HK1194004A

HK1194004A - Pharmaceutical formulations of amyloid inhibiting compounds

Info

Publication number: HK1194004A
Application number: HK14107499.5A
Authority: HK
Inventors: Legore Audley; Garceau Denis
Original assignee: Bhi Limited Partnership
Priority date: 2003-06-23
Filing date: 2014-07-23
Publication date: 2014-10-10

Description

Pharmaceutical formulations of amyloid inhibiting compounds

The present application is a divisional application of the invention patent application having application number 200480024244.8 and application date 2004, 6/21.

RELATED APPLICATIONS

The present application claims priority from the following patent applications: U.S. patent provisional application No. 60/480,984 (attorney docket No. NBI-152-1), U.S. patent provisional application No. 60/512,116 (attorney docket No. NBI-152-2), which was filed on 23/6/2003, on 17/10/2003 (both of which are entitled "pharmaceutical formulations of amyloid inhibiting compounds"), and U.S. patent application No. 10/XXX, XXX (attorney docket No. NBI-152), which was filed on 18/6/2004 and entitled "pharmaceutical formulations of amyloid inhibiting compounds".

Technical Field

The present application relates to U.S. provisional patent application No. 60/436,379 entitled "combination therapy for treating alzheimer's disease" filed on 24/12/2002 (attorney docket No. NBI-154-1), U.S. provisional patent application No. 60/482,214 filed on 23/6/2003 (attorney docket No. NBI-154-2), U.S. utility patent application No. 10/746,138 filed on 24/12/2003 (attorney docket No. NBI-154), and international patent application PCT/CA2003/002011 entitled "therapeutic agent for the treatment of beta-amyloid related diseases" (attorney docket No. NBI-154 PC). This application relates to U.S. patent provisional application No. 60/482,058 (attorney docket No. NBI-156-1), U.S. patent provisional application No. 60/512,135 (attorney docket No. NBI-156-2), filed on 23/6/2003, No. 60/512,135 (both of which are entitled "synthetic methods for preparing compounds for treating amyloidosis"), filed on 17/10/2003, and U.S. patent application No. 10/XXX, No. (attorney docket No. NBI-156), filed on 8/6/2004, entitled "improved drug candidates and methods for their preparation". The present application also relates to U.S. provisional patent application No. 60/480,918 (attorney docket No. NBI-149-1) filed on 23/6/2003, U.S. provisional patent application No. 60/512,017 (attorney docket No. NBI-149-2) filed on 17/10/2003, and U.S. patent application No. 10/XXX, XXX (attorney docket No. NBI-149) filed on 18/6/2004 entitled "method of treating protein aggregation disorders. The present application also relates to U.S. patent provisional application No. 60/480,906 (attorney docket No. NBI-162-1), U.S. patent provisional application No. 60/512,047 (attorney docket No. NBI-162-2), which was applied on 6/10/17/2003, U.S. patent application No. 10/XXX, XXX (attorney docket No. NBI-I62A), which was applied on 18/6/2004, and U.S. patent application No. 10/XXX, XXX (attorney docket No. NBI-162B), which was applied on 23/6/2004 (all of the above applications are entitled "compositions and methods for treating amyloid-related diseases"); and U.S. patent provisional application Nos. 60/480,928 (attorney docket No. NBI-163-1), 60/512,018 (attorney docket No. NBI-163-2), and 10, 17, 2003, and 10, 18, 2004 (attorney docket No. NBI-163), all entitled "compositions and methods for treating amyloid and epilepsy-related diseases", and methods for treating amyloidosis (U.S. patent application No. 08/463,548, now U.S. Pat. No. 5,972,328, attorney docket No. NCI-003CP 4).

The above-mentioned patent applications or patents are expressly incorporated by reference in their entirety into the present application, including, but not limited to, the specification, claims, abstract, and drawings, tables, and figures of such patent applications or patents.

Background

Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibrils. Amyloid is a general term referring to a diverse but specific set of protein deposits (intracellular or extracellular) that occur in many different diseases. Although their appearance is diverse, all amyloid deposits share common morphological properties, are stained with specific dyes (e.g., congo red), and have a red-green birefringence characteristic in polarized light after staining. They also share common ultrastructural features as well as common X-ray diffraction and infrared spectra.

Amyloid-related diseases may be confined to one organ or spread over multiple organs. The first condition is called "local amyloidosis" and the second condition is called "systemic amyloidosis".

Some amyloid diseases can be paroxysmal, but most of these diseases occur as a complication of a preexisting disease. For example, primary amyloidosis (AL amyloid) may occur without any other pathological condition or may occur with plasma cell malignancies or multiple myeloma.

Secondary amyloidosis usually occurs with chronic infection (e.g., tuberculosis) or chronic inflammation (e.g., rheumatoid arthritis). One familial form of secondary amyloidosis is also found in other types of familial amyloidosis, e.g., Familial Mediterranean Fever (FMF). This familial type of amyloidosis is genetically inherited and is common in specific populations. In both primary and secondary amyloidosis, deposits are found in multiple organs and are therefore considered systemic amyloid diseases.

"local amyloidosis" is those amyloidosis that tends to affect a single organ system. Different amyloids are also characterized by the type of protein in the deposit. For example, neurodegenerative diseases (e.g., scrapie, bovine spongiform encephalopathy, creutzfeldt-jakob disease, etc.) are characterized by the presence and accumulation of a protease-resistant form of a prion protein in the central nervous system (known as AScr or PrP-27). Similarly, alzheimer's disease, another neurodegenerative disease, is characterized by neuritic plaques and neurofibrillary tangles. In this case, amyloid plaques found in parenchyma and blood vessels are formed by deposition of fibrillar a β amyloid protein. Other diseases, such as adult-onset diabetes (type II diabetes), are characterized by local accumulation of amyloid fibrils in the pancreas.

Once these amyloids are formed, there is no known and well-accepted therapy or treatment regimen that significantly dissolves amyloid deposits in situ, prevents further amyloid deposition or prevents the onset of amyloid deposition.

Each amyloidogenic protein has an insoluble filament that can undergo conformational changes and constitute a beta-layer form, and form that can be deposited extracellularly or intracellularly. Individual amyloidogenic proteins, although differing in amino acid sequence, share the common characteristic of forming fibrils and binding to other components, such as proteoglycans, amyloid P and complementary components. Furthermore, although the amino acid sequence of each amyloidogenic protein is not identical, similarities are shown, such as regions of ability to bind to the glycosaminoglycan (GAG) portion containing proteoglycan, referred to as GAG binding site, and other regions that promote beta-layer formation. Proteoglycans are macromolecules of various sizes and structures that are distributed almost everywhere in the body. They may be found in the intracellular compartment, on the cell surface, and may serve as part of the extracellular matrix. The overall proteoglycan-containing basic structure includes a core protein and at least one, but often a plurality of, polysaccharide chains (GAGs) attached to the core protein. Many different GAGs have been discovered, including chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, and hyaluronan (hyaluronan).

In certain situations, amyloid fibrils, once deposited, can become toxic to surrounding cells. For example, it has been demonstrated that: senile plaque-forming Α β fibrils are associated with dead neuronal cells, dystrophic axons, astrocytosis, and microglioma in subjects with alzheimer's disease. When tested in vitro, oligomeric (soluble) and fibrillar a β peptides as shown can trigger the activation process of microglia (brain macrophages), which would explain microglioma and brain inflammation found in the brain of patients with alzheimer's disease. Both oligomeric and fibrillar Α β peptides can also cause neuronal cell death in vitro. See, for example, MP Lambert et al, Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998). In another type of amyloidosis, found in type II diabetic patients, the amyloidogenic protein IAPP has been shown to cause β -islet cytotoxicity in vitro when formed into oligomeric or fibrillar forms. Thus, the presence of IAPP in the pancreas of type II diabetics causes loss of beta islet cells (Langerhans) and organ dysfunction that can lead to insulinemia.

Another type of amyloidosis with beta₂Small globular proteins are related and found in patients undergoing long-term hemodialysis. Patients receiving hemodialysis for extended periods of time may be in the carpal tunnel and in multiple jointsForm beta in collagen-rich tissues₂A small globular protein filament. This can lead to severe pain, joint stiffness and joint swelling.

Amyloidosis is also a characteristic of alzheimer's disease. Alzheimer's disease is a severe brain disorder that results in progressive memory loss, which leads to dementia, physiological deficits, and death over a relatively long period of time. As the population of developed countries ages, the number of alzheimer patients reaches a very high percentage.

Patients suffering from alzheimer's disease develop a progressive dementia in adulthood and are accompanied by three major structural changes in the brain: diffusion loss of neurons in various parts of the brain; accumulation of intracellular protein deposits known as neurofibrillary tangles; and the accumulation of extracellular protein deposits called amyloid or senile plaques, accompanied by misshapen nerve endings (oligotrophic axons) and activated microglia (microglioma and astrocytosis). One major component of these amyloid plaques is the amyloid-beta peptide (A β), a 39-43 amino acid protein produced by the cleavage of the β Amyloid Precursor Protein (APP). Extensive research has been directed to the association of A β deposits in Alzheimer's disease, see, e.g., Selkoe, Trends in cell biology 8, 447-. AD is usually produced during the metabolism of amyloid precursor protein ("APP") in the endoplasmic reticulum ("ER"), golgi, or endosomal-lysosomal pathways, and is usually secreted as a 40 ("a β 1-40") or 42 ("a β 1-42") amino acid peptide (Selkoe, annu. rev. cell biol.10, 373-. The role of a β as a major cause of alzheimer's disease is supported by: the appearance of extracellular a β deposits in senile plaques of alzheimer's disease, increased production of a β in cells harboring alzheimer's disease-related mutant genes (e.g., amyloid precursor protein, presenilin I and presenilin II), and toxicity of extracellular soluble (oligomeric) or fibrillar a β to cells in culture. See, e.g., Gervais, Eur.Biopharm.review, 40-42 (autumn 2001); may, DDT 6, 459-62 (2001). Although symptomatic treatment of Alzheimer's disease is available, the disease is not prevented or cured at this time.

Alzheimer's disease is characterized by diffuse and neuritic plaques, cerebral vascular disease, and neurofibrillary tangles. Plaques and vascular amyloid are thought to be formed as deposits of insoluble a β amyloid protein described as either diffusion or fibrils. Both soluble oligomeric a β and fibrillar a β are considered neurotoxic and inflammatory.

Another type of amyloidosis is Cerebral Amyloid Angiopathy (CAA). CAA is the specific deposition of amyloid β fibrils in the walls of leptin ingeal and cerebral cortical arteries, arterioles and veins. It is commonly associated with Alzheimer's disease, Down's syndrome and natural aging, as well as various familial disorders associated with stroke or dementia (see Frangione et al, analog: J. protein Folding disorder.8, suppl.1, 36-42 (2001)).

Current therapies for the treatment of beta-amyloid disease are almost exclusively symptomatic and provide only temporary or partial clinical benefit. Although some pharmaceutical preparations have been described to partially alleviate symptoms, there is currently no comprehensive drug therapy available for the manufacture of, for example, prevention and treatment of alzheimer's disease.

Disclosure of Invention

The present invention provides methods, compositions and formulations for treating amyloidosis. The methods of the invention comprise administering to the subject a therapeutic composition or formulation capable of inhibiting amyloid deposition.

Thus, the compositions and methods of the present invention can be used to inhibit amyloidosis disorders in which amyloid deposition occurs. The methods of the invention may be used therapeutically to treat amyloidosis or may be used prophylactically in patients susceptible to amyloidosis.

In one aspect, the methods of the invention are based, at least in part, on inhibiting the interaction between amyloidogenic proteins and basement membrane components to inhibit amyloid deposition. In particular embodiments, the component of the basement membrane is a glycoprotein or proteoglycan, preferably agrin, perlecan or heparan sulfate proteoglycan. The therapeutic compounds used in the methods of the invention may interfere with the binding of basement membrane components to the binding target of amyloidogenic proteins, thereby inhibiting amyloid deposition. In other embodiments, the therapeutic compound used in the methods of the invention increases clearance of amyloid β from the brain, thereby inhibiting amyloid deposition. In other embodiments, the therapeutic compound used in the methods of the invention may inhibit neurodegeneration or cytotoxicity caused by amyloid (e.g., by soluble or insoluble amyloid, e.g., fibril; by amyloid deposition and/or by amyloid- β, as described herein).

In a preferred aspect, the present invention relates to the use of an alkylsulfonic acid in the treatment of amyloid-related diseases.

Thus, in one aspect, the present invention relates to a method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, thereby inhibiting amyloid deposition.

In another aspect, the invention relates to a method of treating or preventing an amyloid-related disease (e.g., an a β -related disease) in a subject, comprising administering to the subject a therapeutic amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, thereby treating or preventing the amyloid-related disease.

In another aspect, the invention relates to a method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, whereby the compound inhibits interaction between amyloidogenic proteins and basement membrane components to inhibit amyloid deposition.

Another aspect of the invention includes a method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation containing a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, whereby the therapeutic compound is capable of inhibiting amyloid-induced (e.g., induced by soluble or insoluble amyloid proteins, such as fibrils; induced by amyloid deposition and/or by amyloid- β, as described herein) neurodegeneration or cytotoxicity.

In another aspect, the compounds of the present invention relate to a method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, whereby the therapeutic compound increases the clearance of amyloid β from the brain.

In yet another aspect, the invention relates to a method for inhibiting amyloid deposition in a subject comprising orally administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

Another aspect of the invention is a pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance in an amount sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a pharmaceutical composition for treating amyloidosis comprising a therapeutic formulation containing a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance in an amount sufficient to inhibit amyloid deposition in a subject and a pharmaceutically acceptable carrier.

In another aspect, the invention relates to a pharmaceutical composition for treating or preventing an amyloid-related disease (e.g., an a β -related disease) comprising a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance and a pharmaceutically acceptable carrier in an amount sufficient to prevent or treat the amyloid-related disease in a subject.

In yet another aspect, the invention relates to a method for reducing amyloid deposits in a patient with amyloid deposits, comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, thereby reducing amyloid deposits in the patient.

Another aspect of the invention relates to a method for inhibiting binding of a chemokine to a glycosaminoglycan in a subject comprising administering to the subject a therapeutic preparation comprising a therapeutic compound formulated to substantially reduce or prevent gastrointestinal intolerance, thereby inhibiting binding of the chemokine to the glycosaminoglycan.

Another aspect of the invention relates to a method of modulating bacterial interaction with glycosaminoglycans in a human comprising administering to the subject an effective amount of a therapeutic preparation containing a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

In yet another aspect, the invention relates to a method for treating a bacterial infection in a human comprising orally administering to the human an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

In another aspect, the invention relates to a method of modulating viral interaction with glycosaminoglycans in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

Another aspect of the invention relates to a method of treating a viral infection in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

Yet another aspect of the invention relates to a method of preventing, treating or inhibiting cerebral amyloid angiopathy in a subject comprising administering an effective amount of a therapeutic formulation containing a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

In another aspect, the invention relates to a method of preventing, treating or inhibiting cerebral amyloid angiopathy, comprising contacting blood vessel wall cells with a therapeutic formulation containing a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, whereby cerebral amyloid angiopathy is prevented, treated or inhibited.

Another aspect of the invention relates to a method of preventing, treating, or inhibiting alzheimer's disease in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance.

Another aspect of the invention relates to a method of preventing, treating, or inhibiting alzheimer's disease in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance, whereby alzheimer's disease is prevented, treated, or inhibited.

In another aspect, the present invention relates to a packaged pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a container containing a therapeutically effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance; and instructions for using the compound for inhibiting amyloid deposition in a subject.

