WO2003103598A2 - Amidine derivatives for treating amyloidosis - Google Patents
Amidine derivatives for treating amyloidosis Download PDFInfo
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Definitions
- Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibers.
- Amyloid is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.
- specific dyes e.g., Congo red
- Amyloid-related diseases can either be restricted to one organ or spread to several organs. The first instance is referred to as “localized amyloidosis” while the second is referred to as “systemic amyloidosis.”
- amyloidotic diseases can be idiopathic, but most of these diseases appear as a complication of a previously existing disorder.
- primary amyloidosis can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma.
- Secondary amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis).
- a familial form of secondary amyloidosis is also seen in Familial Mediterranean Fever (FMF).
- FMF Familial Mediterranean Fever
- This familial type of amyloidosis as one ofthe other types of familial amyloidosis, is genetically inherited and is found in specific population groups. In these two types of amyloidosis, deposits are found hi several organs and are thus considered systemic amyloid diseases.
- amyloidosis Another type of systemic amyloidosis is found in long-term hemodialysis patients. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition.
- “Localized amyloidoses” are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongif ⁇ rr ⁇ encephalitis, Creutzfeldt-Jakob disease, and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by neuritic plaques and neurofibrillary tangles. In this case, the plaque and blood vessel amyloid is formed by the deposition of fibrillary A ⁇ amyloid protein. Other diseases such as adult-onset diabetes (Type II d abetes) are characterized by the localized accumulation of amyloid in the pancreas.
- Type II d abetes are characterized by the localized accumulation of amyloid in the pancrea
- Each amyloidogenic protein has the ability to organize into ⁇ -sheets and to form insoluble fibrils which maybe deposited extracellularly or intracellularly.
- Each amyloidogenic protein although different in arnino acid sequence, has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P and complement component.
- each amyloidogenic protein lias amino acid sequences which, although different, will show similarities such as regions with the ability to bind to the glycosammoglycan (GAG) portion of proteoglycan (referred to as the GAG binding site) as well as other regions which will promote ⁇ -sheet formation.
- GAG glycosammoglycan
- amyloidotic fibrils once deposited, can become toxic to the surrounding cells.
- a ⁇ fibrils organized as senile plaques have been shown to be associated with dead neuronal cells and microgliosis in patients with Alzheimer's disease.
- a ⁇ . peptide was shown to be capable of triggering an activation process of microglia (brain macrophages), which would explain the presence of microgliosis and brain infiarnmation found in the brain of patients with Alzheimer's disease.
- amyloidogenic protein IAPP has been shown to induce ⁇ -islet cell toxicity in vitro.
- appearance of IAPP fibrils in the pancreas of Type II diabetic patients contributes to the loss ofthe ⁇ islet cells (Langerhans) and organ dysfunction.
- Alzheimer's disease develop a progressive dementia in adulthood, accompanied by three main structural changes in the brain: diffuse loss of neurons in multiple parts of the brain; accumulation of intracellular protein deposits termed neurofibrillary tangles; and accumulation of extracellular protein deposits termed amyloid or senile plaques, surrounded by misshapen nerve terminals (dystrophic neurites).
- a main constituent of these amyloid plaques is the amyloid- ⁇ peptide (A ⁇ ), a 39-43 amino-acid protein that is produced through cleavage ofthe ⁇ -arnyloid precursor protein (APP).
- a ⁇ amyloid- ⁇ peptide
- APP ⁇ -arnyloid precursor protein
- the present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases, hi particular, the invention relates to a method of treating or preventing an amyloid-related disease in a subject comprising administering to the subject a therapeutic amount of an amidine compound.
- the compounds for use in the invention are those according to the following Formula, such that, when administered, amyloid fibril formation, neurodegeneration, or cellular toxicity is reduced or inhibited:
- FIG- 1 Effect of pentamidine-type compounds on A ⁇ (l-40) assembly determined by ThT assay.
- FIG. 2 Effect of pentamidine-like compounds on A ⁇ (l-40) assembly determined by ThT assay.
- FIG. 3 Effect of amidme-type compounds on A ⁇ (l-40) assembly determined by ThT assay.
- FIG.4 Effect of pentamidine-type compounds on IAPP assembly determined by ThT assay.
- the present invention relates to the use of amidine compounds in the treatment of amyloid-related diseases.
- AA amyloidosis is a manifestation of a number of diseases that provoke a sustained acute phase response. Such diseases include chronic inflammatory disorders, chronic local or systemic microbial infections, and malignant neoplasms.
- AA fibrils are generally composed of 8,000 Dalton fragments (AA peptide or protein) formed by proteolytic cleavage of serum amyloid A protein (ApoSAA), a circulating apolipoprotein which once secreted is complexed with HDL and which is synthesized in hepatocytes in response to such cytokines as IL-1, IL-6 and TNF. 5
- Deposition can be widespread in the body, with a preference for parenchymal organs. The . spleen is usually a deposition site, and the kidneys may also be affected. Deposition is also common in the heart and gastrointestinal tract.
- AA amyloid diseases include, but are not limited to inflammatory diseases, such as rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic 0 arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, and Crohn's disease.
- AA deposits are also produced as a result of chronic microbial infections, such as leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, and Whipple's disease.
- Certain malignant neoplasms can also result in AA fibril amyloid deposits. These include such conditions as Hodgkin's lymphoma, renal carcinoma, 5 carcinomas of gut, lung and urogenital tract, basal cell carcinoma, and hairy cell leulcemia.
- AL amyloid deposition is generally associated with almost any dyscrasia of the B lymphocyte lineage, ranging from malignancy of plasma cells (multiple myeloma) to benign monoclonal garnmopathy. At times, the presence of amyloid deposits may be a primary £0 indicator ofthe underlying dyscrasia.
- Fibrils of AL amyloid deposits are composed of monoclonal ixrrmunoglobulin light chains or fragments thereof. More specifically, the fragments are derived from theN- terminal region of he light chain (kappa or lambda) and contain all or part of he variable (V ) domain thereof. Deposits generally occur in the mesenchymal tissues, causing 15 peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune dyscrasias, myelomas, as well as occult dyscrasias. However, it should be noted that almost any tissue, particularly visceral organs such as the heart, may be involved..
- Hereditary Systemic Amyloidoses Hereditary Systemic Amyloidoses
- hereditary systemic amyloidoses There are many forms of hereditary systemic amyloidoses. Although they are relatively rare conditions, adult onset of symptoms and their inheritance patterns (usually autosomal dominant) lead to persistence of such disorders in the general population. Generally, the syndromes are attributable to point mutations in the precursor protein leading to production of variant amyloidogenic peptides or proteins. Table 1 summarizes the fibril ' composition of exemplary forms of these disorders.
- Table 1 The data provided in Table 1 are exemplary and are not intended to limit the scope ofthe invention. For example, more than 40 separate point mutations in the transthyretin gene have been described, all of which give rise to clinically similar forms of familial amyloid polyneuropathy.
- Transthyretin is a 14 kiloDalton protein that is also sometimes referred to as prealbumin. It is produced by the liver and choroid plexus, and it functions in transporting thyroid hormones and vitamin A. At least 50 variant forms of he protein, each characterized by a single amino acid change, are responsible for various fomis of familial amyloid polyneuropathy. For example, substitution of praline for leucine at position 55 results in a particularly progressive form of neuropathy; substitution of methionine for leucine at position 111 resulted in a severe cardiopathy in Danish patients.
- ATTR fibril components can be extracted from such plaques and their structure and sequence determined according to the 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).
- apolipoprotein Al e.g., Gly ⁇ Arg26; Trp - Arg50; Leu -> Arg60
- OpoAT amyloidosis
- HDL high density lipoprotein
- a mutation in the alpha chain of he enzyme lysozyme is the basis of another form of Ostertag-type non-neuropathic hereditary amyloid reported in English families.
- fibrils of the mutant lysozyme protein are deposited, and patients generally exhibit impaired renal function.
- This protein unlike 5 most ofthe fibril-forming ' proteins described herein, is usually present in whole (unfragmented) form (Benson, M.D., etal. CIB Fdn. Symp. 199: 104-131, 1996).
- ⁇ -amyloid peptide is a 39-43 amino acid peptide derived by proteolysis from a large protein known as Beta Amyloid Precursor protein ( ⁇ APP). Mutations in ⁇ APP result in familial forms of Alzheimer's disease, Down's syndrome or senile dementia, 0 characterized by cerebral deposition of plaques composed of A ⁇ fibrils and other components, which are described in further detail below. Known mutations in APP associated with Alzheimer's disease occur proximate to the cleavage sites of ⁇ or gamma- . secretase, or within A ⁇ .
- position 717 is proximate to the site of gamma- secretase cleavage of APP in its processing to A ⁇ , and positions 670/671 are proximate to L5 the site of ⁇ -secretase cleavage. Mutations at any of these residues may result in
- Alzheimer's disease presumably by causing an increase in the amount of .the 42/43 amino acid form of A ⁇ generated from APP.
- a ⁇ peptides of various lengths are well known in the art. Such peptides can be made according to methods known in the art (e.g., Glenner and 10 Wong, Biochem Biophys. Res. Comm. 129: 885-890, 1984; Glenner and Wong, Biochem Biophys. Res. Comm. 122: 113 1-1135, 1984). In addition, various forms ofthe peptides are commercially available.
