EA012429B1 - Methods and compositions for treating amyloid-related diseases - Google Patents

Abstract

Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-related disease.

Description

Related Applications

The application for this patent claims the priority of US patent application No. 10/871514, filed June 18, 2004, US patent application No. 10/871365, filed June 18, 2004, provisional patent application US No. 60/512047, filed October 17, 2003 g., provisional patent application US No. 60/480906, filed June 23, 2003, all are entitled "Methods and compositions for the treatment of amyloid diseases."

The application for this patent is also related to provisional patent application US No. 60/512017, filed October 17, 2003, provisional patent application US No. 60/480918, filed June 23, 2003, and US patent application No. 10/874805, filed June 18 2004, all are entitled “Methods for treating disorders caused by protein aggregation”.

The application for this patent is related to provisional patent application US No. 60/512116, filed October 17, 2003, provisional patent application US No. 60/480984, filed June 23, 2003, and US patent application No. 10/871549, filed June 18, 2004 d., all are entitled “Pharmaceutical formulations of amyloid-inhibiting compounds”.

The application for this patent is related to provisional patent application US No. 60/436379, filed December 24, 2002, provisional patent application US No. 60/482214, filed June 23, 2003, entitled "Combination therapy for the treatment of Alzheimer's disease", patent application US No. 10/746138, filed December 24, 2003, international patent application PCT / CA2003 / 002011, and US patent application No. 10/871537, filed June 18, 2004, all are entitled "Therapeutic drugs for the treatment of diseases associated with β- amyloid peptides. "

The application for this patent is related to provisional patent application US No. 60/512135, filed October 17, 2003, provisional patent application US No. 60/482058, filed June 23, 2003, both are entitled "Synthetic method of obtaining compounds for the treatment of amyloidosis", and US Patent Application No. 10/871543, filed June 18, 2004, entitled "Improved Candidate Pharmaceuticals and Method for Their Preparation."

The application for this patent is related to provisional patent application US No. 60/512018, filed October 17, 2003, provisional patent application US No. 60/482928, filed June 23, 2003, and US patent application No. 10/871512, filed June 18, 2004 g., all are entitled "Methods and compositions for the treatment of diseases associated with amyloids and epileptogenesis."

The application for this patent is related to US patent application No. 08/463548, currently US patent No. 5972328 under the name "Method for the treatment of amyloidosis."

The full contents of each of these patent applications and patents are hereby introduced specifically into this description by reference, including, without limitation, the description, claims and abstract, as well as any figures, tables or figures in them.

BACKGROUND OF THE INVENTION

Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibrils. Amyloid is a generic name that belongs to the group of diverse, but specific protein deposits (intracellular or extracellular) that are observed in various diseases. Being different in location, all amyloid deposits have common morphological properties, are stained with specific dyes (for example, Congo red) and, after staining, have a characteristic red-green birefringence in polarized light. They also have common common ultrastructural features and common X-ray and IR spectra.

Amyloid-related diseases can either be limited to one organ or spread to several organs. The first example is called localized amyloidosis, while the second is called systemic amyloidosis.

Some amyloid diseases can be idiopathic, but most of these diseases appear as complications of a previous disease. For example, primary amyloidosis (AB amyloid) may appear without any other pathology, or it may be the result of plasma cell dysrasia or multiple myeloma.

Typically, secondary amyloidosis is observed to be associated with a chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A familial form of secondary amyloidosis is also observed in other types of familial amyloidosis, such as familial Mediterranean fever (EME). This familial type of amyloidosis is genetically inherited and is found in specific population groups. In both primary and secondary amyloidosis, deposits are found in some organs and, therefore, both amyloidoses are considered as systemic amyloid diseases.

Localized amyloidoses are diseases that include a single organ system. Various amyloids are also characterized by the type of protein present in the deposition. For example, neurodegenerative diseases, such as scrapie, bovine spongiform encephalitis (mad cow disease), Creutzfeldt-Jakob disease, etc., are characterized by the appearance and accumulation of protease-resistant forms of prion protein (called A8st or Prg-27). Similarly, Alzheimer's disease, another neurodegenerative disease, is characterized by neuritic plaques.

- 1 012429 and neurofibrillary tangles. In this case, amyloid plaques found in the parenchyma and blood vessel are formed by the deposition of fibrillar Άβ-amyloid protein. Other diseases, such as adult diabetes (type II diabetes), are characterized by localized accumulation of amyloid fibrils in the pancreas.

In the case of amyloid formation, there is no known, generally accepted therapy or treatment that would result in a noticeable dissolution of the amyloid deposits ίη δίΐιτ which would prevent further amyloid deposits or prevent the initiation of amyloid deposits.

Each amyloidogenic protein is able to undergo a conformational change and create β-folds and form insoluble fibrils that can be deposited outside or inside the cell. All amyloidogenic proteins have a different amino acid sequence, but the same property is to form fibrils and bind to other elements, such as proteoglycan, amyloid P and the complement component. In addition, all amyloidogenic proteins have amino acid sequences that are similar, being different, such as regions capable of binding to the glycosaminoglycan (CAC) site of the proteoglycan (called the CAC binding site), as well as other areas that promote the formation of β-folds. Proteoglycans are macromolecules of various sizes and various structures that are distributed throughout almost the entire body. They can be found in the intercellular compartment, on the surface of the cell and as part of the extracellular matrix. The basic structure of all proteoglycans consists of a nuclear protein and at least one, but often more, polysaccharide chains (CAC) connected to the nuclear protein. Many different SAS have been discovered, including chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin and hyaluronan.

In specific cases, amyloid fibrils, if formed, can become toxic to surrounding cells. For example, it was shown that Άβ-fibrils organized in the form of senile plaques are associated with dead neuron cells, dystrophic neurites, astrocytosis and microgliosis in patients with Alzheimer's disease. The ίη νίίτο test showed that the oligomeric (soluble) and fibrillar Άβ peptides are able to initiate the activation of microglia (macrophages of the brain), which explains the microgliosis and inflammation of the brain found in the brain of patients with Alzheimer's disease. Both oligomeric and fibrillar Άβ peptides can also induce the death of ίη νίίτο neurons. See, for example, M.R. Lashrep, βί a1., Proc. Ναί1. Asai. 8βί I8A 95, 6448-53 (1998).

It was shown that with another type of amyloidosis observed in patients with type II diabetes, the amyloidogenic protein IAPP, if organized into oligomeric forms or into fibrils, induces the toxicity of islet β-cells ίη νίίτο. Consequently, the appearance of IAPP fibrils in the pancreas of patients with type II diabetes contributes to the loss of islet β-cells (Langerhans cells) and organ dysfunction, which can lead to insulinemia.

Another type of amyloidosis is associated with β2-microglobulin and is found in patients undergoing a long course of hemodialysis. In patients undergoing a long course of hemodialysis, β2-microglobulin fibrils appear in the carpal tunnel and in collagen-rich tissues in some joints. This causes severe pain, stiffness and swelling of the joints.

Amyloidosis is also characteristic of Alzheimer's disease. Alzheimer's disease is a brain-destroying disease that leads to progressive memory loss leading to dementia, mental disability, and death over a relatively long time. In the process of population aging in developed countries, the number of patients with Alzheimer's disease reaches the size of the epidemic.

People with Alzheimer's disease develop progressive dementia at maturity, accompanied by three major structural changes in the brain: diffuse death of neurons in many parts of the brain; accumulation of intracellular protein deposits called neurofibrillary tangles; and accumulation of extracellular protein deposits called amyloid or senile plaques surrounded by deformed nerve endings (dystrophic neuritis) and activated microglia (microgliosis and astrocytosis). The main component of these amyloid plaques is the amyloid β-peptide (AS protein of 39-43 amino acids, which is formed by cleavage of the β-amyloid precursor protein (APP). An intensive study was carried out to study the relevance of Άβ deposits in Alzheimer's disease, see, for example, 8е1koye, Тgeiikh ίη Се11 Βίοίοβν 8, 447-453 (1998) .Άβ is easily formed by metabolic processing of amyloid precursor protein (APP) in the endoplasmic reticulum (EB), Golgi apparatus, or in the endosomal-lysosomal metabolic pathway (system) , and, most commonly, is secreted in the form of a peptide containing 40 ('Άβ1-40) or 42 (' Άβ-42) amino acids (8e1koe, Appi. Bev. Ce11 Βίο1. 10, 373-403 (1994)). as the main cause of Alzheimer's disease is confirmed by the presence of extracellular deposits of Aβ in senile plaques characteristic of Alzheimer's disease, increased production of Aβ in cells containing mutant genes associated with Alzheimer's disease, for example, amyloid precursor protein, presenilin I and presenilin II; and toxicity of soluble (oligomeric) or fibrillar Aβ to cells in culture. See on

- 2 012429 example, Ssghai. Eig. Vyurjagt. Βονίο \ ν. 40-42 (Li1ishp 2001); Mau, ΌΌΤ, 459-62 (2001). Although there is symptomatic treatment for Alzheimer's disease, it is currently not preventable or treatable.

Alzheimer's disease is characterized by diffuse and neuritic plaques, cerebral angiopathy, and neurofibrillary tangles. It is believed that amyloid of plaques and blood vessels is formed due to the deposition of insoluble Av-amyloid protein, which can be described as diffuse or fibrillar. It is also believed that both soluble oligomeric Av and fibrillar Av are neurotoxic and inflammatory.

Another type of amyloidosis is cerebral amyloid angiopathy (CAA). CAA is a specific deposition of amyloid β-fibrils on the walls of the liptomeningeal and cortical arteries, arterioles and veins. It is usually associated with Alzheimer's disease, Down's syndrome and normal aging, as well as various family conditions associated with stroke or dementia (see Baptapuet s1 a1., Αιηίΐοίά: 1. Ρτοΐβίη Ρο1άίη§ Όίκοτά. 8, 8рр1. 1, 36рр1. 1, 36ir1. 42 (2001)).

Currently generally available treatment methods for β-amyloid diseases, almost all are only symptomatic, giving only temporary or partial clinical improvement. Although some pharmaceutical agents have been described that offer symptom alleviation, there is currently no comprehensive pharmacological treatment to prevent or treat, for example, Alzheimer's disease.

SUMMARY OF THE INVENTION

The present invention relates to the use of compounds of formula (I) for the treatment of amyloid diseases. In particular, this invention relates to a method for treating or preventing an amyloid disease in a subject, comprising administering to the subject a therapeutic amount of a compound of the invention. The invention also relates to each of the novel compounds of the invention provided herein. Among the compounds for use according to the invention, when the compounds of the following formula (I) are administered, the formation of amyloid fibrils, specific organ dysfunction (eg, neurodegeneration), or cellular toxicity are reduced or inhibited.

In one embodiment, the invention relates to the use of a compound of formula (I) to *

where K. ¹ denotes a substituted or unsubstituted 3-10 membered, containing from 1 to 4 heteroatoms selected from Ν, O and 8, heterocyclyl, 6-10 membered aryl, 8-15 membered arylcycloalkyl or substituted or unsubstituted C ₂ A C1 ₀ alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate or fused rings;

K ² is hydrogen or C1-Ci-alkyl;

Υ is 8O ₃ N;

L ¹ represents a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent;

L ² is a substituted or unsubstituted C ₂ -C ₅ alkyl group, with the proviso that when K ¹ is alkyl, L ^{1 is} absent; with the proviso that when K ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X ⁺ ; K ¹ does not mean phenyl,

1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when K ² is hydrogen, b ² is - (CH2) 3-, b ^{1 is} absent and Υ is 8O3 ^- X ⁺ , K ¹ does not mean n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl , 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6 -hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy- 2-pentyl, 3- ethylbutyric acid, 4-methylpentanoic acid methyl ester or 2,2-diphenylethyl, or a pharmaceutically acceptable salt, ester or prodrug thereof, for treating or preventing an amyloid-related disease or condition, including if the disease or condition is characterized by deposition of β-amyloid .

In accordance with the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof is also useful for treating or preventing deposition of an amyloid or a disease selected from the group consisting of Alzheimer's disease, cerebral amyloid angiopathy, inclusion inclusion myositis, macular degeneration, MO or Down syndrome.

In another embodiment of the invention, the compounds of formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof, are used to prepare a medicament for treating or preventing amyloid-related diseases and conditions, including diseases or conditions characterized by deposition of β-amyloid, and also for the treatment or prevention of a disease selected from the group comprising Alzheimer's disease, cerebral amyloid angiopathy, inclusion inclusion myositis, macular degeneration, MO il and down syndrome.

- 3 012429

In another aspect, the invention relates to a method for treating or preventing an amyloid-related disease, including deposition of β-amyloid, comprising administering to the subject an effective amount of a compound of formula (I)

where B ¹ is a substituted or unsubstituted 3-10 membered, containing from 1 to 4 heteroatoms selected from Ν, O and 8, heterocyclyl, 6-10 membered aryl, 8-15 membered arylcycloalkyl, or substituted or unsubstituted C2-C ₁₀ -alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate rings;

B ² is hydrogen or C1-Ci-alkyl;

Υ is 8O ₃ N;

L ¹ represents a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent;

L ² is a substituted or unsubstituted C ₂ -C ₅ alkyl group, with the proviso that when B ¹ is alkyl, b ^{1 is} absent; with the proviso that when B ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X '; B ¹ does not mean phenyl,

1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when B ² is hydrogen, b ² is - (CH2) 3-, b ^{1 is} absent and Υ is 8O3 ^- X ', B ¹ does not mean n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl , 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6 -hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy- 2-pentyl, 3rd tilmaslyanuyu acid, methyl 4-methylpentanoic acid or 2,2-diphenylethyl, or a pharmaceutically acceptable salt, ester or prodrug thereof.

Compounds of the invention also include a compound of formula (I)

he B ¹ denotes substituted or unsubstituted bicyclo [2.1.2] heptyl or substituted or unsubstituted adamantyl;

B ² is hydrogen or Ci-Xi alkyl;

Υ is 8O ₃ N;

B ¹ is substituted or unsubstituted C1-C5 alkyl or is absent; and

B ² is substituted or unsubstituted C ₂ -C ₅ alkyl or is absent;

provided that B ² is hydrogen, b ² is - (CH ₂ ) ₃ -, b ^{1 is} absent and that B ^{1 is} not

3,4-dimethyl-1-adamantyl or 3,5-dimethyl-1-adamantyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

In yet another aspect, the compounds of the invention are

The invention also provides a pharmaceutical composition for treating or preventing amyloid disease, comprising a compound of the invention and a pharmaceutically acceptable carrier.

The compounds of the invention may act by one of the following mechanisms.

In one embodiment of the invention, the compounds of this description prevent or inhibit the assembly of amyloid protein into insoluble fibrils, which, ίη νίνο, are deposited in various organs, or they contribute to the clearance of previously formed deposits or slow down deposition in patients already having deposits. In another embodiment of the invention, the compound may also prevent the binding of the amyloid protein, in its soluble, oligomeric form or in its fibrillar form, to the cell surface or the adhesion of this protein to the cell surface. In yet another embodiment of the invention, the compound may block amyloid-induced cellular toxicity or macrophage activation. In another embodiment of the invention, the compound may block amyloid-induced neurotoxicity or microglial activation. In another embodiment of the invention, the compound protects cells from amyloid-induced cytotoxicity of islet B cells. In another embodiment of the invention, the compound can increase clearance from a particular organ, for example, the brain, or it lowers the concentration of amyloid protein in such a way that the formation of fibrils is prevented in the target organ.

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The compounds of the invention can be used therapeutically or prophylactically for the treatment of diseases associated with the formation, aggregation or deposition of amyloid fibrils. The compounds of the invention can act to alleviate the course of amyloid disease by any of the following mechanisms (it is assumed that this list is illustrative and not limiting): slowing the rate of formation or deposition of amyloid fibrils; a decrease in the degree of amyloid deposition; inhibition, reduction or prevention of the formation of amyloid fibrils; inhibition of neurodegeneration or cellular toxicity caused by amyloid; inhibition of amyloid-induced inflammation; increased clearance of amyloid; or promoting cleavage of the amyloid protein prior to combining it into fibrils.

The compounds of the invention can be used therapeutically or prophylactically for the treatment of diseases associated with the formation, aggregation or deposition of β-amyloid fibrils. The compounds of the invention can act to alleviate the course of a disease associated with β-amyloid according to any of the following mechanisms (it is assumed that this list is illustrative and not limiting): slowing the rate of formation or deposition of β-amyloid fibrils; a decrease in the degree of β-amyloid deposition; inhibition, reduction or prevention of the formation of β-amyloid fibrils; inhibition of neurodegeneration or cellular toxicity caused by β-amyloid; inhibition of inflammation induced by β-amyloid; increased clearance of β amyloid from the brain; or promoting the cleavage (destruction) of β-amyloid protein before it is combined into fibrils.

The therapeutic compounds of the invention can be effective in controlling β-amyloid deposition either after they enter the brain (after passing through the blood-brain barrier) or from the periphery. When acting from the periphery, a compound can alter the Άβ balance between the brain and plasma in a way that facilitates the removal of Άβ from the brain. It can also increase the catabolism of neural Άβ and change the rate of removal from the brain. An increase in the release of Άβ from the brain leads to a decrease in the concentration of Άβ in the brain and in the cerebrospinal fluid (C8P) and, therefore, helps to reduce Άβ deposition. Or, compounds that penetrate the brain could regulate deposition by acting directly on Άβ in the brain, for example, by keeping it in a non-fibrillar form, promoting its clearance from the brain or slowing down the processing of ΆΡΡ. These compounds could also prevent the interaction of Άβ in the brain with the cell surface and, therefore, prevent neurotoxicity, neurodegeneration and inflammation. They can also reduce the production of Άβ by activated microglia. These compounds can also increase destruction when using macrophages or neural cells.

In one embodiment of the invention, a method of treating Olzheimer's disease (e.g., sporadic form, familial or early AO) is used. The method can also be used prophylactically or therapeutically to treat other cases of β-amyloid deposition, such as in patients with Down syndrome or in patients with cerebral amyloid angiopathy (ΟΛΛ).

In another embodiment of the invention, a method of treating mild cognitive impairment is used. Mild cognitive impairment (MC1) is a condition characterized by a slight but noticeable loss of mental skill, qualification, ability, which is not necessarily associated with the presence of dementia. MC1 often, but not always, precedes Holzheimer's disease.

In addition, the abnormal accumulation of ΆΡΡ and β-amyloid protein in muscle fibers entails the pathology of random myositis of inclusion bodies (1VM) (Akkapak s1 a1., Rgok. No. 111. Asab. 8c1. I8A 93, 1314-1319 (1996); Akkapak s1 a1., Stew! Θρίηίοη ίη P11sita11yuodu 7, 486-496 (1995)). Accordingly, the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which the β-amyloid protein is abnormally deposited in non-neurological sites, for example, for the treatment of 1BM by delivering the compounds to muscle fibers.

In addition, it was shown that Άβ is associated with abnormal extracellular deposits, known as drusen, which accumulate along the basal surface of retinal pigmented epithelium in subjects with age-related macular degeneration (AMO). AMO is the cause of irreversible loss of vision in older people. It is believed that Άβ deposition can be an important component of local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, Druze biogenesis and AMO pathogenesis (ίοΐιηκοη. E1 a1., Prg. IAI. Asab. 8c1. I8A 99 (18), 11830-5 ( 2002)).

Therefore, the present invention relates to the use of the compounds of formula (I) as described herein for the prevention or treatment of amyloid diseases, including, but not limited to, Jzheimer's disease, cerebral amyloid angiopathy, mild cognitive impairment, inclusion inclusion myositis, Down syndrome, macular degeneration, as well as other types of amyloidosis due to 1APP (e.g. diabetes), primary (AB) amyloidosis, secondary (ΆΆ) amyloidosis and amyloidosis due to β ₂ -microglobulin (dialysis).

In type II diabetes (diabetic) amyloidosis (1APP), amyloidogenic protein 1APP

- 5 012429 induces the toxicity of islet β-cells when combined into oligomeric forms or into fibrils. Therefore, the appearance of ΙΑΡΡ fibrils in the pancreas of patients with type II diabetes contributes to the loss of islet β-cells (Langerhans) and organ dysfunction, which leads to insulinemia.

Primary amyloidosis (AB amyloid) is generally known to be associated with plasma cell dysrasia and multiple myeloma. It can also be observed as an idiopathic disease.

Secondary (AA) amyloidosis is usually observed in connection with a chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A familial form of secondary amyloidosis is also observed in familial Mediterranean fever (PME).

Amyloidosis due to _2- microglobulin (dialysis) is observed in patients with a long course of hemodialysis. In patients undergoing a long course of hemodialysis, fibrils from _2- microglobulin appear in the carpal tunnel and in collagen-rich tissues in some joints. This causes severe pain, stiffness and swelling of the joints. These deposits are caused by the inability to maintain low levels of ₂ M in the plasma of patients undergoing hemodialysis. Elevated concentrations of ₂ M protein cause structural changes and may lead to the deposition of the ₂ M modified in the joints in the form of insoluble fibrils.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of compounds of formula (I) as described herein for the treatment of amyloid diseases. For convenience, some definitions or terms referenced in this description are presented below.

Amyloid diseases

AA (reactive) amyloidosis.

Typically, AA amyloidosis is a manifestation of a number of diseases that cause a prolonged reaction in the acute phase. Such diseases include chronic inflammatory disorders, chronic local or systemic microbial infections, and malignant neoplasms. The most common form of reactive or secondary (AA) amyloidosis is observed as a result of prolonged inflammatory conditions. For example, patients with rheumatoid arthritis or familial Mediterranean fever (which is a genetic disease) may develop AA amyloidosis. The terms AA amyloidosis and secondary (AA) amyloidosis are used interchangeably (interchangeably).

AA fibrils usually consist of 8,000 Daltons (Da) fragments (AA peptide or protein) produced by proteolytic cleavage of serum amyloid protein A (ΑροδΑΑ), a circulating apolipoprotein that is synthesized mainly in hepatocytes in response to cytokines such as 1b -1, 1b-b and ΤΝΡ. Secreted ΑροδΑΑ forms complexes with HO. Deposition of AA fibrils can be distributed in the body, mainly in the parenchymal organs. Typically, the place where the deposits are located is the kidneys, and the liver and spleen may also be affected. Deposition is also observed in the heart, gastrointestinal tract and skin.

The main diseases that can lead to the development of 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 Still's disease, Behcet's syndrome and Crohn's disease . AA deposits can also result from chronic microbial infections such as leprosy, tuberculosis, bronchiectasis, decubital ulcers, chronic pyelonephritis, osteomyelitis, and Whipple's disease. Some cancers can also cause AA deposits of fibrillar amyloid protein. These cancers include Hodgkin’s lymphoma, cancer of the kidney, cancer of the colon, lung, and urogenital system, basal cell carcinoma, and Vilosystocellular leukemia. Other underlying conditions that can cause AA amyloidosis are Castleman’s disease and Schnitzler’s syndrome.

ΑΕ Amyloidosis (primary amyloidosis).

ΑΕ Amyloid deposition is usually associated with almost any B line lymphocyte dysrasia, from malignant development of plasma cells (multiple myeloma) to benign monoclonal gammopathy. Sometimes the presence of amyloid deposits can be a direct indicator of underlying dyskrasia. ΑΕ amyloidosis is also described in detail in Siggep! Aegis Tagde! I, 2004, 5 159-171.

Amyloid deposits рил fibrils are composed of monoclonal immunoglobulin light chains or fragments thereof. More specifically, the fragments are formed from the Ν-terminal portion of the light chain (k or λ) and contain the whole variable domain (Y _b ) or part of it. Deposits are found mainly in mesenchymal tissues, causing peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, large joint arthropathy, immune dysrasia, myeloma, and dyskrasia of unknown origin. However, it should be noted that almost all tissues, especially internal organs, such as the kidney, liver, spleen, and heart, can be affected.

Hereditary systemic amyloidoses.

There are many forms of hereditary systemic amyloidosis. Although they are relatively rare conditions, the symptoms in adults and the nature of their inheritance (usually autosomal dominant) lead to the consolidation (resistance) of such disorders in the whole population. Syndromes are caused mainly by point mutations in the precursor protein, which lead to variant amyloidogenic peptides or proteins. In the table. 1 shows the composition of fibrils of typical forms of such disorders.