In yet another aspect, the present invention relates to a packaged pharmaceutical composition for treating amyloidosis in a subject, comprising a container containing a therapeutically effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance; and instructions for using the compound for treating amyloidosis in a subject.

In yet another aspect, the invention relates to a packaged pharmaceutical composition for treating alzheimer's disease in a subject comprising a container containing a therapeutically effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance; and instructions for use of the compound for treating alzheimer's disease in a subject.

Another aspect of the invention is a packaged pharmaceutical composition for treating a viral infection comprising a container holding a therapeutically effective amount of a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance; and instructions for using the compound for treating viral infection.

In another aspect, the present invention relates to a packaged pharmaceutical composition for treating bacterial infections comprising a container containing a therapeutic formulation comprising a therapeutically effective amount of a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance; and instructions for using the compounds to treat bacterial infections.

In another aspect, the invention resides in a packaged pharmaceutical composition for inhibiting the binding of chemokines to glycosaminoglycans comprising a container holding a therapeutically effective amount of a therapeutic preparation containing a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance; and instructions for using the therapeutic compound for inhibiting the binding of a chemokine to a glycosaminoglycan.

In yet another aspect, the invention relates to a method of making a therapeutic formulation comprising mixing a therapeutically effective amount of a therapeutic compound with a pharmaceutically acceptable carrier, wherein the therapeutic formulation is formulated to significantly reduce or prevent gastrointestinal intolerance.

In another aspect, the present invention relates to a pharmaceutical formulation comprising greater than 5% by weight of 3-amino-1-propanesulfonic acid.

In another aspect, the invention relates to a pharmaceutical formulation comprising a therapeutic compound and greater than 1% by weight of an additional agent.

In another aspect, the invention relates to a method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated with an enteric coating, whereby amyloid deposition is inhibited.

In another aspect, the invention relates to a method of inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated with an agent capable of improving the release of the therapeutic compound, thereby inhibiting amyloid deposition.

In addition, another aspect of the invention is a pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a therapeutic compound formulated with an enteric coating such that amyloid deposition is inhibited.

In another aspect, the invention relates to a pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a therapeutic compound formulated with an agent capable of improving the release of the therapeutic compound, thereby inhibiting amyloid deposition.

In another aspect, the present invention relates to a method of formulating a pharmaceutical composition with enhanced gastrointestinal intolerance comprising: admixing a preselected therapeutic compound with a pharmaceutically acceptable carrier, wherein the therapeutic compound's ability to significantly reduce or prevent gastrointestinal intolerance is preselected, thereby forming a gastrointestinal intolerance enhanced pharmaceutical composition.

In another aspect, the invention relates to a method of preventing or treating an amyloid-related disease in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated with an enteric coating, thereby preventing or treating the amyloid-related disease.

In another aspect, the invention relates to a method of preventing or treating an amyloid-related disease in a subject, comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated with an agent capable of improving the release of the therapeutic compound, thereby preventing or treating the amyloid-related disease.

In another aspect, the invention relates to a pharmaceutical composition for preventing or treating an amyloid-related disease in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound formulated with an enteric coating.

In a further aspect, the present invention relates to a pharmaceutical composition for preventing or treating an amyloid-related disease in a subject, comprising a therapeutic compound formulated with an agent capable of improving the release of the therapeutic compound.

Detailed description of the invention

The present invention relates to methods, compositions and formulations for treating amyloidosis. The methods of the invention comprise administering to the subject a therapeutic formulation comprising a therapeutic compound capable of inhibiting amyloid deposition. Thus, the invention relates inter alia to the use of a therapeutic agent (e.g. comprising an alkylsulfonic acid) in the prevention or treatment of amyloid-related diseases including, inter alia, alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, down's syndrome, mild cognitive impairment, and type II diabetes.

I. Amyloid related diseases

The present invention relates to the use of a pharmaceutical composition or formulation comprising a therapeutic compound in the treatment of amyloid-related diseases. Many amyloid-related diseases are known and certainly exist.

AA (reactive) amyloidosis

In general, AA amyloidosis is a clinical manifestation of many diseases that can provoke a sustained acute phase response. Such diseases include chronic inflammatory disorders, chronic local or systemic bacterial infections, and malignancies. The most common form of reactive or secondary (AA) amyloidosis is believed to be the result of a long-standing inflammatory condition. For example, patients with rheumatoid arthritis or familial mediterranean fever (a genetic disease) may develop AA amyloidosis. The terms "AA amyloidosis" and "secondary (AA) amyloidosis" are used interchangeably.

AA fibrils typically comprise 8000 daltons fragments formed by the proteolytic cleavage of serum amyloid A protein (ApoSAA), a circulating apolipoprotein that is synthesized predominantly in hepatocytes and is responsive to cytokines such as IL-1, IL-6, and TNF. Once secreted, ApoSAA complexes with HDL. The deposition of AA fibrils can be throughout the body and is preferably of soft tissue organs. The kidney is usually a site of deposition, and the liver and spleen may also be affected. Such deposits can also be found in the heart, gastrointestinal tract and skin.

Fundamental diseases that can lead to AA amyloidosis include, but are not limited to, inflammatory diseases such as rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, reiter's syndrome, adult stewart's disease, becker's syndrome, and crohn's disease. AA deposition may also be due to chronic bacterial infections, such as caused by leprosy, tuberculosis, bronchiectasis, bedsores, chronic pyelonephritis, osteomyelitis and hubert disease. Certain malignancies may also result in AA fibril amyloid deposition. This includes conditions such as hodgkin's lymphoma, renal malignancies, malignancies of the intestinal, pulmonary and genitourinary tracts, basal cell carcinoma of the skin and hairy cell leukemia. Other conditions that may be associated with AA amyloidosis are Castleman's disease and schnithler's syndrome.

AL amyloidosis (Primary amyloidosis)

AL amyloid deposition is commonly associated with dyscrasia of almost any B lymphocyte lineage, ranging from plasma cell malignancies (multiple myeloma) to benign monogammopathy. Sometimes, the presence of amyloid deposits may be a major indicator of fundamental fluid dyscrasia. Amyloidosis is described in detail in Current Drug Targets, 2004, 5159-.

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 base region (κ or λ) of the light chain and comprises its variable (V)_L) All or part of a zone. Deposition commonly occurs in interstitial tissue, resulting in peripheral and autonomic neuropathy, carpal tunnel syndrome, megaglossia, restrictive cardiomyopathy, arthropathy with major joints, immune dyscrasia, myeloma, and occult dyscrasia. However, it is noted that: almost all tissues, particularly visceral organs such as kidney, liver, spleen and heart, may be involved.

Hereditary systemic amyloidosis

There are many forms of hereditary systemic amyloidosis. Although a relatively rare condition, adult onset symptoms and their genetic patterns (often autosomal dominant) contribute to the persistence of the disease in many populations. Generally, this syndrome can be attributed to point mutations in genes in the precursor protein that result in the production of a protein-denatured genetic peptide or protein. Table 1 summarizes the fibrillar composition of exemplary forms of these diseases.

TABLE 1 fibrillar composition of exemplary amyloid-related diseases

TABLE 1 (continuation)

Data are from Tan SY, Pepys mb. amyloidosis. histopathlogy, 25(5), 403-. Bulletin of the World health organization 1993; 71: 10508; and Merlini et al, Clin Chem Lab Med 2001; 39(11): 1065-75.

The data of table 1 is exemplary and not limiting to the scope of the invention. For example, point mutations in genes of more than 40 independent transthyretin gene species have been described, all of which cause clinical forms similar to familial amyloid polyneuropathy.

Often, inherited amyloid diseases also occur occasionally, and both inherited and sporadic forms of the disease exhibit similar properties associated with amyloid. For example, the most common form of secondary AA amyloidosis occasionally occurs as a result of persistent inflammation and is not associated with familial mediterranean fever. The general discussion below regarding hereditary amyloid disorders may also apply to sporadic amyloidosis.

Transthyretin (TTR) is a 14 kilodalton protein, sometimes also referred to as prealbumin. It is produced by the liver and choroid plexus and functions in the transport of thyroid hormones and vitamin a. At least 50 variants of the protein, each characterized by a single amino acid change, are associated with various forms of familial amyloid polyneuropathy. For example, the substitution of leucine for proline at position 55 results in a particularly aggressive form of neuropathy; the substitution of methionine for leucine at position 111 caused severe heart disease in danish-type patients.

Amyloid deposits isolated from cardiac tissue of patients with systemic amyloidosis have shown that: the deposit is composed of a heterogeneous mixture of TTR and fragments thereof, collectively referred to as ATTR, the entire sequence of which has been characterized. ATTR fibril fractions can be extracted from such plaques and their structure and sequence determined according to methods known in the art (e.g., 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).

Persons having point mutations in the molecule apolipoprotein a1 (e.g., Glye → Arg26, Trpo → Arg50, Leu → Arg60) exhibit an amyloidosis ("ostyta type") characterized by deposition of the protein apolipoprotein AI or fragment thereof. These patients have low levels of High Density Lipoprotein (HDL) and have peripheral neuropathy or renal failure.

Mutations in the alpha chain of lysozyme (e.g., Ile → Thr56 or Asp → His57) are the basis of another auster lattice type of non-neurogenic, hereditary amyloid found in the uk family. Wherein fibrils of mutated lysozyme protein (Alys) are deposited and patients often show impaired renal function. Unlike most of the fibril forming proteins described herein, the proteins usually occur in an integral (unbroken) form (Benson, M.D., et al, CIBA Fdn. Symp.199: 104- "131, 1996).

Immunoglobulin light chains tend to form aggregates of various morphologies, including fibrillar morphology (e.g., AL amyloidosis and AH amyloidosis), granular morphology (light chain deposition disease (LCDD), Heavy Chain Deposition Disease (HCDD), and Light Heavy Chain Deposition Disease (LHCDD)), crystalline morphology (e.g., acquired Farconi syndrome), and microcatheter morphology (e.g., cryoglobulinemia). AL and AH amyloidosis is manifested by the formation of insoluble fibrils of immunoglobulin light and heavy chains, respectively, and/or fragments thereof. In AL fibrils, a greater concentration of λ chains, such as λ VI chains (λ 6 chains), is found than for κ chains. There was also a slight increase in the lambda III chain. Merlini et al, CLIN CHEM LABMED 39 (11): 1065-75 (2001).

Heavy chain Amyloidosis (AH) is generally characterized by aggregation of the heavy chain amyloid protein of the IgG1 subclass. Eulitz et al, PROC NATL ACAD SCI USA 87: 6542-46 (1990).

Comparison of amyloidogenic and non-amyloidogenic light chains has shown that: the former may include substitution or substitution groups that appear to destabilize the folding of the protein and promote aggregation. AL and LCDD differ significantly from other amyloid diseases in that they have a relatively small overall monoclonal light chain, or fragment thereof, formed by the tumor expansion of antibody-producing B cells. AL aggregates are usually ordered fibrils of the lambda chain. LCDD aggregation is a relatively disordered aggregation of both kappa and lambda chains, and is mostly kappa, and in some cases, predominantly kappa IV. Bellotti et al, JOURNAL OFSTRUCTURAL BIOLOGY 13: 280-89(2000). Comparison of amyloidogenic and non-amyloidogenic heavy chains in patients with AH amyloidosis has shown missing and/or altered components. Eulitz et al, PROC NATL ACAD SCI USA 87: 6542-46(1990) (pathogenic heavy chain characterized by a molecular mass significantly lower than that of the non-amyloidogenic heavy chain) and Solomon AMJHEMAT 45(2) 171-6 (1994) (amyloidogenic heavy chain characterized by comprising only the VH-D portion of the non-amyloidogenic heavy chain).

Thus, potential methods of detecting or monitoring patients suffering from or susceptible to AL, LCDD, AH, etc., include, but are not limited to, immunoassay of plasma or urine to detect the presence or inhibitory deposition of amyloidogenic light or heavy chains such as amyloid λ, amyloid κ IV, amyloid γ or amyloid γ 1.

Cerebral amyloidosis

The most frequent type of amyloid in the brain consists mainly of a β peptide fibrils, resulting in dementia associated with sporadic (non-hereditary) alzheimer's disease. In fact, the incidence of sporadic Alzheimer's disease is far greater than that of the forms indicated to be inherited. However, in both types the fibril peptide forming plaques are very similar. Cerebral amyloidosis includes diseases, conditions, pathologies, and other abnormalities of the structure or function of the brain, including its constituent parts, in which the pathogen is amyloid. The brain area affected in amyloid-related diseases may be the matrix comprising the vasculature, or the soft tissue comprising a functional or tissue region, or the neurons themselves. The patient need not receive a positive diagnosis of a specifically identified amyloid-related disease. The term "amyloid-associated disease" includes cerebral amyloidosis.

Amyloid- β peptide ("a β") is a 39-43 amino acid peptide derived from the proteolysis of a large protein known as β amyloid precursor protein ("β APP"). Mutations in β APP result in familial forms of alzheimer's disease, down's syndrome, cerebral amyloid angiopathy, and senile dementia, characterized by cerebral deposition of plaques composed of a β fibrils and other components as described in further detail below. Mutations in APP, known to be associated with Alzheimer's disease, occur near the cleavage site of the beta or gamma secretase, or within A β. For example, position 717 is near the site of gamma-secretase cleavage of APP in processing into a β, while position 670/671 is near the site of beta-secretase cleavage. Mutations in any of these residues may lead to alzheimer's disease, presumably by causing an increase in the amount of the 42/43 amino acid form of a β produced from APP. Familial forms of alzheimer's disease account for only 10% of the total number of patients. Most of the cases of Alzheimer's disease occur as sporadic cases, where APP and A β do not have any mutations. The structure and sequence of a β peptides of various lengths are known in the art. Such peptides can be made according to methods known in the art or extracted from the brain according to known methods (e.g., Glenner and Wong, biochem. biophysis. res. comm.129, 885-90 (1984.) furthermore, peptides can be obtained in various forms from commercial sources APP is expressed in most cells and undergoes constitutive catabolism the main catabolic pathway is via cleavage of the a β sequence by an APP, temporarily called α -secretase, resulting in the release of a soluble extracellular fragment known as APPs α. Science 286: 735-741, 1999) and presenilins have been shown to be associated with gamma-secretase activity (Desstrooper et al, Nature, 391, 387-90 (1998)). The 39-43 amino acid A beta peptide is produced by proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta and gamma secretase sequences. Although A β 40 is a predominant form produced, 5-7% of total A β is present as A β 42 (Cappi et al, int.J.biochem., Cell biol.31, 885-89 (1999)).

The length of the a β peptide appears to significantly alter its biochemical/physiological properties. Specifically, the other two at the C-terminus of a β 42 are highly hydrophilic, which may increase the tendency of a β 42 to aggregate. For example, Jarrett et al demonstrate that A β 42 aggregates very rapidly in vitro as compared to A β 40, suggesting that longer A β may be an important pathological protein involved in neurological plaques in Alzheimer's disease (Jarret et al, Biochemistry 32, 4693-97 (1993)); jarret et al Ann.N.Y.Acad.Sci.695, 144-48 (1993)). This hypothesis is further supported by recent analysis of the contribution of a β to a specific form in gene familial alzheimer's disease ("FAD"). For example, the "London" mutant form of APP linked to FAD (APP V7171) selectively increased production of A β 42/43 relative to A β 40 (Suzuki et al, Science, 264, 1336-40 (1994)), while the "Swedish" mutant form of APP (APPK670N/M671L) increased levels of A β 40 and A β 42/43 (Citron et al, Nature, 360, 672-674 (1992); cai et al, Science259, 514-16, (1993)). In addition, it has been observed that FAD-related mutations in the presenilin-1 ("PS-1") or presenilin-2 ("PS-2") genes will result in increased selectivity for A β 42/43 over A β 40 (Borchelt et al, Neuron 17, 1005-13 (1996)). This finding was further corroborated by the fact that: the selectivity of transgenic mouse models expressing PS mutants for brain A.beta.42 was improved (Borchelt, op cit.; Duff et al, neurogenesis 5(4), 293-98 (1996)). The hypothesis underlying the etiology of Alzheimer's disease is thus: an increase in brain concentration of a β 42 due to an increase in production or release of a β 42 or a decrease in clearance (degradation or brain clearance) is a cause of the pathology of the disease.