- ⁇ amyloid or “amyloid- ⁇ ” refer to amyloid ⁇ proteins or peptides, amyloid ⁇ precursor proteins or peptides, intermediates, and modifications and 15 fragments thereof, unless otherwise specifically indicated.
- a ⁇ refers to any peptide produced by proteolytic processing ofthe APP gene product, especially peptides which are associated with amyloid pathologies, including A ⁇ - 39 , A ⁇ wo, A ⁇ -4 1 , A ⁇ i42, and A ⁇ ws.
- a ⁇ iV may be referred to herein as “A ⁇ (l-42) or simply as “A ⁇ 42 " or “A ⁇ 42” (and likewise for any other amyloid peptides discussed herein).
- ⁇ amyloid amyloid- ⁇
- a ⁇ a ⁇ amyloid
- amyloid refers to amyloidogenic proteins, peptides, or fragments thereof which can be soluble (e.g.,.monomeric or oligomeric) or insoluble (e.g., having fibrillary structure or in amyloid plaque).
- Gelsolin is a calcium binding protein that binds to fragments and actin filaments. Mutations at position 187 (e.g. , Asp- Asn; Asp ⁇ -Tyr) of the protein result in a form of hereditary systemic amyloidosis, usually found in patients from Finland, as well as persons of Dutch or Japanese origin. In afflicted individuals, fibrils formed from gelsolin fragments (Agel), usually consist of amino acids 173-243 (68 kDa carboxyterminal fragment) and are deposited in blood vessels and basement membranes, resulting in corneal dystrophy and cranial neuropathy which progresses to peripheral neuropathy, dystrophic skin changes and deposition in other organs. (Kangas, H., et al. Human Mol. Genet. 5(9): 1237-1243, 1996).
- Agel gelsolin fragments
- mutant alpha chain of fibrinogen (AfibA) and mutant cystatin C (Acys) also form fibrils and produce characteristic hereditary disorders.
- AfibA fibrils form deposits characteristic of a nonneuropathic hereditary amyloid with renal disease; Acys deposits are characteristic of a hereditary cerebral amyloid angiopathy reported in Iceland (Isselbacher, Harrison' s Principles of Internal Medicine, McGraw-Hill, San Francisco, 1995; Benson, et al .
- CAA cerebral amyloid angiopathy
- prion disease Certain forms of prion disease are now considered to be heritable, accounting for up to 15% of cases, which were previously thought to be predominantly infectious in nature.
- patients develop plaques composed of abnormal isoforms ofthe normal prion protein (PrP Sc ).
- PrP Sc A predominant mutant isoform, PrP Sc , also referred to as. AScr, differs from the normal cellular protein in its resistance to protease degradation, insolubility after detergent extraction, deposition in secondary lysosomes, post-translational synthesis, and high ⁇ - pleated sheet content.
- GSS GSS segregates with a mutation at codon 117.
- Mutations at codons 198 and 217 result in a form of GSS in which neuritic plaques characteristic of Alzheimer's disease contain PrP instead of A ⁇ peptide.
- Certain forms of familial CJD have been associated with mutations, at codons 200 and 210; mutations at codons 129 and 178 have been found in both familial CJD and FFI. (Baldwin, supra).
- Amyloid deposition ' either systemic or focal, increases with age.
- fibrils of wild type transthyretin are commonly found in the heart tissue of elderly individuals. These may be asymptomatic, clinically silent, or may result in heart failure.
- Asymptomatic fibrillar focal deposits may also occur in the brain (A ⁇ ), corpora amylacea of the prostate (A ⁇ 2 n ⁇ croglobulin), joints and seminal vesicles.
- a ⁇ peptide fibrils resulting in dementia or sporadic (non-hereditary) Alzheimer's disease.
- sporadic Alzheimer's disease greatly exceeds forms shown to be hereditary.
- Fibril peptides forming these plaques are very similar to those described above, with reference to hereditary forms of Alzheimer's disease (AD).
- Cerebral amyloid angiopathy refers to the specific deposition of amyloid fibrils in the walls of leptomingeal and cortical arteries, arterioles and in capillaries and veins.
- CAA Cerebral sarcoma .
- a ⁇ or the APP gene have been identified and are clinically associated with either dementia or cerebral hemorrhage.
- CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I); the Dutch variant of HCHWA (HCHWA-D; a mutation in A ⁇ ); the Flemish mutation of A ⁇ ; the Arctic mutation of A ⁇ ; the Italian mutation of A ⁇ ; the Iowa mutation of A ⁇ ; familial British dementia; and familial Danish dementia.
- ⁇ 2 microglobulin ⁇ 2 microglobulin
- ⁇ 2 microglobulin is a 11.8 kiloDalton polypeptide and is the light chain of Class I MHC antigens, which are present on all nucleated cells. Under normal circumstances, it is continuously shed from cell membranes and is normally filtered by the kidney. Failure of clearance, such as in the case of impaired renal function, leads to deposition in the kidney and other sites (primarily in collagen-rich tissues of the joints). Unlike other fibril proteins, A ⁇ 2 M molecules are generally present in unfragmented form in the fibrils. (Benson, supra).
- Islet hyalinosis (amyloid deposition) was first described over a century ago as the presence of fibrous protein aggregates in the pancreas of patients with severe hyperglycemia (Opie, EL., JExp. Med. 5: 397-428, 1990).
- islet amyloid composed predominantly of islet amyloid polypeptide (IAPP), or amyl ⁇ n, is a characteristic histopathological marker in over 90% of all cases of Type II diabetes (also known as Non-Insulin Dependent Diabetes, or NTDDM). These fibrillar accumulations result from the aggregation ofthe islet .
- IAPP islet amyloid polypeptide
- NTDDM Non-Insulin Dependent Diabetes
- amyloid polypeptide or amylin, which is a 37 amino acid peptide, derived from a larger precursor peptide, called pro-IAPP.
- IAPP co-localizes and is co-secreted with insulin in response to ⁇ -cell secretagogues.
- This pathological feature is not associated with insulin-dependent (Type 1) diabetes and is a umfying characteristic for the heterogeneous clinical phenotypes diagnosed ' as NTDDM (Type II diabetes).
- IAPP has also been shown to induce ⁇ -islet cell toxicity in vitro, indicating that appearance of IAPP fibrils in the pancreas of Type II or Type I diabetic patients (post- transplantation) could contribute to the loss ofthe ⁇ islet cells (Langerhans) and organ dysfunction.
- pancreatic IAPP leads to a buildup of IAPP-amyloid as insoluble fibrous deposits which eventually replace the insulin-producing ⁇ cells ofthe islet resulting in ⁇ cell depletion and failure (Westermark, P., Grimelius, L., Acta Path. Microbiol Scand., sect. A.
- compounds ofthe present invention may also be used in preparing tissues or cells for transplantation according to the methods described in International Patent Application (PCT) number WO 01/03,680.
- Endocrine organs may harbor amyloid deposits, particularly in aged individuals.
- Hormone-secreting tumors may also contain hormone-derived amyloid plaques, the fibrils of which are made up of polypeptide hormones such as calcitonin (medullary carcinoma of the thyroid), islet amyloid polypeptide (amylin; occurring in most patients with Type H diabetes), and atrial natriuretic peptide (isolated atrial amyloidosis). Sequences and structures of these proteins are well known in the art.
- amyloid disease There are a variety of other forms of amyloid disease that are normally manifest as localized deposits of amyloid. In general, these diseases are probably the result ofthe localized production br lack of cataboHsm of specific fibril precursors or a predisposition of a particular tissue (such as the joint) for fibril deposition. Examples of such idiopathic ' deposition include nodular AL amyloid, cutaneous amyloid, endocrine amyloid, and tumor- related amyloid.
- the compounds ofthe invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid- ⁇ fibril formation, aggregation or deposition.
- the compounds ofthe invention may act to ameliorate the course of an amyloid- ⁇ related disease using any ofthe following mechanisms (this Ust is meant to be illustrative and not limiting): slowing the rate of amyloid- ⁇ fibril formation or deposition; lessening the degree of amyloid- ⁇ deposition; inhibiting, reducing, or preventing amyloid- ⁇ fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid- ⁇ ; inhibiting amyloid- ⁇ induced inflammation; or enhancing the clearance of amyloid- ⁇ from the brain.
- this Ust is meant to be illustrative and not limiting
- Compounds of the invention may be effective in controlling amyloid- ⁇ deposition either following their entry into the brain (following penetration of the ' blood brain barrier) or from the periphery.
- a compound When acting from the periphery, a compound may alter the equilibrium of A ⁇ between the brain and the plasma so as to favor the exit of A ⁇ from the brain.
- An increase in the exit of A ⁇ from the brain would result in a decrease in A ⁇ brain concentration and therefore favor a decrease in A ⁇ deposition.
- compounds that penetrate the brain could control deposition by acting directly on brain A ⁇ , e.g., by mamtaining it in.a non-fibrillar form or favoring its clearance from the brain.
- the method is used to treat Alzheimer's disease (e.g., sporadic or familial AD).
