JP2006501160A - Amidine derivatives for the treatment of amyloidosis - Google Patents

Abstract

The present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases. In particular, the invention relates to a method of treating or preventing an amyloid-related disease in a subject comprising administering to the subject a therapeutic amount of an amidine compound. A compound in use according to the invention is a compound according to the formula below which, when administered, reduces or inhibits amyloid fibril formation, neurolysis, or cytotoxicity.
[Chemical 1]

Description

Detailed Description of the Invention

Related specification herein, U.S. Provisional Patent Application No. 60 / 387,001 (filed July 7, 2002) (which is incorporated herein by reference) claiming priority .

Background of the Invention Amyloidosis relates to a pathological condition characterized by the presence of amyloid fibers. Amyloid is a generic term that refers to a group of various but specific protein deposits (intracellular or extracellular) found in several different diseases. Although different in their development, all amyloid deposits have common morphological properties, stainability with certain dyes (e.g. Congo Red) and, after staining, have characteristic red-green birefringence in polarized light. Have. They also have common superstructural features and exhibit common X-ray diffraction and infrared absorption spectra.

Amyloid-related diseases can be restricted to one organ or can spread to several organs. The first example is called “local amyloidosis”, while the second example is called “systemic amyloidosis”.
Some amyloidosis can be idiopathic, but most of these diseases occur as complications with preexisting diseases. For example, primary amyloidosis may develop without any other pathological findings, or may develop following plasma cell disease or multiple myeloma.

Secondary amyloidosis is usually seen with chronic infection (eg tuberculosis) or chronic inflammation (eg rheumatoid arthritis). A familial form of secondary amyloidosis is also found in Familial Mediterranean Fever (FMF). As one of the other forms of familial amyloidosis, this family form of amyloidosis is commonly inherited and is found in certain populations. In these two types of amyloidosis, deposits are found in several organs and are therefore considered systemic amyloid diseases.
Another type of systemic amyloidosis is found in long-term hemodialysis patients. In each of these cases, different amyloidogenic proteins are involved in amyloid deposition.

“Local amyloidosis” tends to be associated with only one organ system. Different amyloidosis is also characterized by the type of protein present in the sediment. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease, etc. are characterized by the appearance and deposition of protease resistant prion proteins (called AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disease, is characterized by neurite plaques and neurofibrillary tangles. In this case, plaque and vascular amyloid are formed by the deposition of fibrillar Aβ amyloid protein. Other diseases, such as adult-onset diabetes (type II diabetes) are characterized by the local accumulation of amyloid in the pancreas.
Once these amyloids are formed, there is no known widely accepted therapy or treatment that clearly dissolves amyloid deposits in situ.

  Each amyloidogenic protein constitutes a β-sheet and has the ability to form insoluble fibrils that can be deposited extracellularly or intracellularly. Each amyloidogenic protein differs in amino acid sequence, but has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P, and complement components. In addition, each amyloidogenic protein is different, for example, a region that can bind to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as GAG binding site), and other regions that promote β-sheet formation. And having an amino acid sequence showing similarity.

  In certain cases, amyloid fibrils can be toxic to surrounding cells once deposited. For example, Aβ fibrils configured as senile plaques have been shown to be associated with dead neurons and microgliosis in patients with Alzheimer's disease. When tested in vitro, it has been shown that Aβ peptides can initiate the microglial cell (brain macrophage) activation process. This may explain the presence of microgliosis and brain inflammation in the brain of patients with Alzheimer's disease.

  In another type of amyloidosis found in patients with type II diabetes, the amyloidogenic protein IAPP has been shown to induce β-islet cytotoxicity in vitro. Thus, the appearance of IAPP fibrils in the pancreas of type II diabetic patients contributes to loss of beta islet cells (Langerhans) and organ dysfunction.

People suffering from Alzheimer's disease have three major structural changes in the brain: extensive neuronal loss in many parts of the brain, accumulation of intracellular protein deposits called neurofibrillary tangles And progressive dementia in adulthood, accompanied by abnormal nerve endings (accumulation of extracellular protein deposits surrounded by malnourished neurites) called amyloid or senile plaques. The main composition of these amyloid plaques is a 39-43 amino acid protein produced by cleavage of amyloid-β peptide (Aβ), ie, β-amyloid precursor protein (APP).
There are treatments for symptoms in Alzheimer's disease, but currently the disease cannot be prevented or cured.

による化合物である。 SUMMARY OF THE INVENTION This invention relates to the use of amidine compounds in the treatment of amyloid-related diseases. In particular, the present invention relates to a method of treating or preventing an amyloid-related disease in a subject comprising administering to the subject a therapeutic amount of an amidine compound. The compounds for use in the present invention, when administered, reduce or inhibit amyloid fibril formation, neurodegeneration, or cytotoxicity according to the following formula:

It is a compound by.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1: Effect of pentaamidine-type compounds on Aβ (1-40) assembly as measured by ThT assay FIG. 2: on Aβ (1-40) assembly as measured by ThT assay Effect of pentaamidine-like compound Figure 3: Effect of amidine-type compound on Aβ (A-40) assembly as measured by ThT assay Figure 4: Effect of pentaamidine-type compound on IAPP assembly as measured by ThT assay

Detailed Description of the Invention The present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases.
Amyloid-related disease AA (reactive) amyloidosis Generally, AA amyloidosis refers to several diseases that elicit a sustained acute phase response. The diseases include chronic inflammatory diseases, chronic local or systemic microbial infections, and malignant neoplasms.

  AA fibrils are generally hepatocytes that respond to cytokines such as IL-1, IL-6, and TNF, which, when secreted, form a complex with HDL when secreted by serum amyloid A protein (ApoSAA). It consists of a 8,000 Dalton fragment (AA peptide or protein) formed by proteolysis of the circulating apolipoprotein synthesized in the medium. Deposition spreads throughout the body and favors soft tissues. The spleen is usually the site of deposition and the kidneys are also affected. Deposition is also common in the heart and gastrointestinal tract.

  AA amyloid diseases include, but are not limited to, inflammatory diseases such as rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Reiter's disease, adult Still's disease, Behcet's syndrome, and Crohn's disease . AA deposition also occurs as a result of chronic microbial infections such as leprosy, tuberculosis, bronchiectasis, pressure ulcers, chronic pyelonephritis, osteomyelitis, and Whipple's disease. Certain malignant neoplasms can also cause amyloid deposition of AA fibrils. These include conditions such as, for example, Hodgkin's lymphoma, kidney cancer, intestine, lung, and genitourinary tract cancer, basal cell carcinoma, and hair cell leukemia.

AL Amyloidosis AL amyloid deposition is generally associated with almost all cachexia of the B lymphocyte system, ranging from plasma cell malignancies (multiple myeloma) to benign monoclonal immunoglobulinemias. In many cases, the presence of amyloid deposits can be a major indicator of background cachexia.

The fibrils of AL amyloid deposits are composed of monoclonal immunoglobulin light chains or fragments thereof. More specifically, the fragment is derived from the N-terminal region of the light chain (κ or λ) and includes all or part of its variable domain (V _L ). Deposition generally occurs in mesenchymal tissue, peripheral and autonomic neuropathy, carpal tunnel syndrome, giant tongue, restrictive cardiomyopathy, major joint arthropathy, immune cachexia, myeloma, and latent Causes sex cachexia. However, it should be noted that almost all tissues, especially internal organs, can be involved, for example the heart.

Hereditary systemic amyloidosis There are many forms of hereditary systemic amyloidosis. Although they are relatively rare symptoms, the onset of symptoms after adulthood and their genetic pattern (usually autosomal dominant) are linked to the presence of the disease in the general population. Generally, this syndrome is caused by a point mutation of a precursor protein that results in the production of a variant of the amyloidogenic peptide or protein. Table 1 summarizes the fibril composition of representative examples of these diseases.

データはTan SY, Pepys MB. Amyloidosis. Histopathology, 25(5), 403-414 (Nov 1994)から導出された。

Data were derived from Tan SY, Pepys MB. Amyloidosis. Histopathology, 25 (5), 403-414 (Nov 1994).

  The data provided in Table 1 is exemplary and is not intended to limit the scope of the present invention. For example, over 40 distinct point mutations in the transthyretin gene have been described, all of which cause a form of clinically similar familial amyloid polyneuropathy.

  Transthyretin (TTR) is a 14 kDa protein sometimes referred to as prealbumin. It is produced by the liver and choroid plexus, which functions in the transport of thyroid hormone and vitamin A. Variant forms of at least 50 proteins, each characterized by a single amino acid change, are responsible for various forms of familial amyloid polyneuropathy. For example, replacement of proline with leucine at position 55 causes a particularly progressive form of neuropathy, and replacement of methionine with leucine at position 111 causes severe heart disease in Danish patients.

  Amyloid deposits isolated from the heart tissue of patients with systemic amyloidosis consist of a heterogeneous mixture (generally referred to as ATTR) of TTR and its fragments (whose full-length sequence has been identified). The ATTR fibril component can be extracted from the plaque and its structure, and the sequence 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).

  Humans with point mutations in apolipoprotein A1 (eg Gly → Arg26; Trp → Arg50; Leu → Arg60) are characterized by the deposition of apolipoprotein or fragments thereof (AApoAI), a form of amyloidosis (“Oestertag type”) "). These patients have low levels of high density lipoprotein (HDL) and have peripheral neuropathy or renal failure.

  Mutations in the alpha chain of the enzyme lysozyme (eg, Ile → Thr56 or Asp → His57) are based on another form of Oestertag-type non-neuropathic hereditary amyloid that has been reported in British families. At this time, fibrils of the mutant lysozyme protein (Alys) accumulate, and patients generally exhibit impaired renal function. This protein, unlike many fibril-forming proteins, usually exists in all forms (unfragmented forms) (Benson, MD, et al. CIBA Fdn. Symp. 199: 104-131, 1996).

  β-amyloid peptide (Aβ) is a 39-43 amino acid peptide derived by proteolysis from a large protein known as β-amyloid precursor protein (βAPP). Mutations in βAPP cause familial Alzheimer's disease, Down's syndrome, or senile dementia characterized by plaque brain deposition consisting of Aβ fibrils and other components described in more detail below. Known mutations in APP with Alzheimer's disease occur near the β or γ-secretase cleavage site or within Aβ. For example, position 717 is near APP's γ-secretase cleavage site and APP 670/671 is near the β-secretase cleavage site in the processing of APP to Aβ. Mutations at any of these residues can cause Alzheimer's disease and possibly an increase in the amount of 42/43 amino acids of Aβ obtained from APP.

  The structure and sequence of Aβ peptides of various lengths are well known in the art. The peptides can be prepared according to methods known in the art (e.g. Glenner and Wong, Biochem Biophys. Res. Comm. 129: 885-890, 1984; Glenner and Wong, Biochem Biophys. Res. Comm. 122: 1131- 1135, 1984). Furthermore, various forms of the peptide are commercially available.

As used herein, the term “β-amyloid” or “amyloid-β” unless otherwise indicated, refers to amyloid-β protein or peptide, amyloid-β precursor protein or peptide, intermediates, and modifications. , And its fragments. In particular, “Aβ” refers to any peptide produced by proteolytic processing of the APP gene product, particularly Aβ _1-39 , Aβ _1-40 , Aβ _1-41 , Aβ _1-42 , and Aβ _1-43 . Including peptides associated with amyloid pathology.

For naming _purposes , “Aβ _1-42 ” is referred to herein as “Aβ (1-42)”, or simply “Aβ ₄₂ ” or “Aβ42” (any other described herein). The same applies to the amyloid peptide. As used herein, the terms “β-amyloid”, “amyloid-β”, and “Aβ” are synonymous.

  Unless otherwise specified, the term “amyloid” refers to an amyloidogenic protein, peptide, or fragment thereof that can be soluble (eg, monomeric or oligomeric) or insoluble (eg, having a fibrillar structure or in amyloid plaques). To tell.

  Gelsolin is a calcium binding protein that is bound to fragments and actin filaments. A mutation at position 187 of this protein (eg Asp → Asn; Asp → Tyr) is responsible for a form of hereditary systemic amyloidosis and is usually found in Finnish patients and humans of German or Japanese origin. In affected individuals, the fibrils formed from gelsolin fragments (Agel) usually consist of amino acids 173-243 (68 kDa carboxy-terminal fragment) and deposit in blood vessels and basement membranes, corneal dystrophies, and Causes cranial neuropathy (progressing to peripheral neuropathy, dystrophic skin changes and deposition in other organs) (Kangas, H., et al. Human Mol. Genet. 5 (9): 1237-1243, 1996).

  Other mutated proteins, such as mutant alpha chain fibrinogen (AfibA), and mutant cysteine C (Acys) also form fibrils and produce characteristic hereditary diseases. AfibA fibrils form deposits characteristic of non-neuropathic hereditary amyloid in kidney disease; Acys deposits are characteristic of 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 an unmutated form of cysteine C along with amyloid β protein (Nagai, A., et al. Molec. Chem. Neuropathol. 33: 63-78, 1998).

Certain forms of prion disease were once thought to be primarily infectious in nature but are now considered to be hereditary up to 15% (Baldwin, et al., In Research Advances in Alzheinzer's Disease and Related Disorders, John Wiley and Sons, New York, 1995). In such prion diseases, patients form plaques consisting of an abnormal isoform (PrP ^Sc ) of normal prion protein.

