-toluyl-d-tartaric acid and / or (+)-di-p-toluyl-l-tartaric acid And their enantiomeric components by standard techniques such as forming stereoisomeric pairs by free base regeneration. The compounds can also be degraded by the formation of stereoisomeric esters or amides followed by chromatographic separation or removal of chiral auxiliary. Alternatively, the compound can be degraded by using a chiral HPLC column.

The compounds of the present invention are optionally formulated and administered as prodrugs. In general, prodrugs include functional derivatives of the claimed compounds that can be enzymatically activated or converted into more active parent forms. Thus, in the methods of treatment of the present invention, the term “administration” refers to the treatment of various disorders by a specifically disclosed compound or a compound that is not specifically disclosed but is converted to a specific compound in vivo after administration to a patient. Include. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in DESIGN OF PRODRUGS (1985), each of which is incorporated herein by reference in its entirety; 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).

Prodrugs of the invention include phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing Prodrugs, optionally substituted phenolcyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluorouris that can be transformed into more active drugs Dean prodrugs include, but are not limited to.

Enzymes that can be used in the compositions and methods of the invention include alkaline phosphates for converting phosphate-containing prodrugs into free drugs; Arylsulfates for converting sulfate-containing prodrugs into free drugs; Cytosine diamine for converting non-toxic 5-fluorocytosine into anticancer drug, 5-fluorouracil; Cathepsin such as cathepsin B and L and proteases such as seratia proteases, termolysine, subtilisin, carboxypeptidase for converting peptide containing prodrugs into free drugs; D-alanylcarboxypeptidase for replacing a prodrug containing a D-amino acid substituent; Carbohydrate degrading enzymes such as β-galactosidase and neuraminidase to convert glycated prodrugs into free drugs; β-lactamases to convert drugs induced with β-lactams into free drugs; And penicillin amidases, such as penicillin V amidase or penicillin G amidase, for converting drugs derived by phenolicacetyl or phenylacetyl groups, respectively, into free drugs in the amine nitrogen.

Alternatively, antibodies with enzymatic activity known as "abzymes" in the art can be used to convert the prodrugs of the present invention into active drugs. See, eg, Massey, 328 NATURE 457-48 (1987).

C. Pharmaceutical Supplements

In addition to the compounds contemplated herein, the pharmaceutical compositions of the invention optionally include, but are not limited to, for example, diluents, binders, stabilizers, buffers, salts, affinity solvents, preservatives, adjuvants or combinations thereof. At least one suitable auxiliary or carrier is not limited. Pharmaceutically acceptable adjuvants are typically used. Methods and examples for preparing such sterile solutions are disclosed, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)), which is incorporated herein by reference in its entirety. . Pharmaceutically acceptable carriers are usually appropriately selected depending on the method of administration, solubility and / or stability of the compound.

Pharmaceutical excipients and additives useful in the present invention include proteins, peptides, amino acids, lipids and carbohydrates (e.g., sugars including monosaccharides, disaccharides, trisaccharides and oligosaccharides; derived sugars such as alditol, aldonic acid, esterification) Sugars; and polysaccharides), but may be present alone or in combination, including 1-99.99% by weight or parts by weight, alone or in combination. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein or combinations thereof. Representative amino acid components that can act as buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine and aspartame.

Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose; Disaccharides such as lactose, sucrose, trehalose, cellobiose; Polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch; And alditol, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glycitol), miyoinositol.

Pharmaceutical compositions comprising a compound of the present invention may also include a buffer or pH adjuster. Typically the buffer is a salt prepared from an organic acid or base. Exemplary buffers include citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or palmitic acid; Tris; Tromethamine hydrochloride; Phosphate buffers; Or organic acid salts such as any combination.

Additionally, the pharmaceutical compositions of the present invention may optionally contain polyvinylpyrrolidone, picols (polymeric sugars), dexates (eg cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin), polyethylene Glycols, flavoring agents, anti-microbial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., Polymeric excipients / additives such as phospholipids, fatty acids), steroids (eg cholesterol), chelating agents (eg EDTA) and any combinations thereof. Exemplary pharmaceutical additives and / or additives are REMINGTON: THE SCIENCE & PRACTICE OF PHARMACY (19 ^th ed., Williams & Williams (1995)) and PHYSICIAN'S DESK REFERENCE (52 ^nd ed), which are incorporated herein by reference in their entirety. , Medical Economics (1998).

1.Pharmaceutical Compositions for Oral Administration

For oral administration in the form of tablets or capsules, the compounds may be combined with oral nontoxic pharmaceutically acceptable inert media such as ethanol, glycerol, water or mixtures thereof. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may be incorporated into the mixture. Suitable binders are starch; Natural sugars such as gelatin, glucose or beta-lactose; Corn sweeteners; Natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose; Polyethylene glycol; Wax; Or combinations thereof, but is not limited thereto. Lubricants used in such dosage forms include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or combinations thereof. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum or combinations thereof.

Suitable formulations for oral administration include capsules, cachets or tablets each containing a predetermined amount of active ingredient; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; Or in discrete units such as oil-in-water (O / W) liquid emulsions or water / in-oil (W / O) emulsions and bolus.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are typically prepared by mixing the active ingredients in free flowing form, such as powders or granules, optionally with a binder, lubricant, inert diluent, preservative, surface active or dispersant and compacting in a suitable machine. Molded tablets are typically prepared by molding in a suitable machine a mixture of an inert liquid diluent and a moist wet powdered compound. The tablets may optionally be coated or scored and formulated to release slowly or at a controlled rate of the active ingredient contained therein.

The compositions of the present invention may optionally be incorporated into biodegradable polymers to delay release of the compound. The polymer is implanted in the vicinity of where drug delivery is desired, for example a restenosis position. Such biodegradable polymers are described, for example, in Brem et al., 74 J. NEUROSURG. 441-46 (1991). Suitable examples of delayed release compositions include semipermeable matrices of solid hydrophobic polymers containing the compounds of the invention, wherein the matrices are formed into shaped articles, for example in the form of films or microcapsules. Examples of delayed release matrices include polyesters, hydrogels (eg, poly (2-hydroxyethyl-methacrylate)), or poly (vinyl alcohol), polylactide (incorporated herein by reference in its entirety). US Patent No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, LUPRON DEPOT® (Tap Pharmaceuticals, Inc., Chicago, IL) (lactic acid glycolic acid copolymers and Degradable lactic acid-glycolic acid copolymers such as injectable microspheres composed of prolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

2. Pharmaceutical Compositions for Parenteral Administration

As used herein, "parenteral" includes subcutaneous tissue injection, intravenous, intramuscular, intraperitoneal injection or infusion techniques. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, including suspensions and thickeners, including antioxidants, buffers, bacteriostats and solutes that are intended to be isotonic with the blood of the intended recipient. And aqueous and non-aqueous sterile suspensions. The formulations may be present in unit-dose or multi-dose containers, such as sealed ampoules and vials, and immediately before use, in sterile liquid carriers, eg For example, it may be present in freeze-dried conditions where the addition of water for injection is necessary. Temporary injection solutions and suspensions can be prepared from sterile powders, granules, and tablets as described above.

For parenteral administration, sterile suspensions and solutions are required. When intravenous administration is required, isotonic formulations which contain suitable preservatives are generally used. The pharmaceutical composition may be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert carrier. Acceptable liquid carriers include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil and organic solvents such as solketal and glycerol formal. Such formulations may be prepared by dissolving or suspending the active ingredient in a liquid carrier such that the final formulation contains about 0.005% to 30% by weight of the active ingredient, eg, a compound of the present invention.

3. Pharmaceutical Compositions for Other Routes of Administration

Formulations suitable for topical administration in the mouth include lozenges comprising the ingredient in a flavored basis or medium, usually sucrose and acacia or tragacanth; Pastels comprising the active ingredient in an inert substrate or medium such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising a compound administered in a suitable liquid carrier. The liquid form may include suitable flavored suspensions or dispersants such as synthetic and natural gums such as tragacanth, acacia and methyl-cellulose.

Formulations for rectal administration may be provided as suppositories with suitable bases including, for example, cocoa butter or salicylates.

Formulations suitable for vaginal administration may be presented as a pessary, tampo, cream, gel, paste, foam or spray formulation comprising the active ingredient and a suitable carrier.

The compounds can also be used, for example, by coacervation techniques or by interfacial polymerization, e.g., microcapsules, colloidal drug delivery prepared by hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacrylate) microcapsules, respectively. It can be trapped in a system (eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or microemulsions. See MINGTON'S PHARMACEUTICAL SCIENCES (A. Osol ed., 16th ed. (1980)), which is incorporated herein by reference in its entirety.

Compounds contemplated in the present invention are optionally formulated as liposomes. Liposomes are each disclosed in US Pat. No. 5,013,556, which is incorporated herein by reference in its entirety; No. 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. It may be prepared by any suitable method disclosed in USA 4030 (1980). The compounds of the invention can also be administered in the form of liposome delivery systems such as small monolayer vesicles, large monolayer vesicles and multilayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamide or phosphatidylcholine.

Compounds of the invention can also be delivered by using monoclonal antibodies as individual carriers to which the compound molecule is bound. The compounds of the present invention may also be combined with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenols, polyhydroxyethylaspartamidephenols or polyethyleneoxidepolylysines optionally substituted with palmitoyl moieties.

D. Pharmaceutically Acceptable Preservatives

The present invention comprises a stable formulation suitable for pharmaceutical or veterinary use, a preserved solution, a formulation containing a preservative and a multi-use preserved formulation comprising at least one compound contemplated herein in a pharmaceutically acceptable formulation. To provide. Preserved formulations contain phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrile, phenoxyethanol, formamide, chlorobutanol, magnesium chloride ( Containing at least one known preservative, including, for example, hexahydrate), alkylparabens (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzenetonium chloride, sodium dihydroacetate and thymerozal or mixtures thereof do. Suitable concentrates or mixtures are for example in the range of 0.001-5% or 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 without preservatives include 0.1-2% m-cresol (eg, 0.1, 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (eg, 0.5, 0.9, 1.1, 1. 5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerozal (e.g. 0.005, 0.01), 0.001-2.0% phenol (e.g. 0.05, 0.25, 0.28, 0.5 , 0.9, 1.0%), and 0.0005-1.0% alkylparaben (s) (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, 0.27 0.3 , 0.5, 0.75, 0.9, 1.0%).

Other excipients, such as isotonic agents, buffers, antioxidants, preservative enhancers, may optionally be added to the diluent. Isotonic agents, such as glycerin, are usually used in known concentrations. Physiologically acceptable buffers are typically added to provide improved pH control. The formulation may cover a wide pH range in the range of about pH 4 to about pH 10, specifically, about pH 5 to about pH 9, more specifically about 6.0 to about 8.0. According to one aspect of the invention, the formulation of the invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers such as sodium phosphate and phosphate buffered saline (PBS).

Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic Pharmaceutically acceptable solulizers or polysorbate 20 or 80 or poloxamer 184 such as F68 (polyoxyethylene polyoxypropylene block copolymer) and PEG (polyoxyethylene glycol) Other additives, such as 188, Pluronic® polyls, nonionic surfactants such as other block copolymers, and chelating agents such as EDTA and EGTA, are optionally added to the pharmaceutical composition to prevent aggregation. Such additives are particularly useful when a pump or plastic container is used to administer the pharmaceutical composition. The presence of a pharmaceutically acceptable surfactant mitigates the likelihood of aggregation of the composition.

It may be necessary and / or desirable to protect the sensitive or reactive groups of the molecules involved during the process of preparing the compounds of the present invention. These are each represented by PROTECTIVE GROUPS IN ORGANIC CHEMISTRY (1973), which is incorporated herein by reference in its entirety; And GREENE AND WUTS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991). The protecting group can be removed at a convenient subsequent stage using methods known in the art.

E. Combination Therapy

In addition, other therapeutic agents, such as chemotherapeutic agents, immunosuppressants, cytokines, cytotoxins, nucleolytic compounds, radioisotopes, receptors and prodrug activating enzymes that occur naturally or are produced by recombinant technology, may be combined with the compounds of the present invention. Administration or continuous administration may be desirable. The combination administration may be co-administration using a separate formulation or a single pharmaceutical formulation, or continuous administration in any order when there is time for both (or both) active therapeutic agents to exert their biological activity simultaneously. Include.

Compounds of the present invention may optionally contain an antirheumatic agent (eg, methotrexate, aruranopine, arothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquinone sulfate, leflu Nomids, sulfasal), muscle relaxants, anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), anti- analgesics, anti-narcotics, sedatives, local anesthetics, neuromuscular blockers, anticancer agents, antibacterial agents (e.g. aminoglycosides) Antifungal, antifungal, antiviral, carbapenem, cephalosporin, fluoroquinolone, macrolide, penicillin, sulfonamide, tetracycline, other antibacterial agents), anti-psoriasis, corticosteroid, Anabolic steroids, diabetes-related reagents, minerals, nutrients, thyroids, vitamins, calcium-related hormones, anti-diarrheals, anti-cough, anti-emetics, anti-ulcers, laxatives, anticoagulants, Erythrophytin (e.g. epoetin alfa), filgrastim (e.g. G-CSF, Neupogen), sargramostim (GM-CSF, rukin), immunological agents, immunoglobulins , Immunosuppressive agents (eg, basiliximab, cyclosporine, daclizmab), growth hormones, hormone replacement medications, estrogen receptor modulators, acidic agents, paraplegics, alkylating agents, anti-metabolic agents, mitogenic inhibitors, aradio Aradiopharmaceutical, antidepressant, antidepressant, antipsychotic, antianxiety, sleeping, sympathetic, stimulant, donepezil, tacrine, asthma, beta agonists, inhaled steroids, leukotriene inhibitors, methylk Administration with santin, chromoline, epinephrine or analogues thereof, Dornace alfa, cytokines or combinations thereof.

Such anticancer or antimicrobial compounds may also include toxin molecules that are combined, co-formulated and co-administered together with at least one compound of the invention or administered sequentially in any order. The term “toxin” refers to endogenous and exotoxins provided by naturally occurring, mutant, or recombinant bacteria or viruses that can cause any pathological condition in humans and other mammals to cause death, including any toxin shock. Include. The toxin may optionally act to kill pathological cells or tissues. The pathological cells can be cancer or other cells. Such toxins may be, for example, purified or recombinant toxins or toxin fragments comprising at least one functional cytotoxic domain of a toxin, which may be selected from at least one lysine, diphtheria toxin, toxin solution toxin or bacterial toxin. It is not limited. Such toxins include enterotoxigenic E. coli heat-labile enterotoxin (LT), heat-stable enterotoxin (ST), Shigella cytotoxin, Aeromonas endotoxin, and toxic shock syndrome toxin-1 ( TSST-1), Staphylococcus enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcal enterotoxin strains, including but not limited to. Such bacteria include enterotoxin E. coli (ETEC), intestinal hemorrhagic E. coli (e.g. strain of serotype 0157: H7), staphylococci species (e.g., Staphylococcus aureus, Staphylococcus aureus) ), Shigella species (e.g. Shigella Dicenteria, Shigella Flexneri, Shigella Bodi and Shigella Sonnei), Salmonella species (e.g. Salmonella typhi, Salmonella cholera-sus, Salmonella entere) Tertidis), Clostridium species (e.g. Clostridium perfringens, Clostridium difficile, Clostridium botulinum), Campylobacter species (e.g. Campylobacter Philoly, Campylobacter Peters), Helicobacter species (e.g. Helicobacter pylori), Aeromonas species (e.g. Aeromonas sobris, Aeromonas hydrophylan, Aeromonas caviar), Plesiomonas sigeloides, Yercena enterocoli Tiga, Vibri Species (for example, Vibrio cholerae, Vibrio para Molly Tee hee Syracuse), including, Klebsiella species, Pseudomonas aeruginosa and chain strain of Streptococcus species, but is not limited thereto. Stein, ed., INTERNAL MEDICINE1-13 (3rd ed. Little, Brown and Co., Boston) (1990), each of which is incorporated herein by reference in its entirety; EVANS ET AL., BACTERIAL INFECTIONS OF HUMANS: EPIDEMIOLOGY AND CONTROL 239-254 (2d.ed.Plenum Medical Book Co., New York) (1991); Mandel et al., PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES (3d. Ed. Churchill Livingstone) (1990); BERKOW ET AL., THEMERCK MANUAL (16th ed. Merck and Go.) (1992); Wood et al., 76 FEMS MICROBIOLOGY IMMUNOLOGY 121-134 (1991); See Marrack et al., 248 SCIENCE 705-711 (1990).

The compounds of the present invention are optionally administered in combination with at least one immunosuppressant when used to treat or prevent vascular occlusion conditions such as, for example, graft angiopathy. Suitable immunosuppressants include CellCept (Roche Labs.), Gengraf (Abbott Labs., Inc.), Micrhogam (Ortho-Clinical), Neoral (Novartis), Ortho Orthoclone OKT3 (Ortho-Biotech), Prograf (Fujisawa), Rapamune (Wyeth-Ayerst), Sandimmune (Novartis), Thymoglobulin (SangStat), Jenna Zenax (Roche) or combinations thereof, including but not limited to.

The therapeutic agent may be administered in any order and at various times simultaneously or sequentially with the compound of the invention, including the chemotherapeutic agent. "Chemotherapeutic agents" are compounds useful for the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; Alkyl sulfonates such as busulfan, improsulfan and piposulfan; Aziridine, such as benzodopa, carboquone, meturedopa, and uredopa; Ethylimine and methyllamenamine, including altretamine, triethylenemelamine, triethylenephosphoamide, triethylenethiophosphoamide and trimethylolmelamine; Chlorambucil, chlornaphazine, chlorophosphamide, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide Nitrogen mustards such as mechlorethamine oxide hydrochloride, melphalan, nobelbiehinin, phenesterine, prednimustine, trofosfamide, uracil mustard; Nitroreas such as cannustine, chlorozotoxin, fotemustine, lomustine, nimustine, ranimustine; Aclacinomysins, actinomycin, actinomycin, autamycin, azaserrine, bleomycins, cactinomycin, calcicheomycin, calicheamicin, karacheamicin Carabicin, carminomycin, carzinophilin, chromoinycins, dactinomycin, daunorubicin, detorubicin, 6-dia Crude-5-oxo-L-norleucine, toxin leucine, epirubicin, esorubicin, edamubicin, idambicin, marcelomycin, mitomycins, mycophenolic acid , Nogalamycin, olivemycins, peplomycin, potfiromycin, promycin, quallamycin, rholamubicin, rodorubicin, streptonigrin (streptonigrin), streptozocin, tubercidine antibiotics such as din), ubenimex, zinostatin, zorubicin; Antimetabolic agents such as methotrexate and 5-fluorouracil ((5-FU); denopterin, methotrexate, pteropterin, trimetrexate and Such as folic acid analogues; fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; purine analogs; ancitabine, azacytidine (azacitidine), 6-azauridine, carmofur, cytarabine, didioxyuridine, doxyfluridine, enocitabine, floxuridine, 5-FU and Pyrimidine analogs such as: calosterone, dromostanolone propionate, androgen, such as epitiostanol, mepitiostane, testolactone; aminogluteteti Aminoglutethimide, mitotane, trilose anti-adrenals such as trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldoglamide glycosides; aminorubilin Acid; amsacrine; bestrabucil; bisantrene; edatraxate; depopamide; defofamine; demecolcine; diaziquone; epony Elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; Mitoxantrone; Mopidamol; Nitracin; Pentostatin; Phennamet; Pyrarubicin; Podophyllinic acid; 2-ethylhydrazide; Procarbazine; PSK®; Razoxane; Sizofrran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2 ', 2 "-trichlorotriethylamine; urethane; vindesine; decarbazine; mannomustine; mitobronitol; mitolacitol; mitoractol; Pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, for example Paclilitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemci Gemcitabine; 6-thioguanine; mercaptopurine; mercaptopurine; metotrexate; platinum analogs such as cisplatin and carboplatin; Blastine (vinblastine); platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone (m) itoxantrone; vincristine; vinorelbine; navelbine; navelbine; novantron; teniposide; daunomycin; aminopterin; xeloda Ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylronitin (DMFO); retinoic acid; esperamicins; capecitabine and pharmaceutically acceptable salts, acids or derivatives thereof. This definition also includes, for example, tamoxifen, lalosifen, which inhibits 4 (5) -imidazole, 4 hydroxytamoxifen, trioxyphene, keoxyphene, onapristone and toremiphene. (raloxifene), anti-estrogen including aromatase; Anti-androgens and pharmaceutically acceptable salts, acids or derivatives such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin Antihormones that control or inhibit hormonal action of the same tumor are included.

The therapeutic agent may comprise a cytokine. The term “cytokine” is a generic term for proteins released by cell populations that act as intercellular mediators on other cells. As used herein, the term "cytokine" includes proteins of natural source or recombinant cell cultures of native cytokines and biologically active equivalents. Examples of such cytokines are lymphokines, monokines and traditional polypeptide hormones. Human growth hormone, N-methionyl human growth hormone, and bovine growth hormone among cytokines; Parathyroid hormone; Thyroxine; insulin; Proinsulin; Relaxin; Growth hormones such as prorelaxin; Glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); Liver growth hormone; Fibroblast growth factor; Prolactin; Placental lactogen; Tumor necrosis factor-α and -β; Miller-inhibiting substances; Mouse gonadotropin-associated peptide; Inhibin; Activin; Vascular endothelial growth factor; Integrin; Thrombopoietin (TPO); Nerve growth factors such as NGF-β; Platelet growth factor; Transforming growth factors (TGFs) such as TGF-α and TGF-β; Insulin-type growth factor-I and -II; Erythropoietin (EPO); Osteoinductive factors; Interferons such as interferon-α, -β and -γ; Colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); Granulocyte-macrophage-CSF (GM-CSF); And granulocyte-CSF (GCSF); IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL- Interleukins (ILs) such as 15; Tumor necrosis factor such as TNF-α or TNF-β; And polypeptide factors including other LIFs and kit ligands (KLs).

