Amidine derivatives for treating amyloidosis

专利摘要:
The present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases. In particular, the present invention relates to methods of treating or preventing amyloid-related diseases in a subject comprising administering to the subject a therapeutic amount of an amidine compound. Among the compounds for use in the present invention are compounds of formula (X) in which amyloid fiber formation, neurodegeneration, or cytotoxicity is reduced or inhibited when administered: <Formula X>
公开号:KR20040036908A
申请号:KR10-2004-7002085
申请日:2002-09-03
公开日:2004-05-03
发明作者:로버트 제이. 칼리푸；시앙퀴 콩；시앙푸 우；웬슈오 루
申请人:뉴로겜 인터내셔널 리미티드；
IPC主号:

专利说明:

Amidine derivatives for treating amyloidosis {AMIDINE DERIVATIVES FOR TREATING AMYLOIDOSIS}
[3] Background of the Invention
[4] Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibers. Amyloid is a generic term for various but specific (intracellular or extracellular) protein deposits found in many different diseases. Although diverse in development, all amyloid deposits have common morphological properties, are stained with specific dyes (eg, Congo red), and show red / green birefringence under polarization after dyeing. They also share common superstructure features and common X-ray diffraction and infrared spectra.
[5] Amyloid-related diseases may be limited to one organ and may be interspersed in several organs. The first occurrence is called "local amyloidosis" and the second is called "systemic amyloidosis".
[6] Some amyloid diseases may be idiopathic, but most of these diseases appear as complications of existing diseases. For example, primary amyloidosis can occur without any other condition, or after a plasma cell disease or multiple myeloma develops.
[7] Secondary amyloidosis is commonly observed in connection with chronic infection (eg tuberculosis) or chronic inflammation (eg rheumatoid arthritis). The familial form of secondary amyloidosis can also be found in the family of Famiial Mediterranean Fever (FMF). The familial form of amyloidosis, like other forms of familial amyloidosis, is inherited and appears in certain populations. In both types of amyloidosis, deposits are found in some organs and are therefore considered systemic amyloid diseases.
[8] Another form of systemic amyloidosis is found in patients with prolonged hemodialysis. In each of these cases, different amyloidogenic proteins are involved in amyloid deposition.
[9] "Topical amyloidosis" has a tendency associated with single organ systems. Different amyloids are also characterized by the form of protein present in the deposits. For example, degenerative neurological diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob, etc. are known to be prion (called AScr or PrP-27) in the central nervous system. ) Is characterized by the appearance and accumulation of protein-resistant forms of the protein. Similarly, Alzheimer's disease, another degenerative neurological disease, is characterized by neuritis plaques and neuronal fiber concentrates. In this case, plaques and vascular amyloids are formed by the deposition of fibrous Aβ amyloid protein. Adult-onset diabetes (type II diabetes), for example, is characterized by local accumulation of amyloid in the pancreas.
[10] Once these amyloids are formed, there are no known widely accepted therapies or therapies that significantly dissolve amyloid deposits in situ.
[11] Each amyloidogenic protein can be organized into β-sheets to form insoluble fibrils that can be deposited extracellularly or intracellularly. Each amyloidogenic protein, although different in amino acid sequence, has the same property of forming fibrils and binding to other components such as proteoglycans, amyloid P and complement components. Moreover, each amyloidogenic protein has different amino acid sequences but will promote β-sheet formation as well as regions capable of binding to the glycosaminoglycan (GAG) portion of the proteoglycan (referred to as the GAG binding site). It will show similarity with other areas.
[12] In certain cases, amyloid fibrils can be toxic to surrounding cells once deposited. For example, Aβ fibrils organized as senile plaques have been shown to be associated with necrotic neurons and microgliosis in patients with Alzheimer's disease. In vitro tests, Αβ peptides have been shown to trigger the activation process of microglia (brain macrophages), which accounts for the presence of brain inflammation and microgliomas found in the brains of patients with Alzheimer's disease. something to do.
[13] In other forms of amyloidosis observed in patients with type II diabetes, the amyloidogenic protein IAPP showed β-islet cytotoxicity in vitro. Therefore, the appearance of IAPP fibrils in the pancreas of type II diabetic patients causes the loss of β-islet cells (langerhans) and organ dysfunction.
[14] Patients with Alzheimer's disease develop advanced dementia in adulthood and are accompanied by three major structural changes in the brain, including the loss of proliferation of neurons in many parts of the brain; Accumulation of intracellular protein deposits called neuronal fiber concentrates; And accumulation of extracellular protein deposits called amyloid or senile plaques surrounded by malformed nerve endings (ditrophic neurites). The major component of these amyloid plaques is the amyloid-β peptide (Aβ), a 39-43 amino acid protein produced through cleavage of the β-amyloid precursor protein (APP). Although symptomatic therapy for Alzheimer's disease exists, the disease cannot be prevented or treated at present.
[1] Related application
[2] This application is directed to US Provisional Application No. 60 / 316,761 filed on August 31, 2001, Representative Event No. NBI-105-1, and US Provisional Application No. 60 / 387,001, filed June 7, 2002. Claiming priority of NBI-105-2), both of which are incorporated herein by reference.
[18] 1-Effect of pentamidine-type compounds on Aβ (1-40) assembly determined by ThT assay.
[19] Figure 2-Effect of pentamidine-like compounds on Aβ (1-40) assembly determined by ThT assay.
[20] Figure 3-Effect of amidine-type compounds on Aβ (1-40) assembly determined by ThT assay.
[21] Figure 4-Effect of pentamidine-type compounds on IAPP assembly determined by ThT assay.
[22] Detailed description of the invention
[23] The present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases.
[24] Amyloid-Related Diseases
[25] AA (reactive) amyloidosis
[26] In general, AA amyloidosis occurs in a number of diseases that cause sustained acute phase reactions. Such diseases include chronic inflammatory diseases, chronic local or systemic microbial infections, and malignant neoplasms.
[27] AA fibrils are generally protein secretions of serum amyloid A protein (ApoSAA), a circulating apolipoprotein that is complexed with HDL and synthesized in hepatocytes in response to cytokines such as IL-1, IL-6 and TNF. It consists of 8,000 Dalton fragments (AA peptides or proteins) formed by pirate cleavage. Deposition can be interspersed in the body and mainly in parenchymal organs. The spleen is usually the site of deposition, and the kidneys may also be affected. Deposition is also common in the heart and gastrointestinal tract.
[28] AA amyloid disease is an inflammatory disease such as rheumatoid arthritis, childhood chronic arthritis, ankylosing myelitis, psoriasis, psoriatic arthritis, Reiter's syndrome, adult Still's disease, Behcet syndrome, Crohn Include but are not limited to illness. AA deposits may also be produced as a result of chronic microbial infections such as leprosy, tuberculosis, bronchiectasis, pressure sores, chronic pyelonephritis, osteomyelitis, and Whipple's disease. Some malignant neoplasms may cause AA fibril amyloid deposits. These include diseases such as Hodgkin's lymphoma, renal carcinoma, carcinoma of the intestine, lung and urogenital, basal cell carcinoma, and hairy cell leukemia.
[29] AL amyloidosis
[30] AL amyloid deposition is generally associated with diseases of almost all B lymphocyte lineages, from cancer of the plasma cells (multiple myeloma) to benign monoclonal gamma globulinopathy. Sometimes, the presence of amyloid deposits can be the primary indicator of potential illness.
[31] Fibrils of AL amyloid deposits consist of monoclonal immunoglobulin light chains or fragments thereof. More specifically, the fragments are derived from the N-terminal region of the light chain (kappa or lambda) and contain all or part of their variable (V _L ) domains. Deposits generally develop in mesenchymal tissue, such as peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthrosis of large joints, immune diseases, myeloma, Cause latent disease. However, it should be noted that almost all tissues, especially visceral organs such as the heart, can be involved.
[32] Hereditary systemic amyloidosis
[33] There are many forms of hereditary systemic amyloidosis. Although these are relatively rare diseases, such diseases persist in the general population because of the onset of symptoms and their genetic patterns (usually autosomal dominance). In general, the syndrome is due to point mutations in precursor proteins that result in the production of variant amyloidogenic peptides or proteins. Table 1 summarizes the fibril composition of exemplary forms of the disease.
[34] Fibril Peptides / Proteins Genetic variants Clinical syndrome Transthyretin and Intercept (ATTR) Met30, many others Familial amyloid polyneuropathy (FAP), (mainly peripheral nerve) Transthyretin and Intercept (ATTR) Thr45, Ala60, Ser84, Met111, Ile122 Heart-related Predominance Without Neuropathy N-terminal fragment of Apolipoprotein A1 (apoAI) Arg26 Familial amyloid polyneuropathy (FAP), (primarily peripheral nerves) N-terminal fragment of Apolipoprotein A1 (AapoAI) Arg26, Arg50, Arg 60, Other Ostertag-type, non-neuropathic (mainly related to visceral) Lysozyme (Alys) Thr56, His67 Ostertack-type, non-neuropathic (mainly related to visceral) Fibrogen ∀ chain intercept Leu554, Val 526 Head neuropathy with lattice corneal dystrophy Gelsolin Section (Agel) Asn187, Tyr187 Head neuropathy with lattice corneal dystrophy Cystatin C intercept Glu68 Hereditary cerebral hemorrhage (brain amyloid angiopathy)-Icelandic type Β-amyloid protein (Aβ) derived from amyloid precursor protein (APP) Gln693 Hereditary brain hemorrhage (brain amyloid angiopathy)-dutch type Β-amyloid protein (Aβ) derived from amyloid precursor protein (APP) Ile717, Phe717, Gly717 Family Alzheimer's Disease Β-amyloid protein (Aβ) derived from amyloid precursor protein (APP) Asn670, Leu671 Family dementia-usually Alzheimer's disease Prion Protein (PrP) 51-91 Insertion Derived from Prp Precursor Protein Leu102, Val167, Asn178, Lys200 Familial Creutzfeldt-Jakob disease; Gustman-Strausler-Shinker Syndrome (genetic sponge encephalopathy, prion disease) AA derived from serum amyloid protein (ApoSAA) Familial Mediterranean fever, mainly kidney-related (autosomal recessive) AA derived from serum amyloid protein (ApoSAA) Muckle-Well's syndrome, nephropathy, deafness, hives, limb pain Unknown Cardiac disease with persistent atrial arrest Unknown Skin deposits (blisters, papules, pustulodermal) Tan SY, Pepys MB. Amyloidosis. Histopathology, 25 (5), 403-414 (Nov 1994)]
[35] The data presented in Table 1 is exemplary and is not intended to limit the scope of the invention. For example, more than 40 individual point mutations of the transthyretin gene have been described, all of which cause a clinically similar form to familial amyloid polyneuropathy.
[36] Transthyretin (TTR) is a 14 kilodalton protein, sometimes referred to as prialbumin. It is produced by the liver and choroid plexus and acts in the transport of thyroid hormones and vitamin A. More than 50 variants of these proteins, each characterized by a single amino acid alteration, result in various forms of familial amyloid polyneuropathy. For example, the substitution of leucine with proline at position 55 results in a progressive form of neuropathy, and the replacement of leucine with methionine at position 111 causes severe cardiac disease in Danish patients.
[37] From amyloid deposits isolated from cardiac tissue of patients with systemic amyloidosis, it has been found that the deposits consist of a heterogeneous mixture of TTR and fragments thereof, collectively referred to as ATTR and characterized by their entire sequence. ATTR fibrils components can be extracted from such plaques, and their structure and sequence are determined according to methods known in the art. (Eg, Gustavsson, A., et al., LAboratory Invest. 73: 703-708, 1995; Kametani, F., et al., Biochem. Biophys. Res. Commun. 125: 622-628, 1984; Pras, M., et al., PNAS 80: 539-42, 1983).
[38] A person with a point mutation (eg, Gly → Arg26; Trp → Arg50; Leu → Arg60) in the molecular apolipoprotein Al is a form of amyloidosis (") characterized by deposits of protein apolipoprotein AI or fragments thereof (AApoAI). Ostertag type "). The patient has low levels of high density lipoprotein (HDL) and shows peripheral neuropathy or kidney failure.
[39] Mutations in the alpha chain of the enzyme lysozyme (eg Ile → Thr56 or Asp → His57) are another cause of the Ostertack-type non-neuropathic hereditary amyloid reported in the UK family. Here, fibrils of mutant lysozyme protein (Alys) are deposited and patients generally exhibit impaired renal function. Unlike most fibril-forming proteins described herein, these proteins are typically present in whole (uncut) form (Benson, MD, et al. CIBA Fdn. Symp. 199: 104-131, 1996). .
[40] β-amyloid peptide (Aβ) is a 39-43 amino acid peptide derived by proteolysis from a large protein known as beta amyloid precursor protein (βAPP). Mutations in βAPP cause a familial form of Alzheimer's disease, Down's syndrome or senile dementia, characterized by brain deposition of plaques consisting of Aβ fibrils and other components described in more detail below. Mutations in known APPs associated with Alzheimer's disease occur near the cleavage site of β or γ-secretase or within Aβ. For example, position 717 is close to the γ-secretase cleavage site of APP during processing for Aβ, and position 670/671 is close to the site of β-secretase cleavage. Mutations at any point of these residues can cause Alzheimer's disease and are believed to result from an increase in the amount of Aβ in the form of 42/43 amino acids produced from APP.
[41] The structures and sequences of Aβ peptides of various lengths are known in the art. Such peptides can be prepared according to methods known in the art (eg, Glenner and Wong, Biochem Biophys. Res. Comm. 129: 885-890, 1984; Glenner and Wong, Biochem Biophys. Res. Comm. 122: 113 1-1135, 1984). In addition, various forms of peptides are commercially available.
[42] As used herein, the term “β amyloid” or “amyloid-β” means amyloid β protein or peptide, amyloid β precursor protein or peptide, intermediates, and variants and fragments thereof unless specifically stated. In particular, “Aβ” refers to any peptide produced by proteolytic processing of the APP gene product, in particular amyloid including Aβ _1-39 , Aβ _1-40 , Aβ _1-41 , Aβ _1-42 , and Aβ _1-43 Refers to peptides associated with pathology.
[43] For convenience of naming, "Aβ _1-42 " may be referred to as "Aβ (1-42) or simply" Aβ ₄₂ "or" Aβ42 "(as in any other amyloid amyloid peptide discussed herein). As used herein, the terms "β amyloid,""amyloid-β," and "Aβ" are synonymous.
[44] Unless otherwise specified, the term “amyloid” refers to amyloidogenic proteins, which may be soluble (eg, monomeric or oligomeric) or insoluble (eg, having a fibril structure or in amyloid plaques), Peptides, or fragments thereof.
[45] Gelsolin is a calcium binding protein that binds to sections and actin filaments. Mutations at position 187 of the protein (eg Asp → Asn; Asp → Tyr) cause a form of hereditary systemic amyloidosis commonly found in Finnish patients as well as people of Dutch or Japanese origin. In diseased individuals, fibrils formed from gelsolin fragments typically consist of amino acids 173-243 (68 kDa carboxy-terminal fragments) and are deposited on blood vessels and basal membranes, causing deposition, abnormalities in other organs. It causes head neuropathy and corneal dystrophy that progress to skin changes and peripheral neuropathy (Kangas, H., et al. Human Mol. Genet. 5 (9): 1237-1243, 1996).
[46] Other mutated proteins, such as mutant alpha chains (AfibA) and mutant cystatin C (Acys) of fibrinogen, also form fibrils and cause characteristic genetic diseases. AfibA fibrils form deposits characterized by non-neuropathic hereditary amyloid with kidney disease; Acys deposits are characterized by hereditary cerebral amyloid angiopathy reported in Iceland (Isselbacher, Harrison's Principles of Internal Medicine, McGraw-Hill, San Francisco, 1995; Benson, et al.). In at least some cases, patients with cerebral amyloid angiopathy (CAA) have been shown to have amyloid fibrils containing cytatin C in a non-mutated form with respect to amyloid β protein (Nagai, A., et al. Molec Chem. Neuropathol. 33: 63-78, 1998).
[47] Some forms of prion disease are now thought to be hereditary, accounting for less than 15% of cases previously considered primarily infectious in nature. (Baldwin, et al., In Research Advances in Alzheimer's Disease and Related Disorders, John Wiley and Sons, New York, 1995). In such prion diseases, patients exhibit plaques composed of abnormal isomers of normal prion protein (PrP ^Sc ).
[48] The predominant mutant isoform, also called AScr, PrP ^Sc is resistant to protease degradation, insoluble after surfactant extraction, deposition in secondary lysosomes, post-translational synthesis, and high β-pleat sheet content. In normal cellular proteins. Genetic associations have been found for five or more mutations that cause Creutzfeldt-Jakob disease (CJD), Gustman-Strausler-Shinker syndrome (GSS), and lethal familial insomnia (FFI). (Baldwin) Methods for extracting fibril peptides from scrapie fibrils, determining sequences, and preparing such peptides are known in the art (eg, Beekes, M., et al. J. Gen. 76: 2567-76, 1995).
[49] For example, one form of GSS is involved in PrP mutations at codon 102, and telencephalic GSSs are separated by mutations at codon 117. Mutations in codons 198 and 217 cause the neuritis plaques characteristic of Alzheimer's disease to form GSS, which contains PrP instead of Αβ peptide. Some forms of familial CJD are associated with mutations in codons 200 and 210; Mutations in codons 129 and 178 are both associated with familial CJD and FFI. (Baldwin, supra).
[50] Senile systemic amyloidosis
[51] Amyloid deposition, whether systemic or local, increases with age. For example, fibril of wild type transthyretin (TTR) is commonly found in the heart tissue of the elderly. They may be asymptomatic, clinically silent, or cause heart failure. Asymptomatic fibrillary local deposits may also occur in the brain (Aβ), the corporal amylacea (Aβ ₂ microglobulin) of the prostate, joints and seminal vesicles.
[52] Brain amyloidosis
[53] Local deposition of amyloid is common in the brain, especially in the elderly. The most common form of amyloid consists mainly of Aβ peptide fibrils and causes dementia or sporadic (non-genetic) Alzheimer's disease. Indeed, the incidence of sporadic Alzheimer's disease is much higher than in the case of hereditary forms. Referring to the genetic form of Alzheimer's disease (AD), the fibril peptides forming the plaques are very similar to those described above.
[54] Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid in the walls of the leptoningeal and cortical arteries, arterioles and capillaries and veins. It is associated with Alzheimer's disease, Down's syndrome and normal aging, as well as a number of familial diseases associated with stroke or dementia (Frangione et al., Amyloid: J. Protein Folding disord. 8, Suppl. 1, 36-42 ( 2001). CAA can occur sporadically or genetically. Multiple mutation sites in the Αβ or APP gene have been identified and are clinically associated with other dementia or brain bleeding. Exemplary CAA diseases include hereditary cerebral hemorrhage with Icelandic amyloidosis (HCHWA-I); Dutch variant of HCHWA (HCHWA-D; mutation in Aβ); Flanders-type mutation of Aβ; Arctic mutation of Aβ; Italian mutation of Aβ; Iowa type mutations of Aβ; Familial British dementia; And family Danish dementia.
[55] Dialysis-Related Amyloidosis
[56] Plaques consisting of β ₂ microglobulin (Aβ ₂ M) fibrils are common in patients undergoing prolonged hemodialysis or peritoneal dialysis. β ₂ microglobulin is a 11.8 kilodalton polypeptide and is the light chain of class I MHC antigens present in all nucleated cells. Under normal circumstances, it is released continuously from the cell membrane and normally filtered by the kidneys. Poor scavenging, as in the case of impaired renal function, for example, leads to deposition in the kidneys and other areas (mainly in the collagen-rich tissue of the joints). Unlike other fibril proteins, Aβ ₂ M molecules are generally present in unfinished form in fibrils. (Benson, supra).
[57] Islet Amyloid Polypeptides and Diabetes
[58] Islet vitreatosis (amyloid deposition) has been described over the past century as the presence of fibrous protein aggregation in the pancreas of patients with severe hyperglycemia (Opie, EL., J Exp. Med. 5: 397-428, 1990). Today, islet amyloid consisting predominantly of islet amyloid polypeptide (IAPP), or amylin, is a histopathological marker characteristic in at least 90% of all cases of type II diabetes (non-insulin dependent diabetes mellitus, or NIDDM). These fibrillary accumulations result from the aggregation of amylin or islet amyloid polypeptide (IAPP), a 37 amino acid peptide derived from a larger precursor peptide called pro-IAPP.
[59] IAPP is localized and secreted with insulin in response to β-cell secretagogues. This pathological feature is not associated with insulin-dependent (type I) diabetes and is consistent with the heterogeneous clinical phenotype diagnosed with NIDDM (type II diabetes).
[60] Follow-up studies in cats and immunocytochemical investigations in monkeys have revealed that progressive progression in islet amyloid is associated with a dramatic decrease in the population of insulin-secreting β-cells and an increase in the severity of the disease. More recently, transformation studies have strengthened the link between IAPP plaque formation and β-cell dysfunction, indicating that amyloid deposition is a major factor in type-II diabetes.
[61] IAPP has been shown to induce β-islet cytotoxicity in vitro, which suggests that the appearance of IAPP fibrils in the pancreas of type II or type I diabetic patients (after transplantation) may cause loss of β islet cells (langerhans) and organ dysfunction. It can be a cause. In patients with type II diabetes, the accumulation of pancreatic IAPP produces IAPP-amyloid as an insoluble fibrous deposit, which ultimately replaces islet-producing β cells in the islet, causing β cell depletion and failure (Westermark, P., Grimelius, L., Acta Path.Microbiol.Scand., Sect.A. 81: 291-300, 1973; de Koning, EJP., Et al., Diabetologia 36: 378-384, 1993; and Lorenzo, A., et al., Nature 368: 756-760, 1994).
[62] Diseases caused by necrosis or dysfunction of certain types of cells can be treated by implanting healthy cells of the relevant types of cells into the patient. This approach has been used for patients with type I diabetes. Often, pancreatic islet cells are cultured in vitro prior to transplantation to increase their number, allowing them to be recovered after isolation procedures or to reduce immunogenicity. In many cases, however, islet cell transplantation is not successful due to necrosis of the transplanted cells. The reason for this low success rate is IAPP, which can form fibrils and become toxic to cells in vitro. In addition, IAPP fibrils continue to grow even after cells are transplanted, and are likely to cause cell necrosis or dysfunction. This can occur even when the cells are received from a healthy donor and the patient receiving the transplant does not have a disease characterized by the presence of fibrils. For example, the compounds of the present invention can be used to prepare tissues or cells for transplantation according to the methods described in International Patent Application (PCT) WO 01 / 03,680.
[63] Hormone-derived amyloidosis
[64] Endocrine organs may be latent with amyloid deposits, particularly in the elderly. Hormone-secreting tumors may also contain hormone-derived amyloid plaques, the fibrils of which are polypeptide hormones such as calcitonin (myeloid carcinoma of the thyroid gland), islet amyloid polypeptide (amylin; occurs in most type II diabetics), And atrial natriuretic peptide (isolated atrial amyloidosis). The sequence and structure of such proteins are known in the art.
[65] Other amyloidosis
[66] There are various other forms of amyloid disease that normally appear as local deposits of amyloid. In general, the disease is probably the result of local production of certain fibril precursors or lack of catabolism or predisposition of certain tissues (eg joints) for fibril deposition. Such idiopathic depositions include nodular AL amyloid, cutaneous amyloid, endocrine amyloid, and tumor-associated amyloid.
[67] The compounds of the present invention can be administered therapeutically or prophylactically to treat diseases associated with amyloid-β fibril formation, aggregation or deposition. Compounds of the present invention may act to alleviate the course of amyloid-β related diseases using any of the following mechanisms (this list is intended to be illustrative and not limiting): amyloid-β fibril formation or Lowering of the deposition rate; Relief of the degree of amyloid-β deposition; Inhibit, reduce, or prevent amyloid-β fibrils formation; Inhibition of neurodegeneration or cytotoxicity induced by amyloid-β; Inhibition of amyloid-β induced infections; Or increased clearance of amyloid-β from the brain.
[68] Compounds of the present invention may be effective for controlling amyloid-β deposition after introduction into the brain (after penetration of the blood brain barrier) or from the ends. When acting from the ends, the compound alters the Aβ equilibrium between the brain and plasma so that Aβ release from the brain predominates. Increased A [beta] release from the brain will reduce A [beta] brain concentrations, thus reducing prevalence of A [beta] deposition. Alternatively, compounds penetrating the brain may act directly on the brain Aβ to control deposition, for example, by maintaining it in a non-fibrillated form or predominantly clearing its clearance from the brain.
[69] In a preferred embodiment, the method is used to treat Alzheimer's disease (eg sporadic or familial AD). The method prophylactically or therapeutically treats the development of other clinical amyloid-β deposits, such as in Down syndrome individuals and in patients with cerebral amyloid angiopathy (“CAA”) or hereditary cerebral hemorrhage. It can also be used to