Table 1

Composition of fibrils of typical amyloid diseases

Fibrillar peptnd / protein Genetic option Clinical syndrome ATGR, a protein from transthyretin and fragments Mayo, many others Familial amyloid polyneuropathy (PAR) (mainly peripheral nerves) ATTK protein from transthyretin and fragments Tb45, A1a60, 8eg84, Me (111, Pe122 Cardiac damage, mainly without neuropathy, familial amyloid polyneuropathy, senile (senile) systemic amyloidosis, tendovaginitis Ν-terminal fragment of apolipoprotein A1 (apoA1) Arg26 Familial amyloid polyneuropathy (PAP) (mainly peripheral nerves) Ν-terminal fragment of apolipoprotein A1 (apoA!) Arg26, LgvZO, AgvbO, etc. Type of Oetertag. non-neuropathic (mainly visceral lesion) AAPA from apolipoprotein LI Familial amyloidosis Lysozyme (A1uz) Thb56, H | 5b7 Type Oetertag, non-neuropathic (mainly visceral lesion) Fragment alpha chain fragment Ley554, Wa1 526 Cranial neuropathy with corneal lattice dystrophy

Gelsolin fragment (A @ e1) Azp187, Tut187 Cranial neuropathy with corneal lattice dystrophy Fragment of cystatin C (Asua) 011168 Hereditary cerebral hemorrhage (cerebral amyloid angiopathy) · Icelandic type β-amyloid protein (Αβ) from amyloid precursor protein (APP) S1p693 Dutch hereditary cerebral hemorrhage (cerebral amyloid angiopathy) β-amyloid protein (Αβ) from amyloid precursor protein (APP) Pe717, Pb717, O1u717 Alzheimer's Family Disease β-amyloid protein (Αβ) from an amyloid precursor protein (APP), e.g., LBP 695 O1p618 Alzheimer's disease, Down syndrome, hereditary cerebral hemorrhage with amyloidosis, Dutch type β-amyloid protein (Αβ) from amyloid precursor protein (APP) Azp670, bie 671 Family dementia - possibly Alzheimer's Prion Protein (Prg, argr ^mustache ) from Prg precursor protein (insert 51 - 91) 1_ey102, Wa1167, Aap178. Bw52OO Creutzfeldt-Jakob family disease; Gerstmann-Streussler-Scheinker syndrome (hereditary spongiform encephalopathies, prion diseases) A A ns of whey amyloid protein A (AroZAA) Familial Mediterranean fever, mainly kidney damage (autosomal recessive) AA from Whey Amyloid Protein A (AroZAA) Macle-Wales syndrome, nephropathy, deafness, urticaria, limb pain Unknown Cardiomyopathy with persistent atrial asystole Unknown Skin deposits (bullous, papular, pustulodermal) AN amyloid protein from the immunoglobulin heavy chain (gamma I) ΑγΙ Amyloidosis due to myeloma Aca Amyloid Protein from (p ro) Calcitonin (Pro) calcium TONIN Thyroid medullary carcinomas ΑΑΝΡ amyloid protein from atrial natriuretic factor Isolated Atrial Amyloid Argo from prolactin Prolactinomas ABP / AOAP from AWP peptide British and Danish family dementia

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Data taken from Tap 8Υ, Reruk MV. Atu1o1yok1k. H1k! Ora1y1odu, 25 (5), 403-414 (June 1994), \ UNO / 1Y8 No tep1a! Have 8uotkot! Her, no tep1a1ige ok Atu1o1y apy Atu1o1yok1k. Vi11ape ok Not \ Wo1y Nea1! 1 OgdagUaBop 1993; 71: 10508; and Meth! A1., C1T C1ET LAB May 2001; 39 (11): 1065-75.

The data in the table. 1 are given as examples and are not intended to limit the scope of the invention. For example, more than 40 individual point mutations in the transthyretin gene have been described, each of which gives clinically similar forms of familial amyloid polyneuropathy.

As a rule, any hereditary amyloid disorder can also occur in sporadic form, and both the hereditary and sporadic (random) forms of the disease have the same features with regard to amyloid. For example, the most common form of secondary AA of amyloidosis occurs by chance, for example as a result of persistent inflammation, and is not associated with familial Mediterranean fever. Thus, general information regarding hereditary amyloid disorders can also be attributed to sporadic (random) amyloidosis.

Transthyretin (TTH) is a 14 kilodalton (kDa) protein, sometimes called prealbumin. It is produced by the liver and choroid plexus and functions in the transport of thyroid hormones and vitamin A. At least 50 variant forms of the protein, each of which is characterized by a single amino acid substitution, are responsible for various forms of familial amyloid polyneuropathy. For example, replacing proline instead of leucine at position 55 leads mainly to a progressive form of neuropathy; replacing leucine with methionine at position 111 causes severe cardiopathy in Dutch patients.

On amyloid deposits isolated from the heart tissues of patients with systemic amyloidosis, it can be seen that the deposits consist of a heterogeneous mixture of TTN and its fragments, generally called ATTK, whose full-length sequences are characterized. The components of ATTC fibrils can be extracted (extracted) from such plaques and by methods known in the art, their structure and sequence can be determined (for example, Oykkop, A., e! A1., Baaaaaaaaaaaaaaaa1. 73: 703- 708, 1995; Kate1ash, R., e! A1., Vusyet. Vuryuk. Kek. Sottip. 125: 22-628, 1984; Rgak, M., e! A1., ΡΝΑ8 80: 539-42, 1983).

In people with point mutations in the apolipoprotein A1 molecule (for example, O1y ^ Atd26; Ttr ^ Atd50; Ley ^ Atd60), a form of amyloidosis (type Ok! Iyad) is observed, characterized by deposits of apolipoprotein A1 or its fragments (AaroA1). These patients have low levels of high density lipoprotein (NE) and peripheral neuropathy or renal failure.

A mutation in the α-chain of the lysozyme enzyme (for example, 11е ^ Т1т56 or Acre ^ Нтк57) is the basis of another form of non-neuropathic hereditary amyloid of the type Ok! Nyad observed in English families. In this case, fibrils of the mutant lysozyme protein (A1uk) are deposited, and in patients, as a rule, renal failure is observed. This protein, unlike most proteins that form fibrils, is usually present in its full (unfragmented) form (Venka, MK, e! A1. C1BA Rip. 8 utr. 199: 104-131, 1996) according to this description.

Immunoglobulin light chains tend to form aggregates of various morphologies, including fibrillar (for example, AB amyloidosis and AN amyloidosis), granular (for example, light chain disease (BLC, LCOE), heavy chain disease (BTC, NSEE) and light-heavy chain disease ( BLTC, LNSOE)), crystalline (for example, acquired Farconi syndrome) and microtubular (for example, cryoglobulinemia). The formation of insoluble fibrils of light chains and heavy chains of immunoglobulins and / or fragments thereof is an indicator of AB and AN of amyloidosis, respectively. In AB fibrils, lambda (L) chains, such as λνΐ chains (L6 chains), are found in higher concentrations than Kappa (k) chains. Metish e! a1., C1sh, C1b, BaL Mei 39 (11): 1065-75 (2001). Amyloidosis of heavy chains (AN) is characterized by aggregates of amyloid proteins of the γ chain of 1dO1 subclass. Ευ1ί! Ζ е! A1., Proc. Νίώ. Asai. 8s1. I8A 87: 6542-46 (1990).

A comparison of amyloidogenic light chains with non-amyloidogenic light chains showed that the former may include substitutions that appear to destabilize protein twisting or stimulate aggregation. AB and LSEE were determined from other amyloid diseases due to their relatively small population of monoclonal light chains, which are formed due to the neoplastic growth of antibody-producing B cells. As a rule, AB aggregates are well-organized fibrils of λ-chains. LSEE aggregates are relatively amorphous aggregates of both k- and λ chains, mainly k, sometimes κΐν. Be11o! Th e! A1., 1oitpa1 ok 8yis! yga1 Vyuodu 13: 280-89 (2000). A comparison of amyloidogenic and non-amyloidogenic heavy chains in patients with amyloidosis AN revealed missing and / or altered components. Ει.ι1ίΙζ e! A1., Proc. No.! 1. Asai. 8sk I8A 87: 6542-46 (1990) (pathogenic heavy chains that have a significantly lower molecular weight than non-amyloidogenic heavy chains); and 8o1otope e! A1., At 1 Neta! 45 (2) 171-6 (1994) (amyloidogenic heavy chains, characterized in that they consist solely of the νΠ-Ό site of the non-amyloidogenic heavy chain).

Therefore, possible methods for detecting and monitoring the treatment of subjects with an increased risk of the presence of AB, LCOE, AN, etc. include, but without limitation, immunoassay of plasma or urine on

- 8 012429 the presence or reduced deposition of amyloidogenic light or heavy chains, for example, amyloid λ, amyloid k, amyloid κ VI, amyloid γ or amyloid γ1.

Amyloidosis of the brain.

The most common type of amyloid in the brain consists mainly of Av-peptide fibrils, leading to dementia associated with random (non-hereditary) Alzheimer's disease. In fact, the incidence of sporadic (random) Alzheimer's disease is significantly higher than the forms that are shown to be hereditary. However, the plaque-forming fibrillar peptides are very similar in both types. Amyloidosis of the brain includes such diseases, conditions, pathologies and other abnormalities of the structure or function of the brain, including its components, caused by amyloid. The area of the brain affected by amyloid disease may be a stroma, including the vasculature, or a parenchyma, including functional or anatomical regions, or their neurons. The patient is not necessarily given an accurate diagnosis of a particular, specific amyloid disease. The term amyloid disease (an amyloid-related disease) includes amyloidosis of the brain.

The β-amyloid peptide (Av) is a 39-43 amino acid peptide formed by proteolysis of a large protein known as β-amyloid precursor protein (bAPP). Mutations in bAPP cause familial forms of Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy and senile dementia, characterized by cerebral deposition of plaques consisting of Av fibrils and other components, which are described in more detail below. Known mutations in APP associated with Alzheimer's disease occur directly near the cleavage sites of β- or γ-secretase or in AB. For example, position 717 is the closest to the cleavage site of the γ-secretase APP when it is processed in AB, and position 670/671 is closest to the cleavage site of β-secretase. Mutations in any of these residues can lead to Alzheimer's disease, presumably due to an increase in the amount of Av form from 42/43 amino acids formed from APP. The familial form of Alzheimer's disease makes up only 10% of the test population. Most cases of Alzheimer's are sporadic in which the APP and Av do not contain any mutation. The structure and sequence of Av peptides of various lengths are well known in the art. Such peptides can be obtained by methods known in the art, or can be isolated from the brain by known methods (for example, C1eiegii kopd, Vusyet. Vyuruk. Century. Sott. 129, 885-90 (1984); C1epiegius koid, Vyusket. Vyurkuk. Century Sot. 122, 1131-35 (1984)). In addition, various forms of peptides are commercially available. APP is expressed and constitutively catabolized in most cells. Apparently, the dominant catabolytic pathway is the cleavage of APP within the sequence by an A enzyme, previously called α-secretase, which leads to the release of a soluble ectodomain fragment known as APPka. This cleavage interferes with the formation of the Av peptide. In contrast to this non-amyloidogenic cascade of reactions, APP can also be cleaved by enzymes known as b- and γ-secretase, at the Ν- and C-ends of Av, respectively, with subsequent release of Av into the extracellular space. By now, BACE has been identified as a b-secretase ^ akeg, e! a1. 8c1eise 286: 735-741, 1999), and presenilins are associated with the activity of γ-secretase (Ee 81gooreg e! A1., No. 1 Shge 391, 387-90 (1998)). The Av peptide, containing 39-43 amino acids, is produced by sequential proteolytic cleavage of the amyloid precursor protein (APP) with β- and γ-secretases. Although the Av40 form is predominantly produced, 5–7% of total Av exists in the form of Av42 (Сarra1 e! A1., 1n !. I. Wusket. Ce11 Vu1. 31. 885-89 (1999)).

Apparently, the length of the Av peptide decisively alters its biochemical / biophysical properties. Specifically, the additional two amino acids at the C-terminus of Av42, being highly hydrophobic, appear to increase the susceptibility of Av42 to aggregation. For example, 1agge! 1, e! a1. showed that Av42 aggregates very quickly ίη ugo compared with Av40, which suggests that the longer forms of Av may be important pathological proteins that are involved in the initial seeding of neuritic plaques in Alzheimer's disease (1apte !!, e! a1., Vuset NetMgu 32, 4693-97 (1993); 1aggey, e! A1., Αηη. Ν.Υ. Asai. 8cg 695, 144-48 (1993)). This hypothesis is further supported by recent analyzes of the contribution of specific forms of Av to genetic family forms of Alzheimer's disease ((). For example, the mutant form of APP (ΑΡΡν7171) London associated with селектив selectively increases the production of Av 42/43 forms compared to Av 40 (Zi / ikk e! A1., 8aepse 264, 1336-40 (1994)), while the mutant Swedish APP form (ΑΡΡΚ670Ν / Μ671Ε) raises the levels of both Av40 and Av42 / 43 (Sygop, e! a1., No. 1 Shge 360, 672-674 (1992); Ca1, e! a1., 8aepse 259, 514-16 , (1993)). It was also observed that ΕΑΌ-linked mutations in the presenilin-1 (P81) or presenilin-2 (P82) genes lead to a selective increase in the production of AP42 / 43, but not Av40 (Vogskek, e! A1., No. 17, 1005-13 (1996)). This discovery was confirmed in transgenic mouse models expressing P8 mutants that show a selective increase in Av42 brain (Vogske1 !, see above; ;ιιίΤ е! А1., No. igoyedepegayop 5 (4), 293-98 (1996)). Thus, the main hypothesis about the etiology of Alzheimer's

- 9 012429 is that an increase in the concentration of Αβ42 in the brain due to increased production and release of Αβ42, or a reduced clearance (splitting or clearance from brain tissue) is an event that causes the disease pathology.

Many mutation sites in either the AB or APP gene have been identified and clinically associated with either dementia or cerebral hemorrhage. Typical CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with Icelandic type amyloidosis (HCH ^ A-Ι); Dutch variant НС’НХУА (НСН ^ А-Ό; mutation in Αβ); Flemish mutation Av; Arctic mutation Av; the Italian mutation Av; mutation Av variant of Iowa; family British dementia; and family Danish dementia. CAA can also be sporadic (random).

As used herein, the terms b-amyloid, amyloid-β, and the like, unless otherwise indicated, refer to proteins and peptides of b-amyloid, amyloid-to proteins or precursor peptides, their intermediates and modifications and fragments. In particular, Av refers to any peptide produced by proteolytic processing of the APP gene product, especially peptides that are associated with amyloid pathologies, including Av1-39, Av1-40, Av1-41, Av1-42 and Av1-43. For the convenience of the nomenclature, Av 1-42 may be referred to herein as Av1-42 or simply Av42 or Av42 (and similarly for any other amyloid peptides discussed herein). Used in this description, the terms b-amyloid, amyloid-b and AB are synonymous.

Unless otherwise specified, the term amyloid refers to amyloidogenic proteins, peptides, or fragments thereof, which may be soluble (e.g., monomeric or oligomeric) or insoluble (e.g., having a fibrillar structure or present as amyloid plaques). See, for example, M.R. Batret !, e! A1., Proc. Oh! 1. Asai. 8s1. I8A 95, 6448-53 (1998). Amyloidosis or amyloid disease or an amyloid-related disease refers to a pathological condition characterized by the presence of amyloid fibers. Amyloid is a generic term that refers to the group of different but specific protein deposits (intracellular or extracellular) that are observed in many different diseases. When meeting in various places, all amyloid deposits have common morphological properties, are stained with specific dyes (for example, Congo red) and, after staining, have a characteristic red-green birefringence in polarized light. They also have common common ultrastructural features and common X-ray and IR spectra.

Gelsolin is a calcium-binding protein that binds to actin fragments and filaments. Mutations at position 187 (for example, Acre ^ Akp; Acre ^ Tut) of the protein lead to a form of hereditary systemic amyloidosis, usually found in patients from Finland, as well as from immigrants from the Netherlands and Japan. In diseased people, fibrils formed from gelsolin fragments (Ade1) usually consist of amino acids 173-243 (a carboxy-terminal fragment of 68 kDa) and are deposited in blood vessels and basement membranes, causing corneal dystrophy and cranial neuropathy, which progresses to peripheral neuropathy, degenerative skin changes and deposits in other organs (Kapdak, N., e! a1. Nitap Mo1. Sepe! 5 (9): 1237-1243, 1996)).

Other mutant proteins, such as the mutant α-chain of fibrinogen (AGFA) and mutant cystatin C (Asuk), also form fibrils and cause characteristic hereditary disorders. AIBA fibrils form deposits characteristic of the hereditary cerebral amyloid angiopathy found in Iceland (1kke1basjet, Natkop'k Przarzek oG 1n! Egpa1 MeFsche, MsCsta-HN, 8ap Etap1xo, 1995; Wepkop! It has been shown that in at least a few cases, patients with cerebral amyloid angiopathy (CAA) have amyloid fibrils containing a non-mutant form of cystatin C associated with a b-amyloid protein (Lada1, A., e! A1. Mo1ec. Sit. No. of the teacher! Yo. 33: 63-78, 1998).

Currently, it is believed that some forms of prion disease, which were previously considered predominantly infectious in nature, are hereditary, accounting for up to 15% of cases. (Va1y ^ sh, e! A1., In Kekeatsy Ayuapsek sh A1 / 11epeg E1keake apy Ke1a! Eshhotyetk, 1oyp \ UPeuy 8opk, Yete Uogk, 1995). In case of hereditary and random (sporadic) prion diseases, plaques appear in patients, consisting of abnormal isoforms of normal prion protein (PTP ^8c ).

The predominant mutant isoform, PTP ^8c , also called A8st, differs from normal cellular protein in its resistance to protease cleavage, insolubility after detergent extraction, deposition in secondary lysosomes, post-translational synthesis and a high content of b-folds. A genetic relationship has been established for at least five mutations that cause Creutzfeldt-Jakob disease (STO), Gerstmann-Streussler-Scheinker syndrome (C88) and fatal familial insomnia (ΕΕΙ). (Ba1yMn, see above). Methods for extracting fibrillar peptides from scrapie fibrils, sequencing and preparation of such peptides are known in the art (eg, Veekek, M., e! A1. 1. Sep. U1to1. 76: 2567-76, 1995).

For example, one form of C88 is associated with a PrP mutation at codon 102, while C88 of the end brain

- 10 012429 is characterized by a mutation in codon 117. Mutations in codons 198 and 218 lead to the appearance of form 088, in which the neuritic plaques characteristic of Alzheimer's disease contain Prg instead of the β-peptide. Some forms of familial SSS are associated with mutations at codons 200 and 210; mutations in codons 129 and 178 were found as in family SY. so with EM (Β; · ι1ά \ νίπ. see above).

Cerebral amyloidosis (cerebral amyloidosis).

Local deposition of amyloid is usually found in the brain, in particular in older people. The most common type of amyloid in the brain consists mainly of Av-peptide fibrils, which cause dementia or sporadic (accidental, non-hereditary) Alzheimer's disease. The most common cases of sporadic rather than hereditary cerebral amyloidosis. For example, the incidence of random Alzheimer's disease and accidental CAA is significantly higher than the frequency of family ΑΌ and family CAA. In addition, random and familial forms of the disease cannot be distinguished from each other (they differ only in the presence or absence of a hereditary genetic mutation); for example, clinical symptoms and amyloid plaques resulting from both random and family ΑΌ are very similar, if not identical.

Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils on the walls of the leptomeningeal and cortical arteries, arterioles and veins. It is usually associated with Alzheimer's disease, Down syndrome and normal aging, as well as with a number of family conditions associated with stroke or dementia (see Study on s1 a1., Ashyo1b: 1. Ρτοίοίη Ео1бшд Όίδοτά. 8, 8рр1. 36-42 (2001 )). CAA can be sporadic (random) or family.

Senile (senile) systemic amyloidosis.

Amyloid deposits, either systemic or focal, increase with age. For example, wild-type transthyretin (TTH) fibrils are usually found in the heart tissue of old people. They may be asymptomatic, clinically hidden, or can cause heart failure. Asymptomatic fibrillar focal deposits can be found in the brain (AB), starchy body of the prostate (in _2- microglobulin), joints and seminal vesicles.

Dialysis amyloidosis.

Plaques consisting of fibrils in _2- microglobulin (in ₂ M) usually appear in patients undergoing a long course of hemodialysis or peritoneal dialysis. a ₂ -microglobulin is a polypeptide with a length of 11.8 kDa and is a light chain of MHC class I antigens that are present in all nuclear cells. Under normal circumstances, ₂ M is usually located in the extracellular space, if there is no renal failure, in which case ₂ M is transferred to the tissue, where it polymerizes to form amyloid fibrils. Insufficient clearance, as in the case of renal failure, leads to deposition in the carpal tunnel and other places (mainly in collagen-rich tissues of the joints). Unlike other fibrillar proteins, ₂ M molecules are not produced by cleavage of a more extended precursor protein and are usually present in unfragmented form in fibrils. (Wakey, see above). It has been shown that the conservation and accumulation of this amyloid precursor protein is the main pathogenic process underlying ΌΚ.Α. ΌΚΑ characterized by osteoarthropathy of the peripheral joints (e.g. joint stiffness, pain, swelling, etc.). Isoforms of ₂ M glycated in ₂ M or polymers of ₂ M in tissue are the most amyloidogenic form (as opposed to the native in ₂ M). Unlike other types of amyloidosis in ₂ M, it is mainly limited to bone-articular tissues. Visceral deposits are rare. Occasionally, these deposits can be found in blood vessels and other important anatomical positions.

Despite the improved dialysis methods from the point of view of removal in ₂ M, most patients have high plasma concentrations of ₂ M, which remain significantly higher than normal. These elevated concentrations of ₂ M usually cause diabetic amyloidosis (ΌΚΑ) and the concomitant spread of the disease leading to death.

Islet amyloid polypeptide and diabetes.

Islet hyalinosis (amyloid deposition) was described for the first time more than a century ago as the presence of fibrous protein aggregates in the pancreas of patients with severe hyperglycemia (Opel, E., 1. Exp. Meb. 5: 397-428, 1901). Currently, islet amyloid, consisting predominantly of islet amyloid polypeptide (ΙΑΡΡ), or amylin, is a characteristic histopathological marker in more than 90% of cases of type II diabetes (also known as non-insulin-dependent diabetes, or ΝΙΌΌΜ). These fibrillar clusters result from the aggregation of an islet amyloid polypeptide (ΙΑΡΡ), or amylin, which is a 37 amino acid peptide formed from a longer precursor peptide called (pro-MPP.

ΙΑΡΡ is secreted together with insulin in response to β-cell secretion stimulators. This pathological symptom is not associated with insulin-dependent (type I) diabetes and is a common (unifying) characteristic for heterogeneous clinical phenotypes diagnosed as ΝΣΟΌΜ.

Long-term studies on cats and immunocytochemical studies on monkeys

- 11 012429 showed that a progressive increase in islet amyloid is associated with a sharp decrease in the population of insulin-secreting β-cells and increases the severity of the disease. Later, transgenic studies confirmed the relationship between the formation of ΙΑΡΡ plaques and apoptosis of β-cells and dysfunction, which shows that amyloid deposition is the main factor determining the increase in the severity of type ета diabetes.

It was also shown that ΙΑΡΡ induces the toxicity of islet β-cells ίη νίίτο, indicating that the appearance of ΙΑΡΡ fibrils in the pancreas of patients with type II diabetes and type I (islet transplantation) may contribute to the loss of islet β-cells (Langerhans) and organ dysfunction. In patients with type II diabetes, the accumulation of ΙΑΡΡ in the pancreas causes the formation of oligomeric IΑΡΡ, leading to the creation of an IΑΡΡ-amyloid in the form of insoluble deposits, which ultimately destroy insulin-producing β-cells of the islets, causing depletion and insufficiency of β-cells. (\ Us51gtag. Ρ., Spetejk, b., Forehead Ραΐΐι. Mugoyu1. 8sapb., 8ss1. Α. 81: 291-300, 393; no Κοηίη§, Ε1Ρ., Eί a1., Οίι ^ ΙοΙοβία 36: 37 384, 1993; and Bogep7O, Α., Eί a1., No. Shge 368: 756-760, 1994). Accumulation of [ΑΡΡ in the form of fibrous deposits can also affect the usual ratio of proIΑΡΡ to IΑΡΡ in plasma, increasing this ratio due to the ingress (capture) of IΑΡΡ into deposits. A decrease in β-cell mass can manifest as hyperglycemia and insulinemia. This β-cell mass loss may necessitate insulin treatment.

Diseases caused by the death or inadequate functioning of a particular type or specific cell types can be treated by transplantation of healthy cells of a relevant type to a patient. This method was used to treat type I diabetes patients. Often donor pancreatic islet cells are grown ίη νίίτο before transplantation in order to use them after isolation for treatment, or in order to reduce their immunogenicity. However, in many cases, islet cell transplantation is not successful due to the death of the transplanted cells. One of the reasons for such a small proportion of successful attempts is IΑΡΡ, which combines into toxic oligomers. Toxic effects may occur due to intracellular and extracellular accumulation of fibrillar oligomers. IΑΡΡ oligomers can form fibrils and become toxic to ίη νίίτο cells. In addition, IΑΡΡ fibrils apparently continue to grow after cell transplantation and cause cell death or dysfunction. This can occur even when a disease characterized by the presence of fibrils is not observed in the cells of a healthy donor and in a patient receiving a transplant. For example, the compounds of the present invention can be used to obtain tissues or cells for transplantation according to the method described in international application (PCT) \ UO 01/003680.