- the method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA”) or hereditary cerebral hemorrhage.
- CAA cerebral amyloid angiopathy
- the compounds of he invention can be used prophylactically or therapeutically in the treatment of disorders in which amyloid-beta protein is abnormally deposited at non-neurological locations, such as treatment of IBM by delivery ofthe compounds to muscle fibers.
- the present invention therefore relates to the use of amidine compounds in the prevention or treatment of amyloid-related diseases, including, inter alia, Alzheimer's ⁇ disease, cerebral amyloid angiopathy, inclusion body myositis, Down's syndrome, and type II diabetes.
- amyloid-related diseases including, inter alia, Alzheimer's ⁇ disease, cerebral amyloid angiopathy, inclusion body myositis, Down's syndrome, and type II diabetes.
- Preferred compounds of the invention have at least two amidine moieties (preferably arylarnidines, more preferably benzamidines).
- the present invention relates to the novel use of amidine compounds in the prevention or treatment of amyloid-related diseases, such as those disclosed in U.S. Patent Nos. 5,428,051, 4,963,589, 5,202,320, 5,935,982, 5,521,189, 5,686,456, 5,627,184, 5,622,955, 5,606,058, 5,668,167, 5,667,975, 6,025,398, 6,214,883, 5,817,687, 5,792,782, 5,939,440, 6,017,941, 5,972,969, 6,046,226, 6,294,565 (BI), 6,156,779, 6,326,395, 6,008,247, 6,127,554, 6,172,104, 4,940,723, 5,594,138, 5,602,172, .
- 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 according to the following Formula, such that amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited.
- the invention in another embodiment, 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 according to the following Formula, such that cognitive function is stabilized or further deterioration in cognitive function is prevented, slowed, or stopped in patients with brain amyloidosis, e.g., Alzheimer's disease or cerebral amyloid angiopathy:
- each of Y 1 and Y 2 is independently a direct bond or a linking moiety
- n and q are each independently an integer selected from zero to five inclusive, such that l ⁇ m+q ⁇ 5, or in another embodiment, 2 ⁇ m+q ⁇ 5, or in another embodiment l ⁇ m+q ⁇ 10, or in another embodiment, 2 ⁇ m+q ⁇ l 0; and
- the A group is a carrier moiety selected from substituted or unsubstituted aliphatic and aromatic groups, and combinations thereof; preferably such that the Y l and Y 2 moieties • are bonded to an aromatic group.
- the A group also includes the corresponding moieties ofthe Formulae I- IN herein.
- the invention relates to a method of treating or preventing an amyloid-related disease in a subject (preferably a human) comprising administering to the subj ect a therapeutic amount of a compound according to one of the following Formulae, such that amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited.
- the invention in another embodiment, 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 according to one ofthe following Formulae, such that cognitive function is stabilized or further deterioration in cognitive function is prevented, slowed, or stopped in patients with brain amyloidosis, e.g., Alzheimer's disease or cerebral amyloid angiopathy:
- R al , R bl , R o1 , R ⁇ , R b2 , R c2 , Y 1 , and Y 2 are as defined herein, and A is as defined above;
- each of R 1 and R 2 is independently a hydrogen or a Z group, or two adjacent or proximate Rl and R ⁇ groups, along with the corresponding ⁇ l and ⁇ 2 groups, if present (e.g., in Formula H), talcen together with the ring (e.g., phenyl ring) to which they are bound form a fused ring stracture, e.g., an aromatic or heteroaromatic (e.g., benzofuran) structure, or a cycloalkyl or heterocylic structure;
- a fused ring stracture e.g., an aromatic or heteroaromatic (e.g., benzofuran) structure, or a cycloalkyl or heterocylic structure
- each of R and R is independently selected from the group consisting of hydrogen, substituted or unsubstituted straight or branched alkyl (preferably C 1 -C 5 ), cycloalkyl (preferably C 3 -C 8 ), carbocyclic, aryl (e.g., phenyl), heterocyclic, and heteroaryl;
- each of Rl and R ⁇ is independently selected from the group consisting of substituted or unsubstituted straight or branched alkyl, cycloalkyl, heterocyclic, aryl (including phenyl), and heteroaryl;
- R' is hydrogen (i.e., NH), a C 1 -C
- M is a divalent group such as an alkylene group, i.e., -(CH2)kr- and substituted • analogs thereof (including groups in which a -C ⁇ 2 - moiety is substituted by an oxygen atom), where k is 1 to 12 (preferably 5 to 10, more preferably 6 to 9, most preferably 7 to 8), an allcenylene group (preferably 2 to 12 carbon atoms, more preferably 6 to 9 carbon 5 atoms, including groups with more than one double bond), an alkynylene group (preferably 2 to 12 carbon atoms, more preferably 6 to 9 carbon atoms, including groups with more than one triple bond), an alkoxyalkylene group, an aUcylaminoalkylene group, a thioalkoxyalkylene group, an arylenedialkylene group, an alkylenediarylene group, a heteroarylenedialkylene group, an arylene group, aheteroarylene group, an oligoethereal 0 group such as an
- Z is a substituted or unsubstituted moiety selected from straight or branched alkyl (preferably C 1 -C5), cycloalkyl (preferably C 3 -C 8 ), alkoxy (preferably Ci-C ⁇ ), thioalkyl (preferably Ci-Cs), alkenyl (preferably alkynyl (preferably C 2 -C6), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), 'aryloxyalkyl 0 (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group,
- Z is a substituted or unsubstituted moiety selected from straight or branched alkyl (preferably C 1 -C5), cycloalkyl (preferably C ⁇ -Cg), alkoxy . (preferably Ci-C ⁇ ), thioalkyl (preferably Ci-C ⁇ ), alkenyl (preferably C 2 -C6), alkynyl (preferably QrC ⁇ ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), , aralkyl (e.g., benzyl), aryloxyalkyl (e.g.
- R' and R" are each independently hydrogen, a C 1 -C 5 alkyl, C 2 -Cs alkenyl, C 2 -C 5 alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a -(CH 2 ) 2 ⁇ (CH ) 2 - group;
- n and q are each independently an integer selected from zero to five inclusive;
- m and q are each independently an integer selected from zero to four inclusive, and n and p are each independently an integer selected from zero to four inclusive, such that m+n ⁇ 5 and p+q ⁇ 5, wherein either m or q is at least one; and preferably m and q are one;
- n is an integer selected from one to six inclusive, and n is an integer selected from zero to five inclusive, such that +n ⁇ 6;
- the invention relates to novel compounds, and novel methods of their use as described herein, which are within the scope of the Formulae disclosed herein, and which are not disclosed in the above-referenced U.S. Patents.
- R al , R bl , R o1 , R a2 , R b2 , and R c2 in the above Formulae are preferably a hydrogen, or a substituted or unsubstituted Ci-Cs alkyl or C ⁇ -C 8 alkoxy group or a hydroxy group.
- R a and R b both taken together along with the nitrogen atoms to which they are bound to form a ring structure means that the two R a and R b groups are a moiety which joins the two nitrogen atoms in a heterocycle, such as the following ring structures:
- r is an integer from zero to 4 inclusive
- r is an integer from zero to 2 inclusive
- r is an integer from zero to 6 inclusive, or ⁇ ⁇ .wherein r is an integer zero to 4 inclusive.
- R al and R l or R 32 and R b2 are both taken together along with the nitrogen atoms to which they are bound to form a ring structure which is a nonaromatic ring, or an alicyclic ring, or a monocyclic ring, or a non-fused ring.
- R al , R bl , R cl , R 32 , R b2 , and R c2 are preferably a hydrogen, or a substituted or unsubstituted C ⁇ -C 8 alkyl group, wherein the alkyl substituent is any member ofthe group Z defined above, but not an aryl (e.g., phenyl) or alkyl group.
- Rl is a moiety selected , from the Z group defined above other than an substituted aryl (e.g., phenyl) or heteroaryl group.
- the groups R 1 and R 2 are preferably a hydrogen, a substituted or unsubstituted Ci- C 8 alkyl group, a substituted or unsubstituted C 2 -C 8 alkenyl group, a halogen (particularly bromine), a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted amino group, a nitro group, or a substituted or unsubstituted C ⁇ -C 8 alkoxy group (particularly methoxy).
- Each Y group may be a direct bond, or a "linking moiety" (or “hnking group”) which is a group that is covalently bound to at least two other moieties and may be, for example, a single divalent atom or an oligomethylene group.
- a linking moiety which is a linear chain of carbon atoms may be optionally substituted or unsaturated.
- a linking moiety is relatively small compared to the rest ofthe molecule, and more preferably less than about 250 molecular weight, and even more preferably less than about 75 molecular weight.
- the linldng moiety may also be (CR v R w ) n , CR v SH(CR x R y ) ⁇ , CR v N . w R x (CR y R z ) n , wherein ⁇ each n is independently either 0, 1, 2, or 3, and R v , R w , R x , R y , and R z are each independently hydrogen, a substituted or unsubstituted C 1 -C 5 branched or straight chain alkyl or alkoxy, C 2 -Cs branched or straight chain alkenyl, aryloxycarbonyl, aryl-umnocarbonyl, arylalkyl, acyl, aryl, or C 3 -C 8 ring group.