Compounds of the invention are adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, pridnisolone, 6a-methylpridnisolone, triamcinolone, betamethasone, and dexamethasone), nonsteroidal agents (salicylic acid derivatives) Ie, aspirin; para-aminophenol derivatives, ie, acetominophene; indole and indene acetic acid (indomethacin, sulindac and etodalak), heteroaryl acetic acid (tolmethine, diclofenac and ketorolac), arylpropionic acid (ibpro) Pens and derivatives), anthranilic acid (mephenamic acid and meclofenamic acid), enolic acid (pyoxycamp, tenoxycam, phenylbutazone and oxyphenanthrazone), navmethone, gold compounds (auranopine, aurothio And non-steroidal commercially available non-steroidal agents that can be administered with an inflammatory agent, including glucose, gold sodium thiomalate). Inflammatory drugs include Anaaprox (Roche Labs.), Anthrotec (Searle), Cataflam (Novartis), Celebrex (Pfizer), Clinoril (Merck), Dolobid (Merck), Feldene (Pfizer), Indoxin (Merck), Lodine (Wyeth-Ayerst), Mobic (Boehringer Ingelheim), Motrin (McNeil Consumer), Naprosyn (Roche Labs.), Oris (Wyeth-Ayerst), Orruvail (Wyeth-Ayerst), Pontstel (First Horizon), Lella Relafen (GlaxoSmithKline), Tolectin (Ortho-McNeil), Tororadol (Roche Labs., Inc.), Vioxx (Merck), Voltaren (Novartis) Advair (GlaxoSmithKline), Flovent (GlaxoSmithKline), Pulmicort (AstranZeneca), and Vanceril (Schering), Asacol (Procter & Gamble), Cola These include, but are not limited to, Corazal (Salix), Dipentum (Pharmacia & Upjohn), and Rowasa (Solvay). It is not limited to.

The compound of the present invention can be administered in combination with an antirheumatic agent. Commercially available antirheumatic agents include Anaprox (Roche Labs.), Arava (Aventic), Arthrotec (Searle), Azulfidine (Pharmacia & Upjohn), Cataflam (Cataflam) (Novartis), Celebrex (Pfizer), Celestone (Schering), Cuprimine (Merck), Enbrel (Immunex), Feldene (Pfizer) Gengraf (Abbott), Indocin (Merck), Lodinin (Wyeth-Ayerst), Naprosyn (Roche Labs.), Neoral (Novartis), Pediapred (Celltech), Prednisone (Roxanne), Remicade (Centocor), Solu-Medrol (Pharmacia & Upjohn), Triliate (Purdue Frederick) ) And Voltaren (Novartis).

In addition, the compounds of the present invention include Cardura (Pfizer), Dibenzyline (WellSpring), Hytrin (Abbott), Minipress (Pfizer), and Minizide ( Adrenaline blockers such as Pfizer); Aldoclor (Merck), Aldomet (Merck), Aldoril (Merck), Catapres (Boehringer Ingelheim), Chlorpres (Bertek), and Tenex ( Adrenaline stimulants such as Tenex) (Robins); Alpha / beta adrenergic blockers such as Coreg (GlaxoSmithKline), and Normodyne (Schering); Accupril (Parke-Davis), Aseeon (Solvay), Altas (Monarch), Captopril (Mylan), Enalaprilat (Baxter Anesthesia), Lote Lotensin (Novartis), Mavik (Abbott), Monopril (Bristol-Myers Squibb), Prinivil (Merck), Univasc (Schwarz), Baotec Angiotensin converting enzyme inhibitors such as Merck, and Zestril (AstraZeneca); Lexxel (AstraZeneca), Lotrel (Novartis), Tarka (Abbott), Accurate (Parke-Davis), Lotensin (Novartis), Prinzide Angiotensin converting enzyme inhibitors such as (Merck), Uniretic (Schwarz), Vaeretic (Merck), and Zestoretic (AstraZeneca); Atacand (AstraZeneca), Avapro (Briston-Myers Squibb), Cozaar (Merck), Diovan (Novartis), Micardis (Boehringer Ingelheim), and Thebes Angiotensin II receptor antagonists such as Teveten (Unimed); Antihyperlipidemic agents such as antiarrhythmics (Groups I-IV), bile acid sequestrants, fibric acid derivatives, HMG-CoA reductase inhibitors and nicotinic acid; Beta adrenergic blocking agents; Calcium channel blockers; Muscle contractors; Cardiovascular agents, including cardiovascular dilators, natriuretic peptides, and peripheral cardiovascular agents; And vasopressors, and can be used in combination with cardiovascular agents, including but not limited to.

According to one aspect of the invention the therapeutic agent comprises a low molecular weight toxin including maytansine, calicheamicin, trichothene and CC 1065. According to another aspect of the invention, the therapeutic agent comprises one or more calicheamicin molecules. The absence of antibiotic anticalicheamicins can produce double-stranded DNA breaks at sub-picomolar concentrations. Structural analogs of calicheamicin are disclosed in Hinman et al., Incorporated herein by reference in their entirety. 53 CANCER RESEARCH 3336-42 (1993); Lode et al., 58 CANCER RESEARCH 2925-28 (1998).

The therapeutic agent may comprise one or more enzymatically active toxins and fragments thereof. Examples of such toxins are diphtheria toxin, diphtheria A chain, exotoxin A chain (in Pseudomonas aeruginosa), lysine A chain, aphrin A chain, modexin A chain, alpha-sarsine, diantine protein, phytolac american protein (PAPI , PAPAII, and PAP-S), Momordica Charantia Inhibitors, Curesin, Crotin Sapaonaria Offininals Inhibitors, Geronine, Mitogeline, Restrithroine, Phenombine, Enomsin and Tetricothecene Non-binding active fragments thereof. See, eg, WO 93/21232, which is incorporated herein by reference in its entirety.

The present invention further relates to therapeutic agents having nucleolytic activity such as ribonuclease and deoxyribonuclease. In addition, a variety of radioisotopes are available that produce radioconjugated binding partners. Examples include radioisotopes of Y ⁹⁰ , At ²²² , Ret ⁸⁶ , Re ¹⁸⁶ , Sm ¹⁵³ , Bi ²¹² , P ³² and Lu.

Compounds of the invention may be conjugated with receptors such as streptavidin for use in tumor pretargeting. In brief, the compound-receptor conjugate is administered to the patient and the unbound conjugate is removed from the circulation by the wash. Subsequently, a ligand such as biotin conjugated with a cytotoxic agent is administered.

1.Dose time

According to one aspect of the invention the compound disclosed herein is administered prior to the second therapeutic agent. Administration of the compound may optionally be carried out minutes to hours before administration of the second therapeutic agent. The compound may be administered in arbitrary control for a period of hours to days, possibly weeks and up to several months before administration of the second therapeutic agent.

More specifically, the compounds of the present invention are at least about 1 minute, at least about minutes, at least about minutes, at least about minutes, at least about minutes, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes after the second therapeutic agent is administered. , At least about 5 minutes, at least about 6 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 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, 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, or at least about 60 minutes ago May be administered.

In addition, the compounds of the present invention may contain 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 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 about 23 hours, or at least about 24 hours ago.

In addition, the compounds of the present invention may be administered 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 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, 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, at least about 29 days, at least about 30 days, or at least about 31 days ago.

Compounds of the present invention can be administered 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, at least about 7 weeks, 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 ago.

In addition, the compounds of the present invention may be administered 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 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 ago.

According to another aspect of the present invention, the compound of the present invention may be administered after the therapeutic agent. Administration of the compound may optionally take place minutes to hours after administration of the therapeutic agent. The compound can be administered at any controlled time, from hours to days, possibly weeks and up to months after administration of the therapeutic agent.

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, at least about 7 minutes after the second therapeutic agent is administered. , 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 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, 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, or at least about 60 minutes.

More specifically, the compounds of the present invention are 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 7 hours after the second therapeutic agent is administered. , 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 about 23 hours, or at least about 24 hours.

In addition, the compounds of the present invention are 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 after the second therapeutic agent is administered. About 8 days, at least about 9 days, at least about 10 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, 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, at least About 29 days, at least about 30 days, or at least about 31 days.

Compounds of the present invention may contain 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, at least about 7 weeks, at least about 8 after the second therapeutic agent is administered. 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 Week, at least about 19 weeks, or at least about 20 weeks.

In addition, the compounds of the invention may be 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 7 months, at least after the second therapeutic agent is administered. It may be administered at about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

In addition, the compounds of formula (I) may be used in combination with platelet aggregation inhibitors such as aspirin, coagulants such as coumadin, calcium channel blockers such as dilteazem and nefidipine, and captopril. And in combination with other pharmaceuticals used to treat cardiovascular diseases, including an aniotension converting enzyme (ACE) inhibitor such as enalopril and β blockers such as propanalol. May be administered. The compound may also be administered in combination with a nonsteroidal anti-inflammatory agent such as ibuprofen, indomethacin, sulindac or a COX II inhibitor such as rofecoxib or celecoxib. Can be. In addition, a therapeutic amount of formula (I) may be administered in conjunction with a carticosteroid. They can also be administered in combination with TNF-α modulating agents, for example tumor necrosis factor receptors or tumor necrosis factor monoclonal antibodies (infliximab). Therapeutic amounts of the compounds of formula (I) may also be administered in combination with HMGCoA reductose inhibitors, PPAR-γ agonists, DL elevators or retinoids.

Dosing method

Compounds of the invention are parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intraarticular, intrachondral, intraperitoneal, intracelial, intracelebellar, intracerebroventricular ), Intracolic, intrauterine, gastric, intrahepatic, intramyocardial, intraosseous, pelvic, pericardial, intraperitoneal, endometrial, prostate, lung, intrarectal, intrarenal, intraretinal By any suitable means including intralubrication, intrathoracic, intrauterine, intra bladder, bolus, vaginal, rectal, buccal, sublingual, intranasal or transdermal means It may be administered but is not limited thereto.

A. Lung / Nose Administration

There are some preferred configurations of inhalation devices for administering the compounds of the present invention. For example, delivery by an inhalation device is advantageously reliable, reproducible and accurate. In pulmonary administration, at least one pharmaceutical composition is delivered at an effective particle size to reach the bottom airway of the lung or synuses. The inhalation device optionally delivers small dry particles, typically less than about 10 μm, for example about 1-5 μm, for good respirability.

The pharmaceutical composition of the present invention may be delivered by a suitable inhalation or nasal device. Devices capable of depositing nebulized formulations in a patient's sinus cavity or alveoli include metered dose inhalers, nebulizers, dry powder generators and sprayers, but It is not limited to this. Other devices suitable for direct pulmonary or nasal administration are known in the art.

All such devices can be used to administer the pharmaceutical composition as an aerosol. Such aerosols may comprise solutions (aqueous or nonaqueous) or solid particles. Weighing inhalers, such as the Ventolin® Weighing Inhaler, typically use a propellent gas and need to be operated while inhaling. For example, WO98 / 35888; See WO 94/16970. Dry powder inhalers and Spinhalere ^® powder inhalers, such as Turbuhaler ^® (Astra), Rotahaler ^® (Glaxo), Diskus ^® (Glaxo), Spiros ^® Inhalers (Dura), devices sold by Inhale Therapeutics (Fisons) uses breath-actuation of mixed powders. US Patent Nos. 5,458,135, each of which is incorporated herein by reference in their entirety; 4,668,218; WO 97/25086; WO 94/08552; WO 94/06498; And EP 0 237 507. Nebulizers such as AERx ^® , Aradigm, Ultravent ^® Nebulizer (Mallinckrodt), and AcornII ^® Nebulizer (Marquest Medical Products) produce aerosols from solution while metered dose inhalers and dry powder inhalers produce small particles of aerosol. Specific examples of such commercially available inhalation devices are included as representative of specific devices suitable for the practice of the present invention and do not limit the scope of the present invention.

When the carrier is a solid, suitable formulations for nasal administration administered to the nose include, for example, a coarse powder having a particle size of about 20 to 500 microns, which may bring the container containing the powder closer to the nose. This is accomplished by rapid inhalation through a nasal passage. When the carrier is a liquid, for example, formulations suitable for administration by nasal spray or nasal drop include aqueous or oil solutions with the active ingredient.

1. Spray Dosing

Sprays comprising the pharmaceutical compositions of the present invention can be prepared by passing a nozzle under pressure through a suspension or solution of a compound contemplated herein. The nozzle size and shape, the pressure applied and the liquid feed rate are selected to obtain the desired output and particle size. Electrosprays can be produced, for example, by an electric field connected with a capillary tube or nozzle feed. Typically, the at least one compound particle delivered by the sprayer is 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, Have a particle size of less than about 3 μm, less than about 2 μm, or less than about 1 μm.

Pharmaceutical compositions according to the present invention suitable for use as a sprayer typically have a concentration of about 0.1 mg to about 100 mg, or mg / gm of the compound contemplated by the present invention per mL of solution in aqueous solution. 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 any range or value, including but not limited to mg / gm. Pharmaceutical compositions may include excipients, buffers, isotonic agents, preservatives, surfactants and reagents such as, for example, zinc. In addition, the pharmaceutical compositions may comprise excipients or reagents for the stabilization of compounds such as buffers, reducing agents, bulk proteins or carbohydrates. Bulk proteins useful in pharmaceutical compositions suitable for use in sprayers include albumin, protamine, and the like. Typical carbohydrates useful for use in pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose and the like. The pharmaceutical composition may also include surfactants that can reduce or prevent surface-induced aggregation of the pharmaceutical composition caused by atomization of the solution upon aerosol formation. Various conventional surfactants can be used, such as polyoxyethylene fatty acid esters and alcohols and polyoxyethylene sorbitol fatty acid esters. The amount is generally from 0.001 to 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 be included in the pharmaceutical composition.

2. Administration by nebulizer

The pharmaceutical compositions of the present invention may be administered by nebulizers, such as jet nebulizers or ultrasonic nebulizers. Typically, in a jet nebulizer, a compressed air source is used to produce a high speed air jet through the orifice. As the gas expands under the nozzle, a low pressure region is created that draws the protein composition solution through a capillary that connects to the liquid reservoir. The liquid flow from the capillary is sheared into unstable filaments and drops that are present in the tube to form an aerosol. Formation range, flow rates and baffle types can be used to obtain the desired performance characteristics from a given jet nebulizer. In ultrasonic nebulizers, high frequency electrical energy is used to form vibration, mechanical energy and typically piezoelectric transducers are used. This energy is transferred directly to or through the coupling fluid to form the protein composition to form an aerosol comprising the protein composition. 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, about Less than 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, about It has a particle size of less than 3 μm, less than about 2 μm, or less than about 1 μm.

Pharmaceutical compositions comprising a compound of the invention suitable for use in nebulizers, jets or ultrasounds typically contain a compound contemplated in the present invention at a concentration of about 0.1 mg to 100 mg or mg / gm, or 0.1, 0.2, per mL of solution. 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, Including but not limited to 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 Any range or value that does not occur. Pharmaceutical compositions may include excipients, buffers, isotonic agents, preservatives, surfactants and reagents such as, for example, zinc. In addition, the pharmaceutical composition may comprise compound stabilizing excipients or reagents such as buffers, reducing agents, bulk proteins or carbohydrates. Bulk proteins useful in pharmaceutical compositions suitable for use in sprayers include albumin, protamine, and the like. Typical carbohydrates useful in pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose or combinations thereof. The pharmaceutical composition may also include surfactants that can reduce or prevent surface-induced aggregation of the pharmaceutical composition caused by atomization of the solution upon aerosol formation. Various conventional surfactants can be used, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. The amount is generally in the range of 0.001 to 10% by weight of the formulation. Suitable surfactants for use in the present invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20 and the like. Additional reagents known in the art can also be used in pharmaceutical compositions.

3. Administration by Metered Dose Inhaler

In a metered dose inhaler (MDI), a propellant, a compound of the present invention and any excipients or other additives are contained in the container as a mixture comprising liquefied compressed gas. When a metering valve is operated, 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 The mixture is released as an aerosol having a particle size of less than about 2 μm, or less than about 1 μm.

Preferred aerosol particle sizes can be obtained by formulating the compounds of the invention obtained by a variety of methods known in the art, including but not limited to jet-milling, spray drying, critical point condensation. Suitable metered dose inhalers include those made in 3M or Glaxo using a hydrofluorocabon propellant.

Pharmaceutical compositions for use in metered inhalation devices generally comprise a finely divided powder containing a compound contemplated in the present invention as a suspension in a non-aqueous medium, for example suspended in a propellant with the aid of a surfactant. The propellants are chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons or dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluoro Conventional materials such as alkan-134a), HFA-227 (hydrofluoroalkane-227) can be used. Surfactants may be selected to stabilize the compounds of the present invention as suspensions in a propellant to protect the active agent against chemical degradation. Suitable surfactants include sorbitan trioleate, soya lecithin, oleic acid and the like. In some cases, aerosol solutions are formed using solvents such as ethanol. Those skilled in the art will appreciate that the methods of the present invention may be carried out by pulmonary administration of a compound contemplated by the present invention via a device not disclosed herein.

B. Mucosal Administration

Compositions and methods of the present invention for the administration of compounds contemplated by the present invention in absorption through mucosal surfaces include emulsions and emulsions comprising a plurality of submicron particles, mucoadhesive macromolecules, bioactive peptides An aqueous continuous phase that promotes absorption through the mucosal surface by obtaining a mucoadhesion of the particles. See, eg, US Pat. No. 5,514,670. Mucosal surfaces suitable for application of the compositions of the present invention may include administration of the cornea, conjunctiva, oral cavity, sublingual, nasal, vaginal, lung, abs, intestinal and rectal routes. Pharmaceutical compositions for vaginal or rectal administration, such as suppositories, may contain, for example, polyalkylene glycols, petrolatum, cocoa butter excipients. Pharmaceutical compositions for intranasal administration may be solid, for example containing lactose excipients or may be aqueous or oily solutions of nasal drops. For oral administration, excipients include sugars, calcium stearate, magnesium stearate, pregelinatined starch. See, US Pat. No. 5,849,695 Example.

C. Transdermal Administration

The pharmaceutical compositions of the invention can be administered via the transdermal route using the form of transdermal skin patches. For transdermal administration, the compounds of the invention are encapsulated in delivery devices such as liposomes or polymerizable nanoparticles, microparticles, microcapsules or microspheres (collectively referred to as "microparticles" unless otherwise specified). Any suitable delivery device may include, for example, synthetic polymers such as polyhydroxy acids such as polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyanhydrides and polyphosphazenes, and collagen, poly Microparticles composed of natural polymers such as amino acids, albumin and other proteins, alginates and other polysaccharides and combinations thereof can be used. See US Pat. No. 5,814,599, which is incorporated herein by reference in its entirety. Dosage administration may be continuous rather than intermittent through the dosing regimen to be administered in the form of a transdermal delivery system.

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

Topical compositions include, for example, various carriers, including alcohols, aloe vera gels, allantoin, glycerin, vitamins A and E oils, mineral oils, PPG2 myristyl propionate, or mixtures thereof. By mixing, for example, alcohol solutions, topical cleansers, cleansing cream skin gels, skin lotions and creamy shampoos or gel formulations are formed. Examples of methods for preparing the formulations of such carriers are disclosed in REMINGTON'S PHARMACEUTICAL SCIENCES (1990), which is incorporated herein by reference in its entirety. Pharmaceutical formulations may contain from about 0.005% to about 10% by weight of active ingredient, for example from about 0.01% to 5% by weight of active ingredient.

D. Prolonged Administration

It may be desirable for a compound of the present invention to be administered to a subject for a long period of time, eg, from one week to one year in a single administration. Certain medical devices may be used to provide the desired dosing or continuous intermittence of the patient. The device comprises a pump or other device containing a diffusion device or drug reservoir, optionally a diagnostic or monitoring component for regulating drug delivery. Various slow-release, depot, or implant dosage forms can be used. For example, the dosage form may be a pharmaceutically acceptable non-toxic salt of a compound contemplated herein with low solubility in body fluids such as (a) phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamonic acid, Acid addition salts with polybasic acids such as arginine acid, polyglutamic acid, naphthalene mono or disulfonic acid, polygalactronic acid or mixtures thereof; (b) polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, or mixtures thereof or for example of N, N'-dibenzyl-ethylenediamine or ethylenediamine Salts with organic cations; Or (c) combinations of (a) and (b), eg, zinc tannate salts. In addition, the compounds of the present invention or the relatively insoluble salts just described may be formulated in gel form with, for example, aluminum monostearate gel and, for example, sesame oil suitable for injection. Exemplary salts include, but are not limited to, zinc salts, zinc tannate salts, pamoate salts, and mixtures thereof. Other types of slow-release depot formulations used for injection are, for example, slow degrading, non-toxic, such as polylactic / polyglycolic acid polymers as disclosed in US Pat. No. 3,773,919. It may contain a compound or salt dispersed or encapsulated in a non-antigenic polymer. The compounds or their relatively insoluble salts can also be formulated into cholesterol matrix silica pellets, in particular for use in animals. Additional low-release sustained, stored or implanted formulations such as gas or liquid liposomes are described, for example, in US Pat. Nos. 5,770, 222, incorporated herein by reference; SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS (1978).

Dose measurement ( Dosage Determination )

In general, the compounds contemplated herein may be used alone or in combination with other therapeutic agents in appropriate dosages to minimize potential toxicity while maintaining optimal effectiveness. Dosage regimens using the compounds of the invention may include the type, race, age, weight, sex, medical condition of the patient; The severity of the condition to be treated; Route of administration; Kidney and liver function of the patient; And various elements, including the particular compound employed. The doctor or veterinarian can readily determine and prescribe the effective amount of drug necessary to prevent, count or stop the progression of symptoms.

Optimum precision for obtaining drug concentrations in the range with the greatest effect and with the least toxicity may require a regimen based on the kinetics of the compound relative to the target location. The distribution, equilibrium and elimination of drugs can be considered when determining the optimal concentration for treatment regimen. The dosage of the compounds contemplated in the present invention can be adjusted in combination to achieve the desired effect. On the other hand, they are individually optimized and formulated to achieve the synergistic effect of the administration of the various therapeutic agents, with the condition being less than when the reagents are used alone.

In particular, the toxic and therapeutic effects of the compounds contemplated herein are, for example, to determine LD ₅₀ (dosage disruption for 50% population) and ED ₅₀ (therapeutically effective dosage in 50% population). It can be measured by standard pharmaceutical procedures in cell culture or experimental animals. The dose ratio between toxic and therapeutic effects can be expressed as the LD ₅₀ / ED ₅₀ ratio as the therapeutic index. Compounds that exhibit many therapeutic indices are typically used. Although compounds exhibiting toxin side effects can be used, delivery systems that can target compounds at infected tissue sites should be designed and treated to minimize side effects by minimizing potential damage to uninfected cells. In general, the compounds of the present invention may be administered in a manner that maximizes the effect and minimizes toxicity.

Data obtained from cell culture assays and animal studies can be used to determine the dosage range for use in humans. Doses of such compounds are generally in the range of circulating concentrations that include ED ₅₀ with little or no toxicity. The dosage form used for such administration and the route of administration used may vary. For any compound used in the methods of the present invention, a therapeutically effective dose can be determined initially from cell culture assays. Dosages may be formulated in animal models to obtain a range of circulating plasma concentrations including IC ₅₀ (concentration of test compound to obtain half-maximal inhibition of symptoms) as measured in cell culture. Such information can be used to determine the correct dosage useful for humans. Levels in the plasma can be measured, for example, by high performance liquid chromatography.