The compounds of the invention can also stabilize the concentration ratios ΡτοIΑΡΡ / IΑΡΡ, proinsulin / insulin and C-peptide levels. In addition, as biological markers of effectiveness, the results of various tests, such as the arginine-insulin secretion test, glucose tolerance test and sensitivity tests, can all be used as markers of reduced β-cell mass and / or amyloid deposits accumulation. This class of drugs can be used together with other drugs aimed at insulin resistance, the production of hepatic glucose. Such compounds can prevent insulin therapy while maintaining β-cell function and can be used to preserve islet transplants.

Amyloidosis of hormonal origin.

Endocrine organs can accumulate amyloid deposits, especially in older people. Hormone-secreting tumors may also contain amyloid plaques of hormonal origin, the fibrils of which are composed of polypeptide hormones such as calcitonin (medullary thyroid cancer), atrial natriuretic peptide (isolated atrial amyloidosis). The sequences and structures of these proteins are well known in the art.

Mixed amyloidosis.

There are many other forms of amyloid disease, which usually manifest as localized deposits of amyloid. These diseases result mainly from the localized production or lack of catabolism of specific fibrillar precursors or the predisposition of a particular tissue (such as articular) to fibrillar deposition. Examples of such idiopathic deposition include nodular ΑΕ amyloid, cutaneous amyloid, endocrine amyloid, and tumor-related amyloid. Other diseases associated with amyloid include the diseases described in the table. 1, such as familial amyloid polyneuropathy (ΕΑΡ), senile (senile) systemic amyloidosis, tendovaginitis, familial amyloidosis, such as Ostertag, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, family disease; Gerstmann-Straussler-Scheinker syndrome, hereditary spongiform encephalitis, prion diseases, familial Mediterranean fever, Macle-Wales syndrome, nephropathy, deafness, urticaria, pain in the extremities, skin deposits, multiple myeloma, benign monoclonal gammopathy, macroglobululomeloma, macroglobululomeloma amy isolated thyroid

- 12 012429 atrial loidosis and diabetes.

The compounds of the invention can be used therapeutically or prophylactically for the treatment of diseases associated with the formation, aggregation or deposition of amyloid fibrils, regardless of the clinical picture. The compounds of the invention can alleviate the course of amyloid disease by any of the following mechanisms, but without limitation: slowing the rate of formation or deposition of amyloid fibrils; a decrease in the degree of amyloid deposition; a decrease in the degree of amyloid formation; inhibition, reduction or prevention of the formation of amyloid fibrils; inhibition of amyloid-induced inflammation; increased clearance of amyloid, for example, from the brain; or protecting cells from amyloid-induced (oligomeric or fibrillar) toxicity.

In one embodiment of the invention, the compounds of the invention can be used therapeutically or prophylactically for the treatment of diseases associated with the formation, aggregation or deposition of β-amyloid fibrils. The compounds of the invention can alleviate the course of the disease associated with β-amyloid by any of the following mechanisms (it is assumed that this list is illustrative and not limiting): slowing the rate of formation or deposition of β amyloid fibrils; a decrease in the degree of β-amyloid deposition; inhibition, reduction or prevention of the formation of β-amyloid fibrils; inhibition of neurodegeneration or cellular toxicity caused by β-amyloid; inhibition of inflammation induced by β-amyloid; increased clearance of β-amyloid from the brain; or promoting the cleavage of Άβ.

The compounds of the invention can be effective in controlling β-amyloid deposition either after they enter the brain (after passing through the blood-brain barrier) or from the periphery. When acting from the periphery, the compound can alter the Άβ balance between the brain and plasma so as to facilitate the removal of удалβ from the brain. An increase in the release of Άβ from the brain leads to a decrease in the concentration of Άβ in the brain and, therefore, contributes to a decrease in Άβ deposition. In addition, compounds that penetrate the brain can regulate deposition by acting directly on Άβ in the brain, for example, by keeping it in a non-fibrillar form or by promoting its clearance from the brain. Compounds may slow down processing ΆΡΡ; may increase cleavage when using macrophages or neural cells; or may reduce the production of Άβ by activated microglia. These compounds could also prevent the interaction of Άβ in the brain with the cell surface and, therefore, prevent neurotoxicity, neurodegeneration and inflammation.

In a preferred embodiment of the invention, a method of treating Olzheimer's disease (for example, sporadic or familial AO) is used. The method can also be used prophylactically or therapeutically for the treatment of other clinical cases of β-amyloid deposition, such as in patients with Down syndrome and in patients with cerebral amyloid angiopathy (ΟΛΛ) or in patients with hereditary cerebral hemorrhage, or patients with early Holzheimer's disease.

In another embodiment of the invention, a method of treating mild cognitive impairment is used. Mild cognitive impairment (MC1) is a condition characterized by a mild but noticeable loss of mental ability, which is not necessarily associated with the presence of dementia. MC1 often, but not always, precedes Holzheimer's disease.

In addition, the abnormal accumulation of ΆΡΡ and β-amyloid protein in muscle fibers entails the pathology of random myositis of inclusion bodies (1VM) (Akkapak e! A1., Rgok. No. 111. Asab. 8c1. I8A 93, 1314-1319 (1996) ; Akkapak e! A1., Siggei! Θρίηίοη ίη E11sita11yuodu 7, 486-496 (1995)). Accordingly, the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which the β-amyloid protein is abnormally deposited in non-neurological sites, for example, for the treatment of 1BM by delivering the compounds to muscle fibers.

In addition, it has been shown that Άβ is associated with abnormal extracellular deposits known as drusen, which accumulate along the basal surface of retinal pigmented epithelium in subjects with senile macular degeneration (AKMO). AKMO is the cause of irreversible loss of vision in older people. It is believed that Άβ deposition can be an important component of local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, Druze biogenesis and AMO pathogenesis (boccop. E! A1., Proc. No. 111. Asab. 8sk I8A 99 (18), 11830-5 (2002)).

In another embodiment, the invention relates to a method for treating or preventing an amyloid disease in a subject (preferably a human), comprising administering to the subject a therapeutic amount of a compound according to the formulas below or otherwise provided herein, such that the formation or deposition of fibrils, neurodegeneration is reduced or inhibited or cellular toxicity. In another embodiment, the invention relates to a method for treating or preventing an amyloid disease in a subject (preferably a human), the method comprising administering to the subject a therapeutic amount of a compound according to the formulas below or otherwise provided herein, so that in patients with brain amyloidosis, for example,

- 13 012429 patients with Alzheimer's disease, Down syndrome or cerebral amyloid angiopathy, cognitive function increases or stabilizes or further deterioration of cognitive function is prevented, slowed down or stopped. These compounds may also enhance the quality of daily life of these subjects.

The therapeutic compounds of the invention can treat amyloidosis associated with type II diabetes, for example, stabilizing glycemia, preventing or reducing β-cell mass loss, reducing or preventing hyperglycemia due to β-cell mass loss, and modulating (eg, increasing or stabilizing) insulin production . The compounds of the invention can also stabilize the pro-1APP / 1APP concentration ratio.

The therapeutic compounds of the invention can treat AA (secondary) amyloidosis and / or AB (primary) amyloidosis by stabilizing renal function, reducing proteinuria, increasing creatinine clearance (for example, at least 50% or more or at least 100% or more ), contributing to the remission of chronic diarrhea or weight gain (for example, 10% or more) or reducing serum creatinine. The visceral amyloid content can also be reduced, as determined, for example, by 8AP scintigraphy.

Compounds of the Invention

The present invention relates, at least in part, to the use of certain chemical compounds (and their pharmaceutical preparations) for the prevention or treatment of amyloid diseases, including, but not limited to, Alzheimer's disease, cerebral amyloid angiopathy, inclusion Taurus myositis, Down syndrome, amyloidosis associated with diabetes, hemodialysis-related amyloidosis (β ₂ Μ), primary amyloidosis (e.g., linked to the λ or κ chain), familial amyloid polyneuropathy (EAP), senile (senile) systemic amyloidosis, familial amyloidosis, such as Ostertag, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, Creutzfeldt-Jakob familial disease; Gerstmann-Straussler-Scheinker syndrome, hereditary spongiform encephalitis, prion diseases, familial Mediterranean fever, Macle-Wales syndrome, nephropathy, deafness, urticaria, limb pain, cardiomyopathy, skin deposits, multiple myeloma, benign monoclonal gammopathy, monoclonal gammopathy, gammopathy, myeloma, medullary thyroid cancer, and isolated atrial amyloidosis.

The chemical structures described herein are depicted in accordance with standards known in the art. Since an atom, such as a carbon atom, as it is depicted, has a missing valency, it is assumed that this valency is bound to hydrogen, even if this hydrogen atom is not necessarily depicted. The structures of some compounds of this invention include stereogenic carbon atoms. You should be aware that isomers resulting from such asymmetries (for example, all enantiomers and diastereomers) are included in the scope of the present invention, unless otherwise indicated. That is, unless otherwise indicated, any chiral carbon center may have either (K) - or (8) stereochemistry. Such isomers can be obtained in almost pure form by classical separation methods or by using stereochemically controlled synthesis. In addition, when appropriate, alkenes can have either E- or Ζ-geometry. In addition, the compounds of the present invention can exist in unsolvated as well as solvated with appropriate solvents such as water, THF, ethanol and the like, form. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

The term small molecule refers to a compound which, per se, is not a product of gene transcription or translation (e.g., protein, RNA or DNA) and preferably has a low molecular weight, e.g., less than about 2500 amu

The term nucleophile is usually a term commonly used in the art to mean a chemical group containing a reactive pair of electrons that reacts with a compound to replace a leaving group (usually another nucleophile), as is usually the case in the chemistry of aliphatic compounds by a monomolecular (known as δ _Ν 1) or bimolecular (8 _Ν 2) mechanism. Examples of nucleophiles include non-charge compounds, such as amines, mercaptans and alcohols, and charge groups, such as alkoxides, thiolates, carbanions, and a number of organic and inorganic anions. Examples of anionic nucleophiles include, but are not limited to, simple anions such as azide, cyanide, thiocyanate, formate or chloroformate, and bisulfite. Organometallic reagents such as organo-copper, organozinc, organolithium compounds, Grignard reagents, enolates and acetylides, which are suitable nucleophiles under appropriate conditions.

Similarly, the term electrophile means an atom, molecule or ion capable of accepting an electron pair, in particular a pair of electrons from a nucleophile, as is usually the case in an electrophilic substitution reaction. In an electrophilic substitution reaction, an electrophile binds to a substrate to remove another electrophile, for example, replacing a proton with another electrophile, such as a nitronium ion, in an aromatic substrate (e.g. benzene). Electrophiles include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones and varnish

- 14 012429 tams; and non-cyclic electrophiles include sulfates, sulfonates (e.g. tosylates), chlorides, bromides and iodides. The electrophile, as a rule, may be a saturated carbon atom (for example, a methylene group) associated with a leaving group; however, the electrophile may also be an unsaturated group, such as an aldehyde, keto, ester group, or their conjugated (α, β unsaturated) analog, which forms an adduct upon reaction with a nucleophile.

The term “leaving group” generally refers to a group that is easily displaced and replaced by a nucleophile (for example, an amine, thiol, alcohol or cyanide). Such leaving groups are well known and include carboxylates, Ν-hydroxysuccinimide (ΝΗ8), Ν-hydroxybenzotriazole, halogen (fluorine, chlorine, bromine or iodine), alkoxides and thioalkoxides. Usually, in chemical synthesis using a number of sulfur-containing leaving groups, including alkanesulfonyloxy groups (e.g., C-Cq-alkane, such as methanesulfonyloxy, ethanesulfonyloxy, propansulfoniloksi- and butansulfoniloksigruppy) and halogenated analogs (e.g., halogen _(C1-C4 alkane) sulfonyloxy such as trifluoromethanesulfonyloxy (i.e. triflate), 2,2,2-trichloroethanesulfonyloxy, 3,3,3-tribromopropanesulfonyloxy and 4,4,4-trifluorobutanesulfonyloxy groups) as well as arylsulfonyloxy groups (e.g., C ₆ -C _10- aryl, optionally deputy _{1 to 4} C ₁ -alkyl radicals, such as benzenesulfonyloxy, α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, p-toluenesulfonyloxy (i.e. tosylates), 4-tert-butylbenzenesulfonyloxy, mesitylene sulfonyloxy and 6 ethyl a-naphthylsulfonyloxy groups).

Activated esters can be represented by the formula —CO, where b is a leaving group, typical examples of which include β-hydroxysulfosuccinimidyl and β-hydroxysuccinimidyl groups; groups substituted by electron withdrawing groups (for example, p-nitro, pentafluoro, pentachlor, p-cyano or p-trifluoromethyl); and carboxylic acids activated with carbodiimide to form an anhydride or mixed anhydride, for example, -OSOK or ΟΟ'ΝΚ'ΝΗΡ ¹ '. where K ^a and K ^b are independently a C ₁ -C ₆ alkyl, C ₅ -C ₈ -alkyl (e.g. cyclohexyl), C ₁ -C ₆ perfluoroalkyl or C ₁ -C ₆ alkoxy group. The activated ester can be obtained ίη Phi or can be a separate reagent. Sulfosuccinimidyl esters, pentafluorothiophenol esters and sulfotetrafluorophenol esters are preferred activated esters. However, the ester leaving group may be, for example, a substituted or unsubstituted C ₁ -C ₆ alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl) group, or substituted A C ₆ -C ₁₄ aryl or heterocyclic group such as 2 fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dibromethyl, 2,2,2-trichloroethyl, 3 fluoropropyl, 4-chlorobutyl, methoxymethyl, 1,1-dimethyl -1-methoxymethyl, ethoxymethyl, Ν-propoxymethyl, isopropoxy methyl, Ν-butoxymethyl, tert-butoxymethyl, 1ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 3-methoxypropyl-4-methoxybutyl, fluoromethoxymethyl, 2,2,2-trichloroethoxymethyl, bis- (2- chloroethoxy) methyl, 3-fluoropropoxymethyl, 4-chlorobutoxyethyl, dibromomethoxyethyl, 2-chloroethoxypropyl, fluoromethoxybutyl, 2-methoxyethoxymethyl, ethoxymethoxyethyl, methoxyethoxypropyl, methoxyethoxybutyl, benzyl, phenethyl, 3-phenylphenylphenylphenylphenylphenylphenylbenzyl phenylphenyl methyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthranylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl diphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyl diphenylmethyl or bis (2-nitrophenyl) methyl groups.

The term electron withdrawing group is generally accepted in the prior art and describes the ability of a substituent to pull valence electrons onto itself (for example, π (pi) electrons) from neighboring atoms, for example, the substituent is more electronegative than neighboring atoms, or it pulls electrons onto itself more than hydrogen atom in the same position. The value of Hammett's constant sigma (σ) is a generally accepted measure of the electron-donating and electron-withdrawing ability of a group, especially the value of sigma vapor (σ _₽ ). See, for example, Abgapseb Otdashs SjetMgu LU 1. Matei, 5 ^4L Eb., Ίοΐιη \ Ubeu & δοηκ, 1ps., No. \ ν Wogk, pp. 368-75 (2001). The values of the Hammett constant are usually negative for electron-donating groups (σ _₽ = -0.66 for ΝΗ ₂ ) and positive for electron-withdrawing groups (σ _₽ = 0.78 for nitro group), and σ _p indicates substitution in the para position. Examples of electron withdrawing groups include, but are not limited to, nitro, acyl (ketone), formyl (aldehyde), sulfonyl, trifluoromethyl, halogen (eg, chlorine or fluorine) and cyano groups. In contrast, an electron-donating group denotes a substituent that donates electrons more easily than hydrogen if it occupies the same position in the molecule. Examples include, but are not limited to amino (including alkylamino and dialkylamino), aryl, alkoxy (including aralkoxy), aryloxy, mercapto, and alkylthio and hydroxyl groups.

Used in this description, the concept of aryl groups includes saturated hydrocarbons containing one or more carbon atoms, including linear alkyl groups (for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octal, butyl, decyl and t etc.), cyclic alkyl groups (or cycloalkyl, or alicyclic, or carbocyclic groups) (for example, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched alkyl groups (isopro sawn, tert-butyl, sec-butyl, isobutyl, etc.) and alkyl substituted alkyl groups (e.g., alkyl substituted cycloalkyl groups and cycloalkyl substituted alkyl groups). The term aliphatic group includes organic particles (fragments), which are characterized by linear or branched chains containing, as a rule, 1-22 carbon atoms. In complex structures, chains can be branched, bridged or crosslinked.

Aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups.

In some embodiments of the invention, a linear or branched alkyl group may contain 30 or less carbon atoms in the backbone, for example C | -C3, ₀ for a linear chain or C ₃ -C ₃₀ for a branched chain. In some embodiments of the invention, a linear or branched alkyl group may contain 20 or less carbon atoms in the main chain, for example C ₁ -C ₂₀ for a linear chain or C ₃ -C ₂₀ for a branched chain, and more preferably 18 carbon atoms or less. Similarly, preferred cycloalkyl groups contain 4-10 carbon atoms in a cyclic structure, and more preferably 4-7 carbon atoms in a cyclic structure. The term lower alkyl refers to alkyl groups containing 1-6 carbon atoms in a chain, and to cycloalkyl groups containing 3-6 carbon atoms in a cyclic structure.

Unless the number of carbon atoms is indicated otherwise, lower, as in lower aliphatic, lower alkyl, lower alkenyl, etc., as used herein means that the group (fragment) contains at least one and about less than 8 carbon atoms. In some embodiments of the invention, the linear or branched lower alkyl group contains 6 or less carbon atoms in the main chain (for example, C1-C6 for the linear chain, C3-C6 for the branched chain) and more preferably 4 or less. Similarly, preferred cycloalkyl groups contain 3-8 carbon atoms in a cyclic structure, and more preferably 5-6 carbon atoms in a cyclic structure. The term C ₁ -C ₆ as in _C1-C6 alkyl means alkyl groups containing 1-6 carbon atoms.

In addition, unless otherwise indicated, the term alkyl includes both unsubstituted alkyls and substituted alkyls, the latter term refers to alkyl groups containing substituents that replace one or more hydrogen atoms with one or more carbon atoms in the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halo, hydroxyl group, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, ar lkarbonilamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, tiokarboksilatnuyu, sulfate alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic (including heteroaromatic) groups.

An arylalkyl group means an alkyl group substituted by an aryl group (e.g., phenylmethyl (i.e., benzyl)). Alkylaryl group means an aryl group substituted by an alkyl group (e.g. p-methylphenyl (i.e. p-tolyl)). The term n-alkyl means a linear (i.e. unbranched) unsubstituted alkyl group. An alkylene group is a divalent analogue of the corresponding alkyl group. The terms alkenyl and alkynyl refer to unsaturated aliphatic groups similar to alkyl, but containing at least one double or triple carbon-carbon bond, respectively. Suitable alkenyl and alkynyl groups include groups containing about 2-12 carbon atoms, preferably from 2 to about 6 carbon atoms.

The term aromatic group or aryl group includes unsaturated and aromatic cyclic hydrocarbons, as well as unsaturated and aromatic heterocycles containing one or more cycles. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic, so that a polycyclic system is formed (e.g. tetralin). The arylene group is a divalent analogue of the aryl group. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic, so that a polycyclic system is formed (e.g. tetralin).

The term heterocyclic group includes closed cyclic structures similar to carbocyclic groups in which one or more carbon atoms in the cycle represents a different atom than a carbon atom, for example, a nitrogen, sulfur or oxygen atom. Heterocyclic groups may be saturated or unsaturated. In addition, heterocyclic groups (such as pyrrolyl, pyridyl, isoquinolyl, quinolyl, purinyl and furyl) may have an aromatic character, in which case they may be referred to as heteroaryl or heteroaromatic groups.

Unless otherwise indicated, aryl and heterocyclic groups (including heteroaryl) may

- 16 012429 also be substituted on one or more structural atoms. Examples of heteroaromatic and heteroalicyclic groups may contain 1-3 separate or fused rings with 3-8 members in the cycle and one or more heteroatoms Ν, O or 8. Typically, the term heteroatoms includes atoms other than carbon and hydrogen atoms, preferred examples of heteroatoms include nitrogen , oxygen, sulfur or phosphorus. Heterocyclic groups may be saturated or unsaturated or aromatic.

Examples of heterocycles include, but are not limited to, acridinyl; azocinyl; benzimidazolyl; benzofuranyl; benzothiofuranyl; benzothiophenyl; benzoxazolyl; benzothiazolyl; benzotriazolyl; benzotetrazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolinyl; carbazolyl; 4aH-carbazolyl; carbolinyl; chranyl; chromenyl; cinnolinyl; decahydroquinolinyl; 2H, 6H-1,5,2-dithiazinyl; dihydrofuro [2,3b] tetrahydrofuran; furanyl; furazanil; imidazolidinyl; imidazolinyl; imidazolyl; 1H-imidazolyl; indolenyl; indolinyl; indolisinyl; indolyl; 3H-indolyl; isobenzofuranyl; isochromanil; isoindazolyl; isoindolinyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; methylenedioxyphenyl; morpholinyl; naphtharidinyl; octahydroisoquinolinyl; oxadiazolyl; 1,2,3-oxadiazolyl; 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl; oxalidinyl; oxazolyl; oxalidinyl; pyrimidinyl; phenanthridinyl; phenantrolinyl; phenazinyl; phenothiazinyl; phenoxathiinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidonyl; 4-piperidonyl; piperonyl; pteridinyl; purinyl; piranyl; pyrazolidinyl; pyrazolinyl; pyrazolyl; pyridazinyl; pyridoxazole; pyridoimidazole; pyridothiazole; pyridinyl; pyridyl; pyrimidinyl; pyrrolidinyl; pyrrolinyl; 2H-pyrrolyl; pyrrolyl; quinazolinyl; quinolinyl; 4H-quinolisinyl; quinoxalinyl; quinuclidinyl; tetrahydrofuranyl; tetrahydroisoquinolinyl; tetrahydroquinolinyl; tetrazolyl; 6H-1,2,5-thiadiazinyl; 1,2,3-thiadiazolyl; 1,2,4-thiadiazolyl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; thianthrenyl; thiazolyl; thienyl; thienothiazolyl; thienoxazolyl; thienoimidazolyl; thiophenyl; triazinyl; 1,2,3-triazolyl; 1,2,4-triazolyl; 1,2,5-triazolyl; 1,3,4-triazolyl and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl; furanyl; thienyl; pyrrolyl; pyrazolyl; pyrrolidinyl; imidazolyl; indolyl; benzimidazolyl; 1 Nindazolyl; oxazolidinyl; benzotriazolyl; benzisoxazolyl; oxindolyl; benzoxazolinyl and isatinyl groups. Also included are fused cyclic and spiro compounds containing, for example, the above heterocycles.

A typical hydrocarbon aryl group is a phenyl group having one cycle. Bicyclic hydrocarbon aryl groups include naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl and azulenyl groups, as well as their partially hydrogenated analogues, such as indanyl and tetrahydronaphthyl. Typical tricyclic hydrocarbon aryl groups include aceftylenyl, fluorenyl, phenalenyl, phenanthrenyl and anthracenyl groups.

Aryl groups also include heteromonocyclic aryl groups, i.e. monocyclic heteroaryl groups such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl; and their oxidized analogues, such as the pyridonyl, oxazolonyl, pyrazolonyl, isoxazolonyl and thiazolonyl groups. Suitable hydrogenated (i.e., non-aromatic) heteromonocyclic groups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl and piperidino, piperazinyl, and morpholino and morpholinyl groups.

Aryl groups also include bicyclic heteroaryls, such as indolyl, isoindolyl, indolysinyl, indazolinyl, quinolinyl, isochnolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chimenyl, isinolinazinyl-benzyl-azinolinyl-benzyl-azinol-azinol-azinolinyl groups, as well as partially hydrogenated analogues, such as chromanyl, isochromanyl, indolinyl, isoindolinyl I and tetrahydroindolinyl group. Aryl groups also include fused tricyclic groups such as phenoxathiinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenantrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl and dibenzofuranyl.

Some typical aryl groups include saturated or unsaturated 5- and 6-membered monocyclic groups. In another aspect, each Ag group may be selected from the group consisting of substituted or unsubstituted phenyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxaosolyl, pyridinyl, pyrazinyl, pyrazinyl, pyrazinyl. Other examples include substituted or unsubstituted phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl 17 012429, 2-benzimidazoles flax, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2quinoxaniline, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl groups.

The term amine or amino as used herein refers to an unsubstituted or substituted group of the formula —ΝΚίΒ ³ , where B ^a and B ^b are each independently hydrogen, alkyl, aryl or heterocyclyl, or B ^a and B ^b together with the nitrogen atom with which they are connected, form a cyclic group containing 3-8 atoms in the cycle. Thus, unless otherwise indicated, the term amino includes cyclic amino groups, such as piperidinyl or pyrrolidinyl groups. Thus, the term alkylamino as used herein refers to an alkyl group containing an amino group attached to it. Suitable alkylamino groups include groups containing from about 1 to about 12 carbon atoms, preferably from about 1 to about 6 carbon atoms. The term amino includes compounds or groups in which a nitrogen atom is covalently bonded to at least one carbon atom or heteroatom. The term dialkylamino includes groups in which a nitrogen atom is attached to at least two alkyl groups. The term arylamino and diarylamino includes groups in which a nitrogen atom is bonded to at least one or two aryl groups, respectively. The term alkylarylamino refers to an amino group that is bonded to at least one alkyl group and 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 groups that contain a nitrogen atom bound to a carbon of a carbonyl or thiocarbonyl group.