- “Inhibition" of amyloid deposition includes preventing or stopping of amyloid formation, e.g., fibriUogenesis, inhibiting or slowing down of further amyloid deposition in a subject with amyloidosis, e.g., already having amyloid deposits, and reducing or reversing amyloid fibriUogenesis or deposits in a subject with ongoing amyloidosis.
- amyloid formation e.g., fibriUogenesis
- inhibiting or slowing down of further amyloid deposition in a subject with amyloidosis e.g., already having amyloid deposits
- reducing or reversing amyloid fibriUogenesis or deposits in a subject with ongoing amyloidosis.
- Inhibition of amyloid deposition is determined relative to an untreated subject, or relative to the treated subject prior to treatment, or, e.g., determined by clinically measurable improvement in pancreatic function in a diabetic patient, or in the case of a patient with brain amyloidosis, e.g., an Alzheimer's or cerebral amyloid angiopathy patient, stabilization of cognitive function or prevention of a further decrease in cognitive function (i. e. , preventing, slowing, or stopping disease progression).
- alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (aticyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, de
- alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
- a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C ⁇ -C 6 for straight chain, C3-C6 for branched chain), and more preferably 4 or fewer.
- preferred cycloaUcyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
- the term . 5 Ci-C ⁇ includes al yl groups containing 'l to 6 carbon atoms.
- An "alkylene" group is a divalent moiety derived from the corresponding ahcyl group.
- alkyl includes both "unsubstituted alkyls" and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing one or more hydrogens on one or more carbons ofthe hydrocarbon
- substituents can include, for.example, alkenyl, alkynyl, halogen, hydroxyl, aUcylcarbonyloxy. arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aUcylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl -unino, dialkylamino, arylamino, diarylarnino, and
- alkylarylamino acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, aUcylsulfinyl, sulibnato, sulfamoyl, sulfonamido, nitro, trifiuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
- Cycloalkyls may be further substituted, e.g., with the substituents described above.
- arylalkyl is an alkyl group substituted with an aryl (e. ., ⁇ henylmethyl
- alkylaryl moiety is ah aryl group substituted with an alkyl group (e.g., -methylphenyl (i.e.,p-toly ⁇ )).
- alkyl e.g., -methylphenyl (i.e.,p-toly ⁇ )
- n-alkyl means a straight chain (i.e., unbranched) unsubstituted alkyl group.
- alkenyl includes unsaturated aliphatic groups analogous in length and
- alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), hailched- chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc.), alkyl or alkenyl substituted cycloalkenyl
- alkenyl may further include alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
- a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C ⁇ for straight chain, Cs-Cg for branched chain).
- cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
- C 2 -C6 includes alkenyl groups containing 2 to 6 carbon atoms.
- An "alkenylene" group is a divalent moiety derived from the corresponding alkenyl group.
- aUcenyl includes both "unsubstituted alkenyls" and “substituted alkenyls,” the latter of which refers to alkenyl moieties having substituents replacing one or more hydrogens on one or more carbons of he hydrocarbon backbone.
- substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,.
- alkylcarbonyl alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, a ino (including alkyl amino, diallcylamino, arylarnino, ⁇ arylamino, and alkylarylamino), acylamino
- alkylcarbonylamino, arylcarbonylamino, carbamoyl an ureido amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulf yl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
- alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
- alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cyeloaUcyl or cycloalkenyl substituted alkynyl groups.
- alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
- a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C_-C. for straight chain, C 3 -C6 for branched chain).
- the term C 2 -C6 includes alkynyl groups containing 2 to 6 carbon atoms.
- Ah "alkynylene" group is a divalent moiety derived from the corresponding alkynyl group.
- alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls,” the latter of which refers to alkynyl moieties having substituents replacing one or more hydrogens on one or more carbons ofthe hydrocarbon backbone.
- substituents can include, for example, allcyl groups, aUcynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, diaJkylar nocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, arnino (including alkyl amino, dialkylamino, arylamino, 0 diarylamino, and aUcylarylamino), acylamino (mcluding allcylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkyl
- lower alkyl as used herein means an aUcyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
- Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
- acyl refers to a carbonyl group that is attached through its carbon atom ',0 to ahydrogen (i.e., a formyl), an aliphatic group (e.g., acetyl), an aromatic group (e.g., benzoyl), and the like.
- substituted acyl includes acyl groups where one or more ofthe hydrogen atoms on one or more carbon atoms are replaced by, for example, an alkyl group, alkynyl group, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, 5 aucoxycarbonyl, arninocarbonyl, alkylaminocarbonyl, cUalkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, arnino (including alkyl amino, dialkylamino, arylamino, diarylamino, and aJkylarylarnino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl
- acylamino includes moieties wherein an amino moiety is bonded to an acyl group.
- the acylamino group includes aUcylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
- alkoxyalkyl include allcyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone.
- alkoxy or "alkyloxy” include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
- alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
- substituted alkoxy groups include halogenated alkoxy groups.
- the alkoxy groups can be substituted with groups such as alkenyl, aUcynyl, halogen, • hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, aUcoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including aUcylcarbonylamino, arylc-ffbonylamr ⁇ o, carbamoyl and ureido), amidino, imino, sulfhydryl, aUc
- halogen substituted alkoxy groups include, but are not limited to, fiuoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc., as well as perhalogenated aUcyloxy groups.
- amine or "a ino” includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom;
- alkyiamino includes groups wherein the nitrogen is bound to at least one alkyl group.
- diaUcyla ino includes groups, wherein the nitrogen atom is bound to at least two alkyl groups.
- arylamino and diarylamino include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
- aUcylarylamino refers to an arnino group which is bound to at least one alkyl group and at least one aryl group.
- alkaminoaUcyl refers to an aUcyl, aUcenyl, or alkynyl group substituted with an alkyiamino group.
- amide or "aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
- carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
- moieties which contain a carbonyl include aldehydes, ketones, carboxyMc acids, amides, esters, anhydrides, etc.
- ether or “ethereal” includes compounds or moieties which contain an oxygen bonded to two carbon atoms.
- an ether or ethereal group includes "alkoxyalkyl” which refers to an aUcyl, alkenyl, or alkynyl group substituted with an alkoxy group.
- 'liydroxy or "hydroxyl” includes the groups -OH or -0 ⁇ (with an appropriate counter ion).
- halogen includes fluorine, bromine, chlorine, iodine, etc.
- perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
- ArylenediaUcylene or arylenedialkyl groups include those groups which have an arylene group to which are bound two other alkylene groups, which may be the same or different, and which two alkylene groups are in turn bound to other moieties.
- Examples of arylenedialkylene or arylenediaUcyl groups include the following:
- each R group is independently a hydrogen (preferred) or is selected from the group Z defined above, and l ⁇ f ⁇ S, l ⁇ g ⁇ 8, 0 ⁇ h_f#.
- Alkylenediarylene groups include groups which have an alkylene (or cycloalkylene) group to which are bound two other arylene groups, which may be the same or different, and which two aUcylene groups are in turn bound to other moieties.
- alkylene (or cycloalkylene) group to which are bound two other arylene groups, which may be the same or different, and which two aUcylene groups are in turn bound to other moieties.
- Examples of aUcylenediarylene groups include the following:
- each R group is independently a hydrogen (preferred) or is selected from the. group Z defined above, l ⁇ y ⁇ 10 (preferably l ⁇ y ⁇ 4), l ⁇ f ⁇ 8, l ⁇ g ⁇ 8, 0 ⁇ b ⁇ 4, and 0 ⁇ i ⁇ 4.
- HeteroarylenediaUcylene or heteroarylenediaUcyl groups include those groups which have a heteroarylene group to which are bound two other aUcylene groups, which may be the same or different, and which two alkylene groups are in turn bound to other moieties.
- Examples of heteroarylenedialkylene or heteroarylenediaUcyl groups include the following:
- R' is hydrogen, a C1-C5 aUcyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group), 0, or S, l ⁇ f 8, l ⁇ g ⁇ 8,
- R' is hydrogen, a C1-C5 aUcyl, C2-C5 alkenyl, C 2 -Cs alkynyl, or aryl group
- O or S, l ⁇ f ⁇ 8, l ⁇ g ⁇ 8,
- each R group is independently a. hydrogen (preferred) or is selected from the group Z defined above, l ⁇ f ⁇ 8, l ⁇ g ⁇ 8, and h and i are as indicated.
- An arylene group is an aromatic group which is capable of being connected covalently to other substituents through at least two positions, mcluding the foUowing examples:
- each R group is independently a hydrogen (preferred) or is selected from the group Z defined above, and 0 ⁇ h ⁇ 4; for example:
- a heteroarylene group is a heteroaromatic group which is capable of being connected covalently to other substituents through at least two positions, including the Mowing examples:
- X NR' (wherein R' is hydrogen, a C 1 -C5 alkyl, C 2 -C 5 aUcenyl, C 2 -C5 aUcynyl, or aryl group), 0, or S,
- each R group is independently a hydrogen (preferred) or is selected from the group Z defined above, and h and i are as indicated; for example, the following groups:
- the invention relates to the following heteroarylene groups
- R' is hydrogen, a C 1 -C 5 aUcyl, C 2 -Cs alkenyl, C 2 -C 5 alkynyl, or aryl group), 0, or S; 0 ⁇ f ⁇ 8, 0 ⁇ g ⁇ 8; and each R group is independently a hydrogen (preferred) or is selected from the , group Z defined above.