Multiple sites of mutations in a β or APP have been identified and clinically associated with dementia or cerebral hemorrhage. Exemplary CAA-associated disorders include, but are not limited to: icelandic hereditary cerebral hemorrhage with amyloidosis (HCHWA-I), the Dutch variety of HCHWA (HCHWA-D; mutations of A β); a verander mutation of a β; a north pole mutation of a β; italian mutation of a β; an alexan mutation of a β; hereditary dementia of british origin; and hereditary dementia in denmark. CAA may also be sporadic.

The terms "beta-amyloid" and "amyloid-beta" and the like as used herein, unless otherwise specified, refer to amyloid-beta 0 proteins or peptides, amyloid-beta 1 precursor proteins or peptides, intermediates, and modifications or fragments thereof. In particular, "A β 2" refers to any peptide produced by the APP gene product by a proteolytic process, particularly peptides associated with amyloid pathology, including a β 31-39, a β 1-40, a β 1-41, a β 1-42, and a β 1-43. For convenience of nomenclature, "A β 1-42" is referred to herein as "A β (1-42)" or simply "A β 42" or "A β₄₂"(and the same is true for any other amyloid peptide discussed herein). The terms "beta amyloid", "amyloid-beta" and "a β" are used herein as synonyms.

Unless otherwise specified, the term "amyloid" refers to amyloidogenic proteins, peptides, or fragments thereof, soluble (e.g., monomeric or oligomeric) or insoluble (e.g., having a fibrillar structure or in amyloid plaques). See, for example, MP Lambert et al, Proc. nat' l Acad. Sci. USA 95, 6448-53 (1998). "amyloidosis" or "amyloid disease" or "amyloid-related disease" refers to a pathological condition characterized by the presence of amyloid fibrils. Amyloid is a generic term that refers to a distinct but specific protein deposit (intracellular or extracellular) found in a number of different diseases. Despite their diverse forms, all amyloid deposits share common morphological characteristics, are stained with a dye (e.g., congo red), and are characterized by exhibiting red-green birefringence in polarized light after staining. They also have common superstructure characteristics or common X-ray diffraction and infrared spectra.

Gelsolin is a calcium binding protein that binds to fragments and actin microfilaments. Mutations at position 187 of the protein (e.g., Aspo → Asn; Asp → Tyr) result in inherited forms of systemic amyloidosis, which are common in Finnish patients as well as in the Netherlands and Japan. In individuals with disease, fibrils formed from gelsolin fragments (Agel) typically contain amino acids 173-243(68kDa carboxyl-terminal fragment) and are deposited in blood vessels and basement membranes, leading to corneal dystrophies and intracranial neuropathy which in turn develops peripheral neuropathy, dystrophic skin changes and deposition in other organs (Kangas, H., et al Human mol. Genet.5 (9): 1237-1243, 1996).

Other muteins, such as mutant alpha chains of fibrinogen (AfibA) and variant cystatin C (Acys), also fibrillate and produce characteristic genetic disorders. AfibA fibril formation is characterized by precipitation of nonneurogenic, hereditary amyloid with nephropathy; acy s precipitation is characterized by an inherited cerebral amyloid angiopathy reported in iceland (Isselbacher, Harrison's Principlesef Internal Medicine, McGraw-Hill, San Francisco, 1995; Benson et al). In at least some instances, patients with Cerebral Amyloid Angiopathy (CAA) have been shown to have amyloid fibrils comprising a non-mutant strain of cystatin C and amyloid beta protein (Nagai, A. et al, molecular. chem. neuropathohol.33: 63-78, 1998).

Some forms of prion Disease are now considered to be inherited, accounting for up to 15% of cases, and have previously been considered to be non-infectious in nature (Baldwin et al, inResearch Advances in Alzheimer's Disease and RelatideDisorders, John Wiley and Sons, New York, 1995). In both genetic and sporadic prion diseases, patients produce plaques consisting of abnormal isoforms of normal prion protein (PrPSc).

A predominant mutant isoform, PrP^ScAlso known as AScr, differ from normal cellular proteins in resistance to protease degradation, insolubility after detergent extraction, deposition in secondary lysosomes, post-translational synthesis, and high beta-pleated sheet content. At least 5 genetic associations of mutations leading to Alzheimer's disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS) and severe familial insomnia (FFI) have been established. (Baldwin, supra) methods for extracting fibrillar peptides from scrapie fibrils, determining sequences, and making such peptides are known in the art (e.g., Beekes, M. et al, J.Gen.Virol.76: 2567-76, 1995).

For example, one form of GSS is linked to a PrP mutation at codon 102, while the telencephalic GSS is isolated from the mutation at codon 117. Mutations at codons 198 and 217 result in a form of GSS in which neuritic plaques are characterized by Alzheimer's disease comprising PrP rather than A β peptide. Some forms of familial CJD have been associated with mutations at codons 200 and 210; mutations at codons 129 and 178 have been found in familial CJD and FFI (Baldwin, supra).

Cerebral amyloidosis

Local deposition of amyloid is common in the brain, particularly in older individuals. The most frequent type of amyloid in the brain consists mainly of one beta peptide fibril, which causes dementia or occasional (non-hereditary) alzheimer's disease. The most common cerebral amyloidosis occurs sporadically or familially. For example, sporadic Alzheimer's disease and sporadic CAA occur far more than familial AD and CAA. Furthermore, there is no way to distinguish between sporadic and familial forms of the disease (which differ only in the presence or absence of genetic mutations); for example, the amyloid plaques and clinical symptoms formed in sporadic and familial AD are very similar, if not identical.

Cerebral Amyloid Angiopathy (CAA) refers to the specific deposition of amyloid fibrils on the leptin ingeal and cortical arteries, arterioles and venous walls. It is commonly associated with Alzheimer's disease, Down's syndrome and natural aging, as well as various household conditions associated with stroke or dementia (see Frangione et al, analog: J. protein stabilizing disorder.8, suppl.1, 36-42 (2001)). CAA may be sporadic or genetic.

Systemic amyloidosis of the elderly

Systemic or focal amyloid deposition increases with age. For example, fibrils of wild-Type Transthyretin (TTR) are commonly found in heart tissue of older individuals. These may be asymptomatic, clinically silent, or may lead to heart failure. Asymptomatic fibrillar focal deposition may also occur in the brain (a β), prostate (β)₂Globular proteins), in the amyloids, joints and seminal vesicle.

Dialysis-related amyloidosis (DRA)

The development of beta is also commonly developed in patients undergoing prolonged hemodialysis or peritoneal dialysis₂Small globular proteins (. beta.)₂M) plaques consisting of fibrils. Beta is a₂The small globular protein is an 11.8 kilodalton polypeptide and is a light chain of class I MHC antigens present on all nucleated cells. In the usual case, beta unless renal function is impaired₂M is normally distributed in the intercellular space, when beta₂M is transported into the tissue where it polymerizes to form amyloid fibrils. Failure to clear (e.g., in the case of impaired renal function) results in deposition in the carpal tunnel and other sites, primarily in the collagen-rich tissue of the joint. Unlike other fibrillar proteins, beta₂The M molecules are not produced by the cleavage of longer precursor proteins and are usually present in the fibrils in unbroken form. (Benson, supra). This retention and accumulation of amyloid precursors has been shown to be the most fundamental major pathogenic process of DRAs. DRAs are characterized by osteoarthropathy in the peripheral joints (e.g., joint stiffness, stiffness,Pain, swelling, etc.). Beta in tissue₂Isoform of M, glycated beta₂M, or beta₂M is the most common amyloidogenic form (and native β)₂M is reversed). Unlike other types of amyloidosis, beta₂M is largely confined to the bone joint site. Visceral deposition is very rare. Sometimes, these deposits may involve blood vessels and other important anatomical sites.

Despite having means for removing beta₂Improved dialysis method for M, but plasma beta in most patients₂The M concentration is still significantly higher than normal. These increased beta₂M concentrations often lead to diabetes-associated amyloidosis (DRA) and to death of the cormrobities.

Amylin polypeptide and diabetes mellitus

Pancreatic islet clearing degeneration (amyloid deposition) was first described a century ago because fibrous protein aggregates were found in the pancreas of severely hyperglycemic patients (Opie, el., J exp. med., 5: 397-. Today, islet amyloid (mainly composed of islet amyloid polypeptide (IAPP)) or amylin is a characteristic histopathological marker for more than 90% of all type II diabetes (also known as non-insulin dependent diabetes mellitus, or NIDDM) pathologies. These fibrillar accumulations are due to islet amyloid polypeptide (IAPP) or amylin (a 37 amino acid polypeptide derived from a larger precursor peptide called pro-IAPP).

IAPP is co-secreted with insulin in response to beta cell secretagogues. These pathological features are not linked to insulin-dependent (type I) diabetes and are consistent features of multiple clinical manifestations diagnosed as NIDDM (type II diabetes).

Longitudinal studies in cats and immunocytochemical studies in monkeys have shown that: the progressive elevation of islet amyloid is associated with a dramatic decrease in insulin-secreting beta cells and increases the severity of the disease. In recent years, transgenic studies have demonstrated a relationship between IAPP plaque formation and β cell apoptosis and dysfunction, suggesting that: amyloid deposition is a major factor in increasing the severity of type II diabetes.

IAPP has also been shown to cause β -islet cytotoxicity in vitro, suggesting that the appearance of IAPP fibrils in the pancreas of type II or type I diabetic patients (post islet transplantation) leads to loss of β -cell islets (Langerhans) and organ dysfunction. In type II diabetic patients, accumulation of pancreatic IAPP leads to the formation of oligomeric IAPP, leading to increased deposition of IAPP-amyloid as insoluble fibers, which ultimately leads to destruction of insulin-producing cells of the islets of Langerhans, leading to the failure and invalidation of beta cells (Westermark, P., Grimelius, L., Acta Pats. 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). The accumulation of IAPP as a fibrous deposit also increases the proportion of pro-IAPP to IAPP commonly found in plasma due to trapping of I APP in the deposit. The reduction of beta cells can be demonstrated by hyperglycemia and insulinemia. This loss of beta cell mass may lead to the need for insulin therapy.

Diseases caused by the death or dysfunction of certain types of cells can be treated by transplanting the relevant types of healthy cells to the patient. This approach has been used for the treatment of type I diabetics. Typically, pancreatic islet cells from a donor are cultured in vitro prior to transplantation to restore or reduce their immunity from the isolation process. However, in many instances, islet cell transplantation is unsuccessful due to the death of the transplanted cells. One reason for the low success rate is IAPP, which constitutes a toxic oligomer. The toxic effects may be caused by the accumulation of intracellular or extracellular fibril oligomers. IAPP oligomers can fibrillate and become toxic to cells in vitro. In addition, IAPP fibrils may continue to grow after cell transplantation and cause cell death and dysfunction. This can occur even when 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 may also be used to prepare transplanted cells and tissues according to the methods described in International patent application (PCT) WO 01/003680.

The compounds of the invention may also stabilize the concentration ratio of pro-IAPP/IAPP, pro-insulin/insulin and C-peptide. Furthermore, as a biomarker of efficacy, the results of different tests (e.g. arginine-insulin secretion test, glucose tolerance test, insulin resistance and sensitivity test) can all be used as a marker for the reduction of beta cell mass and/or the accumulation of amyloid deposits. This drug may also be used with other drugs directed to insulin resistance, hepatic glucose production, and insulin secretion. Such compounds may prevent insulin therapy by maintaining beta cell function and may be used to maintain islet transplantation.

Hormone derived amyloidosis

Endocrine organs can contain amyloid deposits, particularly in elderly individuals. Hormone-secreting tumors may also contain hormone-derived amyloid plaques, the fibrils of which are composed of polypeptide hormones such as, for example, calcitonin (medullary thyroid carcinoma) and atrial natriuretic peptide (isolated atrial amyloidosis). These protein sequences and structures are known in the art.

Other amyloidosis

There are various other forms of amyloidosis, which often manifest as local deposits of amyloid protein. In general, these diseases are often the result of local production or metabolic deficiency of specific fibril precursors, or the propensity of specific tissues (e.g., joints) to fibril deposition. Examples of such spontaneous deposits include neoplastic AL amyloid, cutaneous amyloid, endocrine amyloid, and tumor-associated amyloid. Other amyloid-related diseases include those as set forth in table 1, such as Familial Amyloid Polyneuropathy (FAP), senile systemic amyloidosis, Tenosynovium, familial amyloidosis, ostomatosis, non-neurogenic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial creutzfeldt-jakob disease, Gerstmann-Straussler-Scheinker syndrome, hereditary spongiform encephalopathy, prion diseases, familial mediterranean fever, Muckle-Well syndrome, kidney disease, deafness, urticaria, limb pain, cardiomyopathy, skin deposits, multiple myeloma, benign monogammopathy, maculobuilineima, myeloma with amyloidosis, medullary thyroid cancer, isolated atrial amyloid, and diabetes.

The compounds of the present invention may be administered therapeutically or prophylactically to treat diseases associated with fibril formation, aggregation or deposition, regardless of clinical symptoms. The compounds of the present invention use mechanisms to improve amyloid-related disease processes, including but not limited to: reducing the rate of amyloid fibril formation or deposition; reducing the extent of amyloid deposition; inhibiting, reducing or preventing amyloid fibril formation; inhibition of amyloid-induced inflammation; increasing clearance of amyloid from the brain; or to protect cells from amyloid-induced (oligomeric or fibrillar) toxicity.

In one embodiment, the compounds/formulations 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 may be used to ameliorate amyloid- β related diseases using the following mechanism (this list is illustrative and not limiting): reducing the rate of amyloid- β fibril formation or deposition; reducing the extent of amyloid- β deposition; inhibit, reduce or prevent amyloid- β fibril formation; inhibiting neurodegeneration or cytotoxicity caused by amyloid-beta; inhibiting inflammation-induced amyloid- β; increasing clearance of amyloid- β from the brain; or promote more catabolism of a β.

The compounds of the invention may act after their entry into the brain (crossing the blood brain barrier) or peripherally, effectively controlling the deposition of amyloid- β. When acting peripherally, the compounds can alter the equilibrium of a β in the brain and plasma to facilitate its excretion from the brain. An increase in the excretion of a β from the brain will result in a decrease in brain concentrations of a β, thereby promoting a decrease in a β deposition. Furthermore, compounds that permeate the brain may control deposition by acting directly on brain a β, for example by keeping it in a non-fibrillar form or facilitating its clearance from the brain. The compound may slow APP treatment; increased degradation of a β fibrils can be by macrophages or by neuronal cells; or may reduce the production of a β by activated microglia. These compounds may also prevent the interaction of a β with cell surfaces in the brain, thus preventing neurotoxicity, neurodegeneration, or inflammation.

In a preferred embodiment, the method is also used to treat Alzheimer's disease (e.g., sporadic or familial AD). The method may also be used prophylactically or therapeutically to treat other clinical conditions of amyloid- β deposition, such as individuals with Down's syndrome, and patients with cerebral amyloid angiopathy ("CAA"), hereditary cerebral hemorrhage or early Alzheimer's disease.

In another embodiment, the method is used to treat mild cognitive impairment.