The term alkylthio refers to an alkyl group containing a sulfhydryl group connected to it. Suitable alkylthio groups include groups containing from about 1 to about 12 carbon atoms, preferably from about 1 to about 6 carbon atoms.

The term alkyl carboxyl as used herein refers to an alkyl group containing a carboxyl group attached to it.

The term alkoxy as used herein means an alkyl group containing an oxygen atom connected to it. Typical alkoxy groups include groups containing from about 1 to about 12 carbon atoms, preferably from about 1 to about 6 carbon atoms, for example methoxy, ethoxy, propoxy, tert-butoxy, and the like. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy. Alkoxy groups can be substituted by such groups as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, dialkylaminocarbonyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkanoalkyl, alkylato , dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfga dryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic groups. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc., as well as perhalogenated alkoxy groups.

The term acylamino includes groups in which an amino group is attached to an acyl group. For example, the acylamino group includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The terms alkoxyalkyl, alkylaminoalkyl and thioalkoxyalkyl include the above-described alkyl groups, which further include oxygen, nitrogen or sulfur atoms that replace one or more carbon atoms of the hydrocarbon skeleton.

The term carbonyl or carboxy includes compounds and groups that contain a carbon atom linked by a double bond to an oxygen atom. Examples of groups that contain carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term ether or ether includes compounds or groups that contain an oxygen atom bonded to two carbon atoms. For example, an ether or ether group includes an alkoxyalkyl, which refers to an alkyl, alkenyl or alkynyl group substituted with an alkoxy group.

The sulfonate group denotes a -8O ₃ H or -8O ₃ ^- X ⁺ group bonded to a carbon atom, where X ⁺ is a cationic counterionic group. Similarly, a sulfonic acid group, or comprises -8O3N -8O3 ^- X \ linked to a carbon atom where X 'is a cationic group. The term sulfate as used herein refers to a —O8O3H or —O8O / X ′ group bonded to a carbon atom, and a sulfonic acid refers to a —O8O ₃ H or —O8O / X 'group bonded to a carbon atom, where X ^' is a cationic group. According to the present invention, a suitable cationic group may be a hydrogen atom. In some cases, the cationic group may actually be another group in a therapeutic compound that is positively charged at physiological pH, for example, an amino group.

A counterion is required to maintain a neutral total charge. Examples of anionic counter

- 18 012429 ions include halogen, triflate, sulfate, nitrate, hydroxide, carbonate, bicarbonate, acetate, phosphate, oxalate, cyanide, alkylcarboxylate, Ν-hydroxysuccinimide, Ν-hydroxybenzotriazole, alkoxide, thioalkoxide, alkanesulfonyloxy, halogenated oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate or lactobionate. Compounds containing a cationic group covalently bonded to the anionic group may be called internal salts.

The term nitro means -ΝΟ ₂ ; the term halogen or halogen, or halogen (halo) means —E, —C1, —Br or —I; the term thiol, thio or mercapto means 8Η; and the term hydroxyl or hydroxy means —OH.

The term acyl refers to a carbonyl group connected through its carbon atom to hydrogen (i.e., formyl), an aliphatic group (e.g., acetyl), an aromatic group (e.g., benzoyl), and the like. The term substituted acyl includes groups in which one or more hydrogen atoms at one or more carbon atoms are substituted, for example, by an alkyl group, an alkynyl group, a halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylaryls o) acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, alkyl, a group.

Unless otherwise indicated, the chemical groups (fragments) of the compounds of the invention, including the groups discussed above, may be substituted or unsubstituted. In some embodiments of the invention, the term substituted means that the group has substituents other than hydrogen (i.e., in most cases, replace hydrogen) that facilitate the molecule to carry out its intended function. Examples of substituents include fragments (groups) selected from linear or branched alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), alkoxy (preferably C1-Cb), thioalkyl (preferably C1- Sat), alkenyl (preferably C2-Sa), alkynyl (preferably C ₂ -C _b) geterotsiklichecheskoy, carbocyclic, aryl (e.g., phenyl) groups, aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g. phen (yl) hydroxyalkyl) arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and ar ilcarbonyl or other similar acyl group, heteroarylcarbonyl and heteroaryl groups, as well as ΉΒ'Β) _0-3 ΝΒ'Β (e.g., ΝΗ ₂ ), (ΟΕΉ) _0- ΉΝ (e.g., -SI), -ΝΟ ₂ , halogen ( for example, -E, -C1, -Br or -I), (CE'K) _0-3 C (halogen) ₃ (e.g. -CE ₃ ), (CB'B) _0-3 CH (halogen) ₂ , (CB'V) _0-3 CH ₂ (halogen), (CB'VC ₃ SOZH'V. (No. Κ.) 0-3ΉΝΗ) ΝΚ'Κ_, (€ Κ'Κ) ₀ -38 (Ο) 1.2ΝΚ 'Κ, (CH'H) _; CHO, (CH'H) _; O (CH'N) _; H, (CH'H) _; 8 (O) _; Β '(for example, -8О ₃ Н), (CB'V) _0-3 О (CB'V) _0-3 N (for example, -CH ₂ OCH ₃ and -OSH ₃ ), (CB'V) _{0- 3} § (CB'V) _0-3 N (for example, -8Η and -8CH ₃ ), (SK / K) _0-3 OH (for example, -OH), (Sk.'V) _0-3 SOV ', (SC / K) _0-3 (substituted or unsubstituted phenyl), (CB'K) _0-3 (C ₃ -C ₈ cycloalkyl), (CB'B) _0-3 CO ₂ B '(e.g. -CO ₂ H) and (SV'V) _0-3 OM 'group wherein B' and B each independently represents hydrogen, C1-C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl or an aryl group; or a side chain of any naturally occurring amino acid.

In another embodiment of the invention, the substituent can be selected from linear or branched alkyl (preferably C ₁ -C ₅ ), cycloalkyl (preferably C ₃ -C ₈ ), alkoxy (preferably C ₁ Cb), thioalkyl (preferably C ₁ -Cb) , alkenyl (preferably C2-Sa), alkynyl (preferably C ₂ -C _b), heterocyclic, carbocyclic, aryl (e.g., phenyl) groups, aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g. , phen (yl) hydroxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and aryl Arbon or other such acyl group, heteroarylcarbonyl, or heteroaryl groups, as well ΉΒ'Β) _0- ι ₀ ΝΒ'Β (e.g., ΝΗ _2), ΉΒΒ) _0-1 ΉΝ (e.g.,-SI) -IO _2, halogen (e.g. -E, -C1, -Br or -I), (CB'B) _0-10 C (halogen) ₃ (e.g. -CE ₃ ), (CΒΒ) _0-10 CH (halogen) ₂ , ( CΒΒ) _0-10 CΗ ₂ (halogen), (CΒΒ) _0-10 CΟNΒΒ, ΉΒ'Β) _0-10 ΉΝΗ) ΝΒ'Β, (CΒΒ) ο- ₁ ο8 (Ο) ₁ -2NΒ'Β, (CΒ 'Β) ο-1οСΗΟ, (СΒ'Β) ο- ₁ οΟ (СΒ'Β) ο- ₁ οΗ, (ϋΒ ^''^^)^' (e.g. -8О3Н), (e.g. -СН2ОСН3 and - OCH3), (CH'H) 8 (CH'H) _; H (e.g., -8Η and -8SN3), ΉΒ'Β'ΉιΉΗ (e.g., -OH), (SΒ'Β) _0- 1 ₀ SΟΒ '(SV'V) _0-10 (substituted or unsubstituted phenyl), (СΒ'Β) _0- 1 ₀ (С ₃ -С ₈ -cycloalkyl), (СΒ'Β) _0- 1 ₀ СΒ ₂ Β '(for example, -CO ₂ I) and ΉΒ'Β'Ή ^ ΉΒ' groups , or the side chain of any naturally occurring amino acid; where Β 'and Β, each independently, is hydrogen, a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl or aryl group, or Β' and Β together represent a benzylidene group or - (CH2) 2 O (CH2) 2 group.

It should be understood that substitution or substitution includes the implied condition that such substitution is carried out in accordance with the valency of the substituted atom and substituent, and that substitution results in a stable compound, such as, for example, which does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination etc. It is intended that the term “substituted” as used herein includes all of the acceptable substituents of the organic compound. In a broad aspect, permissible substituents include acyclic

- 19 012429 cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents may be one or more.

In some embodiments, the substituent may be selected from the group consisting of, for example, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, _C1-C6 alkylcarbonyloxy, arylcarbonyloxy, C1-C ₆ -alkoksikarboniloksi, aryloxycarbonyloxy, _C1-C6 alkylcarbonyl, _C1-C6 alkoxycarbonyl, C1 -C6 alkoxy, C1 -C6 alkylthio, arylthio, heterocyclyl, arylalkyl (including heteroaryl) groups.

In one embodiment, the invention relates to compounds of formula (I)

BUT?

where K ¹ represents a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, arylcycloalkyl, bicyclic or tricyclic group, a fused bicyclic or tricyclic group or a substituted or unsubstituted C ₂ -C _{1 0} -alkyl group;

K ^{2 is} selected from the group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl and benzimidazolyl;

Υ denotes 8O ₃ ^- X ⁺ , O8O3 ^- X ⁺ or 8 8O3 ^- X ⁺ ;

X 'is hydrogen, a cationic group or an ester forming group; and each of b ¹ and b ² denotes, independently, a substituted or unsubstituted C1-C ₅ -alkyl group or is absent, or to a pharmaceutically acceptable salt thereof, provided that when K ¹ is alkyl, b ^{1 is} absent.

In another embodiment, the invention relates to compounds of formula (II)

K ² Oh. .N- (0) *, - (СН ₂ ) „- ¥

K — b (P) where K ¹ is a substituted or unsubstituted cyclic, bicyclic, tricyclic or benzoheterocyclic group or a substituted or unsubstituted C2-C10 alkyl group;

K ² is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl and benzimidazolyl, or bonded to K ¹ to form a heterocycle;

Υ denotes 8O ₃ ^- X ⁺ , O8O3 ^- X ⁺ or 8 8O3 ^- X ⁺ ;

X 'is hydrogen, a cationic group or an ester forming group;

m is 0 or 1;

n is 1, 2, 3 or 4;

B denotes a substituted or unsubstituted O-C ₅ -alkyl group or is absent, or to a pharmaceutically acceptable salt thereof, provided that when K ¹ is alkyl, b is absent.

In another embodiment, K ² is hydrogen. In yet another embodiment of the invention, K ¹ is linear alkyl, for example ethyl, n-pentyl, n-heptyl or n-octyl. In another embodiment, K ¹ is tert-butyl. In yet another alternative embodiment of the invention, K ¹ is C ₇ -C ₁₀ bicycloalkyl or tricycloalkyl, for example, such as tricyclo [3.3.1.0 ^3,7 ] decyl (or adamantyl), bicyclo [2.1.2] heptyl or indolyl. In another alternative embodiment, K ¹ is tetrahydronaphthyl.

In one embodiment of the invention, L ² is - (CH 2) 3 -. In another further embodiment, L ² is - (CH2) ₄ - or - (CH ₂ ) ₅ -. In a still further embodiment of the invention, L ² is - (CH2) 2. In a still further embodiment of the invention, L ² is substituted alkyl, for example —CH 2 (CHOH) —CH 2 -.

In another embodiment of the invention, L ² is, or absent, CH ₂ CH ₂ .

In another embodiment of the invention, K ¹ is branched alkyl, for example tert-butyl. In another embodiment, K ¹ is adamantyl. In another embodiment of the invention, K ¹ is cyclic alkyl, for example, cyclopropyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Cycloalkyl groups may be further substituted, for example, with additional alkyl groups or other groups that facilitate the molecule to carry out its intended function. In another embodiment of the invention, K ¹ is alkyl substituted with a propargyl moiety (for example, —CH = C—). In another embodiment, K ¹ is cyclohexyl substituted with one or more methyl or propargyl groups.

In other embodiments, L ¹ is a C1-C2 alkyl linker group (e.g., —CH (CH3) - or - (CH2) 2-). In another embodiment, K ¹ is phenyl. In some embodiments of the invention, K ^{1 is} substituted with a methoxy group. In other embodiments, b ¹ is C3, for example

- 20 012429

- (CH ₂ ) ₃ - or C (CH ₃ ) ₂ -. In some embodiments, L ^{1 is} substituted, for example, with an alkoxy, carboxylate (—COOH), benzyl, amido (—C = O — OH —) or ester (C = O — C — O) group. In some embodiments of the invention, the ester group is a methyl, ethyl, propyl, butyl, cyclohexyl ester group. In other embodiments, the ester group may be a propenyl group. In other embodiments, b ^{1 is} substituted with a carboxylate group. In another embodiment of the invention, K ^{1 is} substituted with a substituted amide group, wherein the amide group is substituted with an alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl group. In another embodiment of the invention, the alkyl K ¹ group is substituted with —C = O — OH — OH, C = O — OH, or an amido group. In some embodiments of the invention, the amido group is substituted by an alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl, etc.), benzyl or aryl group. In another embodiment, the amido group is substituted with —CH (CH2) 2 - group. K 'itself may be substituted with phenyl or may be branched or linear alkyl. In some embodiments of the invention, K 'may also be substituted with a thioether group. Examples of thioethers include 8-Me, 8-E! etc. In some embodiments of the invention, the alkyl K ¹ group is substituted with both an aryl and a thioether group and an amido group. In other embodiments of the invention, the alkyl K ¹ group may be substituted with both a thioether and a carboxylate group. In other embodiments, alkyl K ¹ groups are substituted with hydroxyl. K ¹ groups, for example, alkyl K ¹ groups, can also be substituted with both a thioether and a hydroxyl group. In other embodiments of the invention, K ¹ groups, for example, alkyl K ¹ groups, are substituted with a cyano group. Examples of K ¹ groups containing —CY fragments include C (CH3) ₂ CH, cyclohexyl substituted with one or more cyano groups, and

etc.

In other embodiments, the alkyl K ¹ groups are substituted with aryl groups. The ryl groups may be, for example, substituted phenyl. Substituted phenyl may be substituted with one or more substituents, such as hydroxy, cyano and alkoxy. In other embodiments, alkyl K ¹ groups are substituted with tetrazolyl or substituted or unsubstituted benzyl.

In other embodiments, L ¹ is —C (CH3) 2-CHOH. In yet another embodiment, L ¹ is —C (CH3) ₂ CH (OMe) -. In another embodiment, K ¹ is substituted or unsubstituted phenyl. In yet another embodiment of the invention, K ¹ is parasubstituted phenyl. Examples of substituents include, but are not limited to, fluorine, chlorine, bromine, iodine, methyl, tert-butyl, alkoxy, methoxy, etc. In another embodiment, K ^{1 is} substituted at the meta position. Examples of substituents include methoxy, chloro, methyl, tert-butyl, fluoro, alkyl, alkoxy, iodine, trifluoroalkyl, methoxy, etc. In another embodiment of the invention, K ¹ is phenyl substituted with similar substituents in the ortho position. In another embodiment, b ¹ contains a cycloalkyl moiety, for example cyclopentyl. In another embodiment of the invention, L ¹ contains an alkenyl group and, optionally, a substituted aryl group with substituents similar to those described above.

In some embodiments, K ¹ is cyclopropyl or cyclohexyl. In some embodiments, the cyclopropyl or cyclohexyl group is substituted with an ether group or an alkyl group. In some further embodiments, the ether group is a benzyl ether group.

In another embodiment of the invention in which K ¹ is alkyl, it is substituted with groups such as phenyl or hydroxy.

In other embodiments, a compound of the invention is selected from the group consisting of

- 21 012429

- 22 012429

- 23 012429

- 24 012429

- 25 012429

- 26 012429

- 27 012429

ΖΙ g Ζϊ

- 28 012429

- 29 012429

- 30 012429

- 31 012429

- 32 012429

- 33 012429

- 34 012429

- 35 012429

and their pharmaceutically acceptable salts, esters and prodrugs.

In yet another embodiment, the invention relates to compounds of formula (III)

where A is nitrogen or oxygen;

K ¹¹ denotes hydrogen, a salt-forming cation, an ester-forming group, - (CH _; ), .- O. or, if A is nitrogen, A and K ¹¹ together may be a residue of a natural or unnatural amino acid or its salt or ester;

denotes hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl or benzimidazolyl;

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

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

K ³ , K ^3a , K ⁴ , K ^4a , K ⁵ , K ^5a , K ⁶ , K ^6a , K ⁷ and K ^7a each independently represent hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two K groups at two adjacent cyclic atoms together with the atoms in the cycle form a double bond, provided that one of K ³ , K ^3a , K ⁴ , K ^4a , K ⁵ , K ^5a , K ⁶ , K ^6a , K ⁷ and K ^7a denotes a fragment (111a)

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

K ^{A, K, K,} K ^a and K ^E are independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl and benzimidazolyl;

and their pharmaceutically acceptable salts and esters, provided that the compound is not 3- (4-phenyl-1,2,3,6-tetrahydro-1-pyridyl) -1-propanesulfonic acid.

In a further embodiment of the invention, η is 2, 3 or 4.

In another embodiment, K ¹¹ is a salt forming cation. Examples of salt forming cations include pharmaceutically acceptable salts as described herein, as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In another embodiment of the invention, K ¹¹ is an ester forming group. An ester forming group includes groups which, when bound, form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl or cycloalkyl. In another embodiment, A is oxygen.

- 36 012429

In another embodiment of the invention, K ³ and K ^4, together with the carbon atoms to which they are bonded, form a double bond. In another embodiment of the invention, K ^A , K ⁱⁿ , K ^s , K ⁱⁿ and K ^E each are hydrogen. K ^A , K ^c , K ^c and K ^E each are hydrogen, and K ^c is halogen such as fluorine, chlorine, iodine or bromine.

In another embodiment, K ³ or K ^5a denotes a fragment of formula (111a).

In another embodiment, K ⁴ , K ⁵ , K ^6, and K ⁷ are each hydrogen. In another further embodiment of the invention, K ^4a , K ^5a , K ^6a and K ^7a are each hydrogen.

In another embodiment, K ^3a is hydroxyl, cyano or acyl.

In another further embodiment of the invention, K ¹¹ and A, together, are a residue of a natural or unnatural amino acid or a pharmaceutically acceptable salt or ester thereof. Examples of amino acid residues include esters and salts of phenylalanine and leucine.

In another embodiment of the invention, m is 0, 1 or 3.

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

and their pharmaceutically acceptable salts, esters and prodrugs.

In yet another embodiment, the invention relates, at least in part, to compounds of formula (IV)

where A is nitrogen or oxygen;

K ¹¹ denotes hydrogen, a salt-forming cation, an ester forming group, - (CH ₂ ) _x -p, or, if A denotes nitrogen, A and K ¹¹ together may be a residue of a natural or unnatural amino acid or its salt or ester;

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

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

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

K ⁴ , K ^4a , K ⁵ , K ^5a , K ⁶ , K ^6a , K ^7, and K ^7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or K ⁴ and K ⁵ together with the atoms in the cycle with which they are bonded form a double bond, or K ⁶ and K ⁷ together with the atoms in the cycle with which they are bonded form a double bond;

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

K ⁸ , K ⁹ , K ¹⁰ , K ¹¹ and K ¹² are independently selected from the group: hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl and benzimidazolyl;

and their pharmaceutically acceptable salts and esters.

In another embodiment, K ¹¹ is a salt forming cation. Examples of salt forming cations include pharmaceutically acceptable salts as described herein, as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In another embodiment of the invention, K ¹¹ is an ester forming group. An ester forming group includes groups which, when bound, form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl or cycloalkyl. In another embodiment, A is oxygen.

In another embodiment of the invention, m is 0 or 1. In another further embodiment of the invention, η is 2, 3 or 4. In another further embodiment of the invention, K ⁴ , K ⁵ , K ⁶ and K ⁷ are each hydrogen. K ^4a , K ^5a , K ^6a and K ^7a may also be hydrogen. Examples of K ⁸ , K ⁹ , K ¹⁰ , K ¹¹ and K ¹² include hydrogen. In another embodiment of the invention, K ⁸ , K ⁹ , K ¹¹ and K ¹² are each hydrogen, and K ¹⁰ is halogen (e.g. fluorine, chlorine, bromine or iodine), nitro or alkyl (e.g. methyl, ethyl, butyl) . In another embodiment, AK ¹¹ may be an amino acid residue, for example, a phenylalanine residue. In another embodiment, K ⁹ , K ¹⁰ , K ^11, and K ¹² are each hydrogen and K ^{8 is} 37 012429

3CH is not hydrogen, for example halogen, for example fluorine, chlorine, bromine or iodine. In another embodiment of the invention, the compound is

and their pharmaceutically acceptable salts, esters and prodrugs.

In another embodiment, the invention includes compounds of formula (V)

О (СНаМ-З --- А - О (V) where А is nitrogen or oxygen;

B ¹¹ is hydrogen, a salt-forming cation, an ester forming group, - (CH ₂ ) _x -p, or, if A is nitrogen, A and B ¹¹ together may be a residue of a natural or unnatural amino acid or its salt or ester;

denotes hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl or benzimidazolyl;

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

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

aa is the residue of a natural or unnatural amino acid;

t is 0, 1, 2 or 3;

¹⁴ represents hydrogen or a protecting group;

¹⁵ denotes hydrogen, alkyl or aryl, and their pharmaceutically acceptable salts and prodrugs.

In another embodiment, B ¹¹ is a salt forming cation. Examples of salt forming cations include pharmaceutically acceptable salts as described herein, as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In another embodiment of the invention, B ¹¹ is an ester forming group. An ester forming group includes groups which, when bound, form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl or cycloalkyl. In another embodiment, A is oxygen.

In one embodiment of the invention, η is 2, 3 or 4. In some embodiments of the invention, m is 0. In some embodiments of the invention, Α-B ¹¹ is the residue of a natural or unnatural amino acid or its salt or ester. Examples of amino acid residues include, but are not limited to, leucine or phenylalanine residues and their pharmaceutically acceptable salts and esters. Examples of possible esters include methyl, ethyl and tert-butyl.

In another embodiment of the invention, m is 1. Examples of aa include residues of natural and unnatural amino acids, such as phenylalanine, glycine and leucine.

In another embodiment of the invention (aa), _t is pH-pH or its ester.

In some embodiments, ¹⁵ is hydrogen or substituted alkyl, arylalkyl example.

The term non-natural amino acid refers to any derivative of a natural amino acid, including Ό forms, and derivatives of α- and β-amino acids. It is noted that some amino acids, for example, hydroxyproline, which are classified as non-natural amino acids in this description, can be found in nature in a particular organism or specific protein. Amino acids with many different protecting groups suitable for direct use in solid phase peptide synthesis are commercially available. In addition to the twenty basic most common natural amino acids, the following examples of unnatural amino acids and amino acid derivatives can be used according to the invention (conventional abbreviations are given in parentheses): β-alanine (β-ΑΒΑ), γ-aminobutyric acid (ΟΑΒΑ), 2-aminobutyric acid (2-bb ), a ^ -dehydro ^ -aminobutyric acid (8Αυ), 1-aminocyclopropane-1-carboxylic acid (ACRS), aminoisobutyric acid (ΑΛ), 2aminothiazoline-4-carboxylic acid, 5-aminovalerianic acid (5-Ανα), 6 -aminohexanoic acid (6-ΑΗχ), 8-amino-octanoic acid (8-AOS), 11-am inoundecanoic acid (11-Αυη), 12-aminododecanoic acid (12-Αί6ο), 2-aminobenzoic acid (2-Α4), 3-aminobenzoic acid (3Α4), 4-aminobenzoic acid (4-Α4), 4-amino-3- hydroxy-6-methylheptanoic acid (Statin, 81a1te, δία), aminooxyacetic acid (Aoa), 2-aminotetralin-2-carboxylic acid (ATC), 4-amino5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), paraminophenylalanine (4- ΝΗ ₂ -Ρ4), biphenylalanine (Βίρ), parabromophenylalanine (4-ΒΓ-Ρ4), orthochlorophenylalanine (2-0144), metachlorophenylalanine

- 38 012429 (3-C1-P1e), parachlorophenylalanine (4-C1-P1e), methachlortyrosine (3-C1-Tug), parabenzoylphenylalanine (Bra), tert-butyl glycine (TLC), cyclohexylalanine (C1a), cyclohexyl 2,3-diaminopropionic acid (Org), 2,4-diaminobutyric acid (Oi), 3,4-dichlorophenylalanine (3,4C1 ₂ -P1e), 3,4-difluorophenylalanine (3,4-P ₂ -P1e), 3 5-diiodotyrosine (3.5-1 ₂ -Tug), orthofluorophenylalanine (2-PP1e), metafluorophenylalanine (3-P-P1e), parafluorophenylalanine (4-P-P1e), metafluorothyrosine (3-P-Tug), homoserin (Hke), homophenylalanine (H £ e), homothyrosine (H! Yr), 5-hydroxytryptophan (5-OH-Tgr), hydroxyproline (Nur ), paraiodophenylalanine (4-1-P1e), 3-iodotyrosine (3-1-Tug), indoline-2-carboxylic acid (1bc), isonipecotinic acid (Ιηρ), metamethyl tyrosine (3-Me-Tug), 1-naphthylalanine (1-№a1) 2naftilalanin (2-№a1) paranitrofenilalanin (4--R1e NiO _2), 3-nitrotyrosine (3--Tug NiO _2), norleucine (№1e), norvaline (№ua) , ornithine (O), orthophosphothyrosine (H ₂ PO ₃ -Tug), octahydroindole-2-carboxylic acid (O1c), penicillamine (Rep), pentafluorophenylalanine (p5-Rye), phenylglycine (R1d), pipecolinic acid (Prgr) (RGA), pyroglutamic acid (RSI), sarcosine (8AG), tetrahydroisoquinoline-3 β-carboxylic acid (T1c), thienylalanine and thiazolidine-4-carboxylic acid (thioproline, T1) In addition, N-alkylated amino acids, as well as amino acids with amine-containing side chains (such as Luke and Ot), in which the amine is acylated or alkylated.