[70] In addition, abnormal accumulation of APP and amyloid-β proteins in muscle fibers has been associated with the pathology of sporadic inclusion body myositis (IBM) (Askanas, V., et al. (1996) Proc. Natl. Acad. Sci. USA 93 : 1314-1319; Askanas, V. et al. (1995) Current Opinion in Rheumatology 7: 486-496). Thus, the compounds of the present invention can be used prophylactically or therapeutically in the treatment of diseases in which amyloid-β proteins are abnormally deposited in non-nerve positions, such as by delivering the compounds to muscle fibers to treat IBM. .
[71] Accordingly, the present invention relates in particular to the use of amidine compounds in the prevention or treatment of amyloid-related diseases including Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, Down's syndrome, and type II diabetes.
[72] Preferred compounds of the invention have two or more amidine residues (preferably arylamidine, more preferably benzamidine).
[73] In one particular embodiment, the present invention is disclosed, for example, in U.S. Pat. , 6,046,226, 6,294,565 (B1), 6,156,779, 6,326,395, 6,008,247, 6,127,554, 6,172,104, 4,940,723, 5,594,138, 5,602,172, 5,206,236, 5,843,980, 4,933,347, 5,723,5,916 To a novel use of amidine compounds in the prophylaxis or treatment of amyloid-related diseases as described herein in its entirety.
[74] In another embodiment, the invention relates to an amyloid in a subject (preferably human) comprising administering to the subject a therapeutic amount of a compound of the formula: such that amyloid fibril formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited A method of treating or preventing a related disease. In another embodiment, the present invention is directed to a method wherein the cognitive function is stabilized or further damage to the cognitive function is prevented, delayed or stopped in a patient with cerebral amyloidosis, such as, for example, Alzheimer's disease or cerebral amyloid angiopathy. A method of treating or preventing an amyloid-related disorder in a subject (preferably human) comprising administering to a subject a therapeutic amount of a compound of:
[75] <Formula X>
[76]
[77] Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
[78] Each Y ¹ and Y ² is independently a direct bond or a linkage moiety;
[79] m and q are each independently integers selected from 0 to 5, for example 1 ≦ m + q ≦ 5, or in other embodiments, 2 ≦ m + q ≦ 5, or in other embodiments 1 ≦ m + q ≦ 10, or in other embodiments, 2 ≦ m + q ≦ 10;
[80] The A group is a substituted or unsubstituted aliphatic and aromatic group, and combinations thereof, preferably allowing the Y ¹ and Y ² residues to be bonded to the aromatic group.
[81] The A group is preferably a divalent group (ie m + q = 2), for example an alkylene group (ie-(CH ₂ ) _k -and its substituted homologues (-CH ₂ -moiety in the group is oxygen Group substituted by atoms, where k is 1 to 12 (preferably 6 to 9, more preferably 7 to 9), alkenylene group (preferably 2 to 12 carbon atoms, more preferably 6) To 9 carbon atoms, including groups having one or more double bonds, alkynylene groups (preferably from 2 to 12 carbon atoms, more preferably 6 to 9 carbon atoms, including groups having one or more triple bonds), Alkoxyalkylene groups, alkylaminoalkylene groups, thioalkoxyalkylene groups, arylenedialkylene groups, heteroarylenedialkylene groups, arylene groups, heteroarylene groups, oligoetheric groups such as oligo (alkylene Oxide) groups, or arylene-di (oligoalkyleneoxide) groups, these Angle (e. G., Hydroxy alkylene group with Z as defined below as groups) are substituted or unsubstituted.
[82] Group A also includes the corresponding moieties of Formulas I-IV herein.
[83] In a preferred aspect of the present invention, the present invention provides a method of administering to a subject a therapeutic amount of a compound of the formula and pharmaceutically acceptable salts thereof to reduce or inhibit amyloid fibril formation or deposition, neurodegeneration, or cytotoxicity A method of treating or preventing amyloid-related diseases in a subject (preferably human) comprising the same. In another embodiment, the present invention is directed to a method wherein the cognitive function is stabilized or further damage to the cognitive function is prevented, delayed or stopped in a patient with cerebral amyloidosis, such as, for example, Alzheimer's disease or cerebral amyloid angiopathy. A method of treating or preventing amyloid-related diseases in a subject (preferably human), comprising administering to the subject a therapeutic amount of one of the compounds and pharmaceutically acceptable salts thereof:
[84]
[85]
[86]
[87]
[88]
[89]
[90] Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , R ^c2 , Y ¹ , and Y ² are as defined herein and A is as defined above;
[91] Each R ¹ and R ² is independently a hydrogen or Z group, or two adjacent or adjacent R ¹ and R ² groups are present with corresponding X ¹ and X ² groups [eg, as in formula (II)) And together with the ring to which they are bonded (eg phenyl ring) to form a fused ring structure such as an aromatic or heteroaromatic (eg benzofuran) structure or a cycloalkyl or heterocyclic structure ;
[92] Each R ³ and R ⁴ is independently hydrogen, substituted or unsubstituted straight or branched chain alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), carbocyclic, Aryl (eg, phenyl), heterocyclic, and heteroaryl;
[93] Each R ^{1 *} and R ^{2 *} is independently selected from the group consisting of substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, heterocyclic, aryl (including phenyl), and heteroaryl;
[94] Each X ¹ and X ² is independently a direct bond, or an oxygen, NR ′ group wherein R ′ is hydrogen (ie NH), C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl group), sulfonamide group (ie, NHSO ₂ or SO ₂ NH), carbonyl, amide (ie, NHCO or CONH), C ₁ -C ₅ alkylene group (eg,- CH _2- ), a C ₂ -C ₅ alkenylene group (eg, E or Z —CH═CH—), a C ₂ -C ₅ alkynylene group, or a sulfur atom, or a combination thereof (eg, OCH ₂ —, —CH ₂ O—, E or Z —OCH═CH— or —CH═CHO—);
[95] M is a divalent group, such as an alkylene group (ie,-(CH ₂ ) _k -and substituted homologues thereof, including groups in which the -CH ₂ -moiety is substituted by an oxygen atom), where k Is 1 to 12 (preferably 5 to 10, more preferably 6 to 9, most preferably 7 to 8), an alkenylene group (preferably 2 to 12 carbon atoms, more preferably 6 to 9 carbon atoms, including groups having at least one double bond), alkynylene groups (preferably from 2 to 12 carbon atoms, more preferably from 6 to 9 carbon atoms, including groups having at least one triple bond), alkoxy Alkylene group, alkylaminoalkylene group, thioalkoxyalkylene group, arylenedialkylene group, alkylene diarylene group, heteroarylenedialkylene group, arylene group, heteroarylene group, oligoether group [Example For example oligo (alkylene oxide) groups, or arylene-di (oligoalkyleneoxa De) group], and each of them [e.g., a hydroxy alkylene group (such _{as: - (CH 2) 0-6 (} CHOH) (CH 2) 0-6 -); Or substituted with other moieties such as that (for _{example: (- (CH 2) 0-6} (CHCO 2 alkyl) (CH _{2) 0-6} -, including _{- (CH 2) 0-6 (CHZ} ) (CH 2) _Or a Z group as defined herein, such as _0-6- );
[96] Z is straight or branched chain alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), alkoxy (preferably C ₁ -C ₆ ), thioalkyl (preferably C ₁ -C ₆ ), alkenyl (preferably C ₂ -C ₆ ), alkynyl (preferably C ₂ -C ₆ ), heterocyclic, carbocyclic, aryl (eg phenyl), aryl Oxy (eg phenoxy), aralkyl (eg benzyl), aryloxyalkyl (eg phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and Arylcarbonyl or other such acyl groups, heteroarylcarbonyl, or heteroaryl groups, (CR'R ") _0-3 NR'R" (eg, -NH ₂ ), (CR'R ") _0-3 CN (eg -CN), NO ₂ , halogen (eg F, Cl, Br, or I), (CR'R ") _0-3 C (halogen) ₃ (eg , -CF ₃ ), (CR'R ") _0-3 CH (halogen) ₂ , (CR'R") _0-3 CH ₂ (halogen), (CR'R ") _0-3 CONR'R", (CR'R ") _0-3 (CNH) NR'R", (CR'R ") _{0- 3} S (O) _1-2 NR'R ", (CR'R") _0-3 CHO, (CR'R ") _0-3 O (CR'R") _0-3 H, (CR'R " ) _0-3 S (O) _0-3 R '(e.g. -SO ₃ H), (CR'R ") _0-3 O (CR'R") _0-3 H (e.g.- CH ₂ OCH ₃ and -OCH ₃ ), (CR'R ") _0-3 S (CR'R") _0-3 H (e.g., -SH and -SCH ₃ ), (CR'R ") _{0 -3} OH (e.g., -OH), (CR'R ") _0-3 COR ', (CR'R") _0-3 (substituted or unsubstituted phenyl), (CR'R ") _{0- 3} (C ₃ -C ₈ cycloalkyl), (CR'R ") _0-3 CO ₂ R '(eg -CO ₂ H), or (CR'R") _0-3 OR' group, or Substituted or unsubstituted residue selected from the side chains of any naturally occurring amino acid;
[97] In other embodiments, Z is a straight or branched chain alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), alkoxy (preferably C ₁ -C ₆ ), thioalkyl (Preferably C ₁ -C ₆ ), alkenyl (preferably C ₂ -C ₆ ), alkynyl (preferably C ₂ -C ₆ ), heterocyclic, carbocyclic, aryl (eg , Phenyl), aryloxy (eg phenoxy), aralkyl (eg benzyl), aryloxyalkyl (eg phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl , Alkylcarbonyl and arylcarbonyl or other acyl groups, heteroarylcarbonyl, or heteroaryl groups, (CR'R ") _0-10 NR'R" (e.g., -NH ₂ ), ( CR'R ") _0-10 CN (eg -CN), NO ₂ , halogen (eg F, Cl, Br, or I), (CR'R") _0-10 C (halogen) ₃ (eg -CF ₃ ), (CR'R ") _0-10 CH (halogen) ₂ , (CR'R") _0-10 CH ₂ (halogen), (CR'R ") _0-10 CONR'R ", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", (CR'R ") _0-10 CHO, ( CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (O) _0-3 R '(e.g., -SO ₃ H), ( CR'R ") _0-10 O (CR'R") _0-10 H (e.g., -CH ₂ OCH ₃ and -OCH ₃ ), (CR'R ") _0-10 S (CR'R" ) _0-3 H (eg -SH and -SCH ₃ ), (CR'R ") _0-10 OH (eg -OH), (CR'R") _0-10 COR ', ( CR'R ") _0-10 (substituted or unsubstituted phenyl), (CR'R") _0-10 (C ₃ -C ₈ cycloalkyl), (CR'R ") _0-10 CO ₂ R '( For example, —CO ₂ H), or (CR′R ″) a _0-10 OR ′ group, or a substituted or unsubstituted moiety selected from the side chain of any naturally occurring amino acid;
[98] Wherein R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together benzyl A leaden group or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group;
[99] m and q are each independently an integer selected from 0 to 5, in Formula I, m and q are each independently an integer selected from 0 to 4, and n and p are each independently selected from 0 to 4, m + n ≦ 5 and p + q ≦ 5, wherein one of m or q is at least 1, preferably m and q are 1;
[100] In formula (II), m is an integer selected from 1-6, n is an integer selected from 0-5, m + n ≦ 6;
[101] In formula (III), m, n, p, and q are each independently integers selected from 0-3, m + n ≦ 4, p + q ≦ 4, and m + q ≧ 1 (preferably m = q = 1);
[102] In formulas IV and IVb, m and n are each independently an integer selected from 0 to 3, p and q are each independently an integer selected from 0 to 4, m + n ≦ 4, p + q ≦ 5, and m + q≥1 (preferably m = q = 1).
[103] Chemical structures herein are shown in accordance with conventional standards known in the art. Thus, if an atom, for example a carbon atom, is shown to have unsatisfied valence electrons, then that valence is assumed to be satisfied by the hydrogen atom even if the hydrogen atom is not explicitly shown.
[104] In another embodiment, the present invention relates to novel compounds and novel methods of their use as described herein, which are within the scope of the formulas described herein and are not described in the above referenced US patents. will be.
[105] In the above formula, the groups R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are preferably hydrogen or a substituted or unsubstituted C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy group or hydroxide Roxy group. Preferred R ^a1 and R ^a2 groups are hydrogen, hydroxy, alkyloxy groups (especially lower alkyloxy groups such as methoxy), aryloxy, acyloxy, and aroyloxy (ie R- (C = O)- O-, wherein R is aliphatic or aromatic.
[106] The phrase “R ^a and R ^b together with the nitrogen atom to which they are attached form a ring structure” means that the two R _a and R _b groups are residues that connect two nitrogen atoms in the heterocycle:
[107] , Where r is an integer from 0 to 4,
[108] , Where r is an integer from 0 to 2,
[109] , Where r is an integer from 0 to 6, or
[110] , Where r is an integer of 0 to 4.
[111] In another embodiment of the invention, for example, in a compound of Formula II, R ^a1 and R ^b1 or R ^a2 and R ^b2 are non-aromatic rings, alicyclic rings or monocyclic rings together with the nitrogen atoms to which they are attached To form a ring structure.
[112] In certain embodiments of formula II, for example, R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are preferably hydrogen or a substituted or unsubstituted C ₁ -C ₈ alkyl group ( Wherein the alkyl substituent is any member of the group Z as defined above, but is not an aryl (eg phenyl) or an alkyl group. Similarly, in certain embodiments of formula II, R ¹ is a moiety selected from members of the above-defined group Z that are not substituted aryl (eg phenyl) or heteroaryl groups.
[113] The groups R ¹ and R ² are preferably hydrogen, a substituted or unsubstituted C ₁ -C ₈ alkyl group, a substituted or unsubstituted C ₂ -C ₈ alkenyl group, a halogen (particularly bromine), a substituted or unsubstituted Aryl or heteroaryl groups, substituted or unsubstituted amino groups, nitro groups, or substituted or unsubstituted C ₁ -C ₈ alkoxy groups (particularly methoxy).
[114] Each Y group is a "linking moiety" (or "linking group") that is a direct bond, or a group covalently bonded to two or more residues, eg, a single divalent atom or oligomethylene group. Linking moieties that are linear chains of carbon atoms may be optionally substituted or unsaturated.
[115] Preferably the linking moiety is smaller than the rest of the molecule, more preferably less than about 250 molecular weight, and even more preferably less than about 75 molecular weight. Particularly preferred linking moieties are-(CH ₂ ) _n- (wherein n is 1, 2, or 3), -NR'- where R 'is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ egg Kenyl, C ₂ -C ₅ alkynyl, or an aryl group), -S-, -O-,-NH-CH _2- , and -CH = CH- (both E and Z configuration), or a combination thereof . The linking moiety is also (CR ^v R ^w ) _n , CR ^v OR ^w (CR ^x R ^y ) _n , CR ^v SH (CR ^x R ^y ) _n , CR ^v NR ^w R ^x (CR ^y R ^z ) _n , ( CR ^v R ^w ) _n O (CR ^x R ^y ) _n, wherein each n is independently 0, 1, 2, or 3, and R ^v , R ^w , R ^x , R ^y , and R ^z are Each independently hydrogen, substituted or unsubstituted C ₁ -C ₅ branched or straight chain alkyl or alkoxy, C ₂ -C ₅ branched or straight chain alkenyl, aryloxycarbonyl, arylaminocarbonyl, arylalkyl, acyl, Aryl, or C ₃ -C ₈ ring group.
[116] "Inhibition" of amyloid deposition prevents or arrests amyloid formation, eg, fibrillation, for example, inhibiting or delaying further amyloid deposition in a subject with amyloidosis already having amyloid deposits. Reducing or reversing amyloid fibrillation reactions or deposits in subjects with ongoing amyloidosis. Inhibition of amyloid deposition is determined for untreated subjects or for pre-treatment subjects, for example by an increase in clinically measurable pancreatic function in diabetic patients, or for cerebral amyloidosis, eg, In patients with Alzheimer's or cerebral amyloid angiopathy, stabilization of cognitive function or prevention of further reduction in cognitive function (ie, preventing, retarding, or stopping disease progression).
[117] The term "alkyl" refers to straight chain alkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched chain alkyl groups (isopropyl, tert-butyl, isobutyl , Etc.), saturated aliphatic groups including cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups do. Unless otherwise specified, the term alkyl further includes alkyl groups further comprising oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone.
[118] In some embodiments, straight or branched chain alkyl has up to 6 carbon atoms in its main chain (eg, C ₁ -C _{6 for} straight chains, C ₃ -C _{6 for} branched chains), more preferably 4 or less It has a carbon atom of. Similarly, preferred cycloalkyls have 3-8 carbon atoms in their ring structure, more preferably 5 or 6 carbons in their ring structure. The term C ₁ -C ₆ includes alkyl groups containing 1 to 6 carbon atoms. An "alkylene" group is a divalent moiety derived from the corresponding alkyl group.
[119] Moreover, unless otherwise specified, the term alkyl includes both “unsubstituted alkyl” and “substituted alkyl”, the latter of which is an alkyl moiety having a substituent replacing at least one hydrogen on at least one carbon of the hydrocarbon backbone Refers to. The substituent is, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl , Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkyl amino, dialkylamino , Arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, Arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or It may include a heteroaromatic moiety. Cycloalkyls can be further substituted, for example, with the substituents described above.
[120] An "arylalkyl" moiety is an alkyl group substituted with aryl (eg, phenylmethyl (ie benzyl)). An "alkylaryl" moiety is an aryl group substituted with an alkyl group (eg, p-methylphenyl (ie p-tolyl)). The term "n-alkyl" refers to a straight (ie unbranched) unsubstituted alkyl group.
[121] The term "alkenyl" contains one or more double bonds or unsaturated aliphatic groups similar in length and possible substitutions with the alkyl. For example, the term “alkenyl” refers to a straight chain alkenyl group (eg, ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, desenyl, etc.), branched chains. Alkenyl groups, cycloalkenyl (alicyclic) groups (cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc.), alkyl or alkenyl substituted cycloalkenyl groups, and cyclo Alkyl or cycloalkenyl substituted alkenyl group. The term alkenyl may further comprise alkenyl groups comprising oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone.
[122] In certain embodiments, a straight or branched alkenyl group has up to 6 carbon atoms (eg, C ₂ -C _{6 for} straight chains, C ₃ -C _{6 for} branched chains) in its main chain. Similarly, cycloalkenyl groups may have 3-8 carbon atoms in their ring structure, more preferably 5 or 6 carbons in their ring structure. The term C ₂ -C ₆ includes alkenyl groups containing 2 to 6 carbon atoms. An "alkenylene" group is a divalent residue derived from the corresponding alkenyl group.
[123] Moreover, unless otherwise specified, the term alkenyl includes both “unsubstituted alkenyl” and “substituted alkenyl”, the latter of which replaces one or more hydrogens on one or more carbons of the hydrocarbon backbone An alkenyl moiety having a substituent. Such substituents are, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates (and lower alkyl esters thereof) , Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, Amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino , Sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, hete Heterocyclyl, it may include alkylaryl, or an aromatic or heteroaromatic moiety.
[124] The term "alkynyl" contains one or more triple bonds or unsaturated aliphatic groups similar in length and possible substitutions with the alkyl. For example, the term "alkynyl" refers to straight chain alkynyl groups (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, decinyl, etc.), branched alkynyl groups And cycloalkyl or cycloalkenyl substituted alkynyl groups. Unless otherwise specified, the term alkynyl further includes alkynyl groups comprising oxygen, nitrogen, sulfur or phosphorus atoms that replace one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight or branched alkynyl group has up to 6 carbon atoms (eg, C ₂ -C _{6 for} straight chains, C ₃ -C _{6 for} branched chains) in its main chain. The term C ₂ -C ₆ includes alkynyl groups containing 2 to 6 carbon atoms. An "alkynylene" group is a divalent residue derived from the corresponding alkynyl group.
[125] Moreover, unless otherwise specified, the term alkynyl includes both “unsubstituted alkynyl” and “substituted alkynyl”, the latter of which replaces one or more hydrogens on one or more carbons of the hydrocarbon backbone It refers to an alkynyl moiety having a substituent. Such substituents are, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates, alkylcarbonyl, aryl Carbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkyl amino, di Alkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkyl Thio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or room Group, or it may include a heteroaromatic moiety.
[126] Unless otherwise specified, the term "lower alkyl" as used herein means an alkyl group as defined above having from 1 to 5 carbon atoms in its major distortion structure. "Lower alkenyl" and "lower alkynyl" have, for example, a chain length of 2-5 carbon atoms.
[127] The term “acyl” refers to a carbonyl group linked through a carbon atom to hydrogen (ie formyl), aliphatic groups (eg acetyl), aromatic groups (eg benzoyl), and the like. The term "substituted acyl" includes acyl groups in which one or more hydrogens on one or more carbon atoms are replaced with substituents. Substituents are, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates, alkylcarbonyl, arylcarbonyl , Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkyl amino, dialkylamino , Arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, Arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or Heteroaromatic moiety.
[128] The term "acylamino" includes residues in which amino residues are bonded to acyl groups. For example, acylamino groups include alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
[129] The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups as described above further comprising oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone.
[130] The term "alkoxy" or "alkyloxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups.
[131] Alkoxy groups are, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy Carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkyl amino, dialkylamino, aryl Amino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio , Thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or Groups, such as for interrogating aromatic moiety may be substituted. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like, as well as perhalogenated alkyloxy groups. Does not.
[132] The term "amine" or "amino" includes compounds in which the nitrogen atom is covalently bonded with one or more carbon or heteroatoms.
[133] The term "alkylamino" includes groups bound to one or more alkyl groups of nitrogen groups. The term "dialkylamino" includes groups in which the nitrogen atom is bonded to two or more alkyl groups.
[134] The terms "arylamino" and "diarylamino" include groups in which nitrogen is each bonded to one or two or more aryl groups.
[135] The term "alkylarylamino" refers to an amino group bonded to one or more alkyl groups and one or more aryl groups.
[136] The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group substituted with an alkylamino group.
[137] The term "amide" or "aminocarbonyl" includes compounds or moieties that include a nitrogen atom bonded to a carbon of a carbonyl or thiocarbonyl group.
[138] The term "carbonyl" or "carboxy" includes compounds or moieties containing carbon linked by double bonds bonded to oxygen atoms. Examples of residues containing carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, acid anhydrides, and the like.
[139] The term "ether" or "etherogenic" includes compounds or moieties containing oxygen bonded to two carbon atoms. For example, ether or etheric groups include “alkoxyalkyl”, which refers to alkyl, alkenyl, or alkynyl groups substituted with alkoxy groups.
[140] The term "hydroxy" or "hydroxyl" means an -OH or -O ^- group (with suitable counter ions).
[141] The term "halogen" includes fluorine, bromine, chlorine, iodine, and the like. The term "perhalogenated" generally refers to a moiety in which all hydrogen has been replaced with halogen atoms.
[142] The arylenedialkylene or arylenedialkyl group includes a group having an arylene group to which two different alkylene groups, which are the same or different, are bonded, and the two alkylene groups may in turn be bonded to other moieties. Examples of arylenedialkylene or arylenedialkyl groups include:
[143] And
[144]
[145] Wherein each R group is independently hydrogen (preferred) or is selected from the above defined Z groups and 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, 0 ≦ h ≦ 4.
[146] Alkylenediarylene groups include groups having an alkylene (or cycloalkylene) group to which two different arylene groups, which are identical or different, are bonded, which in turn may be bonded to other moieties. Examples of alkylenediarylene groups include:
[147]
[148] Wherein each R group is independently hydrogen (preferred) or is selected from the above defined Z groups, 1 ≦ y ≦ 10 (preferably 1 ≦ y ≦ 4), 1 ≦ f ≦ 8, 1 ≦ g ≦ 8 , 0 ≦ h ≦ 4, and 0 ≦ i ≦ 4.
[149] Heteroarylenedialkylene or heteroarylenedialkyl groups include groups having heteroarylene groups to which two different alkylene groups, which are identical or different, are bonded, which in turn may be bonded to other moieties. Examples of heteroarylenedialkylene or heteroarylenedialkyl groups include the following:
[150]
[151] Wherein 0 ≦ h ≦ 3 and 0 ≦ i ≦ 3, X = NR ′, O or S, 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, and R ′ is hydrogen, C ₁ -C ₅ alkyl , C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or an aryl group.
[152]
[153] Wherein 0 ≦ h ≦ 2, and X = NR ′, O or S, 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ − C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl groups.
[154]
[155] Wherein 0 ≦ h ≦ 3, 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, or
[156]
[157] Where 0 ≦ h ≦ 2
[158] Wherein each R group is independently hydrogen (preferred) or is selected from Z groups as defined above, wherein 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, and h and i are as described.
[159] Arylene groups are aromatic groups capable of covalently bonding to other substituents through two or more positions, including the following examples:
[160]
[161]
[162] Wherein each R group is independently hydrogen (preferred) or is selected from a Z group as defined above and 0 ≦ h ≦ 4; E.g:
[163] to be.
[164] Heteroarylene groups are heteroaromatic groups capable of covalently bonding to other substituents through two or more positions, including the following examples:
[165]
[166] Wherein 0 ≦ h ≦ 3, and 0 ≦ i ≦ 3, and X = NR ′, O, or S, wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, A C ₂ -C ₅ alkynyl or aryl group,
[167]
[168] Wherein 0 ≦ h ≦ 2, and X═NR ′, O, or S, and R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group ego,
[169]
[170] Wherein 0 ≦ h ≦ 3, or
[171]
[172] Where 0 ≦ h ≦ 2,