Mild cognitive impairment ("MCI") is a condition characterized by: the state with mild but measurable impairment in thinking skills is not necessarily linked to the presence of paralytic dementia. MCI usually, but not necessarily, leads to secondary alzheimer's disease.

In addition, abnormal accumulation of APP and amyloid- β proteins in muscle fibers has been shown to be pathologically associated with sporadic Inclusion Body Myositis (IBM) (Askanas, V.et al, (1996) Proc. Natl. Acad. Sci. USA 93: 1314-. Thus, the compounds of the present invention may be used prophylactically or therapeutically for the treatment of diseases in which amyloid- β protein is abnormally deposited at non-neurological sites, such as IBM by delivering the compounds to muscle fibers.

Furthermore, it has been demonstrated that a β is associated with abnormal extracellular deposition known as drusen, where it accumulates along the basal plane of the retinal pigment epithelium in individuals with age-related macular degeneration (ARMD). ARMD is a cause of irreversible vision loss in older individuals. It is believed that a β deposition may be an important component of local inflammatory events leading to atrophy of the retinal pigment epithelium, drusen formation, and the pathogenic cause of ARMD (Johnson et al, proc. natl. acad. sci. usa 99(18), 11830-5 (2002)).

In another embodiment, the present invention also relates to a method for treating or preventing an amyloid-related disease in a subject (preferably a human) comprising: administering to a subject a therapeutic amount of a compound according to the general formula below or a compound described in the specification, thereby reducing or inhibiting amyloid fibril formation or deposition, neurodegeneration, or cytotoxicity. In another embodiment, the invention relates to a method of treating or preventing an amyloid-related disease in a subject (preferably a human) comprising administering to the subject a therapeutic amount of a compound of the formula or otherwise described herein, thereby improving or stabilizing cognitive function, or preventing, slowing, or preventing further deterioration of cognitive function, in a patient suffering from cerebral amyloidosis (e.g., alzheimer's disease, down's syndrome, or cerebral amyloid angiopathy). These compounds may also improve the quality of daily life of these subjects.

The therapeutic compounds of the invention can treat amyloidosis associated with type II diabetes by, for example, stabilizing blood glucose, preventing or reducing loss of beta cell mass, reducing or preventing hyperglycemia due to loss of beta cell mass, and modulating (e.g., increasing or stabilizing) insulin production. The compounds of the invention may also stabilize the ratio of pre-IAPP/IAPP concentration.

The therapeutic compounds of the invention may also treat AA (secondary) amyloidosis and/or AL (primary) amyloidosis by stabilizing renal function, reducing proteinuria, increasing creatinine clearance rate (e.g., at least 50% or more or at least 100% or more), or by causing relief of chronic diarrhea, weight gain (e.g., 10% or more).

Process of the invention

In one embodiment, the invention includes a method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound described herein, thereby inhibiting amyloid deposition. Thus, in another embodiment, the invention relates to a method of treating or preventing an amyloid-related disease, such as an a β -related disease, in a subject comprising administering to the subject a therapeutic amount of a therapeutic formulation comprising a therapeutic compound of the invention

The formulations of the invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid- β fibril formation, aggregation or deposition. The formulations of the present invention may act to ameliorate the processes of amyloid- β related diseases using the following mechanism (this list is illustrative and not limiting): reducing the rate of amyloid- β fibril formation or deposition; reducing the extent of amyloid- β deposition; inhibiting, reducing or preventing amyloid- β fibril formation; inhibiting neurodegeneration or cytotoxicity caused by amyloid-beta; inhibiting inflammation-induced amyloid- β; or increase clearance of amyloid- β from the brain.

The formulations of the invention can effectively control amyloid- β deposition either after entry into the brain (after penetration of the cerebral vessel wall) or from the periphery. Without being bound by any theory, the compounds of the formulation of the present invention may alter the equilibrium of a β between brain and plasma when acting peripherally, thereby facilitating the clearance of a β from the brain. An increase in clearance of a β from the brain will result in a decrease in brain concentration of a β and thus contribute to a decrease in a β deposition. Alternatively, compounds of the formulations of the invention that permeate the brain may control deposition by acting directly on brain a β, for example by keeping it in a non-fibrillar form or promoting its clearance from the brain, or protecting cells from the toxic effects of a β. In another embodiment, the compound may also prevent amyloid protein in soluble form, or oligomeric form, or fibrillar form from binding or adhering to the cell surface and causing cell damage or poisoning.

In a particular embodiment, the method is used to treat Alzheimer's disease (e.g., sporadic or familial A β). The method may also be used prophylactically or therapeutically to treat clinical symptoms of amyloid- β deposition, for example, in subjects with Down syndrome and subjects with cerebral amyloid angiopathy ("CAA") or hereditary cerebral hemorrhage.

In certain embodiments, the therapeutic agents of the present invention are capable of inhibiting the interaction between amyloidogenic proteins and basement membrane components (e.g., glycoproteins or proteoglycans), thereby inhibiting amyloid deposition. The ability of the compounds of the invention to inhibit the interaction between an amyloidogenic protein and a glycoprotein or proteoglycan-containing basement membrane component can be determined by an in vitro binding assay, such as the mass spectrometry method described in this specification (example 5) or U.S. Pat. No. 5,164,295, which is incorporated herein by reference in its entirety.

The present invention relates to a method for inhibiting amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic formulation as described herein comprising a therapeutic compound comprising at least one sulfonate group covalently bonded to a substituted or unsubstituted aromatic or aliphatic molecule.

In yet another embodiment, the invention encompasses a method for inhibiting the binding of a chemokine to a glycosaminoglycan comprising administering a therapeutic preparation comprising a therapeutic compound described herein.

In yet another embodiment, the invention relates to a method of modulating the interaction between a bacterium and a glycosaminoglycan in a human comprising administering to the human a therapeutic preparation comprising a therapeutic compound described herein. Accordingly, the present invention relates to a method for treating a bacterial infection in a human comprising administering to the human a therapeutic formulation comprising a therapeutic compound of the present invention. In a particular embodiment, the invention relates to a method of treating a subject afflicted with chlamydia comprising administering to the subject a therapeutic formulation comprising a therapeutic compound described herein.

In another embodiment, the invention includes a method for modulating the interaction of a virus and a glycosaminoglycan in a subject comprising administering to the subject a therapeutic preparation comprising a therapeutic compound described herein. More generally, another embodiment of the invention is a method for treating a viral infection in a subject comprising administering to the subject a therapeutic formulation comprising a therapeutic compound of the invention. In a specific embodiment, the invention is a method of treating a subject suffering from HSV, comprising administering to the subject a therapeutic formulation comprising a therapeutic compound described herein.

In addition, a specific embodiment of the present invention is a method of reducing amyloid deposits in a subject having amyloid deposits, the method comprising administering to the subject an effective amount of a therapeutic formulation comprising a therapeutic compound described herein, thereby reducing amyloid deposits in the subject.

Another embodiment of the present invention relates to a method of preventing, treating or inhibiting cerebral amyloid angiopathy in a subject comprising administering to the subject a therapeutic formulation comprising a therapeutic compound of the present invention. Furthermore, the present invention includes a method for preventing, treating, or inhibiting cerebral amyloid vascular disease comprising contacting a blood vessel wall cell with a therapeutic formulation comprising a therapeutic compound of the present invention, thereby preventing, treating, or inhibiting cerebral amyloid vascular disease. Furthermore, the present invention includes a method for preventing, treating, or inhibiting cerebral amyloid vascular disease comprising contacting a blood vessel wall cell with a therapeutic compound of the therapeutic formulation of the present invention, thereby preventing, treating, or inhibiting cerebral amyloid vascular disease.

Said "inhibition of amyloid deposition" includes reducing, preventing or stopping amyloid formation, e.g. fibrillation, inhibiting or slowing further amyloid deposition in a subject suffering from amyloidosis (e.g. already carrying amyloid deposits), and reducing or reversing amyloid fibrillation or deposition in a subject with persistent amyloidosis. For example, the degree of amyloid deposition inhibition is predicted by immediate application, and lies within the following ranges, which include, for example: substantially completely eliminating or reducing amyloid deposition. Inhibition of amyloid deposition is determined relative to an untreated subject, or relative to a subject treated prior to treatment, or by clinically observable improvement in pancreatic function, stabilization of cognitive function, or reduction in further reduction of cognitive function (e.g., prevention, slowing, or progression of tissue disease), or improvement in parameters such as the concentration of a β or tau in CSF in diabetic patients, or cerebral amyloidosis patients (e.g., alzheimer's disease or cerebral amyloid angiopathy patients). In certain embodiments, amyloid deposition may be inhibited by, for example: inhibiting the interaction between amyloidogenic proteins and basement membrane components, increasing clearance of amyloid β from the brain, or inhibiting neurodegeneration or cytotoxicity due to amyloid (e.g., by soluble or insoluble amyloid proteins, e.g., fibrils, by amyloid deposition and/or amyloid β, as described herein), or protecting the brain from adverse effects of a β.

The term "basement membrane" refers to an extracellular matrix comprising glycoproteins and proteoglycans, which includes laminin, type IV collagen, plasmin aggregates, polyproteins, perlecan, and Heparan Sulfate Proteoglycans (HSPGs). In a particular example, amyloid deposition is inhibited by interfering with the interaction of amyloidogenic proteins and glycosaminoglycan sulfates (e.g., HSPGs). Glycosaminoglycan sulfates are known to be present in all types of amyloid (see Snow, A.D. et al, Lab. invest.56, 120-123 (1987)) and to simultaneously undergo amyloid deposition and HSPG deposition in animal models of amyloidosis (see Snow, A.D. et al, Lab. invest.56, 665-675 (1987)).

As used herein, "treating" a subject includes: for the purpose of treating, curing, or alleviating, altering, complementing, ameliorating, improving, or affecting the disease or condition, a symptom of the disease or condition, or a risk (or predisposition) of the disease or condition, administering or administering to a subject, a cell or tissue taken from a subject, who has, has symptoms of, or is at risk of (or susceptible to) an amyloid-related disease or condition. The term "treatment" refers to any indication of success in the treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter, such as a reduction, alleviation, attenuation of symptoms, or making the injury, pathology, or condition more tolerable to the subject; reducing the rate of degeneration or decline; so that the endpoint of degeneration is less debilitating; improving a physical or psychological condition of a subject; or, in some cases, prevent the onset of dementia. Treatment or amelioration of symptoms can be based on subjective or objective parameters, including: physical examination, mental assessment, or cognitive tests (e.g., CDR, MMSE, ADAS-Cog), or other tests known in the art. For example, the methods of the present invention successfully treat dementia in a subject by reducing the rate of or ameliorating the extent of cognitive decline.

In a specific example, the term "treating" includes maintaining the subject's CDR rating at its baseline rating or 0. In another specific example, the term "treating" includes reducing the "CDR" level of a subject by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more. In another embodiment, the term "treating" further includes reducing the rate of rise of the CDR level of the subject as compared to a historical control. In another specific example, the term includes decreasing the rate of increase of the CDR level of the subject to about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% of the rate of increase of the historical control or untreated control.

In another specific example, the term "treating" also includes maintaining the score of the subject in the MMSE. The term "treating" includes increasing the MMSB score of a subject by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points. The term also includes the rate of reduction of the MMSE score of a subject as compared to a historical control group. In another specific example, the term includes that the MMSE score of a subject can be reduced by about 5% or less, about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less of the historical control or untreated control.

In yet another specific example, the term "treating" further includes maintaining the subject's score in ADAS-Cog. The term "treating" includes reducing the subject's score in ADAS-Cog by about 1 point or more, about 2 points or more, about 3 points or more, about 4 points or more, about 5 points or more, about 7.5 points or more, about 10 points or more, about 12.5 points or more, about 15 points or more, about 17.5 points or more, about 20 points or more, or about 25 points or more. The term also includes the rate of increase in the ADAS-Cog score of a subject compared to a historical control. In another specific example, the term includes reducing the rate of increase of the ADAS-Cog scoring CDR rating of a subject to about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% of the rate of increase of the historical control or untreated control.

In another specific example, the term "treating", e.g., for AA or AL amyloidosis, includes an increase in serum creatinine clearance rate, e.g., an increase in creatinine clearance rate of 10% or more, 20% or more, 50% or more, 80% or more, 90% or more, 100% or more, 150% or more, 200% or more. The term "treating" also includes reducing Nephrotic Syndrome (NS). It also includes slowing chronic diarrhea and/or increasing body weight by 10% or more, 15% or more, or 20% or more.

Without wishing to be bound by theory, in some aspects, the pharmaceutical compositions of the present invention comprise a compound capable of preventing or inhibiting amyloid fibril formation in the brain or other vital organs (local effect) or throughout the body (systemic effect). The pharmaceutical compositions of the invention can effectively control amyloid deposition after they enter the brain (after penetrating the blood brain barrier) or from the periphery. When acting peripherally, the compounds of the pharmaceutical composition may alter the equilibrium of amyloidogenic peptides between the brain and plasma and facilitate the excretion of amyloidogenic peptides from the brain. It may also favor clearance (or catabolism) of amyloid (soluble) and then prevent amyloid fibril formation and deposition due to reduction of amyloid pools in specific organs (e.g., liver, spleen, pancreas, kidney, joints, brain, etc.). An increase in the excretion of amyloidogenic peptides from the brain will result in a decrease in brain concentration of amyloidogenic peptides and thus promote amyloidogenic peptide deposition. In particular, the agent can reduce the levels of amyloid peptides (e.g., CSF and a β 40 and a β 42 in plasma), or the agent can reduce the levels of amyloid peptides (e.g., a β 40 and a β 42 in CSF) and increase their levels in plasma. Alternatively, compounds that penetrate the brain may control deposition by acting directly on the cerebral amyloidogenic peptide, for example by keeping it in a non-fibrillar form or facilitating its clearance from the brain, by enhancing its degradation in the brain, or by protecting brain cells from the adverse effects of the amyloidogenic peptide. An agent may also cause a decrease in the concentration of amyloid protein (i.e., in a particular organ, the critical concentration required to trigger amyloid fibril formation or deposition is not obtained). In addition, the compounds described herein can inhibit or reduce the interaction of amyloid with cell surface components (e.g., glycosaminoglycan or proteoglycan-containing basement membrane components). The compounds may also prevent amyloid peptide binding or adhesion to the cell surface, a process known to cause cell damage or toxicity. Similarly, the compounds may block amyloid-induced cytotoxicity or microglia activation or amyloid-induced neurotoxicity, or inhibit amyloid-induced inflammation. The compound may also reduce the rate or amount of amyloid aggregation, fibril formation, or deposition, or the compound may reduce the extent of amyloid deposition. The above mechanism of action should not be considered as limiting the scope of the invention and the invention can be practiced without the above information.

The terms "substantially" or "significant" refer to a change or increase in an identifiable characteristic by a noticeable or measurable amount, or wherein the change would be a noticeable, measurable, or unacceptable effect, such as a detrimental effect. Likewise, the term "substantially reduces or prevents gastrointestinal intolerance" includes a noticeable or measurable reduction or prevention of gastrointestinal intolerance, i.e., as opposed to an unnoticeable or immeasurable reduction or prevention. For example, the number of nausea, vomit, and gastrointestinal related pain or prolonged discomfort can be used as a measure of the effect of a therapeutic formulation of the present invention on the reduction or prevention of gastrointestinal intolerance. Furthermore, the term "will significantly affect the ability of a therapeutic agent" means that the ability of the therapeutic agent is affected, but not affected in an unacceptable manner to the extent that the benefit is compromised, and thus does not significantly affect the ability of the therapeutic agent.