Examples of compounds of the invention include, but are not limited to.

and their pharmaceutically acceptable salts, esters and prodrugs.

In another embodiment, the invention relates, at least in part, to compounds of formula (VI)

where η is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

Ά is oxygen or nitrogen;

K ¹¹ is hydrogen, a salt-forming cation, an ester forming group, - (CH ₂ ) _x -p, or, if Ά is nitrogen, Ά and K ¹¹ together can be a residue of a natural or unnatural amino acid or its salt or ester;

denotes hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl or benzimidazolyl;

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

K ¹⁹ is hydrogen, alkyl or aryl,

Υ ¹ is oxygen, sulfur, or nitrogen;

Υ ² represents carbon, nitrogen or oxygen;

K ²⁰ is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl and benzimidazolyl;

K ²¹ is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl and benzimidazolyl, or is absent if Υ ² is oxygen;

- 39 012429

H ²² is hydrogen, alkyl, mercatoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzimidazolyl; or H ²² is hydrogen, hydroxyl, alkoxy or aryloxy if Υ ¹ is nitrogen; or H ^{22 is} absent if Υ is oxygen or sulfur; or H ²² and H ²¹ may be linked to form a cyclic moiety if Υ ¹ is nitrogen;

H ²³ is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl or benzimidazolyl, or is absent if Υ ² is nitrogen or oxygen;

or their pharmaceutically acceptable salts.

In another embodiment of the invention, H ¹¹ is a salt-forming cation. Examples of salt forming cations include pharmaceutically acceptable salts as described herein, as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In another embodiment of the invention, the salt is a sodium salt. In yet another embodiment of the invention, A is oxygen.

In another embodiment, Υ ¹ is sulfur and H ^{22 is} absent.

In another embodiment, Υ ² is oxygen and H ^{21 is} absent. Examples of H ²⁰ include benzyl, aryl (e.g. phenyl), alkyl, cycloalkyl (e.g. adamantyl), etc. In another embodiment, Υ ² is nitrogen and H ²¹ is hydrogen. In another embodiment of the invention, H ²¹ is benzyl. In another further embodiment of the invention, H ²¹ and H ²² are coupled to form a pyridyl ring. In another embodiment, Υ ¹ is sulfur.

Examples of compounds of the invention include

80з№

and their pharmaceutically acceptable salts, esters and prodrugs.

In another embodiment, the invention relates to compounds of formula (VII)

where η is 2, 3 or 4;

A is oxygen or nitrogen;

H ¹¹ is hydrogen, a salt-forming cation, an ester-forming group, - (CH ₂ ) _x -p,

- 40 012429 or, if A is nitrogen, A and B ¹¹ together may be a residue of a natural or unnatural amino acid or its salt or ester;

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

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

denotes an ordinary bond or oxygen, nitrogen or sulfur;

ζ is 0, 1, 2, 3, 4 or 5;

m is 0 or 1;

²⁴ selected from the group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl and benzimidazolyl;

each B ²⁵ is independently selected from hydrogen, halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclyl or heterocyclyl, and their pharmaceutically acceptable salts, esters and prodrugs.

In one embodiment, B ¹¹ is hydrogen. In another embodiment, A is oxygen. For example, η may be 3, and m may be 1. In another embodiment, B ²⁴ is hydrogen or benzyl.

In some embodiments, ζ is 0, 2, or 3. In other embodiments, B ²⁵ is hydroxyl or alkoxy, for example methoxy, ethoxy, etc. In some embodiments of the invention, substituents B ²⁵ may be linked to the formation of fused rings (e.g., to form a methylenedioxyphenyl moiety).

Examples of compounds of the invention include

and their pharmaceutically acceptable salts, esters and prodrugs. Other compounds of the invention include

and their pharmaceutically acceptable salts, esters and prodrugs.

The invention relates to both salts and acidic / basic forms of the compounds of the invention. For example, the invention relates not only to specific salts of the compounds depicted as salts in this specification, but the invention also includes other pharmaceutically acceptable salts and an acidic and / or basic form of the compound. The invention also relates to salts of the compounds shown in this description.

Compounds according to the invention are also presented below in table. 2.

- 41 012429

table 2 GO Compound structure / tension in 2-phenyl-1-sulfopropyl- 1,2,3,6- tetrahydropyridine ABOUT one ΝΗ from 4- (3-phenylpropyl) -1-sulfopropylpyridine E 3- (4-cyano-4-phenylpiperidin-1-yl) -1-propanesulfonic acid ONE HUNDRED- G 3- [4- (4-fluorophenyl) -1DZ> 6-tetrahydropyridin-1-yl] -1-propanesulfonic acid FROM 3- [4- (4-bromophenyl) -4-hydroxypiperidin-1-yl] -1-propanesulfonic acid ^βγ ΧΖΑΟ ^ν · '''^ ³ ° ^3Η N 3 - [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl] -1 - propanesulfonic acid I 3- (4-acetyl-4- fenilpiperidin- 1- yl) -1-propanesulfonic acid On ^removal of L 3- [4- (4-chlorophenyl) - 1,2,3,6-tetrahydropyridin-1-yl] - 1-propanesulfonic acid C1 - (XU - ’ζ TO 3- (4-phenylpiperazin-1-yl) -1-propanesulfonic acid zo ₃ n b 3- [4- (4-chlorophenyl) piperazin-1-yl] - 1- propanesulfonic acid C1 - m 3- [4- (2-fluorophenyl) piperazin-1-yl] - 1- propanesulfonic acid R N 3- [4- (4-nitrophenyl) piperazin-1-yl] - 1- propanesulfonic acid Ο ₂ Ν— · ζ —ν '^ _ν ^{/ Χ} ^^' £ Ο ₃ Η R 3- [4- (4-fluorophenyl) piperazin-1-yl] - 1- propanesulfonic acid

- 42 012429

nine 3- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) propanoic acid to 3- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) butanoic acid hydrochloride HC1 8 3- (3,4-dimethoxybenzyl) amino) - 1- propanesulfonic acid ^ SU

X ¹ L-RIE-L-Rke-Taurine

Υ X-Vos-b-RNs-homoTau-b-OE (

Ah, „Ah γοΑ ό n o Ζ B-pc-homot ay-b-pye-oe! hydrochloride CC _n X)? Οχ о ί - -А N. А А, 0 .. Н, я- Ύ - Ν γ - 0 but С | · AA L- (Ν- Boc) - RN- (3-aminopropane-1-sulfonyl) - L-Pb, sodium salt Sul ^ U ί O_o a ⁷ n-LALA * o-A0 n about A AB L- (L ^G - Boc) - Rye - (3-aminopropane-1 - sulfonyl) - L-PHe, methyl ester Ce,. And r V o _{h ζ} ο G 0 but c AC Ν-benzyloxycarbonyl-3-amino-2-hydroxy-1-propanesulfonic acid sodium salt 0, -. o-A-ν ^/ Α ^/ ^ ' ⁵ ° 3 ^Ν3 Y ⁷ n he

- 43 012429

Αϋ Ν-benzyloxycarbonyl-4-amino-1-butanesulfonic acid sodium salt 0 II ^ x. / x. ASH O ¹ Ν - - V / ⁿ ΑΕ Y-benzyloxycarbonyl-3-amino-L-propanesulfonic acid sodium salt 0 / 'ΐ, / 1 ! yn ΑΓ 3 - {[(benzhydrylamino) carbonyl] amino} - 1 - propanesulfonic acid Ι] ΝΗ ΝΗ Λ. ..5CH to V Υ 0 AC 3 - [(phenylacetyl) amino] - 1- propanesulfonic acid sodium salt n one y / x G TT Ч№ θ AN 3- {[(benzylamino) carbonyl] amino} -1-propanesulfonic acid sodium salt 0 ct n n ΑΙ 3- {[(hexylamino) carbonyl] amino} -1-propanesulfonic acid sodium salt 0 eleven n n HELL 3 - {[(dodecylamino) carbonyl] amino} - 1- propanesulfonic acid sodium salt 0 n n ΑΚ 3 - {[(adamantylamino) carbonyl] amino} - 1- propanesulfonic acid sodium salt and n Αί 3 - {[2- (4-isobutylphenyl) propanoyl] amino) - 1-propanesulfonic acid sodium salt .- .. ΝΗ. .. ·. „.8Ο ₃ No. yX? "

- 44 012429

AM 3- {[(benzylamino) carbonothioyl] amino} - 1-propanesulfonic acid sodium salt a _Λ I / V ΝΗ Г4Н '' 8О: 34а С / whether cCP-dibenzylamino-1-propanesulfonyl) - b- phenylalanine sodium salt ___ ~ with _r No. - ---, 0: x σ 'ύ Αν 3-dibenzylamino-1-propanesulfonic acid O ζ ~ .gzstsn Α \ ν 3- [((1,3-benzodioxol-5-yl) methyl) amino] - 1-propanesulfonic acid o. ΝΗ 5C ‘, N Ον ΑΧ 3- (3,4-dimethoxybenzylamino) - 1-propanesulfonic acid X>, -x -χ Λ Λ at у ^{ΝΗ 3} ° ^mark `` О '' ΑΥ 3- (3,4,5-trimethoxybenzylamino) - 1- propanesulfonic acid Th Οχ ΑΖ 3- (2,3-dimethoxybenzylamino) · 1- propanesulfonic acid / ABOUT.. 0 ΒΑ 3- (3,5-dimethoxybenzylamino) - 1- propanesulfonic acid ~ ^ζ '' νη- ^λ ^ '' ^ 3Ο ₃ η t ^ 0 ΒΒ 3- (2,4-dimethoxybenzylamino) - 1 - propanesulfonic acid уу м '-' зо., N 0-k -1, ^{n /} 0— Sun 3- (3,4-dihydroxybenzylamino) - 1- propanesulfonic acid BUT. , -χ / X χ-χ γ- at N 80, N σ .ζ n BUT

- 45 012429

Β \ ν 3- (1-adamantyl) amino) - 1- propanesulfonic acid ή in 3- (tert-butyl) amino) - 1- propanesulfonic acid ΒΥ 3- (2-norbornyl) amino) -1-propanesulfonic acid and ΒΖ 3- (2 “adamantyl) amino) - 1- propanesulfonic acid nu SS 5-amino-1- pentanesulfonic acid Si b-amino-1- hexanesulfonic acid CE 3-isobutylamino-1-propanesulfonic acid one ' SS 3- isopropylamino-1- propanesulfonic acid n 5C ' ₃ N cn 3-isoamylamino-1-propanesulfonic acid n one C1 3- (cyclopropylamino) - 1 - propanesulfonic acid N cl 3- (cyclopentylamino) -1- propanesulfonic acid N SC 3- (cycloheptylamino) -1 - propanesulfonic acid ⁿ 'GOSCH ^ l ^ ZOzN

- 46 012429 ''

±

U- (3-aminopropane-1-sulfonyl) - phenylalanine, ethyl ether

O O ί ¹ O

AND O _____________________ cyclopentyl sulfamic acid sodium salt of cycloheptyl sulfamic acid sodium salt

4-IODINE-2U- (3-sulfopropyl) - b-phenylalanine amide

3- (ethylamino) - 1- propanesulfonic acid __H ____________________________________________________________

3- (3,5-dimethyl-1-adamantylamino) -1-propanesulfonic acid

3- cyclohexylamino-2-hydroxy-1-propanesulfonic acid

5O, N

3- (3-pentyl) amino-1-propanesulfonic acid, ⁿ

3- (tert-amyl) amino-1-propanesulfonic acid

3- (1,1-dimethyl-2-hydroxyethyl) amino) - 1- propanesulfonic acid

- 47 012429

ϋΐ 3- (1-carboxy-1-methylethylamino) - 1- propanesulfonic acid o ЦО / 5О, n ^Н ° Λ ϋσ 3- [(1K, 25) -2-methylcyclohexyl] amino-1-lropansulfonic acid ^ '^' SN οκ 3- (2,3-dimethylcyclohexyl) amino-1-propanesulfonic acid CH b 3-neopentylamino-1-propanesulfonic acid ΒΜ 3- cumylamino-1- propanesulfonic acid ΒΝ IN 3- [(1 K.) - 1-indanamino] -1- propanesulfonic acid 00 ΒΡ 3- (Ν-tert-butylcarbamyl) amino-1-propanesulfonic acid 1 ⁰ -O D _Λ 'Οΐ IN 3- (1,2-dimethyl-1-propyl) amino-1-propanesulfonic acid sn, H, C. $ 0 ₅ n CH ₃ ΒΚ 3- (methylcyclohexyl) amino-1-propanesulfonic acid N.S '' '-' '' Β8 3- (2-methyl-1-butyl) amino-1-propanesulfonic acid VT __ 3-pivaloylamino-1-propanesulfonic acid

- 48 012429

ai 2- (tert-6outl) amino-1 - ethanesulfonic acid \ N o 1 ° ϋν 3- (cyclohexanomethyl) amino-1-propanesulfonic acid and ⁿ 3 '(1, b diethylpropargyl) amino-1-propanesulfonic acid / ---. W ', Un Y \ ⁿ 0' 0 βΧ 3- (1-ethynylcyclohexyl) amino-1-propanesulfonic acid ST “ ΟΥ 3- (2-hydroxy-2-phenyl) amino-1-propanesulfonic acid ό °° ι> ζ 3 - ((5) - 1- (4-methoxyphenyl) ethyl] amino-1-propanesulfonic acid ΕΑ 3- (4-bromophenethyl) amino-1-propanesulfonic acid Tue - 'ν /' χχ- 'he ΕΒ 3 - ((8) - 1-indanamino] - 1-propanesulfonic acid ^ U-O o., O in The EU 3-cyclobutylamino-1-propanesulfonic acid \ -U ... he ⁿ o'o Εϋ 3- (3.3,5-trimethylcyclohexyl) amino] · 1-propanesulfonic acid % Y ~ ”'

H, CH ₃ HER 3- (2-indanamino) - 1 - propanesulfonic acid

- 49 012429

, n

3- (4-biphenylamino) - 1- propanesulfonic acid n

3 - ((1 K, 28) - 2-hydroxy-1- (methoxymethyl) - 2-phenethyl] amino-1-propanesulfonic acid

3 - [(1K, 2K, ZK, 58) -1,2,6,6-tetramethylbicyclo [3.1.1.] Hept-3-yl] amino-1-propanesulfonic acid

3- (2-methoxy-1-methylethyl) amino-1-propanesulfonic acid

EP

3 - ((1 K) - 2-benzyl-1-hydroxyethyl] amino-1-propanesulfonic acid n

CH ₂ OH

3- | (15) - 2- benzyl-1- hydroxyethyl] amino-1- propanesulfonic acid n

N .., Λ-δΟ-, Μ

, VP.on n

N ..

30, N

3- (Ν- methyl- Ν- tert-butylamino) -1- propanesulfonic acid A

I, h

3- [(ΙΚ., 28) - 2-hydroxyindan-1-amino] -1-propanesulfonic acid

3 - [(18) - 1- (hydroxymethyl) -2-methylpropyl] amino-1-propanesulfonic acid

N N.

• 50 ₃ N sn ₂ he

- 50 012429

- 51 012429

- 52 012429

- 53 012429

- 54 012429

- 55 012429

- 56 012429

NYA 0 H5 h about NT 'θ'ρ-ςΧ., neither Ην sk. BUT Ηνν nx OK SOUTH" about ΗΥ ΗΖ A ^ n ° ΙΑ 4? ΊτΆ

- 57 012429

- 58 012429

and 0 ΙΚ 02νν Ιί I ° 0 ΙΜ _ΧΧΧ ~ Λ “ 0 ΙΝ 0 ΙΟ ΙΡ άχ ^ γ ΙΚ fifteen ΙΤ

- 59 012429

- 60 012429

l = ss ------------ ΓΚζ-'γ ^ ’ 1H l l zk B X + hm 3Ν ——Y thirty hu ° Sp S ..-... L

- 61 012429

LY fifteen SG ^ A LT ΤΎΧ whether ^ OL < IV ABOUT LUU lh X. ⁰ O LU Ο ... · Υν L2 +4 KA 1 ϊ ν Γί ^ Ο ⁰ sq

- 62 012429

- 63 012429

- 64 012429

n ί / ° s Η and bk ίί χ ίΜ Eh— ίΝ ίθ Wow. ίΡ 1-9 FROM

It should be noted that in the above table and throughout the invention, if the atom does not depict hydrogen atoms, but hydrogen atoms are required or are necessary from a chemical point of view to form a stable compound, then it is understood that these hydrogen atoms are present in the compound.

In one embodiment, this invention does not apply to compounds described in international applications \ ¥ O 00/64420 and \ UO 96/28187. In this embodiment, the invention does not relate to methods of using the compounds described in international applications XVO 00/64420 and XVO 96/28187 for the treatment of diseases or disorders described in these applications. In another embodiment, the invention relates to methods of using the compounds described in international applications ^ O 00/64420 and ^ O 96/28187, for the methods described in this application, which are not described in international applications XVO 00/64420 and XVO 96/28187. As in the international application XVO 00/64420, and in the international application XVO 96/28187 are incorporated by reference into this description in its entirety.

In another embodiment, the invention relates to methods of the invention in which they are used, and pharmaceutical compositions in which contain the compounds from table. 2Ά. In another embodiment, the compounds of the invention do not include compounds from the table. 2Ά.

- 65 012429

“Ύγ> B ^ 4CHCH ₂ CH ₂ CH ₂ WHO Table 2A with SS— but-η woo ^-0 from ^<χ γ ' ^Ν ' αι ₃ SSrOi ^.

Βη-ς M-CH; CH ₂ CR ₂ g 8OzN

about a

- 66 012429

- 67 012429

- b8 012429

d — Ο8Ο ₃ Ν3 —Ο8Ο ₃ Ν3 —O5O ₃ Eeyore

ΝβΟ (ZOSNgSSNgmSShiZOzGcha

Ν— CH ₂ CH ₂ CH ₂ 8O ₂ N

Ν— СН ₃ СН ₂ СН28Оз№ (МАО ₂ 8СН ₂ СН ₂ СН ₂ СН ₂ ) ₂ О

CH ₂ ZO ₂ On

CH ₂ healthy

- 69 012429

Eun ₂ CH ₂ CH ₂ CH ₃ ZO ₃ Ma

CH ₃ C (CH ₂ O8OzMa) s

MH ₂ CH ₂ CH ₂ OZOZN

Ν3θ ₃ 8ΝΗσΗ ₂ εΗ ₂ Ο8θ3Ν3

XN ₂ C (CH ₂ OZO ₃ Ma) ₃

Ν.1Ο, 5._

₂ Ο8Ο ₃ Ν3 —08 O _e Ya

POC ₂ O— —Ο8Ο ₃ Ν3

NM (СН ₂ СН ₂ О8Оз№) 2

NaОз8ННСН ₂ СН ₂ СН ₂ О8Оз№

ΝίΟ, δΟ—

--οεο ₃ Ν3 —ΟΒη —O5О ₃ Ma

Ν _& θ38Ν (0Η ₂ 0Η ₂ Ο8θ3Ν3) ₂

- 70 012429

- 71 012429

It should be understood that the use of any of the compounds described herein or the compounds described in the applications identified in the Related Applications section is included in the scope of the present invention and is intended to be encompassed by the present invention, and each of the applications is expressly (explicitly) introduced into this description at least for these purposes, and, in addition, they are specially (unequivocally) introduced for all other purposes.

Subjects and patient populations

The term “subject” includes living organisms in which amyloidosis can occur or which are susceptible to amyloid diseases, for example, Alzheimer's disease, Down syndrome, CAA, dialysis ( ₂ M) amyloidosis, secondary (AA) amyloidosis, primary (ΑΣ) amyloidosis, hereditary amyloidosis, diabetes etc. Examples of subjects include humans, chickens, ducks, Peking ducks, geese, monkeys, deer, cows, rabbits, sheep, goats, dogs, cats, mice, rats, and their transgenic species. The introduction to the subject of the compositions according to this description can be carried out by known methods at such doses and for such a time that allows you to effectively modulate the aggregation of amyloid-induced toxicity in the subject, as further described in this description. The effective amount of a therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the amount of amyloid deposits in the patient’s body, the age, gender, weight of the subject, and the ability of the therapeutic compound to modulate

- 72 012429 to aggregate the amyloid in the body of the subject. The drug regimen can be correlated in such a way as to elicit an optimal therapeutic response. For example, you can take daily in the form of several divided doses or, depending on the indications, the dose can be proportionally reduced.

In some embodiments of the invention, the subject needs treatment with the methods of this invention and is selected for treatment based on such a need. Subjects requiring such treatment are well known in the art and include subjects that are defined as having a disease or disorder, with amyloid deposition or amyloidosis, have a symptom of such a disease or disorder, or subjects with an increased risk of such a disease or disorder, and who, on based on a diagnosis, such as a medical diagnosis, improvement due to therapy (e.g., cure, healing, prevention, mitigation, relief, treatment, weakening, positive dynamics, or Impact on the disease or disorder, symptom of the disease or disorder or increased risk of the disease or disorder).

In a typical aspect of the invention, the subject is a human. For example, a subject may be a person over 30 years old, a person over 40 years old, a person over 50 years old, a person over 60 years old, a person over 70 years old, a person over 80 years old, a person over 85 years old, a person over 90 years old or a person over 95 years old. The subject may be a woman, including a woman during menopause, who is receiving hormone (estrogen) replacement therapy. The subject may be a man. In another embodiment of the invention, the subject is younger than 40 years old.

The subject may be a person with an increased risk of Alzheimer's disease, for example being over 40 years old or having a predisposition to Alzheimer's disease. Alzheimer's predisposition factors identified or suspected in the scientific literature include, among others, a genotype predisposing a subject to Alzheimer's disease; environmental factors predisposing to Alzheimer's disease; a history of viral and bacterial agents predisposing to Alzheimer's disease; and vascular factors predisposing the subject to Alzheimer's disease. A subject may also have one or more increased risk factors for a cardiovascular disease (e.g., coronary artery atherosclerosis, angina pectoris and myocardial infarction) or a cerebrovascular disease (e.g., intracranial or extracranial arterial sclerosis, stroke, fainting, and transient cerebrovascular disease ), such as hypercholesterolemia, hypertension, diabetes, smoking, or coronary artery disease, cerebrovascular disease and cardiovascular disease in Veronese or a family history. Typically, hypercholesterolemia is defined as a serum concentration of total cholesterol above about 5.2 mmol / L (about 200 mg / dl).

It is believed that some genotypes predispose to Alzheimer's disease. These genotypes include missense mutations in presenilin-1, presenilin-2 and amyloid precursor protein (APP) associated with Alzheimer's disease, and α-2-macroglobulin and LCR-1 genotypes, which are thought to increase the risk diseases of random (sporadic) (late) Alzheimer's disease. E. Wap Shep, e! A1., 1. Keigo8C1. 22 (21), 9298-304 (2002); 1.1. Οοΐο, e! A1., 1. Mo1. Keigo8C1. 19 (1-2), 37-41 (2002). Another genetic risk factor for Alzheimer's is ApoE, a gene that encodes the apolipoprotein E (especially the apoE4 genotype), a component of low density lipoprotein particles. \ D.1. 8! N !! that !! eh, e! A1., Αηηυ. Βеν. Igoyasg 19, 53-77 (199b). The molecular mechanisms by which various ApoE alleles alter the likelihood of developing Alzheimer's disease are unknown, however, the role of ApoE in cholesterol metabolism is consistent with a growing body of evidence linking cholesterol metabolism to Alzheimer's disease. For example, the continued use of cholesterol-lowering drugs, such as statins, has recently been associated with a lower incidence of Alzheimer's disease, and it has been shown that cholesterol-lowering drugs reduce the pathology of transgenic mouse APPs. These and other studies suggest that cholesterol may affect APP processing. It has been suggested that ApoE4 alters the directional migration of Av (to and from the brain) and contributes to the retention of Av in the brain. It was also suggested that ApoE4 promotes the processing of APP with the formation of Av. It is believed that environmental factors predispose the subject to Alzheimer's disease, including exposure to aluminum, although the epidemiological data are not clear. In addition, an earlier infection with certain viral or bacterial agents, including the herpes virus and syphilis, may predispose the subject to Alzheimer's disease. Finally, other factors predisposing to Alzheimer's disease may include risk factors for cardiovascular or cerebrovascular disease, including cigarette smoking, hypertension, and diabetes. The risk of Alzheimer's disease also covers any other predisposing factors not listed above or already defined, and includes an increased risk of Alzheimer's disease caused by head trauma, drug therapy, diet or lifestyle.