In addition, dosage administration of the pharmaceutical compositions of the present invention may be optimized using a pharmacokinetic / pharmacodynamic modeling system. For example, one or more dosing regimens can be selected so that a pharmacokinetic / pharmacodynamic model can be used to measure the pharmacokinetic / pharmacodynamic profiles of the one or more dosing regimens. A dosing regimen for administration may then be selected to obtain the desired pharmacokinetic / pharmacodynamic response based on the pharmacokinetic / pharmacodynamic profile. See WO 00/67776, which is incorporated herein by reference in its entirety.

Although formulated or not formulated in the same composition, methods for determining effective dosages for treatment and prevention for the disclosed pharmaceutical compositions or disclosed drug combinations are known in the art. For therapeutic purposes, the term "jointly effective amount" as used herein is to be sought by a researcher, skilled practitioner, physician or clinician, which includes alleviating the symptoms of the disease or disorder to be treated. Refers to the amount of each active compound or pharmaceutical agent alone or in combination, which elicits a biological or medical response in a tissue system, animal or human. For prophylactic purposes (ie, inhibiting the onset or progression of a disorder), the term "jointly effective amount" refers to a disease in a subject, pursued by a researcher, skilled practitioner, physician or clinician. The amount of each active compound or pharmaceutical reagent alone or in combination thereof that inhibits the onset or progression of Thus, the present invention provides for example sub-therapeutic treatment when (a) each therapeutic agent is administered independently in a therapeutically or prophylactically effective amount, and (b) at least one therapeutic agent in the combination is administered alone. -therapeutic or subprophylactic, but administered in a therapeutic or prophylactic amount when administered in combination with a second or additional therapeutic agent according to the invention, and (c) both therapeutic agents When administered in a sub-therapeutic or subprophylactic amount, but when administered together provides a combination of two or more therapeutic agents that are administered therapeutically or prophylactically. Combinations of three or more therapeutic agents are possible in a similar manner. Combination treatment methods include co-administration of a single formulation containing all active ingredients; More than one simultaneous administration; And administration of two or more reagents formulated separately.

Dose Dosages )

The pharmaceutical composition of the present invention may be administered two, three or four times a day by dividing a single daily dose or the total daily dose. For oral administration, the daily administration of the composition can vary from a wide range of about 0.0001 to about 1,000 mg per patient, per day. The range is more specifically about 0.001 mg / kg to 10 mg / kg per day, about 0.1-100 mg, about 1.0-50 mg or about 1.0-20 mg per adult (about 60 kg) body weight.

For oral administration, the pharmaceutical composition may contain 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 for symptomatic adjustment of the patient being treated. Or 250, 300, 350, 400, 450, 500, 550, 600, 650, or 700 mg of the active ingredient.

For injections it is usually convenient to provide by intravenous route in an amount of about 0.01-30 mg, about 0.1-20 mg or about 0.1-10 mg per adult (about 60 kg) per day. For other animals, the dose calculated for 60 kg can likewise be administered.

The daily dosage of the pharmaceutical composition may vary from a wide range of about 5 mg to about 1000 mg per adult per day. For oral administration, the pharmaceutical composition may optionally be selected from 5.0, 10.0, 15.0, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, for symptomatic adjustment of the treated patient. It is provided in the form of tablets containing 600, 650 or 700 mg of active ingredient. Typically an effective amount of drug is provided at a dosage level of about 0.1 mg / kg to about 20 mg / kg of body weight per day. According to one aspect of the invention the dosage level is from about 0.2 mg / kg to about 10 mg / kg of body weight per day. According to another aspect of the invention, the dosage level is about 0.5 mg / kg to about 10 mg / kg of body weight per day. The compound may be administered about 1 to about 10 times per day.

Dosages of the compounds of the invention may optionally be 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, 93, 94, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / dose or any range of values or fractions thereof or in single or multiple doses About 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, 11,0 11.5, 11.9, 12,0 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 14.9, 15, 15.5 , 15.9, 16.0, 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, 2 7, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, Obtaining a 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000ug / mL serum concentration or any range, value or fraction thereof.

In a non-limiting embodiment, the treatment of a human or animal may be provided in a single or periodic dose of 0.1 to 100 mg / kg of a compound of the invention, for example 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 per day, or 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, At least one of 37, 38, 39, or 40 days, or alternatively or additionally 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, At least one of 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks, or alternatively or additionally 1, 2, 3, 4, 5, 6, 7, At least any of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years May be provided in single or fused doses by single, fused or repeated administration in combination thereof.

In particular, the pharmaceutical composition of the present invention may be administered at least once a week over several weeks. According to one aspect of the invention, the pharmaceutical composition is administered at least once a week over several weeks to months. According to another aspect of the invention, the pharmaceutical composition is administered over 4 to 8 weeks. According to another aspect of the invention, the pharmaceutical composition is administered once a week over four weeks.

More specifically, the pharmaceutical composition is at least once a day for about two days, at least once a day for about three days, at least once a day for about four days, at least once a day for about five days, about At least once a day for six days, at least once a day for about seven days, at least once a day for about eight days, at least once a day for about nine days, at least once a day for about ten days, about At least once a day for 11 days, at least once a day for about 12 days, at least once a day for about 13 days, at least once a day for about 14 days, at least once a day for about 15 days, about At least once a day for 16 days, at least once a day for about 17 days, at least once a day for about 18 days, at least once a day for about 19 days, at least once a day for about 20 days, about At least once a day for 21 days, at least once a day for about 22 days, at least once a day for about 23 days, at least once a day for about 24 days, at least once a day for about 25 days, about At least once a day for 26 days, At least once a day for 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 about 30 days or at least once a day for about 31 days Can be.

Alternatively, the composition of the present invention may be about once a day, about two days once, about three days once, about four days once, about five days once, about six days once, about seven days once, About once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days Once a day, about 17 days once, about 18 days once, about 19 days once, about 20 days once, about 21 days once, about 22 days once, about 23 days once, about 24 days 1 Can be administered once, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days or about 31 days.

The present pharmaceutical composition may alternatively be about once a week, about two weeks once, about three weeks once, about four weeks once, about five weeks once, about six weeks once, about seven weeks one. Once, about 8 weeks once, about 9 weeks once, about 10 weeks once, about 11 weeks once, about 12 weeks once, about 13 weeks once, about 14 weeks once, about 15 weeks once, About 16 weeks once, about 17 weeks once, about 18 weeks once, about 19 weeks once or about 20 weeks once.

Alternatively, the pharmaceutical composition of the present invention may be about once a month, about two months once, about three months once, about four months once, about five months once, about six months once, about seven months one. Can be administered once, about 8 months, about 9 months, about 10 months, about 11 months or about 12 months.

Alternatively, the pharmaceutical composition of the present invention may contain at least once a week for about two weeks, at least once a week for about three weeks, at least once a week for about four weeks, at least once a week for about five weeks, At least once a week for about 6 weeks, at least once a week for about 7 weeks, at least once a week for about 8 weeks, at least once a week for about 9 weeks, at least once a week for 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 once a week for about 15 weeks, At least once a week for about 16 weeks, at least once a week for about 17 weeks, at least once a week for about 18 weeks, at least once a week for about 19 weeks, or at least once a week for about 20 weeks Can be.

Alternatively, the pharmaceutical composition may be at least once a week for about one month, at least once a week for about two months, at least once a week for about three months, at least once a week for about four months, about five months At least once a week, at least once a week for about 6 months, at least once a week for about 7 months, at least once a week for about 8 months, at least once a week for about 9 months, about 10 months At least once a week, at least once a week for about 11 months, or at least once a week for about 12 months.

How to use the compound

A. Heparan Sulfate Proteoglycan Regulation

The present invention includes compositions and methods comprising the identification of compounds for treating and preventing blood vessels, particularly cardiovascular disease. More specifically, the present invention relates to compositions and methods for the treatment and prevention of smooth muscle cell proliferation, such as "anti-proliferative" compounds effective in the synthesis of proteoglycans. Methods for screening compounds or molecules that induce HSPG synthesis include, but are not limited to, the addition of compounds for assaying and measuring HSPG synthesis, including the production of Syndecan, Glypican, and perlecan. no. Methods for measuring induction of perlecan synthesis are also contemplated herein. Although some aspects of the invention have been described with respect to perlecans, it is important to note that the compositions, methods and assays described herein apply equally to other HSPGs, including syndecane and glypacan. HSPG production is important for regulating SMC proliferation and the methods and compositions described herein provide high levels of screening for molecules that induce HSPG production and regulate SMC proliferation.

Additionally, the present invention includes compositions and methods for gene therapy comprising administering a composition comprising a nucleic acid effective for 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 to a cell, eg, a circulating tissue cell, such as an endothelial cell. Such vectors are known in the art and can be administered in formulations that enhance the uptake of the vector by the cell.

The invention also includes compositions and methods for inducing the synthesis or expression of HSPGs, including HSPGs such as syndecane, glypican and perlecan, and also inducing active fragments of HSPG such as active fragments of perlecan and Compositions and methods for synthesis. As used herein, when HSPG is referred to, the entire molecule or fragment is included. For example, perlecan refers to the entire perlecan molecule or fragment thereof. Fragments of perlecan may have the same or different effects on cells. All of these fragments and activities are contemplated in the present invention.

The major extracellular HSPG in the vascular matrix is perlecan, a protein originally identified in basement membranes. It interacts with extracellular matrix proteins, growth factors and receptors. Perlecan is also present in basement membranes and other extracellular matrix structures other than blood vessels. It consists of Mr.-450,000kDa core protein, where three HS chains of Mr-70kDa are bound to one end of the molecule. Perlecan core proteins have complex functional organic tissue composed of five consecutive domains with homology to molecules involved in the regulation of cell proliferation, lipoprotein binding and cell adhesion. N-terminal domain I (aa-1-195) contains the binding site for the HS chain. Domain II contains four repeat units having homology with the ligand-binding site of the LDL receptor. Domain III is homologous to domains IVa and IVb of laminin and is believed to mediate cell adhesion.

SMC hyperproliferation is a major symptom of atherosclerosis and increases the failure rate, particularly in vascular surgery such as stenosis and angioplasty. Proliferation of arterial SMCs in response to local injury is a major feature of many vascular proliferative disorders. Although not limited to this theory, it is generally believed that endothelial cells regulate the growth of stratum SMC. In normal blood vessels, SMCs are stationary, but when the endothelial damage occurs, they multiply. A large number of naturally occurring growth regulators derived from the endothelium tightly regulate SMC proliferation in vivo.

Although not limited to specific mechanisms, it is believed that endothelial HSPG mediates quiescence in SMC. In stationary SMC without serum, perlecan synthesis is induced. For example, perlecan inhibits DNA synthesis and SMC proliferation and perlecan blocking stimulates DNA synthesis in the absence of serum and growth factors. Introduction of perlecan and other HSPGs is an important phenomenon to inhibit SMC growth. Known antiproliferative agents do not inhibit SMC proliferation when the effect of perlecan is blocked. Accordingly, the present invention includes compositions and methods for modulating perlecan and other HSPG synthesis, expression and amounts taught to maintain SMC in a stationary state. Such methods and compositions of the present invention also include compositions and methods for treating and preventing vascular disorders, and more particularly, conditions associated with SMC proliferation. In particular, such conditions include atherosclerosis and restenosis.

The invention also includes, but is not limited to, compositions and methods for the treatment and prevention of vascular occlusion conditions, including neovascular endothelial hyperplasia, restenosis, graft angiopathy, cardiac allograft, atherosclerosis and atherosclerosis. no. Such methods and compositions include methods for inhibiting smooth muscle cell (SMC) growth and proliferation and inducing quiescence in smooth muscle cells. The invention further includes compositions and methods comprising the synthesis and expression of HSPG, such as syndecane, glypican and perlecan, eg, perlecan synthesis and gene expression.

Neovascular endovascular hyperplasia usually occurs after various types of vascular injury and vein graft's response to harvest and surgical transplantation into the hypertensive arterial circulation. In neovascular endothelial hyperplasia, smooth muscle cells in the middle layer of the vascular wall are activated, isolated, multiply and migrate to the inner layer. As a result, abnormal neovascular endothelial cells are cytokine, pro-inflammatory molecules, including chemokines, and adhesion molecules that stimulate a series of events that lead to occlusive neovascular disease and consequently graft damage. Expresses.

SMC proliferation in response to local infection is a major feature of vascular proliferative disorders such as atherosclerosis and restenosis after vasodilation. Although not limited to this theory, it is generally believed that endothelial growth regulates the growth of the underlying SMC. In normal blood vessels, SMCs are quiescent but they multiply when endothelial damage occurs. The endothelium not only produces a variety of growth hormones, but also produces major growth inhibitors. HSPG acts as a barrier to cationic and macromolecules, protects the main structural components of the basement membrane, type IV collagen from proteolytic attacks, cytokines and basic fibroblast growth factor (bFGF), vascular endothelial Binds growth factors, including but not limited to, growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and transforming growth factor B (TGF-β) Acts as a receptor for cytokines, regulates mesodermal cell fates, positions the heart, acts as a vasculogenesis and angiogenesis after ischemic injury, Affects the interaction between cells and adhesion proteins and blood vessels, and induces the proliferation of smooth muscle cells during atheroogenesis and increases cell distribution. Components of vascular cell membranes and extracellular matrices believed to modulate various vascular functions, including inhibiting chemotaxis and affecting the metabolism of lipoproteins and the nonthrombogenic properties of endothelial cells to be. In addition, HSPGs are believed to have different functions at different locations. For example, cell surface HSPGs act as co-receptors for growth factors to support cell growth while extracellular HSPGs can inhibit cell growth.

Although endothelial HSPGs are generally thought to inhibit SMC proliferation, it is unknown whether SMC synthesizes antiproliferative HSPGs that act as self-secreting inhibitors. Although not limited to specific mechanisms, it is generally believed that HSPGs inhibit DNA synthesis and SMC proliferation, while blocking HSPGs cause DNA synthesis stimulation even in the absence of serum and growth hormone. In fact, known antiproliferative agents do not inhibit SMC proliferation when the effects of HSPGs are blocked.

Examples of HSPGs include syndecane, glypican and perlecan, which occur in the cardiovascular system. Vascular SMCs express syndecans 1, 2 and 4, glypican-1 and perlecan. However, the regulation of HSPG expression in these cells is not known. Cell growth stimulants such as platelet induced growth factor (PDGF), thrombin, serum oxidized low density lipoprotein (LDL) and lysolecithin are known to reduce HSPG, in particular perlecan. In contrast, cellular antiproliferative agents, TGF-β, apolipoprotein E and heparin stimulate HSPGs.

The present invention includes compositions and methods for the treatment and prevention of smooth muscle cell proliferation, including vascular obstruction. Such methods include administering a composition comprising a therapeutic agent that can inhibit SMC proliferation. Administration of a therapeutic agent effective to inhibit SMC proliferation, such as the above-mentioned thiazolidinedione compositions, is, for example, to humans or animals suspected of having or having angiopathy or who have undergone angioplasty or other endothelial injury surgery. Is carried out. Effective amounts are administered to humans and animals in stable and effective dosages. Routes of administration include, but are not limited to, intravenous, subcutaneous tissue, nasal and inhalation therapy. Such treatment may be combined with other treatments or other activities of the patient, such as changes due to exercise or diet.

The compounds of the present invention are also useful for cardiac stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, bleeding, atherosclerosis, atherosclerosis, restenosis, diabetes Atherosclerosis, hypertension, arterial hypertension, renal vascular hypertension, syncope, shock, cardiovascular syphilis, heart damage, pulmonary heart disease, basal pulmonary hypertension, heart rhythm damage, heart isobeat, heart flutter, heart flutter (Persistent or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal cardiac tachycardia, regular and narrow QRS tachycardia, specific arrhythmias, ventricular fibrillation , His bundlearrythmias, atrioventricular block, bundle branch block, myocardial ischemia, heart Arterial disease, chest tightness, myocardial infarction, cardiomyopathy, dilatation congestive cardiomyopathy, limited cardiomyopathy, coronary heart disease, endocarditis, pericarditis, cardiac arrest tumors, aortic and peripheral aneurysms, aortic dissection, aortic inflammation Occlusion of the abdominal aorta and its branches, peripheral vascular disorders, arterial occlusion, peripheral atherosclerosis, obstructive thrombosis, functional peripheral arterial disease, Raynaud's syndrome and diseases, terminal blue disease, erythropalgia, venous disease, venous thrombo Cells, tissues, organs, animals, including cis, varicose veins, arteriovenous fistula, lymphedema, lied edema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury and dyslipidemia Or useful for the treatment or prevention of at least one cardiovascular disease in a patient. Such methods include the administration of an effective amount of a composition or pharmaceutical composition, optionally comprising at least one compound, to a cell, tissue, organ, animal or patient in need of such control, treatment or treatment.

1. HSPG Activity Assessment

The present invention includes compositions and methods for detecting therapeutic agents that may be effective for SMC proliferation. Such assays are contemplated herein and may be used to detect reagents that affect the amount or activity of HSPGs, eg, perlecan, in such assays. For example, in one assay, perlecan is introduced into the cell by a specific inducer and the response is measured. Potential therapeutic agents are then added to a replicate assay and the effect on perlecan induction is measured. Such methods and compositions are used to detect therapeutic agents that can inhibit perlecan or increase the induction of perlecan or have no such effect at all. Such therapeutic agents can then be used in animals with SMC proliferative conditions.

The present invention also includes compositions comprising compounds identified by the above methods to have the desired activity. The composition is useful for the treatment of cells, tissues or whole organs. Such compositions are effective amounts for the treatment of biological conditions including but not limited to atherosclerosis, graft angiopathy, cardiac allograft angiopathy, restenosis and graft atherosclerosis after heart transplantation It is formulated using a method to be administered. The composition may contain other compounds, including a compound having a desired activity or a compound having an activity and a pharmaceutical adjuvant required for administration of the compounds. The composition may additionally be administered alone or in combination with other pharmaceutical compositions and surgical methods for treating smooth muscle cell proliferation and vascular occlusion, including but not limited to pre, post and post PTCA surgery. Can be.

In the assays of the invention, the compound initially has an unknown activity, effect or effects. The activity of the compound is unknown in that the activity of the compound in the assays of the present invention has not yet been measured. The compound may have many other known activities and may be a compound having different therapeutic uses. Any reagent that reacts the cells or components of the assay 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 the specific activity of biological components involved in known cellular responses. The assay provides a measurable response in which the activity of the unknown compound is measured. The reaction can be measured by methods known in the art, for example by ELISA. One aspect of the invention includes measuring the effect of a compound on SMC proliferation in response to an HSPG-inducing agent.

According to one aspect of the invention, a compound that is believed to affect HSPG synthesis is added to cells in the assay. The response of the cells can be assessed by measuring HSPG synthesis levels assessed by methods known to those skilled in the art and comparing the amount of HSPG synthesis in untreated cells. The compound may have a stimulating effect, an inhibitory effect, a stabilizing effect or no effect at all.

According to another aspect of the invention, a composition suspected of affecting SMC proliferation is added to smooth muscle cells in a growth medium or serum-free medium. Cell proliferation changes can be assessed by methods known in the art and compared to proliferation of cells not treated with the compound. The composition may have a stimulating effect, an inhibitory effect, a stable effect or no effect at all.

Compositions having an HSPG stimulatory effect, in particular a perlecan stimulatory effect, are useful for antiproliferative treatment, in particular for inhibiting SMC proliferation and thus for vascular occlusion. For example, selective activators of perlecan include small organic molecules, peptides, peptoids or polynucleotides that act directly to allow the perlecan to regulate biological activity and increase the biological stability of the protein. In addition, selective activators of perlecan can increase perlecan biosynthesis by increasing the transcription of the perlecan gene, increasing the biological stability of the perlecan mRNA, or by increasing the translation of perlecan mRNA into the protein. In addition, selective activators of perlecan can block or reduce the effect of reagents or proteins that inhibit perlecan's activity.

The invention also includes compositions and methods for assays that can be used to identify selective activators or inhibitors of perlecan. Such assays readily measure the amount of perlecan and its activators up-regulating and down-regulating inhibitors. Generally, such assays are promoter-based assays that identify compounds that affect perlecan and partially purified proteins or lysates recombined from cells expressing perlecan in the presence or absence of compounds of interest. Essays on perlecan biological activity in, but not limited to. Evaluation of perlecan includes quantitation of perlecan protein using biological activity assays and ELISA or Western blot measurements or quantification of perlecan RNA using RT-PCR or Northern blot.

Both methods for directly or indirectly evaluating changes in perlecan are contemplated by the present invention. Essay methods contemplated in the present invention rely on indirect evaluation of perlecan through evaluation of a measure of perlecan activity or expression.

In addition, direct measurements of changes in the amount of perlecan protein can be performed using other immunological methods, such as western blots, densitometric measurements or ELISA methods. Alternatively, direct measurements of changes in perlecan RNA amount can be performed using RT-PCR or Northern assays known in the art. Evaluation is also performed directly by using lysates of cells and purified or partially purified perlecan proteins, which are proteins in recombinant or natural form. Methods for assessing biological activity are known in the art.

Another method of identifying and measuring compounds affecting perlecan is to identify compounds that interact with the promoter region of the perlecan gene or to identify effective proteins that interact with the promoter region and are important in the transcriptional regulation of perlecan expression. It involves doing. Generally, the method comprises a vector comprising an indicator region controlled by a regulatory sequence, such as an enzyme, in the regulatory sequence of the Perlecan gene and in the promoter-reporter construct. The protein product of the indicator region is referred to herein as a receptor enzyme or receptor protein. The regulatory region of the perlecan sequence has a nucleotide range of about -4000 to +2000, for example, -2500 to +1200, eg, -1500 to +800, when the transcription start position is +1. It includes.

The cells are transformed with the vector and then treated with the compound of interest. For example, transformed cells are treated with a compound that is believed to affect the transcription of perlecan and the activity level of the perlecan regulatory sequence is compared with the activity level in cells not treated with the compound. The activity level of the perlecan regulatory sequence can be measured by measuring the amount of receptor protein or by measuring the activity of the receptor controlled by the regulatory sequence. An increase in receptor protein or receptor enzyme activity has a stimulatory effect on perlecan by positively affecting the promoter, while a decrease in receptor protein or receptor enzyme activity has a negative effect on the promoter, thus perlecan.

Additionally, the present invention includes compositions and methods for identifying perlecan proteins or selective inhibitors of biological activity. Selective inhibitors of perlecan are small organic molecules, peptides, peptoids or polynucleotides that act directly to control the perlecan or its promoter region or to reduce the biological stability of the protein. In addition, selective inhibitors of perlecan can reduce perlecan biosynthesis by reducing transcription of the perlecan gene, reducing the biological stability of the perlecan mRNA, or reducing the translation of the perlecan mRNA into proteins. In addition, selective inhibitors of perlecan can block or reduce the effect of reagents or proteins that increase the activity of perlecan.

Table 1 shows examples known to induce HSPG.