"modulation of amyloid deposition" includes the inhibition and enhancement of amyloid deposition or fibril formation as described above. Thus, the term "modulating" includes 1) preventing or arresting amyloid formation or accumulation, inhibiting or slowing further amyloid aggregation in a subject suffering from amyloidosis (e.g., already having amyloid aggregation), and reducing or reversing amyloid aggregation in a subject suffering from amyloidosis, and 2) increasing amyloid deposition, e.g., increasing the rate and amount of amyloid deposition in vivo or in vitro. Amyloid-enhancing compounds may be used in animal models of amyloidosis, for example, to cause the development of amyloid deposits in animals over a relatively short period of time or to increase amyloid deposits over a selected period of time. Amyloid-enhancing compounds may be used in screening assays for compounds that inhibit amyloidosis in vivo, for example, in animal models, cellular assays for amyloidosis and in vitro assays. Such compounds may be used, for example, in assays that provide faster or more sensitive compounds. Modulation of amyloid aggregation is measured relative to an untreated subject or relative to a subject prior to treatment.

The term "therapeutic agent" includes agents formulated to perform a predetermined therapeutic function (e.g., prevent, treat or inhibit amyloidosis) and to reduce or prevent gastrointestinal intolerance (i.e., nausea and vomiting). The reduction or prevention of gastrointestinal intolerance may, for example, depend on direct physical contact in the stomach or indirect central effects on the central nervous system.

In certain embodiments, the reduction or prevention of gastrointestinal intolerance is dependent at least on the therapeutic compound administered to the subject. In one embodiment, a therapeutic compound having one desirable therapeutic function is selected for inclusion in a therapeutic formulation based on its ability to reduce or prevent gastrointestinal intolerance. In certain embodiments, the compounds are modified to produce therapeutic compounds having a desired therapeutic function and the ability to reduce or prevent gastrointestinal intolerance. For example, the compounds may be structurally modified (e.g., by addition of suitable substituents or alteration of pharmaceutically acceptable counterions) or otherwise reformulated so that the compounds have desirable therapeutic functions and the ability to reduce or prevent gastrointestinal intolerance.

In certain additional embodiments, the reduction or prevention of gastrointestinal intolerance is independent of the therapeutic compound administered to the subject. For example, in one embodiment, the reduction or prevention of gastrointestinal intolerance is not dependent on a compound having the formula 3-amino-1-propanesulfonic acid ester/X, where X is a counterion, or forms an ester with the sulfonate, such as 3-amino-1-propanesulfonic acid or its sodium salt. In a particular embodiment of the invention, the reduction or prevention of gastrointestinal intolerance is dependent on additional agents, such as enteric coatings or modified release agents.

In another embodiment, at least one additional agent is included in the therapeutic formulation, wherein the additional agent is different from the therapeutic compound. In a particular embodiment, the additional agent imparts at least one desired property to the therapeutic formulation. In a particular embodiment, the desired property, at least in part, reduces or prevents gastrointestinal intolerance. Thus, in an additional embodiment, an additional agent may be used in the therapeutic formulation to reduce or prevent gastrointestinal intolerance, either alone or in combination with other methods of reducing or preventing intolerance. For example, the tablet may be enteric coated or may be, for example, a modified release agent to control any rapid release of the therapeutic compound in the stomach or intestine in order to protect against any possible gastrointestinal intolerance caused by the therapeutic formulation.

In one embodiment of the invention, the reduction or prevention of gastrointestinal intolerance may also be accomplished by reducing or preventing local discomfort resulting from high pH values resulting from dissolution of the therapeutic compound in the stomach after administration of the therapeutic compound. As another additional advantage of the therapeutic formulations of the present invention, the reduction of gastrointestinal intolerance may also result in improved compliance of the subject (e.g., patient) to whom the formulation is administered.

In another particular embodiment, the therapeutic compound of the invention is an alkylsulfonic acid. The term "alkylsulfonic acid" includes substituted or unsubstituted alkylsulfonic acids, and substituted or unsubstituted lower alkylsulfonic acids. Of note are amino-substituted compounds, and the present invention relates to substituted or unsubstituted amino-substituted alkylsulfonic acids, and substituted or unsubstituted amino-substituted lower alkylsulfonic acids, an example of which is 3-amino-1-propanesulfonic acid. It should also be noted that the term "alkylsulfonic acid" as used in this specification is to be interpreted as a synonym for "alkanesulfonic acid".

In certain embodiments, the present invention relates to a substituted or unsubstituted alkylsulfonic acid, substituted or unsubstituted alkylsulfuric acid, substituted or unsubstituted alkylthiosulfonic acid, substituted or unsubstituted alkylthiosulfuric acid, or an ester or amide thereof, including pharmaceutically acceptable salts thereof. For example, the present invention relates to a compound, i.e., a substituted or unsubstituted alkyl sulfonic acid, or an ester or amide thereof, including pharmaceutically acceptable salts thereof. In another embodiment, the present invention relates to a compound, i.e. a substituted or unsubstituted lower alkyl sulfonic acid, or an ester or amide thereof, including pharmaceutically acceptable salts thereof. Similarly, the present invention includes a compound, i.e., a (substituted-or unsubstituted-amino-) substituted alkylsulfonic acid, or an ester or amide thereof, including pharmaceutically acceptable salts thereof. In yet another embodiment, the compound is a (substituted-or unsubstituted-amino-) -substituted lower alkyl sulfonic acid, or an ester or amide thereof, including pharmaceutically acceptable salts thereof.

It has been demonstrated that: compositions of alkylsulfonic acids (including, for example, 3-amino-1-propanesulfonic acid and salts thereof) are useful for the treatment of amyloid beta-related diseases, including Alzheimer's disease and cerebral amyloid angiopathy. See WO 96/28187, WO 01/85093 and US5,840,294.

One group of examples of alkyl sulfonic acids has the following structure

Wherein Y is amino (having the formula-NR)^aR^bWherein R is^aAnd R^bEach independently is hydrogen, alkyl, aryl or heterocyclyl, or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a cyclic residue having 3 to 8 atoms in the ring) or a sulfonic acid group (having the formula-SO)₃ ^-X⁺) N is an integer of 1 to 5, and X is hydrogen or a cation (e.g., sodium). Some exemplary alkyl sulfonic acids include the following compounds:

in some cases, the alkylsulfonic acid is a "small molecule," i.e., a product that is not itself a product of gene transcription or translation (e.g., protein, ribonucleic acid, or DNA) and has a relatively low molecular weight, e.g., less than about 2500. In other cases, the compound may be a biological product, such as an antibody or an immunopeptide.

Alkyl sulfonic acids can be prepared by, for example, the general reaction scheme described in the following references: US5,643,562; US5,972,328; US5,728,375; US5,840,294; US 4,657,704; and U.S. patent provisional application No. 60/482,058 (application No. 6/23/2003, attorney docket No. NBI-156-1), U.S. patent provisional application No. 60/512,135 (application No. 10/17/2003, attorney docket No. NBI-156-2), all entitled "synthetic methods for preparing Compounds for treating amyloidosis," and U.S. patent application Nos. 10/__, __, No. (application No. 6/18/2004, attorney docket No. NBI-156, entitled "improved drug candidates and methods for their preparation," the contents of which are incorporated herein by reference in their entirety, or by modification of their methods, using readily available starting materials, reagents, and conventional synthetic methods Simple modifications of one or more substituents that do not adversely affect the essential properties or utility of the compound) can be prepared by a variety of methods known in the art.

In general, the compounds of the present invention may be synthesized by, for example, methods in the general reaction schemes described below, or by modifying them, for example, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to use variants which are known per se and are not mentioned here. Functional and structural equivalents to the compounds described herein that have the same general properties, in which one or more substituents are subject to simple change without adversely affecting the essential properties or the utility of the compound. The reagents of the invention can be readily prepared according to the synthetic routes and schemes described herein, as shown in the specific steps provided. However, one skilled in the art will recognize that: other synthetic routes for forming the reagents of the invention may be used and are provided below by way of example only and not as a limitation of the invention. See, for example, "comprehensive organic transformations", r.larock, VCH press (1989). It will further be appreciated that various protection or deprotection strategies are common practice in the art (see, e.g., "Protective Groups in Organic Synthesis", Greene and Wuts). One skilled in the relevant art will recognize that the choice of any particular protecting group (e.g., amine and carboxyl protecting groups) will depend on the stability of the protecting residue under the subsequent reaction conditions and will understand the appropriate choice. Further elucidation of the knowledge of the person skilled in the art is selected from the following large chemical literature: "Chemistry of the amino acids", J.P.Greenstein and M.Winitiz, John Wiley & Sons, Inc., New York (1961); "Comprehensive organic transformations", R.Larock, VCH publishers (1989); t.d. ocain et al, j.med. chem, 31, 2193-99 (1988); E.M. Gordon et al, J.Med.chem.31, 2199-10 (1988); "Practice of Peptide Synthesis", M.Bodansky and A.Bodansky, Springer-Verlag, New York (1984); "Protective Groups in Organic Synthesis", T.Greene and P.Wuts (1991); "Asymmetric Synthesis: construction of chiral molecules Using amino acids ", G.M.Coppola and H.F.Schuster, John Wiley & Sons, Inc., New York (1987); "The chemical Synthesis of Peptides", J.Jones, Oxford University Press, New York (1991); and "Introduction of Peptide Chemistry", p.d. bailey, John Wiley & Sons, inc., New York (1992).

The chemical structures are drawn here according to the standard usual in the art. Thus, when a drawn atom, such as a carbon atom, appears to have an unsaturated valence bond, that valence bond is considered satisfied by a hydrogen atom, even though the hydrogen atom is not necessarily explicitly drawn. The structure of some of the compounds of the present invention includes a stereogenic carbon atom. It should be understood that: unless otherwise indicated, such asymmetrically occurring isomers (e.g., all enantiomers or diastereomers) are also included within the scope of the present invention. That is, any chiral carbon center can be either the stereochemistry of (R) -or (S) -unless otherwise specified. This isomer can be obtained in substantially pure form by classical separation processes as well as by stereochemically controlled synthesis.

Furthermore, where appropriate, the olefins may include E-or Z-isomers. In addition, the compounds of the present invention may exist in unsolvated forms, solvated forms with acceptable solvents (e.g., water, THF, ethanol, etc.), and polymorphic forms (e.g., including pseudopolymorphic forms). The term "solvate" means an aggregate of molecules comprising one or more compounds and one or more drug solvents (e.g., water, ethanol, etc.).

Other examples of compounds that may be used as compounds of the present invention include those described in the following references: U.S. patent provisional application Nos. 60/480,906 (application No. 6/23/2003, attorney docket No. NBI-162-1) and 60/512,047 (application No. 10/17/2003, attorney docket No. NBI-162-2), 10/__, __ (application No. 6/18/2004, attorney docket No. NBI-162A) and 10/__, __ (application No. 6/18/2004, attorney docket No. NBI-162B), all entitled "compositions and methods for treating amyloid-related diseases"; and U.S. patent provisional application No. 60/480,928 (application No. 6/23/2003, attorney docket No. NBI-163-1), U.S. patent provisional application No. 60/512,018 (application No. 10/17/2003, attorney docket No. NBI-163-2), U.S. patent application No. 10/__, __ (application No. 6/18/2004, attorney docket No. NBI-163), all entitled "compositions and methods for treating amyloid-related and epilieptogenetics-related diseases".

In one embodiment, the invention relates, at least in part, to a composition having a therapeutic compound (i.e., a compound having formula I-a):

wherein

R¹Is a substituted or unsubstituted cycloalkyl, aryl, arylcycloalkyl, bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C₂-C₁₀An alkyl group;

R²selected from the group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzimidazolyl;

y is SO₃ ^-X⁺、OSO₃ ^-X⁺Or SSO₃ ^-X⁺；

X⁺Is hydrogen, a cationic group, or an ester-forming group (i.e., as a prodrug);

and L is¹And L²Independently is substituted or unsubstituted C₁-C₅Alkyl or is absent, or a pharmaceutically acceptable salt thereof, with the proviso that when R is¹When it is an alkyl group, L¹Is absent.

In another embodiment, the invention relates, at least in part, to a composition having a therapeutic compound (i.e., a compound having formula II-a):

wherein:

R¹is a substituted or unsubstituted ring, bicyclic, tricyclic, or benzo-heterocycle or a substituted or unsubstituted C₂-C₁₀An alkyl group.

R²Is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl or benzimidazolyl, or with R¹Are linked to form a heterocyclic ring;

y is SO₃ ^-X⁺、OSO₃ ^-X⁺Or SSO₃ ^-X⁺；

X⁺Is hydrogen, a cationic group, or an ester-forming residue;

m is 0 or 1;

n is 1, 2,3 or 4;

l is substituted or unsubstituted C₁-C₃Alkyl or is absent, or a pharmaceutically acceptable salt thereof, with the proviso that when R is¹In the case of alkyl, L is absent. In a particular embodiment, n is 3 or 4.

In yet another embodiment, the invention relates, at least in part, to a composition having a therapeutic compound (i.e., a compound having formula III-a):

wherein:

a is nitrogen or oxygen;

R¹¹is hydrogen, a salt-forming cation, an ester-forming group, - (CH2)_x-Q, or when a is nitrogen, a and R11 together form a natural or non-natural amino acid residue or a salt or ester thereof;

q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzimidazolyl;

x is 0, 1, 2,3 or 4;

n is 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

R³、R^3a、R⁴、R^4a、R⁵、R^5a、R⁶、R^6a、R⁷and R^7aEach independently is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms and ring atoms together form a double bond. In a particular embodiment, n is 3 or 4. In some embodimentsIn, R³、R^3a、R⁴、R^4a、R⁵、R^5a、R⁶、R^6a、R⁷And R^7aOne is a residue of formula IIIa-A:

wherein:

m is 0, 1, 2,3 or 4;

R^A、R^B、R^C、R^Dand R^EIndependently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzimidazolyl; and pharmaceutically acceptable salts and esters thereof. In certain embodiments, the compound is not 3- (4-phenyl-1, 2,3, 6-tetrahydro-1-pyridinyl) -1-propanesulfonic acid.

An ester-forming group or residue includes groups that, when combined, are capable of forming an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl or cycloalkyl groups. Particular examples of possible esters include methyl, ethyl and tert-butyl. In addition, examples of salt-forming cations include pharmaceutically acceptable salts as described in the specification, and lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In another embodiment, the salt-forming cation is a sodium salt.

In yet another embodiment, the present invention is directed, at least in part, to a composition having a therapeutic compound (i.e., a compound having formula IV):

wherein:

a is nitrogen or oxygen;

x is 0, 1, 2,3 or 4;

n is 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

R⁴、R^4a、R⁵、R^5a、R⁶、R^6a、R⁷and R^7aEach independently is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, arylalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R⁴And R⁵Together with the carbon atom to which they are attached form a double bond, or R⁶And R⁷And the carbon atoms to which they are attached together form a double bond;

m is 0, 1, 2,3 or 4;

R⁸、R⁹、R¹⁰、R¹¹and R¹²Independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzimidazolyl, and pharmaceutically acceptable salts and esters thereof. In a particular embodiment, n is 3 or 4.

In another embodiment, the invention relates, at least in part, to a composition having a therapeutic compound (i.e., a compound having the formula V-a):

wherein:

a is nitrogen or oxygen;

x is 0, 1, 2,3 or 4;

n is 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

aa is a natural or non-natural amino acid residue;

m is 0, 1, 2 or 3;

R¹⁴as hydrogen or a protecting group;

R¹⁵hydrogen, alkyl or aryl, and pharmaceutically acceptable salts and prodrugs thereof, in one particular embodiment n is 3 or 4.