The methods of the present invention can be used for one or more of the following purposes: to prevent Alzheimer's disease, to treat Alzheimer's disease, to weaken

- 73 012429 symptoms of Alzheimer's disease or to regulate the production or levels of amyloid β (Av) peptides. In one embodiment, a person carries one or more mutations in genes that encode a β-amyloid precursor protein, presenilin-1 or presenilin-2. In another embodiment of the invention, the person carries the ε4 Apolipoprotein gene. In another embodiment, a person in a family history has Alzheimer's disease or dementia. In another embodiment of the invention, trisomy 21 (Down syndrome) is observed in humans. In another embodiment of the invention, the subject has a normal or low level of total serum blood cholesterol. In another embodiment of the invention, the level of total serum blood cholesterol is below about 200 mg / dl or below about 180 mg / dl, and it may be in the range of about 150-200 mg / dl. In another embodiment of the invention, the level of total cholesterol LbO is below about 100 mg / dl or below about 90 mg / dl and may be in the approximate range of 30-100 mg / dl. Methods for measuring serum total blood cholesterol and total LbO cholesterol are well known to those skilled in the art and, for example, may include methods described in international application \ ¥ 0 99/38498 on p.11, incorporated by reference in this description. Methods for determining the levels of other sterols (sterols, steroidal alcohols) in serum are described in N. Suhpd, e (a1., 8git 81go1k Όιιπιΐβ 8 (apo1 Ek! Eg Eeyaetd ίη and M11y1u NuregsNo1ek (exiepis RoriIIoy, I. Pyr. 593-600 (1999).

In another embodiment of the invention, the subject has an elevated level of serum total blood cholesterol. In another embodiment of the invention, the level of serum total blood cholesterol is at least about 200 mg / dl or at least about 200 mg / dl and may be in the approximate range of 200-1000 mg / dl. In another embodiment of the invention, the subject has an elevated level of total L cholesterol. In another embodiment of the invention, the level of total L cholesterol is higher than about 100 mg / dl or even higher than about 110 mg / dl and can be in the approximate range of 100-1000 mg / dl.

In another embodiment of the invention, the person is at least about 40 years old. In another embodiment, the person is at least about 60 years old. In another embodiment of the invention, the person is at least about 70 years old. In another embodiment of the invention, the person is at least about 80 years old. In another embodiment of the invention, the person is at least about 85 years old. In another embodiment of the invention, the person is between the ages of about 60-100 years.

In another embodiment of the invention, as shown, the subject is at risk from a diagnostic imaging method of the brain, for example, a method for measuring brain activity, plaque deposition, or brain atrophy.

In yet another embodiment of the invention, the subject is shown to be at risk as determined by a cognitive test, such as a Clinical Dementia Rating (JCS), Cognitive Alzheimer's Disease Rating Scale (AEA8-Sod) or Mental Status Mini-Study (MM8E). A subject may have a score lower than the average on a cognitive test scale compared with a control for a similar age and with known data. The subject also has a decrease in score compared to previous ratings of that subject in the same or similar tests.

When determining the subject's RNS, an indicator is usually evaluated and determined in each of the six cognitive and behavioral categories: memory, orientation, assessment and resolution of problems, social behavior, home, and hobbies and personal care. The assessment may include information about the past provided by the subject, or, preferably, a witness (bogoFog) who knows the subject well. The subject is evaluated and indicators are determined in each of these areas and the total score (rating) is determined (0, 0.5, 1.0, 2.0 or 3.0). A rating is considered normal (qualification score, score) 0. Rating 1 is considered appropriate for mild dementia. A subject with SJS 0.5 is characterized by mild persistent forgetfulness, partial memory of events, and weak, benign forgetfulness. In one embodiment of the invention, a subject is rated with a RNS rating above 0, above about 0.5, above about 1.0, above about 1.5, above about 2.0, above about 2.5, or about 3.0,

Another test is a mini-study of the Mental Status (ММ8Е), described by ЕО1к1ет МНи-тейН-н к (а (е. Аргайс1те (Ной ог ог д г д д Не Не сод сод сод сод сод сод а а ша ша). RkusLaal Kek. 12: 189-198, 1975. MM8E assesses the presence of mental retardation (impairment). See also Eo1k (et □ ((TeheiLy Shadioksch ojetsina. MM8E is a way of assessing the onset of dementia and the presence of a general deterioration in mental activity (general mental retardation) observed in Alzheimer's disease and in case of multiple dementia MI8E is assessed from 1 to 30. MM8E does not evaluate basic cognitive potential, such as the so-called ΙΟ test. Instead, it tests mental abilities. A person with normal mental abilities receives 30 in MM8E objective, impartial test (however, a person with a score of 30 in the MM8E test can get a score much lower in the 10th test.) See, for example, KaiTeg, ί. Heigorkus Shayu S1t. Heigoks1. 10: 55-63, 1998; APNeipeg E1k Akkos Eschogy. 12: 54-57, 1998; ESK, Ars. No. 1. 55: 360-365, 1998; Madsh, Ιηΐ. RkusNodepaCh. 8: 127-134, 1996: Mopk, Ac (a No. 1, 8th, 92: 145-150, 1995. In one embodiment of the invention, scores of a subject below 30 by MM8E at least

- 74 012429 at least once. In another embodiment of the invention, the subject receives scores below about 28, below about 26, below about 24, below about 22, below about 20, below about 18, below about 16, below about 14, below about 12, below about 10, below about 8 , below about 6, below about 4, below about 2, or below about 1.

Another way of assessing cognitive ability, in particular, Alzheimer's disease, is the cognitive Alzheimer's disease rating scale (ΑΌΑδ-0ο§) or its variant, called the standardized Alzheimer's disease rating scale (8ΑΌΑ8). It is commonly used as a measure of effectiveness in clinical trials of drugs for the treatment of Alzheimer's disease and related disorders characterized by impaired cognitive abilities. 8ΑΌΑ8 and ΑΌΑ8-0ο§ are not intended to diagnose Alzheimer's disease; they are applicable to characterize the symptoms of dementia, they are a relatively sensitive indicator of the progression of dementia (see, for example, ^ ο ^ а ^ 5 \ νatu. No.ιιΐΌ1οβν 48: 1511-1517, 1997; and 8ίаηб ^ 8Y, 1. Ch. Sepa. 8ο ^ 44: 712-716, 1996). The annual deterioration in untreated patients with Alzheimer's disease is approximately 8 points per year (see, for example, Waktb, M Ρπιη. Sage Οοιηρηηίοη 1 01ίη Ρ8cu ^ aί ^ in 1000 Αιι ^; 2 (4): 134-138) .

ΑΌΑ8-0ο§ is calculated to determine, using questionnaires, the progression and severity of cognitive impairment observed with по on a 70-point scale. The ΑΌΑ8-0ο§ scale quantifies the number of incorrect answers. Accordingly, a high score on a scale indicates a more severe case of cognitive impairment. In one embodiment of the invention, the subject has a score above 0, above about 5, above about 10, above about 15, above about 20, above about 25, above about 30, above about 35, above about 40, above about 45, above about 50, above about 55, above about 60, above about 65, above about 68 or about 70.

In another embodiment of the invention, the subject does not show symptoms of Alzheimer's disease. In another embodiment of the invention, the subject is a person at least 40 years old who has symptoms of Alzheimer's disease. In another embodiment of the invention, the subject is a person at least 40 years old who has one or more symptoms of Alzheimer's disease.

In another embodiment of the invention, the subject has mild cognitive impairment. In yet another embodiment of the invention, the SOW rating of the subject is 0.5. In another embodiment of the invention, the subject has early Alzheimer's disease. In another embodiment of the invention, the subject has cerebral amyloid angiopathy.

Using the methods of this invention, it is possible to lower the levels of amyloid β-peptides in the plasma or cerebrospinal fluid (SZR) of the subject compared with the levels before treatment by about 10-100% or even about 50-100%.

In an alternative embodiment of the invention, the subject may have an elevated level of amyloid Aβ ₄₀ or Aβ ₄₂ peptide in the blood and SZR before treatment, according to the methods of the present invention, above about 10 pg / ml, or above about 20 pg / ml, or above about 35 pg / ml, or even above about 40 pg / ml. In another embodiment of the invention, the elevated level of amyloid Aβ ₂ peptide may be in the approximate range of from 30 to 200 pg / ml or even up to about 200 pg / ml.

One of ordinary skill in the art understands that as Alzheimer's disease progresses, measured levels of amyloid β-peptide in the plant protection system may decrease compared to elevated levels before the onset of the disease. This effect is attributed to increased deposition, i.e. capture of the β-peptide in the brain instead of the normal clearance from the brain to the plant protection system.

In an alternative embodiment of the invention, the subject may have an elevated level of amyloid Aβ ₄₀ peptide in the blood and prior to treatment, according to the methods of the present invention, more than about 5 pg Aβ ₄₂ / ml, or more than about 50 pg Aβ ₄₀ / ml, or more than about 400 pg / ml. In another embodiment of the invention, the elevated level of the amyloid Aβ ₄₀ peptide may be in the range of about 200 pg / ml to about 800 pg / ml, even up to about 1000 pg / ml.

In another embodiment of the invention, the subject may have an increased level of amyloid Aβ ₄₂ peptide in the SZR before treatment, according to the methods of the present invention, more than about 5 PG / ml, or more than about 10 PG / ml, or more than about 200 PG / ml, or more than about 500 pg / ml. In another embodiment of the invention, the level of amyloid β-peptide may be in the range of from about 10 pg / ml to about 1000 pg / ml, or even from about 100 pg / ml to about 1000 pg / ml.

In another embodiment of the invention, the subject may have an increased level of amyloid Aβ ₄₀ peptide in the SZR before treatment according to the methods of the present invention, more than about 10 pg / ml, or more than about 50 pg / ml, or even more than about 100 pg / ml. In another embodiment of the invention, the level of amyloid β-peptide may be in the range from about 10 pg / ml to about 1000 pg / ml.

The amount of amyloid β-peptide in the brain, SZR, blood or plasma of a subject can be determined by enzyme-linked immunosorbent assay (Ε ^ I8Α), or by quantitative immunoblotting methods, or quantitative ZEOEOTOR well known to specialists in this field of technology, such as disclosed Ζ4η§, eί a1 ., 1. Βίο1. Oh. 274, 8966-72 (1999) and ΖΗηηβ, eί a1., VyusEetZyu 40,

- 75 012429

5049-55 (2001). See also A.K. νβ ^ δ, e! A1., ECA Ce11 Βίο1. 20 (11), 713-21 (2001); R. Egeis / ik, e! A1., Kar1b Sottip. Mazz 8res1got. 17 (12), 1291-96 (2003); Β.Μ. Ai81ep, e! A1., 1. Rurbbe 8e1. 6, 459-69 (2000); and Bau18, e! A1., VyuTesyttsiev 27, 1258-62 (1999). These tests are performed on brain or blood samples that are prepared by a method well known to those skilled in the art. Another example of the method used to determine the levels of amyloid Λβ peptides is immunoassay labeled europium (E [A). See, for example, international application \ UO 99/38498, p. eleven.

The methods of the invention can be used as therapy of a subject with Alzheimer's disease or dementia, or the methods of the invention can be used as a prophylaxis of Alzheimer's disease or dementia in a subject predisposed to them, as if the subject, for example, has a mutation in the APP gene, ApoE gene or presenilin gene. A subject may have (or may be susceptible to development, or may be suspected of) vascular dementia, senile dementia (senile dementia), mild cognitive impairment, or early Alzheimer's disease (or he may be predisposed to develop these diseases, or they may suspect him). In addition to Alzheimer's disease, the subject may have another amyloid disease, such as cerebral amyloid angiopathy, or the subject may have amyloid deposits, especially amyloid β deposits in the brain.

Amyloid Disease Treatment

The present invention relates to methods of using the compounds and their pharmaceutical compositions for the treatment and prevention of amyloid diseases. The pharmaceutical compositions of the invention can be used therapeutically or prophylactically for the treatment of diseases associated with the formation, aggregation, or deposition of amyloid fibrils (e.g., AE of amyloid protein (λ or κ chain, e.g., amyloid λ, amyloid k, amyloid XIV, amyloid λVI, amyloid γ, amyloid γ1), AB, IAPP, β ₂ Μ, AA or AN of amyloid protein).

The pharmaceutical compositions of the invention can act to alleviate the course of amyloid disease by any of the following mechanisms (it is assumed that this list is illustrative and not limiting): slowing the rate of formation or deposition of amyloid fibrils; a decrease in the degree of amyloid deposition; inhibition, reduction or prevention of the formation of amyloid fibrils; inhibition of neurodegeneration or cellular toxicity caused by amyloid; inhibition of amyloid-induced inflammation; increased clearance of amyloid from the brain; increased cleavage of Av in the brain; or promoting clearance of amyloid protein prior to combining it into fibrils.

Modulation of amyloid deposition includes both inhibition, as defined above, and an increase in amyloid deposition or the formation of fibrils. Thus, the term modulation is intended to cover the prevention or termination of the formation or accumulation of amyloid, the inhibition or retardation of further formation or accumulation of amyloid in a subject suffering from amyloidosis, for example, already having amyloid deposition, and the reduction or reversal of the formation or accumulation of amyloid in a subject, patient amyloidosis; and an increase in amyloid deposition, for example, an increase in the rate or amount of amyloid deposition ίη νίνο or ίη νίίΓο. Compounds that increase the amyloid content can be used in animal models of amyloidosis, for example, in order to create amyloid deposits in animals for a shorter period of time, or to increase amyloid deposits for the desired period of time. Compounds that increase the amyloid content can be used for screening for compounds that inhibit ίη νίνο amyloidosis, for example, in animal models, in cell analyzes and in ίη νίίτο amyloidosis analyzes. Such compounds can be used, for example, to conduct faster and more accurate (sensitive) assays for compounds. Modulation of amyloid deposition is determined by comparison with an untreated subject or by comparison with a treated subject before treatment.

Inhibition of amyloid deposition includes the prevention or termination of amyloid formation, for example, fibrillogenesis, clearance of an amyloid, for example, soluble Av, from the brain, inhibition or retardation of further deposition of amyloid in a subject with amyloidosis, for example, already having amyloid deposition, and the reduction or reversal of amyloid fibrillogenesis or deposits in a subject already having amyloidosis. Inhibition of amyloid deposition is determined by comparison with the untreated subject or by comparison with the treated subject before treatment, or, for example, is determined by clinically (measurable) significant improvement, or, for example, if the subject has cerebral amyloidosis, for example, Alzheimer's disease or cerebral amyloid angiopathy, stabilization cognitive function or by preventing further deterioration of cognitive function (i.e., preventing, slowing or stopping the progression of the disease) or by improving performance, x as the concentration of Av or tau in C8E.

The treatment, therapy of a subject as described herein includes administering a composition of the invention to a subject or administering it to a subject, or using the composition of this invention to a cell or tissue of a subject or introducing it into a cell or tissue of a subject with

- 76 012429 with an amyloid disease or condition, with a symptom of such a disease or condition or with an increased risk of such a disease or condition (or predisposed to such a disease or condition), for the purpose of curing, healing, mitigating, alleviating, altering, curing, weakening, positive dynamics or exposure to the disease or disorder, a symptom of the disease or disorder, or an increased risk of the disease or disorder (or predisposition to the disease or disorder). The term “treatment” refers to any indication of success in therapy or to a decrease in the intensity of a lesion, pathology or condition, including any objective or subjective indicator, such as pain relief; remission; the weakening of symptoms, or what makes the lesion, pathology or condition more acceptable to the subject (makes them easier to tolerate); slowing the rate of worsening or progression of the disease; what contributes to the less debilitating last moment of dystrophy; improvement of physical or mental condition; or, in some situations, warning of the onset of dementia. Treatment or relief of symptoms can be carried out taking into account objective or subjective indicators; including the results of a physical examination, psychiatric evaluation, or cognitive test, such as SPK, MM8E, AEA8-Sod, or another test known in the art. For example, the methods of the invention can successfully treat dementia by slowing down or decreasing the degree of cognitive impairment.

In one embodiment of the invention, the term treatment includes maintaining the initial RNC rating of the subject or at zero level. In another embodiment of the invention, the term treatment includes reducing a subject's RNS rating by about 0.25 or more, by about 0.5 or more, by about 1.0 or more, by about 1.5 or more, by about 2.0 or more about 2.5 or more or about 3.0 or more. In another embodiment of the invention, the term treatment also includes reducing the rate of increase of a subject's RNS rating compared to control previous data. In another embodiment of the invention, the term includes reducing the rate of increase of a subject's RNS rating by 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% or more compared to the previous control increase data or with control data increase in the absence of treatment.

In another embodiment of the invention, the term treatment also includes maintaining the subject’s MM8E score. The term treatment includes an increase in the number of MM8E scores 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 reducing the rate of decrease in the subject's MM8E score compared to previous controls. In another embodiment of the invention, the term includes reducing the rate of decrease in a subject’s MM8E score 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, about 100% or less compared to the previous control reduction data or control reduction data in the absence of treatment.

In yet another embodiment of the invention, the term treatment includes maintaining a subject's AEA8-Sod score. The term treatment includes reducing a subject's AEA8-Soda score of 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 a decrease in the rate of increase in a subject's AEA8-Soda score compared to previous controls. In another embodiment of the invention, the term includes reducing the rate of increase in a subject's AEA8-Soda score by 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, about 100% or more compared to control previous increase data or with control increase data in the absence of treatment.

In another embodiment of the invention, the term treatment, for example AA or AB of amyloidosis, includes an increase in serum creatinine, for example, an increase in creatinine clearance by 10% or more, by 20% or more, by 50% or more, by 80% or more, by 90% or more, 100% or more, 150% or more, 200% or more. The term treatment may also include remission of nephrotic syndrome (N8). It may also include remission of chronic diarrhea and / or weight gain, for example, by 10% or more, 15% or more, or 20% or more.

Without any connection with theory, in some aspects, the pharmaceutical compositions of the invention contain a compound that prevents or inhibits the formation of amyloid fibrils either in the brain or in another important organ (acting locally, locally), or in the body as a whole (acting

- 77 012429 systemically). The pharmaceutical compositions of the invention can effectively control amyloid deposition either after they (the compositions) enter the brain (after penetrating the blood-brain barrier) or from the periphery. When acting from the periphery, the compound in the pharmaceutical composition can alter the equilibrium of the amyloidogenic peptide between the brain and plasma in such a way as to facilitate the removal (exit) of the amyloidogenic peptide from the brain. The compound may also promote clearance (or catabolism) of amyloid protein (soluble), and then prevent the formation and deposition of amyloid fibrils due to a decrease in the pool of amyloid protein in a specific organ, for example, liver, spleen, pancreas, kidney, joints, brain, etc. . An increase in the yield (removal) of amyloidogenic peptide from the brain leads to a decrease in the concentration of amyloidogenic peptide in the brain and, therefore, helps to reduce the deposition of amyloidogenic peptide. In particular, the agent can lower the levels of amyloid β-peptides, such as Άβ40 and Άβ42, in C8B and in plasma, or the agent can lower the levels of amyloid β-peptides, for example Άβ40 and Άβ42, in C8B and increase them in plasma. Or compounds that penetrate the brain can control deposition by acting directly on the amyloidogenic peptide of the brain, for example, by keeping it in a non-fibrillar form or by promoting its clearance from the brain, increasing its cleavage in the brain, or protecting brain cells from the harmful effects of the amyloidogenic peptide. The agent can also cause a decrease in the concentration of amyloidogenic protein (i.e., in a particular organ, so that the dangerous (critical) concentration necessary to stimulate the formation or deposition of amyloid fibrils is not reached). In addition, the compounds described herein can inhibit or reduce the interaction between an amyloid and a component of the cell surface, for example, the glycosaminoglycan or proteoglycan component of the basement membrane, resulting in the inhibition or decrease of this interaction causes the observed neuroprotective or cell protective effect. For example, the compound can also prevent the binding or adhesion of the amyloid peptide to the cell surface, a process that is known to cause cell damage or toxicity. Similarly, a compound can block amyloid-induced cellular toxicity, or microglia activation, or amyloid-induced neurotoxicity, or inhibit amyloid-induced inflammation. The compound may also reduce the rate or amount of amyloid aggregation, formation or deposition of fibrils, or the compound reduces the degree of amyloid deposition. The above mechanisms of action should not be construed as limiting the scope of the invention in view of the fact that the invention can be practiced without such information.

The term amyloid-β disease (or a disease associated with amyloid-β, these terms used herein are synonymous) can be applied to mild cognitive impairment; vascular dementia; early Alzheimer's disease; Alzheimer's disease, including random (sporadic, non-hereditary) Alzheimer's disease and familial (hereditary) Alzheimer's disease; age-related cognitive decline; cerebral amyloid angiopathy (CAA); hereditary cerebral hemorrhage; senile dementia (senile dementia); Down syndrome; myositis of inclusion bodies (ΙΒΜ); or age-related macular degeneration (ΆΚΌΜ). According to some aspects of the invention, amyloid-β is a peptide containing 39-43 amino acids, or amyloid-β is an amyloidogenic peptide produced using β-PP.

Mild cognitive impairment (MC1) is a condition characterized by a slight but noticeable loss of mental skill, qualification, ability, which is not necessarily associated with the presence of dementia. MC1 often, but not always, precedes Alzheimer's disease. This is the diagnosis that is most often associated with small memory problems, but it can also be characterized by mild insufficiency of other thinking skills, such as language skills or planning skills. However, as a rule, a person with MS1 has much more significant memory problems than would be expected from a person at his age or with his education. As the condition progresses, the physician can change the diagnosis to mild to moderate cognitive impairment, which is well known in the art.

Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils on the walls of the leptomingeal and cortical arteries, arterioles, and in the capillaries and veins. It is usually associated with Alzheimer's disease, Down syndrome and normal aging, as well as with various family conditions associated with stroke or dementia (see Btaidiyu, s1 a1., Ashu1o1b: T Prgoesh Bo1bshd Όίδοτά. 8, 8рр1. 1, 36-42. (2001)). CAA can be random or hereditary. Many mutation sites in either the Aβ or APP gene have been identified and clinically associated with either dementia or cerebral hemorrhage. Examples of CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with Icelandic type amyloidosis (HCH ^ A-Ι); Dutch version of HCH ^ A (HCH ^ AE; mutation in Άβ); Flemish mutation Ar; Arctic mutation Άβ; Iowa Aβ mutation; familial british dementia. It is known that cerebral amyloid angiopathy is associated with cerebral hemorrhage (or hemorrhagic stroke).

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In addition, the abnormal accumulation of APP and amyloid-β protein in muscle fibers is directly associated with the pathology of random myositis of inclusion bodies (ΙΒΜ) (Akkapak e! A1., Prg. Ν; · ι11. Asab. 8c1. I8A 93, 1314-1319 ( 1996); Akkapak e! A1., Siggep! Θρίπίοη ίη Kyeisha1yododu 7, 486-496 (1995)). Accordingly, the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which β-amyloid protein is abnormally deposited in non-neurological sites, for example, for treatment by delivery of the compounds to muscle fibers.

In addition, AB has been shown to be associated with abnormal extracellular deposits, known as drusen, which accumulate along the basal surface of retinal pigmented epithelium in people with age-related macular degeneration (ACME). AKME is the cause of irreversible loss of vision in older people. It is believed that Av deposition can be an important component of local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, Druze biogenesis and pathogenesis of ARMB (ίοΐιηκοη. Е! А1., Ргок. No. I. Asab. 8с1. И8А 99 (18), 11830--18 5 (2002)). Therefore, the invention also relates to the treatment or prevention of age-related macular degeneration.

The invention also relates to a method for preventing or inhibiting amyloid deposition in a subject. For example, such a method consists in administering to the subject a therapeutically effective amount of a compound capable of reducing the concentration of an amyloid (e.g., AB of an amyloid protein (related to λ or κ chains, e.g., amyloid λ, amyloid K, amyloid κίν, amyloid λVI, amyloid γ, amyloid γ1 ), Av, 1APP, β ₂ Μ, AA, AN of amyloid protein or other amyloids), so that amyloid accumulation or deposition is prevented or inhibited.

In another aspect, this invention relates to a method for preventing, reducing or inhibiting amyloid deposition in a subject. For example, such a method comprises administering to the subject a therapeutically effective amount of a compound capable of inhibiting amyloid (e.g., AB amyloid protein (related to λ or k-chains, e.g., amyloid λ, amyloid k, amyloid κίν, amyloid λVI, amyloid γ, amyloid γ1) , Av, 1APP, in ₂ M, AA, AN amyloid protein or other amyloids), so this amyloid deposition is prevented, reduced or inhibited.