B. Heparanase Modulation

HSPGs are key components of the subendothelial extracellular matrix and the basal membranes of blood vessels. Rosenberg et al., 99 J. CLIN. INVEST. See 2062-70 (1997). The basement membrane is a continuous sheet of extracellular matrix composed of collagen and non-collagen proteins and proteoglycans that separate parenchymal cells from stratum intercellular connective tissue. They have characteristic permeability and play a role in maintaining tissue structure.

In addition to HSPGs, the basal lamina mainly constitutes a complex network of adhesion proteins, fibronectin, laminin, collagen and vitronectin. Wight et al. , 6 CURR. OPIN. LIPIDOL. See 326-334 (1995). Heparan sulfate (HS) is an important structural component of the base layer. Each adhesive protein interacts with the HS side chain of HSPGs in the matrix. Thus, HSPGs act as a barrier to extravasation of metastases and inflammatory cells. HS cleavage by endoglycosidase heparanase produced by metastatic tumor cells and inflammatory cells disrupts the filtration properties of lamina. In addition, degradation of HS may aid in disassembly of the extracellular matrix and thus promote cell migration by allowing blood born cells to escape into the bloodstream. See Vlodavsky et al., 12 INVASION METASTASIS 112-127 (1992).

Heparanase activity has been described in many tissues and cell types, including liver, placenta, platelets, fibrinoblasts, neutrophils, activated T and B-lymphocytes, monocytes and subendothelial cells (7-16). . Nakajima et al., (31) CANCER LETT. 277-283 (1986); Nakajima et al., 36 J. CELL. BIOCHEM. 157-167 (1988); Ricoveri et al., 46 CANCER RES. 3855-3861 (1986); Gallagher et al., 250 BIOCHEM. J. 719-726 (1988); Dempsey et al., 10 GLYCOBIOLOGY 467 (2000); Goshen et al., 2 MOL. HUM. REPROD. 679 (1996); Parish et al., 76 IMMUNOL CELLBIOL. 104-113 (1998); Gilat et al., 181 J. Exp. MED. 1929-1934 (1995); Graham, et al., 39 BIOCHEM. MOL. BIOL. INT. 56371 (1996); Pillarisetti et al., 270 J. BIOL. CHEM. See 29760-29765 (1995).

There is a growing interest in heparan sulphate compounds and their associated enzymes due to changes in normal activity and possible associations between tumor invasiveness and tumor metastasis activity. Important processes in tissue invasion by blood-producing tumor cells and leukocytes include pathways through which they pass through the vascular endothelial cell layer and then break down the basal lamina or basal membrane and extracellular matrix with secreted proteases and glycosidases. . Nakajinia et al., 220 SCIENCE 611-613 (1983); See Vlodavsky et al., 12 INVASION METASTASIS 112-127 (1992).

Heparanase activity is known to correlate with the potential for metastasis of animal and human tumor cell lines. Nakajima et al., 31 CANCER LETT. 277-283 (1986); Nakajima et al., 212 PROG CLIN BIOLRES. 113-122 (1986); Freeman et al., 325 BIOCHEM. J. 229-237 (1997); Vlodavsky et al., 5 NAT. MED. 793-802 (1999); See Hulett et al., 5 NAT MED. 803-809 (1999). It is also known to regulate growth factor activity. Many growth factors remain bound to heparan sulphate in a storage form and are separated by heparanase during angiogenesis to improve the survival rate of cancer cells.

Serum heparanase levels in rats are higher than levels of size after injection of rats into classical adenocarcinoma cells. In addition, heparanase activity in the serum of rats with MTLn3 tumors is associated with its metastatic range. In addition, serum / urine heparanase activity in cancer patients has been shown to increase especially 2-4 fold in the presence of tissue metastases. Since the degradation of HS is essential for the pathway of metastatic tumor cells and leukocytes that cross the basement membrane, the study of heparanase inhibitors offers the potential for the development of novel and highly selective anti-transition and anti-inflammatory drugs.

Thus, the present invention further relates to compounds which modulate heparanase activity. Such compounds include malignant and nonmalignant cell growth, leukemia, acute leukemia, acute lymphocytic leukemia (ALL), B-cells, T-cells or FAB ALL, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymph Sexual leukemia (CLL), hairy leukemia, myelodyplastic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma , Nasopharyngeal carcinoma, malignant histiocytosis, hypercalcemia of neoplastic syndrome / cancer, solid tumor, adenocarcinoma, sarcomas, malignant melanoma, hemangioma, metastasis, cancer-related bone resorption, cancer-related bone pain It is useful for the treatment and / or prevention of cancer, including but not limited to.

According to another aspect of the present invention, the compounds contemplated herein are useful for modulating heparanase activity as a means of treating and preventing autoimmune diseases.

As a background, in the usual route to the treatment of disease in infected tissues, local palliative immune effector cells in the body are activated after recognizing antigens that infect organs as foreign bodies. When activated, these effector cells in the body synthesize and secrete signal molecules (chemokines, lymphokines and cytokines) that attract additional immune effector cells at the site of infection. Is also activated. Once activated, these effector cells can be present in the vascular system and enter the infected tissue and begin to attract or destroy the infectious agent and the infected tissue. This process continues until the infection disappears.

However, sometimes the immune system may not work or overdrive the initial outcome, resulting in debilitating of the body, leading to life-threatening chronic and acute diseases. This is because (1) the immune system incorrectly recognizes cell surface molecules on normal tissues as foreign molecules, (2) the synthesis and secretion of chemokines, cytokines, and lymphokines does not stop after the disease is gone (3) It can occur when the immune system overreacts to an apparent infection and over destroys the surrounding normal tissue.

Normally when activated, activated effector cells attract the effector cells to the blood vessels around the infected area. To be such an "effective" activating cell, one must leave blood vessels and enter infected tissue. The presence in the circulatory system and the process of entry into the infected tissue comprises two distinct steps. First, immune effector cells must bind to the luminal / apical surface of the vessel wall. This is accomplished through the interaction of adhesion molecules on immune effector cells with locally upregulated cognate receptors on endothelial cells that line blood vessels around the site of infection.

Second, after binding to the apical surface and before entering infected tissue, immune-activated cells must destroy the basement membrane (BM) and extracellular matrix (ECM) of the vessel, which surrounds the base of the vessel and confers its shape and strength. . The BM and ECM consist of structural proteins embedded in fibers composed of complex carbohydrate-containing structures (glucosaminoglycans), the main component of which is heparin sulfate proteoglycan (HSPG). To break this barrier, immune effector cells must weaken or destroy it, which is accomplished through local secretion of proteases and heparanases.

Thus, inhibition of heparanase with the compounds of the present invention has been found to be useful in the treatment of arthritis and other autoimmune diseases. More specifically, the compounds of the present invention are rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative disease, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus nephritis, Antiphospholipid syndrome, iridocyclitis / uveitis / optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis / Vacner's granulomatosis, sarcoidosis, orchitis ) / Vasectomy reverse procedures, allergy / atopic disease, asthma, allergic rhinitis, allergic eczema, allergic contact dermatitis, allergic conjunctivitis, irritable pneumonia, organ transplantation, organ transplant rejection, graft-versus-host disease (graft-versus-host disease), systemic inflammatory response syndrome, pneumonia syndrome, gram positive pneumonia, gram negative pneumonia, cultured negative pneumonia, fungal pneumonia, Neutropenic fever, urinary tractemia, meningococcalemia, trauma / bleeding, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory disease, Crohn's pathology, sickle cell anemia, diabetes, nephropathy, atopic disease, hypersensitivity reactions, allergic rhinitis, hay fever, seasonal allergic rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic hypersensitivity, dermatitis, pernicious anemia, hemolytic Hypoglycemia, graft rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant rejection, skin allograft rejection, Cartilage graft rejection, bone graft rejection, small intestine graft rejection, fetal thyroid graft rejection, parathyroid graft rejection, xenograft rejection of any organ or tissue, allograft Department, antireceptor hypersensitivity, Graves' disease, Raynaud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, -mediated cytotoxicity, type III hypersensitivity reaction, POEMS syndrome (polyneuropathy, organomegaly) , Endocrine disease, monoclonal gamma globulin disease, and skin change syndrome), polyneuropathy, organomegaly, endocrine disease, monoclonal gamma globulin disease, skin change syndrome, antiphospholipid syndrome, swelling, scleroderma, mixed combination Tissue disease, idiopathic Addison disease, diabetes, chronic active hepatitis, vitiligo, vasculitis, post-MI heart incision syndrome, type IV hypersensitivity, contact dermatitis, irritable pneumonia, allograft rejection, granulomas caused by intracellular organisms, drug sensitivity Syndrome, metabolic / idiopathic, Wilson's disease, hemochromatosis, alpha-1-antitrypsin deficiency, diabetic nephropathy, Hashimoto's disease, osteoporosis, hypothalamic-pituitary-adrenal axis assessment, basal gallbladder sclerosis (prim ary biliary cirrhosis, thyroiditis, encephalomyelitis, cajuncia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, skin disease, psoriasis, alopecia, kidney syndrome, nephritis, Glomerulonephritis, acute kidney injury, hemodialysis, uremia, toxicity, preeclampsia, ankylosing spondylitis, Behcet's disease, blister-like blisters, cardiomyopathy, peritoneal sprue dermatosis, chronic fatigue immunodeficiency syndrome (CFEDS), chronic infection demyelinating polyneuropathy, Chuck-Strauss syndrome, Scar-like swelling, CREST syndrome, Cryogenic plaque, Discus lupus, Necessary mixed cold globulinemia, Fibromyalgia-fibromyalitis, Graves' disease, Galang-Barré syndrome, Hashimoto's disease, Idiopathic Thrombocytopenia (ITP), IgA nephropathy, insulin dependent diabetes mellitus, juvenile arthritis, lichen planus, Ménière's disease, multiple sclerosis, pemphigus Bulgaris, polyarteritis nodule, cochlear syndrome, polychondritis, polysecretory syndrome, rheumatoid polymyalgia, polymyositis and skin myositis, basal agammaglobulinemia, Raynaud's phenomenon, lighter syndrome, rheumatic fever, Sjogren's syndrome, muscular anxiety syndrome, Takayasu aorticitis, temporal arteritis / macrocellular aoritis, Wegener's granulomas; okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiotherapy (eg, but not limited to toasthernia, anemia, cachexia), It is useful for treating or preventing at least one autoimmune related disease of a cell, tissue, organ, animal or patient, including but not limited to chronic salicylate poisoning.

1. Heparanase Assays

The present invention further relates to methods of assaying heparanase activity. Thus, the effects of the compounds of the present invention can be assessed using such assays. Future candidate compounds useful in the methods of treatment of the present invention can also be assessed using the assays discussed herein. The present invention also relates to enzymes having glycosaminoglycan-degenerating activity, chondroitinase, heparan sulfate endoglycosidase, heparan sulfate exoglycosidase, polysaccharide lyase, keratanase, Compositions and methods for assays for measuring glycosidase activity, including but not limited to hyaluronidase, glucanase, amylase and other glycosidase and enzymes.

Thus, in one aspect, the present invention includes compositions and methods for measuring cell and enzyme activity. Such assays can be used to measure activity qualitatively and quantitatively. In addition, the assays contemplated by the present invention for determining the presence of such activity can be used in methods of diagnosing metastasis, likelihood of metastasis and inflammatory conditions. In addition, the assays of the present invention can also be used to screen for compounds that alter, stimulate or inhibit the activity of cells and enzymes.

Existing heparanase assays require the preparation of radiolabeled substrates and the separation of degraded products from undigested substrates. Goshen et al., 2 MOL. HUM.REPROD. 679-84 (1996); Nakajima et al., 31 CANCER LETT. See 277-83 (1986). Other heparanase assays require the measurement of HS chain degradation by biosynthetic radiolabeling of matrix-related HSPGs and gelfiltration analysis of radiolabelled material released from the matrix. See Vlodasky et al., 12 INVASION METASTASIS 112-27 (1992).

Solid-phase heparanase assays are developed to measure enzyme activity using radiolabels released from chemically and biosynthetically radiolabeled heparin and HS chains when they are attached to solid supports. have. Essays using such methods are taught in US Pat. No. 4,859,581, which is incorporated herein by reference in its entirety.

Previous studies have also radiolabeled both heparin and HS by iodination at naturally occurring glucosamine residues or by partially N-acetylation of di-N-sulfide substrates. Such procedures are very dangerous because they require the use of radioactive iodine, which is a strong emitter. For example, sensitive radioactive assays for heparanase require affinity chromatography of heparanase-degraded products in histidine-rich glycoprotein Sepharose columns. Freeman and Parish, 325 BIOCHEM. See J. 229-37 (1997).

There is also a non-radioactive assay applicable to heparanase. One assay for heparanase involves measuring the optical density (at 230 nm) of unsaturated uronic acid formed upon the decomposition of heparin. Color-based assays for measuring heparanase activity use heparin's ability to interfere with color development while proteins interact with the brilliant Coomassie brilliant blue. Kahn and Newman, 196 ANAL. BIOCHEM. See 373-76 (1991).

In other heparanase assays, a composition comprising biotin-HS is mixed with a biological sample, such as a tumor sample, bodily fluid, or other fluid suspected of having heparanase activity to form a reaction mixture. Such samples may be pretreated to remove contaminating or reactive substances such as endogenous biotin. After incubation, the fraction or part of the reaction mixture is removed and placed on a biotin-binding plate. After washing with buffer, streptavidin-enzyme conjugate is added to the biotin-binding plate. Reagents for the enzyme are added to form a detectable color product. For example, a reduction in collar formation from a known standard state indicates that there is heparanase activity in the sample. Biotin-binding plates, for example, comprise means for binding biotin to a solid surface. See WO 02/23197, which is incorporated herein by reference in its entirety.

In general, methods for measuring heparanase activity include attaching one binding partner to a substrate for the enzyme to be measured. Incubation with a sample containing the enzyme to be measured allows the activity of the enzyme to be measured in the reaction mixture. Depending on the amount required, some or all of the reaction mixture is then mixed with the complementary binding partner and the binding partners bind to each other. This is the first binding reaction. Washing is performed after incubation is performed for binding. A binding partner complementary to the first binding partner attached to the substrate is added. Such complementary binding partner may be the same as or different than the first complementary binding partner. This is the second binding reaction. Complementary binding partners in the second binding reaction are labeled in a detectable manner. For example, complementary binding partners are labeled with enzymes that produce a detectable color change in the presence of appropriate reaction conditions.

Some methods include using binding partners, including but not limited to biotin and streptavidin. Other methods of binding one of the binding partners, such as biotin, can be used in the biotin-binding step, binding the binding biotin to the plate, or detecting the available biotin. The number of biotin or other binding partners available for the second binding is a quantitative result of the assay. "Complementary binding partner" means one of a pair of binding partners, such as biotin and streptavidin or an antibody and antigen thereof. Biotin is the complementary binding partner of streptavidin; Streptavidin is a complementary binding partner of biotin. Antibodies that specifically bind biotin are also complementary binding partners of biotin.

The binding partner labeled in the method, ie, enzyme labeled-streptavidin, can be labeled by any detection marker, including but not limited to enzymes, dyes, chemiluminescence and other methods known in the art. Can be. One such method involves labeling with an enzyme that provides a detectable color change in an individual. These methods can be used in both safe, easy, effective, qualitative and quantitative methods.

Using this method, the amount of enzyme activity in a sample can be measured. The method can also be used to detect compounds that can inhibit enzymatic activity. For example, a composition comprising a candidate compound is added to a known amount of heparanase before or during the culturing of heparanase and its substrate-binding partner. If the compound alters the activity of heparanase, the assay method of the present invention will show a change in the amount of detectable label. Such assays are used to treat candidate compounds with high levels of detection of activity. See International Publication WO 02/23197, incorporated herein by reference.

C. Inflammation Modulation

The present invention relates to compositions and methods comprising compounds and molecules having specific biological effects and useful as therapeutic agents. In particular, the present invention relates to compositions and methods comprising compounds and molecules effective for inflammation. More specifically, the present invention relates to compositions and methods comprising compounds and molecules effective for inhibiting infections caused by the presence or accumulation of glycated proteins or AGEs. The invention also provides for the treatment of biological conditions including inflammation-induced diseases such as vascular complications of type I and type II diabetes-induced angiopathy, other angiopathies, microangiopathies, nephropathy, Alzheimer's syndrome and atherosclerosis. Provided compositions and methods, but not limited to these.

The present invention is useful for inhibiting infection or cellular activation by glycated proteins or AGEs. Pharmaceutical inhibition of AGE-induced cell activation provides the basis for therapeutic intervention of many diseases, in particular diabetic complications and Alzheimer's disease. Therapeutic approaches to inhibit AGE-induced infections include, but are not limited to, blocking of proteins' glycation, blocking of AGE-receptor interactions, and blocking of AGE-induced signaling or signaling-related inflammatory responses.

For example, the method of the present invention blocks the AGE effect by inhibiting AGE induced signaling. The sequence of these signaling events that induce inflammation is not clear, but suppressing these signaling events results in reduction or disappearance of the inflammation. Compounds blocking AGE-induced upregulation of inflammatory molecules are measured using screening assays. The present invention includes compositions and methods that include a compound or molecule, such as a thizolidinedione compound provided herein.

Another aspect of the invention includes compositions and methods comprising a compound that blocks glycated protein-induced inflammation. Another aspect of the invention includes tizolidinediones that can inhibit the AGE effect. Another aspect of the invention employs a composition comprising a compound having a formula contemplated herein, which blocks glycated protein-induced inflammation.

Enhancing the formation and accumulation of glycated proteins and AGEs is believed to play a major role in the pathogenesis of diabetic complications and atherosclerosis, thereby advancing a range of diabetic complications, including nephropathy, retinopathy and neuropathy. There is a great deal of in vivo evidence suggesting that diabetes-related complications can be reduced by 1) preventing glycation of proteins, 2) crosslink breakdown in glycated proteins, and 3) blocking the interaction of glycated proteins with receptors. . Despite the importance of AGEs in the pathogenesis of diabetic microangiopathy, there were no commonly available drugs known to block AGE formation.

Aminoguanidine that prevents AGE formation is actively used as a therapy for diabetic angiopathy. However, it is not clear whether these drugs usually affect the glucose metabolism or glycosylation of proteins. In addition, some studies report that although aminoguanidine reduces AGE formation, it does not inhibit glomerular basement thickness or improve endothelial function in diabetic rats. See, eg, Birrell et al., 43 DIABETOLOGIA 110-16 (2000); Wada et al., 42 DIABETOLOGIA 743-47 (1999); Soulis et al., 50 KIDNEY INT. See 627-34 (1996).

In addition to AGE formation inhibitors, AGE cross-link breakers are also actively used in the treatment for angiopathy. N-phenacrylthiazolium bromide (PTB) is a prototype AGE crosslinking breaker that reacts and degrades with covalent AGE-induced protein crosslinking. Although PTB reduces AGE accumulation, it does not prevent vascular permeability. Cooper et al., 43 DIABETOLOGIA 660-64 (2000); See Oturai et al., 49 (8) METABOLISM 996-1000 (2000).

Inhibition of response with AGE receptors is another approach to the treatment of related conditions. RAGE, a known receptor for AGEs, is a possible therapeutic target. RAGE blocking also inhibits AGE-induced inflammation. However, due to the multiple functions of RAGE and the occurrence of long-term side effects of AGE accumulated in plasma, this method is not commonly performed in humans. Using the compositions and methods of the present invention, more specific inhibitory compounds can be used for treatment.

Endothelium is a target organ that causes damage in diabetes. Laight et al., 15 DIABETES METAB. RES. REV. 274-82 (1999); Stehouwer et al., 34 CARDIOVASC. See 55-68 (1997). Up-regulation of molecules associated with endothelial inflammation, such as IL-6 and monocyte chemoattractant protein-1 (MCP-1), leads to endothelial dysfunction and angiopathy. Stehouwer et al., 34 CARDIOVASC. 55-68 (1997); Libby, 247 J. INTERN. MED. 349-58 (2000); Van Lente, 293 CLINIC.CHIMICA. ACTA. See 31-52 (2000).

A holistic approach to the treatment and understanding of diabetes mellitus and its complications is to regulate and interfere with cytokine producing genes and to inhibit AGE-induced inflammation.

The effect of the compounds of the present invention on the inhibition of glycated protein- and AGE-induced inflammation can be measured using the assays disclosed in US Provisional Application No. 60 / 259,306, which is incorporated herein by reference in its entirety herein. have. Such assays include the determination of the specific activity of biological components associated with known cellular responses. The assay provides a measurable response in which the activity of the compound is measured. One aspect of the invention involves measuring the effect of a compound on the inflammatory response by cells on the presence of a stimulant. Another aspect of the invention includes an assay comprising endothelial cells stimulated by the addition of glycated proteins, stimulants. Endothelial cells respond by the production of specific cytokines. The amount of cytokine produced is measured by measurement protocols known in the art. The compound of the present invention is then added to the assay and the production of cytokines is measured. The biological effect of a compound can be measured by comparing the assay with no compound and the assay with the compound. The compound may have an inhibitory effect, a stimulating effect or no effect at all. Compounds for treating inflammation include those having an inhibitory effect.

Essays include endothelial cells whose inflammatory response is stimulated by the presence of glycated proteins, glycated human serum albumin. Such endothelial cells produce cytokines. The method according to the invention comprises measuring the amount of cytokine IL-6 and another aspect of the invention comprises measuring the amount of cytokine MCP-1. Preferably, even if not needed, the amount of cytokine produced is measured using an immunization method such as an ELISA assay. The method of the present invention is not limited by the type of assay used to measure the amount of cytokine produced, and methods well known in the art and any methods to be developed later correspond to compounds having stimulant and known activity. It can be used to measure the amount of cytokines produced.

IL-6 is a pro-inflammatory cytokine 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. See 291-300 (2000). IL-6 also contributes to nephropathy by promoting the growth of renal intervascular cells. Kado et al. , 36 ACTA. DIABETOL. See 67-72 (1999). Serum IL-6 levels in diabetic subjects are much higher than normal healthy controls (3.48 +/- 3.29 pg / mL vs 0.784 +/- 0.90 pg / mL, mean +/- SD). Bladder IL-6 levels are also a good indicator of diabetic nephropathy. Serum IL-6 is useful for the evaluation of atherosclerosis and nephropathy.

MCP-1, another pro-inflammatory cytokine, has been shown to be highly expressed in human atherosclerosis and is considered to progress the pathology by acting as an arterial blood wall in the middle of monocyte recruitment. Libby, 247 J. INTERN. MED. See 349-58 (2000). Recent results indicate that MCP-1 is also an important pathogenic molecule 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 production of IL-6 and MCP-1. The effect of glycated albumin on IL-6 production is comparable to that of TNF-α, known as an inducer of IL-6. Since the role of these cytokines in vasculature is well established, screening for compounds that block AGE-induced cytokines provides a new approach to identifying therapeutic agents that block AGE-induced inflammation in vivo. .