In another embodiment, the invention relates, at least in part, to a composition having a therapeutic compound (i.e., a compound having formula V I-a):

wherein:

n is 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

a is nitrogen or oxygen;

R¹¹is hydrogen, a salt-forming cation, an ester-forming group, - (CH2)_x-Q, or when a is nitrogen, a and R11 together form naturalOr a salt or ester thereof;

x is 0, 1, 2,3 or 4;

R¹⁹is hydrogen, alkyl or aryl;

Y¹is oxygen, sulfur, or nitrogen;

Y²is carbon, nitrogen, or oxygen;

R²⁰is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzimidazolyl;

R²¹is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzimidazolyl; or if Y is²Oxygen, then absent;

R²²is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzimidazolyl; or if Y is¹Is nitrogen, then R²²Is hydrogen, hydroxy, alkoxy or aryloxy; if Y is¹Is oxygen or sulfur, then R²²Is absent; or if Y is¹Is nitrogen, R²²And R²¹Joined to form a cyclic residue;

or a pharmaceutically acceptable salt thereof. In a particular embodiment, n is 3 or 4.

In another embodiment, the invention relates, at least in part, to a composition having a therapeutic compound (i.e., a compound having formula VII-a):

wherein:

n is 2,3, or 4;

a is nitrogen or oxygen;

x is 0, 1, 2,3 or 4;

g is a direct bond or oxygen, nitrogen, or sulfur;

z is 0, 1, 2,3, 4 or 5;

m is 0 or 1;

R²⁴selected from the group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, aralkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzimidazolyl;

each R is²⁵Independently selected from hydrogen, halogen, cyano, hydroxy, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclyl, or heterocyclyl, and pharmaceutically acceptable salts thereof. In a particular embodiment, n is 3 or 4.

Additional compounds include, for example, therapeutic compounds of formula (II-B):

wherein:

x is oxygen or nitrogen;

z is C as O, S (O)₂OR P (O) OR⁷；

m and n are each independently 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

R¹and R⁷Each independently hydrogen, metal ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, a residue which together with X forms a natural or non-natural amino acid residue, or- (CH)₂)_p-Y；

Y is hydrogen or a heterocyclic group selected from thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl and benzimidazolyl;

p is 0, 1, 2,3 or 4;

R²each independently is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;

R³independently selected from the group consisting of hydrogen, amino, cyano, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, substituted or unsubstituted aryl, heteroaryl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzimidazolyl, and pharmaceutically acceptable salts, esters, and prodrugs thereof.

In another embodiment, m is 0, 1 or 2. In another embodiment, n is 0, 1 or 2, e.g., 1 or 2. In another embodiment, R³Is aryl, heteroaryl or phenyl. In another embodiment, Z is S (O)₂。

In another embodiment, the therapeutic compound of the present invention has formula (II-B)

Wherein:

x is oxygen or nitrogen;

m and n are each independently 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

R¹is hydrogen, a metal ion, an alkyl group, a mercaptoalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a residue which forms a natural or unnatural amino acid residue together with X, or- (CH)₂)_p-Y；

each R is⁴Independently selected from hydrogen, halogen, hydroxyl, thiol, amino, cyano, nitro, alkyl, aryl, carboxyl or heterocyclyl;

j is absent, or is oxygen, nitrogen, sulfur, or a divalent residue including, but not limited to, lower alkylene, alkyleneoxy, alkyleneamino, alkylenethio, alkyleneoxyalkyl, alkyleneaminoalkyl, alkylenethioalkyl, alkenyl, alkenyloxy, alkenylamino, or alkenylthio; and

q is 1, 2,3, 4 or 5, and pharmaceutically acceptable salts and prodrugs thereof. In a particular embodiment, n is 1 or 2.

In yet another embodiment, the therapeutic compound of the present invention is a compound of formula (III-B):

wherein:

x is oxygen or nitrogen;

m and n are each independently 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

q is 1, 2,3, 4 or 5;

p is 0, 1, 2,3 or 4;

R²is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;

R⁵selected from the group consisting of hydrogen, halogen, amino, nitro, hydroxyl, carbonyl, thiol, carboxyl, alkyl, alkoxy, alkoxycarbonyl, acyl, alkylamino, and acylamino;

j is absent, or is oxygen, nitrogen, sulfur, or a divalent residue including, but not limited to, lower alkylene, alkyleneoxy, alkyleneamino, alkylenethio, alkyleneoxyalkyl, alkyleneaminoalkyl, alkylenethioalkyl, alkenyl, alkenyloxy, alkenylamino, or alkenylthio; and pharmaceutically acceptable salts, esters, and prodrugs thereof. In a particular embodiment, n is 1 or 2.

In yet another embodiment, the therapeutic compound of the invention is:

wherein:

x is oxygen or nitrogen;

m and n are each independently 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

q is 1, 2,3, 4 or 5;

p is 0, 1, 2,3 or 4;

R⁵selected from the group consisting of hydrogen, halogen, amino, nitro, hydroxyl, carbonyl, thiol, carboxyl, alkyl, alkoxy, alkoxycarbonyl, acyl, alkylamino, and acylamino; and

pharmaceutically acceptable salts, esters, and prodrugs thereof. In another embodiment, m is 0. In a particular embodiment, n is 1 or 2.

In another embodiment, the invention relates to a therapeutic compound of formula (V-B):

wherein:

z is C as O, S (O)₂OR P (O) OR⁷；

m and n are each independently 0, 1, 2,3, 4,5, 6, 7, 8, 9 or 10;

R²is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl; and is

R⁶Is a substituted or unsubstituted heterocyclyl residue. In another embodiment, m is 0 or 1. In another embodiment, n is 0 or 1. In another embodiment, R⁶Is thiazolyl,Azolyl, pyrazolyl, indolyl, pyridyl, thiazinyl, thienyl, benzothienyl, dihydroimidazolyl, dihydrothiazolyl, thiazolyl, indolyl, pyridyl, thienyl, and the like,Oxazolinyl, thiazolinyl, tetrahydropyrimidinyl, orAn oxazine group. In yet another embodiment, Z is S (O)₂. In a particular embodiment, n is 1 or 2.

In certain embodiments of the invention, the therapeutic formulation of the invention may further comprise a pharmaceutically acceptable inactive ingredient and a therapeutic compound having the formula 3-amino-1-propanesulfonate/X (wherein X is a counterion or forms an ester with a sulfonate), wherein the ester or counterion comprises an alcohol group or a positively charged atom or residue, respectively, that does not significantly affect the ability of the therapeutic formulation to reduce or prevent gastrointestinal intolerance. In a preferred embodiment, the cationic group is hydrogen (H) and the compound is 3-amino-1-propanesulfonic acid. In certain other embodiments, the hydrogen is substituted with a pharmaceutically acceptable cation or an alcohol group or equivalent thereof, and the compound is a salt or ester of the acid.

Pharmaceutically acceptable salts or esters of the therapeutic compounds within the scope of the present invention do not significantly affect the ability of the therapeutic formulation to reduce or prevent gastrointestinal intolerance. For example, the cation may be a pharmaceutically acceptable alkali metal, alkaline earth metal, higher valent ion (e.g., aluminum ion), polycationic counterion, or ammonium, and the alcohol group may be a pharmaceutically acceptable alcohol group. In a particular embodiment, the pharmaceutically acceptable salt is a sodium salt, however, other salts are contemplated within their pharmaceutically acceptable range.

In general, therapeutic compounds suitable for use in the therapeutic formulations of the present invention include at least one sulfonate group covalently bonded to a substituted or unsubstituted aryl or aliphatic group.

In another embodiment, the therapeutic compound has at least one sulfonate group covalently bonded to a substituted or unsubstituted aliphatic group. In a similar embodiment, the therapeutic compound has at least two sulfonate groups covalently bonded to a substituted or unsubstituted aliphatic group. In another embodiment, the therapeutic compound has at least one sulfonate group covalently bonded to a substituted or unsubstituted lower alkyl group. In similar embodiments, the therapeutic compound has at least two sulfonate groups covalently bonded to a substituted or unsubstituted lower alkyl group.

In yet another embodiment, the therapeutic compound has at least one sulfonate group covalently bonded to an amino-substituted aliphatic group. In a similar embodiment, the therapeutic compound has at least two sulfonate groups covalently bonded to an amino-substituted aliphatic group. In yet another embodiment, the therapeutic compound has at least one amino-substituted lower alkyl covalently bonded sulfonate group. In similar embodiments, the therapeutic compound has at least two sulfonate groups covalently bonded to an amino-substituted lower alkyl group.

As used herein, a "sulfonate group" is a-SO group bound to a carbon atom₃-H or-SO₃X group, wherein X is a cationic group or an ester group. Similarly, a "sulfonic acid" has one SO bound to a carbon atom₃And (4) an H group. As used herein, a "sulfate ester" has one-O-H or-OX group bound to a carbon atom, where X is a cationic group or an ester group. And the "sulfuric acid" compound has one-OH group bonded to a carbon atom. According to the invention, suitable cationic groups may be hydrogen atoms. In some cases, the cationic group may be a group on the therapeutic compound that is actually electropositive at physiological pH, such as an amino group.

Such compounds containing a cationic group covalently bound to the therapeutic compound itself are referred to as "internal salts" or "zwitterions". For example, the compound 3-amino-1-propanesulfonic acid may be formed from an internal salt or zwitterion under suitable conditions.

Unless otherwise defined, chemical residues herein may be substituted or unsubstituted. In some embodiments, the term "substituted" means that the residue has a substituent, other than hydrogen, on the residue that allows the molecule to perform its intended function. Non-limiting examples of substituents are selected from the following residues: straight or branched alkyl (preferably C)₁-C₅) Cycloalkyl (preferably C)₃-C₈) Alkoxy (preferably C)₁-C₆) Thioalkyl (preferably C)₁-C₆) Alkenyl (preferably C)₂-C₆) Alkynyl (preferably C)₂-C₆) Heterocyclyl, carbocyclyl, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl(e.g., benzyl), aryloxyalkyl (e.g., phenoxyalkyl), arylacetamido, alkylaryl, heteroarylalkyl, alkylcarbonyl and arylcarbonyl groups or other such acyl, heteroarylcarbonyl, or heteroaryl groups, (CR 'R')_0-3NR 'R' (e.g., -NH)₂)、(CR’R”)_0-3CN (e.g., -CN), -NO₂Halogen (e.g., -F, -Cl, -Br or-I), (CR 'R')_0-3C (halogen)₃(e.g., -CF)₃)、(CR’R”)_0-3CH (halogen)₂、(CR’R”)_0-3CH₂(halogen), (CR 'R')_0-3CONR’R”、(CR’R”)_0-3(CNH)NR’R”，(CR’R”)_0-3S(O)_1-2NR’R”、(CR’R”)_0-3CHO、(CR’R”)_0-3(CR’R”)_0-3H、(CR’R”)_0-3S(O)_0-3R' (e.g., -SO)₃H、-OSO₃H)、(CR’R”)_0-3O(CR’R”)_0-3H (e.g., -CH)₂OCH₃and-OCH₃)、(CR’R”)_0-3S(CR’R”)_0-3H (e.g., -SH and-SCH)₃)、(CR’R”)_0-3OH (e.g., -OH), (CR' R ")_0-3COR’、(CR’R”)_0-3(substituted or unsubstituted phenyl), (CR 'R')_0-3(C₃-C₈Cycloalkyl), (CR 'R')_0-3CO₂R' (e.g., -CO)₂H) Or (CR 'R')_0-3An OR' group, OR the side chain of an amino acid of any natural origin; wherein R 'and R' are each independently hydrogen, C₁-C₅Alkyl radical, C₂-C₅Alkenyl radical, C₂-C₅Alkynyl groups, and aryl groups. "substituents" may also include, for example, halogen, carboxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and diarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, aminomethaneAcyl and ureido), imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, aralkyl, and aryl or heteroaryl residues.

It is understood that "substituted" and "substituted" include the implicit premise that such substitution is consistent with the allowed valences of the substituted atom or substituent, and that the substitution results in a stable compound that, for example, does not spontaneously transform by rearrangement, cyclization, elimination, and the like. As used herein, "substituted" includes all permissible substituents of organic compounds. In a broader aspect, the permissible substituents include aliphatic and cyclic, straight and branched carbocyclic and heterocyclic radicals, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more of the same or different for suitable organic compounds.

In certain embodiments, one substituent may be selected from, for example: halogen, trifluoromethyl, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkylcarbonyloxy, arylcarbonyloxy, C₁-C₆Alkoxycarbonyloxy, aryloxycarbonyloxy, C₁-C₆Alkylcarbonyl group, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, arylthio, heterocyclyl, aralkyl, and aryl (including heteroaryl).

In general, the therapeutic compounds of the present invention are small molecules. By "small molecule" is meant that the compound itself is not the product of gene transcription or translation (e.g., protein, RNA, or DNA). Preferably "small molecule" means a low molecular weight compound, for example less than 7500 atomic mass units, more preferably less than 5000 atomic mass units, more preferably less than 1000 atomic mass units.

The terms used in the specification"amine" or "amino" refers to a substituted or unsubstituted compound of formula-NR^aR^bWherein R is^aAnd R^bEach independently is hydrogen, alkyl, aryl, or heterocyclyl, R^aAnd R^bTogether with the nitrogen atom to which they are attached form a cyclic residue having 3 to 8 atoms in the ring. Thus, unless otherwise indicated, the term "amino" includes cyclic amino residues, such as piperidinyl or pyrrolidinyl. Thus, the term "alkylamino" as used in this specification denotes an alkyl group having an amino group attached thereto. Suitable alkylamino groups are those having from 1 to about 12 carbon atoms, for example from 1 to about 6 carbon atoms. The term "amino" includes compounds or residues in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "dialkylamino" includes groups in which the nitrogen atom is attached to at least two alkyl groups. The terms "arylamino" and "diarylamino" include nitrogens in which the nitrogen atom is attached to at least 1 or 2 aryl groups, respectively. The term "alkylarylamino" refers to an amino group attached to at least one alkyl group or at least one aryl group. The term "alkylaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group substituted with an alkylamino group. The term "amide" or "aminocarbonyl" includes compounds or residues in which one nitrogen atom is attached to the carbon of a carbonyl or thiocarbonyl group.

The term "aliphatic radical" includes straight or branched chain organic compounds characterized by having 1 to 22 carbon atoms. Aliphatic groups include alkyl, alkenyl, and alkynyl groups. The chains may be branched or cross-linked. Alkyl includes saturated hydrocarbons having one or more carbon atoms, including straight chain alkyl and branched chain alkyl. The term "alicyclic group" includes a closed ring structure of three or more carbon atoms.

Alicyclic groups include cycloalkanes or naphthalenes which are saturated cyclic hydrocarbons, unsaturated cycloalkenes having two or more double bonds, and cyclic acetylenes having one triple bond. They do not include aromatic groups. Examples of cycloalkanes include cyclopropane, cyclohexane, and cyclopentane. Examples of the cyclic olefins include cyclopentadiene and cyclooctatetraene. Alicyclic groups also include polycyclic rings, e.g., fused ring structures, and substituted alicyclic groups, e.g., alkyl-substituted alicyclic groups. Polycyclic or polycyclic groups include two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl) in which one or more carbons are common to two adjoining rings, e.g., the rings are fused or spiro rings. Rings that are connected by non-adjacent atoms are referred to as "bridged rings".

As used herein, "alkyl" includes saturated hydrocarbon groups having one or more carbon atoms, straight-chain alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Cycloalkyl (or "cycloalkyl" or "alicyclic" or "carbocyclyl"), for example, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Branched alkyl groups such as isopropyl tert-butyl, sec-butyl, isobutyl, etc.; alkyl-substituted alkyl groups, such as alkyl-substituted cycloalkyl and cycloalkyl-substituted alkyl.