[173] Wherein each R group is independently hydrogen (preferred) or is selected from a Z group as defined above, h and i are as defined above, for example the following groups:
[174]
[175] Similarly, the present invention provides the following heteroarylene groups
[176] , Wherein X = NR ′, O or S; 0 ≦ f ≦ 8, 0 ≦ g ≦ 8, wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl groups; Each R group is independently hydrogen (preferred) or is selected from said Z group.
[177] In general, the term "aryl" includes groups comprising 5-membered and 6-membered monocyclic aromatic groups which may contain 0-4 heteroatoms, for example benzene, pyrrole, furan, thiophene, thiazole , Isothioazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine and the like.
[178] The term "aryl" also includes polycyclic aryl groups, for example tricyclic, bicyclic groups such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzo Imidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, diazapurin or indolizine.
[179] In addition, aryl groups having heteroatoms in the ring structure may be referred to as "aryl heterocycle", "heterocycle", "heteroaryl" or "heteroaromatic".
[180] Aromatic rings may be substituted with the substituents described above, for example halogen, hydroxy, alkyl (eg tolyl), alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate , Alkylcarbonyl, alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio Carbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (alkylcarbonylamino, Arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, It may be substituted at one or more ring positions by sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.
[181] Aryl groups may also be conjugated or linked with non-aromatic alicyclic or heterocyclic rings to form polycycles (eg tetralin).
[182] The term “heterocyclic” or “heterocycle” includes any formed ring comprising heteroaryl and heteroatoms or atoms other than carbon. The ring may be saturated or unsaturated and contain one or more double bonds. Examples of preferred heterocyclic groups include pyridyl, furanyl, thiophenyl, morpholinyl and indolyl groups. The term “hetero atom” includes any elemental atom that is not carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
[183] "Arylene" groups are divalent moieties derived from aryl.
[184] Oligoetheric groups such as oligo (alkyleneoxide) groups include polyethylene glycol (PEG) and short chain homologues thereof, and include-[(CR ₂ ) _s O] _t (CR ₂ ) _s- , 1 ≦ t ≦ 6, 1 ≦ s ≦ 6, and each R group is independently hydrogen (preferred) or is selected from Z groups as defined above.
[185] The arylene-di (oligoalkylene oxide) group is an aryl group having two oligoalkylene oxide groups bonded to an aryl group and thereby bonded to other moieties, including the following examples:
[186]
[187] Wherein “aryl” is an arylene moiety, 1 ≦ t ≦ 6, 0 ≦ s ≦ 6, and each R group is independently hydrogen (preferred) or is selected from Z groups as defined above. Preferred arylene-di (oligoalkyleneoxide) groups comprise the formula:
[188]
[189] Wherein 1 ≦ t ≦ 6, 0 ≦ s ≦ 6, 0 ≦ h ≦ 4, and each R group is independently hydrogen (preferred) or is selected from the Z groups defined above.
[190] The term "substituted" means that the molecule can carry out its desired function and that the residue has a substituent located on that residue that is not hydrogen. Examples of substituents include straight or branched chain alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), alkoxy (preferably C ₁ -C ₆ ), thioalkyl (preferably Is C ₁ -C ₆ ), alkenyl (preferably C ₂ -C ₆ ), alkynyl (preferably C ₂ -C ₆ ), heterocyclic, carbocyclic, aryl (eg phenyl) , Aryloxy (eg phenoxy), aralkyl (eg benzyl), aryloxyalkyl (eg phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcar Carbonyl and arylcarbonyl or other such acyl groups, heteroarylcarbonyls, or heteroaryl groups, (CR'R ") _0-3 NR'R" (eg, -NH ₂ ), (CR'R ") _0-3 CN (eg -CN), NO ₂ , halogen (eg F, Cl, Br or I), (CR'R ") _0-3 C (halogen) 3 (eg -CF ₃ ), (CR'R ") _0-3 CH (halogen) ₂ , (CR'R") _0-3 CH ₂ (halogen), (CR'R ") _0-3 CONR'R", ( CR'R ") _0-3 (CNH) NR'R", (CR'R ") _{0- 3} S (O) _1-2 NR'R ", (CR'R") _0-3 CHO, (CR'R ") _0-3 O (CR'R") _0-3 H, (CR'R " ) _0-3 S (O) _0-3 R '(e.g. -SO ₃ H), (CR'R ") _0-3 O (CR'R") _0-3 H (e.g.- CH ₂ OCH ₃ and -OCH ₃ ), (CR'R ") _0-3 S (CR'R") _0-3 H (eg, -SH and -SCH ₃ ), (CR'R ") _{0 -3} OH (e.g., -OH), (CR'R ") _0-3 COR ', (CR'R") _0-3 (substituted or unsubstituted phenyl), (CR'R ") _{0- 3} (C ₃ -C ₈ cycloalkyl), (CR'R ") _0-3 CO ₂ R '(eg -CO ₂ H), or (CR'R") _0-3 OR' group or natural A moiety selected from the side chains of the amino acid; Wherein R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or an aryl group, or R ′ and R ″ together with benzylidene Groups or — (CH ₂ ) ₂ O (CH ₂ ) ₂ groups. Preferably the substitution enhances the ability of the compounds of the invention to perform the desired action (eg inhibits the formation of amyloid deposits).
[191] In the compounds of the present invention, it is preferred that m = 1 and n = 0, 1 or 2. The compound of formula (I) is preferably p = 0, 1 or 2 and q = 1. Particularly preferably the molecules of formula (I) are symmetrical and therefore R ^a1 = R ^a2 , R ^b1 = R ^b2 , R ^c1 = R ^c2 , m = q, n = p and Y ¹ = Y ² . Likewise, in the molecule of formula (I) it is preferred that R ¹ = R ² and X ¹ = X ² .
[192] One of the preferred compounds of the present invention is a compound of formula la:
[193]
[194] Where M is
[195] ego,
[196] Here, in a preferred aspect, R ^a1 and R ^b1 together, or R ^a2 and R ^b2 together represent C ₂ to C ₃ alkylene; R ^c1 and R ^c2 are H; R ^h1 is H; R ^h2 is OCH ₃ or O (C ₆ H ₄ ) R, wherein R is H or lower alkyl, X is O, NR 'or S, where R' is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl groups.
[197] In another group of preferred compounds of formula (Ia) both R ^a1 and R ^b1 or R ^a2 and R ^b2 together represent C ₂ linear saturated alkylene; R ^c1 and R ^{c2 are-} (lower alkyl) -OH; R ^h1 and R ^h2 are each H. The "lower alkyl" groups of R ^c1 and R ^c2 are preferably ethylene.
[198] In another group of preferred compounds of formula (la), R ^a1 and R ^b1 together or R ^a2 and R ^b2 together represent C ₄ alkylene; R ^c1 and R ^c2 are H (preferably), lower alkyl, cycloalkyl, aryl, hydroxyacyl, aminoalkyl or alkylaminoalkyl; R ^h1 and R ^h2 are independently selected from the group consisting of H (preferably), lower alkyl, halogen, alkoxy, aryloxy or arylalkoxy.
[199] Another group of preferred compounds of Formula (Ia) are those in which R ^a1 , R ^a2 , R ^b1 and R ^b2 are H, and R ^c1 and R ^c2 are isopropyl ^or- (CH ₂ ) ₃ N (CH ₃ ) ₂ ; R ^h1 and R ^h2 are H.
[200] In another group of preferred compounds of formula (Ia), R ^a1 and R ^b1 together or R ^a2 and R ^b2 together represent a phenylene group optionally substituted with up to 3 -CONHR ^d NR ^e R ^f groups, R ^d is lower alkyl, R ^e and R ^f are each independently selected from the group consisting of H or lower alkyl; R ^c1 , R ^c2 , R ^h1 and R ^h2 are H.
[201] Particularly preferred compounds of formula (Ia) are those in which R ^h1 , R ^h2 , R ^b1 , R ^c1 , R ^b2 and R ^c2 are H and the R ^a1 and R ^a2 groups are hydroxy or methoxy.
[202] Another group of preferred compounds are those of Formula Ib:
[203]
[204] Where M is ego,
[205] X is O, NR 'or S, wherein R' is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group; R ^h1 and R ^h2 are each independently selected from the group consisting of H, lower alkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, alkoxy, aryloxy or oxyarylalkyl; R ¹ and R ² are each independently selected from the group consisting of H, lower alkyl, alkoxy, alkylaryl, aryl, aryloxy, aminoalkyl, aminoaryl or halogen; Each R ^a1 , R ^a2 , R ^b1 , and R ^b2 group is selected from the group consisting of H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, hydroxy or alkylaryl; Or R ^a1 and R ^b1 together or R ^a2 and R ^b2 together represent C ₂ -C ₁₀ alkyl, hydroxyalkyl or alkylene; Each R ^c1 and R ^c2 group is independently H, hydroxy, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkyl Aryl.
[206] Other groups of preferred compounds are those of Formula Ic:
[207]
[208] Where M is ego,
[209] X is S, O or NR ', wherein R' is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group; R ^b1 , R ^b2 , R ^c1 and R ^c2 are each independently selected from the group consisting of H, lower alkyl, alkoxy, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl or alkylaminoalkyl; R ¹ and R ² are H, lower alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, aryl, aminoalkyl, alkylaminoalkyl or halogen; R ^a1 and R ^a2 are -OY, or R ^a1 and R ^b1 together or R ^a2 and R ^b2 together represent the following formula,
[210]
[211] Where R ⁵ is ego,
[212] Y is H or lower alkyl; Each of X ¹ and X ² is — (CH ₂ ) _n — and n is an integer from 0 to 2; R ^h1 and R ^h2 are each independently selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxy or oxyarylalkyl.
[213] Another group of preferred compounds is a compound of formula (Ic),
[214] Where M is-(CH ₂ ) _n- ,
[215] n is an integer from 2 to 16 (or 2 to 12, or 2 to 10); Each of X ¹ and X ² is O, NH or S; R ^a1 , R ^a2 , R ^b1 and R ^b2 are H, or R ^a1 and R ^b1 together or R ^a2 and R ^b2 together represent-(CH ₂ ) _m- ; Where m is 2, 3 or 4; R ¹ and R ² are each H, OCH ₃ , NO ₂ or NH ₂ ; R ^c1 and R ^c2 are H, CH ₃ or CH ₂ CH ₃ . In other embodiments, when X ¹ is O or S, both R ¹ and R ^c1 can not be H; When X ² is O or S, both R ² and R ^c2 may not be H.
[216] Other groups of preferred compounds are those of the formula
[217]
[218] Wherein R ^a1 , R ^a2 , R ^b1 and R ^b2 are independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl ; R ^a1 and R ^b1 together or R ^a2 and R ^b2 together represent C ₂ -C ₁₀ alkylene; R ^c1 and R ^c2 are independently H, hydroxy, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl; And R 'is H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl.
[219] Other groups of preferred compounds are those of formula Ie:
[220]
[221] Wherein M is an alkylene group (eg, C ₂ to C ₁₆ ) and X ¹ and X ² are oxygen.
[222] In another group of preferred compounds of formula (Ie), R ^a1 and R ^b1 together, or R ^a2 and R ^b2 together represent C ₂ linear saturated alkylene; R ^c1 and R ^c2 are H.
[223] Another group of preferred compounds of the invention are compounds of formula IIa:
[224]
[225] Where E is
[226] ego,
[227] Wherein Y ¹ , Y ² , Z, and R ¹ are as defined above; n is 0 to 4; Y ² is preferably O, NH, S, a substituted or unsubstituted methylene group or a direct bond; Z is a hydrogen atom, or Z may preferably be an alkyl, aryl, alkoxy, aryloxy, hydroxy, substituted or unsubstituted amino, nitro, sulfo or halogen group; R ^a1 , R ^b1 and R ^c1 are independently hydrogen, lower alkyl, aromatic, hydroxy or alkoxy; B is a direct bond or a substituted or unsubstituted alkylene or biphenylene group or mixed biphenylene-alkylene group containing 1 to 16 carbon atoms,-[(CH ₂ ) _n O] _m (CH ₂ ) _n- Group or heterocyclic group, m is 1-6, n is 2-6.
[228] Compounds of formula IIb belong to the present invention:
[229]
[230] Wherein n is 2, 3, 4, 5, 6, 7, 8, 9 or 10; R is hydrogen, hydroxy, halogen, phenyl, biphenyl, naphthyl, alkoxy, carboxy, alkoxycarbonyl, aryloxycarbonyl or aryloxy.
[231] Preferred groups of compounds are those of the formula IIIa:
[232]
[233] Where M is
[234] ego,
[235] Wherein X is S, O or NR ', wherein R' is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group; R ^a1 , R ^a2 , R ^b1 and R ^b2 are each independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, hydroxyalkyl, aminoalkyl or alkylaminoalkyl; Or R ^a1 and R ^b1 together, or R ^a2 and R ^b2 together represent C ₂ to C ₁₀ alkyl, hydroxyalkyl or alkylene; R ^a1 and R ^b1 together, or R ^a2 and R ^b2 together are of the formula:
[236]
[237] Wherein n is 1 to 3, and R ¹⁰ is H or -CONHR ¹¹ NR ¹⁵ R ¹⁶ , wherein R ¹¹ is lower alkyl, and R ¹⁵ and R ¹⁶ are each independently composed of H and lower alkyl Independently from; R ^c1 and R ^c2 are H, hydroxy, lower alkyl, cycloalkyl, aryl, alkylaryl, alkoxyalkyl, hydroxycycloalkyl, alkoxycycloalkoxy, hydroxyalkyl, aminoalkyl or alkylaminoalkyl; R ^h1 and R ^h2 are each independently selected from the group consisting of H, lower alkyl, halogen, aryl, arylalkyl, aminoalkyl, aminoaryl, alkoxy, aryloxy or oxyarylalkyl.
[238] Another group of preferred compounds are those of Formula IIIb:
[239]
[240] Wherein each of the pair of R ^a1 and R ^{b1 and} the pair of R ^a2 and R ^{b2 is-} (CH ₂ ) _m -where m is 2 to 4 and R ^c1 and R ^c2 are independently H or lower alkyl ; M substituted with a lower alkyl group is selected from the group consisting of —CH═CH—CH ₂ —CH ₂ —, —CH ₂ —CH═CH—CH ₂ —, and —CH═CH—CH═CH—.
[241] Another group of preferred compounds are those of Formula IIIc:
[242]
[243] Wherein R ¹ and R ² are independently H or —CONHR ⁵ NR ⁶ R ⁷ , R ⁵ is lower alkyl, and R ⁶ and R ⁷ are each independently selected from the group consisting of H and lower alkyl; R ^a1 , R ^a2 , R ^b1 , and R ^b2 are independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl, or R ^a1 and R ^b1 together, or R ^a2 and R ^b2 together represent C ₂ -C ₁₀ alkylene; R ^c1 and R ^c2 are independently H, hydroxy, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl; R ^c3 and R ^c4 are independently H, hydroxy, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl or alkylaryl; And R 'is H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, alkylaryl or halogen.
[244] Another embodiment of the invention relates to pharmaceutical compositions comprising any of the compounds according to the formula of the invention for the treatment of amyloid related diseases and methods of making such pharmaceutical compositions.
[245] The compounds of the present invention can be formulated for proper dispersion in vivo. For example, the blood-brain barrier (BBB) blocks many high-hydrophilic compounds. The compounds can be formulated, for example, with liposomes, to ensure that the more hydrophilic therapeutic compounds of the invention are passed through the BBB. For methods of making liposomes, see US Pat. No. 4,522,811; 5,374,548; 5,374,548; And 5,399,331. Liposomes can include one or more residues (“target residues”) that are selectively transferred to specific cells or organs to provide the desired drug delivery. (See, eg, V. V. Ranade (1989) J. Clin. Pharmacol. 29: 685).
[246] Exemplary residues of interest include folate or biotin (see, eg, US Pat. No. 5,416,016 to Low et al.); Mannoside (Umezawa et al. (1988) Biochem. Biophys. Res. Commun. 153: 1038); Antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357: 140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39: 180); Surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physio. 1233: 134); gpl20 (Schreier et al. (1994) J. Biol. Chem. 269: 9090); See also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346: 123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4: 273. In a preferred embodiment, the therapeutic compound of the invention is formulated into liposomes, and in a more preferred embodiment, the liposomes comprise the desired moiety.
[247] To ensure that the compounds of the invention pass through the BBB, these compounds can be coupled with the BBB transit vector. (For BBB transit vectors and mechanisms, see Beckel, et al., Adv. Drug Delivery Reviews, vol. 46, pp. 247-279,2001). Exemplary transit vectors include OX26 monoclonal antibodies or cationized albumin against transferrin receptors, and these proteins perform absorption-mediated and receptor-mediated cell transduction through BBB, respectively.
[248] Examples of other BBB migration vectors aimed at shifting the receptor-mediated migration system into the brain include insulin, insulin-like growth factor (IGF-I, IGF-II), agiotensin II, atrial and cerebral natriuretic peptide (ANP, BNP), interleukin I (IL-1), and transferrin. BBB Transfer Vectors for Absorption-Mediated Cell Transduction The objective mechanisms include cationic moieties such as horseradish peroxides, cationized albumin or cationized immunoglobulins combined with cationized LDL, albumin or polylysine. Small amounts of basic oligopeptides such as dinopine homolog E-2078 and ACTH homologue evirati can also pass through the brain via absorption-mediated cell transduction and potential migration vectors.
[249] Another BBB migration vector targets a system for transferring nutrients to the brain. Examples of such BBB migration vectors are hexose residues such as glucose, monocarboxylic acids such as lactic acid, natural amino acids such as phenylalanine, amines such as choline, basic amino acids, For example, arginine, nucleosides such as adenosine, purine bases such as adenine and thyroid hormones such as triiodothyridine. In addition, antibodies directed to extracellular regions of nutrient carriers can be used as migration vectors. Other possible vectors include angiotensin II and ANP, which may be involved in the regulation of BBB acceptability.
[250] In some cases, the bond connecting the therapeutic compound with the migration vector is cleaved, and the bioactive compound can then be released and delivered to the brain. Exemplary linking groups include disulfide bonds, ester-based bonds, thioether bonds, amide bonds, acid-reactive bonds and schiff base bonds. An avidin / biotin linker in which avidin covalently binds with a BBB drug transfer vector can be used. Avidin itself may be a drug delivery vector.
[251] In order to administer a therapeutic compound by methods other than parenteral administration, it may be necessary to coat the compound with a substance that prevents the inactivation of the compound or to administer the compound with the substance. For example, the therapeutic compound may be included in an appropriate carrier, eg, liposomes or diluents, and administered to the subject. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
[252] Liposomes can include water-oil-water CFC emulsions and conventional liposomes (Strejan et al., (1984) J. Neuroimmunol. 7: 27).
[253] Therapeutic compounds may also be administered parenterally, intraperitoneally, in spinal cord or in the brain. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under the general conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
[254] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (here water-soluble) or dispersions and sterile powders for the instant preparation of sterile injectable solutions or dispersions. In all cases, the composition should be sterile and in a solution that is easily injectable. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
[255] The vehicle may be, for example, a solvent or dispersion medium comprising water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycols, etc.), appropriate mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The action of microorganisms can be inhibited by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride or polyalcohols such as mannitol and sorbitol. The injectable composition can be delayed absorbed by including an absorption retardant such as aluminum monostearate or gelatin in the composition.
[256] The required amount of therapeutic compound can be incorporated in a suitable solvent with one or a mixture of ingredients enumerated above, followed by preparation of sterile injectable solutions by filtration sterilization. Generally, dispersions can be prepared by incorporating the therapeutic compound into a sterile vehicle that contains a basic dispersion medium and the other required ingredients enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is a vacuum drying and lyophilization method which provides a powder of the active ingredient (ie, the therapeutic compound) and additional required ingredients from its presterilized-filtered solution. to be.
[257] The therapeutic compound may be administered orally, for example with an inert diluent or an absorbable edible carrier. The therapeutic compound and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed in tablets, or incorporated directly into the subject's food. For oral therapeutic administration, the therapeutic compound may be incorporated with excipients and used in the form of digestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. The percentage of therapeutic compound in the compositions and formulations may of course vary. The amount of therapeutic compound in such therapeutically useful compositions is such that an appropriate dosage can be obtained.
[258] Particular preference is given to formulating parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitably in a single dosage for the subject being treated, each unit of a therapeutic compound calculated to provide the desired therapeutic effect in combination with the required pharmaceutical vehicle. It includes a predetermined amount. The specification for the dosage unit form of the invention is defined by the inherent limitations in the art of incorporating a therapeutic compound for (a) the unique properties of the therapeutic compound and the specific therapeutic effect to be achieved and (b) the amyloid deposition of the subject and Is written directly accordingly.
[259] Accordingly, the present invention includes pharmaceutical compositions comprising a compound of formula (including its pharmaceutically acceptable salts) described herein in a pharmaceutically acceptable carrier for aerosol, oral and parenteral administration. In addition, the present invention includes compounds or salts thereof that can be lyophilized and reorganized to form a pharmaceutically acceptable composition for administration by intravenous, intramuscular or subcutaneous injection. Administration can also be intradermal or transdermal.
[260] Compounds of the formulas described herein and pharmaceutically acceptable salts thereof in accordance with the present invention may be administered by inhalation or orally as a solid or may be administered intramuscularly or intravenously as a solution, suspension or emulsion. Alternatively, the compound or salt may also be administered as a liposome suspension, administered intravenously or intramuscularly.
[261] In addition, pharmaceutical compositions suitable for administration as aerosols by inhalation may be provided. These compositions comprise a plurality of solid particles of a solution or suspension or compound or salt of the desired compound of any formula herein or a salt thereof. The desired composition can be sprayed in a small space. Spraying can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising a compound or salt. Liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns. Solid particles can be obtained, for example, by micronization, by processing the solid compounds of any of the formulas described herein or salts thereof in a suitable manner known in the art. Most preferably, the size of the solid particles or droplets may be about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose.
[262] Preferably, administered as an aerosol When the appropriate pharmaceutical composition is in the form of a liquid, the composition may comprise a water soluble compound of any of the formulas described herein or a salt thereof in a carrier comprising water. Surfactants may be present that reduce the surface tension of the composition sufficiently to form droplets within the desired size range upon spraying.
[263] The active compound is administered at a therapeutically effective dose sufficient to inhibit amyloid deposition in the subject. The "therapeutically effective" dosage is preferably at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, more preferably at least about 80%, relative to the untreated subject. This is suppressed. For Alzheimer's patients, a “therapeutically effective” dose stabilizes mental action or prevents further decline of mental action (ie, prevents, slows down or stops disease development).
[264] The ability of compounds to inhibit amyloid deposition can be assessed in animal model systems that can be predictive of the effects of inhibiting amyloid deposition in human diseases such as transgenic mice expressing human APP or other relevant animal models in which Aβ deposition is observed. Can be. Similarly, the ability of a compound to prevent or reduce mental damage in a model system can be indicative of an effect in humans. Alternatively, the ability of the compound can be assessed by measuring the ability of the compound to inhibit amyloid fibril formation in vitro using, for example, the fibrogenesis assays described herein including ThT, CD or EM assays. . Binding of the compound to amyloid fibrils can also be measured using MS analysis as described herein.
[265] The invention also relates to prodrugs of compounds of the formulas disclosed herein. Prodrugs are compounds that are converted to the active form in vivo (see, eg, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chap. 8). It can be used to alter the body's kinetics of a particular compound (eg, to allow compounds that cannot normally enter the reaction site of the protease), or to alter the pharmacokinetics of a particular compound. For example, carboxylic acid groups can be esterified with methyl or ethyl groups to provide esters. When the ester is administered as a subject, the ester is cleaved enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically to provide anionic groups. Anionic groups are esterified with residues (eg, acyloxymethyl esters) cleaved to give intermediate compounds, followed by degradation to give the active compound. The prodrug moiety can be metabolized in vivo by esterases by other mechanisms with carboxylic acids.
[266] Examples of prodrugs and their uses are known in the art (see, eg, Berge et al. (1977) "Pharmaceutical Salts", J Pharm. Sci. 66: 1-19). It may be prepared in situ during final isolation and purification or may be prepared by separately reacting the purification compound with the appropriate derivatizing agent in free acid form. Carboxylic acids can be converted to esters by treatment with alcohols in the presence of a catalyst.
[267] Examples of cleavable carboxylic acid prodrug moieties are substituted or unsubstituted, branched or unbranched lower alkyl ester moieties (eg, ethyl ester, propyl ester, butyl ester, pentyl ester, cyclopentyl ester, hexyl ester, cyclohexyl) Esters), lower alkenyl esters, lower dialkyl-amino, lower-alkyl esters (eg dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy lower alkyl esters (eg pivaloyloxymethyl Esters), aryl esters (phenyl esters), aryl-lower alkyl esters (eg benzyl esters), substituted aryl and aryl-lower alkyl esters, eg substituted with methyl, halo or methoxy substituents, Amides, lower-alkyl amides, lower dialkyl amides and hydroxy amides.