- aryl includes groups, including 5- and 6-membered single- ring aromatic groups that may include from zero to four heteroatoms, for example, groups derived from benzene, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
- aryl includes multicyclic aryl groups, e.g., groups derived from tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
- aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles,” “heterocycles,” “heteroaryls” or “heteroaromatics”.
- An aromatic ring can be substituted at one or more ring positions with such . substituents as described above, as for example, halogen, hydroxyl, aUcyl (e.g.
- Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g. , tetralin).
- heterocyclic or “heterocycle” includes heteroaryls as well as any ring formed which incorporate a heteroatom or an atom which is not carbon.
- the ring may be saturated or unsaturated and may contain one or more double bonds.
- preferred heterocyclic groups include pyridyl, furanyl, thiophenyl, morpholinyl, and indolyl groups.
- heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
- arylene is a divalent moiety derived from an aryl group.
- An oligoethereal group such as- an oligo(alkyleneoxide) group, includes polyethyleneglycol (PEG) and short chain analogs thereof including — [(CR2) s O]t(CR2)s — , wherein l ⁇ t ⁇ 6 and l ⁇ s ⁇ 6, and each R group is independently a hydrogen (preferred) or is selected from the group Z defined above.
- PEG polyethyleneglycol
- R group is independently a hydrogen (preferred) or is selected from the group Z defined above.
- An arylene-di(oligoaUcyleneoxide) group is an aryl group which has two oligoaUcyleneoxide groups bound to it which in turn are bound to other moieties, and include the following examples:
- arylene- di(oligoahcyleneoxide) groups include:
- each R group is independently a hydrogen (preferred) or is selected from the group Z defined above.
- substituted means that the moiety has substituents placed on the moiety other than hydrogen which allow the molecule to perform its intended function.
- substituents include moieties selected from straight or branched aUcyl (preferably C 1 -C 5 ), cycloaUcyl (preferably C 3 -C 8 ), aUcoxy (preferably C ⁇ -C frustration), thioaUcyl (preferably C ⁇ -C 6 ), alkenyl (preferably C 2 -C ⁇ ), aUcynyl (preferably C 2 -C6), heterocyclic, carbocyclic, aryl (e.g. , phenyl), aryloxy (e.g.
- phenoxy aralkyl (e.g. , benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl .and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR'R")o- 3 NR'R" (e.g., -NH 2 ), (CR'R")o_ 3 CN (eg., -CN), N0 2 , halogen (e,g., F, CI, Br, or I), (CR'R")o_ 3 C(halogen) 3 (e.g., -CF 3 ), (CR'R")o_ 3 CH(halogen) 2 ,
- aralkyl e.g. , benzyl
- aryloxyalkyl e.g., phenyloxyalkyl
- (CR'R")o- 3 C 3 -C 8 cycloalkyl
- (CR'R")o- 3 C0 2 R' e.g., -C0 2 H
- (CR'R")o- 3 OR' group or the side chain of any naturally occurring arnino acid
- R' and R" are each independently hydrogen, a C 1 -C 5 alkyl, Q 2 -C5 alkenyl, C 2 -Cs alkynyl, or aryl group, or R' and R" taken together are a benzylidene group or a -(CH 2 ) 2 0(CH 2 ) 2 - group.
- substitutions enhance the ability ofthe compounds ofthe invention to perform its intended function, e.g., inhibit formation of amyloid deposits.
- X 1 X 2 in molecules of Formula I.
- One group of preferred compounds ofthe invention are those of Formula la:
- R andR together, or R andR together, represent a C 2 to C 3 alkylene;
- R cl and R° 2 are H;
- R hl is H;
- R h2 is OCH 3 or 0(C 6 H 4 )R, wherein R is H or lower-alkyl, and
- X is 0, NR' (wherein R' is hydrogen, a C 1 -C5 alkyl, C 2 -C5 alkenyl, C 2 - Cs aUcynyl, or aryl group), or S.
- ⁇ ' is hydrogen, a C 1 -C5 alkyl, C 2 -C5 alkenyl, C 2 - Cs aUcynyl, or aryl group
- R al and R bl together, or R a2 and R b2 together represent a C 2 linear, saturated aUcylene;
- R 01 and R c2 are -(lower aUcyl)- OH; and
- R hl and R h2 are each H.
- the "lower aUcyl" group of R cl and R c2 are preferably ethylene.
- R andR l together, or R 32 and R b2 together, represent a C aUcylene
- R cl and R c2 are H (preferred), lower alkyl, . cycloaUcyl, aryl, hydroxyaUcyl, aminoaUcyl or alkylaminoalkyl
- R hl and R h2 are independently selected from the group consisting of H (preferred), lower alkyl, halogen, alkoxy, aryloxy, or arylalkoxy.
- R al , R ⁇ , R l and R 2 are H; R cl and R 02 are isopropyl or -(CH 2 ) 3 N(CH 3 ) 2 ; and R M and R 112 are H.
- R a2 and R 2 together, represent a phenylene group which is optionally substituted with up to three -CONHR d NR e R f groups where R d is lower aUcyl and R e and R f are each independently selected from the group consisting of H or lower alkyl; and R o1 , R ⁇ , R M , and * 2 are H.
- An especially preferred compound of Formula la has R hl , R M , R l , R o1 , R b2 , and R 02 being H, and al and R" 2 groups being hydroxy or methoxy.
- Another group of preferred compounds are those of Formula lb:
- R ⁇ and R 1 ⁇ are each independently selected from the jgroup consisting of H, loweralkyl, aryl, aUcylaryl,- aminoalkyl, aminoaryl, halogen, alkoxy, aryloxy, or oxyarylalkyl;
- R 1 and R 2 are each independently selected from the group consisting of H, loweralkyl, alkoxy, aUcylaryl, aryl, aryloxy, aminoaUcyl, aminoaryl, or halogen; and each R aI , R" 2 , R l , and R b2 group is independently selected from the group consisting of H, loweraUcyl, aUcoxyaUcyl, hydroxyalkyl, aminoaU
- R l , R b2 , R cl , and R° 2 are each independently selected from the group consisting of H, loweraUcyl, alkoxy, alkoxyalkyl, cycloaUcyl, aryl, hydroxyaUcyl, aminoalkyl or aUcylaminoalkyl;
- R 1 and R 2 are H, lower aUcyl, alkoxy, aUcoxyalkyl, hydroxyaUcyl, cycloaUcyl, aryl, aminoalkyl, alkylaminoalkyl or halogen;
- R al and R ⁇ are - OY, or R al and R bl together, or R a2 and R ⁇
- Y is H or lower alkyl; each of X 1 and X 2 are -(CH 2 ) n -, where n is an integer from 0 to 2; and R hl and R l ⁇ are each independently selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxy, or oxyarylalkyl.
- Yet another group of preferred compounds are those of Formula lc, wherein M is -(CH 2 ) n - where n is an integer from 2 to 16 (or 2 to 12, or 2 to 10); each of X 1 and X 2 is O, NH, or S; R al , R 32 , R bl , and R 2 are H; or R al and R bl together, or R ⁇ and R 2 together represent ⁇ (CH 2 ) m -, wherein m is 2, 3, or 4; each of R 1 and R 2 are H, OCH 3 , N0 2 or NH 2 ; R cl and R c2 are-H, CH 3 or CH 2 CH 3 .
- R 1 and R Gl cannot be H
- X 2 is O or S
- R 2 and R c2 cannot be H.
- Another group of preferred compounds are those of Formula Id:
- each R al , R a2 , R l , and R b2 are independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloaUcyl, aryl, or aUcylaryl; or two R Bl and R bI together, or R ⁇ and R b2 together represent C 2 -C ⁇ o aUcylene;
- R cl and 02 are independently H, hydroxy, loweraUcyl, alkoxyalkyl, hydroxyaUcyl, aminoalkyl, aUcylaminoaUcyl, cycloalkyl, aryl, or aUcylaryl; and
- R' is H, loweraUcyl, alkoxyalkyl, hydroxyaUcyl, aminoalkyl, aUcylaminoaUcyl, cycloaUc
- M is an aUcylene group (e.g., C 2 to C ⁇ _), and X 1 and X 2 are oxygen.
- R al and R bl together, or R" 2 and R b2 together, represent a C 2 linear, saturated aUcylene; R cl and R° 2 are H.