The preferential variant isoform, PrP ^Sc (also called AScr), is resistant to protease degradation, insoluble after detergent extraction, deposition in secondary lysosomes, post-translational synthesis, and high β-pleated sheet content In that it differs from normal cellular proteins. Genetic association has been established for at least 5 mutations, causing Creutzfeldt-Jacob disease (CJD), Gerstmann-Straeussler-Scheinker syndrome (GSS), and lethal familial insomnia (FIT) (Baldwin, supra) . Methods for extracting fibril peptides derived from scrapie fibrils, sequencing, and methods for making the peptides are known to those skilled in the art (eg Beekes, M., et al. J. Gen. Virol. 76: 2567- 76, 1995).

  For example, one form of GSS is associated with a PrP mutation at codon 102, while the telencephalon GSS segregates with a mutation at codon 117. Mutations at codons 198 and 217 result in a form of GSS where the neurite plaques characteristic of Alzheimer's disease contain PrP instead of Aβ peptide. A particular form of familial CJD is associated with mutations at codons 200 and 210; mutations at codons 129 and 178 were found in both familial CJD and FFI (Baldwin, supra).

Senile systemic amyloidosis Amyloid deposits increase with age, either systemically or locally. For example, wild type transthyretin (TTR) fibrils are commonly found in the heart tissue of the elderly. These can be asymptomatic, clinically silent, or cause heart failure. Asymptomatic SeiHara fibers topical deposition also the brain (A [beta]), amyloid bodies (A [beta] ₂ microglobulin) prostate can occur at the joints and seminal sac.

Cerebral Amyloidosis Local deposition of amyloid is common in the brain, especially in the elderly. The most common type of amyloid is composed primarily of Aβ peptide fibrils, causing dementia or sporadic (non-hereditary) Alzheimer's disease. In fact, the onset of sporadic Alzheimer's disease goes far beyond the form considered to be hereditary. The fibril peptides that form these plaques are very similar to those mentioned above in the inherited form of Alzheimer's disease (AD).

  Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the buffy coat and cortical arteries, in the walls of arterioles, and in capillaries and veins. It is commonly associated with Alzheimer's disease, Down's syndrome, and normal aging, and various familial conditions associated with stroke or dementia (Frangione et al., Amyloid: J. Protein Folding Disord. 8, Suppl: 1, 36-42 (2001)). CAA can occur sporadically or can be genetic. Many mutation sites in either the Aβ or APP genes are clinically associated with either dementia or cerebral overflow. Exemplary CAA diseases include Icelandic (HCHWA-I), HCHWA German (HCHWA-D; mutation in Aβ), Aβ Flemish mutation, Aβ Arctic mutation, Aβ Italian mutation, Aβ Includes, but is not limited to, IA mutation, familial British dementia, and hereditary cerebral hyperemia with amyloidosis of familial Danish dementia.

Dialysis-related amyloidosis beta ₂ - plaques consisting microglobulin (Aβ _{2 M)} fibrils commonly occurs in patients receiving long term hemodialysis or peritoneal dialysis. β ₂ -microglobulin is a 11.8 kDa polypeptide and is the light chain of class I MHC antibodies that are present on all nucleated cells. Under normal circumstances it flows continuously from the cell membrane and is usually filtered by the kidneys. Clearance dysfunction (eg, in the case of renal dysfunction, etc.) causes deposition in the kidney and other sites (mainly in collagen-rich tissues of the joint). Unlike other fibrillar proteins, Aβ ₂ M molecules are generally present in unfragmented form in fibrils (Benson, supra).

Islet amyloid polypeptide and diabetes Islet hyaline (amyloid deposits) was first described more than 100 years ago as the presence of fibrous protein aggregates in the pancreas of patients with severe hypertension (Opie, EL. , JExp. Med. 5: 397-428, 1990). Today, islet amyloid, predominately composed of islet amyloid polypeptide (IAPP), or amylin is characteristic in over 90% of all cases of type II diabetes (non-insulin dependent diabetes or NIDDM). Histopathological marker. The accumulation of these fibrils is due to aggregation of the 37 amino acid peptide islet amyloid polypeptide (IAPP) or amylin derived from a larger precursor called pro-IAPP.

  IAPP is localized with insulin and secreted together in response to beta cell secretagogues. This pathological feature is not associated with insulin-dependent (type I) diabetes and is consistent with another clinical phenotype diagnosed as NIDDM (type II diabetes).

  Long-term studies in cats and immunocytochemical studies in monkeys show that progressive increases in islet amyloid are associated with a dramatic decrease in insulin-secreting β-cells and increased disease severity . More recently, genetic engineering studies have strengthened the relationship between IAPP plaque formation and β-cell dysfunction, indicating that amyloid deposition is a major factor in type II diabetes.

  IAPP has also been shown to induce β-islet cytotoxicity in vitro, indicating that the appearance of IAPP fibrils in the pancreas of type II or type I diabetic patients (after transplantation) It has been shown that it may contribute to cell (Langerhans) loss and organ dysfunction. In patients with type II diabetes, the accumulation of IAPP in the pancreas results in the accumulation of IAPP-amyloid as an insoluble fiber deposit that gradually replaces the islet insulin-producing beta cells, resulting in beta cell depletion and dysfunction. Cause (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).

  Diseases caused by the death or dysfunction of one or more specific types of cells can be treated by transplanting healthy cells of the appropriate type of cells into a patient. This method is used in type I diabetic patients. Often pancreatic islet cells are cultured in vitro prior to transplantation to increase their number, recover from isolation procedures, or decrease their immunogenicity. However, in many instances, islet cell transplantation is unsuccessful because the transplanted cells die. One reason for the low success rate is IAPP, which can form fibrils and can be toxic to cells in vitro. Furthermore, IAPP fibrils are likely to continue to grow after the cells are transplanted causing cell death or dysfunction. This can happen even if the cells are 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 also be used in preparing tissues or cells for transplantation according to the methods described in International Application (PCT) No. WO 01 / 03,680.

Hormone-derived amyloidosis Endocrine organs can contain amyloid deposits, particularly in the elderly. Hormone-secreting tumors can also contain hormone-derived amyloid plaques whose fibrils are polypeptide hormones such as calcitonin (medullary thyroid cancer), islet amyloid polypeptide (amylin; most with type II diabetes ), And atrial natriuretic peptide (single atrial amyloidosis). The sequences and structures of these proteins are well known in the art.

Various amyloidosis There are various other forms of amyloid disease that are usually manifested as local deposition of amyloid. In general, these diseases are probably the result of localized production or catabolism of specific fibril precursors, or a predisposition to specific tissues (eg joints) in fibril deposition. Examples of idiopathic deposition include nodular AL amyloid, endocrine amyloid, and tumor-associated amyloid.

  The compounds of the present invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid-β fibril formation, aggregation, or deposition. The compounds of the present invention use any of the following mechanisms (this list is meant to be exemplary and not limiting) to improve the process of amyloid-β related diseases; the formation or deposition of amyloid-β fibrils To slow the rate; to reduce the degree of amyloid-β deposition; to inhibit, reduce or prevent the formation of amyloid fibrils; to inhibit neurodegeneration or cytotoxicity induced by amyloid-β; It can act to inhibit beta-induced inflammation; or to enhance amyloid-beta clearance from the brain.

  The compounds of the present invention may be effective in controlling the deposition of amyloid-β after either translocation to the brain (crossing the blood-brain barrier) or translocation from the periphery. When acting from the periphery, the compound can alter the balance of Aβ between the brain and plasma so as to facilitate the excretion of Aβ from the brain. Increased excretion of Aβ from the brain results in a decrease in the brain concentration of Aβ and thus facilitates a decrease in Aβ deposition. Alternatively, a compound that migrates to the brain may control deposition by acting directly on brain Aβ, for example, by keeping it in a non-fibrillar form, or by facilitating its excretion from the brain. it can.

  In a preferred embodiment, the method is used to treat Alzheimer's disease (eg, sporadic or familial AD). The method may also be used prophylactically or to treat the clinical occurrence of amyloid-β deposits (eg, in persons with Down's syndrome and in patients with cerebral amyloid angiopathy (“CAA”) or hereditary cerebral hyperemia). It can be used therapeutically.

  Furthermore, abnormal accumulation of APP and amyloid-β protein in muscle fibers has been implicated in 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). Accordingly, the compounds of the present invention can be used prophylactically or therapeutically in the treatment of diseases that abnormally deposit amyloid-β protein in non-neural locations, such as the treatment of IBM by delivery of the compound to muscle fibers. obtain.

The present invention thus relates to the use of amidine compounds in the prevention or treatment of amyloid-related diseases, in particular Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, Down's syndrome, and type II diabetes.
Desirable compounds of the present invention have at least two amidine moieties (preferably arylamidines, more preferably benzoamidines).

  In one particular embodiment, the present invention relates to amyloid-related diseases, such as U.S. Pat.Nos. No. 5,667,975, No. 6,025,398, No. 6,214,883, No. 5,817,687, No. 5,792,782, No. 5,939,440, No. 6,017,941, No. 5,972,969, No. 6,046,226, No. 6,294,565, No. 6,156,779 No. 5,594,138, 5,602,172, 5,206,236, 5,843,980, 4,933,347, 5,668,166, 5,817,686, 5,723,495, 4,619,942, 5,792,782, 5,639,755, 5,643,935, and 5,578,631, respectively And the novel use of amidine compounds in the prevention or treatment of the diseases disclosed in US Pat.

[式中、
Ｒ^ａ１、Ｒ^ｂ１、Ｒ^ｃ１、Ｒ^ａ２、Ｒ^ｂ２、およびＲ^ｃ２は、独立して、水素、Ｚであるか、
またはＲ^ａ１とＲ^ｂ１、またはＲ^ａ２とＲ^ｂ２は、それらが結合している窒素原子と一緒になって環構造を形成し；
Ｙ^１とＹ^２は、それぞれ独立して、直接結合または結合部分であり；
ｍとｑは、それぞれ独立して、０から５から選択される整数であって、そしてその結果１＜ｍ＋ｑ＜５であり、または別の具体的態様において、２＜ｍ＋ｑ＜５であり、または別の態様において、１＜ｍ＋ｑ＜１０であり、または別の具体的態様において、２＜ｍ＋ｑ＜１０であり；そして
Ａは、置換もしくは非置換の脂肪族性および芳香族性の基、およびそれらの組み合わせから選択されるキャリアー部分であり；
好ましくは、その結果Ｙ^１とＹ^２部分が芳香族性の基と結合している] による化合物を、治療量で投与することを含む方法に関する。 In another specific embodiment, the present invention provides a method of treating or preventing an amyloid-related disease in a subject (preferably a human), the subject comprising amyloid fibril formation or deposition, neurodegeneration, or cytotoxicity. Wherein the compound comprises administering a therapeutic amount of a compound according to the formula: In another specific embodiment, the present invention provides a method for treating or preventing an amyloid-related disease in a subject (preferably a human), wherein the subject has cerebral amyloidosis, such as Alzheimer's disease or cerebral amyloid angiopathy. The following formula that stabilizes the cognitive function or prevents, delays or stops further cognitive deterioration:

[Where
R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are independently hydrogen, Z,
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;
Y ¹ and Y ² are each independently a direct bond or a binding moiety;
m and q are each independently an integer selected from 0 to 5 and, as a result, 1 < m + q < 5, or in another embodiment, 2 < m + q < 5, or In another embodiment, 1 < m + q < 10, or in another embodiment, 2 < m + q < 10; and A is a substituted or unsubstituted aliphatic and aromatic group, and A carrier portion selected from a combination of:
Preferably, the result is that the Y ¹ and Y ² moieties are bound to an aromatic group.] Relates to a method comprising administering a therapeutic amount.

A is preferably a divalent group (ie m + q = 2), for example alkylene, ie — (CH ₂ ) _k — {where k is 1 to 12 (preferably 6 to 9, more preferably 7 to 9 And substituted analogs thereof (including groups wherein the —CH ₂ — moiety is replaced by an oxygen atom), alkenylene (preferably having 2 to 12 carbon atoms, more preferably 6 to 9 Alkynylene (preferably having 2 to 12 carbon atoms, more preferably 6 to 9 carbon atoms, including groups having 1 carbon atom and having one or more double bonds). And a group having one or more triple bonds), alkoxyalkylene, alkylaminoalkylene, thioalkoxyalkylene, arylene alkylene, heteroarylene alkylene, arylene, A loarylene, an oligoetheric group, such as an oligo (alkylene oxide), or an arylene-di (oligoalkylene oxide), wherein each group is substituted (with Z as defined below, for example with a hydroxyalkylene). Or may be unsubstituted.

A also includes corresponding portions of Formulas I-IV herein.
In a desirable embodiment of the present invention, the present invention provides a method for treating or preventing an amyloid-related disease in a subject (preferably a human), comprising administering to the subject a therapeutic amount of one compound of the formula: As a result, it relates to methods comprising reducing or inhibiting the formation or deposition of amyloid fibrils, neurodegeneration, or cytotoxicity. In another specific embodiment, the present invention provides a method of treating or preventing an amyloid-related disease in a subject (preferably a human), wherein one compound of the following formula is administered to the subject in a therapeutic amount: As a result, it relates to a method comprising stabilizing or preventing further delaying or stopping cognitive function in patients with cerebral amyloidosis (eg Alzheimer's disease or cerebral amyloid angiopathy).