[268] It will be appreciated that the structure of some compounds of the present invention may include steric carbon atoms. Thus, unless otherwise indicated, isomers resulting from such asymmetry (eg, all enantiomers and diastereomers) are understood to be within the scope of the present invention. That is, unless otherwise specified, any chiral carbon center may be of (R) or (S) stereochemistry. Such isomers can be obtained in substantially pure form by conventional separation techniques and by stereochemically controlled synthesis. Furthermore, alkenes may include the E or Z geometric isomers as appropriate.
[269] Certain embodiments of the present invention may include base functional groups, such as amino or alkylamino groups, and thus may form pharmaceutically acceptable salts having pharmaceutically acceptable acids. "Pharmaceutically acceptable salts" in this respect refer to the relatively nontoxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention or by reacting the purified compounds of the invention in free base form with appropriate organic or inorganic acids separately and separating the salts formed.
[270] Representative salts include hydrohalides (including hydrobromide and hydrochloride), sulfates, bisulfates, phosphates, nitrates, acetates, valerates, oleates, palmitates, stearates, laurates, benzoates, lactates Phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthyrate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethylsulfonate and laurylsulfonate salts Include. (See, eg, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
[271] In other instances, the compounds of the present invention may include one or more acidic functionalities to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In this case the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the invention.
[272] The salts can similarly be prepared in situ during the final separation and purification of the compounds or the purified compounds of the free acid type can be prepared by appropriate bases such as hydroxides, carbonates of pharmaceutically acceptable metal cations. Or by separately reacting with bicarbonate, ammonia, pharmaceutically acceptable organic primary, secondary or tertiary amines. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
[273] Those skilled in the art will recognize many equivalents to the specific embodiments and methods described herein and may be specified using routine experimentation. Such equivalents are intended to be included within the scope of the following claims. All patents, patent applications, and references cited herein are expressly incorporated herein by reference in their entirety. The invention is illustrated by the following examples and should not be construed as being limited thereto.
[15] Summary of the Invention
[16] The present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases. In particular, the present invention relates to methods of treating or preventing amyloid-related diseases in a subject comprising administering to the subject a therapeutic amount of an amidine compound. Among the compounds for use in the present invention are compounds of the formula wherein, when administered, amyloid fibril formation, neurodegeneration, or cytotoxicity is reduced or inhibited:
[17]
[274] Synthesis of the amidine compounds of the present invention is U.S. Patents 5,428,051, 4,963,589, 5,202,320, 5,935,982, 5,521,189, 5,686,456, 5,627,184, 5,622,955, 5,606,058, 5,668,167 5,667,975, 6,025,398, 6,214,883, 5,817,687, 5,792,782, 5,939,440, 6,017,941, 5,972,969, 6,046,226, 6,294,565 (B1), 6,156,779,695,156,695,695,695 No. 6,008,247, 6,127,554, 6,172,104, 4,940,723, 5,206,236, 5,843,980, 4,933,347, 5,668,166, 5,817,686, 5,723,495, 4,619,942, 5,792,78,5,792,78 5,639,755, 5,643,935, 5,602,172, 5,594,138 and 5,578,631. Many compounds can be purchased from Sigma Aldrich Co., Milwaukee, USA. In addition, the compounds may be synthesized according to techniques recognized in the art.
[275] Test compounds may be purchased from commercial sources or synthesized and analyzed by thioflavin T fluorescence analysis (“ThT assay”). Alternatively, the compounds may be screened for test compounds by circular decroism ("CD"), electron microscopy ("EM") or mass spectrometry ("MS") analysis. MS assays provide data on the ability of compounds to bind amyloid proteins, and ThT, EM and CD assays provide data on the inhibition of fibrogenesis.
[276] The thioflavin T fluorescence assay for fibrosis is based on the principle that the fluorescent dye, thioflavin T, binds site-specifically with pyrilla and does not bind with non-aggregated Αβ peptides. See LeVine III, H., 1993, Protein Science 2: 404-410. In binding, thioflavin T generates characteristic fluorescence (Naiki, H., et al., 1996, Lab. Invest. 74: 374-383) that can be easily detected. The dye is believed to interact with the stacked cross-β wrinkled sheet, a common structural motif of all amyloids. LeVine III, H., 1995, Amyloid: Int. J. Exp. Clin Invest. See 2: 1.6. Thioflavin T is widely used to analyze the effects of compounds on fibrogenesis of Aβ peptides and other amyloid proteins. Bronfman, P.C., et al., 1995, Neuroscience Lett. 218: 201-203). In this assay, the test compound was Aβ (1-40) containing 5 mM thioflavin T in 0.02 M Tris / 0.02 M acetate / 0.15 M NaCl / 0.005% azide / pH 7.40 at 37 ° C. in 384 well microplates. (20 μM) or a solution of IAPP (10 μM). Detection (ex 430 nm / em 485 nm) was performed at various time intervals using a micro fluorescence reader. As illustrated in the figure, the increase in fluorescence confirms the appearance of amyloid or intermediates during amyloid preparation. (In general, compounds that inhibit fibrosis provide less amount of fluorescence in the assay because when bound to fibrils, the fluorescence of ThT increases.)
[277] Protocol : Aβ Peptide: Aβ (1-40) 95% purity (American Peptide Company, Inc. (Sunnyvale, CA)) is non-aggregated in trifluoroacetic acid and 0.02 μM filter in hexafluoroisopropanol (HFIP) (Wattman Anotop 25 Plus, 0.02 μm, Cat. No. 6809 4102). A solution of Aβ (1-40) or IAPP at 600 μm in HFIP was stored at −80 ° C. Mixture Analysis: The mixture was added to 384 well microplates to prepare two combined solutions (Corning Costa approximately 3705).
[278] i) Solution A consists of test compound in 0.02M Tris / 0.02M acetate / 0.15M NaCl / 0.01% azide pH 7.40, or buffer alone (control).
[279] ii) Solution B consisted of 40 μΜ Aβ (1-40) or 20 μΜ IAPP, Thioflavin T 10 mM in 0.02 M Tris / 0.02 M acetate / 0.15 M NaCl pH 7.40. The solution was prepared by drying the Αβ peptide under nitrogen and then resuspending it in 0.04 M Tris base using sonication for 15 minutes. The solution was adjusted to 7.40 ± 0.02 by addition of 0.04M acetic acid in average volume containing 0.3M NaCl. A small amount of 20 mM thioflavin T was added to the solution to give a final concentration of 5 μM thioflavin T.
[280] iii) Microplates were loaded with 40 μM of Solution A followed by 40 μM of Solution B so that the final 20 μM Aβ (1-40) or 10 μM IAPP, 5 μM thioflavin T and 0.02M Tris / 0.02M acetate / 0.15M NaCl A test compound of a given concentration in /0.005% azide, pH 7.40 was provided.
[281] The plate was sealed and loaded with a microplate fluorescence detector. Fluorometric Data Analysis: HTS-7000 Bio Assay Reader, Perkin Elmer, was used to perform the motor operation for about 1 day. Analyzes were performed at 15 minute intervals and shaken for 1 minute before each analysis. The bandpass filter used was excitation 430 nm and light emission 485 nm.
[282] Similarly, in electron microscopy ("EM") analysis, each sample was sonicated for 1 minute to break up large chunks before testing. Samples (5 μM equiv) were placed on freshly cut mica and air dried. Mica was placed in Balzers High-vacuum, Freeze-Etch Unit (model 301), blocked with platinum (30 ° angle) and coated with carbon film. The replica was removed from the mica by floatation and moved onto a 300-mesh copper grid. Samples were measured using a Joel 2000FX transmission scanning microscope.
[283] In the circular dechromism (CD) analysis, the samples were transferred to 0.1 cm path-length Quartz Cuve and CD scans were performed using a Jasco J-715 spectropolarimeter. The analysis was performed at 190 ° C. at 37 ° C., at 0.1 nm resolution and at 1 nm bandwidth.
[284] In mass spectrometry (“MS”), samples were prepared in an aqueous solution containing 20% ethanol, 200 μM test compound and 20 μM dissolved Aβ40. Each sample pH value was adjusted to 7.4 (± 0.2) by addition of 0.1% aqueous sodium hydroxide. The solution was then analyzed by electrospray ionization mass spectrometry using an aqueous ZQ 4000 mass spectrometer. Samples were introduced by direct injection at a flow rate of 25 μl / min within 2 hours after sample preparation. The source temperature was maintained at 70 ° C. and the cone voltage was used at 20V in all assays. Data was worked using Masslynx 3.5 software. MS analysis provided data on the ability of compounds bound to Aβ, and ThT, EM and CD analyzes provided data on inhibition of fibrogenesis.
[285] Selected compounds of the present invention are shown in Table 2 below. While certain salts have been described (eg hydrochloride), free bases and other pharmaceutically acceptable salts are within the scope of the present invention.
[286] TABLE 2 Structure and Activity of Some Compounds of the Invention in Soluble Aβ40 Assay
[287]
[288]
[289]
[290]
[291]
[292]
[293]
[294]
[295]
[296]
[297]
[298]
[299]
[300]
[301]
[302] ]
[303] In each assay, "+" = activity; "-" = Inert; "pr" = promotion; "nd" or blank = not measured.
[304] The following compounds of Table 3 can also be used according to the manner herein.
[305] Table 3 Additional Exemplary Compounds for Use in the Methods of the Present Invention
[306]
[307]
[308]
[309]
[310]
[311] The chart below is obtained from ThT analysis.
[312]
[313]
[314]
[315]
[316] The invention also relates to novel compounds and their synthesis. Thus, the following examples are provided to illustrate how to prepare some of these compounds.
[317] Common cotton
[318] The compound was purchased from Aldrich. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F ₂₅₄ plastic-support plates. Solvents are reagent grades unless otherwise stated. ¹ H (500 MHz) and ¹³ C (125 Hz) were recorded on a Varian Inova 500. Chemical shifts were reported on ppm δ scale. Infrared (IR) spectra were performed on a Perkin Elmer Spectra One Analyzer (nit compound on NaCl plate).
[319] 1,4-bis (4-amidinoanilino) butane
[320]
[321] Step 1: 1,4-bis (4-cyanoanilino) butane
[322]
[323] A mixture of 4-fluorobenzonitrile (3 g, 0.025 mol), 1,4-diaminobutane (0.6 g, 0.006 mol), triethylamine (5 ml) and DMSO (16 ml) was stirred at 150 ° C. for 3 hours. Heated. The mixture was then poured into ice water (250 ml) and the precipitate collected by filtration. Recrystallization of the crude product (0.58 g) from DMSO / H ₂ O (6: 1) gave the product as a light yellow solid (0.48 g, yield 27.6%).
[324] Step 2: 1,4-bis (4-amidinoanilino) butane
[325]
[326] A mixture of 1,4-bis (4-cyanoanilino) butane (0.44 g, 1.52 mmol) in ethanol (30 ml) and dioxane (10 ml) was cooled to 0 ° C. and saturated with HCl gas. The resulting mixture was stirred at room temperature until IR indicated disappearance of the nitrile absorption peak at ˜2200 cm ⁻¹ . Diethyl ether (100 ml) was added and the precipitate formed was collected and washed with diethyl ether. The solid obtained was then placed into a 50 ml round bottom fleece. Ethanolic ammonia (2M, 30 ml) was added slowly via syringe. The resulting mixture was refluxed for 3 hours and then cooled to room temperature. Diethyl ether (100 ml) was added to induce precipitation. The precipitate formed was collected, washed with ether and recrystallized from H ₂ O to give 0.50 g of product, 99% yield.
[327] Linear Dibenzamidine and Diimidazolino Compounds
[328]
[329] Step 1: α, ω-bis (4-cyanophenoxy) alkanes
[330] Sodium (1.2 g, 0.05 mole) was triturated into small pieces and slowly added to a stirred solution of anhydrous ethanol (40 ml). After the sodium was completely dissolved, 4-cyanophenol (6 g, 0.05 mol) was added followed by dropwise addition of 1,4-dibromobutane (5.4 g, 0.025 mol). The resulting mixture was stirred with reflux for 1-2 days and then cooled to room temperature. The white solid formed in the reaction was collected by vacuum filtration, washed with water and dried under vacuum. The resulting product, 1,4-bis (4-cyanophenoxy) butane (7.18 g, 98% yield) was used without further purification in the next step. Similar compounds with n = 3,5,6,7,8,9 and 10 were prepared and yields were 70-95%. ¹ H and ¹³ C NMR of the compounds were consistent in structure.
[331] Step 2: Dibenzamidine and Diimidazolino Compound
[332] A mixture of α, ω-bis (4-cyanophenoxy) alkane (3.42 mmol), dioxane (15 ml) and ethanol (40 ml) was cooled to 0 ° C. Anhydrous HCl gas was passed through the mixture into the bubble until saturated. The mixture was stirred at room temperature until IR nitrile absorption was attenuated at 2200 cm ^-1 .
[333] Then, diethyl ether (100 ml) was added and a white precipitate formed. The precipitate was collected by vacuum filtration, washed with diethyl ether and placed in a 50 ml round bottom flask. Ethanolic ammonia solution (2M, 30 ml; during the preparation of dibenzamidine) or ethylenediamine (1.5 M, 30 ml; during the preparation of the diimidazolino compound) in MeOH was slowly added via syringe. The resulting mixture was stirred at reflux for 3 hours. After the mixture was cooled to room temperature, diethyl ether (100 ml) was added. The white precipitate formed was collected and washed with diethyl ether. The solid was then recrystallized from HCl (2N) to give the desired product. Dibenzamidine compounds with n = 3-10 have been prepared and yields range from 60 to 85%. Diimidazolino compounds with n = 4-10 were prepared and yields were 50-92%.
[334] 1- (4-amidino) phenoxy-8-bromooctane, hydrobromide
[335]
[336] Step 1: 1- (4-cyano) phenoxy-8-bromooctane
[337] 4-cyanophenol (2.38 g, 20 mmol), K ₂ CO ₃ (anhydrous, 25 mmol) and DMF (50 ml) were placed in a 100 ml round bottom flask. The mixture was stirred at rt for 30 min. When the mixture was broken, 8-bromooctanol (20 mmol) was added dropwise via syringe. The mixture was then refluxed for 5 hours, then cooled to room temperature and poured into ice water (200 ml). White precipitate formed and was collected by vacuum filtration. After silica gel flash column chromatography (eluent: 20-40% ethyl acetate in hexane), the pure product (4.1 g, 88.7% yield) was obtained as a white solid.
[338] Step 2: 8- (4-amidinophenoxy) octanol
[339] The corresponding amidine compound was obtained by successive treatments with saturated ethanol hydrochloride solution and ethanol ammonia similarly as described above.
[340] Step 3: 1- (4-amidinophenoxy) -8-bromooctane, hydrobromide
[341] 8- (4-amidinophenoxy) octanol (2.14 g, 6.8 mmol) and dichloromethane (30 ml) were placed in a 50 ml round bottom flask. The mixture was cooled to 0 ° C. and PBr ₃ (3.4 mmol, 0.5 equiv) was added dropwise via syringe. The mixture was then stirred at rt overnight. The white solid starting material gradually dissolved and turned into a yellow oil phase that did not mix with dichloromethane. After the reaction was completed, water was added to quench the reaction, and dichloromethane was evaporated under reduced pressure to give a white solid as a crude product. Silicagel flash column chromatography (eluent CHCl ₃ / MeOH / AcOH 94/5/1) followed by recrystallization with HBr / CH ₃ CN (2N) to give the pure product (white solid, 780 mg, 31% yield). )
[342] 9- (4-amidinophenoxy) nonanoic acid, hydrochloride
[343]
[344] Step 1: 9- (4-cyanophenoxy) nonanol
[345] In a 100 ml round bottom flask, 4-cyanophenol (2.38 g, 20 mmol) and K 2 CO 3 (anhydride, 25 mmol) were mixed in DMF (50 ml). The mixture was stirred at rt for 30 min. When the mixture was broken, 9-bromononanol (20 mmol) was added dropwise via syringe. The mixture was then refluxed for 5 hours, cooled to room temperature and poured into ice water (200 ml). The white precipitate formed was collected by vacuum filtration. After silica gel column chromatography (eluent: 20-40% ethyl acetate in hexane), the pure product (4.8 g, 98% yield) was obtained as a white solid.
[346] Step 2: 9- (4-cyanophenoxy) nonanoic acid
[347] PDC (19 g, 61 mmol, 6 equiv) was added as a solution of 9- (4-cyanophenoxy) nonanol (2.5 g, 10.2 mmol) in DMF (50 mL). The mixture was stirred overnight at 50 ° C., then cooled to room temperature and poured into ice water (150 ml). The mixture was extracted using ethyl acetate (4x50ml). The combined organic layers were washed with brine and dried over sodium sulphate. Purification by silica gel flash column chromatography (eluent: 25-50% ethyl acetate in hexanes) gave the product as a white solid (1.65 g, 62% yield).
[348] Step 3: 9- (4-cyanophenoxy) nonanoic acid, ethyl ester
[349] In a 100 ml round bottom flask, thionyl chloride (0.88 ml, 12 mmol) was added with anhydrous ethanol (50 ml). The mixture was stirred for 10 minutes, and then 9- (4-cyanophenoxy) nonanoic acid (1.65 g, 6.02 mmol) was added in portions. The reaction was monitored by TLC. After the reaction was completed, ethanol was removed under reduced pressure. Ether (100 ml) and saturated sodium bicarbonate solution (100 ml) were added. The organic phase was separated and dried over sodium sulphate. After evaporation of the solvent, the product was obtained as a white solid (1.6 g, 87.7% yield).
[350] Step 4: 9- (4-amidinophenoxy) nonanoic acid hydrochloride
[351] 9- (4-cyanophenoxy) nonanoic acid ethyl ester (1.6 g, 5.28 mmol) was dissolved in a mixture of ethanol and dioxane (50/10 ml) in a sealed 100 ml round bottom flask. The mixture was saturated with HCl (g) at 0 ° C. and stirred at room temperature until the IR disappeared at 2200 cm ⁻¹ nitrile absorption. Ethanol / dioxane was then removed under reduced pressure and ether (100 ml) was added to cause precipitation. The precipitate was collected and put directly into anhydrous 100 ml flask. Ethanolic ammonia (2M, 40 ml) was added via syringe. The mixture was refluxed for 3 hours, then the solvent was removed and ether was added to cause precipitation. The solid formed was collected and recrystallized from HCl (2N). The final product was obtained as colorless needles (0.56 g, 32.3%).
[352]
[353] Partially substituted pentamidine
[354]
[355] Step 1: 1,5-bis (4-cyano-2-methoxyphenoxy) pentane
[356]
[357] Sodium (0.3 g, 0.014 mol) was triturated into small pieces and slowly added to a stirred solution of anhydrous ethanol (30 ml). After the sodium was completely dissolved, 4-hydroxy-3-methoxybenzonitrile (2 g, 0.013 mol) was added, followed by the dropwise addition of 1,5-dibromopentane (0.9 mol, 0.007 mol). The resulting mixture was stirred at reflux for 2 days and then cooled to room temperature. The light brown precipitate in the mixture was collected, washed with water and dried in vacuo. The product obtained (1.45 g, 73%) was used directly in the next step without purification. ¹ H and ¹³ C NMR of the compounds were consistent with the time of rescue.
[358] Step 2: corresponding pentamidine
[359] A mixture of substituted 1,5-bis (4-cyanophenoxy) pentane (in this example, R ₁ = methoxy and R ₂ = hydrogen) (1.8 g, 4.91 mmol) and ethanol (50 ml) was brought to 0 ° C. Cooled to. The mixture was passed through the anhydrous HCl as bubbles until saturated. The mixture was stirred at room temperature until IR indicated that nitrile absorption had disappeared at 2200 cm ^-1 . Diethyl ether (100 ml) was then added and the white precipitate formed was collected by vacuum filtration and washed with diethyl ether.
[360] The white solid obtained was placed in a 50 ml round bottom flask and ammonia ethanol solution (2M, 30 ml) was slowly added via syringe. The resulting mixture was stirred at reflux for 3 hours. After the mixture was cooled to room temperature, diethyl ether (100 ml) was added and a white precipitate formed. The precipitate was collected and washed with diethyl ether. The solid was then recrystallized from 2N HCl to afford the desired product (0.92 g, 40% yield). In a similar manner, the corresponding compounds with R ₁ = bromine and R ₂ = bromine were synthesized in 53% yield.
[361] Compound # 139
[362]
[363] Of 1,5-bis (4-cyanophenoxy) pentane (153 mg, 0.5 mmol), sodium carbonate (180 mg, 1.7 mmol) and hydroxyamine hydrochloride (278 mg, 4 mmol) in 80% ethanol (10 ml) The mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature. Some solids precipitated out and were removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified on preparative RP-HPLC (Vidac C18, 215 nm, 50 ml / min, 0% to 90% MeCN in H ₂ O with 0.1% TFA) and lyophilized to give a white solid (127.2 mg, 42%). Heptane and nonan homologues were prepared in the same manner.
[364] Compound # 55
[365]
[366] Step 1: 4-cyanobenzoyl chloride (1 g, 6 mmol) with cold solution (0 ° C.) of 1,5-diaminopentane (0.35 ml, 3 mmol) and triethylamine (0.98 ml, 7 mmol) in DMF (10 ml) Was added. The mixture was stirred overnight to room temperature and then diluted with water. The precipitated beige solid was collected by filtration and dried in vacuo to give the corresponding amide (1 g, 92%).
[367] Step 2: Cool a suspension of 1,5-bis- (4-cyanobenzamido) pentane (465 mg, 1.3 mmol) in a mixture of pure ethanol (25 ml) and 1,4-dioxane (20 ml) to 0 ° C. And saturated with anhydrous HCl and the resulting mixture was stirred for 60 hours at room temperature. The solvent was evaporated under reduced pressure. A brown solid was obtained. A mixture of solid and ammonium carbonate (2.5 g, 25 mmol) in ethanol (25 ml) was stirred overnight at room temperature. A small amount of activated carbon was added and the mixture was then filtered over celite. The solvent was evaporated under reduced pressure. The crude product was purified by preparative RP-HPLC (bydak C18, 215 nm, 50 ml / min, 0% to 90% MeCN in H ₂ O with 0.1% TFA) and lyophilized to give the title compound (410 mg) as a white solid. , 51%). Heptane and nonan homologues were prepared in the same manner.
[368] Compound # 54
[369]
[370] Step 1: A mixture of 4-hydroxybenzaldehyde (2.7 g, 22 mmol), 1,5-dibromopentane (1.35 mL, 10 mmol) and potassium carbonate (5.2 g) in anhydrous DMF (25 ml) for 5 hours Heated to 100 ° C. in an oil bath. The mixture was cooled to rt and then water (100 ml) was added. The solid formed was collected by filtration, washed with water and dried in vacuo. The desired bis-aldehyde was obtained as a brown solid (2.8 g, 89%).
[371]
[372] Step 2: Diisopropyl (cyanomethyl) phosphonate (0.86 ml, 4.2 mmol) was added at 0 ° C. as a suspension of sodium hydride (4.4 mmol) in THF. The mixture was stirred at rt for 1 h. A solution of bis-aldehyde (2 mmol) in THF was added. The mixture was stirred for 2 h at rt, then diluted with ethyl acetate, then washed with water, sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The crude solid was washed with a mixture of ethyl acetate and hexanes (1 to 10, 10 ml) and dried in vacuo to give bisnitrile (0.51 g, 71% yield).
[373]
[374] Step 3: A suspension of bis-nitrile (0.48 g, 1.34 mmol) in ethanol (20 ml) was saturated with HCl at 0 ° C. The mixture was stirred at rt for 3 days. The solvent was evaporated under reduced pressure. The solid was then dissolved in 2N NH ₃ in ethanol (20 ml) and the mixture was heated at reflux for 2 hours. The mixture was cooled to rt and the solvent was evaporated under reduced pressure. The resulting solid was dried in vacuo and then recrystallized from 2N HCl by addition of a few drops of ethanol. The solid was collected by filtration, rinsed with water, dried in vacuo overnight and the title compound was obtained as a light yellow solid (0.44 g, 71%).
[375] Compound # 137
[376]
[377] Step 1: A mixture of 4-hydroxybenzylcyanide (2.56 g, 19.2 mmol), 1,7-dibromoheptane (1.49 ml, 8.7 mmol), potassium carbonate (11 g) in DMF (30 ml) was added. Heated using an oil bath at 100 ° C. for an hour. The mixture was cooled to rt and diluted with water (150 ml). Solids precipitated out. The solid was collected by filtration and rinsed with water. It was then dissolved in ethyl acetate and then washed with 10% NaOH (3 × 20 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting solid was dried in vacuo to give 1,7-bis (4-cyanomethylphenoxy) heptane as a dark brown solid (2.58 g, 82%).
[378]
[379] Step 2: A solution of 1,5-bis (4-cyanomethylphenoxy) heptane (750 mg, 5.07 mmol) in a mixture of 1,4-dioxane (10 ml) and pure ethanol (10 ml) was purged with HCl. Saturated at &lt; RTI ID = 0.0 &gt; The mixture was then stirred for 3 days at room temperature. The solvent was evaporated under reduced pressure and the residue was dried in vacuo. The residue was dissolved in 2N ammonia in ethanol (20 ml) and the mixture was heated at reflux for 3 hours. The solvent was evaporated under reduced pressure. The crude solid was recrystallized from 2N HCl / acetone. The crystals were collected and dried in vacuo. The title compound was obtained from an off-white solid (655.3 mg, 60%).
[380] Compound # 51
[381]
[382] Step 1: A solution of borane: tetrahydrofuran complex (10 ml, 10 mmol) was added at 0 ° C. as a solution of bis-nitrile (510 mg, 1.53 mmol). The mixture was then heated to reflux for 18 hours and then cooled using an ice water bath. Methanol (10 ml) was added slowly to quench excess reagent. The resulting mixture was heated at reflux for 15 minutes, and then the solvent was removed under reduced pressure. The residue was co-distilled three times with methanol and then a mixture of methanol (20 ml) and concentrated hydrochloric acid (6 ml) was suspended. The mixture was heated at reflux for 1.5 h. The mixture was then reduced to about 5 ml under reduced pressure. A white fine solid formed. The mixture was diluted with ethanol and cooled to -10 ° C. The solid was collected by filtration, rinsed with cold ethanol and dried in vacuo overnight. 1,5-bis (4- (2-aminoethyl) phenoxy) pentane dihydrochloride was obtained as a white fine powder (564.6 mg, 89%).
[383]
[384] Step 2: N, N'-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (0.78 g, 2.5 mmol) was added to 1 in a mixture of THF (5 ml) and dichloromethane (20 ml). , 5-bis (4- (2-aminoethyl) phenoxy) pentane dihydrochloride (470 mg, 1.13 mmol) and Hunig base (0.435 mmol) were added. The mixture was stirred at rt for 2 days. Excess reagent was quenched with 1,2-ethylenediamine. The mixture was diluted with chloroform, then washed with 1N HCl, saturated sodium carbonate, brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (0.5% to 1% MeOH in CHCl 3).
[385]
[386] Step 3: A solution of 4M HCl in 1,4-dioxane (5 ml) was added as a solution of protected bis guanidino compound (246 mg, 0.297 mmol) in 1,4-dioxane (10 ml). The mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure. The product was dissolved in water, then the aqueous solution was lyophilized and the title compound was obtained as a white solid (146.4 mg, 99%).