Baseline responsiveness to stimulants for cytokine production by endothelial cells is established, and thus the method includes compounds with unknown activity as long as they contain control levels for screening assays. It adds. The effect of a compound on the baseline response is measured by comparing the amount of cytokine produced in the presence of a stimulant with the amount of cytokine produced in the presence of a stimulant and a compound of the invention. In one method, a compound having an inhibitory effect on inflammation of cells in the presence of glycated albumin is used as a therapeutic agent. One or more compounds may be added to the screening assay. Combinations or combinations of compounds may be added. Different amounts and formulations of compound are added to determine the effect of the screening assay. Screening assays can also be used to determine compounds that have no stimulating compounds or assay effects.

Table 2 shows examples of inhibiting pro-inflammatory cytokines IL-6 and MCP-1.

The invention also includes compositions comprising compounds identified by the method of the invention to have the desired activity. This composition has utility in the treatment of cells, tissues or whole organisms. Such compositions include, but are not limited to, effective amounts for treating biological conditions including type I or type II diabetes-induced angiopathy, other angiopathies, microangiopathies, renal failure, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis. Formulated for administration. Such compositions may also include a compound having the desired activity or a pharmaceutical adjuvant necessary for administering the compounds.

Compounds of the invention also include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemically initiated juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, negative serum reactive arthrosis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythema, Antiphospholipid Syndrome, Iris Cystitis / Uveitis / Ocular Neuritis, Idiopathic Pulmonary Fibrosis, Systemic Vasculitis / Wagner Granulomatosis, Sarcoidosis, Testicular / A vasectomy, Surgery, Allergy / Atopic Disease, Asthma, Allergic Rhinitis, Eczema, Allergy Contact dermatitis, allergic conjunctivitis, irritable pneumonia, transplantation, organ transplant rejection, transplant-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, triglyceride deficiency fever, urinary tract Septicemia, meningococcalemia, trauma / bleeding, burns, ionizing radiation exposure, acute pancreatitis, adult Respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory disease, Crohn's disease, sickle cell anemia, diabetes, nephropathy, atopic disease, endometriosis reaction, allergic rhinitis, hay fever, rhinitis rhinitis, conjunctivitis, endometriosis, asthma, Urticaria, systemic hypersensitivity, dermatitis, pernicious anemia, hemoemia, platelet deficiency, organ or tissue rejection, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant rejection, Skin allograft rejection, cartilage transplant rejection, bone graft rejection, small intestine transplant rejection, fetal thymus transplant rejection, parathyroid graft rejection, organ or tissue xenograft rejection, allograft rejection, anti-receptor hypersensitivity reaction, Grave disease, Raynaud Disease, type B insulin-resistant diabetes, asthma, myasthenia gravis mediated cytotoxicity, type III hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, Endocrine diseases, monoclonal gamma globulin disease and skin change syndrome), polyneuropathy, organomegaly, endocrine disease, monoclonal gamma globulin disease, skin change syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed combination Tissue disease, idiopathic Addison's disease, diabetes, chronic active hepatitis, vitiligo, vasculitis, post-MI heart incision syndrome, type IV hypersensitivity, contact dermatitis, irritable pneumonia, allograft rejection, granulomas due to intracellular organs, drug sensitivity, metabolic nature Idiopathic, Wilson's disease, hemochromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis, hypothalamic pituitary adrenal axis assessment, primary biliary sclerosis, appreciative adenitis, encephalomyelitis, cachexia, cystic fibrosis, newborn Chronic Lung Disease, Chronic Obstructive Pneumonia Disease (COPD), Familial Hematopoietic Phagocyte Lymphocytosis, Skin Disease, Psoriasis, Alopecia, Kidney Syndrome, Nephritis, Glomerulonephritis Enteritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, ankylosing myelitis, Behcet's disease, bullous swelling, cardiomyopathy, non-tropic spruce dermatitis, chronic fatigue immunodeficiency syndrome (CFIDS), chronic inflammatory dyslexia Conditions, Chuck-Strauss syndrome, scar-like swelling, CREST syndrome, cold aggregate disease, discoid lupus, essential mixed cold globulinemia, fibromyalgia-fibromyalitis, Graves' disease, acute idiopathic neuritis (Guillain-Barre), Hashimoto appreciation Adenitis, idiopathic thrombocytopenia, purpura (ITP), IgA kidney disease, insulin-dependent diabetes mellitus, adolescent arthritis, lichen planus, Ménière's disease, multiple sclerosis, common swelling, nodular polyarteritis, nasal liver syndrome, polychondritis, polysecretory syndrome, rheumatoid Sexual polymyalgia, polymyositis and dermatitis, primary angammagglobulinemia, Raynaud's syndrome, Reiter syndrome, rheumatic fever, shock Syndrome, muscle rigidity syndrome, Takayasu's arteritis, temporal arteritis / giant cell arteritis, Wegner granulomatosis; cells, tissues, organs, animals, including okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (including but not limited to tosthenia, anemia, cachexia), chronic salicylate poisoning, and the like Or for the treatment or prevention of one or more autoimmune related diseases in a patient. See, eg, The Merck Manual, 12th-17th Editions, Merck & Company, Rahway, NJ (1972, 1977, 1982, 1987, 1992, 1999); Pharmacotherapy Handbook, Wells et al., Eds., Second Edition, Appleton and Lange, Stamford, Conn. (1998, 2000).

D. Hyperproliferative Diseases

Some compounds of the present invention have cytotoxic activity and thus include, but are not limited to, malignant and nonmalignant cell growth, leukemia, acute leukemia, acute lymphocytic leukemia (ALL), B-cells, T-cells or FAB ALL, acute myeloid Leukemia (AML), Chronic Promyelocytic Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), Hair Cell Leukemia, Myelodysplastic Syndrome (MDS), Lymphoma, Hodgkin's Disease, Malignant Lymphoma, Non-Hodgkin's Lymphoma, Burkitt's Lymphoma , Multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic cancer, nasopharyngeal carcinoma, malignant histiocytosis, malignant neoplastic syndrome / hypercalcemia, solid cancer, adenocarcinoma, sarcoma, malignant melanoma, hemangioma, metastasis, cancer-related bones It is useful for treating or preventing one or more hyperproliferative diseases in cells, tissues, organs, animals or patients suffering from absorption, cancer related bone pain, or a combination thereof.

Drug-Coated Medical Devices

The compounds of the present invention can be used alone or in combination with other drugs to effectively prevent and treat vascular diseases, particularly vascular diseases caused by injury and / or transplantation. Various medical treatments used to treat vascular disease may eventually lead to other complications. Balloon dilatation, for example, is a process for increasing blood flow through an artery and is the main cardiovascular restenosis treatment. However, as mentioned above, this process typically inevitably causes some damage to the vessel wall, which further exacerbates the problem later. While other processes and diseases can cause similar damage, the compounds of the present invention are not used for restenosis and related complications after percutaneous transvascular coronary angioplasty and other similar arterial / venous treatments such as liver, lung, bladder, kidney, brain, prostate Describe the binding of conduits that carry arteries, veins, and other blood in other organs or parts of the body, such as the neck, legs, and the like.

Local delivery of the compound of the invention and optionally other therapeutic agents from the stent prevents revascularization and remodeling of blood vessels through the stent action of the stent. Drug coated stents can also prevent multiple components of neovascular endothelial hyperplasia or restenosis, as well as reduce inflammation and thrombosis. Topical administration of a compound of the present invention and other therapeutic agents to a splinted coronary artery can have a therapeutic effect. For example, higher tissue concentrations of the compounds of the invention and other therapeutic agents may achieve local delivery availability over systemic administration. In addition, reduced systemic toxicity can be achieved using local delivery rather than systemic administration while maintaining high tissue concentrations. In using local delivery from the stent rather than systemic administration, a single procedure will be sufficient in terms of patient compliance. Another advantage of the combination of therapeutic agents and / or compounds is that by reducing the dosage of each therapeutic agent, it is possible to reduce restenosis, inflammation and thrombosis while limiting toxicity. Topical stent-based therapy is a means of improving the treatment rate (efficiency / toxicity) of anti- restenosis, anti-inflammatory and anti-thrombosis therapeutics.

While the compounds exemplified herein have been described in connection with the treatment of restenosis and other related complications, topical delivery of the compounds of the invention may be used to treat a variety of conditions using a therapeutic device, either alone or as part of a therapeutic combination, or It can be used to improve the function and / or life of. For example, an intraocular lens placed to restore vision after cataract surgery is endangered by secondary cataract formation. Secondary cataracts are often the result of excessive cell growth on the surface of the lens and can be minimized by combining the drug or drugs with the device. Failure due to tissue growth or accumulation of protein material in, above, and around the device, such as hydrocephalus shunts, dialysis grafts, premature ejaculation bag attachments, ear drains, pacemakers, and implantable defibrillator leads Other medical devices that are easy to carry may benefit from the device-drug / drug combination. Other surgical devices, sutures, anastomotic devices, intervertebral discs, bone pins, suture supports, hemostatic barriers, clamps, screws, plates, clips, vascular grafts, tissue adhesives and sealants, tissue props, various types of dressings, bone substitutes, endometrium The device and vascular support can be benefited using the drug-device combination. Certain types of medical devices may be coated with the compounds of the present invention in some manner, either alone or as part of a therapeutic combination that enhances the therapeutic effect relative to a single use of the device or therapeutic agent.

In addition to various medical devices, coatings may include vinca alkaloids (such as vinblastine, vincristine and vinoreblin), paclitaxel, epipodophyllotoxins (eg etoposide, teniposide), antibiotics (dactinomycin (actino) Mycin D) daunorubicin, doxorubicin and idarubicin), anthracycline, mitoxanthrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzymes (L-asparagine as a whole metabolize and have this ability Non-proliferative / antimitotic agents such as L-aspraginase), which does not synthesize their asparagine; Antiplatelet agents such as G (GP) IIb / IIIa inhibitors and vitronectin receptor antagonists; Nitrogen mustard (mechloretamine, cyclophosphamide and analogues, melfaran, chlorambucil), ethyleneimine and methylmelamine (hexamethylmelamine and thiotepa), alkyl sulfonate-busulfan, nitrosoureas (carr Antiproliferative / antimitotic agent alkylating agents such as mustin (BCNU) and analogs, streptozosin), trazene-dacarbazinin (DTIC); Folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, phloxuridine and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)) Antiproliferative / antimitotic agent metabolites such as; Platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotan, aminoglutetimide; Hormones (eg estrogens); Anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); Fibrin degradants (tissue plasminogen activators, streptokinase and urekinase), aspirin, dipyridamole, ticlopidine, clopidogrel, absiksimab; Antimigration agents; Antisecretory agents (brepiddine); Anti-inflammatory agents such as adrenocorticosteroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, trimcinolone, betamethasone and dexamethasone), nonsteroidal agents (salicylic acid derivatives, ie aspirin); Para-aminophenol derivatives, namely acetominophene; Indole and indene acetic acid (indometacin, sulindac and etodalak), heteroaryl acetic acid (tolmethine, diclofenac and ketorolac), arylpropionic acid (ibuprofen and derivatives), anthranilic acid (mefenamic acid, and meclofenamic acid) ), Enolic acid (pyoxycham, tenoxycam, phenylbutazone, and oxypenttrazone), nabumethone, gold compounds (auranopine, aurothioglucose, gold sodium thiomalate); Immunosuppressive agents (cyclosporin, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, myophenolate mofetil); Angiogenesis agents; Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF); Angiotensin receptor blocker; Oxynitrate donors; Antisense oligonucleotides and combinations thereof; It can be used to deliver a compound of the invention in combination with other therapeutic agents including cell cycle inhibitors, mTOR inhibitors, and growth factor signal inducing kinase inhibitors.

While a number of stents can be used in accordance with the present invention, for convenience, only a limited number of stents will be described herein. Those skilled in the art will appreciate how many stents will be used in connection with the present invention. In addition, as described above, other medical devices may also be used.

Stents are often used as the coronary structure on the left side of the lumen to alleviate the disorder. Typically, the stent is inserted into the lumen in its unexpanded form and then automatically inflated or inflated with the aid of a secondary device in place. A general dilation method is performed using a catheter-attached dilator balloon, which is inflated in the constricted blood vessel or in the body passage to shear and destroy the disorder associated with the wall component of the blood vessel to obtain an enlarged lumen.

The stent is similar to an inflatable cylinder and may include a window structure in the vessel, conduit or lumen to keep the vessel, conduit or lumen open to prevent re-stenosis of the arterial section after vasodilation. The stent is circumferentially expanded to maintain an expanded structure that is circumferentially or radially rigid. The stent is axially flexible and when bent in a band, the stent prevents the component from projecting outward.

Stents can be created using a number of methods. For example, the stent can be made from hollow or molded stainless steel tubes that can be processed using lasers, electro blast mills, chemical etching or other means. The stent is inserted into the body and placed in the unexpanded form at the desired site. Inflation is performed intravascularly by a balloon catheter and the final diameter of the stent is a function of the diameter of the balloon catheter used. It should be noted that the stent according to the invention can be made of shape memory materials, including suitable alloys of nickel and titanium or stainless steel.

The structure formed of stainless steel can be made self-expandable by structuring the stainless steel in a predetermined manner by twisting it into a ribbon structure. After the stent has been formed, it can be compressed by the insertion means to occupy a small enough space for insertion into blood vessels or other tissues, the insertion means including a suitable catheter, flexible rod. The moment the stent leaves the catheter, the stent can expand into the desired structure, which is either automatic or caused by a change in pressure, temperature or electrical stimulation.

The stent may also be modified to include one or more reservoirs. Each reservoir may be open or closed as needed. These reservoirs can be specifically designed to hold the therapeutic agent / therapeutic combination to be delivered.

Regardless of the design of the stent, it is desirable to administer the therapeutic / therapeutic combination in sufficient specificity and in sufficient concentration to provide an effective dosage to the diseased area. In this regard, the reservoir size in the band should be such that the therapeutic / therapeutic combination dosage can be applied to the desired location and desired amount.

Alternatively, the entire inner and outer surface of the stent can be coated with a therapeutic dose / therapeutic combination. This coating technique may vary depending on the therapeutic / therapeutic combination. This coating technique may also vary depending on the material including the stent or other lumen medical device.

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

Many non-edible polymers can be used in combination with the compound. According to one aspect of the invention, the polymer matrix comprises two layers. The base layer comprises a solution of poly (ethylene-covinylacetate) and polybutyl methacrylate. The compound is incorporated into the base layer. The outer layer contains other polybutyl methacrylates and acts as a diffusion inhibitor to prevent the compounds from rapidly eluting. The thickness of the outer layer or top coat determines the rate at which the compound elutes from the matrix. The compound elutes from the matrix by diffusion through the polymer matrix. The polymer is permeable, allowing solids, liquids, and gases to be released therefrom. The overall thickness of the polymerizable matrix is from about 1 micron to about 20 microns or more. It is important to use a primer layer and metal surface treatment before the polymeric matrix is immobilized on the medical device. For example, acid washing, alkaline (basic) washing, salinization and parylene deposition can be used as part of the overall process described above.

Poly (ethylene-co-vinylacetate), polybutylmethacrylate 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 submerged in the solution. The solution is sprayed onto the stent and then dried. This solution can be electrically charged with one polarity and the stent is electrically charged with the opposite pole. In this way, the solution and the stent are attracted to each other. When using the spray process, waste can be reduced and more precise control of the coating thickness is possible. Other methods include spin coating and plasma polymerization.

Drug coated stents include Johnson & Johnson, Inc. (New Brunswick, NJ), Guild Corporation (Santa Clara, CA), Medtronic Inc. (Minneapolis, Minnesota), Cook Group Inc. It is manufactured by a number of companies, including Rating (Bloomington, Indiana), Abbott Labs, Incorporated (Abbott Park, Illinois), and Boston Scientific Corporation (Natic Massachusetts). See, eg, US Pat. No. 6,273, 913; US Patent Application 20020051703; WO 02/26271; And WO 02/26139, each incorporated herein by reference.

Expression profiles and Microarray  How to use

The present invention includes a number of microarrays that can be used to study and regulate gene expression for treatment using the compounds of the present invention. For example, the microarrays of the invention include human microarrays, vascular microarrays, inflammatory microarrays, cancer microarrays, apoptosis microarrays, oncogene and tumor suppressor microarrays, cell-cell interaction microarrays, cytokine and cytokine receptors. It can be derived from representatives of certain organs or cell types, including microarrays, blood microarrays, cell cycle microarrays, neuroarrays, mouse microarrays, and murine microarrays or combinations thereof. Microarrays can represent diseases including cardiovascular disease, angiopathy condition, inflammatory disease, autoimmune disease, nervous system disease, immune disease, various cancers, infectious diseases, endocrine disorders and hereditary diseases.

Alternatively, microarrays useful for evaluating the efficacy of the compounds of the present invention exhibit certain tissue types, including but not limited to heart, liver, prostate, lung, nerve, muscle or connective tissue; For example, coronary endothelial cells, umbilical artery endothelial cells, umbilical vein endothelial cells, aortic endothelial cells, skin microvascular endothelial cells, pulmonary artery endothelial cells, myometrial microvascular endothelial cells, keratinocyte epithelial cells, bronchial epithelial cells, breast epithelial cells Prostate epithelial cells, renal cortical epithelial cells, renal proximal tubular epithelial cells, bovine airway epithelial cells, renal epithelial cells, umbilical artery smooth muscle, neonatal skin fibroblasts, pulmonary artery smooth muscle, skin fibroblasts, neural progenitor cells, skeletal muscle, astrocytes , Aortic smooth muscle, intervascular cells, coronary smooth muscle, bronchial smooth muscle, uterine smooth muscle, lung fibroblasts, osteoblasts, prostate stromal cells, or a combination thereof.

The invention also includes a microarray comprising a gene expression profile comprising at least one polynucleotide sequence comprising complementary and homologous sequences, said gene expression profile being generated from a cell type treated with a compound of the invention In addition, coronary endothelial cells, umbilical artery endothelial cells, umbilical vein endothelial cells, aortic endothelial cells, skin microvascular endothelial cells, pulmonary artery endothelial cells, myometrial microvascular endothelial cells, keratinocyte epithelial cells, bronchial epithelial cells, and breast epithelial cells. Prostate epithelial cells, renal cortical epithelial cells, renal proximal tubular epithelial cells, bovine airway epithelial cells, renal epithelial cells, umbilical artery smooth muscle, neonatal skin fibroblasts, pulmonary artery smooth muscle, skin fibroblasts, neural progenitor cells, skeletal muscle, astrocytes , Aortic smooth muscle, intervascular cells, coronary smooth muscle, bronchial smooth muscle, uterine smooth muscle, lung Is selected from hair cells, the group consisting of osteoblasts, and prostate stromal cells.

The present invention includes microarrays comprising one or more protein-binding agents, wherein protein expression profiles are generated from cell types treated with the compounds of the present invention and further include coronary endothelial cells, umbilical artery endothelial cells, umbilical vein endothelial cells, Aortic endothelial cells, cutaneous microvascular endothelial cells, pulmonary artery endothelial cells, myometrial microvascular endothelial cells, keratinocyte epithelial cells, bronchial epithelial cells, breast epithelial cells, prostate epithelial cells, neocortical epithelial cells, renal proximal tubular epithelial cells, Bovine airway epithelial cells, renal epithelial cells, umbilical artery smooth muscle, neonatal skin fibroblasts, pulmonary artery smooth muscle, skin fibroblasts, neural progenitor cells, skeletal muscle, astrocytes, aortic smooth muscle, intervascular cells, coronary artery smooth muscle, bronchial smooth muscle, uterus Smooth muscle, lung fibroblasts, osteoblasts and prostate stromal cells.

More particularly, the present invention includes methods for reproducibly measuring and evaluating the expression of a particular mRNA or protein in a particular cell set. One method involves laser capture microdissection (LCM), T7 base RNA amplification, production of cDNA from amplified RNA, and DNA microarray containing immobilized DNA molecules for a variety of specific genes, including HSPGs such as perlecan. Are combined and used to generate gene expression analysis profiles for a very small number of specific cells. Desired cells are individually identified or attached to the substrate by laser capture techniques, and the captured (captured) cells are separated from residual cells. RNA can be extracted from the captured cells, amplified by about 1 million times using a T7-based amplification technique, and cDNA can be prepared from the amplified RNA. Various kinds of specific DNA molecules and DNA molecules that hybridize to specific polynucleotides of the microarray are immobilized on a suitable substrate. CDNA prepared from the captured cells was applied to the microarray under conditions that allowed the cDNA to hybridize to fixed DNA on the microarray. Expression profiles of captured cells are obtained from analysis of hybridization results using specific immobilized DNA molecules on microarrays and cDNA prepared from amplified RNA or amplified RNA of captured cells. Hybridization results indicate that genes probed on microarrays hybridize to cDNA obtained from captured cells and / or specific gene expression amounts. This hybridization result shows the gene expression profile of the captured cells. Gene expression profiles of captured cells can be used to compare gene expression profiles of different sets of captured cells. For example, gene expression profiles can be generated from cells treated (and not treated) with the compounds of the present invention. These similarities and differences provide useful information for measuring differences between the same cell types under different conditions, more particularly changes in gene expression for treatment of the compounds of the invention.

The techniques used for gene expression analysis can also be applied to protein expression profiles. The whole protein can be isolated from the sample and hybridized to a microarray comprising a plurality of protein binders which can include antibodies, receptor proteins and small molecules. Using several assays known in the art, hybridization can be detected and analyzed as described above. For fluorescence detection, algorithms can be used to extract protein expression profile representatives of specific cell types. In this regard, changes in protein expression for cell therapy with the compounds of the invention can be assessed.

Thus, in one embodiment, the present invention relates to a gene population obtained using a specific tissue or cell tissue to detect changes in the gene electron level obtained by exposing the selected tissue or cell to a candidate drug, such as a compound of the invention. At least one corresponding microarray. Biological samples derived from living organisms or established cell lines can be exposed to candidate drugs in vivo or in vitro. Thereafter, gene transcripts of tissues or cells, mainly mRNA, are isolated by known methods. SAMBROOK ET AL., MOLECULAR CLONING: A LAB. MANUAL (2001). The isolated transcript is contacted with the microarray under conditions such that the transcript hybridizes with the corresponding probe to form a hybridized pair. Thus, microarrays provide a model of transcriptional reactivity after exposure to certain drug candidates. Hybridization signals are detected in hybridization pairs to obtain gene expression profiles.

Gene and / or protein profiles and microarrays can be used to identify compounds that activate or deactivate certain genes, such as perlecan or other HSPGs. Compounds that increase the rate of transcription of the protein or stimulate, maintain or stabilize the activity are considered activation and compounds that decrease or inhibit the rate of protein activation are considered inactive. The biological effects of the compounds also reflect the biological state of the cells. This condition is characterized by cellular components. One aspect of the biological state of a cell is the transcriptional state. The transcriptional state of a cell includes the identification and amount of constituent RNA species, especially mRNA, in a given set of conditions. Thus, gene expression profiles, microarrays and algorithms discussed herein are used to characterize and analyze the transcriptional status of certain cells or tissues after exposure to activating or inactivating compounds, especially compounds of the invention.