Where the compound is

[式中、Ｒ^ａ１、Ｒ^ｂ１、Ｒ^ｃ１、Ｒ^ａ２、Ｒ^ｂ２、Ｒ^ｃ２、Ｙ^１、およびＹ^２は、本明細書で定義した通りであり；そして
Ａは上記で定義した通りであり；
それぞれのＲ^１とＲ^２は、独立して、水素であるか、またはＺであるか、または
２つの隣接した もしくは最も近いＲ^１およびＲ^２は、対応するＸ^１とＸ^２に沿って、存在するならば(例えば式 II において)、それらが結合している環(例えばフェニル環)と一緒になって、縮合環構造、例えば芳香族性もしくはヘテロ芳香族性構造(例えばベンゾフラン)、またはシクロアルキルもしくはヘテロ環構造を形成し；

[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. ;
Each R ¹ and R ² is independently hydrogen or Z, or two adjacent or nearest R ¹ and R ² are along corresponding X ¹ and X ² , If present (e.g. in Formula II), together with the ring to which they are attached (e.g. phenyl ring), fused ring structures, e.g. aromatic or heteroaromatic structures (e.g. benzofuran), or cyclo Forms an alkyl or heterocyclic structure;

Each R ³ and R ⁴ is independently hydrogen, substituted or unsubstituted linear or branched alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), Selected from the group consisting of carbocycle, aryl (eg phenyl), heterocycle, and heteroaryl;
Each R ^{1 *} and R ^{2 *} is independently selected from the group consisting of substituted or unsubstituted linear or branched alkyl, cycloalkyl, heterocycle, aryl (including phenyl), and heteroaryl Is;

Each X ¹ and X ² is independently a direct bond or oxygen, NR ′ {where R ′ is hydrogen (ie NH), C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C _2- C ₅ alkynyl, or aryl}, sulfonamide (ie, NHSO ₂ or SO ₂ NH), carbonyl, amide (ie, NHCO or CONH), C ₁ -C ₅ alkylene (eg, —CH ₂ —), C ₂ —C ₅ alkenylene (eg, E or Z—CH═CH—), C ₂ -C ₅ alkynylene, or a sulfur atom, or combinations thereof (eg, —OCH ₂ —, —CH ₂ O—, E, or Z—) OCH = CH- or -CH = CHO-);
M is a divalent group such as alkylene, ie, — (CH ₂ ) _k — {where k is 1 to 12 (preferably 5 to 10, more preferably 6 to 9, most preferably 7 to 8). And substituted analogs thereof (including groups wherein the —CH ₂ — moiety is replaced by an oxygen atom), alkenylene (preferably having 2 to 12 carbon atoms, more preferably 6 to 9 carbons) Alkynylene (preferably having 2 to 12 carbon atoms, more preferably 6 to 9 carbon atoms, and including groups having one and more than one double bond), and Including groups having one or more triple bonds), alkoxyalkylene, alkylaminoalkylene, thioalkoxyalkylene, arylene alkylene, alkylene diarylene, heteroarylene alkylene, An arylene, heteroarylene, oligoetheric group, such as an oligo (alkylene oxide), or an arylene-di (oligoalkylene oxide);

Each group may be substituted (eg with Z as defined herein, eg with hydroxyalkylene, eg with — (CH ₂ ) _0-6 (CHOH) (CH ₂ ) _0-6 —); or other such substituted moieties, _{e.g., - (CH 2) 0-6 (} CHCO 2 alkyl) (CH _{2) 0-6)} - containing _{- (CH 2) 0-6 (CHZ} ) (CH ₂ ) may be _0-6- or unsubstituted;

Z is linear or branched 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₎ heterocycle, carbocycle, aryl (e.g. phenyl), aryloxy (e.g. phenoxy), aralkyl (e.g. benzyl) , Aryloxyalkyl (eg phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl, or other such acyl, heteroarylcarbonyl or heteroaryl, (CR′R ″) _{0— 3} NR'R _{"(e.g., -NH 2), (CR'R"} ) 0-3 CN ( e.g. -CN), NO , Halogen (e.g., F, Cl, Br or I,), (CR'R _{") 0-3} C _{(halogen) 3} (e.g., -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 ′ (eg —SO ₃ H), (CR′R ″) _0-3 O (CR′R ″) _0-3 H, (eg − 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 Shi Chloroalkyl), (CR′R ″) _0-3 CO ₂ R ′ (eg —CO ₂ H), or (CR′R ″) _0-3 OR ′, or from the side chain of any naturally occurring amino acid Selected, substituted or unsubstituted moieties;

In another specific embodiment, Z is linear or branched 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 ), heterocycle, carbocycle, aryl (eg phenyl), aryloxy (eg phenoxy ), Aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl, or other such acyl, heteroarylcarbonyl or heteroaryl, ( CR′R ″) _0-10 NR′R ″ (eg, —NH ₂ ), (CR′R ″) _0-10 CN (e.g. -CN), NO _2, halogen (e.g. F, Cl, Br or _{I,), (CR'R ")} 0-10 C ( _{halogen) 3} (e.g., -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, (R'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 ( e.g. -SH and -SCH _3), (CR ' R _{") 0-10} OH (eg _{-OH), (CR'R") 0-10} COR ', (CR'R ") 0-10 ( also replaced Ku is 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 ″) _0-10 OR ′, or a side chain of any natural amino acid;
Where R ′ and R ″ are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl, or R ′ and R ″ are , Together, benzylidene or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —;
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,
n and p are each independently an integer selected from 0 to 4,
The result is m + n < 5 and p + q < 5;
Where either m or q is at least 1;
And preferably m and q are 1;
In Equation II:
m is an integer selected from 0 to 6,
n is an integer selected from 0 to 5,
The result is m + n < 6;
In Formula III,
m, n, p, and q are each independently an integer selected from 0 to 3,
The result is m + n < 4, p + q < 4, and m + q > 1 (preferably m = q = 1);
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)], and pharmaceutically acceptable salts thereof.

  The chemical structures herein are described according to conventional standards known to those skilled in the art. Therefore, an atom (for example, a carbon atom) described without satisfying the valence is considered to be satisfied with a hydrogen atom even if the hydrogen atom is not necessarily clearly described.

  In another specific embodiment, the present invention relates to the novel compounds described herein and methods for their use. The compounds and methods are within the formulas disclosed herein and are not disclosed in the above US patents.

R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 in the above formula are preferably hydrogen, substituted or unsubstituted C ₁ -C ₈ alkyl, or C ₁ -C ₈ alkoxy, Or hydroxy. Desirable R ^a1 and R ^a2 are hydrogen, hydroxyl, alkyloxy (especially lower alkyloxy, such as methoxy), aryloxy, acyloxy, and aroyloxy (ie R— (C═O) —O—, where R is aliphatic Or aromatic))).

｛ここで、ｒは０から４の整数である｝、

｛ここで、ｒは０から２の整数である｝、

｛ここで、ｒは０から６の整数である｝、または

｛ここで、ｒは０から４の整数である｝
の環構造中の２個の窒素原子をつなぐ部分であることを意味する。 The phrase “R ^a and R ^b together with the nitrogen atom to which they are attached forms a ring structure” means that two R ^a and R ^b are heterocycles, for example:

{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}
It is a part which connects two nitrogen atoms in the ring structure.

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 together with the nitrogen atom to which they are attached, are combined with a non-aromatic ring Or a ring structure that is an aliphatic ring, or a single ring, or a non-fused ring.

In some embodiments of formula II, for example, R ^a1 , R ^b1 , R ^c1 , R ^a2 , R ^b2 , and R ^c2 are preferably hydrogen or substituted or unsubstituted C ₁ -C ₈ alkyl Where the alkyl substituent is any member of Z as defined above but is not aryl (eg phenyl) or alkyl. Similarly, in certain embodiments of formula II, R ¹ is a moiety selected from Z as defined above other than substituted aryl (eg, phenyl) or heteroaryl.

R ¹ and R ² are preferably hydrogen, substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₂ -C ₈ alkenyl, halogen (particularly bromine), substituted or unsubstituted aryl or heteroaryl, substituted Or unsubstituted amino, nitro, or substituted or unsubstituted C ₁ -C ₈ alkoxy (especially methoxy).

  Each Y can be a direct bond or a linking moiety (or linking group) that is covalently bonded to at least two other moieties, such as a divalent atom or an oligomethylene group. A linking moiety that is a straight chain of carbon atoms may be optionally substituted or unsaturated.

Preferably, the binding moiety is relatively small compared to the rest of the molecule, more preferably has a molecular weight of less than 250, and even more preferably has a molecular weight of less than about 75. In particular, the preferred linking moiety is — (CH ₂ ) _n — {where n is 1, 2, or 3}, —NR ′ — {where R ′ is hydrogen, C ₁ -C ₅ alkyl. , C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl}, —S—, —O—, —NH—CH ₂ —, and —CH═CH— (both E and Z types). Or a combination thereof. The binding moieties are 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 {where each n is independently 0, 1, 2, or 3 and R ^v , R ^w , R ^{x 1} , 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, aryloxy carbonyl, arylaminocarbonyl, arylalkyl, acyl, it may be aryl, or _C 3 -C ₈ ring}.

  “Inhibition” of amyloid deposition is prevention or cessation of amyloid formation (eg, fibril formation), further inhibition or delay of amyloid deposition in subjects with amyloidosis (eg, already amyloid deposition has occurred), and afflicted with amyloidosis Reduction or reversion of amyloid fibril formation or amyloid deposits in a patient undergoing treatment. Inhibition of amyloid deposition is determined relative to an untreated subject or relative to a treated subject prior to treatment, e.g., of pancreatic function in diabetic patients or having cerebral amyloidosis (e.g. Alzheimer's disease or brain In the case of patients with amyloid angiopathy) it is determined by a clinically measurable improvement of stabilization of cognitive function or prevention of further cognitive decline (ie prevention, delay or cessation of disease progression).

  The term “alkyl” refers to linear alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched alkyl (isopropyl, tert-butyl, isobutyl, etc.), Including saturated aliphatic, including cycloalkyl (aliphatic ring) (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl. Unless otherwise indicated, the term alkyl further includes alkyls that can further include oxygen, nitrogen, sulfur, or phosphorous atoms replaced with one or more carbons of the hydrocarbon backbone.

In certain embodiments, straight chain or branched alkyl has 6 or fewer (eg, C ₁ -C ₆ for straight chain, C ₃ -C _{6 for} branched chain) in its backbone, Preferably it has 4 or fewer carbon atoms. Likewise, preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbon atoms in the ring structure. The term “C ₁ -C ₆ ” includes alkyl groups containing 1 to 6 carbon atoms. “Alkylene” is a divalent group derived from the corresponding alkyl.

  Further, unless otherwise specified, the term “alkyl” includes “unsubstituted alkyl” and “substituted alkyl”, where the latter is a substituent substituted with one or more hydrogens on one or more carbons of the hydrocarbon backbone. Refers to an alkyl moiety having The substituent is, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, Carbamoyl and ureido), amidino, imino, sulfhydrides , Alkylthio, arylthio, thiocarboxylate, sulfate, alksulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocycle, alkylaryl, or aromatic or heteroaromatic moieties . Cycloalkyls can be further substituted, eg, with the substituents described above.

  An “arylalkyl” moiety is an alkyl substituted with an aryl (eg, phenylmethyl (ie, benzyl)). An “alkylaryl” moiety is an aryl substituted with alkyl (eg, p-methylphenyl (ie, p-tolyl)). The term “n-alkyl” means a straight chain (ie, unbranched), unsubstituted alkyl.

  The term “alkenyl” includes unsaturated aliphatic groups that are similar to alkyl above in terms of length and possible substituents, but contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl (eg, ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched alkenyl, cycloalkenyl (aliphatic ring) (cyclobutenyl, Cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc.), alkyl or alkenyl substituted cycloalkenyl, and cycloalkyl or cycloalkenyl substituted alkenyl. The term alkenyl may further include alkenyl containing oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.

In certain embodiments, a straight chain or branched alkenyl has 6 or fewer carbon atoms in its backbone (eg, C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). . Similarly, a cycloalkenyl can have from 3 to 8 carbon atoms in its ring structure, and more preferably has 5 or 6 carbons in the ring structure. The term C ₂ -C ₆ includes alkenyl containing 2 to 6 carbon atoms. “Alkenylene” is a divalent moiety derived from the corresponding alkenyl group.

  Further, unless otherwise specified, the term “alkenyl” includes both “unsubstituted alkenyl” and “substituted alkenyl”, the latter replacing one or more hydrogens on one or more carbons of the hydrocarbon backbone. An alkenyl moiety having a substituent. The substituent is, for example, alkyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate (and its lower alkyl ester), alkylcarbonyl, arylcarbonyl, alkoxycarbonyl , Aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (alkyl Carbonylamino, arylcarbonylamino, carbamoyl, and ureido), a Midino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocycle, alkylaryl, or aromatic or heteroaromatic May contain sex parts.