Thus, the present invention relates to, for example, substituted or unsubstituted alkyl sulfonic acids, i.e., substituted or unsubstituted linear alkyl sulfonic acids, substituted or unsubstituted cycloalkyl sulfonic acids, and substituted or unsubstituted branched alkyl sulfonic acids.

In certain embodiments, a straight or branched chain alkyl group may have 30 or fewer carbon atoms in the backbone, e.g., C for straight chain₁-C₃₀And for the side chain C₃-C₃₀. In certain embodiments, a straight or branched chain alkyl group may have 20 or fewer carbon atoms in its backbone, e.g., C for straight chain₁-C₂₀Or for the branch C₃-C₂₀And, more particularly, for example, 18 or less carbon atoms.

In addition, examples of the cycloalkyl group have 4 to 10 carbon atoms in their cyclic structure, for example, 4 to 7 carbon atoms in the cyclic structure.

The term "lower alkyl" refers to alkyl groups having 1 to 8 carbon atoms in the chain, and cycloalkyl groups having 3 to 8 carbon atoms in the ring structure. "lower" in "lower alkyl" means that the residue has at least 1 and less than 8 carbon atoms, unless the number of carbon atoms is otherwise indicated. In certain embodiments, the linear or branched lower alkyl group has 6 or fewer carbon atoms in its backbone (e.g., C for linear₁-C₆For branched chain C₃-C₆) For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, the cycloalkyl group can have 3 to 8, such as 5 to 6, carbon atoms in the ring structure. "C₁-C₆The term "C" in alkyl group₁-C₆"means that the alkyl group contains 1 to 6 carbon atoms.

Furthermore, unless otherwise specified, the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls," where the latter refers to alkyls having substituents replacing a hydrogen on one or more carbon atoms of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, carboxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfonyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, substituted aryl, alkylaryl, or aryl (including heteroaryl).

The terms "alkenyl" and "alkynyl" refer to unsaturated alkyl-like aliphatic groups, including straight or branched chains, and ring structures, but which contain at least one double or triple bond, respectively. Suitable alkenyl and alkynyl groups include those having from 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon atoms.

The term "aryl" includes unsaturated cyclic hydrocarbons containing one or more rings. Typically, the term "aryl" includes 5-or 6-membered monocyclic aryl groups which may contain zero to four heteroatoms, for example selected from: benzene, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,Oxazole, isoOxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term aryl includes polycyclic radicals, e.g. radicals derived from tricyclic, bicyclic rings, e.g. naphthalene, benzoAzole, benzodiOxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indolyl, benzofuranyl, purinyl, deazapurinine, or indolizine.

These aryl groups having heteroatoms in the ring structure are also referred to as "aryl heterocycles", "heteroaryls", or "heteroaryls".

The aryl group may also be bridged with alicyclic or non-aromatic heterocyclic groups to form a polycyclic (e.g., tetralin). Aryl groups having heteroatoms in the ring structure may also be referred to as aryl heterocycles, heteroaryls, or heteroaromatics, wherein, for example, any ring formed is incorporated with one atom or a non-carbon atom. The ring may be saturated or unsaturated and may contain one or more double bonds. Some examples of heterocyclyl groups include pyridyl, furyl, thienyl, morpholinyl, and indolyl.

The term "heteroatom" includes any atom other than carbon and hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.

Heterocyclyl also includes groups in which the closed ring structure of one or more of the atoms in the ring is an element other than carbon, such as nitrogen, sulfur or oxygen. The heterocyclic group may be saturated or unsaturated and heterocyclic groups such as pyrrole and furan may have aromaticity. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Examples of heteroaromatic and heteroalicyclic groups also have from 1 to 3 separate or fused rings of 3 to about 8 members and having one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, substituted and unsubstituted,Oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, and pyrrolidinyl.

Therapeutic formulations of the invention

The present invention also relates to a pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a therapeutic agent as defined herein in an amount sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a pharmaceutical composition for treating amyloidosis, comprising a therapeutic agent as defined in the present specification in an amount sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically acceptable carrier.

In another embodiment, the invention relates to a pharmaceutical composition for treating or preventing amyloid-related diseases (e.g., type II diabetes) or a β -related diseases (e.g., alzheimer's disease, cerebral amyloid angiopathy, including somatic myositis, macular degeneration, down's syndrome, and hereditary cerebral hemorrhage) comprising a therapeutic formulation comprising a therapeutic compound formulated to significantly reduce or prevent gastrointestinal intolerance sufficient to prevent or treat the amyloid-related disease in a subject and a pharmaceutically acceptable carrier.

In certain embodiments, the therapeutic compound of the therapeutic formulations of the present invention interacts with the binding site of a basement membrane glycoprotein or proteoglycan in an amyloidogenic protein and thereby inhibits the binding of the amyloidogenic protein to the basement membrane component. Basement membrane glycoproteins and proteoglycans include laminin, type IV collagen, plasmin, agrin, perlecan, and Heparan Sulfate Proteoglycan (HSPG). In a particular embodiment, the therapeutic compound inhibits the interaction between an amyloidogenic protein and agrin, perlecan, or HSPG. Furthermore, the motivation for consistent binding sites for HSPG in amyloidogenic proteins has also been described (see, e.g., Cardi and Weintraub (1989), Arteriosclerosis 9: 21-32).

Accordingly, the present invention includes a packaged pharmaceutical composition for inhibiting amyloid deposition in a subject comprising a container containing a therapeutically effective amount of a compound described herein; and instructions for using the compound to inhibit amyloid deposition in a subject. In certain embodiments, the disease associated with such amyloid deposition is selected from alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, down's syndrome, mild cognitive impairment, type II diabetes, and hereditary cerebral hemorrhage.

The term "container" includes any receptacle for holding the therapeutic agent. For example, in one embodiment, the container is a package containing the formulation. In other embodiments, the container is not a package containing the formulation, i.e., the container is a receptacle, such as a box or vial, containing the packaged or unpackaged formulation and instructions for use of the formulation. In addition, packaging techniques are also well known in the art. It will be appreciated that instructions for use of the therapeutic formulation may be contained on the package containing the formulation and that the instructions form an enhanced functional relationship with the packaged product. However, it is to be understood that the instructions may contain information relating to the compound performing its intended function (e.g., reducing or preventing gastrointestinal intolerance).

In another embodiment, the invention includes a packaged pharmaceutical composition for treating amyloidosis in a subject, comprising a container holding a therapeutically effective amount of a compound described herein; and instructions for using the compound to treat amyloidosis in a subject.

In yet another embodiment, the present invention relates to a packaged pharmaceutical composition for treating a viral infection comprising a container holding a therapeutically effective amount of a therapeutic agent as described herein; and instructions for using the compounds to treat viral infections.

Another embodiment of the invention relates to a packaged pharmaceutical composition for treating bacterial infections comprising a container holding a therapeutically effective amount of a therapeutic preparation of the invention; and instructions for using the compounds to treat bacterial infections.

In another aspect, the invention resides in a packaged pharmaceutical composition for inhibiting the binding of a chemokine to a glycosaminoglycan comprising a therapeutic preparation of the invention in a therapeutically effective amount; and instructions for using the therapeutic compound to inhibit binding of a chemokine to a glycosaminoglycan.

The therapeutic formulations of the present invention may also include a combination of two or more therapeutic compounds. The invention therefore relates to a therapeutic preparation for the treatment of alzheimer's disease, comprising 3-amino-1-propanesulfonic acid and a second drug for other symptoms, such as the secondary symptoms of alzheimer's disease. In certain embodiments, the "second drug" may be a cholinesterase inhibitor, such as an acetylcholinesterase or butyrylcholinesterase inhibitor, for example, 9-aminotetrahydroacridine, donepezil, rivastigmine, or galantamine. In another embodiment, the second drug may be a NMD antagonist, such as memantine.

In yet another embodiment, the second drug may be an antioxidant, vitamin E, estrogen, non-steroidal anti-inflammatory agent (e.g., aspirin or naproxen), cholesterol modifying agent such as stephagin, or ginkgo biloba.

The therapeutic formulations of the present invention may further comprise a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any material that is compatible with the activity of the compound, is physiologically acceptable to the subject, and does not significantly affect the ability of the therapeutic formulation to perform its intended function, or to reduce or prevent gastrointestinal intolerance, such as coatings, antibacterial and antifungal agents, and absorption delaying agents. Supplemental actives may also be included in the composition so long as they do not significantly affect the ability of the therapeutic formulation to reduce or prevent emesis.

The active agent is administered at an effect of a therapeutically effective dose sufficient to inhibit amyloid deposition in the subject. A "therapeutically effective dose" preferably inhibits amyloid deposition by at least about 20%, more preferably by at least about 40%, more preferably by at least about 60%, and more preferably by at least about 80%, relative to an untreated subject. The ability of the compound to inhibit amyloid deposition can be assessed in an animal model system that predicts efficacy in inhibiting amyloid deposition in human diseases. Alternatively, the ability of the compound to inhibit amyloid deposition may be assessed by examining the ability of the compound to inhibit the interaction between an amyloidogenic protein and a component of the basement membrane, for example as described in US5,164,295, which is expressly incorporated herein by reference, or by mass spectrometry as described in example 5.

The term "subject" includes living organisms in which amyloidosis may occur or which are susceptible to amyloid disease, including, for example, Alzheimer's Down syndrome, mild cognitive impairment, CAA, dialysis phaseOff (beta)₂M) powder-like degeneration, secondary (AA) amyloidosis, primary (AL) amyloidosis, hereditary amyloidosis, diabetes, and the like. Examples of subjects include humans, monkeys, cattle, sheep, goats, dogs, and cats. The term "subject" includes animals (e.g., mammals, e.g., cats, dogs, horses, pigs, cows, goats, sheep, rodents, e.g., mice or rats, rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys, gorillas, and humans)), as well as chickens, ducks, beijing ducks, geese, and transgenic species thereof.

In certain embodiments of the invention, the subject is in need of treatment by the methods of the invention and is selected for treatment based on the need. Subjects in need of treatment are technically identified and include those that have been demonstrated to have a disease or disorder associated with amyloid-deposition or amyloidosis, and have symptoms of, or are at risk of, such a disease or disorder, and would be expected to benefit from treatment (e.g., cure, prevent, alleviate, ameliorate, alter, remedy, ameliorate, improve, or affect the disease or disorder, and symptoms of the disease or disorder, or risk of the disease or disorder) based on diagnosis, e.g., medical diagnosis.

The compositions of the present invention can be administered to a subject using known procedures, at dosages and for periods of time sufficient to inhibit amyloid deposition in the subject. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on factors such as, for example, the amount of amyloid that has been deposited at a clinical site in the subject, the age, sex, and weight of the patient, and the ability of the therapeutic compound to inhibit amyloid deposition in the subject. Dosage ranges can be adjusted to provide the best therapeutic response. For example, multiple individual doses may be taken daily or the dose may be reduced proportionally according to the urgency of the treatment condition. One non-limiting example of an effective dose of a therapeutic compound of the invention (e.g., 3-amino-1-propanesulfonic acid) is 1-500 mg/kg body weight/day. One of ordinary skill in the art will be able to study the relevant factors and determine, without undue experimentation, an effective amount of a therapeutic compound.

The actual dosage level of the active ingredient in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and which is non-toxic to the patient.

In particular, the selected dosage level will depend upon a variety of factors well known in medicine, including the activity of the particular compound of the invention employed, the time of administration, the rate of secretion of the compound employed, the duration of the treatment, other drugs, compounds or materials of use in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated.

A physician, such as a physician or veterinarian, having ordinary skill in the art can readily determine the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can initially administer a compound of the invention in a pharmaceutical composition in a lower dose (than that required to achieve the desired therapeutic effect) and then gradually increase the dose until the desired effect is achieved.

The regimen may affect the composition of the effective amount. The therapeutic agent may be administered before or after the onset of amyloidosis. Furthermore, multiple individual doses, as well as staggered doses, may be taken daily or continuously, or may be continuously infused, or may be bolus injections (a bolus injections). In addition, the dosage of the therapeutic agent may be increased or decreased proportionally to the requirements of treatment or prevention.

In certain embodiments, it is particularly advantageous to formulate the composition in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subjects being treated; each containing a predetermined amount of a therapeutic compound calculated to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier. The specification for the dosage unit form of the invention is determined by and directly dependent on the following factors: (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved; and (b) limitations inherent in the art of mixing/formulating such therapeutic compounds for treating amyloid deposits in a subject.

Another aspect of the invention includes methods for treating amyloidosis, inhibiting amyloid deposition; or a pharmaceutical composition for preventing or treating amyloid-related diseases, such as, for example, A β -related diseases, such as, for example, Alzheimer's disease, cerebral amyloid angiopathy, including somatic myositis, macular degeneration, Down's syndrome, mild cognitive impairment, and hereditary cerebral hemorrhage. The therapeutic formulation described above may be included in a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutic compound formulated in an amount to significantly reduce or prevent gastrointestinal intolerance, in an amount sufficient to treat or inhibit amyloidosis, or in an amount sufficient to inhibit deposition, or in an amount sufficient to prevent or treat amyloid-related diseases. In one embodiment, the pharmaceutical composition of the invention comprises a therapeutic compound having the formula 3-amino-1-propanesulfonate/X (wherein X is a counterion or forms an ester with a sulfonate), wherein the ester or counterion comprises an alcohol group or a positively charged atom or residue, respectively, that does not significantly affect the ability of the therapeutic formulation to reduce or prevent gastrointestinal intolerance. One preferred specific example of a cationic group is hydrogen, H⁺And the compound is 3-amino-1-propanesulfonic acid.

In another embodiment, the present invention relates to a method of formulating a pharmaceutical composition with enhanced gastrointestinal intolerance comprising: admixing a preselected therapeutic compound with a pharmaceutically acceptable carrier, wherein the therapeutic compound's ability to significantly reduce or prevent gastrointestinal intolerance is preselected, thereby forming a gastrointestinal intolerance enhanced pharmaceutical composition.

The term "gastrointestinal intolerance enhanced pharmaceutical composition" includes pharmaceutical compositions containing the therapeutic compounds of the present invention, which compounds are preselected based on their ability to significantly reduce or prevent gastrointestinal intolerance.

Administration of drugs

The formulations of the present invention include those suitable for oral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by methods known in the art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound which produces a therapeutic effect. Generally, starting from 1%, the amount is from about 1% to 99% of active ingredient, preferably from about 5% to 70%, most preferably from about 10% to about 30%.

Methods of preparing these formulations or compositions include the step of admixing a compound of the present invention with a carrier, and one or more accessory ingredients. In general, the formulation can be prepared by: the compounds of the present invention are uniformly and intimately admixed with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaped.

Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules; or solutions or suspensions dissolved in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil liquid emulsion; or elixirs or syrups; or lozenges (using an inert base, such as gel and glycerin, or sucrose and acacia) or mouthwashes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The compounds of the present invention may also be administered in the form of pills, dry dragees or pastes.