权利要求:
Claims (49)
[1" claim-type="Currently amended] A method of treating or preventing amyloid-related diseases of a subject comprising administering to the subject a therapeutic amount of an amidine compound.
[2" claim-type="Currently amended] The method of claim 1, wherein the compound is a bis (amidine) compound and the disease is Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, Down syndrome, or type II diabetes.
[3" claim-type="Currently amended] The method of claim 1, wherein said compound is a bis (amidine) compound.
[4" claim-type="Currently amended] The method of claim 1, wherein the compound is a bis (benzamidine) compound.
[5" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula X>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
Each Y ¹ and Y ² is independently a direct bond or a linkage moiety;
m and q are each independently an integer selected from 0 to 5, 2≤m + q≤5,
The A group is a substituted or unsubstituted aliphatic and aromatic group, and combinations thereof, wherein the Y ¹ and Y ² residues are bonded to the aromatic group,
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR 'R ") _0-10 CONR'R", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", (CR'R ") _0-10 CHO, (CR'R") _0-10 O (CR'R ") _0-10 H, (CR'R") _0-10 S (O) _0-3 R ' , (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0 -10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cyclo Alkyl), (CR'R ") _0-10 CO ₂ R 'or (CR'R") _0-10 OR' group, or a substituted or unsubstituted moiety selected from the side chain of any natural amino acid. High;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group.
[6" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula I>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
Each Y ¹ and Y ² is independently a direct bond or a linkage moiety;
Each R ¹ and R ² is independently a hydrogen or Z group, or two adjacent or adjacent R ¹ and R ² groups together with the ring to which they are attached form a fused aromatic or heteroaromatic, cycloalkyl or heterocyclic structure;
Each X ¹ and X ² is independently an alkylene group, oxygen, an NR ′ group wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or Aryl groups), sulfonamide groups, carbonyl, amides, C ₁ -C ₅ alkylene groups, C ₂ -C ₅ alkenyl groups, C ₂ -C ₅ alkynyl groups, or sulfur atoms, or combinations thereof, or Is a direct bond;
M is an alkylene group, an alkenylene group, an alkynylene group, an alkoxyalkylene group, an alkylaminoalkylene group, a thioalkoxyalkylene group, an arylenedialkylene group, an alkylenediarylene group, a heteroarylenedialkylene group, Arylene groups, heteroarylene groups, oligoether groups or oligo (alkyleneoxide) groups, or arylene-di (oligoalkyleneoxide) groups, each of which is substituted or unsubstituted;
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR _{'R ") 0- 10CONR'R",} (CR'R ") 0-10 (CNH) NR'R", (CR'R ") 0-10 S (O) 1-2 NR'R", ( CR'R ") _0-10 CHO, (CR'R") _0-10 O (CR'R ") _0-10 H, (CR'R") _0-10 S (O) _0-3 R ', (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0- 10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cycloalkyl _{), (CR'R ") 0-10 CO} 2 R ' , or (CR'R") _0-10 oR' group, or a substituted selected from a side chain of any naturally occurring amino acids in the unsubstituted moiety And;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group;
m and q are each independently integers selected from 0 to 4, n and p are each independently integers selected from 0 to 4, m + n ≦ 5, p + q ≦ 5, and m or q One is more than one.
[7" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula II>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently a Z group other than hydrogen, a substituted aryl group, or a substituted alkyl group, or R ^a1 and R ^b1 or R ^a2 And R ^b2 together with the nitrogen atom to which they are attached form a ring structure;
Each Y ¹ is a direct bond or a linkage moiety;
Each R ¹ is hydrogen or a Z group, or two adjacent or adjacent R ¹ groups together with the corresponding X ¹ group form the fused aromatic, heteroaromatic, cycloalkyl or heterocyclic structure with the ring to which they are attached;
X ¹ is an alkylene group or oxygen, an NR ′ group where R ′ is hydrogen, a C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, sulfone Amide groups, carbonyls, amides, C ₁ -C ₅ alkylene groups, C ₂ -C ₅ alkenyl groups, C ₂ -C ₅ alkynylene groups, or sulfur atoms, or combinations or direct bonds thereof;
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR 'R ") _0-10 CONR'R", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", (CR'R ") _0-10 CHO, (CR'R") _0-10 O (CR'R ") _0-10 H, (CR'R") _0-10 S (O) _0-3 R ' , (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0 -10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cyclo _{alkyl), (CR'R ") 0-10 CO} 2 R ' , or (CR'R") _0-10 oR' group, or a substituted selected from a side chain of any naturally occurring amino acids in the unsubstituted moiety And;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group;
m is each independently an integer selected from 0 to 6, n is an integer selected from 0 to 4, and m + n ≤ 6.
[8" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula III>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
Each Y ¹ and Y ² is independently a direct bond or a linkage moiety;
Each R ¹ and R ² is independently a hydrogen or Z group, or two adjacent or adjacent R ¹ and R ² groups together with the ring to which they are attached form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic structure;
Each of R ³ and R ⁴ is independently selected from the group consisting of hydrogen, substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, carbocyclic, aryl, heterocyclic, and heteroaryl;
Each X ¹ and X ² is independently an alkylene group, oxygen, an NR ′ group wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or Aryl groups), sulfonamide groups, carbonyl, amides, C ₁ -C ₅ alkylene groups, C ₂ -C ₅ alkenyl groups, C ₂ -C ₅ alkynyl groups, or sulfur atoms, or combinations thereof, or Is a direct bond;
M is an alkylene group, an alkenylene group, an alkynylene group, an alkoxyalkylene group, an alkylaminoalkylene group, a thioalkoxyalkylene group, an arylenedialkylene group, an alkylenediarylene group, a heteroarylenedialkylene group, Arylene groups, heteroarylene groups, oligoether groups or oligo (alkyleneoxide) groups, or arylene-di (oligoalkyleneoxide) groups, each of which is substituted or unsubstituted;
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR 'R ") _0-10 CONR'R", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", (CR'R ") _0-10 CHO, (CR'R") _0-10 O (CR'R ") _0-10 H, (CR'R") _0-10 S (O) _0-3 R ' , (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0 -10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cyclo _{alkyl), (CR'R ") 0-10 CO} 2 R ' , or (CR'R") _0-10 oR' group, or a substituted selected from a side chain of any naturally occurring amino acids in the unsubstituted moiety And;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group,
m, n, p and q are each independently integers selected from 0 to 3, m + n ≦ 4, p + q ≦ 4, and m + q ≧ 1.
[9" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula IV>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
Each Y ¹ and Y ² is independently a direct bond or a linkage moiety;
Each R ¹ and R ² is independently a hydrogen or Z group, or two adjacent or adjacent R ¹ and R ² groups together with the ring to which they are attached form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic structure;
R ³ is selected from the group consisting of hydrogen, substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, carbocyclic, aryl, heterocyclic, and heteroaryl;
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR 'R ") _0-10 CONR'R", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", (CR'R ") _0-10 CHO, (CR'R") _0-10 O (CR'R ") _0-10 H, (CR'R") _0-10 S (O) _0-3 R ' , (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0 -10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cyclo _{alkyl), (CR'R ") 0-10 CO} 2 R ' , or (CR'R") _0-10 oR' group, or a substituted selected from a side chain of any naturally occurring amino acids in the unsubstituted moiety And;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group,
m and n are each independently an integer selected from 0 to 3, and p and q are each independently an integer selected from 0 to 4, m + n ≦ 4, p + q ≦ 5, and m + q ≧ 1
[10" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula IVb>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
Each Y ¹ and Y ² is independently a direct bond or a linkage moiety;
Each R ¹ and R ² is independently a hydrogen or Z group, or two adjacent or adjacent R ¹ and R ² groups together with the ring to which they are attached form a fused aromatic or heteroaromatic, cycloalkyl or heterocyclic structure;
R ³ is selected from the group consisting of hydrogen, substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, carbocyclic, aryl, heterocyclic, and heteroaryl;
Each X ¹ and X ² is independently an alkylene group, oxygen, an NR ′ group wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or Aryl groups), sulfonamide groups, carbonyl, amides, C ₁ -C ₅ alkylene groups, C ₂ -C ₅ alkenyl groups, C ₂ -C ₅ alkynyl groups, or sulfur atoms, or combinations thereof, or Is a direct bond;
M is an alkylene group, an alkenylene group, an alkynylene group, an alkoxyalkylene group, an alkylaminoalkylene group, a thioalkoxyalkylene group, an arylenedialkylene group, an alkylenediarylene group, a heteroarylenedialkylene group, Arylene groups, heteroarylene groups, oligoether groups or oligo (alkyleneoxide) groups, or arylene-di (oligoalkyleneoxide) groups, each of which is substituted or unsubstituted;
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR 'R ") _0-10 CONR'R", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", _{(CR'R ") 0-10 CHO, (} CR'R") 0- 10O (CR'R ") 0-10 H, (CR'R") 0-10 S (O) 0-3 R ', (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0- 10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cycloalkyl _{), (CR'R ") 0-10 CO} 2 R ' , or (CR'R") _0-10 oR' group, or a substituted selected from a side chain of any naturally occurring amino acids in the unsubstituted moiety And;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group,
m and n are each independently an integer selected from 0 to 3, and p and q are each independently an integer selected from 0 to 4, m + n ≦ 4, p + q ≦ 5, and m + q ≧ 1
[11" claim-type="Currently amended] The method of claim 1, wherein the compound is selected from compounds of the formula: and pharmaceutically acceptable salts thereof such that amyloid fiber formation or deposition, neurodegeneration, or cytotoxicity is reduced or inhibited.
<Formula V>