The term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substituents to the alkyls described above, but containing at least one triple bond. For example, the term “alkynyl” refers to straight chain alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched alkynyl, and cycloalkyl or cycloalkenyl substituted alkynyl. Including. Unless otherwise stated, the term alkynyl further includes alkynyls containing oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched alkynyl has 6 or fewer carbon atoms in its backbone (eg, C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term C ₂ -C ₆ includes alkynyl containing 2 to 6 carbon atoms.
“Alkynylene” is a divalent moiety derived from the corresponding alkynyl group.

Further, unless otherwise specified, the term alkynyl includes both “unsubstituted alkynyl” and “substituted alkynyl”, where the latter is a substituent substituted with one or more hydrogens on one or more carbons of the hydrocarbon backbone. Refers to an alkynyl moiety having
The substituent is, for example, alkyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl Dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, Carbamoyl and ureido), amidino, imino, sulfhydryl, Alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, or an aromatic or heteroaromatic moiety.

  Unless otherwise specified, “lower alkyl” as used herein means alkyl as defined above, and has 1 to 5 carbon atoms in its skeletal structure. “Lower alkenyl” and “lower alkynyl” have a length of, for example, 2 to 5 carbon atoms.

  The term “acyl” refers to a carbonyl attached to the carbon atom through the carbon atom with a hydrogen (ie, formyl), an aliphatic group (eg, acetyl), an aromatic group (eg, benzoyl), and the like. . The term “substituted acyl” refers to one or more hydrogen atoms on one or more carbon atoms such as alkyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy Carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (alkyl amino, dialkylamino, arylamino, diarylamino , And alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, carbamo Amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocycle, alkylaryl, Or an acyl substituted by an aromatic or heteroaromatic moiety.

  The term “acylamino” includes moieties wherein an amino moiety is bonded to an acyl. For example, acylamino includes alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido.

  The terms “alkoxyalkyl”, “alkylaminoalkyl”, and “thioalkoxyalkyl” include alkyls as described above further comprising an oxygen, nitrogen, or sulfur atom replacing one or more carbons of the hydrocarbon backbone.

  The term “alkoxy” or “alkyloxy” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl covalently bonded to an oxygen atom. Examples of alkoxy include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy include halogenated alkoxy.

  Alkoxy is, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkyl Aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, carbamoyl, And ureido), amidino, imino, sulfhydride Groups such as alkyl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocycle, alkylaryl, or aromatic or heteroaromatic moieties Can be substituted. Examples of halogen substituted alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like, and perhalogenated alkyloxy.

The term “amine” or “amino” includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
“Alkylamino” includes groups wherein the nitrogen is bound to at least one alkyl. The term “dialkylamino” includes groups wherein the nitrogen atom is bound to at least two alkyls.
The terms “arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl, respectively.

The term “alkylarylamino” refers to an amino linked to at least one alkyl and at least one aryl.
The term “alkylaminoalkyl” refers to an alkyl, alkenyl, or alkynyl substituted with an alkylamino.
The term “amide” or “aminocarbonyl” includes compounds or moieties which contain a nitrogen atom bonded to the carbon of a carbonyl or thiocarbonyl.

The term “carbonyl” or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.
The term “ether” or “etheric” includes compounds or moieties which contain an oxygen bonded to two carbon atoms. For example, an ether or group of ethers includes “alkoxyalkyl” and refers to alkyl, alkenyl, or alkynyl substituted with alkoxy.

“Hydroxy” or “hydroxyl” includes —OH, or —O ⁻ (with the appropriate counter ion).
The term “halogen” includes fluorine, bromine, chlorine, iodine and the like. The term “perhalogenated” generally refers to a moiety in which all hydrogens are replaced by halogen atoms.

[式中、それぞれのＲは、独立して、水素(望ましい)であるか、または上記のＺで定義された基から選択され、そして１＜ｆ＜８であり、１＜ｇ＜８であり、０＜ｈ＜４である] を含む。 Arylene alkylene or arylene alkyl has an arylene in which two other alkylenes (which may be the same or different) are bound, and the two alkylenes are then bound to other moieties Contains groups. Examples of arylene alkylene or arylene alkyl are:

Wherein each R is independently hydrogen (desirable) or selected from the groups defined for Z above and 1 < f < 8 and 1 < g < 8 , 0 < h < 4].

[式中、それぞれのＲは、独立して、水素(望ましい)であるか、または上記のＺで定義された基から選択され、１＜ｙ＜１０(好ましくは１＜ｙ＜４)であり、１＜ｆ＜８であり、１＜ｇ＜８であり、０＜ｈ＜４であり、そして０＜ｉ＜４である] を含む。 An alkylene diarylene is an alkylene (or cycloalkylene) in which two other arylenes (which may be the same or different) are bonded, and the two alkylenes are then bonded to another moiety. A group having Examples of alkylene diarylene are:

[Wherein each R is independently hydrogen (desirable) or selected from the groups defined for Z above and 1 < y < 10 (preferably 1 < y < 4). 1 < f < 8, 1 < g < 8, 0 < h < 4, and 0 < i < 4.

  A heteroarylene alkylene or heteroarylene alkylene is bonded to two other alkylenes, which may be the same or different, and the two alkylenes are in turn connected to different moieties; Includes groups having heteroarylene.

[式中、０＜ｈ＜３であり、そして０＜ｉ＜３であり、そしてＸ＝ＮＲ'｛ここで、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝、Ｏ、またはＳであり、１＜ｆ＜８であり、１＜ｇ＜８である]、または

[式中、０＜ｈ＜２であり、そしてＸ＝ＮＲ'｛ここで、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝、Ｏ、またはＳであり、１＜ｆ＜８であり、１＜ｇ＜８である]、または

[式中、０＜ｈ＜３であり、１＜ｆ＜８であり、１＜ｇ＜８である]、または

[式中、０＜ｈ＜２である]を含む。ここで、それぞれ、Ｒは、独立して、水素(望ましい)であるか、または上記のＺで定義された基から選択され、１＜ｆ＜８であり、１＜ｇ＜８であり、そしてｈおよびｉは示された通りである。 Examples of heteroarylene alkylene or heteroarylene dialkyl are:

Wherein 0 < h < 3 and 0 < i < 3, and X = NR ′ {where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl}, O, or S, 1 < f < 8, 1 < g < 8], or

[Wherein 0 < h < 2 and X = NR ′ {where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl. Are O, S, 1 < f < 8 and 1 < g < 8], or

[Where 0 < h < 3, 1 < f < 8 and 1 < g < 8], or

[Wherein 0 < h < 2]. Wherein each R is independently hydrogen (desirable) or selected from the groups defined above for Z, 1 < f < 8, 1 < g < 8, and h and i are as indicated.

[式中、それぞれのＲは、独立して、水素(望ましい)であるか、または上記のＺで定義された基から選択され、そして０＜h＜４である]の例を含み、例えば

である。 Arylene is an aromatic group that can be covalently bonded to other substituents in at least two places:

Wherein each R is independently hydrogen (desirable) or selected from the groups defined above for Z and 0 < h < 4, for example,

It is.

[式中、０＜ｈ＜３であり、そして０＜ｉ＜３であり、そしてＸ＝ＮＲ'｛ここで、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝、Ｏ、またはＳである]、または

[式中、０＜ｈ＜２であり、そしてＸ＝ＮＲ'｛ここで、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝、Ｏ、またはＳである]、または

[式中、０＜ｈ＜３である]、または

[式中、０＜ｈ＜２である]を含む。
ここで、それぞれのＲは、独立して、水素(望ましい)であるか、または上記のＺで定義された基から選択され、そしてｈおよびｉは、示された通りである。例えば、Ｒは、下記の基である。

A heteroarylene is a heteroaromatic group that can be covalently bonded to another substituent via at least two moieties, such as the following examples:

[Wherein 0 < h < 3 and 0 < i < 3, and X = NR ′ {where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, Is C ₂ -C ₅ alkynyl, or aryl}, O, or S], or

Wherein 0 < h < 2 and X = NR ′ {where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl Is}, O, or S], or

[Where 0 < h < 3], or

[Wherein 0 < h < 2].
Wherein each R is independently hydrogen (desired) or selected from the groups defined for Z above, and h and i are as indicated. For example, R is the following group.

[式中、Ｘ＝ＮＲ'｛ここで、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである}、Ｏ、またはＳであり、
０＜ｆ＜８であり、
０＜ｇ＜８であり、そして
それぞれのＲは、独立して、水素(望ましい)であるか、または上記のＺで定義した基から選択される]のヘテロアリーレンに関する。 Similarly, the present invention provides:

Wherein X = NR ′ {wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl}, O, or S Yes,
0 < f < 8,
0 < g < 8, and each R is independently hydrogen (desirable) or is selected from the group defined above for Z].

  In general, the term “aryl” includes groups containing 5- and 6-membered monocyclic aromatic groups which may contain from 0 to 4 heteroatoms such as benzene, pyrrole, furan, thiophene. , Thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine and the like.

Furthermore, the term “aryl” includes polycyclic aryls, for example, tricyclic, bicyclic, eg, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl , A group derived from quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
Aryl having heteroatoms in the ring structure may also be referred to as “aryl heterocycle”, “heterocycle”, “heteroaryl”, or “heteroaromatic”.

  An aromatic ring is a substituent as defined above, e.g., halogen, hydroxyl, alkyl (e.g. tolyl), alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl , Alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, cyano, amino (alkylamino, dialkyl Amino, arylamino, diarylamino, and alkylarylamino), a Ruamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, It can be substituted at one or more ring positions with a cyano, azide, heterocycle, alkylaryl, or aromatic or heteroaromatic moiety.

Aryl can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycyclic ring (eg, tetralin).
The term “heterocyclic” or “heterocycle” includes heteroaryl and any rings formed that incorporate heteroatoms or atoms that are not carbon. The ring may be saturated or unsaturated and may contain one or more double bonds. Examples of desirable heterocyclic groups include pyridyl, furanyl, thiophenyl, morpholinyl, and indolyl. The term “heteroatom” includes any atom other than carbon or hydrogen. Desirable heteroatoms are nitrogen, oxygen, sulfur, and phosphorus.

“Arylene” is a divalent moiety derived from aryl.
Oligo ethereal groups, for instance oligo (alkylene oxide) is polyethylene glycol (PEG), and _{^{- [(CR 2) s O}} ] t (CR 2) s - { and where a 1 <t <6, and 1 < s < 6 and each R independently comprises a short analog thereof containing hydrogen (desirable) or selected from the groups defined above for Z}.

[式中、“アリール”は、アリーレン部分であり、１＜ｔ＜６であり、０＜ｓ＜６であり、そしてそれぞれのＲは、独立して、水素(望ましい)、または上記のＺで定義した基から選択される]を含む。望ましいアリーレン−ジ(オリゴアルキレンオキシド)は、

[式中、１＜ｔ＜６であり、０＜ｓ＜６であり、０＜ｈ＜４であり、そしてそれぞれのＲは、独立して、水素(望ましい)、または上記のＺで定義した基から選択される]を含む。 Arylene-di (oligoalkylene oxide) is an aryl having two oligoalkylene oxides attached to it (in turn attached to another moiety), the following examples:

[Wherein “aryl” is an arylene moiety, 1 < t < 6, 0 < s < 6, and each R is independently hydrogen (desirable) or Z as defined above Selected from defined groups]. The preferred arylene-di (oligoalkylene oxide) is

[Wherein 1 < t < 6, 0 < s < 6, 0 < h < 4, and each R is independently defined as hydrogen (desirable) or Z as defined above Selected from the group].

The term “substituted” means that the moiety has a substituent present in a moiety other than hydrogen that the molecule may have its intended function. Examples of substituents are linear or branched 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 ), heterocycle, carbocycle, aryl (eg phenyl), aryloxy (eg phenoxy), aralkyl A moiety selected from (e.g. benzyl), aryloxyalkyl (e.g. phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl, and arylcarbonyl, or other such acyl, heteroarylcarbonyl, or _{heteroaryl, (CR'R ") 0-3 NR'R"} ( e.g. -NH _2), (CR'R ") _-3 CN (e.g. -CN), NO _2, halogen (e.g., F, Cl, Br or _{I,), (CR'R ")} 0-3 C ( _{halogen) 3} (e.g., -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 ′ (eg, —SO ₃ H), (CR′R ″) _0-3 O (CR ′ R ″) _0-3 H (eg —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), ( _{R'R ") 0-3 (C 3 -C} 8 _{cycloalkyl), (CR'R") 0-3 CO} 2 R '( for example, -CO ₂ H), or (CR'R _") 0-3 OR ', Or the side chain of any natural amino acid {where R' and R "are each independently hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or It is aryl or R ′ and R ″ taken together include a moiety selected from benzylidene or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —.
Preferably, the substituent enhances the ability of the compounds of the invention to perform the intended function, for example, the ability to inhibit the formation of amyloid deposits.

In the compounds of the present invention, it is desirable that m = 1 and n = 0, 1, or 2. In compounds of formula I, preferably p = 0, 1, or 2, and q = 1. The molecules described in Formula I are symmetric, so R ^a1 = R ^a2 , R ^b1 = R ^b2 , R ^c1 = R ^c2 , m = q, n = p, and Y ¹ = Y ² . Similarly, in the molecule of formula I, it is desirable that R ¹ = R ² and X ¹ = X ² .