The present invention also relates to a method for modulating, for example, minimizing, damaging cells associated with an amyloid, comprising the step of administering a compound capable of reducing the concentration of an amyloid (e.g., AB amyloid protein (related to λ or k-chains, e.g., amyloid λ, amyloid k, amyloid κίν, amyloid λVI, amyloid γ, amyloid γ1), Av, 1APP, β ₂ Μ, AA, AN of an amyloid protein or other amyloid), so that this cell damage caused by amyloid is modulated. In some aspects of the invention, methods for modulating amyloid-induced cell damage comprise the step of administering a compound capable of lowering the concentration of amyloid or reducing the interaction of amyloid with the cell surface.

The invention also includes a method for directly or indirectly preventing cell death in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound capable of preventing amyloid-mediated (e.g., AB amyloid protein (related to λ or κ chains, e.g., amyloid λ, amyloid κ, amyloid κίν, amyloid λVI, amyloid γ, amyloid γ1), AB, 1APP, β, AA, AN amyloid protein or other amyloid) events that lead directly or surely, to the death of cells.

In one embodiment of the invention, a method of treating Alzheimer's disease (e.g., accidental or familial AO) is used. The method can also be used prophylactically or therapeutically to treat other clinical cases of amyloid-in deposition, for example, patients with Down syndrome and cerebral amyloid angiopathy (CAA) or hereditary cerebral hemorrhage.

The compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which the amyloid b-peptide is abnormally deposited in non-neurological sites, for example, for the treatment of ΓΒΜ delivery of compounds to muscle fibers, or for the treatment of macular degeneration by delivery of the compound (compounds) of the invention to the basal surface retinal pigmented epithelium.

The present compound also encompasses a method for modulating amyloid-induced cell damage, comprising the step of administering a compound capable of lowering the concentration of Av, or capable of minimizing the interaction of Av (soluble oligomeric or fibrillar) with the cell surface, so that said amyloid-induced cell damage is modulated. In some aspects of the invention, methods for modulating cell damage caused by amyloid comprise the step of administering a compound capable of lowering the concentration of Av or weakening the interaction of Av with the cell surface.

In addition, according to this invention, there is provided a method for preventing cell death in a subject’s body, said method comprising administering to a subject a therapeutically effective amount of a compound capable of preventing mediated Av events that

- 79 012429 lead, directly or indirectly, to cell death.

The present invention also includes a method for modulating amyloid-induced cell damage, comprising the step of administering a compound capable of lowering the concentration of 1APP, or capable of minimizing the interaction of 1APP (soluble oligomeric or fibrillar) with the cell surface, so that said amyloid-induced cell damage is modulated. In some aspects of the invention, methods for modulating cell damage caused by amyloid comprise the step of administering a compound capable of lowering the concentration of 1APP or weakening the interaction of 1APP with the cell surface.

According to the present invention, a method for preventing cell death in a subject’s body is further encompassed, said method comprising administering to the subject a therapeutically effective amount of a compound capable of preventing events associated with 1APP that lead, directly or indirectly, to cell death.

The invention also includes methods and compositions that are useful in the treatment of amyloidosis. The methods of the invention include administering to a subject a therapeutic compound that inhibits amyloid deposition. Accordingly, the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs. The methods of the invention can be used therapeutically to treat amyloidosis, or can be used to prevent diseases in subjects predisposed to (hereditary) amyloidosis or with an identified increased risk of developing amyloidosis, for example hereditary, or with an identified increased risk of developing amyloidosis. In some embodiments, the invention includes a method of inhibiting the interaction between an amyloidogenic protein and a component (component) of the basement membrane to inhibit amyloid deposition. The component of the basement membrane is a glycoprotein or proteoglycan, preferably heparan sulfate proteoglycan. The therapeutic compound used in this method may inhibit the binding of a basement membrane component to a targeted binding site on an amyloidogenic protein, thereby inhibiting amyloid deposition.

In some aspects, the methods of the invention comprise administering to a subject a therapeutic compound that inhibits amyloid deposition. Inhibition of amyloid deposition includes the prevention of amyloid formation, the inhibition of further amyloid formation in a subject with amyloidosis, and the reduction of amyloid deposits in a subject with amyloidosis. Inhibition of amyloid deposition is determined with respect to the untreated subject or with respect to the treated subject prior to treatment. In one embodiment of the invention, amyloid deposition is inhibited by inhibiting the interaction between the amyloidogenic protein and the basement membrane component. The term basement membrane refers to an extracellular matrix containing glycoproteins and proteoglycans, including laminin, type IV collagen, fibronectin, perlecane, agrin, dermatan sulfate and heparan sulfate proteoglycan (H8P6). In one embodiment of the invention, amyloid deposition is inhibited by an obstacle to the interaction between the amyloidogenic protein and a sulfonated glycosaminoglycan, such as H8PC, dermatan sulfate, perlecane or argin sulfate. It is known that sulfonated glycosaminoglycans are present in all types of amyloids (see 8iote e! A1., Ba. 1 batch1. 56, 120-23 (1987)), and amyloid deposition and H8RS deposition occur by chance on animal models of amyloidosis (see 8iote e ! a1., ba b. 1 piece 1. 56, 665-75 (1987) and Segouche, R. e! a1. Art. Furniture. et. 3, 361-370 (2003)). The consensus motifs of the binding site with H8RS in amyloidogenic proteins have been described (see, for example, Sagbt apb.

The ability of a compound to prevent or block the formation or deposition of an amyloid may lie in its ability to bind to a non-fibrillar, soluble amyloid protein and maintain its solubility.

The ability of a therapeutic compound of the invention to inhibit the interaction between an amyloidogenic protein and a glycoprotein or proteoglycan component of a basement membrane can be evaluated by a narrow binding assay, such as the assay described in 0ΟΆ. 5164295, the contents of which are incorporated into this description by reference. Alternatively, the ability of a compound to bind to an amyloidogenic protein or to inhibit the binding of a basement membrane component (e.g., H8RS) to an amyloidogenic protein (e.g., Άβ) can be measured by mass spectrometry, in which a soluble protein, such as Άβ, 1APP, β2Μ, is incubated with the compound. A compound that binds, for example, to Άβ, causes a change in the mass spectrum of the protein. Typical protocols for mass spectrometric analysis using Άβ and 1APP can be found in the examples, the results are shown in table. 3. The protocol can be easily modified to adjust the accuracy of the data, for example, by adjusting the amount of protein and / or compound used. Thus, for example, it is possible to detect the binding of test compounds, the binding of which is not determined using less sensitive testing protocols.

Alternative methods for screening compounds are available, and an experienced practitioner can easily apply them to obtain an indicator of the ability of test compounds to bind, for example, to fib

- 80 012429 Rillian Av. One such screening assay is UV spectroscopy. In a typical protocol, the test compound (20 μM) is incubated with 50 μM Λβ fibers (1-40) for 1 h at 37 ° C in physiological saline buffered with TS (20 mM Tg, 150 mM NaCl, pH 7.4 containing 0.01 sodium azide ) After incubation, the solution is centrifuged for 20 min at 21,000 d to precipitate AB strands (1-40) together with any bound test compound. The amount of test compound remaining in the supernatant can then be determined by reading the absorbance. Then, the fraction of the bound test compound can be calculated by comparing the amount remaining in supernatants after incubation with Av with the amount remaining during control incubations in the absence of Av fibers. As a positive control, thioflavin T and Congo red can be introduced into each analysis, each of which, as is known, binds to Av fibers. Before analysis, the test compound is diluted to 40 μM, which is twice the concentration in the final test, and then scanned on a He \\ 1e11 Raskagb 8453 IU / U18 spectrophotometer to determine if the optical density is sufficient for detection.

In another embodiment, the invention relates to a method for improving cognitive function in a subject suffering from amyloid disease. The method includes administering an effective amount of a therapeutic compound of the invention so that cognitive function is enhanced. The cognitive function of a subject can be tested using methods known in the art, such as Clinical Dementia Rating (JCS), Mental Status Mini-Study (MM8E) or Alzheimer's Disease Cognitive Rating Scale (AOA8-Sod).

In another embodiment, the invention relates to a method for treating a subject from an amyloid disease. The method includes cognitive testing of a subject prior to administering a compound of the invention, administering an effective amount of a compound of the invention to a subject, and cognitive testing of the subject after administration of the compound, so that treatment of the subject is carried out if the subject's score in said cognitive test improves.

The terms improvement, improved (increased, increased) cognitive (cognitive) ability (function) are used in the context of the present invention if there is a statistically significant difference in the normal state between the behavior of subjects treated by the methods of the invention, compared with the previous placebo group members benchmarks or between successive tests of the same subject.

In one embodiment of the invention, the RNC of the subject retains a value of 0. In another embodiment of the invention, the RNR of the subject decreases (i.e. improves) by about 0.25 or more, by about 0.5 or more, by about 1.0 or more, by about 1.5 or more, about 2.0 or more, about 2.5 or more, about 3.0 or more. In another embodiment of the invention, the rate of increase in a subject's RNS rating is reduced by 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% or more compared with the previous control increase data or with control data of increase in the absence of treatment.

In one embodiment of the invention, the MM8E score of the subject is maintained. Or the MM8E score can increase 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. In another embodiment of the invention, the rate of decrease in the subject’s MM8E score is reduced compared to previous control data. For example, the rate of decrease in a subject’s MM8E score is reduced by 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, about 100% or more compared with the previous control data reduction or control data reduction in the absence of treatment.

In one embodiment, the invention relates to a method for treating, slowing or stopping an amyloid disease associated with cognitive impairment (cognitive impairment) by administering to the subject an effective amount of a therapeutic compound, wherein the annual cognitive decline of the subject on an AEA8-Sod scale is less than 8 points per year, less than 6 points per year, less than 5 points per year, less than 4 points per year, or less than 3 points per year. In yet another embodiment, the invention relates to a method for treating, slowing down or terminating an amyloid disease associated with cognitive function by administering to the subject an effective amount of a therapeutic compound so that the cognitive function of the subject on an AIA8-Sod scale remains constant throughout the year. The term constant includes fluctuations (deviations) of not more than 2 points. Staying constant involves fluctuations of two points or less in either direction. In yet another embodiment of the invention, the cognitive function of the subject improves by 2 points or more per year, by 3 points or more per year, by 4 points or more per year, by 5 points or more per year, by 6 points or more per year, by 7 points or more per year, 8 points or more per year, etc. on a scale of AIA8-Sod. In another

- 81 012429 alternatively, the rate of increase in the subject's оценкиδ-Sod score compared to previous controls is reduced. For example, the rate of increase in a subject's оценкиδ-Soda score may decrease by 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, about 100% or more compared with the control previous data increase or with control data increase in the absence of treatment.

In another embodiment of the invention, the ratio of Av42: Av40 in C8E or plasma of a subject is reduced by about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, or about 50% or more. In another embodiment of the invention, Av levels in a subject’s cerebrospinal fluid are reduced by about 15% or more, about 25% or more, about 35% or more, about 45% or more, about 55% or more, about 75% or more, or about 90% or more.

It should be understood that wherever values and ranges of values are presented in this description, for example, the age of subject populations, dose and blood levels, it is intended that all values and ranges covered by these values and ranges be included within the scope of the present invention. In addition, all values and ranges may also be above or below the limits of the interval.

In addition, the invention relates to any new chemical compound described herein. That is, the invention relates to new compounds and new methods for their use according to this description, which are included in the scope of the claims disclosed in this description and which are not disclosed in the cited patents and patent applications.

Synthesis of Compounds of the Invention

Typically, the compounds of the present invention can be obtained by methods illustrated in the General reaction schemes, for example, described below, or by modifications of these methods, using readily available starting materials, reagents and conventional synthesis methods. In these reactions, it is also possible to use variants that are known per se but not mentioned here. Also included are the functional and structural equivalents of the compounds described herein, which have the same general properties, and one or more simpler substituent variants are obtained that do not adversely affect the basic properties or usefulness of the compound.

Compounds of the present invention can be easily obtained according to the schemes and protocols of the syntheses described herein, illustrated by the specific methods presented. However, those skilled in the art will understand that other synthetic methods for preparing the compounds of this invention can be used and that the following methods are given as an example only and are not limiting of the invention. See, for example, SotrgeNepkle Ogdash TgapkGogta! Yupk Lü V. Lägosk, νΟΗ Rübkögk (1989). It is also clear that a different standard strategy for introducing and removing protective groups is used (see, for example, Рgo! Esyue Ogoirk 1p Ogdashs 8up! Bek1k bp Ogiepe apy ki!). Specialists in the relevant field of technology know that the choice of any particular protective group (for example, a protective amino or carboxyl group) depends on the stability of the protective fragment in the conditions of subsequent reactions and will understand what choice should be made.

Samples of extensive chemical literature are selectively presented below to illustrate the knowledge of specialists in the given field of technology: Heyepk! Yes apy Μ. ktk /, 1bn kyeu & 8opk, 1ps., No. \ ν Υο ^ k (1961); SotrgekPuye Ogdashs TgapkGogtaiopk B.V. Lagosk, ν (и и Ь Ь к Ь ег к (1989); Τ.Ό. Osas, e! A1., I. May. Cl. 31, 2193-99 (1988); Ε.Μ. Oogyop, e! a1., I. May.No. 31, 2199-10 (1988); Prgasse OG Rerye 8up111ek1k b.M. Wojapkku apy. Wojapk / ku, 8rgdegve Ve ^ 1ad, No. \ ν Υο ^ k (1984); Proc! es ! 1ye Ogoyrk sh Ogdashs 8up! Bk1k bw T. Oheepe apy R kik (1991); Αkutte! Ps 8up1bek1k: Sopk! ! er, 1o1t kyeu & 8opk, 1ps., No. \ ν Υο ^ k (1987); T1e SNetyu 8yp1bek1k о ГРёйк bу I. 1opec, OhGogy Itueguu Рgekk, № \ ν Υο ^ к (1991); and 1st SNeyiktsu LU R.O. VaPeu, 1oLn kyeu & 8op k, 1ps., \ e \\ Υο ^ k (1992).

The synthesis of the compounds of the invention is carried out in a solvent. Suitable solvents are substances that are liquid at room temperature and at normal pressure or that remain in a liquid state at the temperature and pressure of the reaction. Suitable solvents are not particularly limited provided that they do not interfere with the reaction itself (i.e., they are preferably inert solvents) and they dissolve a certain amount of reagents. Depending on the circumstances, the solvents may be distilled or degassed. Solvents may be, for example, aliphatic hydrocarbons (eg, a mixture of hexanes, heptanes, naphtha, petroleum ether, cyclohexane or methylcyclohexane) and halogenated hydrocarbons (eg, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene); aromatic hydrocarbons (e.g. benzene, toluene, tetrahydronaphthalene (tetralin), ethylbenzene or xylene); simple

- 82 012429 ethers (e.g., diglyme, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran or methyltetrahydrofurans, dioxane, dimethoxyethane or diethylene glycol dimethyl ether); nitriles (e.g. acetonitrile); ketones (e.g. acetone); esters (e.g. methyl acetate or ethyl acetate); and mixtures thereof.

As a rule, after the end of the reaction, the product is isolated from the reaction mixture by conventional methods. For example, the solvent is removed by evaporation or filtration if the product is a solid, optionally in a vacuum. Upon completion of the reaction, water can be added to the residue, the acidified or alkalized aqueous layer and filtered, but care should be taken when handling substances that are unstable in water. Similarly, water with a hydrophobic solvent can be added to the reaction mixture to extract the target compound. The organic layer can be washed with water, dried with anhydrous magnesium sulfate or sodium sulfate and the solvent evaporated, obtaining the desired compound. The desired compound thus obtained can, if necessary, be purified, for example, by recrystallization, reprecipitation, chromatography, or salt conversion by addition of an acid or a base.

The compounds of the invention may be supplied in solution in a suitable solvent or in a solvent-free form (for example, in lyophilized form). In another aspect of the invention, the compounds and buffers necessary for carrying out the methods of the invention may be packaged as a kit, optionally including a container. The kit can be used to treat or prevent amyloid disease in accordance with the methods described herein and may contain instructions for use in the method of the invention. Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives or metal chelators. Additional components of the kit are present in the form of pure compositions or in the form of aqueous solutions or solutions in organic solvents that contain one or more additional components of the kit. In addition, any component or all components of a set optionally contain buffers.

The term container includes any container for storing a therapeutic compound. For example, in one embodiment of the invention, the container is a package that contains a compound. In other embodiments of the invention, the container is not a package containing a substance, i.e. the container is a container, such as a box or bottle (vial), which contains a packaged compound or unpacked compound and instructions for use of the compound. In addition, packaging methods are well known in the art. It should be understood that the instructions for use of the therapeutic compound may be in packages containing the therapeutic compound, which helps with this compound.

Pharmaceuticals

In another embodiment, the present invention relates to pharmaceutical compositions containing agents of any formula as described herein for the treatment of amyloid disease, as well as methods for producing such pharmaceutical compositions.

Typically, the agents of the present invention can be obtained by methods illustrated in the General reaction schemes, for example, in patents and patent applications referred to in this description, or by a modification of these methods, using readily available starting materials, reagents, and conventional synthesis methods. Variants that are known per se but are not mentioned in this description can also be used in these reactions. Also included are the functional and structural equivalents of the agents described herein that have the same general properties, and one or more simpler substituent variants are obtained that do not adversely affect the basic properties or usefulness of the compound.

The agents of the invention can be supplied in solution in a suitable solvent or in a solvent-free form (for example, in lyophilized form). In another aspect of the invention, the agents and buffers necessary for implementing the methods of the invention may be packaged as a kit. The kit may be used in accordance with the methods described herein and may contain instructions for use in the method of the invention. Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives or metal chelators. Additional components of the kit are present in the form of pure compositions or in the form of aqueous solutions or solutions in organic solvents that contain one or more additional components of the kit. In addition, any component or all components of a set optionally contain buffers.

The therapeutic agent can also be administered parenterally, intraperitoneally, intraspinally or intracerebrally. It is possible to prepare dispersions in glycerol, liquid polyethylene glycols and their mixtures, and in oils. Under normal storage conditions, these preparations may contain a preservative to prevent the growth of microorganisms.

To introduce a therapeutic agent by a method other than parenteral, it is necessary to coat the agent with a material to prevent its inactivation or introduce the agent together with this material. For example, a therapeutic agent can be administered to a subject in a suitable carrier, for example,

- 83 012429 liposomes, or diluent. Pharmaceutically acceptable diluents include saline and aqueous buffers. Liposomes include CCE emulsions water-in-oil-in-water, as well as conventional liposomes (81e) ag1 e1 a1., I. No. ι.ΐΓοίιηιηιιηο1. 7, 27 (1984)).

Pharmaceutical compositions suitable for use as an injection include sterile aqueous solutions (if they are soluble in water) or dispersions, and sterile powders for the immediate preparation of injectable solutions or dispersions. In all cases, the composition must be sterile and must be liquid to such an extent that it can be easily filled with a syringe. It must be stable under conditions of production and storage and must be protected from contamination by microorganisms such as bacteria and fungi.

Suitable pharmaceutically acceptable carriers include, but are not limited to, any non-immunogenic pharmaceutical adjuvants suitable for oral, parenteral, nasal, mucosal, transdermal, intravascular (intravascular) (IV), intraarterial DA), intramuscular (GM), and subcutaneous (8C) applications, such as phosphate-buffered saline (PB8).

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerin, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. Appropriate fluidity can be maintained by using, for example, a coating such as lecithin, maintaining the desired particle size in the case of dispersion, and using surfactants. The action of microorganisms can be prevented using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, the composition of the composition includes isotonic agents, for example, sugars, sodium chloride or polyhydric alcohols, such like mannitol and sorbitol. Prolonged absorption of the injectable compositions can be accomplished by introducing into the composition an agent that slows down absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by introducing the desired amount of therapeutic agent into a suitable solvent with one or a combination of the above ingredients, if required, followed by sterilization by filtration. Typically, dispersions are prepared by introducing a therapeutic agent into a sterile vehicle that contains a basic dispersion medium and the desired other ingredients listed above. In the case of sterile powders for preparing sterile injectable solutions, the methods of preparation are vacuum drying and lyophilization, whereby the powder of the active ingredient (i.e., therapeutic agent) plus the desired additional ingredient from its solution previously sterilized by filtration are obtained.

The therapeutic agent can be administered (per) orally, for example, with an inert diluent or an assimilable food carrier. The therapeutic agent and other ingredients may also be enclosed in a hard or soft gelatin capsule, compressed into tablets, or administered directly to a subject's food. For oral therapeutic use, the therapeutic agent can be administered with excipients and used in the form of tablets for ingestion, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of therapeutic agent in the compositions and preparations, of course, may vary. The amount of therapeutic agent in such compositions for use in therapy is such that the desired dose is obtained.

For ease of use and uniformity of dosage, it is particularly preferable to prepare parenteral compositions in the form of unit dosage forms. The unit dosage form as described herein refers to physically discrete units applicable as single doses for people undergoing treatment; moreover, each unit contains a predetermined amount of a therapeutic agent, which, together with the desired therapeutic carrier, is calculated to cause the desired therapeutic effect. The technical requirements for the standard dosage forms of the invention are dictated and directly determined (depend on) (a) by the individual characteristics (characteristics) of the therapeutic agent and the specific expected therapeutic effect, and (b) the limitations inherent in the preparation of mixtures of this therapeutic agent for the treatment of amyloid deposition in subjects.

Therefore, the present invention includes pharmaceutical preparations containing agents of the formulas herein, including pharmaceutically acceptable salts thereof, in pharmaceutically acceptable carriers for aerosol, oral and parenteral administration. The present invention also includes such agents, or salts thereof, which are lyophilized and which can be reconstituted to form pharmaceutically acceptable preparations for intravenous, intramuscular or subcutaneous injection. The introduction may also be intradermal or transdermal (intradermal and transdermal). According to the present invention, the agent according to the formulas in this description and its pharmaceutically acceptable salts can be administered orally or by inhalation as a solid or can be administered intramuscularly or intravenously as a solution, suspension or emulsion. Or, agents or salts may also be administered by inhalation, intravenously or intramuscularly in the form of a liposome suspension.

Pharmaceutical formulations suitable for use as an aerosol, in

- 84 012429 galization. These preparations contain a solution or suspension of the desired agent of any formula as described herein, or a salt thereof, or a plurality of solid particles of the agent or salt. A given preparation can be placed in a small chamber and sprayed. Spraying can be carried out using compressed air or ultrasound, and many droplets of liquid or solid particles containing an agent or salts are formed. Liquid droplets or solid particles should have a size of about 0.5-5 microns. Solid particles can be obtained by treating a solid agent according to any formula in this description, or its salt, by any suitable method known in the art, for example, by very fine grinding. For example, the size of solid particles or droplets is about 1-2 microns. In order to achieve this, industrial sprayers (nebulizers) are used.

A pharmaceutical preparation suitable for use in an aerosol may be in the form of a liquid, the preparation contains a water-soluble agent of any formula as described herein, or a salt thereof, in a carrier containing water. A surfactant may be present that reduces the surface tension of the preparation sufficiently so that droplets of the desired size form when sprayed.

Compositions for oral administration also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Typical suspending agents for preparing suspensions include methyl cellulose, sodium carboxymethyl cellulose, tragacanth and sodium alginate; typical surfactants include lecithin and polysorbate 80; typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweeteners, flavoring agents, and colorants disclosed above.

The pharmaceutical compositions can also be coated by conventional methods, typically ρΗ or time-dependent coatings, so that the agent of the invention is released in the gastrointestinal tract near a given site of application or at different times to achieve the desired effect. Such dosage forms typically include, but are not limited to, one of the following agents: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, waxes and shellac.

Other compositions useful for systemically delivering agents of the invention include sublingual, buccal and nasal dosage forms. Such compositions typically contain one or more excipients, such as sucrose, sorbitol and mannitol; and binders such as Arabian acacia resin, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Also included may be the swallowing agents disclosed above, lubricants, sweeteners, colorants, antioxidants, and taste and odor enhancers.

It is also possible topical (local) use of the compositions of this invention, for example, by direct application of a layer or distribution of the composition on the epidermal or epithelial tissue of a subject, or transdermal use with a patch. Such compositions include, for example, lotions, creams, solutions, gels, and solids. These topical compositions may contain an effective amount, usually at least about 0.1% or even about 15% of the agent of the invention. Suitable carriers for topical (local) use usually remain on the skin as a continuous film and are not easily removed by skin respiration or water. Typically, the carrier is inherently an organic compound and can disperse or dissolve the therapeutic agent. The carrier may contain pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents, and the like.

In one embodiment of the invention, the active agent is used in a therapeutically effective dose sufficient to inhibit amyloid deposition in a subject. For example, a therapeutically effective dose inhibits deposition of at least about 20%, or at least about 40%, or even at least about b0%, or at least about 80% compared to untreated subjects. In a patient with Alzheimer's disease, a therapeutically effective dose stabilizes cognitive function or prevents further deterioration of cognitive function (i.e., preventing, slowing or stopping the progression of the disease). Accordingly, the present invention encompasses therapeutic drug substances. By a medicinal product or medicinal substance is meant an agent that has a beneficial healing or prophylactic effect on a specific disease or condition of a person or animal.