Microarray techniques and methods for analyzing the results are known in the art. US Patent 6,263, 287 6,239, 209; 6,218,122; 6,197,599; 6,156,501; 5,874,219; 5,837,832; 5,700,637; 5,445,934; US Patent Application 2001/0014461 A1; 2001/0039016 A1; 2001/0034023 A1; WO 01/94946; And WO 01/77668. See Haab et al., 2 GENOME BIOLOGY 1-12 (2001); Brown et all. 97 PROC. NATL. ACAD. SCI. USA 262-7 (2000); Getz et al., 97 PROC. NATL. ACAD.SCI. USA 12079-84 (2000); Harrington et al., 3 CURRENT OPIONION MICROBIOL 85-91 (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 GENE 10-14 (1999); Lipshutz et al., 21 NATURE GENET 5-9 (19990: Eisen et al., 95 PROC. NATL. ACAD. SCI. USA 14863-68 (1998); Ermolaeva et al., 20 NATURE GENET 19-23 (1998) Hacia et al., 26 NUCELEIC ACDIS 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 ACID RES. 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); Shena et al., 270 SCIENCE 467-70 (1995).

Database creation, database access and how to use it

The present invention includes a number of methods for providing diagnostics and predictions relating to biomolecules, including HSPGS, in particular perlecan. The invention also includes methods for providing diagnostics and predictions related to the efficacy of the compounds of the invention. The invention also provides a method of providing an expression profile database, and a method of generating a database of normal and diseased tissue.

The expression profile database may be an internal database designed to include annotated information about expression profiles generated through other sources and methods to assess the effects of the compounds of the present invention. Such information may be stored in cDNAs related to information, sequences, tissues or cell sources related to the compounds of the present invention such as patient information, dosage and administration information related to expression profiles including age, cancer or tumor type, for example. Technical information, sequences from external sources, expression profiles for certain genes and related disease states or disease pathways, databases of expression profiles related to specific disease states, and methods of preparation. Expression profiles can be based on protein and / or polynucleotide microarrays that are commercially available or available from proprietary sources. The database can be divided into two parts: one for storing sequences and related expression profiles and one for storing related information. This database can be stored as a private database with a firewall in a central computer facility. However, the present invention is not limited to these and expression profile databases can be published to the public.

The database may be a network system that connects a network server with a customer. The network may be a conventional network system including a local area network (LAN) or a wide area network (WAN) known in the art (eg Ethernet). The server may include software for providing an interface for accessing database information that processes user requests and providing information to a customer machine. The server may support the World Wide Web and may support web sites and web browsers for use by customers. Customer / server environments, database servers, and networks are well documented in industrial, commercial, and patent literature.

Through a web browser, a customer can create a search request to retrieve data, such as a microarray database and an expression profile database. For example, a user may click on user interface elements such as buttons, pulled down menus, and scroll bars. The customer's request is passed to a web application, which generates a questionnaire that can be used to gather information from a system database based on microarray or expression data obtained by the customer and / or other phenotypic or genotyping information. In particular, the customer submits expression data based on the microarray expression profile obtained from a patient treated with a compound of the present invention and uses the system to compare the expression data contained in the database with the system of the client's expression data. Can be diagnosed. As an example, the system compares the expression profile submitted by the customer with the expression profile contained in the database and then provides the client with diagnostic information based on the best match of the customer expression profile with the database profile. Thus, in one embodiment, control of the expression profile assists the physician in determining the efficacy of treatment with a compound of the present invention. Based on this control, the physician can change or adjust the treatment plan.

The website also provides hypertext links to published databases such as GenBank and related databases stored by the National Center for Biotechnology Information (NCBI), part of the National Library of Medicine, as well as gene expression analysis, genetic disorders, and scientific literature. Provide a link that provides relevant information about. Information, including identifiers, identifier types, biomolecule sequences, common cluster identifiers (GenBAnk, Unigene, Incyte template identifiers, etc.) and species names associated with each species.

The present invention provides a system for evaluating and comparing useful biometric information, particularly expression profiles and other information, in connection with the compositions and methods of the present invention. The computer system includes a computer processor, a suitable memory functionally coupled to the computer processor, and a computer process stored in a memory performed by the computer processor, and the expression profile of the biomolecule sequence obtained from the patient may include the expression profile of the biomolecule sequence in the database and The method may further include means for matching the sequence identification information. More particularly, the computer system is used to match expression profiles generated from biological samples treated with the compounds of the present invention to expression profiles and other information in a database.

In addition, a system for evaluating and collating information contained in a biomolecule database is provided for matching expression profiles generated from patients treated with a compound of the present invention to expression profiles and sequence identification information of biomolecule sequences in the biomolecule database. It includes a computer program that includes computer code that provides an algorithm.

The present invention involves the use of a graphical user interface (GUI) to access expression profile information stored in a biomolecule database. The GUI may consist of two frames. The first frame may contain a selectable list of biomolecule databases that can be accessed by the user. If a biomolecule database is selected for the first frame, the second frame can display the information resulting from pairing matching with the expression profile database along with the phenotype or genotype information other than the customer provided expression profile described above.

The second frame of the GUI may contain a list of biomolecule sequence expression information and profiles contained in the selected database. The second frame also allows the user to select a subset containing all biomolecule sequences and to act on the list of biomolecule sequences. The user can select a subset of biomolecule sequences by selecting a selection box associated with each biomolecule sequence. Tasks that can be performed include, but are not limited to, downloading all listed biomolecule sequences with classification information in a database spreadsheet, storing selected subsets of biomolecule sequences in user files, and storing all listed biomolecule sequences without classification information in the database. Downloading to the spreadsheet and displaying the classification information on a subset of the selected biomolecule sequences.

If the user displays classification information on a subset of the selected biomolecule sequences, a second GUI may be provided to the user. The second GUI may contain a list of one or more external databases used to create the expression profile database described above. In addition, for each external database, the GUI may present a list of one or more disciplines associated with each external database. The GUI allows the user to select or deselect one or more fields displayed in the second GUI. The GUI allows the user to select or deselect each of one or more external databases.

The method of the invention also relates to the commercial use of the compositions and methods of the invention. In one embodiment, the method relates to providing an expression profile database comprising a database provided to a consumer, ie, to a patient, doctor, health care provider, researcher, and pharmaceutical provider and manufacturer, in accordance with the use of a compound of the invention. Marketing, sales or licensing of the compositions and methods of the invention.

The method of the present invention includes establishing a distribution system for distributing the pharmaceutical composition of the present invention for sale and optionally establishing a sales group for marketing the pharmaceutical composition.

The present invention also provides a method for performing target discovery comprising identifying a test compound as described above by one or more drug discovery methods, which modulate the degree of expression of a gene or the activity of a gene product, such as perlecan. To; The therapeutic profile of the identified drug or analogue thereof is conducted for efficacy and toxicity in the animal; And formulating a pharmaceutical composition comprising one or more therapeutic agents identified as having an acceptable treatment profile; And optionally to license or sell rights for the development of the identified drug.

The invention is illustrated in more detail by the following Preparation Examples and Examples, which should not be construed as limiting the scope of the invention. Also, various other modifications, embodiments, and equivalents will be apparent to those skilled in the art without departing from the spirit of the invention and / or the scope of the appended claims.

Preparation Example 1

1- [4- (2-bromoethoxy) phenyl] -1-ethanone

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. After adding a part of dibromoethane (38 mL) to the reaction mixture, the reaction mixture was refluxed under a nitrogen atmosphere for 36 hours. The reaction mixture was cooled to room temperature and filtered, the residue was washed with acetone (2x100 mL), the filtrates were combined and concentrated under reduced pressure. Crude 10-15% ethyl acetate / pet. Chromatography on silica gel with ether (2 L) gave 7 g (20%) of the target compound as a white solid. Mp.58-61 ℃

Preparation Example 2

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

Step (i):

3-[(6-0- (dioxy-aL-manopyranosyl) -β-glucopyranosyl) oxy] -2- (3, 4-dimethoxyphenyl) -5,7-dimethoxy-4H-1 -Benzopyran-4-one

Rutin hydrate (1) (80 g, 120.5 mmol) and potassium carbonate (320 g, 2319 mmol) were added to a 2 L three-neck round bottom plastic and a reflux condenser with nitrogen atmosphere and dropping funnel was prepared. And acetone (1.5 L) was added. Dimethyl sulfate (160 mL) was added dropwise to the reaction mixture. 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 off. The residue was washed with acetone (1 L) followed by methanol (500 mL) and the filtrates were combined and concentrated under reduced pressure to afford the target compound (80 g, 91%) as a yellow gummy solid.

Step (ii):

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

The compound (80 g, 110 mmol) obtained in step (i) was placed in a 2 L single neck round bottom flask and hydrochloric acid (20%, 1 L) was added at 25 ° C. 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 under vacuum to give the target compound (27.5 g, 70%) as a pale yellow solid. Mp.192-194 ℃

Preparation Example 3

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

A mixture of the compound obtained in Preparation Example 2 (25 g, 69.6 mmol), the compound obtained in Preparation Example 1 (21.5 g, 88.4 mmol) and potassium carbonate (77 g, 557 mmol) was added to a 1 L round bottom flask, and DMF (400 mL) was added. To the reaction mixture. The reaction mixture was heated to 80 ° C. for 3 hours under nitrogen atmosphere with stirring. The reaction mixture was cooled to 25 ° C. and slowly poured into ice cold water (1 L). The separated solid was filtered off and washed with water (2x500 mL). Triturated with methanol, filtered and filtered under vacuum to afford the target compound (31.5 g, 87%) as a pale brown solid. Mp.143-144 ℃

Preparation Example 4

4-fluorophenylacetate

4-fluorophenol (20 g, 178.5 mmol) was added to a 1 L one-necked round bottom flask and sodium hydroxide solution (12 g in 100 mL water) was added. 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 at the same temperature for 15 minutes and 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 target compound (26 g, 95%) as a white solid.

Preparation Example 5

(2-hydroxy-4-fluorophenyl) -l-ethanone

A mixture of 4-fluorophenylacetate (25 g, 223 mmol) and aluminum chloride (89 g, 670 mmol) obtained in Preparation Example 4 was placed in a 1 L one-necked round bottom flask and equipped with an air condenser and calcium chloride guard tube. It was. The reaction mixture was slowly heated to 120-125 ° C. for 30 minutes and then to 165 ° C. (generation of HCl gas was observed). The mixture was stirred at the same temperature for 30 minutes and then cooled to room temperature. Water (500 mL) was added followed by 6N HC1 (150 mL). The mixture was extracted with chloroform (3x 200 mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the target compound (21 g, 84%) as a white solid.

Preparation Example 6

1- (5-fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) -2-propen-1-one

Sodium hydroxide solution in a mixture of (2-hydroxy-4-fluorophenyl) -l-ethanone (3 g, 19.7 mmol) obtained in Preparation Example 5 and 4-fluorobenzaldehyde (4.37 g, 19.7 mmol) in methanol It was slowly added under 0 ℃, N ₂ atmosphere. The mixture was stirred at 0-10 ° C. for 10 hours. Water (100 mL) was added followed by 6N HC1 (15 mL). The separated solid was filtered and dried in vacuo to give 3 g (41%) of the target compound as a yellow solid.

Preparation Example 7

6-fluoro-2- (4-methoxyphenyl) -3-hydroxy-4H-4-chromenone

The chalcon product (3.0 g, 11 mmol) obtained in Preparation Example 6 was dissolved in methanol (30 mL) and cooled to 0 ° C. Sodium hydroxide solution (20 mL, 20%) was added to the mixture and the reaction mixture was stirred at the same temperature for 5-10 minutes. Hydrogen peroxide was added to the mixture and stirred at 0-10 ° C. for 1 hour. Water (100 mL) was added followed by 6N HCI (30 mL). The separated solid was filtered and dried under vacuum to yield 1.0 g (32%) of the target compound as a yellow solid.

Preparation Example 8

1- (4- {2- [6-fluoro-2- (4-methoxyphenyl) -4-oxo-4H-3-chromenoxyoxy} phenyl) -1-ethanone

A mixture of the product obtained in Preparation Example 7 (0.3 g, 1.04 mmol), the compound obtained in Preparation Example 1 (0.25 g, 1.04 mmol) and potassium carbonate (0.86 g, 6.2 mmol) was placed in a 1 L round-bottomed flask and DMF ( 15 mL) was added to the mixture. The mixture was heated to 80 ° C. under nitrogen atmosphere for 3 hours under stirring. The reaction mixture was cooled to 25 ° C. and poured slowly into ice cold water (1 L). The separated solid was filtered off and washed with water (2x500 mL). Triturate with methanol, filter and dry under vacuum to afford the target compound (0.4 g, 85%) as a pale brown solid.

Preparation Example 9

N-methyl anthranilic acid

To a solution of methyl-N-methyl anthranilate (20 g, 121 mmol) in methanol (100 mL) in a 250 mL one-neck round bottom flask was added a solution of NaOH (9.69 g, 242 mmol) in 25 mL of water at 0-10 ° C. The reaction mixture was heated to 50 ° C. for 6 hours and then cooled to room temperature. Methanol was completely removed from the reaction mixture and water (100 mL) was added. The mixture was washed with ether (3x50 mL) and the aqueous layer was acidified with cold 2N HC1 (pH-5-6). The separated solid was filtered, washed with water (2x50 mL) and dried under vacuum to give 17.0 g (93%) of the target compound as a white solid. mp-178-180 ℃

Preparation Example 10

2-bromo-l- (4-methylphenyl) -l-ethanone

To a stirred solution of 20 g (150 mmol) of 4-methylacetophenone in 100 mL of cold acetic acid was added dropwise at 10-15 ° C. a catalytic amount of HBr (0.5 mL) followed by 21.40 g (134 mmol) of bromine dissolved in acetic acid (30 mL). . 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%).

Preparation Example 11

2- (4-methylphenyl) -2-oxoethyl-2-methylaminobenzoate

To a solution of N-methyl anthranilic acid (10.Og, 66 mmol) obtained in Preparation Example 9 in 100 mL of dimethyl formamide in a 250 mL one-necked round bottom flask was added KOH (3.89 g, 69 mmol) solution in 10 mL of water. The mixture was stirred at 25-35 ° C. for 45 minutes. The mixture was cooled to 10 ° C. and bromoketone (16.9 g, 79 mmol) obtained in Preparation 10 was added. The reaction mixture was stirred at room temperature for 10 hours and then poured into ice cold water (500 mL). The separated solid was filtered off, washed with water (2 × 100 mL) and dried under vacuum to afford the target compound (11.0 g, 58%) as a white solid. Mp: 96-98 ° C.

Preparation Example 12

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

Polyphosphoric acid (PPA, 80 g) was heated to 140 ° C. under nitrogen atmosphere in a 250 mL one-neck round bottom flask. A small amount of 2- (4-methylphenyl) -2-oxoethyl-2-methylaminobenzoate (10 g, 35 mmol) obtained in Preparation Example 11 was added and the mixture was stirred at 140 ° C. for 6 hours. The mixture was cooled to 25-35 ° C. and ice cold water was added and the mixture stirred for 30 minutes. The separated solid was filtered, washed with water and dried in vacuo to give the target compound (6.0 g, 73%) as a brown solid. Mp. 216-218 ° C.

Preparation Example 13

4- (2-bromoethoxy) benzaldehyde

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 one portion of dibromoethane (46 g) was added and the reaction mixture was stirred at 25-35 ° C. for 96 hours under nitrogen atmosphere. The reaction mixture was cooled to 25-35 ° C. and 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. Crude product was 10-15% ethyl acetate / pet. Purification by column chromatography on silica gel using ether gave the target compound (8.50 g, 45%) as a white solid.

Preparation Example 14

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

A mixture of the hydroxy compound (3.0 g, 11 mmol) obtained in Preparation Example 12, the bromoketo compound (2.43 g, 10 mmol) and potassium carbonate (6.24 g, 45 mmol) obtained in Preparation Example 1 was placed in a 1 L round bottom flask. DMF (30 mL) was added. The mixture was heated to 80 ° C. under stirring and kept at this temperature for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25 ° C. and poured slowly into ice cold water (1 L). The separated solid was filtered off and washed with water (2x500 mL). Trituration with methanol, filtration and drying in vacuo gave the target compound (2.8 g, 64%) as a pale brown solid.

Preparation Example 15

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

Step (i)

To a solution of 4-hydroxybenzoic acid (15 g, 108.6 mmol) in ethanol (200 mL) was added SOC1 ₂ (16 mL, 217.4 mmol) at 10 ° C. under anhydrous condition. The mixture was heated to reflux for 7 hours with stirring. After completion of the reaction, the mixture was concentrated in vacuo and the residue was neutralized with aqueous NaHCO ₃ solution until pH was 7.0. The separated solid was filtered, washed with water (2x50 mL) and dried under vacuum to afford the desired compound in 89% yield (16 g).

Step (ii)

A mixture of 4-hydroxybenzoester (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 nitrogen atmosphere. 1,2-dibromoethane (34 g, 180.7 mmol) was added to the mixture at the same temperature and stirred for 6 hours. The mixture was filtered and the residue washed with acetone (2x25 mL). The filtrates were collected, collected and concentrated. The residue was purified by crystallization with hexanes to give the desired desired product in 96% yield (6.0 g).

Preparation Example 16

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

2- (3,4-dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone (4 g, 11.17 mmol) obtained in Preparation Example 2 in DMF (20 mL), Preparation Example The mixture of 4- (2-bromo-ethoxy) -benzoic acid ethyl ester (3.66 g, 13.40 mmol) and K ₂ CO ₃ (4.62 g, 33.51 mmol) obtained in 15 was stirred at 80 ° C. for 9 hours under a nitrogen atmosphere. It was. The mixture was poured into water (60 mL) and stirred for 30 minutes. The separated solid was filtered, washed with water (2x20 mL) and dried under vacuum to afford the desired product in 68% yield (4.2 g).

Preparation Example 17

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

4- {2- [2- (3,4-dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H obtained in Preparation Example 16 in a mixture of methanol (40 mL) and dioxane (40 mL). To a solution of -chromen-3-yloxy] -ethoxy} -benzoic acid ethyl ester (4 g, 7.27 mmol) was added a solution of KOH (2.0 g, 36.36 mmol) in water (10 mL) at 25-35 ° C. and the mixture Stir at 60 ° C. for 6 hours. The solvent was removed from the mixture under vacuum and the residue acidified with cold HC1. The separated solid was filtered, washed with cold water (2 × 3 mL) and dried under vacuum. The crude product was further crystallized and purified with ethanol to give the desired acid in 84% yield (3.2 g).

Preparation Example 18

2- (Toluene-4-sulfonylamino) -succinic acid

To a stirred solution of L-Aspergine (15 g, 100 mmol), NaOH (4.4 g, 110 mmol) in a mixture of water (75 mL) and dioxane (75 mL) was added p-toluenesulfonyl chloride (20.9 g, 110 mmol). Add at 0 ° C. 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. After stirring for 1 hour, dioxane was removed from the mixture under vacuum. The residue was washed with ethyl acetate (2x30 mL) to collect an aqueous layer and acidified with concentrated hydrochloric acid at 0 ° C. with very slow stirring. The separated solid was filtered and washed with cold water (2x30 mL) to give the desired product in 59% yield (17 g). mp: 198-200 ° C.

Preparation Example 19

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

Step (i):

3-Amino-2- (toluene-4-sulfonylamino) -propionic acid

Bromine (0.36 mL, 6.99 mmol) was added very slowly dropwise to a cold (0 ° C.) NaOH (1.95 g, 48.95 mmol) stirred solution in water (8.7 mL). After 5 minutes some cold solution of Preparation 18 (2.0 g, 6.99 mmol) and NaOH (0.55 g) in water (6.4 mL) were added. 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 the slow addition of concentrated HCl. The separated solid was filtered, triturated with cold EtOAc (2 × 25 mL) and dried under vacuum to afford the desired compound in 61% yield (1.1 g). mp: 225-226 ° C.

Step (ii)

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

To the cold (0 ° C.) compound (2 g, 7.75 mmol) stirred solution obtained in step (i) in ethanol (20 mL) was added SOC1 ₂ (1.25 mL, 17.05 mmol) under unhydrous conditions. The mixture was heated to reflux for 12 hours with stirring. After the reaction was completed, the mixture was concentrated in vacuo to give the hydrochloride of the target compound in 90% yield (2.0 g). This was used for next step without further purification.

Preparation Example 20

4- (3,4-dimethoxyphenylcarboxamido) -1-methyl-3-propyl-1H-5-pyrazolecarboxamide

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 charged with a nitrogen balloon It was placed in a 1 liter three-neck round bottom plastic equipped with a pressure equalizing addition funnel and septum. To the mixture was added a solution of 3,4-dimethoxy-1-benzenecarbonylchloride (21.5 g, 107.5 mmol) in dichloromethane (100 mL) through a pressure equilibration addition funnel at 0 ° C. under nitrogen atmosphere for 0.5 h. After adding the reaction temperature to 25 ℃, the contents were stirred for 12 hours. Dichloromethane was removed from the reaction mixture under reduced pressure and the resulting solid was washed with cold water (2 × 150 mL), filtered and dried under vacuum to give 33 g (89%) of the target compound as a white solid. Mp: 176-178 ° C.

Preparation Example 21

5- (3,4-dimethoxyphenyl) -1-methyl-3-propyl-6,7-dihydro-1H-pyrazole [4,3-d] pyridin-7-one

4- (3,4-dimethoxyphenylcarboxamido) -1-methyl-3-propyl-1H-5-pyrazolecarboxamide (17 g, 49.13 mmol) obtained in Preparation Example 20 in tert-butanol (350 mL) Was added to a 1 L one-necked round bottom flask equipped with a reflux condenser, and potassium tert-butoxamide (16.55 g, 147.38 mmol) was carefully added thereto to reflux the contents under nitrogen atmosphere for 63 hours. The reaction mixture was cooled to 25-35 ° C. and tert-butanol was completely removed under vacuum. To the residue was added under stirring with cold water (200 mL) followed by dilute hydrochloric acid (3N) until the pH was constant at 7. The solid formed was filtered and dried under vacuum to yield 13 g (81%) of the target compound as a white solid. Mp: 210-212 ℃

Preparation Example 22

1- [4- (2-bromoethylamino) phenyl] -l-ethanone

P-aminoacetophenone (20 g, 148.1 mmol) in 60% NaH (5.93 g, 247.08 mmol) in DMF (80 mL) in a 1 L two-necked round bottom flask equipped with a pressure equilibration addition funnel and bulkhead The solution was added dropwise at 0 ° C. under a nitrogen atmosphere via a pressure equilibration addition funnel and the contents were stirred at 25 ° C. for 2 hours. Then, 1,2-dibromoethane (97.48 g, 518.5 mmol) was added dropwise to the stirred solution and the contents were stirred at 90 ° C. for an additional 18 hours. The reaction mixture was cooled to 25-35 ° C. and cold water (650 mL) was added carefully with stirring. The organic phase was extracted with ethyl acetate (3x200 mL) and the combined organic phases were washed with water (2x100 mL) followed by brine. The separated organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Crude 15-20% ethyl acetate / pet. Chromatography on silica gel with ether (3 Lit) gave 5.lg (14%) of the target compound as a pale yellow solid. Mp: 92-94 ° C.