[式中、Ｍは、

であり；
望ましい態様において、Ｒ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ａ２は一緒になって、Ｃ_２−Ｃ_３アルキレンを表し；
Ｒ^ｃ１とＲ^ｃ２はＨであり；
Ｒ^ｈ１はＨであり；そして
Ｒ^ｈ２は、ＯＣＨ_３、またはＯ(Ｃ_６Ｈ_４)Ｒ｛式中、ＲはＨまたは低級−アルキルである｝であり；そして
Ｘは、Ｏ、ＮＲ'｛式中、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキル、またはアリールである｝、またはＳである]の化合物である。 One group of desirable compounds of the invention is of formula Ia:

[Wherein M is

Is;
In a desirable embodiment, R ^a1 and R ^{b1 taken} together or R ^a2 and R ^{a2 taken} together represent C ₂ -C ₃ alkylene;
R ^c1 and R ^c2 are H;
R ^h1 is H; and R ^h2 is OCH ₃ , or O (C ₆ H ₄ ) R, where R is H or lower-alkyl}; and X is O, NR ′ { Wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkyl, or aryl}, or S].

In another group of desirable compounds of formula Ia, R ^a1 and R ^{b1 taken} together or R ^a2 and R ^{b2 taken} together represent a C ₂ -linear saturated alkylene;
R ^c1 and R ^c2 are — (lower alkyl) —OH; and R ^h1 and R ^h2 are each H. “Lower alkyl” for R ^c1 and R ^c2 is preferably ethylene.

In yet another group of desirable compounds of formula Ia, R ^a1 and R ^{b1 taken} together or R ^a2 and R ^{b2 taken} together represent C ₄ -alkylene;
R ^c1 and R ^c2 are H (preferred), lower alkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl, or alkylaminoalkyl;
R ^h1 and R ^h2 are independently selected from the group consisting of H (desirable), lower alkyl, halogen, alkoxy, aryloxy, or arylalkoxy.

In yet another group of desirable compounds of Formula Ia, R ^a1 , R ^a2 , R ^b1 , and R ^b2 are H;
R ^c1 and R ^c2 are isopropyl, or — (CH ₂ ) ₃ N (CH ₃ ) ₂ ; and R ^h1 and R ^h2 are H.

In a further group of desirable compounds of formula Ia, R ^a1 and R ^b1 together or R ^a2 and R ^b2 together form phenylene {optionally up to 3 -CONHR ^d NR ^e R ^f (formula Wherein R ^d is lower alkyl; and R ^e and R ^f are each independently substituted with H or selected from the group consisting of lower alkyl]; and R ^c1 , R ^c2 , R ^h1 , and R ^h2 are H.
Particularly desirable compounds of formula Ia have R ^h1 , R ^h2 , R ^b1 , R ^c1 , R ^b2 , and R ^c2 that are H, and R ^a1 and R ^a2 that are hydroxy or methoxy.

[式中、Ｍは、

であり；
Ｘは、Ｏ、ＮＲ'｛式中、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝、またはＳであり；
Ｒ^ｈ１とＲ^ｈ２は、それぞれ独立して、Ｈ、低級アルキル、アリール、アルキルアリール、アミノアルキル、アミノアリール、ハロゲン、アルコキシ、アリールオキシ、またはオキシアリールアルキルからなる群から選択され；
Ｒ^１とＲ^２は、それぞれ独立して、Ｈ、低級アルキル、アルコキシ、アルキルアリール、アリール、アリールオキシ、アミノアルキル、アミノアリール、またはハロゲンからなる群から選択され；そして
それぞれのＲ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、およびＲ^ｂ２は、独立して、Ｈ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、ヒドロキシ、またはアルキルアリールからなる群から選択されるか、または
Ｒ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、Ｃ_２−Ｃ_１０アルキル、ヒドロキシアルキル、またはアルキレンを表し；そして
それぞれのＲ^ｃ１とＲ^ｃ２は、独立して、Ｈ、ヒドロキシ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノ、アルキルアミノアルキル、シクロアルキル、ヒドロキシシクロアルキル、アルコキシシクロアルキル、アリール、またはアルキルアリールである]の化合物である。 Another group of desirable compounds is of formula Ib:

[Wherein M is

Is;
X is O, NR ′ {wherein R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl}, or S;
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; and each 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, hydroxy, or alkylaryl; Or R ^a1 and R ^{b1 taken} together, or R ^a2 and R ^{b2 taken} together represent C ₂ -C ₁₀ alkyl, hydroxyalkyl, or alkylene; and each R ^c1 and R ^c2 are independently H, hydroxy, lower alkyl, alkoxyal Le, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, compounds cycloalkyl, hydroxyalkyl cycloalkyl, alkoxyalkyl cycloalkyl, aryl or alkylaryl,.

[式中、Ｍは、

であり；
Ｘは、Ｓ、Ｏ、またはＮＲ'｛式中、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝であり；
Ｒ^ｂ１、Ｒ^ｂ２、Ｒ^ｃ１、およびＲ^ｃ２は、それぞれ独立して、Ｈ、低級アルキル、アルコキシ、アルコキシアルキル、シクロアルキル、アリール、ヒドロキシアルキル、アミノアルキル、またはアルキルアミノアルキルからなる群から選択され；
Ｒ^１とＲ^２は、Ｈ、低級アルキル、アルコキシ、アルコキシアルキル、ヒドロキシアルキル、シクロアルキル、アリール、アミノアルキル、アルキルアミノアルキル、またはハロゲンであり；
Ｒ^ａ１とＲ^ａ２は−ＯＹであるか、またはＲ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、

｛式中、Ｒ^５は、

(ここで、Ｙは、Ｈまたは低級アルキルである)である｝を表し；
それぞれのＸ^１とＸ^２は、−(ＣＨ_２)_ｎ−(ここで、ｎは０から２の整数である)であり；そして
Ｒ^ｈ１とＲ^ｈ２は、それぞれ独立して、Ｈ、低級アルキル、ハロゲン、アルコキシ、アリールオキシ、またはオキシアリールアルキルからなる群から選択される]の化合物である。 Another group of desirable compounds is of formula Ic:

[Wherein M is

Is;
X is S, O, or NR ′, where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl;
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 are taken together, or R ^a2 and R ^b2 are taken together,

{Wherein R ⁵ is

Where Y is H or lower alkyl;
Each X ¹ and X ² is — (CH ₂ ) _n — (where n is an integer from 0 to 2); and R ^h1 and R ^h2 are each independently H, lower alkyl And selected from the group consisting of halogen, alkoxy, aryloxy, or oxyarylalkyl.

Yet another group of desirable compounds is of formula Ic:
[Wherein M is — (CH ₂ ) _n — {wherein n is an integer of 2 to 16 (or 2 to 12, or 2 to 10)};
Each 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 are taken together, or R ^a2 and R ^b2 are taken together, — (CH ₂ ) _m — { Where m is 2, 3, or 4};
Each R ¹ and R ² is H, OCH ₃ , NO ₂ , or NH ₂ ;
R ^c1 and R ^c2 are H, CH ₃ , or CH ₂ CH ₃ ]. In another embodiment, when X ¹ is O or S, both R ¹ and R ^c1 cannot be H;
And when X ² is O or S, both R ² and R ^c2 cannot be H.

[式中、それぞれのＲ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、およびＲ^ｂ２は、独立して、Ｈ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、またはアルキルアリールからなる群から選択されるか、
またはＲ^ａ１とＲ^ｂ１の２つは一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、Ｃ_２−Ｃ_１０アルキレンを表し；
Ｒ^ｃ１とＲ^ｃ２は、独立して、Ｈ、ヒドロキシ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、またはアルキルアリールであり；そして
Ｒ'は、Ｈ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、またはアルキルアリールである]の化合物である。 Another group of desirable compounds is of formula Id:

Wherein each R ^a1 , R ^a2 , R ^b1 , and R ^b2 is independently H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl. Or selected from the group consisting of
Or two of R ^a1 and R ^{b1 taken} together or R ^a2 and R ^{b2 taken} 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 It is an alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl] compound.

[式中、Ｍは、アルキレン(例えばＣ_２−Ｃ_１６)であり；そして
Ｘ^１とＸ^２は、酸素である]の化合物である。
望ましい式 Ie の別のグループにおいて、Ｒ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、Ｃ_２−直鎖飽和アルキレンを表し；Ｒ^ｃ１とＲ^ｃ２はＨである。 Another group of desirable compounds is of formula Ie:

Wherein M is alkylene (eg C ₂ -C ₁₆ ); and X ¹ and X ² are oxygen.
In another group of the preferred formula Ie, R ^a1 and R ^{b1 taken} together or R ^a2 and R ^{b2 taken} together represent C ₂ -linear saturated alkylene; R ^c1 and R ^c2 are H is there.

[式中、Ｅは、

であり；
Ｙ^１、Ｙ^２、Ｚ、およびＲ^１は、上記で定義した通りであり；
ｎは、０〜４であり；
Ｙ^２は、好ましくはＯ、ＮＨ、Ｓ、置換もしくは非置換メチレンであるか、または直接結合であり；
Ｚは、水素原子であり得るか、またはＺは、好ましくはアルキル、アリール、アルコキシ、アリールオキシ、ヒドロキシ、置換もしくは非置換アミノ、ニトロ、スルホ、またはハロゲンであり得；
Ｒ^ａ１、Ｒ^ｂ１、およびＲ^ｃ１は、独立して、水素、低級アルキル、芳香族性、ヒドロキシル、またはアルコキシであり；そして
Ｂは、直接結合、または１から１６個の炭素原子を含む置換もしくは非置換アルキレンであるか、またはビフェニレンであるか、またはビフェニレン−アルキレンの組み合わせであるか、−[(ＣＨ_２)_ｎＯ]_ｍ(ＣＨ_２)_ｎ−｛式中、ｍは１から６であり、そしてｎは２から６である｝であるか、またはヘテロ環である]の化合物である。 Another group of desirable compounds of the invention is of formula IIa:

[Where E is

Is;
Y ¹ , Y ² , Z, and R ¹ are as defined above;
n is 0-4;
Y ² is preferably O, NH, S, substituted or unsubstituted methylene, or is a direct bond;
Z can be a hydrogen atom or Z can preferably be alkyl, aryl, alkoxy, aryloxy, hydroxy, substituted or unsubstituted amino, nitro, sulfo, or halogen;
R ^a1 , R ^b1 and R ^c1 are independently hydrogen, lower alkyl, aromatic, hydroxyl, or alkoxy; and B is a direct bond or a substituent containing 1 to 16 carbon atoms or It is unsubstituted alkylene, biphenylene, or a combination of biphenylene-alkylene, or — [(CH ₂ ) _n O] _m (CH ₂ ) _n — {wherein m is 1 to 6 And n is 2 to 6} or is a heterocycle].

[式中、ｎ＝２、３、４、５、６、７、８、９、または１０であり；そして
Ｒ＝水素、ヒドロキシ、ハロゲン、フェニル、ビフェニル、ナフチル、アルコキシ、カルボキシ、アルコキシカルボニル、アリールオキシカルボニル、またはアリールオキシである]である。 The compound of formula IIb is also

[Wherein n = 2, 3, 4, 5, 6, 7, 8, 9, or 10; and R = hydrogen, hydroxy, halogen, phenyl, biphenyl, naphthyl, alkoxy, carboxy, alkoxycarbonyl, aryl Oxycarbonyl or aryloxy].

[式中、Ｍは、

であり；
Ｘは、Ｓ、Ｏ、またはＮＲ'｛式中、Ｒ'は、水素、Ｃ_１−Ｃ_５アルキル、Ｃ_２−Ｃ_５アルケニル、Ｃ_２−Ｃ_５アルキニル、またはアリールである｝であり；
Ｒ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、およびＲ^ｂ２は、それぞれ独立して、Ｈ、低級アルキル、アルコキシアルキル、シクロアルキル、アリール、アルキルアリール、ヒドロキシアルキル、アミノアルキル、またはアルキルアミノアルキルからなる群から選択されるか、またはＲ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、Ｃ_２−Ｃ_１０アルキル、ヒドロキシアルキル、またはアルキレンを表すか、またはＲ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、

｛式中、ｎは、１から３の数であり、そしてＲ^１０は、Ｈ、または−ＣＯＮＨＲ^１１ＮＲ^１５Ｒ^１６(ここでＲ^１１は低級アルキルであり、そしてＲ^１５とＲ^１６は、それぞれ独立して、Ｈおよび低級アルキルからなる群から選択される)である｝であり；そして
Ｒ^ｃ１とＲ^ｃ２は、Ｈ、ヒドロキシ、低級アルキル、シクロアルキル、アリール、アルキルアリール、アルコキシアルキル、ヒドロキシシクロアルキル、アルコキシシクロアルコキシ、ヒドロキシアルキル、アミノアルキル、またはアルキルアミノアルキルであり；
そしてＲ^ｈ１とＲ^ｈ２は、それぞれ独立して、Ｈ、低級アルキル、ハロゲン、アリール、アリールアルキル、アミノアルキル、アミノアリール、アルコキシ、アリールオキシ、またはオキシアリールアルキルからなる群から選択される]の化合物である。 Another group of desirable compounds is Formula IIIa:

[Wherein M is

Is;
X is S, O, or NR ′, where R ′ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl;
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 taken} together, or R ^a2 and R ^{b2 taken} together represent C ₂ -C ₁₀ alkyl, hydroxyalkyl, or alkylene, or R ^a1 and R ^b1 Together or R ^a2 and R ^b2 are together,

{Wherein n is a number from 1 to 3 and R ¹⁰ is H or —CONHR ¹¹ NR ¹⁵ R ¹⁶ (where R ¹¹ is lower alkyl and R ¹⁵ and R ¹⁶ are each Independently selected from the group consisting of H and lower alkyl); and R ^c1 and R ^c2 are H, hydroxy, lower alkyl, cycloalkyl, aryl, alkylaryl, alkoxyalkyl, hydroxycyclo Alkyl, alkoxycycloalkoxy, hydroxyalkyl, aminoalkyl, or alkylaminoalkyl;
And 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] It is.