Wherein R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are each independently hydrogen, a Z group, or R ^a1 and R ^b1 or R ^a2 and R ^b2 are both nitrogen atoms to which they are attached Together to form a ring structure;
The A group is selected from substituted or unsubstituted aliphatic and aromatic groups, and combinations thereof, and the Y ¹ and Y ² residues are bonded to the aromatic group;
Z is straight or branched chain alkyl, cycloalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl , Heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, (CR'R ") _0-10 NR'R", (CR'R ") _0-10 CN, NO ₂ , Halogen, (CR'R ") _0-10 C (halogen) ₃ , (CR'R") _0-10 CH (halogen) ₂ , (CR'R ") _0-10 CH ₂ (halogen), (CR 'R ") _0-10 CONR'R", (CR'R ") _0-10 (CNH) NR'R", (CR'R ") _0-10 S (O) _1-2 NR'R", (CR'R ") _0-10 CHO, (CR'R") _0-10 O (CR'R ") _0-10 H, (CR'R") _0-10 S (O) _0-3 R ' , (CR'R ") _0-10 O (CR'R") _0-10 H, (CR'R ") _0-10 S (CR'R") _0-3 H, (CR'R ") _{0 -10} OH, (CR'R ") _0-10 COR ', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR'R ") _0-10 (C ₃ -C ₈ cyclo _{alkyl), (CR'R ") 0-10 CO} 2 R ' , or (CR'R") _0-10 oR' group, or a substituted selected from a side chain of any naturally occurring amino acids in the unsubstituted moiety And;
R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or an aryl group, or R ′ and R ″ together are benzylidene groups Or a-(CH ₂ ) ₂ O (CH ₂ ) ₂ -group.
[12" claim-type="Currently amended] The method of claim 1, wherein the amyloid related disease is Aβ amyloid-related disease.
[13" claim-type="Currently amended] The method of claim 1, wherein the amyloid related disease is Alzheimer's disease, cerebral amyloid angiopathy, Down syndrome or inclusion body myositis.
[14" claim-type="Currently amended] The method of claim 1, wherein the amyloid related disease is type II diabetes.
[15" claim-type="Currently amended] The method of claim 1, wherein the subject is a human.
[16" claim-type="Currently amended] The method of claim 5, wherein the ring structure is selected from the following formula:
, Where r is an integer from 0 to 4,
, Where r is an integer from 0 to 2,
, Where r is an integer from 0 to 6, or
, Where r is an integer from 0 to 4,
Z and R ^c are as defined in claim 5.
[17" claim-type="Currently amended] The compound of claim 5, wherein each R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 is hydrogen, a hydroxy group, a substituted or unsubstituted C ₁ -C ₈ alkyl. Or a C ₁ -C ₈ alkoxy group.
[18" claim-type="Currently amended] The method of claim 5, wherein each R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 is an aromatic group or a heteroaromatic group.
[19" claim-type="Currently amended] The method according to claim 5, wherein each R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are R ³ groups as defined in claim 9.
[20" claim-type="Currently amended] The method of claim 5, wherein each Y ¹ and Y ² group is a linking moiety of less than about 75 molecular weight.
[21" claim-type="Currently amended] The method of claim 5, wherein each Y ¹ and Y ² is a direct bond.
[22" claim-type="Currently amended] The compound of claim 6, wherein each R ¹ and R ² group is independently hydrogen, substituted or unsubstituted C ₁ -C ₈ alkyl group, substituted or unsubstituted C ₁ -C ₈ alkenyl group , Halogen, substituted or unsubstituted aryl or heteroaryl group, substituted or unsubstituted amino group, nitro group or substituted or unsubstituted C ₁ -C ₈ alkoxy group.
[23" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is-[(CH ₂ ) _s O] _t (CH ₂ ) _s- , t is 1 to 6, s is 2 to 6 way.
[24" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is a phenylenedialkylene group.
[25" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group allylenedialkylene group is of the formula:

Wherein each R group is hydrogen or is selected from a Z group as defined in claim 5 and 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, 0 ≦ h ≦ 4
[26" claim-type="Currently amended] The substituted or unsubstituted C ₂ -C ₈ alkylene group according to any one of claims 6, 8 and 10, a substituted or unsubstituted C ₁ -C ₈ alkenylene group, substituted Or an unsubstituted C ₂ -C ₈ alkynylene group.
[27" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is

(Wherein 1 ≦ t ≦ 6, 0 ≦ s ≦ 6, 0 ≦ h ≦ 4, and each R group is independently hydrogen or selected from Z groups as defined in claim 5), or

(Wherein 1≤y≤10 (preferably 1≤y≤4), 1≤f≤8, 1≤g≤8, 0≤h≤4, and 0≤i≤4, and each R group is independent) Hydrogen or Z group as defined in claim 5)
Way to be.
[28" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
How to be.
Wherein 0 ≦ h ≦ 3, 0 ≦ i ≦ 3, X = NR ′, O or S, 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, where R ′ is hydrogen, C ₁ − C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group)
[29" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
How to be.
Wherein 0 ≦ h ≦ 2, X = NR ′, O or S, 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group)
[30" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
or
(Where 0 ≦ h ≦ 3, 1 ≦ f ≦ 8, and 1 ≦ g ≦ 8)
How to be.
(Wherein 0 ≦ h ≦ 2, 1 ≦ f ≦ 8, 1 ≦ g ≦ 8, and each R group is independently hydrogen or selected from Z groups as defined in claim 5)
[31" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
How to be.
(Wherein each R group is independently hydrogen or is selected from Z group as defined in claim 5 and 0 ≦ h ≦ 4)
[32" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
How to be.
Wherein 0 ≦ h ≦ 3, 0 ≦ i ≦ 3, X is NR ′, O or S, where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group)
[33" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
How to be.
Wherein 0 ≦ h ≦ 2, X is NR ′, O or S, and R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl Term)
[34" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is