Preparation Example 23

1- (4- {2- [5- (3,4-dimethoxyphenyl) -1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazole [4,3-di Paradin-6-yl] ethylamino} phenyl) -1-ethanone

5- (3,4-Dimethoxyphenyl) -1-methyl-3-propyl-6,7-dihydro-lH-pyrazole [4,3-difaridin-7-one obtained in Preparation Example 21 ( 2 g, 6.09 mmol), the mixture of 1- [4- (2-bromoethylamino) phenyl] -l-ethanone (1.55 g, 6.405 mmol) and potassium carbonate (4.213 g, 3.5 mmol) obtained in Preparation Example 22. Was added to a 100 mL round bottom flask and DMF (20 mL) was added. The reaction mixture was stirred at 25 ° C. for 16 h under nitrogen atmosphere. The reaction mixture was slowly poured into ice cold water (100 mL). The separated solid was filtered, washed with water (2x5 mL) and dried under vacuum to give 2.6 g (87%) of the target compound as a pale yellow solid. Mp: 182-184 ℃

Preparation Example 24

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

A mixture of 2-amino-4,5-dimethoxybenzoic acid (29.6 g, 0.15 mol) and formamide (0.6 mol, 24 mL) was vigorously stirred under a nitrogen atmosphere. The mixture was heated to 145 ° C. for 4 hours. After the reaction mixture was cooled completely, 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 2.5 g of the desired product in 40% yield. Mp: 295-296 ° C. (lit 296-297 ° C.).

Example 1

5-[-1- (4- {2- [2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4-oxo-4h-3-chromenoxyoxy] ethoxy} phenyl) ethyl Lidene] -1,3-thiazolan-2,4-dione

A mixture of the compound (31 g, 59.6 mmol), thiazoliden-1,3-dione (40 g, 341 mmol), benzoic acid (14.5 g, 118.8 mmol) and piperidine (10.1 g, 118.8 mmol) obtained in Preparation Example 3 Was added to a 1 L round bottom flask and toluene (600 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 with 0.5-1% MeOH / CHC1 ₃ (5 L) to give 22 g (60%) of the target compound as a white solid. Mp: 205-206 ℃

Example 2

Example 2 was carried out according to the method of Example 1 above.

Example 3

Example 3 was carried out according to the method of Example 1 above.

Example 4

Example 4 was carried out according to the method of Example 1 above.

Example 5

Example 5 was carried out according to the method of Example 1 above.

Example 6

Example 6 was carried out according to the method of Example 1 above.

Example 7

Example 7 was carried out according to the method of Example 1 above.

Example 8

Example 8 was carried out according to the method of Example 1 above.

Example 9

Example 9 was carried out according to the method of Example 1 above.

Example 10

Example 10 was carried out according to the method of Example 1 above.

Example 11

Example 11 was carried out according to the method of Example 1 above.

Example 12

Example 12 was carried out according to the method of Example 1 above.

Example 13

5-[-l- (4- {2- [6-fluoro-2- (4-methoxyphenyl) -4-oxo-4H-3-chromenyloxy] ethoxy} phenyl) ethylidene] -1 , 3-thiazolan-2,4-dione

Compound obtained in Preparation Example 8 (0.35 g, 0.72 mmol), thiazoliden-1,3-dione (0.54 g, 4.68 mmol), benzoic acid (0.19 g, 1.56 mmol), and pyridine (0.13 g, 1.56 mol) ) Was placed in a 50 mL one-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 current-limiting 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 silica gel column chromatography. The product was eluted with 0.5-1% MeOH / CHC1 ₃ (5 L) to afford 0.32 g (75%) of the target compound as an off white solid. Mp: 210-212 ° C.

Example 14

The compound was prepared according to the method disclosed in Example 13.

Example 15

The compound was prepared according to the method disclosed in Example 13.

Example 16

The compound was prepared according to the method disclosed in Example 13.

Example 17

The compound was prepared according to the method disclosed in Example 13.

Example 18

The compound was prepared according to the method disclosed in Example 13.

Example 19

The compound was prepared according to the method disclosed in Example 13.

Example 20

The compound was prepared according to the method disclosed in Example 13.

Example 21

The compound was prepared according to the method disclosed in Example 13.

Example 22

The compound was prepared according to the method disclosed in Example 13.

Example 23

The compound was prepared according to the method disclosed in Example 13.

Example 24

5- [1- (4- {2- [1-methyl-4-oxo-2- (4-methylphenyl) -1,4-dihydro-3-quinolinyloxy] ethoxy) phenyl} methylidene] -1,3-thiazolan-2,4-dione

A mixture of the compound (150 mg, 0.36 mmol), taazoliden-1,3-dione (64 mg, 0.54 mmol), benzoic acid (88 mg, 0.72 mmol) and pyridine (61 mg, 0.72 mmol) obtained in Preparation Example 14 was prepared. To a 1 L one-necked round bottom flask was added toluene (600 mL). The round bottom flask was equipped with a Dean Stark instrument connected with 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 with 0.5-1% MeOH / CHC1 ₃ (5 L) to give 100 mg (54%) of the target compound as a brown solid. Mp: 250-252 ℃

Example 25

The compound was prepared according to the method disclosed in Example 24.

Example 26

The compound was prepared according to the method disclosed in Example 24.

Example 27

The compound was prepared according to the method disclosed in Example 24.

Example 28

The compound was prepared according to the method disclosed in Example 24.

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

4- {2- [2- (3,4-dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy obtained in Preparation 17 in DMF (20 mL). ] -Ethoxy} -benzoic acid (3 g, 5.74 mmol), and the 3-amino-2- (toluene-4-sulfonylamino) -propionic acid ethyl ester (2.22 g, 6.89 mmol) obtained in Preparation Example 19 were added to EDCI ( 1.64 g, 8.61 mmol), HOBt (1 g, 7.46 mmol) and N-methyl morpholine (2.0 g, 20.09 mmol) were added at 25-35 ° C. under nitrogen atmosphere. The mixture was stirred at the same temperature for 12 hours. After the reaction was completed, the mixture was poured into water (60 mL) and stirred for 30 minutes. The separated solid was filtered off, washed with water (2x20 mL) and dried under vacuum. The crude product was further crystallized with ethanol to give 51% yield (2.3 g) of the desired product.

Example 30

The compound was prepared according to the method disclosed in Example 29.

Example 31

The compound was prepared according to the method disclosed in Example 29.

Example 32

The compound was prepared according to the method disclosed in Example 29.

Example 33

The compound was prepared according to the method disclosed in Example 29.

Example 34

The compound was prepared according to the method disclosed in Example 29.

Example 35

The compound was prepared according to the method disclosed in Example 29.

Example 36

The compound was prepared according to the method disclosed in Example 29.

Example 37

The compound was prepared according to the method disclosed in Example 29.

Example 38

The compound was prepared according to the method disclosed in Example 29.

Example 39

The compound was prepared according to the method disclosed in Example 29.

Example 40

The compound was prepared according to the method disclosed in Example 29.

Example 41

The compound was prepared according to the method disclosed in Example 29.

Example 42

The compound was prepared according to the method disclosed in Example 29.

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

3- (4- {2- [2- (3,4-dimethoxy-phenyl) -5,7-dimethoxy-4- obtained in Example 29 in a mixture of ethanol (10 mL) and dioxane (10 mL) To an ethyl ester solution of oxo-4H-chromen-3-yloxy] -ethoxy} -benzoylamino) -2- (toluene-4-sulfonylamino) -propionic acid (500 mg, 0.73 mmol) in water (5 mL) K ₂ CO ₃ (300 mg, 2.19 mmol) solution was added at 25-35 ° C. and the mixture was stirred at the same temperature for 24 hours. The solvent was then removed from the mixture under vacuum and the residue acidified with cold HCl. The separated solid was filtered, washed with cold water (2 × 5 mL) and dried under vacuum to give the desired acid in 52% yield (250 mg).

Example 44

The compound was prepared according to the method disclosed in Example 43.

Example 45

The compound was prepared according to the method disclosed in Example 43.

Example 46

5-[(E, Z) -1- (4- {2- [5- (3,4-dimethoxyphenyl) -1-methyl-7-oxo-3-propyl-6,7-dihydro-1H -Pyrazol [4,3-d] pyridin-6-yl] ethylamino} phenyl) ethylidene] 1,3-thiazolan-2,4-dione

1- (4- {2- [5- (3,4-dimethoxyphenyl) -l-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyra obtained in Production Example 23 Sol [4,3-dipyridin-6-yl] ethylamino} phenyl) -1-ethanone (2.4 g, 4.91 mmol), thiazolidene-2,4-dione (2.87 g, 24.54 mmol), benzoic acid ( 1.20 g, 9. 81 mmol) and piperidine (0.84 g, 9.81 mmol) were placed in a 100 mL one-neck round bottom flask and toluene (60 mL) was added thereto. The round bottom flask (RBF) was equipped with a Dean Stark instrument connected to a current condenser. The reaction mixture was heated to reflux for 35 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and stirred for 1 hour. The solid product formed was filtered off. The pure product obtained by trituration of the solid with isopropanol (5 mL) was filtered and dried under vacuum to give the target compound as a pale green solid (1.51 g, 2.56 mmol). Mp: 215-218 ° C.

Example 47

The compound was prepared according to the method disclosed in Example 43.

Example 48

The compound was prepared according to the method disclosed in Example 46.

Example 49

The compound was prepared according to the method disclosed in Example 46.

Example 50

The compound was prepared according to the method disclosed in Example 46.

Example 51

The compound was prepared according to the method disclosed in Example 46.

Example 52

The compound was prepared according to the method disclosed in Example 46.

Example 53

The compound was prepared according to the method disclosed in Example 46.

Example 54

The compound was prepared according to the method disclosed in Example 46.

Example 55

The compound was prepared according to the method disclosed in Example 46.

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

Compound 3- [2- (4-acetyl-2-fluoro-phenoxy) -ethoxy] -2- (4-fluoro-phenyl) -methyl-lH-quinolin-4-one (0.45 g, 1.0 mmol), 2,4-thiazolidendione (0.703 g, 6.01 mmol), benzoic acid (225 mg, 1.84 mmol) and piperidine (150 mg, 1.76 mmol) were placed in a 1-necked round bottom flask and toluene (50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with a reflux condenser. The reaction mixture was heated with stirring under nitrogen atmosphere for 72 hours. 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 target compound as a white solid.

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

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (2-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (400 mg, 0.86 mmol ), 2,4-thiazolidendione (504 mg, 4.3 mmol), benzoic acid (250 mg, 2.04 mmol) and piperidine (160 mg, 1.88 mmol) were added to a 50 mL one-necked round bottom flask and toluene ( 50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 in vacuo. The residue was purified by column chromatography and then washed with ether to give 200 mg (41%) of the target compound as an off white solid.

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

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (4-fluoro-phenyl) -1-methyl-lH-quinolin-4-one (39 g, 9 mmol), 2,4 A mixture of thiazolidendione (63.5 g, 54 mmol), benzoic acid (22.2 g, 18.1 mmol) and piperidine (16 g, 18.79 mmol) was placed in a 1 neck round bottom flask and toluene (500 mL) was added thereto. The RBF was equipped with a Dean Stark mechanism connected to a current-limiting capacitor. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and concentrated in vacuo. The residue was purified by column chromatography using 0-1% MeOH-CHCl ₃ to afford 24 g (50%) of the target compound as a light brown solid.

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

Compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (3,4-dimethoxy-phenyl) -6-fluoro-chromen-4-one (0.5 g, 1.04 mmol) , 2,4-thiazolidendione (0.79g, 6.6mmol), benzoic acid (0.27g, 2.2mmol), and piperidine (0.19g, 2.23mmol) mixture in a 1-necked round bottom flask, toluene ( 35 mL) was added. The RBF was equipped with a Dean Stark mechanism connected to a current-limiting capacitor. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C. and filtered by stirring at room temperature for 6 hours. The solid was triturated with i-PrOH (20 mL) and filtered to give 0.38 g (63%) of the target compound as an off white solid.

Example 60

5- [l- (4- {2- [2- (4-chloro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -ethoxy} -phenyl ) -Ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (4-chloro-phenyl) -l-methyl-lH-quinolin-4-one (1.19 g, 2.45 mmol), 2 A mixture of, 4-thiazolidendione (1.72g, 14.70mmol), benzoic acid (0.59g, 4.83mmol), and piperidine (0.415g, 4.82mmol) was placed in a 1-neck round bottom flask and toluene (100mL) Was added. The RBF was equipped with a Dean Stark instrument connected with 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 in vacuo. The residue was purified by column chromatography using 6% MeOH-CHCl ₃ to afford 0.73 g (30%) of the target compound as a light brown solid.

Example 61

5- [1- (3- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Methoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -methyl-lH-quinolin-4-one (1.0 g, 2.22 mmol) ), A mixture of 2,4-thiazolidendione (1.56 g, 13.36 mmol), benzoic acid (325 mg, 2.67 mmol) and piperidine (325 mg, 3.82 mmol) was placed in a 1-necked round-bottomed flask and toluene (30 mL) was added. ) Was added. The RBF was equipped with a Dean Stark instrument connected with 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 using column chromatography to give 488 mg (40%) of the target compound as a light brown solid.

Example 62

5- [I- (4- {2- [1-ethyl-2- (4-fluoro-phenyl) -4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy}- Phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -l-ethyl-2- (4-fluoro-phenyl) -l-quinolin-4-one (0.6 g, 1.35 mmol), 2 A mixture of, 4-thiazolidendione (0.946 g, 8.08 mmol), benzoic acid (200 mg, 1.64 mmol) and piperidine (200 mg, 2.35 mmol) was added to a 1-neck round bottom flask and toluene (30 mL) was added thereto. It was. The RBF was equipped with a Dean Stark instrument connected with 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 afford 333 mg (45%) of the target compound as a light brown solid.

Example 63

5- [1- (4- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Methoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -methyl-lH-quinolin-4-one (1.75 g, 3.89 mmol) ), 2,4-thiazolidendione (2.74g, 23.38mmol), benzoic acid (475mg, 3.89mmol) and piperidine (331mg, 3.89mmol) mixture in a 1-neck round bottom flask and toluene (30mL) Was added. The RBF was equipped with a Dean Stark instrument connected with 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 afford 830 mg (39%) of the target compound as a light brown solid.

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] -thiazolidine-2,4-dione

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-thiazolidendione (0.502 g, 4.29 mmol), benzoic acid (190 mg, 1.55 mmol) and piperidine (145 mg, 1.70 mmol) were mixed in a 1-neck round bottom flask and toluene (50 mL) was added. ) Was added. The RBF was equipped with a Dean Stark instrument connected with a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 and filtered. The solid was treated with i-PrOH for 2 hours under reflux and then filtered. The solid was washed with hexane and purified by column chromatography to give 200 mg (41%) of the target compound as a white solid.

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

Compound 3- [2- (4-acetyl-phenylamino) -ethoxy] -2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.4 g, 0.93 mmol), 2 A mixture of, 4-thiazolidendione (0.65 g, 5.6 mmol), benzoic acid (225 mg, 1.84 mmol) and piperidine (180 mg, 2.11 mmol) was placed in a 1-neck round bottom flask and toluene (100 mL) was added thereto. . The RBF was equipped with a Dean Stark instrument connected with 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-CHC1 ₃ to give 200 mg (41%) of the target compound as a yellow solid.

Example 66

5- {2- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzylidene) -thiazoli Dean-2,4-dione

Compound 4- {2- [2- (4-fluoro-phenyl) -l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzaldehyde (0.3 g, 0.719 mmol), a mixture of 2,4-thiazolidendione (0.168 g, 1.43 mmol), benzoic acid (30 mg, 0.24 mmol) and piperidine (30 mg, 0.35 mmol) were placed in a 1-necked round bottom flask and toluene ( 50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 yield 200 mg (54%) of the target compound as a brown solid.

Example 67

5- (4- {2- [2- (4-Bromo-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy} -benzylidene) -Thiazolidine-2,4-dione

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-thiazolidendione (0.178 g, 1.5 mmol), benzoic acid (63 mg, 0.51 mmol) and piperidine (45 mg, 0.52 mmol) were added to a 1-neck round bottom flask and toluene ( 50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with a reflux capacitor. 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 under vacuum to give 80 mg (53%) of the target compound as a light brown solid.

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

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (5-fluoro-2-methyl-phenyl) -methyl-lH-quinolin-4-one (0.25 g, 0.56 mmol), 2,4-thiazolidendione (0.394 g, 3.37 mmol), benzoic acid (142 mg, 1.16 mmol) and piperidine (100 mg, 1.17 mmol) were placed in a 1-necked round-bottomed flask and toluene ( 50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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-CHC1 ₃ to give 80 mg (26%) of the target compound as a brown solid.

Example 69

5- [1- (3- {2- [2- (4-fluoro-2-methyl-phenyl) -l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (4-fluoro-2-methyl-phenyl) -methyl-lH-quinolin-4-one (0.25 g, 0.56 mmol), 2,4-thiazolidendione (0.394 g, 3.37 mmol), benzoic acid (150 mg, 1.22 mmol) and piperidine (100 mg, 1.17 mmol) were placed in a 1-necked round bottom flask and toluene ( 50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 afford 120 mg (39%) of the target compound as a brown solid.

Example 70

5- [1- (4- {3- [2- (4-fluoro-phenyl) -l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -propyl-phenyl) -Ethylidene] -thiazolidine-2,4-dione

Compound 3- [3- (4-acetyl-phenoxy) -propyl] -2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.40 g, 0.898 mmol), 2, A mixture of 4-thiazolidendione (0.631 g, 5.39 mmol), benzoic acid (225 mg, 1.82 mmol) and piperidine (175 mg, 2.05 mmol) was placed in a 1-neck round bottom flask and toluene (30 mL) was added thereto. . The RBF was equipped with a Dean Stark instrument connected with 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-CHC1 ₃ to give 130 mg (27%) of the target compound as a white solid.

Example 71

5- [1- (3- {3- [2- (4-Fluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -propyl} -phenyl ) -Ethylidene] -thiazolidine-2,4-dione

Compound 3- [3- (3-acetyl-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -methyl-lH-quinolin-4-one (0.45 g, 1.011 mmol), 2 A mixture of, 4-thiazolidendione (0.710 g, 6.06 mmol), benzoic acid (300 mg, 2.46 mmol) and piperidine (300 mg, 3.52 mmol) was added to a 1-neck round bottom flask and toluene (50 mL) was added thereto. It was. The RBF was equipped with a Dean Stark instrument connected with 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-CHC1 ₃ to give 187 mg (34%) of the target compound as a light brown solid.

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

Compound 3- [3- (4-acetyl-2-chloro-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -1- methyl-lH-quinolin-4-one (0.40 g, 0.86 mmol), 2,4-thiazolidendione (0.603 g, 5.16 mmol), benzoic acid (150 mg, 1.23 mmol) and piperidine (300 mg, 3.52 mmol) were placed in a 1-necked round bottom flask and toluene ( 50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 afford 140 mg (30%) of the target compound as a light brown solid.

Example 73

5- [1- (4- {2- [7-fluoro-2- (4-fluoro-phenyl) -l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-fluoro-2- (4-fluoro-phenyl) -methyl-lH-quinolin-4-one (0.40 g, 0.89 mmol), a mixture of 2,4-thiazolidendione (0.521 g, 4.45 mmol), benzoic acid (200 mg, 1.63 mmol) and piperidine (150 mg, 1.76 mmol) was placed in a 1-necked round bottom flask and toluene (50 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 0.5-1% MeOH-CHCl ₃ to afford 100 mg (21%) of the target compound as a brown solid.

Example 74

5- [1- (4- {2- [2- (3,4-Difluoro-phenyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinoline-3- Yloxy] -ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -7-fluoro-l-methyl-lH-quinolin-4-one ( 0.40 g, 0.85 mmol), 2,4-thiazolidendione (0.50 g, 4. 28 mmol), benzoic acid (190 mg, 1.55 mmol) and piperidine (145 mg, 1.70 mmol) were placed in a 1-neck round bottom flask. Toluene (50 mL) was added thereto. The RBF was equipped with a Dean Stark instrument connected with 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 for 10 hours under reflux, filtered, washed with hot MeOH and dried to afford 125 mg (26%) of the target compound as a white solid.

Example 75

5- [1- (4- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]- Methoxy} -3-fluoro-phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-2-fluoro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -methyl-lH-quinolin-4-one ( 0.40 g, 0.856 mmol), 2,4-thiazolidendione (0.701 g, 5.99 mmol), benzoic acid (200 mg, 1.64 mmol) and piperidine (200 mg, 2.35 mmol) were placed in a 1-neck round bottom flask and Toluene (30 mL) was added to the. The RBF was equipped with a Dean Stark instrument connected with 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 1-2% MeOH-CHCl ₃ to afford 170 mg (35%) of the target compound as a light brown solid.

Example 76

5- [I- (4- {2- [7-chloro-2- (3,4-difluoro-phenyl) -l-methyl-4-oxo-1,4-dihydro-quinolin-3-yljade -Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-chloro-2- (3,4-difluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.60 g, 1.2 mmol), a mixture of 2,4-thiazolidendione (0.872 g, 7.0 mmol), benzoic acid (151 mg, 1.2 mmol), and piperidine (105 mg, 1.2 mmol) were placed in a 1-neck round bottom flask. Toluene (20 mL) was added thereto. The RBF was equipped with a Dean Stark instrument connected with 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 afford 150 mg (21%) of the target compound as a white solid.

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

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -7-chloro-2- (3,4-difluoro-phenyl) -l-methyl-lH-quinoline-4 Round a mixture of -one (0.50 g, 0.96 mmol), 2,4-thiazolidendione (0.677 g, 5.0 mmol), benzoic acid (117 mg, 0.96 mmol), and piperidine (95 mg, 0.96 mmol) To the bottom flask was added toluene (20 mL). The RBF was equipped with a Dean Stark instrument connected with 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 afford 120 mg (20%) of the target compound as a white solid.

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

Compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -6-fluoro-2- (4-fluoro-phenyl) -methyl-lH-quinolin-4-one (0.4 g, 0.82 mmol), a mixture of 2,4-thiazolidendione (0.581 g, 4.96 mmol), benzoic acid (650 mg, 5.32 mmol) and piperidine (500 mg, 5.87 mmol) was placed in a 1-necked round-bottomed flask and toluene (30 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 afford 80 mg (16%) of the target compound as a light brown solid.