- Another group of preferred compounds ofthe invention are those of Formula Ha:
- Y 1 , Y 2 , Z, and R 1 are as defined above; n is 0 - 4; Y 2 is preferably 0, NH, S, a substituted or unsubstituted methylene group, or a direct bond; Z may be a hydrogen atom, or Z is preferably alkyl, aryl, alkoxy, aryloxy, hydroxy, a substituted or unsubstituted arnino, nitro, sulfo, or halogen group; R al , R bl , and R cl are independently hydrogen, lower alkyl, aromatic, hydroxyl, or alkoxy; and B is a direct bond or a substituted or unsubstituted aUcylene group containing from 1 to 16 carbon atoms, or abiphenylene group, or a combination biphenylene-aUcylene group, the group -[(CH 2 ) n O] tn (CH 2 ) n - where mis 1
- R al , R" 2 , R l , andR b2 are each independently selected from the group consisting of H, lower alkyl, aUcoxyaUcyl, cycloaUcyl, aryl, aUcylaryl, hydroxyaUcyl, aminoaUcyl, or alkylaminoalkyl; or R al and R bl together, or R ⁇ and R b2 together represent a C 2 to C 1 0 alkyl, hydroxyaUcyl, or alkylene; or R al and R bl together, or R ⁇ and R b2 together are:
- n is a number from 1 to 3
- R 10 is H or -CONHR n NR 15 R 16
- R 11 is lower 'alkyl and R 15 and R l ⁇ are each independently selected from the group consisting of H and lower alkyl
- R cl and R° 2 are H, hydroxy, lower alkyl, cycloalkyl, aryl, aUcylaryl, alkoxyalkyl, hydroxycycloalkyl, alkoxycycloalkoxy, hydroxyaUcyl, aminoaUcyl or alkylarninoalkyl
- R hl and R M are.each independently selected from the group consisting of H, lower alkyl, halogen, aryl, arylalkyl, aminoaUcyl, aminoaryl, alkoxy, aryloxy, or oxyarylalkyl.
- R 1 and R 2 are independently H or -CONHR 5 NR 6 R 7 , wherein R 5 is lower alkyl, R 6 and R 7 are each independently selected from the group consisting of H and lower alkyl;
- R al , R a2 , R l , and R b2 are independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloaUcyl, aryl, or alkylaryl, or R al and R bl together, or R 22 and R 2 together represent C 2 -C ⁇ o aUcylene;
- R o1 and R° 2 are independently H, hydroxy, lower allcyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, aUcylaminoaUcyl, cycloaUcyl, aryl, or alkylaryl;
- the present invention relates to pharmaceutical compositions comprising compounds according to any of the Formulae herein for the . treatment of an amyloid-related disease, as well as methods of manufacturing such pharmaceutical compositions.
- the compounds ofthe invention can be formulated to ensure proper distribution in vivo.
- the blood-brain barrier (BBB) excludes many highly hydrophiHc compounds.
- BBB blood-brain barrier
- they can be formulated, for example, in liposomes.
- methods of 5 manufacturing liposomes see, e.g., U.S. Patent Nos.4,522,811; 5,374,548; and 5,399,331.
- the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs ("targeting moieties"), thus providing targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin. Pharmacol. 29:685).
- targeting moieties moieties which are selectively transported into specific cells or organs
- Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent No. 0 5,416,016 to Low et al); mannosides (Umezawa et al. (1988) Biochem. Biophys. Res.
- the therapeutic compounds ofthe invention are formulated in liposomes; in a more preferred embodiment, the liposomes include a targeting moiety.
- BBB transport vectors include cationized albumin or the 0X26 monoclonal antibody to the transferrin receptor; . these proteins undergo absorptive-mediated and receptor-mediated transcytosis through the BBB, respectively.
- BBB transport vectors examples include factors such as insulin, msulin-like growth factors (IGF-L IGF-II), angiotensin EC, atrial and brain natriuretic peptide (ANP, BNP), interleuldn I (IL-1) and transferrin. Monoclonal antibodies to the receptors which bind these factors may also be used as BBB transport vectors.
- BBB transport vectors targeting mechanisms for absorptive-mediated transcytosis include catiomc moieties such as cationized LDL, albumin or horseradish peroxidase coupled with polylysine, cationized albumin or cationized immunoglobulins.
- Small basic oligopeptides such as the dvnorphin analogue E-2078 and the ACTH analogue ebiratide can also cross the brain via absorptive-mediated transcytosis ' and are potential transport vectors.
- BBB transport vectors target systems for transporting nutrients into the brain.
- BBB transport vectors include hexose moieties, e.g. glucose, monocarboxylic acids, e.g. lactic acid, neutral amino acids, e.g. phenylalanine, amines, e.g. choline, basic arnino acids, e.g. arginine, nucleosides, e.g. adenosine, purine bases, e.g. adenine, and thyroid hormone, e.g. triiodothyridine.
- Antibodies to the extracellular domain of nutrient transporters can also be used as transport vectors.
- Other possible vectors include angiotensin II and ANP, which maybe involved in regulating BBB permeability.
- the bond linking the therapeutic compound to the transport vector may be cleaved following transport into the brain in order to liberate the biologically active compound.
- exemplary linkers include disulfide bonds, ester-based linkages, thioether
- Avidin/biotin linkers in which avidin is covalently coupled to the BBB drug transport vector, may also be used. Avidin itself may be a drug transport vector.
- the therapeutic compound may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
- the therapeutic compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
- Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
- Liposomes include water-in-oil-in-water CGF emulsions as weU as conventional liposomes (Strejan et al, (1984) J. Neuroimmunol. 7:27).
- the therapeutic compound may also be administered parenterally, intraperitoneaUy, intraspinally, or intracerebrally.
- Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage • and use, these preparations may contain a preservative to prevent the growth of microorganisms.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable . under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol,.polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
- Prolonged absorption ofthe injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
- Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder ofthe active ingredient (i,e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the therapeutic compound- can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
- the therapeutic compound and other ingredients may also be enclosed in a hard or soft sheU gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
- the 5 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 ofthe therapeutic compound in the compositions and preparations may, of course, be varied.
- the amount ofthe therapeutic compound in such therapeutically useful compositions is such that a suitable dosage wiU be obtained.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical
- the present invention therefore includes pharmaceutical formulations comprising the compounds ofthe Formulae described herein, including pharmaceuticaUy acceptable salts thereof, in pharmaceutically acceptable carriers for aerosol, oral and parenteral administration. Also, the present invention includes such compounds, or salts thereof, which have been lyophilized and which may be reconstituted to form pharmaceutically
- acceptable formulations for administration as by intravenous, intramuscular, or subcutaneous injection. Administration may also be intradermal or transdermal.
- a compound ofthe Formulae described herein, and pharmaceutically acceptable salts thereof maybe administered orally or through inhalation as a solid, or may be administered intramuscularly or intravenously as a solution, 30 suspension or emulsion. Alternatively, the compounds or salts may also be administered by inhalation, intravenously or intramuscularly as a liposomal suspension.
- Pharmaceutical formulations are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension ofthe desired compound of any Formula herein, or a salt thereof, or a plurality of solid particles of the compound or salt. The desired formulation may be placed in a small chamber and nebulized.
- Nebulization may be accomphshed by compressed air or by ultrasonic energy to form a plurality of Hquid droplets or solid particles comprising the compounds or salts.
- the • liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns.
- the solid particles can be obtained by processing the solid compound of any Formula described herein, or a salt thereof, in any appropriate manner known in the art, such as by micronization. Most preferably, the size ofthe solid particles or droplets will be from about 1 to about 2 microns. En this respect, commercial nebulizers are available to achieve this purpose.
- the formulation suitable for adrninistration as an ' aerosol when the pharmaceutical formulation suitable for adrninistration as an ' aerosol is in the form of a liquid, the formulation will comprise a water-soluble compound of any Formula described herein, or a salt thereof, in a carrier which comprises water.
- a surfactant may be present which lowers the surface tension of he formulation sufficiently to result in the formation of droplets within the desired size range when subjected to nebulization.
- Active compounds are administered at a therapeutically effective dosage sufficient to inhibit amyloid deposition in a subject.
- a "iherapeuticaUy effective" dosage preferably inhibits amyloid deposition by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
- a ''therapeutically effective" dosage stabilizes cognitive function or prevents a further decrease in cognitive function (i.e., preventing, slowing,, or stopping disease progression).
- the ability of a compound to inhibit amyloid deposition can be evaluated in an animal model system that may be predictive of efficacy in inhibiting amyloid deposition in human diseases, such as a transgenic mouse expressing human APP or other relevant animal models where A ⁇ deposition is seen. Likewise, the ability of a compound to prevent or reduce cognitive impairment in a model system may be indicative of efficacy in humans. Alternatively, the ability of a compound can be evaluated by examining the ability of the compound to inhibit amyloid fibril formation in vitro, e.g., using a fibriUogenesis assay such as that described herein, including a ThT, CD, or EM assay. Also the binding of a compound to amyloid fibrils maybe measured using a MS assay as described herein.
- the present invention is also related to prodrugs ofthe compounds ofthe Formulae disclosed herein.
- Prodrugs are compounds which are converted in vivo to active forms (see, e.g., R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp. 8).
- Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typicaUy enter the reactive site ofthe protease) or the pharmacolcinetics for a particular compound.
- a carboxyhc acid group can be esterified, e.g., with a methyl group or an ethyl group to yield an ester.
- the ester is administered to a subject, the ester is cleaved, enzymaticaUy ornon-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
- An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
- the prodrug moieties may be metabolized in vivo by esterases or by other mechanisms to carboxylic acids.
- prodrugs examples include but not limited to, Berge et al. (1977) 'Tharmaceutical Salts", J. Pharm. Sci. 66:1-19).