(Wherein 0 ≦ h ≦ 3) or
How to be.
(Wherein 0 ≦ h ≦ 2, and each R group is independently hydrogen or is selected from Z group as defined in claim 5)
[35" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is

How to be.
[36" claim-type="Currently amended] The method according to any one of claims 6, 8 and 10, wherein the M group is
How to be.
Wherein X is NR ', O or S, R' is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or aryl group, 0 ≦ f ≦ 8, 0 ≦ g ≦ 8, wherein each R group is independently hydrogen or selected from Z groups as defined in claim 5)
[37" claim-type="Currently amended] The method of claim 2, wherein m is 1, n is 0, 1 or 2, p is 0, 1 or 2, and q is 1. 10.
[38" claim-type="Currently amended] The compound according to any one of claims 5, 6, 8, 9 and 10, wherein R ^a1 = R ^a2 , R ^b1 = R ^b2 , R ^c1 = R ^c2 , m = q, n = p, and Y ¹ = Y ² .
[39" claim-type="Currently amended] The method of claim 6, 8, or 10, wherein R ¹ = R ² and X ¹ = X ² .
[40" claim-type="Currently amended] The method of claim 5, wherein the pharmaceutically acceptable salt is a hydrohalide salt or a 2-hydroxyethanesulfonate salt.
[41" claim-type="Currently amended] The method of claim 1 wherein said compound is selected from the compounds shown in Tables 2 and 3.
[42" claim-type="Currently amended] A pharmaceutical composition for treating an amyloid related disease comprising the compound of any one of claims 5-11.
[43" claim-type="Currently amended] 12. The compound of any one of claims 5 to 11, wherein the linking moiety is-(CH ₂ ) _n- , where n is 1, 2 or 3, -NR ^3- , wherein R ³ is As defined in claim), -NH-, -S-, -O-,-NH-CH ₂ -or -CH = CH- or a combination thereof.
[44" claim-type="Currently amended] Compounds of the formula: or pharmaceutically acceptable salts thereof

Wherein n is an integer from 7 to 10 and R is Br or CO ₂ H)
[45" claim-type="Currently amended] A pharmaceutical composition comprising the compound of any one of claims 5-11.
[46" claim-type="Currently amended] Use of the compound of any one of claims 5 to 11 in the manufacture of a medicament for the treatment or prevention of amyloid related diseases.
[47" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 44.
[48" claim-type="Currently amended] The method of claim 1, wherein the amidine compound causes the cognitive function to be stabilized or further impairment of the cognitive function is prevented, the development of the disease is prevented, retarded or stopped in an Alzheimer's disease patient.
[49" claim-type="Currently amended] The compound of claim 5, wherein Z is a straight or branched chain C ₁ -C ₅ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, heterocyclic, carbocyclic, phenyl, phenoxy, benzyl, phenyloxyalkyl, arylacetamidoyl, alkylaryl, heteroaralkyl, alkyl Carbonyl, arylcarbonyl, heteroarylcarbonyl, or heteroaryl group, -NH ₂ , -CN, NO ₂ , F, Cl, Br, I, -CF ₃ , (CR'R ") _0-3 NR ' R ", (CR'R") _0-3 (CNH) NR'R ", (CR'R") _0-3 S (O) _1-2 NR'R ", (CR'R") _{0-3 CHO, (CR'R ") 0-3 O} (CR'R") 0-3 H, -SO 3 H, -CH 2 OCH 3, -OCH 3, -SH, -SCH 3, -OH, (CR 'R ") _0-3 COR', (CR'R") _0-3 (substituted or unsubstituted phenyl), (CR'R ") _0-3 (C ₃ -C ₈ cycloalkyl), -CO ₂ H or (CR'R ") a substituted or unsubstituted residue selected from _0-3 OR 'groups.

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同族专利:

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公开号 | 公开日

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JP2005504053A|2005-02-10|

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MXPA04001153A|2005-02-17|

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US20040006092A1|2004-01-08|

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EP1420773A1|2004-05-26|

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IL160208D0|2004-07-25|

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CN1658852A|2005-08-24|

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WO2003017994A1|2003-03-06|

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US20040147531A1|2004-07-29|

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CA2455497A1|2003-03-06|

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EA200400135A1|2004-08-26|

---

BR0212078A|2004-09-28|

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US20070021483A1|2007-01-25|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-08-31|Priority to US31676101P

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2001-08-31|Priority to US60/316,761

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2002-06-07|Priority to US38700102P

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2002-06-07|Priority to US60/387,001

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2002-09-03|Application filed by 뉴로겜 인터내셔널 리미티드

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2002-09-03|Priority to PCT/CA2002/001353

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2004-05-03|Publication of KR20040036908A

优先权:

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申请号 | 申请日 | 专利标题

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US31676101P| true| 2001-08-31|2001-08-31|

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US60/316,761|2001-08-31|

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US38700102P| true| 2002-06-07|2002-06-07|

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US60/387,001|2002-06-07|

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PCT/CA2002/001353|WO2003017994A1|2001-08-31|2002-09-03|Amidine derivatives for treating amyloidosis|