Example 79

5- [1- (3-Chloro-4- {2- [2- (3,4-difluoro-phenyl) -6-fluoro-1-methyl-4-oxo-1,4-dihydro- Quinolin-3-yloxy] -ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -6-fluoro-1-methyl-lH-quinoline- Round a mixture of 4-one (1.4 g, 2.70 mmol), 2,4-thiazolidendione (1.96 g, 16.7 mmol), benzoic acid (600 mg, 4.91 mmol) and piperidine (470 mg, 5.51 mmol) To the bottom flask was added toluene (30 mL). The RBF was equipped with a Dean Stark instrument connected with 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 afford 40 mg (8%) of the target compound as a light brown solid.

Example 80

5- [1- (3-chloro-4- {2- [2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yljade -Ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione

Compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -methyl-lH-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) were placed in a 1-necked round bottom flask and toluene ( 1000 mL) was added. The round bottom flask was equipped with a Dean Stark instrument connected with 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 with 0.3-0.9% MeOH / CHC1 ₃ to afford 37 g (32%) of the target compound as an off white solid.

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

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), a mixture of 2,4-thiazolidendione (330 mg, 2.82 mmol), benzoic acid (132 mg, 1.08 mmol) and piperidine (96 mg, 1.13 mmol) in a 50 mL one-necked round bottom flask Toluene (15 mL) was added. The RBF was equipped with a Dean Stark instrument connected with 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 target compound as a white solid.

Example 82-91

The following compounds are readily prepared by those skilled in the art using the methods described above:

Example compound 82 5- [1- (3-Chloro-4- {2- [2- (3,4-difluoro-phenyl) -4-oxo-4H-chromen-3-yloxy] -ethoxy} -phenyl ) -Ethylidene] -thiazolidine-2,4-dione 83 5- [l- (3-chloro-4- {3- [2- (3,4-difluoro-phenyl) -4-oxo-4H-chromen-3-yl] -propoxy} -phenyl) -Ethylidene] -thiazolidine-2,4-dione 84 5- [1- (3-Chloro-4- {3- [2- (3,4-difluoro-phenyl) -4-oxo-4H-chromen-3-yloxy] -propyl} -phenyl) -Ethylidene] -thiazolidine-2,4-dione 85 5- [1- (3-chloro-4- {3- [2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yl ] -Propoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione 86 5- [1- (3-chloro-4- {3- [2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yljade -Propyl} -phenyl) -ethylidene] -thiazolidine-2,4-dione 87 5- [1- (3-Chloro-4- {2- [5- (3,4-difluoro-phenyl) -1,3-dimethyl-7-oxo-1,7-dihydro-pyrazolo [ 4,3-d] pyrimidin-6-yl] -ethoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione 88 5- [l- (3-chloro-4- {3- [5- (3,4-difluoro-phenyl) -1,3-dimethyl-7-oxo-1,7-dihydro-pyrazolo [ 4,3-d] pyrimidin-6-yl] -propoxy} -phenyl) -ethylidene] -thiazolidine-2,4-dione 89 3- [2- (3-Chloro-4- {2- [2- (3,4-difluoro-phenyl) -4-oxo-4H-chromen-3-yloxy] -ethoxy} -phenyl ) -Acetylamino] -2- (toluene-4-sulfonylamino) -propionic acid ethyl ester 90 3- [2- (3-chloro-4- {2- [2- (3,4-difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yljade -Ethoxy} -phenyl) -acetylamino] -2- (toluene-4-sulfonylamino) -propionic acid ethyl ester 91 3- (4- {2- [2- (3,4-Difluoro-phenyl) -1-methyl-4-oxo-1,4-dihydroquinolin-3-yloxy] -ethoxy} -benzoyl Amino) -2- (toluene-4-sulfonylamino) -propionic acid ethyl ester

Similarly, other starting materials and intermediates are prepared by the application or application of known methods, for example the methods described in the following reference examples or the apparent chemical equivalents thereof (Ref: (i) J. HET. CHEM., 1999 (36) 141; (ii) (a) J. MED. CHEM. 1996 (39), 2939-2952; (b) J. HET. CHEM., 1972 (9) 887; (b) INDIANJ. CHEM. SECT (1990) (29) 77; (c) TETRAHEDRON LETT., 1997 (38) 3581; (d) CHEM.PHARM.BULL. 1992 (40) 1170 See Example of Preparation of Bromoketone).

 Pharmaceutically acceptable salts include compounds of formula (I), for example, in the solvents of ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol or mixtures thereof, for example sodium hydroxide, sodium methoxide , Sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide or a mixture thereof with 1 to 4 equivalents of base. Organic bases such as lysine, arginine, diethanolamine, choline, tromethamine, guanidine or derivatives thereof or mixtures thereof may also be used. Alternatively, acids present in a solvent such as ethyl acetate, ether, alcohol, acetone, THF, dioxane, or mixtures thereof such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methane Acid addition salts are prepared by treatment with sulfonic acid, acetic acid, citric acid, malic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, or other mixtures. Salts of amino acid groups or other groups can be prepared by reacting a compound of formula (I) with each group in the presence of a solvent such as an alcohol and a ketone or a mixture thereof.

Various polymorphs of the compounds of general formula (I) according to the invention use different solvents or mixtures, for example for recrystallization; Crystallization is performed at different temperatures; Or by crystallizing the compound of formula (I) under different conditions by using various cooling modes ranging from very fast cooling to very slow cooling during crystallization. Heating or melting the compound after slow cooling or fast cooling can also yield polymorphs. The presence of the polymorph can be measured by solid probe NMR spectra, IR spectra, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

Pharmaceutically acceptable solvates of the compounds of formula (I) which form part of the present invention dissolve the compounds of formula (I) in the presence of a solvent, for example water, methanol, ethanol and the like, and other crystallization techniques. It can be prepared by conventional methods of recrystallization using.

The regioisomers of compounds of formula (I) can be prepared by adjusting the reaction conditions, for example by using reaction reagents from acid to base or base to acid, or by reacting free base hydrazine with diketone instead of salt. In addition, the molar ratio can change the formation of regioisomers.

Claims (59)

A compound of formula (I), a tautomeric form thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof:

In the food,

Is One)

or 2)

ego L is

Is, Q is

ego; R ¹ , R ² and R ³ are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy Groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, ar Alkyl group, alkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsul Fonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, Heteroarylthio group, aralkylthio group, aryl Sialic skill group, a carboxy acid or a derivative thereof, a sulfonic acid or a derivative thereof, R ^1, R ² And two of R ³ in combination optionally form a 5- or 6-membered saturated cyclic ring having 1 to 3 heteroatoms, wherein said heteroatom is O, S or N; 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, cycloal Kenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, aralkyl groups, aralkenyl groups, Aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, Aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, Aralkylsulfinyl groups, alkylthio groups, sub Thio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, aralkoxyalkyl group, fused heteroarylcycloalkyl group, fused heteroarylcycloalkenyl group, fused heteroarylheterocyclyl group, Carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof; A, B, D and J are independently O, S, N,> CH or (-CH _2- ) _n ; '----' is any chemical bond; E is O, S or -NR; K is N, C or CH; Y and Z are independently O, —NR, (—CH ₂ —) _u or 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 an integer from 0 to 2; p, t, m, s, v are independently integers from 0 to 5; R and R ⁵ are independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, Acyl group, aryl group, aralkyl group, heterocyclyl group, or heteroaryl group; In addition 'Ar' is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group. The compound of claim ¹ , wherein R ¹ , R ² , R ³ And R ⁴ is optionally 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 Carbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, Substituted by an aralkylthio group or, optionally, a heterocyclyl sulfonyl group substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally Substituted morpholinyl groups, thiomorpholinyl groups, It is a substituent on the blood and possess FER group, a heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group compound. A compound of formula (II), a tautomeric form thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof:

(II) In the food, R ¹ , R ² and R ³ are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy Groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, ar Alkyl group, alkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsul Fonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, Heteroarylthio group, aralkylthio group, aryl Sialic skill group, a carboxy acid or a derivative thereof, a sulfonic acid or a derivative thereof, R ^1, R ² And two of R ³ in combination optionally form a 5- or 6-membered saturated cyclic ring having 1 to 3 heteroatoms, wherein said heteroatom is O, S or N; 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, cycloal Kenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, aralkyl groups, aralkenyl groups, Aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, Aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, Aralkylsulfinyl groups, alkylthio groups, sub Thio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, aralkoxyalkyl group, fused heteroarylcycloalkyl group, fused heteroarylcycloalkenyl group, fused heteroarylheterocyclyl group, Carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof; A, B, D and J are independently O, S, N,> CH or (-CH _2- ) _n ; '----' is any chemical bond; E is O, S or -NR; Y and Z are independently O, —NR, (—CH ₂ —) _u or 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 is O, S or -NR; F is O, S or -NR; Y ¹ and Y ² Is independently O or S; n and u are independently integers from 0 to 2; s is an integer from 0 to 5; R and R ⁵ are independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, Acyl group, aryl group, aralkyl group, heterocyclyl group, or heteroaryl group; In addition 'Ar' is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group. 4. A compound according to claim 3, wherein R ¹ , R ² , R ³ And R ⁴ is optionally 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 Carbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, Substituted by an aralkylthio group or, optionally, a heterocyclyl sulfonyl group substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally Substituted morpholinyl groups, thiomorpholinyl groups, It is a substituent on the blood and possess FER group, a heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group compound. A compound of formula (III), a tautomeric form thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof:

(III) In the food, R ¹ , R ² and R ³ are independently hydrogen, hydroxy group, halogen, nitro group, carboxy group, carbamoyl group, optionally substituted amino group, alkyl group, cycloalkyl group, alkoxy group, cycloalkoxy Groups, alkenyl groups, cycloalkenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, ar Alkyl group, alkoxy group, heterocyclyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, heteroarylcarbonyl group, alkylsul Fonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, Heteroarylthio group, aralkylthio group, aryl Sialic skill group, a carboxy acid or a derivative thereof, a sulfonic acid or a derivative thereof, R ^1, R ² And two of R ³ in combination optionally form a 5- or 6-membered saturated cyclic ring having 1 to 3 heteroatoms, wherein said heteroatom is O, S or N; 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, cycloal Kenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, aralkyl groups, aralkenyl groups, Aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, hetero aralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, Aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, Aralkylsulfinyl groups, alkylthio groups, sub Arylthio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, aralkoxyalkyl group, fused heteroarylcycloalkyl group, fused heteroarylcycloalkenyl group, fused heteroarylheterocyclyl group , Carboxylic acid or derivative thereof, or sulfonic acid or derivative thereof; '----' is any chemical bond; E is O, S or -NR; Z is O, —NR, (—CH ₂ —) _u or 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- ; u is an integer from 0 to 2; s is an integer from 0 to 5; R and R ⁵ are independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, Acyl group, aryl group, aralkyl group, heterocyclyl group, or heteroaryl group; In addition R ′ and R ″ independently of one another are 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 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 heterocyclyl sulfonyl group. The compound of claim 5, wherein R ¹ , R ² , R ³ And R ⁴ is optionally 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 Carbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, Substituted by an aralkylthio group or, optionally, a heterocyclyl sulfonyl group substituted by halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally Substituted morpholinyl groups, thiomorpholinyl groups, It is a substituent on the blood and possess FER group, a heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group compound. 6. The compound of claim 5, wherein one or both of R ′ and R ″ are independently substituted by halogen, hydroxyl group, nitro group, amino group, or alkyloxy group. 6. Compounds according to claim 5, wherein one or both of R 'and R "are independently substituted by a heterocyclyl group comprising a morphonyl group, thiomorphoin or piperazine. The compound of formula (III) according to claim 5, wherein

A compound of formula (IV), a tautomeric form thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof:

(IV) In the food, 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, al Kenyl 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 Groups, aralkylthio groups, aryloxy Kiel group, a carboxy acid or a derivative thereof, a sulfonic acid or a derivative thereof, R ^1, R ² And two of R ³ in combination optionally form a 5- or 6-membered saturated cyclic ring having 1 to 3 heteroatoms, wherein said heteroatom is O, S or N; 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, cycloal Kenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, aralkyl groups, aralkenyl groups, Aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, Aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, Aralkylsulfinyl groups, alkylthio groups, sub Thio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, aralkoxyalkyl group, fused heteroarylcycloalkyl group, fused heteroarylcycloalkenyl group, fused heteroarylheterocyclyl group, Carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof; D and J are independently O, S, N,> CH or CH ₂ Is; '----' is any chemical bond; E is O, S or -NR; K is N, C or CH; Z is O, —NR, (CH ₂ ) _u or 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 is O, S or -NR; F is O, S or -NR; Y ¹ and Y ² Is independently O or S; u is an integer from 0 to 2; s is an integer from 0 to 5; R and R ⁵ are independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, Acyl group, aryl group, aralkyl group, heterocyclyl group, or heteroaryl group; In addition 'Ar' is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group. The compound of claim 10, wherein R ¹ , R ² , R ³ And R ⁴ is optionally 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 Carbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, Substituted by an aralkylthio group, or optionally a heterocyclyl sulfonyl group substituted by a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is optionally Substituted morpholinyl groups, thiomorpholinyl groups, It is a substituent on the blood and possess FER group, a heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group compound. The compound of formula (IV) according to claim 10, wherein the compound is

. A compound of formula (V), a tautomeric form thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof:

(V) In the food, R ¹ , R ² And R ³ is 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, arylsul Phenyl group, heteroarylsulfonyl group, aralkylsulfinyl group, alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, aralkylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group, Aralkylthio Group, Aryloxyal Group, a carboxy acid or a derivative thereof, a sulfonic acid or a derivative thereof, R ^1, R ² And two of R ³ in combination optionally form a 5- or 6-membered saturated cyclic ring having 1 to 3 heteroatoms, wherein said heteroatom is O, S or N; 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, cycloal Kenyl groups, alkoxyalkyl groups, alkenyloxy groups, cycloalkenyloxy groups, acyl groups, acyloxy groups, aryl groups, aryloxy groups, aroyl groups, aroyloxy groups, aralkyl groups, aralkenyl groups, Aralkynyl group, aralkoxy group, heterocyclyl group, heterocyclinyl group, heteroaryl group, heteroaralkyl group, heteroaryloxy group, heteroaralkoxy group, alkoxycarbonyl group, aryloxycarbonyl group, Aralkoxycarbonyl group, heteroarylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, heteroarylsulfinyl group, Aralkylsulfinyl groups, alkylthio groups, sub Thio group, heteroarylthio group, aralkylthio group, aryloxyalkyl group, aralkoxyalkyl group, fused heteroarylcycloalkyl group, fused heteroarylcycloalkenyl group, fused heteroarylheterocyclyl group, Carboxylic acids or derivatives thereof, or sulfonic acids or derivatives thereof; A, B, D and J are independently O, S, N,> CH or (-CH _2- ) _n ; E is O, S or -NR; K is N, C or CH; L is

ego; Y and Z are independently O, —NR, (—CH ₂ —) _u or 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 ₁ , X ₂ , X ₃ and X ₄ are independently O, S or -NR; X is O, S or -NR; n and w are independently an integer from 0 to 2; p, t and v are independently integers from 0 to 5; R is independently hydrogen, potassium, sodium, hydroxy group, halogen, nitro group, optionally substituted amino group, alkyl group, alkoxy group, alkenyl group, alkoxyalkyl group, cycloalkenyloxy group, acyl group, Aryl group, aralkyl group, heterocyclyl group, or heteroaryl group; In addition 'Ar' is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl group. The compound of claim 13, wherein R ¹ , R ² , R ³ And R ⁴ is optionally 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, aryl Oxycarbonyl group, heteroaryl group, heterocyclyl group, aralkyl group, alkylsulfonyl group, alkylsulfinyl group, arylsulfonyl group, arylsulfinyl group, alkylthio group, arylthio group, heteroarylthio group , An aralkylthio group, or optionally a heterocyclyl sulfonyl group substituted by a halogen, hydroxyl group, nitro group, amino group, alkyloxy group or combinations thereof, wherein the heterocyclyl group is Optionally substituted morpholinyl group, thiomorpholinyl group, It is a substituent on the blood and possess FER group, a heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group compound. 14. Compounds of formula (V) according to claim 13, which are

A method of treating or preventing a disease mediated by an inflammatory response or smooth muscle cell proliferation in humans or animals comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. The method of claim 16, wherein the inflammatory response comprises diabetic vascular complications including diabetic retinopathy, microangiopathy, renal failure and Alzheimer's disease. The method of claim 16, wherein the inflammatory response is due to accumulation of glycated protein or late glycation product. The method of claim 18, wherein the glycated protein or late glycation product accumulation is mediated by pro-inflammatory cytokines. The method of claim 19, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-α or MCP-1. The method of claim 16, wherein the smooth muscle cell proliferation is inhibited by inducing expression of perlecan. The method of claim 16, wherein the smooth muscle cell proliferation is mediated by pro-inflammatory cytokines. The method of claim 22, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-α or MCP-1. A method of treating or preventing undesirable inflammation in humans or animals comprising administering to a human or animal suffering from undesirable inflammation a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. Treatment or prevention of undesirable smooth muscle cell proliferation in humans or animals, comprising administering to a human or animal suffering from undesirable smooth muscle cell proliferation a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1 Way. 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 therapeutically or prophylactically effective amount of a compound according to claim 1. The method of claim 26, wherein the disease or disorder mediated by cell adhesion molecules is an inflammatory disorder or a cardiovascular disease. The method of claim 27, wherein the inflammatory disorder is rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, or multiple sclerosis. The method of claim 27, wherein the cardiovascular disease is atherosclerosis, restenosis, coronary artery disease, angina pectoris, arterial disease, diabetes mellitus, diabetic kidney disease or diabetic retinopathy. The method of claim 26, wherein the cell adhesion molecule is VCAM-1. The method of claim 26, wherein the platelet aggregation inhibitor, antithrombotic agent, calcium channel blocker, angiotensin converting enzyme inhibitor, β blocker, non-steroidal anti-inflammatory agent, COX II inhibitor, corticosteroid, TNF-α modulator, HMGCoA reductose inhibitor, PPAR further comprising administering a therapeutically or prophylactically effective amount of one or more other medicaments comprising a -γ agonist, an HDL synergist, or a retinoid. The method of claim 31, wherein the one or more other medicaments are aspirin, dilteazem, nepidipine, captopril, enalapril, propanol, ibuprofen, indomethacin, sulindac, rofecoxib, celecoxib, The method is etanercept or infliximab. A method of treating or preventing cancer in a human or animal comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 34. The method of claim 33, wherein the cancer comprises melanoma, prostate cancer, leukemia, lymphoma, non-small cell lung cancer, cancer of the central nervous system, breast cancer, bowel cancer, ovarian cancer or kidney cancer. A method of inhibiting smooth muscle cell proliferation in humans or animals comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. A method of inhibiting an inflammatory response in human or animal endothelial cells comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. A method of treating or preventing organ transplantation angiogenesis in a human or animal comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 38. The method of claim 37, wherein the organ is liver, kidney, heart, lung, pancreas, pancreatic islet, or skin. 38. The method of claim 37, further comprising administering a therapeutically or prophylactically effective amount of an immunosuppressive agent. 40. The method according to claim 39, wherein the immunosuppressive agents are CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandy Method of Sandimmmune, Thimoglobulin or Zenapax. The method of claim 39, wherein the administration is oral, parenteral, subcutaneous, intramuscular, intravenous, intraarterial, bronchial, abdominal, articular, cartilage, intraluminal, intraperitoneal, cerebellar, intraventricular, intestinal, cervical Intraorbital, Intraperitoneal, Intrahepatic, Intramyocardial, Drained, Intrapelvic, Intracardia, Intraperitoneal, Intrapleural, Intraprostate, Intrapulmonary, Rectal, Intrahepatic, Intraretinal, Intra spinal, Intravitreal, Intrathoracic, Intrauterine , Intra bladder, bolus, vaginal, rectal, buccal, sublingual, nasal or transdermal administration. The method of claim 39, wherein the immunosuppressive agent is administered prior to the composition. The method of claim 39, wherein the immunosuppressive agent is administered after the composition. The method of claim 39, wherein the immunosuppressive agent is administered simultaneously with the composition. A method for treating or preventing restenosis in a human or animal comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. A method for treating or preventing atherosclerosis in a human or animal comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. A method for treating a disease mediated by inflammation in a human or animal comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.  48. The method of claim 47, wherein said disease mediated by inflammation is an autoimmune disease.  49. The method of claim 48, wherein the autoimmune disease is alopecia areata, ankylosing myelitis, antiphospholipid syndrome, autoimmune Addison disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous stools, cardiomyopathy, non-tropic spruce dermatitis , Chronic Inflammatory Immune Disorder Syndrome (CFIDS), Chronic Inflammatory Ductus Polyneuropathy, Chuck-Strauss Syndrome, Scar-Like, CREST Syndrome, Cryogenic Aggression, Crohn's Disease, Discoid Lupus, Essential Mixed Cold Globulinemia, Fiber Myalgia-fibromyalitis, Graves' disease, acute idiopathic neuritis, Hashimoto's appetite, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, purple opathy (ITP), IgA kidney disease, insulin dependent diabetes mellitus, adolescent arthritis, squamous cell, Meniere's disease, mixed Connective tissue disease, multiple sclerosis, myasthenia gravis, myofascial swelling, pernicious anemia, polyarteritis, polychondritis, polysecretory syndrome, rheumatic polymyalgia Muscle pain, polymyositis and dermatitis, primary angammagglobulinemia, primary biliary sclerosis, psoriasis, Raynaud's syndrome, Reiter syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, anabolic syndrome, systemic lupus erythematosus, Takayasu's arteritis, transient arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo or Wegner's granulomatosis. A method for treating or preventing metastasis in a human or animal comprising administering to a human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. A method of modulating perlecan activity in a human or animal comprising administering to a human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1. A method of modulating heparinase in humans or animals comprising administering to a human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1. A stent coated with a composition comprising a compound according to claim 1. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or solvent. The pharmaceutical composition of claim 54 in the form of a tablet, capsule, powder, syrup, solution, suspension. A medical device coated with a composition comprising the compound of claim 1. 59. The medical device of claim 56, wherein the medical device includes a shunt, a cochlear bag attachment device, an ear drain tube, a pacemaker and an implantable defibrillator lead, a suture, a staple, an anastomotic device, an intervertebral disc, a bone pin, a suture support. A medical device that is a hemostatic barrier, clamp, screw, plate, clip, vascular implant, tissue adhesive or sealant, tissue strut, bone substitute, endovascular device, or vascular support. A method for treating or preventing cardiovascular disease in a human or animal comprising administering to a human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1. 59. The method of claim 58, wherein the cardiovascular disease is atherosclerosis, restenosis, coronary artery disease, angina pectoris, arterial disease, diabetes, diabetic kidney disease or diabetic retinopathy.