[式中、Ｒ^ａ１とＲ^ｂ１のペア、およびＲ^ａ２とＲ^ｂ２のペアは、一緒になって、それぞれ−(ＣＨ_２)_ｍ−(式中、ｍは、２から４である)を表し；
Ｒ^ｃ１とＲ^ｃ２は、独立して、Ｈまたは低級アルキルであり；そして
Ｍ(低級アルキルで置換されていてもよい)は、−ＣＨ＝ＣＨ−ＣＨ_２−ＣＨ_２−、−ＣＨ_２−ＣＨ＝ＣＨ−ＣＨ_２−、および−ＣＨ＝ＣＨ−ＣＨ＝ＣＨ−からなる群から選択される]の化合物である。 Yet another group of desirable compounds is Formula IIIb:

[Wherein the pair of R ^a1 and R ^{b1 and} the pair of R ^a2 and R ^b2 together represent — (CH ₂ ) _m —, where m is 2 to 4, respectively. ;
R ^c1 and R ^c2 are independently H or lower alkyl; and M (optionally substituted with lower alkyl) is —CH═CH—CH ₂ —CH ₂ —, —CH ₂ —CH ═CH—CH ₂ —, and —CH═CH—CH═CH—.

[式中、Ｒ^１とＲ^２は、独立して、Ｈまたは−ＣＯＮＨＲ^５ＮＲ^６Ｒ^７｛式中、Ｒ^５は、低級アルキルであり、Ｒ^６とＲ^７は、それぞれ独立して、Ｈおよび低級アルキルからなる群から選択される｝であり；
Ｒ^ａ１、Ｒ^ａ２、Ｒ^ｂ１、およびＲ^ｂ２は、独立して、Ｈ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、またはアルキルアリールからなる群から選択されるか、またはＲ^ａ１とＲ^ｂ１は一緒になって、またはＲ^ａ２とＲ^ｂ２は一緒になって、Ｃ_２−Ｃ_１０アルキレンを表し；
Ｒ^ｃ１とＲ^ｃ２は、独立して、Ｈ、ヒドロキシ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、またはアルキルアリールであり；
Ｒ^ｃ３とＲ^ｃ４は、独立して、Ｈ、ヒドロキシ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル,アルキルアミノアルキル、シクロアルキル、アリール、またはアルキルアリールであり；そして
Ｒ'は、Ｈ、低級アルキル、アルコキシアルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、シクロアルキル、アリール、アルキルアリール、またはハロゲンである]の化合物である。 Another group of desirable compounds is of formula IIIc:

[Wherein, R ¹ and R ² are independently H or —CONHR ⁵ NR ⁶ R ⁷ {wherein R ⁵ is lower alkyl, and R ⁶ and R ⁷ are each independently H And selected from the group consisting of lower alkyls;
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 taken} together or R ^a2 and R ^{b2 taken} 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 It is an alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, alkylaryl, or halogen] compound.

  In another specific embodiment, the present invention relates to a pharmaceutical composition comprising a compound of any formula herein for treating an amyloid-related disease, and a method for producing the pharmaceutical composition.

  The compounds of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) eliminates many highly hydrophilic compounds. In order to ensure that the more hydrophilic therapeutic compounds of the invention pass through the BBB, they can be formulated, for example, in liposomes. See, for example, US Pat. Nos. 4,522,811; 5,374,548; and 5,399,331 for methods of producing liposomes. Liposomes contain one or more moieties (“target moieties”) that are selectively transported to specific cells or organs, thereby effecting targeted drug delivery (eg, VV Ranade (1989) J. Clin. Pharmacol. 29: 685).

Examples of target parts are
Folate or biotin (see, eg, US Pat. No. 5,416,016, Low et al.);
Mannoside (Umezawa et al. (1988) Biochem. Biophys. Res. Commun. 153: 1038);
Antibodies (PG 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. Physiol. 1233: 134);
gp120 (Schreier et al. (1994) J. Biol. Chem. 269: 9090); see also K. Keinanen; MLLaukkanen (1994) FEBS Lett. 346: 123; JJ Killion; IJFidler (1994) Immunomethods 4: 273 thing)
including. In desirable embodiments, the therapeutic compounds of the invention are formulated in liposomes, and in more desirable embodiments, the liposomes include a targeting moiety.

  Indeed, in order to pass the compounds of the present invention through the BBB, they can be combined with a BBB transport vector (for review of the BBB transport vector and mechanism, see Bickel, et al., Adv. Drug Delivery Reviews, vol. 46, pp 247-279, 2001). Examples of transport vectors include cationized albumin or OX26 monoclonal antibody against transferrin receptor. Each of these proteins performs absorption-mediated and receptor-mediated transcellular transport through the BBB.

  Examples of other BBB transport vectors targeting the receptor-mediated transport system to the brain are insulin, insulin-like growth factor (IGF-I, IGF-II), angiotensin II, atrial and brain natriuretic peptide (ANP, BNP). ), Interleukin I (IL-1), and transferrin. Monoclonal antibodies against receptors that bind to these factors can also be used as BBB transport vectors. BBB transport vector targeting mechanisms in absorption-mediated transcellular transport include cationic moieties such as cationized LDL, albumin, or horseradish peroxidase coupled to polylysine, cationized albumin, or cationized immunoglobulin, for example. including. Small basic oligopeptides such as the dynorphin analog E-2078, and the ACTH analog evilatide can be delivered to the brain via absorption-mediated transcellular transport and are potential transport vectors.

  Another BBB transport vector targets a system for transporting nutrients to the brain. Examples of such BBB transport vectors include hexose moieties such as glucose, monocarboxylic acids (eg lactic acid), natural amino acids (eg phenylalanine), amines (eg choline), basic amino acids (eg arginine), nucleosides ( Adenosine), purine bases (eg, adenine), and thyroid hormones (eg, triiodothyridine). Antibodies against the extracellular domain of nutrient transporters can also be used as transport vectors. Another possible vector includes angiotensin II and ANP. These may be involved in controlling BBB permeability.

  In some cases, the bond that binds the therapeutic compound to the transport vector can be cleaved after transport to the brain to release the biologically active compound. Examples of linkers include disulfide bonds, ester-based bonds, thioether bonds, amide bonds, acid labile bonds, and Schiff base bonds. An avidin / biotin linker, where avidin is covalently linked to a BBB drug transport vector, can also be used. Avidin itself can be a drug transport vector.

  In order to administer a therapeutic compound by other than parenteral administration, it may be necessary to coat or administer the compound with a substance that prevents its inactivation. For example, the therapeutic compound can be administered to the subject in a suitable carrier (eg, a liposome) or diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes (Strejan et al. (1984) J. Neuroimmunol. 7: 27).

  The therapeutic compound may also be administered parenterally, intraperitoneally, spinal cord, or brain. Dispersions can be made in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

  Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile for the immediate manufacture of sterile injectable solutions or suspensions. Contains treated powder. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It 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.

  The excipient can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The 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 dispersion and by the use of surfactants. Protection from the action of microorganisms can be achieved by various antimicrobial and antimicrobial agents (eg, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, it will be desirable to include isotonic agents, such as sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

  Appropriate injectable solutions can be prepared by combining the required amount of the therapeutic compound with one or a combination of the above-listed ingredients and then sterile filtering if necessary in a suitable solvent. Generally, it is manufactured by combining a therapeutic compound with a sterile excipient, including the basic dispersion medium listed above and the other required ingredients. In the case of a sterilized powder to produce a sterilized injectable solution, the desired manufacturing method is to add a powder of any additional desired ingredients in addition to the active ingredient (ie, therapeutic compound) to its aforementioned Vacuum drying and lyophilization obtained from sterile filtered solutions.

  The therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The therapeutic compounds and other ingredients can also be enclosed in hard or soft gelatin capsules, compressed into tablets, or mixed directly into the subject's diet. For oral therapeutic administration, the therapeutic compound can be combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of therapeutic compound in the composition and the method of manufacture may of course vary. The amount of therapeutic compound in the therapeutically useful composition is that amount which results in proper administration.

It is particularly beneficial to formulate parenteral compositions in unit dosage systems for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as one dosage form for the subject being treated, where each unit comprises the necessary pharmaceutical excipients and In combination, the therapeutic compound calculated to produce the desired therapeutic effect is included in a predetermined amount. Details for the unit dosage form of the present invention are:
(a) the unique nature of the therapeutic compound and the particular therapeutic effect to be achieved; and
(b) limitations inherent in the field of mixing therapeutic compounds for the treatment of amyloid deposition in a subject;
Follow and depend directly on it.

  The invention therefore includes compounds of the formulas described herein (including pharmaceutically acceptable salts thereof) in a pharmaceutically acceptable carrier for aerosol, oral and parenteral administration. ). The invention also includes a compound or salt thereof that is lyophilized and can be reconstituted to form a pharmaceutically acceptable formulation for administration by intravenous, intramuscular, or subcutaneous injection. . Administration can also be intradermal or transdermal.

  In accordance with the present invention, the compounds of the formulas described herein and their pharmaceutically acceptable salts can be administered orally or by inhalation as a solid, or as a solution, suspension or emulsion, intramuscularly or It can be administered intravenously. Alternatively, the compound or salt thereof can be administered by inhalation, as a liposome suspension, intravenously or intramuscularly.

  Also provided are pharmaceutical formulations suitable for administration by inhalation as an aerosol formulation. These formulations comprise a solution or suspension of the desired compound of any formula herein or a salt thereof, or a plurality of solid particles of the compound or salt. The desired formulation can be placed in a small chamber and atomized. Atomization can be accomplished by compressed air or ultrasonic energy to form a plurality of droplets or solid particles comprising the compound or salt. The droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns. The solid particles are obtained by processing a solid compound of any formula described herein or a salt thereof in any suitable manner known in the art, for example by micronization. Most preferably, the size of the solid particles or droplets is from about 1 to about 2 microns. In this regard, commercially available nebulizers are available to achieve this goal.

  Preferably, when a pharmaceutical formulation suitable for administration as an aerosol is in liquid form, the formulation is soluble in water with any of the compounds of the formulas described herein, or salts thereof, It is included in the carrier. There may be a surfactant that, when subjected to nebulization, reduces the surface tension of the formulation enough to result in the formation of droplets in the desired size range.

  The active compound is administered in the subject in a therapeutically effective amount sufficient to inhibit amyloid deposition. A “therapeutically effective amount” is preferably at least about 20%, more preferably at least about 40%, even more preferably at least 60%, even more preferably up to at least about 80% relative to an untreated subject. At least inhibits amyloid deposition. In the case of Alzheimer's disease patients, a “therapeutically effective” amount stabilizes cognitive function or prevents further cognitive decline (ie, prevents, delays or stops disease progression).

  The ability of a compound to inhibit amyloid deposition is an animal model system that can be expected to be effective in inhibiting amyloid deposition in human disease, for example, in transgenic mice expressing human APP, or when Aβ deposition is It can be evaluated with other relevant animal models found. Similarly, the ability of a compound to prevent or reduce cognitive impairment in a model system can be effective in humans. Alternatively, the ability of a compound can be determined by testing the ability of the compound to inhibit amyloid fibril formation in vitro, including, for example, ThT, CD, or EM assays, as described herein. The assay can be used to evaluate. Compound binding to amyloid fibrils can also be measured using an MS assay, as described herein.

  The present invention also relates to prodrugs of the compounds of the formulas disclosed herein. Prodrugs are compounds that are converted to the active form in vivo (see, eg, R. B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp. 8). Prodrugs can be used to alter biodistribution (eg, compounds that typically do not contain protease reactive sites) or to alter the pharmacokinetic properties of a particular compound. For example, a carboxylic acid group is esterified with, for example, a methyl group or an ethyl group to obtain an ester. When the ester is administered to a subject, the ester is cleaved reductively, oxidatively or hydrolytically with an enzyme or non-enzyme to exhibit an anionic group. Anionic groups can be esterified with moieties (eg, acyloxymethyl esters) that are subsequently cleaved to reveal intermediate compounds that decompose to give the active compound. Prodrug moieties can be metabolized in vivo by esterases or by other mechanisms to carboxylic acids.

  Examples of prodrugs and their uses are well known in the art (see, eg, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19). Prodrugs may be prepared by reacting the purified compound in its free acid form with the appropriate derivatizing agent, either as is during the final isolation and purification of the compound or separately. Carboxylic acids can be converted to esters by treatment with an alcohol in the presence of a catalyst.