In solid dosage forms of the invention (capsules, tablets, pills, dragees, powders, granules and the like) suitable for oral administration, the active ingredient is admixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate or any of the following: fillers or supplements such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose or acacia; humectants, such as glycerol; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; adsorbents such as kaolin and bentonite; lubricants, such as stone dust, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl and mixtures thereof; and a colorant. In capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers and hard-filled capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The compounds of the present invention are effective when administered orally. Thus, the preferred route of administration is oral. The therapeutically active substance may be coated with a material to protect the compound from the action of acids and other conditions that may inactivate the compound. The compounds of the present invention may be formulated to ensure normal distribution in vivo. For example, the Blood Brain Barrier (BBB) excludes many highly hydrophilic compounds, and to ensure that the therapeutic compounds of the present invention cross the BBB, they can be formulated in liposomes. Methods of making liposomes see, e.g., U.S.4,522,811, US5,374,548 and US5,399,331 liposomes can include one or more residues (targeting residues) that are selectively released into specific cells and organs, and thus provide targeted drug release (see, e.g., v.v. rahade (1989), j.clin.pharmacol.29: 685). Exemplary residues include folic acid and biotin (see, e.g., US5416016, Low et al), mannoside (Umerzawa et al, (1988) biochem. biophysis. res. commun.153: 1038); antibodies (P.G.Blueman et al (1995) FEBS Lett.357: 140; M.Owais et al (1995) antibodies.Agents Chemother.39: 180); surface protein A receptors (Briscoe et al (1995) am. J. physiol, 1233: 134); gp 120(Schreier et al (1994) J.biol.chem.269: 9090); see also k.keinanen; l.laukkanen (1994) FEBS Lett 346: 123; j.j.killion; fidler (1994), Immunomethods 4: 273.

in order to administer the therapeutic compound, it may be necessary to coat the compound, or administer a material with the compound, to prevent inactivation; for example, the therapeutic compound may be administered to the subject in a suitable carrier, such as a liposome, or a diluent. Liposomes include water-in-oil-in-water CGF as well as conventional liposomes (Strejan et al, J. Meuroimemunol. 7, 27 (1984)).

The therapeutic compound may be administered orally, for example, using an inert diluent or an ingestible edible carrier. The therapeutic compound and other ingredients may also be encapsulated in a hard or soft gelatin capsule, compressed into a tablet, or included directly in the subject's diet. For oral administration, the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the composition and formulation can, of course, be varied. The amount of therapeutic compound in a therapeutically useful composition is such that a suitable dosage is obtained.

The term "pharmaceutically acceptable carrier" includes a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in transporting or delivering a compound of the invention to a subject so as to be capable of its intended function. Typically, the compound is transported or transported from one organ, or part of the body, to another organ, or part of the body. Each "carrier" is in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient; or "acceptable" in the sense that it does not affect the ability of the therapeutic formulation to reduce or prevent gastrointestinal intolerance. Some examples of pharmaceutically acceptable carrier materials that may be used include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelling; talc powder; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a buffer solution; and other non-toxic, pharmaceutically acceptable substances used in pharmaceutical products known in the art.

Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring, releasing, coating, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), 2, 6-di-tert-butyl-p-cresol (BHT), lecithin, propyl lactate, alpha-tocopherol, and metal chelate agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agents. The molded tablets may be made by molding in a suitable machine a powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, can optionally be scored or prepared with coatings or shells, such as enteric coatings and other coatings known in the pharmaceutical arts. These compounds may also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes or microspheres. It may be sterilized, for example, by filtration through a bacterial-retaining filter, or by including a sterile solid composition, which may be dissolved in sterile water, or other sterile injectable medium, prior to use. These compositions may also optionally comprise opacifying agents and/or may comprise agents which release the active ingredient only, or preferentially, in specific parts of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding components that can be used include polymers and waxes. The active ingredient may also be formulated, where appropriate, in microencapsulated form with one or more of the above-mentioned excipients.

In addition to the compounds of the invention, the powders may contain excipients, for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol; oils (particularly cottonseed, groundnut, corn, germ, olive, castor, and sesame oils); sorbitan esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying or suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active materials, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be achieved by including various antibacterial and antifungal agents, such as palaebia, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of injectable pharmaceutical products can be brought about by agents delaying absorption, for example, aluminum monostearate and gelatin.

The compositions of the present invention may also be administered topically in a subject, for example, by directly applying or spreading the composition on the epidermis or epithelial tissue of the subject, or transdermally via a "patch". Such compositions include, for example, detergents, creams, solutions, gels, and solids. These topical compositions preferably comprise an effective amount, e.g., at least about 0.1%, preferably from about 1% to about 5%, of a compound of the present invention. Suitable carriers for topical administration are preferably in the form of a continuous film which remains on the skin and does not shed as a result of perspiration or water immersion. Typically, the carrier is organic in nature and is capable of having the therapeutic compound dispersed or dissolved therein. The carrier may include pharmaceutically acceptable lubricants, emulsifiers, thickeners, solvents, and the like.

In a particular example, the pharmaceutical formulation comprises greater than about 0.1%, such as greater than about 1%, such as greater than about 2%, such as greater than about 3%, such as greater than about 4%, such as greater than about 5%, such as greater than about 10%, such as greater than about 20%, such as greater than about 30%, such as greater than about 40%, such as greater than about 50%, such as greater than about 60%, such as greater than about 70%, such as greater than about 80%, such as greater than about 90%, such as greater than about 95%, such as greater than about 99%, of the therapeutic compound, such as an alkylsulfonic acid, such as a 3-amino-1-propanesulfonic acid compound, based on the weight of the formulation. In a specific embodiment, the pharmaceutical formulation comprises about 12.6% ± 0.5% by weight of the therapeutic compound. In another specific embodiment, the pharmaceutical formulation comprises about 95.2% ± 0.5% by weight of the therapeutic compound. The remainder of the pharmaceutical formulation may be comprised of additional agents as described herein.

In another specific example, the pharmaceutical formulation comprises more than about 1%, such as more than about 2%, such as more than about 3%, such as more than about 4%, such as more than about 5%, such as more than about 6%, such as more than about 7%, such as more than about 8%, such as more than about 9%, such as more than about 10%, such as more than about 20%, such as more than about 30%, such as more than about 40%, such as more than about 50%, such as more than about 60%, such as more than about 70%, such as more than about 80%, such as more than about 90%, such as more than about 95%, such as more than about 99%, based on the weight of the formulation, of an additional agent, such as an agent that improves the release of the therapeutic compound or an enteric coating. It is understood that these percentages are ranges that apply, either individually or in combination, to one or more other agents of the formulation. Thus, in certain embodiments, additional agents may be used in therapeutic formulations to impart good properties thereto, for example, to reduce or prevent gastrointestinal intolerance, either alone or in combination with other methods of reducing or preventing intolerance. Exemplary other agents are described herein. For example, to protect against any possible gastrointestinal intolerance caused by the therapeutic formulation, the tablet may be enteric coated or a release-modifying agent may be added to control any rapid release of the therapeutic compound in the stomach or intestine. In a particular embodiment, the pharmaceutical formulation comprises about 9.3 ± 0.5% of the additional agent, based on the weight of the formulation. In another specific embodiment, the pharmaceutical formulation comprises about 8.8 ± 0.5% of the additional agent, based on the weight of the formulation. In another specific embodiment, the pharmaceutical formulation comprises about 5.6 ± 0.5% of the additional agent, based on the weight of the formulation.

In a particular locationIn particular embodiments of the invention, the therapeutic compound is selected from: agents that improve the release of the therapeutic compound, such as hydroxypropyl methylcellulose (HPMC); glidants/diluents; silicated microcrystals (silicated mycrythrostelline); fillers, such as dibasic calcium phosphate groups; binders/disintegrants, e.g.Lubricants, such as stearic acid powder or magnesium stearate; inner coatings (subcoat), e.g.II, white; overcoat (topcoat), e.g.II white sumTransparent; enteric coatings, e.g.And any combination thereof. The following materials were purchased from Colorcon (WestPoint, PA):II White、Clear、several specific examples of the present invention are discussed in the following examples.

Equivalent technical scheme

Those of skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific steps, specific examples, claims, and embodiments described herein. Such equivalents are considered to be included within the scope of the present invention and are encompassed by the appended claims.

It is also understood that when values or ranges are provided, for example, for the subject's overall age, dosage, and blood level, all values and ranges encompassed by such values and ranges are encompassed within the scope of the invention. Moreover, all numbers falling within this range, as well as the upper and lower limits of a range of numbers are contemplated as applications of the present invention.

The issued patents, published patent applications, used throughout this application by reference are all incorporated by reference into this application. It is to be understood that any compound described herein and in what is considered to be part of the "related applications" is within the scope and encompassed by the present invention and is expressly incorporated herein for at least these purposes and further expressly incorporated herein for other purposes.

Examples

The invention is further illustrated by the following examples, which should not be construed as further limiting the invention.

Example 1 gelatin capsules for oral administration

Unit formulations for 100mg and 400mg white gelatin capsules are provided in Table 2.

Table 2: unit formula of 100mg and 400mg gelatin capsules

MS: manufacturer standard grade; NF: national prescription level; USP: united states Pharmacopeia grade.

The results of some studies have shown that: the administration of 3-amino-1-propanesulfonic acid sodium salt in solid dosage forms (capsules) is associated with digestive symptoms, i.e., regurgitation and vomiting. Additional experiments have shown that the digestive symptoms are at least partly due to local irritation caused by excessive pH generated during dissolution of the sodium salt of amino-1-propanesulfonic acid in the stomach. Other tests (solid dosage forms) on dogs have shown that the free acid is more resistant than the sodium salt form.

Furthermore, the hygroscopic nature of the acid form makes it a desirable active pharmaceutical ingredient. For example, to further protect against any possible gastrointestinal intolerance due to the acid form, the tablet may be enteric coated and a release-modifying agent may be added to control any rapid release of the drug in the stomach and intestines.

EXAMPLE 2 enteric coated tablets

White enteric-coated tablets of 100mg and 400mg were prepared according to the following formulation in which the drug substance (which was manufactured by removing sodium using ion exchange) was densified by granulating with water due to its low density and fluffiness. Unit formulas for 100mg and 400mg enteric-coated tablets are provided in table 3.

Table 3: unit formula of 100 and 400 enteric coated tablets

The in vitro (dissolution rate) and PK data for the 100mg enteric coated tablets used in the initial phase I study indicate that these tablets will result in an acceptable PK and good tolerability.

EXAMPLE 3 modified Release coated tablets

Clinical studies have shown that the role of enteric coatings and drug release modifiers in the drug's Pharmacokinetic (PK) profile and its tolerability will be significant. Therefore, in order to obtain specific drug properties (in terms of PK, tolerability and product stability), drug release modifying agents are formulated into tablets. To improve the physical stability of the product under accelerated conditions (acceptability in film coatings and moisture resistance), the enteric coating system is modified by increasing the amount of enteric coating and adding an outer coating.

A 50mg sized modified release coated tablet is prepared containing bulk drug substance beta-amino-1-benzenesulfonic acid and inactive ingredients (silicified microcrystalline cellulose, calcium hydrogen phosphate), hydroxypropyl methylcellulose, starch, stearic acid, magnesium stearate, andIIwhite (outer and inner coating) and). The unit formula for 50mg of the modified release coated tablets is provided in table 4.

Table 4: unit formula of 50mg modified release coated tablet

Example 4 modified Release coated tablets

Some minor modifications were made to the coating of the formulation in example 3: used as an overcoat in example 3Clear toII White substitution, andIIWhite was also used as an inner coating. Andthe Clear is similar to the flow of the water,II White is an HPMC-based formulation with a sealing function and thus likewise with an improved enteric coatingMoisture resistance of the film.

The coating system variation of the outer coating is a process variation that facilitates scaling up the product formulation size, i.e., facilitates the transition from applying one coating to another during the coating operation by preventing clogging of the spray gun during the transition from the enteric coating step to the outer coating application step.

50mg modified release coated tablets are provided in Table 5 for unit formulation

Table 5: unit formula of 50mg modified release coated tablet

Characterization as determined by the methods of the united states pharmacopeia (united states pharmacopeia 25, method B, page 2017) indicated that the dissolution rates of the two 50mg modified release coated tablets (examples 3 and 4) were comparable.

Further, in order to improve stability of appearance, i.e., white color, by increasingIIWhite amounts the following modified release coated tablets were prepared.

Table 6: unit formula of 50mg modified release coated tablet

Example 5 Mass Spectrometry

The binding of a compound to amyloid fibrils can be measured using a mass spectrometry ("MS") assay as described below.

Samples were prepared as an aqueous solution containing 20% ethanol 20 μ M of the test compound and 20uM of dissolved a β 40. The pH was adjusted to 7.4(± 0.2) by the addition of 0.1% aqueous sodium hydroxide. The solution was then analyzed by electrospray ionization mass spectrometry using a Waters ZQ 4000 mass spectrometer. The sample was introduced by direct infusion at a flow rate of 25L/min over 2 hours of preparation of the sample. For all analyses, the source temperature was maintained at 70 ℃ and the cone voltage was maintained at 20V. Data were processed using Masslynx 3.5 software.

The resulting MS assay data provides insight into the ability of compounds to bind to a β.

Claims

1. A formulation for oral treatment or prevention of an amyloid-related disease or condition while reducing or preventing gastrointestinal intolerance, comprising a substance selected from 3-amino-1-propanesulfonic acid and comprising an enteric coating.

2. The formulation of claim 1, wherein the amyloid-related disease or condition is selected from the group consisting of alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, down's syndrome, mild cognitive impairment, cognitive decline, and hereditary cerebral hemorrhage.

3. The formulation of claim 1, wherein said amyloid-related disease or condition is treated prophylactically or therapeutically.

4. The formulation of claim 1, wherein the formulation further comprises a pharmaceutically acceptable carrier.

5. The formulation of claim 4, comprising an agent that improves the release of the substance, a glidant/diluent, a filler, a binder/disintegrant, a lubricant, an inner coating, an outer coating, and any combination thereof.

6. The formulation of claim 5, wherein the agent that modifies the release of the substance is hydroxypropyl methylcellulose.

7. The formulation of claim 5, wherein the glidant/diluent is a silicated microcrystalline.

8. The formulation of claim 5, wherein the filler is dibasic calcium phosphate.

9. The formulation of claim 5, wherein the binder/disintegrant is

10. The formulation of claim 5, wherein the lubricant is stearic acid powder.

11. The formulation of claim 5, wherein the lubricant is magnesium stearate.

12. The formulation of claim 5, wherein the inner coating isIIWhite。

13. The formulation of claim 5, wherein the outer coating isII White orClear。

14. The formulation of claim 5, wherein the enteric coating is

15. The formulation of claim 1, wherein the formulation is present in an amount sufficient to inhibit amyloid-induced neurodegeneration or cytotoxicity, and a pharmaceutically acceptable carrier.

16. The formulation of claim 4, wherein the amyloid-related disease is cerebral amyloid vascular disease.

17. The formulation of claim 4, wherein the amyloid-related disease is Alzheimer's disease.

18. The formulation of claim 1, wherein the formulation comprises the substance and greater than 1% by weight of additional agent.

19. The formulation of claim 18, wherein the additional agent is an enteric coating.

20. The formulation of claim 18, wherein the additional agent is an agent that modifies the release of the substance.

21. The formulation of claim 1, wherein the formulation is for inhibiting amyloid deposition.

22. The formulation of claim 1 in the form of an enterically coated tablet having the following unit formula:

ingredient mg/tablet

Core(s)

Coating film

II White inner coating 14.00

Enteric coating 42.00

Total weight 756.00

Or

Ingredient mg/tablet

Core(s)

Coating film

II White inner coating 14.00

Enteric coating 42.00

Total weight 756.00.

23. The formulation of claim 1 in the form of a modified release coated tablet having the following unit formula:

ingredient mg/tablet

Core(s)

Coating film

II White inner coating 7.00

Enteric coating 35.00

Clear overcoat 3.50

Total weight 395.50.

24. The formulation of claim 1 in the form of a modified release coated tablet having the following unit formula:

ingredient mg/tablet

Core(s)

Coating film

II White inner coating 7.00

Enteric coating 35.00

II White outer coating 3.50

Total weight 395.50.

25. The formulation of claim 1 in the form of a modified release coated tablet having the following unit formula:

ingredient mg/tablet

Core(s)

Coating:

II White inner coating 7.00

Enteric coating 35.00

II White outer coating 7.00

Total weight 399.00.