- the prodrugs can be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form with a suitable derivatizing agent.
- Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst.
- cleavable carboxyhc acid prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., ethyl esters, propyl esters, butyl esters, pentyl esters, cyclopentyl esters, hexyl esters, cyclohexyl esters), lower alkenyl esters, dilower aUcyl-amino lower-aUcyl esters (e.g., dimemylaminoethyl ester), 5 acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower aUcyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituent
- the structures of some ofthe compounds of this invention 0 include stereogenic carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention unless indicated otherwise. That is, unless otherwise stipulated, any chiral carbon center maybe of either (R)- or (S)-stereochemistry. Such isomers can be obtained in substantially pure form by classical separation techniques and by L5 stereochemically controlled synthesis. Furthermore, alkenes caninclude either the E- or Z- geometry, where appropriate.
- Certain embodiments ofthe present compounds can contain a basic functional group, such as amino or aUcyla ino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
- pharmaceutically !0 acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds ofthe present invention. These salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
- Representative salts include the hydrohalide (including hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethylsulfonate, and laurylsulphonate salts and the like.
- hydrohalide including hydrobromide and hydrochloride
- the compounds ofthe present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
- pharmaceutically acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds ofthe present invention.
- salts can likewise be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
- a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
- Representative alkali or alkaline earth salts include the Uthium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
- Representative organic amines ' useful for the formation of base addition salts include ethyl-mine, (fiethylamine, ethylenediamine, ethanolamine, die anolamine, piperazine and the like.
- Test compounds were purchased from commercial sources or synthesized and screened by thioflaviti T fluorescent assay ("ThT assay”). Alternatively, one could screen test compounds by circular dichroism (“CD”), electron microscopy (“EM”), or mass spectroscopy (“MS”) assays.
- CD circular dichroism
- EM electron microscopy
- MS mass spectroscopy
- the thioflavin T fluorescent assay for fibriUogenesis is based on the principle that the fluorescent dye, thioflavin T, binds specifically to fibrillar, but not to unaggregate A ⁇ peptide (LeVine HI, H., 1993, Protein Science 2:404-410). Upon binding, thioflavin T develops a characteristic fluorescence (Naiki, H., et al., 1996, Lab. Invest.74: 374-383) • which can be easily detected. The dye is believed to interact with the stacked cross- ⁇ pleated sheets, the common structural motif of all amyloid (LeVine HI, H., 1995, Amyloid: Int. J. Exp. Clin Invest..2:1.6).
- Tl ⁇ oflavin T is widely used to assay the effect of compounds on fibriUogenesis of A ⁇ peptide and other amyloid proteins (Bronfman, P.C, et al., 1995, Neuroscience Lett.218:201-203).
- test compounds are incubated with a solution of A ⁇ (1-40) (20 ⁇ M) or LAPP (10 ⁇ M) containing 5 uM Thioflavin T, in 0.02M Tris/0.02M acetate/0.15M NaCl/0.005% azide/pH 7.40 at 37°C in sealed 384 well microplates. Readings (ex 430 nrn/em ' 485nm) are taken at various time intervals with a microplate fluorescence reader.
- a ⁇ peptide A ⁇ (1-40) 95% purity (American Peptide Company, ⁇ nc, Sunnyvale, Cai. USA) is disaggregated in trifluoroacetic acid and filtered through a 0.02 ⁇ M filter, (Whatman Anotop 25 plus, 0.02 ⁇ m, Catalogue no. 6809 4102) in hexafluoroisopropanol (HFIP). Solutions of A ⁇ (1-40) or LAPP at 600 ⁇ m in HFEP are stored at -80°C. Assay mixture: The mixture is prepared as two solutions which are combined upon addition to the 384 well microplate (Corning Costar cat. 3705).
- Solution A consists of test compounds in 0.02M Tris/0.02M acetate/0.15M NaCl 0.01 % azide at pH 7.40 or buffer alone (control),
- Solution B consists of A ⁇ (1-40) 40 ⁇ M or LAPP 20 ⁇ M, Thioflavin T 10 mM in 0.02M Tris/0.02M acetate/0.15M NaCl at pH 7.40. This solution is prepared by drying the A ⁇ peptide under nitrogen and then resuspending this in 0.04M Tris base with 15 minutes sonication. An equal volume of 0.04M acetic acid containing 0.3 M NaCl is added and the solution is adjusted to 7.40 ⁇ 0.02. A smaU volume of 20 mM Thioflavin T is added to the solution to give a final 5 ⁇ M concentration of Thioflavin T.
- microplate is loaded with 40 ⁇ L of solution A followed by 40 ⁇ L of solution
- the plate is sealed and loaded into the microplate fluorescence reader.
- Fluorescence measurement data analysis The HTS-7000 Bio Assay Reader, Perkin Elmer, is used to perform kinetic runs of about 1 day. Readings were talcen at 15 minute intervals, with one minute shaking before each read. Bandpass filters used were: excitation 430 nm, emission 485 mm.
- each sample was sonicated for 1 min to disrupt large clumps before testing.
- the sample (5- ⁇ L aliquot) was placed on freshly cleaved mica and aUowed to air dry.
- the mica was placed in a Balzers High-vacuum, Freeze-EtchUnit (model 301), shadowed with platinum (30° angle), and coated with a carbon film.
- the repHca was removed from the mica by flotation and transferred onto a 300-mesh copper grid. Samples were examined using a Joel 2000 FX transmission electron microscope.
- CD circular dichroism
- MS mass spectroscopy
- the present invention also relates to novel compounds and the synthesis thereof. Accordingly, the following examples are presented to illustrate how some of those compounds may be prepared.
- Step 1 a, a>-bis(4-cyanophen ⁇ sXy)alkanes
- Step 1 l-(4-cyano)phenoxy-8-bromooctane
- amidine compounds were obtained by serial treatments with saturated ethanolic hydrochloride solution and ethanolic ammonia analogously as described above.
- Step 3 l-(4-amidinophenoxy)-8-bromooctane, hydrobromide
- Step 3 9-(4-cyanophenoxy)nonanoic acid, ethyl ester
- thionyl chloride (0.88 mL, 12 mmol) was added to • • anhydrous ethanol (50 mL).
- the mixture was stirred for 10 min, then 9-(4- cyanophenoxy)nonanoic acid (1.65 g, 6.02 mmol) was added in one portion.
- the reaction was monitored by TLC. Upon completion ofthe reaction,.ethanol was removed under 5 reduced pressure. Ether (100 mL) and saturated sodium bicarbonate solution (100 mL) was added. The organic phase was separated and dried over sodium sulfate.
- the product (1.6 g, 87.7 % yield) was obtained as a white sohd after evaporation ofthe solvent.
- Step 4 9-(4-amidinophenoxy)nonanoic acid hydrochloride
- Step 1 l,5-Bis(4-cyano-2-methoxyphenoxy)pentane
- the white solid obtained was placed into a 50-mL round-bottom flask and ammonia ethanol solution (2 M, 30 mL) was added slowly via syringe. The resulting mixture was stirred at reflux for 3h. After the mixture was cooled to room temperature, diethyl ether (100 mL) was added and a white precipitate formed. The precipitate was collected and washed
- the crude product was purified by preparative RP-HPLC (Vydac C18, 215 nm, 50 mL/min, 0 % to 90 % MeCN in H 2 0 containing 0.1 % TFA) and lyophilized to give a white solid, 127.2 mg, 42%.
- the heptane and nonane anolags were prepared in the same way. .
- Step 1 To a cold solution (0 °C) of 1,5-diaminopentane (0.35 mL, 3 mmol) and triethylamine (0.98 mL, 7 mmol) in DMF (10 mL) was added 4-cyanobenzoyl chloride (1 g, 6 mmol). The mixture was stirred overnight at room temperature, and then diluted with
- Step 2 A suspension ofthe l,5-bis-(4-cyanobenzamido)pentane (465 mg, 1.3 rnmol), in a mixture of absolute ethanol (25 mL) and 1,4-dioxane (20 mL), was cooled to 0 °C, saturated with dry HCl, and the resulting mixture was stirred for 60 hours at room
- Step 1 A mixture of 4-hydroxybenzaldehyde (2.7 g, 22 mmol), 1,5-dibromopentane (1.35 mL, 10 mmol) and potassium carbonate (5.2 g) in dry DMF (25 mL) was heated at 100 °C with an oil bath for 5 hours. The mixture was cooled to room temperature, then water (100 mL) was added. The sohd that formed was collected by filtration, rinsed with water and dried in vacuo. The desired bis-aldehyde was obtained as a brownish sohd, 2.8 g, 89 %.
- Step 2 Diisopropyl (cyanomethyl)phosphonate (0.86 mL, 4.2 mmol) was added to suspension of sodium hydride (4.4 mmol) in THF at (0 °C). The mixture was stirred at room temperature for 1 hour. A solution ofthe bis-aldehyde (2 mmol) THF was added. The mixture was stirred at room temperature for 2h, then diluted with ethyl acetate, washed subsequently with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The crude solid was washed with a mixture of ethyl acetate and hexane (1 to 10, 10 mL) the dried in vacuo to afford the bis-nitrile, 0.51 g, 71 % yield.