  Examples of cleavable carboxylic acid prodrug moieties include substituted and unsubstituted, lower or non-branched lower alkyl ester moieties (e.g., ethyl ester, propyl ester, butyl ester, pentyl ester, cyclopentyl ester, hexyl ester, cyclohexyl Ester), lower alkenyl ester, di-lower alkyl-amino lower alkyl ester (e.g. dimethylaminoethyl ester), acylamino lower alkyl ester, acyloxy lower alkyl ester (e.g. pivaloyloxymethyl ester), aryl ester (phenyl ester), aryl -Lower alkyl esters (e.g. benzyl esters), substituted (e.g. substituted with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters Includes stear, amide, lower alkyl amide, di-lower alkyl amide, and hydroxy amide.

  It is mentioned that the structure of some compounds of the invention contains stereoisomeric carbon atoms. It is to be understood that isomers arising from such asymmetry (eg, all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Unless otherwise specified, any chiral carbon center can be either (R) or (S) -stereochemical. Such isomers are obtained in substantially pure form by classical separation methods and by stereologically controlled synthesis. In addition, alkenes can contain either E or Z-geometric isomers, where appropriate.

  In certain embodiments of the compounds of the present invention, it may contain a basic functional group (eg amino or alkylamino) and thus form a pharmaceutically acceptable salt with a pharmaceutically acceptable acid. The term “pharmaceutically acceptable salts” refers in this embodiment to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the invention. These salts can be reacted as is during the final isolation and purification of the compounds of the invention, or alternatively, by reacting the purified free base form of the compounds of the invention with a suitable organic or inorganic acid. Can be manufactured.

  Typical salts are hydrohalides (hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearin Acid salt, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonic acid Salt, lactobionate, 2-hydroxyethyl sulfonate, and lauryl sulfate, etc. (see, eg, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm, Sci. 66: 1-19) ).

  In another case, the compounds of the invention may contain one or more acidic functional groups and thus form a pharmaceutically acceptable salt with a pharmaceutically acceptable base. The term “pharmaceutically acceptable salts” refers in these examples to the relatively non-toxic inorganic and organic base addition salts of the compounds of the invention.

  These salts can be used as such in the final isolation and purification of the compound, or alternatively, the purified free acid form of the compound can be combined with a suitable base, eg, a pharmaceutically acceptable metal cation. Or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Typical alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, 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.

  Those skilled in the art will recognize, or be able to ascertain using no more routine experimentation, or many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the following claims. All patents, patent specifications, and literature cited herein are hereby expressly incorporated by reference in their entirety. The invention is further illustrated by the following examples (which should not be considered limiting).

  The synthesis of the amidine compound of the present invention is described in U.S. Pat.Nos. 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, 6,326,395, 6,008,247, 6,127,554, 6,940, 3,4, No. 5,668,166, No. 5,817,686, No. 5,723,495, No. 4,619,942, No. 5,792,782, No. 5,639,755, No. 5,643,935, No. 5,602,172, No. 5,594,138, and No. 5,578,631. Many of the compounds can also be purchased from Sigma-Aldrich Co. (Milwaukee, USA). The compounds can also be synthesized according to art recognized techniques.

  Test compounds were purchased from commercial sources or synthesized and screened by Thioflavin T fluorescence assay (“ThT assay”). Alternatively, test compounds were screened by circular dichroism (“CD”), electron microscopy (“EM”), or mass spectrometry (“MS”) assays. MS assays show data for the ability of compounds to bind to amyloid protein, while ThT, EM, and CD assays show data for inhibition of fibril formation.

  The thioflavin T fluorescence assay in fibril formation is based on the principle that the fluorescent dye thioflavin T specifically binds to fibrils and does not bind to unaggregated Aβ peptides (LeVine III, H., 1993, Protein Science 2: 404-410). After binding, thioflavin T emits characteristic fluorescence that can be easily detected (Naiki, H., et al., 1996, Lab. Invest. 74: 374-383). The dye is thought to interact with overlapping cross-β-pleated sheets, a common structural motif of all amyloids (LeVine III, H., 1995, Amyloid: Int. J. Exp. Clin Invest. 2 : 1.6). Thioflavin T is widely used to assay the effect of compounds on fibril formation of Aβ peptides and other amyloid proteins (Bronfman, PC, et al., 1995, Neuroscience Lett. 218: 201-203). In this assay, the test compound is Aβ (1-40) (20 μM) containing 5 μM Thioflavin T, 0.02 M Tris / 0.02 M acetate / 0.15 M NaCl / 0.005% azide (pH 7.40). Alternatively, incubate at 37 ° C. in a sealed 384 well microplate with a solution of IAPP (10 μM). Measurements (excitation 430 nm / emission 485 nm) are performed at various time intervals with a microplate fluorescence reader. The increase in fluorescence means the expression of amyloid or an intermediate in amyloid formation, as illustrated in the figure (in general, inhibition of fibril formation because ThT fluorescence becomes larger when bound to fibrils) (The resulting compounds have lower assay fluorescence).

Protocol: Aβ peptide: Aβ (1-40) 95% purity (American Peptide Company, Inc, Sunnyvale, Cal. USA) was disaggregated in trifluoroacetic acid and 0.02 μm filter (Whatman Anotop 25 plus, 0.0. Filter in hexafluoroisopropanol (HFIP) at 02 μm, catalog number 6809 4102). A solution of 600 μM Aβ (1-40) or IAPP in HFIP is stored at −80 ° C. Assay mixture: The mixture is prepared as two solutions that are combined when added to the 384 well microplate (Corning Costar cat. 3705).
i) Solution A consists of test compound or buffer alone (control) in 0.02 M Tris / 0.02 M acetate / 0.15 M NaCl / 0.01% azide (pH 7.40).
ii) Solution B consists of 40 μM Aβ (1-40), or 20 μM IAPP, 10 mM Thioflavin T in 0.02 M Tris / 0.02 M acetate / 0.15 M NaCl, pH 7.40. This solution is prepared by drying Aβ under nitrogen, then sonicating it again in 0.04 M Tris base for 15 minutes. An equal volume of 0.04M acetic acid containing 0.3M NaCl is added and the solution is adjusted to 7.40 ± 0.02. A small amount of 20 mM Thioflavin T is added to the solution to obtain a final concentration of 5 μM Thioflavin T.
iii) Place 40 μL of solution A in a microplate, then 40 μL of solution B, in 0.02 M Tris / 0.02 M acetate / 0.15 M NaCl / 0.005% azide (pH 7.40), A final concentration of 20 μM Aβ (1-40) or 10 μM IAPP, 5 μM thioflavin T, and the indicated concentration of test compound are obtained.

  The plate was sealed and subjected to a microplate fluorescence reader. Fluorometric analysis: Approximately one day of kinetic measurement was performed using The HTS-7000 Bio Assay Reader, Perkin Elmer. Measurements were taken at 15 minute intervals with shaking for 1 minute before each measurement. A bandpass filter was used (excitation 430 nm, emission 485 mm).

  Similarly, in an electron microscope (“EM”) assay, each sample was sonicated for 1 minute to break up large chunks prior to testing. Samples (5 μl aliquots) were placed on freshly cut mica and air dried. Mica was placed in a Balzers High-vacuum, Freeze-Etch Unit (model 301), shaded with platinum (at an angle of 30 °), and coated with a carbon film. The replica was removed from the mica by floating and transferred to a 300 mesh copper mesh. Samples were tested using a Joel 2000 FX transmission electron microscope.

  In a circular bicolor (“CD”) assay, samples were transferred to a quartz cuvette with a 0.1 cm optical path length and a CD scan was performed using a Jasco J-715 spectropolarimeter. Measurements were performed at 37 ° C. between 190 and 240 nm with a resolution of 0.1 nm and a bandwidth of 1 nm.

  In mass spectrometry (“MS”), samples were prepared as an aqueous solution containing 20% ethanol, 200 μM test compound, and 20 μM solubilized Aβ40. The pH value of each sample was adjusted to 7.4 (± 0.2) by adding 0.1% aqueous sodium hydroxide. The solution was then analyzed by electrospray ionization mass spectrometry using a Waters ZQ 4000 massspectrometer. Samples were introduced by direct injection within 2 hours at a flow rate of 25 μl / min. In all analyses, the source temperature was kept at 70 ° C. and the cone voltage was 20V. Data was processed using Masslynx 3.5 software. The MS assay shows data for the ability of compounds to bind to Aβ, while the ThT, EM, and CD assays show data for inhibition of fibril formation.

  Some selected compounds of the invention are shown in Table 2 below. Although specific salts (eg, hydrochloride salts) are depicted, the free base and other pharmaceutically acceptable salts are within the scope of the present invention.

Table 2: Structure and activity of some compounds of the invention in the soluble Aβ assay

示したそれぞれのアッセイにおいて、"+"= 活性; "-" = 不活性; "pr" = 促進; "nd" または空欄 = 測定せず。

In each assay shown, “+” = activity; “-” = inactivity; “pr” = promotion; “nd” or blank = not measured.

The compounds in Table 3 can also be used according to the methods described herein.
Table 3: Further exemplary compounds for use in the methods of the invention

The chart below is the result of the ThT assay.

  The invention also relates to novel compounds and their synthesis. Therefore, the following examples are presented to illustrate how some compounds are prepared.

General The drug was purchased from Aldrich. Analytical thin layer chromatography (TLC) was performed on a silica gel 60F ₂₅₄ plastic back plate. Solvents were reagent grade unless otherwise noted. ¹ H (500 MHz) and ¹³ C (125 MHz) were recorded on a Varian Innova 500. Chemical shifts were recorded in parts per million (ppm) on a δ scale. Infrared absorption (IR) spectra were measured with a Perkin-Elmer Spectra One spectrometer (no operation compound, on NaCl plate).

1,4-bis (4-amidinoanilino) butane

４−フルオロベンゾニトリル(３ｇ, ０.０２５mol)と、１,４−ジアミノブタン(０.６ｇ, ０.００６mol)と、トリエチルアミン(５ml)と、ＤＭＳＯ(１６ml)の混合物を、１５０℃で、３時間撹拌しながら加熱した。次に混合物を凍らせた水(２５０ml)に注ぎ、沈殿物を濾過によって集めた。粗生成物(０.５８ｇ)を、ＤＭＳＯ／Ｈ_２Ｏ(６：１)から再結晶し、生成物を明黄色の固体として得た(０.４８ｇ, 収率２７.６％)。 Step 1: 1,4-bis (4-cyanoanilino) butane

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 mixed at 150 ° C. with 3 Heated with stirring for hours. The mixture was then poured into frozen water (250 ml) and the precipitate was collected by filtration. The crude product (0.58 g) was recrystallized from DMSO / H ₂ O (6: 1) to give the product as a light yellow solid (0.48 g, 27.6% yield).

Step 2: 1,4-bis (4-amidinoanilino) butane

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 the IR showed no nitrile absorption peak at 2200 cm ⁻¹ . Diethyl ether (100 ml) was added and the formed precipitate was collected and washed with diethyl ether. The resulting solid was placed in a 50 ml round bottom flask. 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 that formed was collected, washed with ether and recrystallized from H ₂ O to give 0.50 g of product (99% yield).

Linear dibenzoamidine and diimidazolino compounds

Step 1: Sodium α, ω-bis (4-cyanophenoxy) alkane (1.2 g, 0.05 mol) was cut into small pieces and slowly added to a solution of dry ethanol (40 ml) with stirring. After complete dissolution of the sodium, 4-cyanophenol (6 g, 0.05 mol) was added followed by the dropwise addition of 1,4-dibromobutane (5.4 g, 0.025 mol). The resulting mixture was refluxed for 1-2 days with stirring and 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 directly in the next step without purification. Similar compounds with n = 3, 5, 6, 7, 8, 9, and 10 were prepared, yields ranging from 70-95%. ¹ H- and ¹³ C-NMR of the compound was consistent with the structure.

Step 2: Dibenzoamidine and diimidazolino compound A mixture of α, ω-bis (4-cyanophenoxy) alkane (3.42 mmol), dioxane (15 ml) and ethanol (40 ml) was cooled to 0 ° C. Dry HCl gas was bubbled through the mixture until saturation. The mixture was stirred at room temperature until the absorption of the nitrile at 2200 cm ⁻¹ of IR disappeared. 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; in the preparation of dibenzoamidine) or ethylenediamine in MeOH (1.5M, 30 ml; in the preparation of diimidazolino compound) was slowly added via syringe. The resulting mixture was refluxed for 3 hours with stirring. After the mixture was cooled to room temperature, diethyl ether (100 ml) was added. The white precipitate that formed was collected and washed with diethyl ether. The solid was recrystallized with HCl (2N) to give the desired product. Dibenzoamidine compounds having n = 3-10 were prepared and the yields ranged from 60-85%. Diimidazolino compounds having n = 4-10 were prepared and the yield ranged from 50-92%.

1- (4-Amidino) phenoxy-8-bromooctane hydrobromide

Step 1: 1- (4-Cyano) phenoxy-8-bromooctane In a 100 ml round bottom flask, 4-cyanophenol (2.38 g, 20 mmol), K ₂ CO ₃ (anhydride, 25 mmol), DMF (50 ml) was added. The mixture was stirred at room temperature for 30 minutes. When the mixture became cloudy, 8-bromooctanol (20 mmol) was added dropwise via a syringe. The mixture was then refluxed for 5 hours, cooled to room temperature and poured into frozen water (200 ml). A white precipitate formed and was collected by vacuum filtration. The pure product was obtained as a white solid after flash column chromatography on silica gel (eluent: 20-40% ethyl acetate in hexane) (4.1 g, 88.7% yield).

Step 2: 8- (4-Amidinophenoxy) octanol The corresponding amidine compound was obtained by successive treatment with saturated ethanolic hydrogen chloride solution and ethanolic ammonia in a similar manner as described above.

Step 3: 1- (4-Amidinophenoxy) -8-bromooctane hydrobromide In a 50 ml round bottom flask 8- (4-amidinophenoxy) octanol (2.14 g, 6.8 mmol) and dichloromethane (30 ml) was added. The mixture was cooled to 0 ° C. and PBr ₃ (3.4 mmol, 0.5 eq) was added dropwise via syringe. The mixture was then stirred overnight at room temperature. The white solid starting material was gradually dissolved into a yellow oil phase that was immiscible with dichloromethane. When the reaction was complete, water was added to quench the reaction and the dichloromethane was evaporated under reduced pressure to give a white solid as the crude product. Pure product was obtained after flash column chromatography on silica gel (eluent: CHCl ₃ / MeOH / AcOH 94/5/1) and then recrystallized from HBr / CH ₃ CN (2N) ( White solid, 780 mg, 31% yield).

9- (4-Amidinophenoxy) nonanoic acid hydrochloride

Step 1: 9- (4-Cyanophenoxy) nonanol 4-Cyanophenol (2.38 g, 20 mmol) and K ₂ CO ₃ (anhydride, 25 mmol) in DMF (50 ml) in a 100 ml round bottom flask. Mixed. The mixture was stirred at room temperature for 30 minutes. When the mixture became cloudy, 9-bromononanol (20 mmol) was added dropwise via a syringe. The mixture was then refluxed for 5 hours, cooled to room temperature and poured into frozen water (200 ml). The white precipitate that formed was collected by vacuum filtration. After flash column chromatography on silica gel (eluent: 20-40% ethyl acetate in hexane), the pure product was obtained as a white solid (4.8 g, 98% yield).

Step 2: 9- (4-Cyanophenoxy) nonanoic acid To a solution of 9- (4-cyanophenoxy) nonanol (2.5 g, 10.2 mmol) in DMF (50 ml) was added PDC (19 g, 61 mmol, 6 eq). Was added. The mixture was stirred at 50 ° C. overnight, cooled to room temperature and poured into frozen water (150 ml). The mixture was extracted with ethyl acetate (4 x 50 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Purification by flash column chromatography on silica gel (eluent: 25-50% ethyl acetate in hexane) gave the product as a white solid (1.65 g, 62% yield).

Step 3: 9- (4-Cyanophenoxy) nonanoic acid, ethyl ester In a 100 ml round bottom flask, thionyl chloride (0.88 ml, 12 mmol) was added to absolute 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 one portion. The reaction was monitored by TLC. After completion of the reaction, 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 sulfate. The product was obtained as a white solid after distillation of the solvent (1.6 g, 87.7% yield).

Step 4: 9- (4-Amidinophenoxy) nonanoic acid hydrochloride 9- (4-Cyanophenoxy) nonanoic acid ethyl ester (1.6 g, 5.28 mmol) was added with ethanol in a sealed 100 ml round bottom flask. Dissolved in a mixture of dioxane (50/10 ml). The mixture was saturated at 0 ° C. with HCl (g) and stirred at room temperature until the IR showed no nitrile absorption at 2200 cm ⁻¹ . Ethanol / dioxane was removed under reduced pressure and ether (100 ml) was added to induce precipitation. The precipitate was collected and placed directly into a dry 100 ml flask. Ethanolic ammonia (2M, 40 ml) was added via syringe. The mixture was refluxed for 3 hours, after which the solvent was evaporated and ether was added to induce precipitation. The formed solid was collected and recrystallized from HCl (2N). The final product was obtained as colorless needles (0.56 g, 32.3%).
¹ H NMR (500 MHz, DMSO-d6): 11.96 (s, 1H), 9.16 (s, 2H), 8.85 (s, 2H), 7.80 (d, 2H, J = 8.5 Hz), 7.13 (d, 2H , J = 8.5 Hz), 4.06 (t, 2H, J = 6.5 Hz), 2.18 (t, 2H, J = 7.5Hz), 1.73-1.70 (m, 2H), 1.49-1.46 (m, 2H), 1.40 -1.38 (m, 2H), 1.30-1.27 (m, 6H);
¹³ C NMR (125 MHz, DMSO-d6): 174.46, 164.71, 163.08, 130.15, 119.23, 114.74, 68.08, 33.66, 28.66, 28.57, 28.47, 28.40, 25.34, 24.46.

Some substituted pentaamidines

ナトリウム(０.３ｇ, ０.０１４mol)を小片に切り、撹拌しながら、乾燥エタノール(３０ml)の溶液に、ゆっくりと加えた。ナトリウムが完全に溶解した後、４−ヒドロキシ−３−メトキシベンゾニトリル(２ｇ, ０.０１３mol)を加え、次に１,５−ジブロモペンタン(０.９ml, ０.００７mol)を滴下した。得られた混合物を２日間撹拌しながら還流し、室温まで冷却した。混合物中の明褐色の沈殿物を集め、水で洗浄し、真空下で乾燥させた。得られた生成物(１.４５ｇ, ７３％)を、精製することなく次の段階に直接用いた。該化合物の^１Ｈ−および^１３Ｃ−ＮＭＲは、該構造と矛盾しなかった。 Step 1: 1,5-bis (4-cyano-2-methoxyphenoxy) pentane

Sodium (0.3 g, 0.014 mol) was cut into small pieces and slowly added to a solution of dry ethanol (30 ml) with stirring. After the sodium was completely dissolved, 4-hydroxy-3-methoxybenzonitrile (2 g, 0.013 mol) was added followed by dropwise addition of 1,5-dibromopentane (0.9 ml, 0.007 mol). The resulting mixture was refluxed with stirring for 2 days and cooled to room temperature. The light brown precipitate in the mixture was collected, washed with water and dried under vacuum. The resulting product (1.45 g, 73%) was used directly in the next step without purification. ¹ H- and ¹³ C-NMR of the compound was consistent with the structure.

Step 2: The corresponding pentaamidine substituted 1,5-bis (4-cyanophenoxy) pentane (in this example R ₁ = methoxy and R ₂ = hydrogen) (1.8 g, 4.91 mmol) and dioxane (15 ml ), And ethanol (50 ml) were cooled to 0 ° C. Dry HCl gas was bubbled into the mixture until it was saturated. The mixture was stirred at room temperature until the IR showed no nitrile absorption at 2200 cm ⁻¹ . Diethyl ether (100 ml) was added and the white precipitate that formed was collected by vacuum filtration and washed with diethyl ether. The resulting white solid was placed in a 50 ml round bottom flask and ammonia-ethanol solution (2M, 30 ml) was slowly added with a syringe. The resulting mixture was refluxed for 3 hours with stirring. 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 recrystallized from 2N HCl to give the desired product (0.92 g, 40% yield). In a similar manner, the corresponding compound R ₁ = bromine and R ₂ = bromine was synthesized in 53% yield.

Compound # 139

1,5-bis (4-cyanophenoxy) pentane (153 mg, 0.5 mmol), sodium carbonate (180 mg, 1.7 mmol) and hydroxylamine hydrochloride (278 mg, 4 mmol) in 80% ethanol (10 ml) Was refluxed for 2 hours. The mixture was cooled to room temperature. Some solid precipitated and was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by preparative RP-HPLC (Vydac 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 nonane analogs were prepared in a similar manner.

Compound # 55

Step 1: To a cooled (0 ° C.) solution of 1,5-diaminopentane (0.35 ml, 3 mmol) and triethylamine (0.98 ml, 7 mmol) in DMF (10 ml) was added 4-cyanobenzoyl chloride (1 g). 6 mmol). The mixture was stirred at room temperature overnight and diluted with water. The precipitated beige solid was collected by filtration and dried in vacuo to give the corresponding amide (1 g, 92%).

Step 2: A suspension of 1,5-bis- (4-cyanobenzamido) pentane (465 mg, 1.3 mmol) in a mixture of absolute ethanol (25 ml) and 1,4-dioxane (20 ml) was added at 0 ° C. Cooled to saturate with dry HCl and the resulting mixture was stirred at room temperature for 60 hours. The solvent was evaporated under reduced pressure. A brownish solid was obtained. A mixture of the solid and ammonium carbonate (2.5 g, 25 mol) in ethanol (25 ml) was stirred at room temperature overnight. A small amount of activated carbon was added and the mixture was filtered through celite. The solvent was evaporated under reduced pressure. The crude product was purified by preparative RP-HPLC (Vydac 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 as white As a solid (410 mg, 51%). Heptane and nonane analogs were prepared in a similar manner.

Compound # 54

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 dry DMF (25 ml) was added. Heated at 100 ° C. in an oil bath for 5 hours. The mixture was cooled to room temperature and then water (100 ml) was added. The formed solid was collected by filtration, washed with water and dried in vacuo. The desired bis-aldehyde was obtained as a brownish solid (2.8 g, 89%).

Step 2: Diisopropyl (cyanomethyl) phosphonate (0.86 ml, 4.2 mmol) was added to a suspension of sodium hydride (4.4 mmol) in THF at 0 ° C. The mixture was stirred at room temperature for 1 hour. A solution of bis-aldehyde (2 mmol) in THF was added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed successively with water, saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The crude solid was washed with a mixture of ethyl acetate and hexane (1 to 10, 10 ml) and dried in vacuo to give bis-nitrile (0.51 g, 71% yield).

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 room temperature 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 refluxed for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting solid was dried in vacuo and recrystallized from 2N HCl with the addition of a few drops of ethanol. The solid was collected by filtration, rinsed with water and dried overnight in vacuo to give the title compound as a light yellow solid (0.44 g, 71%).

Compound # 137

Step 1: 4-hydroxybenzyl cyanide (2.56 g, 19.2 mmol), 1,7-dibromoheptane (1.49 ml, 8.7 mmol) and potassium carbonate (11 g) in DMF (30 ml). The mixture was heated in an oil bath at 100 ° C. for 3 hours. The mixture was cooled to room temperature and diluted with water (150 ml). A solid precipitated. The solid was collected by filtration and washed with water. It was then dissolved in ethyl acetate and washed successively 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 tan solid (2.58 g, 82%).

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 absolute ethanol (10 ml) was added HCl at 0 ° C. Saturated with The mixture was stirred at room temperature for 3 days. 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 refluxed 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 as an off-white solid (655.3 mg, 60%).

Compound # 51

Step 1: A solution of borane-tetrahydrofuran complex (10 ml, 10 mmol) was added to a solution of bis-nitrile (510 mg, 1.53 mmol) at 0 ° C. The mixture was refluxed for 18 hours and cooled in an ice bath. Excess reagent was quenched by the slow addition of methanol (10 ml). The resulting mixture was refluxed for 15 minutes and then the solvent was removed under reduced pressure. The residue was coevaporated three times with methanol and then suspended in a mixture of methanol (20 ml) and concentrated HCl (6 ml). The mixture was refluxed for 1.5 hours. The mixture was reduced to about 5 ml under reduced pressure. A fine white solid formed. The mixture was diluted with ethanol and cooled to -10 ° C. The solid was collected by filtration, washed with cold ethanol and dried in vacuo overnight. 1,5-bis (4- (2-aminoethyl) phenoxy) pentane dihydrochloride was obtained as a fine white powder (564.6 mg, 89%).

Step 2: N, N′-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxyamidine (0.78 g, 2.5 mmol) was added to a mixture of THF (5 ml) and dichloromethane (20 ml) in 1 , 5-bis (4- (2-aminoethyl) phenoxy) pentane dihydrochloride (470 mg, 1.13 mmol) and Hunig's base (0.435 ml) were added to a suspension. The mixture was stirred at room temperature for 2 days. Excess reagent was quenched with 1,2-ethylenediamine. The mixture was diluted with chloroform, washed successively 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 ) to give a white foamy solid (246.5 mg, 26%).

Step 3: 4M HCl in 1,4-dioxane (5 ml) was added to a solution of the protected bis-guanidine 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 evaporated under reduced pressure. The product was dissolved in water and then the aqueous solution was lyophilized to give the title compound as a white solid (146.4 mg, 99%).

Figure 1: Effect of pentaamidine-type compounds on Aβ (1-40) assembly as measured by ThT assay Figure 2: Effect of pentaamidine-like compounds on Aβ (1-40) assembly as measured by ThT assay Figure 3: Effect of amidine-type compound on Aβ (A-40) assembly as measured by ThT assay. Figure 4: Effect of pentaamidine-type compounds on IAPP assembly as measured by ThT assay

Claims (6)

A method of treating or preventing an amyloid-related disease, such as Alzheimer's disease, cerebral amyloid angiopathy, or type II diabetes, in a subject, comprising administering to the subject a therapeutically effective amount of an amidine compound. . A method of treating or preventing an amyloid-related disease in a subject that reduces or inhibits amyloid fibril formation or deposition, neurodegeneration, or cytotoxicity:

Administering a therapeutic amount of any one of the compounds to the subject. formula:

Compound. formula:

Compound. formula:

Compound. formula:

Any one of the compounds.

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