- Step 3 A suspension ofthe bis-nitrile (0.48 g, 1.34 mmol) in ethanol (20 mL) was saturated with HCl at 0 °C. The mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure. The solid was then dissolved in 2 N NH 3 in ethanol (20 mL) and the mixture was heated at reflux for 2h. The mixture was cooled to room-temperature and the solvent was evaporated under reduced pressure. The resulting soHd was dried in vacuo, then recrystallized from 2 N HCl with the addition of a few drops of ethanol. The solid was collected by filtration, rinsed with water and dried overnight in vacuo, giving the title compound as a light yellow solid, 0.44 g, 71 %. Compound #137
- Step 1 Am t ⁇ e of4-hy ⁇ roxybenzylcyanide (2.56 g, 19.2 mmol), 1-7- dibromoheptane (1.49 mL, 8,7 mmol), potassium carbonate (11 g) in DMF (30 mL) was heated with an oil bath at 100 °C for 3 hours. The mixture was cooled to room temperature and diluted with water (150 mL). A sohd precipitated. The solid was collected by filtration and rinsed with water. It was then dissolved in ethyl acetate, washed subsequently with 10% NaOH (3 20 mL), brine (30 mL) and dried ' over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting solid was dried in vacuo to give the 1,7- bis(4-cyanomethylphenoxy)heptane as a tan solid, 2.58 g, 82 %.
- Step 2 A solution of l,5-bis(4-cyanomethylphenoxy)heptane (750 mg, 5.07 mmol) in a mixture of 1,4-dioxane (10 mL) and absolute ethanol (10 mL) was saturated with HCl at 0 °C. The mixture was then stirred at room temperature for the 3 days. The solvent was evaporated under reduced pressure and the residue was dried in vacuo. The residue was ' dissolved in 2 N ammonia in ethanol (20 mL) and the mixture was heated at reflux for 3h. The solvent was evaporated under reduced pressure. The crude solid was recrystallized from 2 N HCl / acetone. The crystals were collected and dried in vacuo. The title compound was obtained as an off-white solid, 655.3 mg, 60 %.
- Step 1 A solution of borane:tefrahydrofura ⁇ complex (10 mL, 10 mmol) was added to a solution ofthe bis-nitrile (510 mg, 1.53 mmol) at 0 °C. The mixture was then heated at reflux for 18 hours, then cooled with an ice bath. The excess of reagent was quenched by the slow addition of methanol (10 mL). The resulting mixture was heated at reflux for 15 minutes, then the solvent was removed under reduced pressure. The residue was coevapotated 3 times with methanol, then suspended in mixture of methanol (20 rnL) and concentrated HCl (6 mL). The mixture was heated at reflux for 1.5 hour. The mixture was then reduce to about 5 mL under reduced pressure.
- the mixture was diluted with chloroform, washed subsequently with 1 NHC1, saturated sodium carbonate,brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure.
- the crude product was purified by flash chromatography on silica gel (0.5 % to 1% MeOH in CHC1 3 ) giving a white foamy sohd 246.5 mg, 26 %.
- Step 3 A solution of 4 M HCl in 1,4-dioxane (5 mL) was added to a solution ofthe protected bis guanidino compound (246 mg, 0.297 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for one day. The solvent was evaporated under reduced pressure. The product was dissolved in water, then the aqueous soultion was lyophilized, giving the title compound as a white solid, 146.4 mg, 99 %.
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Application Number | Priority Date | Filing Date | Title |
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JP2004510719A JP2006501160A (en) | 2002-06-07 | 2003-06-09 | Amidine derivatives for the treatment of amyloidosis |
AU2003251418A AU2003251418A1 (en) | 2002-06-07 | 2003-06-09 | Amidine derivatives for treating amyloidosis |
CA002488493A CA2488493A1 (en) | 2002-06-07 | 2003-06-09 | Amidine derivatives for treating amyloidosis |
EP03757414A EP1572129A4 (en) | 2002-06-07 | 2003-06-09 | Amidine derivatives for treating amyloidosis |
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US38700102P | 2002-06-07 | 2002-06-07 | |
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EP (1) | EP1572129A4 (en) |
JP (1) | JP2006501160A (en) |
AU (1) | AU2003251418A1 (en) |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005079780A1 (en) * | 2004-01-23 | 2005-09-01 | Neurochem (International) Limited | Amidine derivatives for treating amyloidosis |
EP1663959A1 (en) * | 2003-09-05 | 2006-06-07 | University Of North Carolina At Chapel Hill | Novel amidine compounds for treating microbial infections |
EP1682518A1 (en) * | 2003-10-24 | 2006-07-26 | University Of North Carolina At Chapel Hill | Dicationic triaryl analogs as anti-protozoan agents |
EP1719767A1 (en) * | 2005-05-05 | 2006-11-08 | The University of North Carolina at Chapel Hill | Synthesis and antiprotozoal activity of dicationic 3,5-diphenylisoxazoles |
US7262223B2 (en) * | 2004-01-23 | 2007-08-28 | Neurochem (International) Limited | Amidine derivatives for treating amyloidosis |
JP2008533151A (en) * | 2005-03-14 | 2008-08-21 | トランス テック ファーマ,インコーポレイテッド | Benzazole derivatives, compositions and methods of use as beta-secretase inhibitors |
FR2933692A1 (en) * | 2008-07-10 | 2010-01-15 | Univ Nancy 1 Henri Poincare | NOVEL COMPOUNDS, THEIR USE AS MEDICAMENTS, AND PROCESS FOR THEIR PREPARATION |
US8454979B2 (en) | 2009-02-20 | 2013-06-04 | Meisho Co., Ltd. | Immunopotentiating composition and process for producing same |
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HRP20220401T3 (en) * | 2008-02-14 | 2022-05-27 | Eli Lilly And Company | Novel imaging agents for detecting neurological dysfunction |
Citations (1)
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WO2003017994A1 (en) * | 2001-08-31 | 2003-03-06 | Neurochem (International) Limited | Amidine derivatives for treating amyloidosis |
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US6635668B1 (en) * | 1998-07-22 | 2003-10-21 | The University Of North Carolina At Chapel Hill | Imidazoline receptor binding compounds |
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- 2003-06-09 EP EP03757414A patent/EP1572129A4/en not_active Withdrawn
- 2003-06-09 WO PCT/US2003/017992 patent/WO2003103598A2/en not_active Application Discontinuation
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WO2003017994A1 (en) * | 2001-08-31 | 2003-03-06 | Neurochem (International) Limited | Amidine derivatives for treating amyloidosis |
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1663959A1 (en) * | 2003-09-05 | 2006-06-07 | University Of North Carolina At Chapel Hill | Novel amidine compounds for treating microbial infections |
EP1663959A4 (en) * | 2003-09-05 | 2007-10-31 | Univ North Carolina | Novel amidine compounds for treating microbial infections |
EP1682518A1 (en) * | 2003-10-24 | 2006-07-26 | University Of North Carolina At Chapel Hill | Dicationic triaryl analogs as anti-protozoan agents |
EP1682518A4 (en) * | 2003-10-24 | 2007-08-01 | Univ North Carolina | Dicationic triaryl analogs as anti-protozoan agents |
WO2005079780A1 (en) * | 2004-01-23 | 2005-09-01 | Neurochem (International) Limited | Amidine derivatives for treating amyloidosis |
US7262223B2 (en) * | 2004-01-23 | 2007-08-28 | Neurochem (International) Limited | Amidine derivatives for treating amyloidosis |
JP2008533151A (en) * | 2005-03-14 | 2008-08-21 | トランス テック ファーマ,インコーポレイテッド | Benzazole derivatives, compositions and methods of use as beta-secretase inhibitors |
EP1719767A1 (en) * | 2005-05-05 | 2006-11-08 | The University of North Carolina at Chapel Hill | Synthesis and antiprotozoal activity of dicationic 3,5-diphenylisoxazoles |
US7951827B2 (en) | 2005-05-05 | 2011-05-31 | The University Of North Carolina At Chapel Hill | Synthesis and antiprotozoal activity of dicationic 3,5-diphenylisoxazoles |
FR2933692A1 (en) * | 2008-07-10 | 2010-01-15 | Univ Nancy 1 Henri Poincare | NOVEL COMPOUNDS, THEIR USE AS MEDICAMENTS, AND PROCESS FOR THEIR PREPARATION |
WO2010004231A3 (en) * | 2008-07-10 | 2010-03-04 | Universite Henri Poincare Nancy 1 | Novel compounds, use thereof as medicaments, and method for the preparation thereof |
US8703825B2 (en) | 2008-07-10 | 2014-04-22 | Universite De Lorraine | Compounds, use thereof as medicaments, and method of preparation thereof |
US8454979B2 (en) | 2009-02-20 | 2013-06-04 | Meisho Co., Ltd. | Immunopotentiating composition and process for producing same |
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WO2003103598A3 (en) | 2006-03-09 |
CA2488493A1 (en) | 2003-12-18 |
NO20040497L (en) | 2004-04-14 |
AU2003251418A1 (en) | 2003-12-22 |
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JP2006501160A (en) | 2006-01-12 |
EP1572129A2 (en) | 2005-09-14 |
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