In the case of AA and ΑΣ amyloidosis, the agent can improve or stabilize a particular organ function. As an example, renal function can be stabilized or improved by 10% or higher, 20% or higher, 30% or higher, 40% or higher, 50% or higher, b0% or higher, 70% or higher, 80% or higher or higher than 90%.

In the case of IΑΡΡ, the agent can maintain or improve the function of islet β-cells, determined by the concentration of insulin or the ratio Ρ ^ ο-IΑΡΡ / IΑΡΡ. In another embodiment of the invention, the ratio

- 85 012429

Progo-1APP / 1APP is increased by about 10% or more, about 20% or more, about 30% or more, about 40% or more, or about 50%. In another embodiment of the invention, the ratio rises to 50%. In addition, a therapeutically effective amount of an agent can effectively improve glycemia or insulin levels.

In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to treat AA (secondary) amyloidosis and / or AB (primary) amyloidosis by stabilizing renal function, reducing proteinuria, increasing creatinine clearance (for example, by at least 50% or more, or at least 100% or more), remission of chronic diarrhea or weight gain (for example, 10% or more). In addition, the agents can be used in a therapeutically effective dose sufficient for positive dynamics in nephrotic syndrome.

In addition, the active agents can be administered in a therapeutically effective dose sufficient to reduce the subject's deposition of amyloid protein, such as Λβ40 or Λβ42. For example, a therapeutically effective dose reduces amyloid deposition by at least about 15%, or at least about 40%, or even at least about 60%, or at least about 80%, relative to untreated subjects.

In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to increase an amyloid protein, for example, Av40 or Av42, in the blood, C8P, or plasma of a subject. For example, a therapeutically effective dose will increase the concentration by at least about 15%, or at least about 40%, or even at least about 60%, or at least about 80% relative to untreated subjects.

In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to maintain the subject's COB rating at the initial or level 0. In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to lower the COB rating a subject of 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 3 0 or more. In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to lower the rate of increase in the SER of the subject compared to control previous data or control data obtained in untreated patients. In another embodiment of the invention, the therapeutically effective dose is sufficient to lower the rate of increase in the rating of SOW (relative to untreated subjects) by about 5% or more, by about 10% or more, by about 20% or more, by 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% or more.

In yet another embodiment of the invention, the active agents are administered in a therapeutically effective dose sufficient to maintain the subject's MM8E scores. In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to increase the number of MM8E scores 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. In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to reduce the rate of decrease in the subject’s MM8E score compared to previous controls. In another embodiment of the invention, the active agents are administered in a therapeutically effective dose sufficient to reduce the rate of decrease in the subject’s MM8E score 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 than about 100% or less compared to control previous reduction data or with cont Role reduction data in the absence of treatment.

In yet another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to maintain the subject's AO8-Sod scores. In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to reduce the subject's AOA8-Sod score by 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. In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to reduce the rate of increase in the subject's AO8-Sod score compared to previous control or control data obtained in the absence of treatment. In another embodiment of the invention, a therapeutically effective dose is sufficient to reduce the rate of

- 86 012429 increase in the AEA8-Soda score of a subject (relative to untreated subjects) by 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, about 100% or more.

In another embodiment, the active agents are administered in a therapeutically effective dose sufficient to lower the Λβ42: Λβ40 ratio in C8P or subject plasma by about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, or about 50% or more.

In another embodiment of the invention, the active agents are used in a therapeutically effective dose sufficient to lower the level of AB in the C8P or plasma of the subject by about 15% or more, about 25% or more, about 35% or more, about 45% or more, about 55% or more, or about 75% or more, or about 95% or more.

The toxicity and therapeutic efficacy of such agents can be determined by standard pharmaceutical methods in cell cultures or in experimental animals, for example, with the aim of determining LE 50 (dose lethal for 50% of the population) and EA 50 (dose therapeutically effective in 50% of the population). The ratio of doses causing a toxic and therapeutic effect is the therapeutic index, it can also be expressed as the ratio L050 / E050, and usually the larger the therapeutic index, the higher the efficiency. When agents that have side effects are used, care should be taken to create a delivery system that targets such agents on the affected tissue in order to minimize the potential damage to the unaffected cells and thereby reduce the side effect.

It is clear that the appropriate doses depend on a number of factors known to the ordinary doctor, veterinarian or researcher. Doses (a) of a low molecular weight substance vary, for example, depending on the characteristics, size (dimensions) and condition of the subject or sample being treated, in addition, they depend on the method of administration of the composition, if applicable, and on the action which, by assumption by a medical practitioner, a low molecular weight substance should render on the subject. Typical doses include milligrams or micrograms of a low molecular weight substance per kilogram of weight of a subject or sample (for example, about 1-500 μg / kg, about 100 μg / g to 5 mg / kg, or about 1-50 μg / kg). It is clear, in addition, that the corresponding doses depend on the activity of the substance. Such suitable doses may be determined by the assay methods described herein. If an animal (for example, a human) needs to administer one or more of these compounds, the doctor, veterinarian or researcher prescribes a relatively low dose, increasing it sequentially until the desired answer is received. In addition, it is clear that the specific dose level for any particular animal subject depends on many factors, including the activity of the particular agent used, age, body weight, general health, gender and nutrition of the subject, time of administration, route of administration, rate of excretion, and any combination medicinal substances.

The ability of an agent to inhibit amyloid deposition can be evaluated on an animal model system that helps predict the effectiveness of inhibiting amyloid deposition in human diseases, for example, a transgenic mouse expressing human APP, or other animal models in which Av deposition is observed, or, for example, animal model of AA amyloidosis. Similarly, an agent’s ability to prevent or reduce cognitive impairment (cognitive impairment) in a model system can be an indicator of effectiveness in humans. Alternatively, the agent’s ability can be assessed by examining the agent’s ability to inhibit the formation of amyloid fibrils νίϋΌ, for example, the analysis of fibrillogenesis, for example, as described herein, including T1T, SI or EM analysis. You can also determine (measure) the binding of the agent to amyloid fibrils M8 analysis according to this description. The agent’s ability to protect cells from amyloid-induced toxicity is assessed by biochemical analysis, determining the percentage of cell death caused by amyloid protein. The ability of an agent to modulate renal function can also be assessed on a suitable animal model system.

The therapeutic agent of the invention can also be used with νί \ Ό to inhibit amyloid deposition or treat certain amyloid diseases, such as in ₂ M amyloidosis and other dialysis amyloidoses. Ex νί \ Ό the use of the therapeutic agents of the invention can be accomplished by contacting body fluids (e.g., blood, plasma) with the therapeutic compound of this invention, so that the therapeutic compound can perform its intended function and then administer this fluid from the body to the subject. The therapeutic compound of the invention may fulfill its function ex νπν> (e.g., dialysis filter), t νί \ Ό (e.g., administered with body fluid), or both. For example, the therapeutic compound of the invention can be used to lower plasma levels of ₂ M and / or to maintain ₂ M in a soluble form ex νίνΌ, w νί \ Ό or both ex νίνΌ and w νί \ Ό.

- 87 012429

Blood-brain barrier

Regardless of the specific mechanism by which the compound exerts its biological effect, this compound prevents or treats amyloid diseases, such as, for example, Alzheimer's disease, CΆΆ, diabetes-related amyloidosis, AB amyloidosis, Down syndrome or β ₂ Μ amyloidosis. The compound may reverse amyloid deposition or promote amyloid deposition, or the compound may promote plaque clearance or slow down deposition. For example, the compound may decrease the concentration of amyloid in the brain of a subject compared to an untreated subject. The compound can penetrate the brain through the blood-brain barrier (BBB) to manifest its biological effect. The compound may retain the amyloid in non-fibrillar form, or the compound may increase the clearance rate of soluble amyloid from the brain of a subject compared to an untreated subject. The compound can also increase the rate of Άβ cleavage in the brain before combining into fibrils. The compound can also act on the periphery, causing a change in the equilibrium concentration of amyloid protein in the two compartments (i.e., the systemic versus (νκ) central), in which case the compound does not have to penetrate the brain in order to lower the concentration of Άβ in the brain (sync -effect, penetration, seepage effect).

The agents of the invention that exhibit the physiological effect of ίη νίνο in the brain may be more applicable if they facilitate access to target cells in the brain. Non-limiting examples of brain cells are neurons, glial cells (astrocytes, oligodendrocytes, microglia), brain vessels (muscle cells, endothelial cells), and cells that contain the membranes of the brain. The blood-brain barrier (BBB) usually restricts access to brain cells, acting both as a physical and as a functional blockade, which separates the brain parenchyma from the systemic circulation (see, for example, RaLpbde, e! A1., Ί. Eigou | go1 .5 (6), 556-69 (1999); KiT e! A1., Ket. Eigox! 22, 11-28 (1999)). Molecules (substances) in the bloodstream usually have easier access to brain cells in one of two ways: lipid-mediated transport (transport) via BBB via free diffusion or active (or catalyzed) transport.

The agents of the invention can be prepared in such a way as to improve the distribution of ίη νίνΌ, for example, in the form of powder or liquid tablets or a solution for oral administration or in the form of a nasal spray, drops in the nose, gel or ointment, using a tube or catheter, syringe, cocktail , swab (compress) or as an infusion under the mucous membrane. For example, the blood-brain barrier (BBB) eliminates many highly hydrophilic agents. In order to guarantee the penetration of the more hydrophilic therapeutic agents of the invention through BBB, they can be prepared, for example, in liposomes. For methods for the production of liposomes, see, for example, patents 0 4522811; 5374548 and 5399331. Liposomes may contain one or more parts, fragments that are selectively transferred to specific (specific) cells or organs (targeting (directing) particles (fragments), or guidance groups, guidance groups, or transport vectors), thereby providing delivery of targeted drug substance (see, for example, U. U. Kanabe 1. C1t. RNagtaso. 1. 29, 685 (1989)). ^ Logically, agents can be associated with targeting groups that facilitate penetration through the blood-brain barrier. In one embodiment, the method of the present invention uses a polyamine bound to an agent that is a low molecular weight compound and is useful for inhibiting, for example, Άβ deposition.

To facilitate the transport (transfer) of the agents of the invention via BBB, they can be combined with a transport vector via BBB (for a review of the vectors and mechanisms of transport via BBB see Vyuke1, e! A1., Abν. Aegis OeNuegu Keu1e \\ 'to 46, 247 -79 (2001)). Typical transport vectors include albumin cations or OX26 monoclonal transferrin receptor antibody; these proteins undergo absorption-mediated and receptor-mediated, respectively, transcytosis via BBB. Natural cell metabolites that can be used as targeting groups include, but are not limited to, putrescine, spermidine, spermine, or OH. Other typical targeting groups include folate or biotin (see, for example, US Pat. No. 5,416,016); mannosides (Ite / a ^ a, e! a1., VusNet, VyurNuk. Kek. Sottip. 153, 1038 (1988)); antibodies (R.S.It means e! a1., REV8 Le !!. 357, 140 (1995); M. O ^ a1k, e! a1., A ^ m ^ o. Adegik Cetoieg. 39, 180 (1995) ); receptor of surfactant protein Ά (Bpxoe, e! a1., At. 1. RNukyu1 1233, 134 (1995)); dp120 (8cbg1e1, e! a1., 1. w1, cf. 269, 9090 (1994); see also K. Ks ^ sis apb M.B. Gaikka ^^ REV8 bе !!. 346, 123 (1994); 1.1. Kshop apb 1.1. P1b1eg, Attendance! 4, 273 (1994)).

Examples of other transport vectors via BBB that target receptor-mediated transport systems to the brain include factors such as insulin, insulin-like growth factor (UR-1 and UR-11), angiotensin II, atrial and cerebral natriuretic peptides (AYR and VYR) and transferrin . Monoclonal antibodies to receptors that bind these factors can also be used as transport vectors via BBB. The mechanisms for targeting transport vectors via BBB in the case of absorption-induced transcytosis include cationic fragments, such as cationic bb, albumin or horseradish peroxidase coupled to polylysine, cationic albumin or cationic immunoglobulins. Low molecular weight oligopeptides such as

- 88 012429 analogue of dinorphin E-2078 and ACTH analogue of ebiratides can also penetrate the brain through the absorption-mediated transcytosis and potential transport vectors.

Other transport vectors through the BBB target systems to transfer nutrients to the brain. Examples of such BBB transport vectors include hexose particles, for example glucose, and monocarboxylic acids, for example lactic acid, and neutral amino acids, for example phenylalanine, and amines, for example choline, and basic amino acids, for example arginine, nucleosides, for example adenosine, and purine bases, for example adenine, and thyroid hormone, for example trinodtiridin. Antibodies to the extracellular domain of nutrient carriers can also be used as transport vectors. Other possible vectors include angiotensin II and ΑΝΡ, which may be involved in the regulation of BBB permeability.

In some cases, the bond connecting the therapeutic agent to the transport vector can be cleaved after transfer (transport) to the brain in order to release the biologically active agent. Typical linkers include disulfide bonds, ester bonds, thioether bonds, amide bonds, weak acid coupling and Schiff base coupling. Avidin / biotin linkers may also be used in which avidin is covalently linked to the drug transport vector via BBB. Avidin itself may be a drug transport vector.

Transcytosis, including receptor-mediated transport of the compositions across the blood-brain barrier, may also be applicable to the agents of the invention. Transferrin receptor mediated delivery is disclosed in US Pat. Nos. 5,672,683; 5,384,988; 5,527,527; 5977307 and 6015555. Transferrin-mediated transport is also known. R.M. Epiep, e! A1., Ρΐιαηηαοοί. Exp Tneg. 278, 1491-98 (1996); H.1. Lie, 1. Ρΐιαηηαοοί. Exp Tneg. 292, 1048-52 (2000). ECE receptor mediated delivery is disclosed in Υ. Oedis, e! a1., Βίοοοηρίβ. Oh. 10, 32-37 (1999), and transcytosis is described in Α. Seg1e1 e! A1., 1. Aegis of Tagde !. 8, 435-46 (2000). Fragments of insulin were also used as carriers for delivery across the blood-brain barrier. M. Eiki1a, e! A1., RNagt. Kek. 11, 1681-88 (1994). The delivery of agents by the conjugate of neutral avidin and cationic human albumin is also described. Υ. 8. Capd, e! A1., RNagt. Kek. 1, 1257-64 (1994).

To increase the penetration of the agents of the invention across the blood-brain barrier, other modifications can be made using methods and derivatives known in the art. For example, US Pat. No. 6,024,977 discloses covalent polar lipid conjugates for targeting the brain and central nervous system. US patent 5017566 discloses derivatives of cyclodextrin containing inclusion complexes of lipoid forms of redox (redox) targeted (targeting) particles of dihydropyridine. U.S. Patent 5,023,252 discloses the use of pharmaceutical compositions containing a neurologically active drug substance and a compound facilitating the transport of the drug across the blood-brain barrier, including macrocyclic ester, diester, amide, diamide, amidine, diamidine, thioether, dithioether, thioamide, ketone or. US Pat. No. 5,024,998 discloses solutions of water-insoluble drug compounds with cyclodextrin derivatives for parenteral use. US Pat. No. 5,039,794 discloses the use of the metastatic tumor exit factor to facilitate the transport of compounds across the blood-brain barrier. US Pat. No. 5,112,863 discloses the use of Acylamino derivatives of acids as antipsychotic drugs for delivery across the blood-brain barrier. US Pat. No. 5,214,146 discloses a method for delivering therapeutic agents across the blood-brain barrier at locations of increased permeability due to brain damage. US 5,153,179 discloses acylated glycerol and derivatives for use in a medicament for increased penetration through cell membranes. US patent 5177064 discloses the use of lipoid phosphonate derivatives of nucleoside antiviral agents for delivery across the blood-brain barrier. US 5,254,342 discloses receptor-mediated transcytosis across the blood-brain barrier using a transferrin receptor in combination with pharmaceutical compounds that intensify or accelerate this process. US patent discloses the treatment of epilepsy with imidates of anticonvulsant sulfamate. US 5,270,312 discloses substituted piperazines as agents for the central nervous system. US 5,282,876 discloses conjugates of dopamine-based fatty acid drug substances. US Pat. No. 5,389,623 discloses the use of lipid dihydropyridine derivatives of anti-inflammatory steroids or steroid sex hormones for delivery across the blood-brain barrier. US 5405834 discloses prodrugs derived from thyrotropin-releasing hormone. US Pat. No. 5,413,996 discloses conjugates of acyloxyalkylphosphonates with neurologically active drug substances for the anionic isolation of such drug substances in brain tissue. US patent 5434137 discloses methods for the selective opening of abnormal brain capillaries using infusion of bradykinin into the carotid artery. US patent 5442043 discloses a peptide conjugate, namely a conjugate of a peptide with biological activity, not able to penetrate the blood-brain barrier, and a peptide that does not exhibit biological activity, but is able to pass through the blood-brain barrier due to the receptor

- 89 012429 mediated endocytosis. US patent 5466683 discloses water-soluble analogues of an anticonvulsant compound for the treatment of epilepsy. U.S. Patent 5,525,727 discloses compositions for separate absorption and retention in brain tissue, which are a conjugate of narcotic analgesics and their agonists and antagonists with the lipid form of dihydropyridine, which forms a redox salt when absorbed through the blood-brain barrier, which prevents separate return to the systemic circulation.

Nitric oxide is a vasodilating factor of the peripheral vasculature in normal body tissue. An increase in the formation of nitric oxide under the action of nitric oxide synthase causes vasodilation without reducing blood pressure. An increase in blood flow through the brain, independent of blood pressure, increases cerebral bioavailability of the compositions formed in the blood. This increase in nitric oxide can be stimulated by the administration of L-arginine. As the amount of nitric oxide increases, cerebral blood flow increases accordingly, and drugs in the blood stream are carried away by an increased current in the brain tissue. Therefore, L-arginine can be used in the pharmaceutical compositions of the invention to increase the delivery of agents to brain tissue after the pharmaceutical composition is introduced into the blood stream of a subject almost simultaneously with a blood-increasing amount of L-arginine, as described in international application \ UO 00/56328.

Other examples of modifications that increase penetration through the blood-brain barrier are described in published international (PCT) application UO 85/02342, which discloses a drug composition containing a glycerolipid or its derivative. PCT published application UO 089/11299 discloses a chemical conjugate of an antibody with an enzyme that is delivered specifically to the site of brain damage to activate a separately administered neurologically active prodrug. PCT application UO 91/04014 discloses methods for delivering therapeutic and diagnostic agents across the blood-brain barrier by encapsulating drugs in liposomes targeting brain tissue using transport-specific receptor ligand antibodies. Published international application PCT \ UO 91/04745 discloses transport (transport) through the blood-brain barrier using cell surface adhesion molecules and fragments thereof to increase permeability in close contact with vascular endothelium. PCT published international application XVO 91/14438 discloses the use of a modified chimeric monoclonal antibody to facilitate the transport of substances across the blood-brain barrier. PCT published international application VO 94/01131 discloses lipidated proteins, including antibodies. PCT Published International Application VO 94/03424 discloses the use of amino acid derivatives as drug conjugates to facilitate transport across the blood-brain barrier. PCT published international application VO 94/06450 discloses conjugates of neurologically active drug substances with a targeted redox particle such as dihydropyridine and containing an amino acid bond and an aliphatic residue. PCT published international application VO 94/02178 discloses antibody-targeted liposomes for delivery across the blood-brain barrier. PCT published international application VO 95/07092 discloses the use of drug-growth factor conjugates for drug delivery across the blood-brain barrier. PCT published international application VO 96/00537 discloses polymer microspheres as injectable particles of a drug carrier substance for delivery to deliver bioactive agents to sites (sites) in the central nervous system. PCT published international application VO 96/04001 discloses omega-3 conjugates of fatty acids with neurologically active drug substances for delivery across the blood-brain barrier. PCT published international application VO 96/22303 discloses conjugates of fatty acids and glycerolipids with neurologically active drug substances for delivery across the blood-brain barrier.

Typically, one of ordinary skill in the art can readily obtain the ester, amide or hydrazide of an agent of the invention, for example, from the corresponding carboxylic acid and a suitable reagent. For example, a compound containing a carboxyl group or its reactive equivalent may be reacted with a hydroxyl-containing compound or its reactive equivalent so as to produce the corresponding ester. See., Eg, the t, 'οιηrgeepbue Ogdashs T ^ o ^ £ aη8 that! ^ Οη8, 2' ¹ Eb., Ly KS Lagos, νί, Ή и и Ь ега ега Ιοίιη ΧνίΚν & δοηδ, b! B. (1989); MAGS'8 Abvаnseb Ogdash Сштщ! Gu, 5 ^{! B} Еб., Bу Μ.Β. 8THE APB 1. MAG, Ιοίιη ΧνίΕν & δοηδ, b! B. (2000).

Prodrugs

The present invention also relates to prodrugs of agents of the formulas disclosed herein. Prodrugs are agents that turn into active forms (see, for example, K.V. 81Kegtap, 1992, Thie Ogdashs Szetzgu ο £ Aegid Beidp apg Egid As! Jup, Asabetu Prge§8, Chp. 8). Prodrugs can be used to alter biodistribution (for example, to allow agents that are usually not included in the reactive site of the protease) or the pharmacokinetics of a particular agent. For example, a carboxyl group can be esterified, for example, with a methyl group or an ethyl group to form an ester. When an ester is administered to a subject, it is cleaved,

90 012429 enzymatically or non-enzymatically, by reduction, oxidation or hydrolysis, releasing the anionic group. The anionic group can be esterified with particles (for example, acyloxymethyl ether), which are cleaved, releasing an intermediate agent, which then decomposes to form an active agent. Particles of prodrugs can be metabolized by ίη νίνο by esterases or by other mechanisms to carboxylic acids.

Examples of prodrugs and their use are well known in the art (see, for example, Vegde, e1 a1., P11agtasei11ca1 Zaik, ί. Rnag. 8c1. 66, 1-19 (1977)). Prodrugs can be prepared with ίΐη δίΐιι during the final isolation and purification of the agents, or by separate reaction of the purified agent as a free acid with a suitable derivatizing agent. Carboxylic acids can be converted into esters by treatment with alcohol in the presence of a catalyst.

Examples of digestible carboxylic acid prodrugs include substituted and unsubstituted, branched or linear alkyl esters (e.g. ethyl esters, propyl esters, butyl esters, pentyl esters, hexyl esters, cyclohexyl esters), lower alkenyl esters, esters (di (lower alkyl) amino lower alkyl) esters (e.g., dimethylaminoethyl ether), esters (acylaminone lower alkyl) esters, (acyloxy lower alkyl) esters (e.g. pivaloido simethyl ether), aryl esters (phenyl ether), esters (aryl-lower alkyl) esters (e.g. benzyl ether), esters (substituted (e.g. with substituents methyl, halogen, methoxy) aryl and aryl-lower alkyl) esters, amides, (lower alkyl) amides, di (lower alkyl) amides and hydroxyamides.

Pharmaceutically Acceptable Salts

Some variants of the agents of the present invention may contain a basic functional group, such as amino or alkylamino, and therefore they are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this case, the term pharmaceutically acceptable salts refers to the relatively non-toxic salts of the addition of inorganic and organic acids to the agents of the present invention. These salts can be obtained ίη δίΐιι in the process of final isolation and purification of the agents of the invention or in a separate reaction of the purified agent of the invention in the form of a free base with a suitable organic or inorganic acid, thereby isolating the salt that forms.

Typical salts include hydrohalides (including hydrobromide and hydrochloride), sulfates, bisulfates, phosphates, nitrates, acetates, valerates, oleates, palmitates, stearates, laurates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates, per , mesylates, glucoheptonates, 2-hydroxyethanesulfonates and lauryl sulfonates and the like. See, for example, Vegde, e1 a1., P11agtaseiNsa1 8a8, 1. Rnagt. 8s1. 66, 1-19 (1977).

In other cases, the agents may actually contain one or more acidic functional groups and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term pharmaceutically acceptable salts in these examples refers to the relatively non-toxic salts of the addition of inorganic and organic bases to the agents of the present invention.

These salts can also be obtained ίη δίΐιι during the final isolation and purification of the agents of the invention, or by separately reacting the purified agent of the invention in the free acid form with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Typical alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts. Typical organic amines suitable for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

Pharmaceutically acceptable salts also include, for example, derivatives of agents modified by the preparation of acidic and basic salts from them, as described in more detail below and elsewhere in this invention. Examples of pharmaceutically acceptable salts include salts of mineral and organic acids with basic residues, such as amino groups; and organic alkali salts with acidic residues such as carboxyl groups. Pharmaceutically acceptable salts include the usual non-toxic salts or the quaternary ammonium salts of the starting agents obtained, for example, by the action of inorganic or organic acids. Such conventional non-toxic salts include those obtained by the action of inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; and salts obtained by the action of organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palm, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilibenzoic, 2 fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic and isethionic acid. Pharmaceutically acceptable salts can be synthesized by conventional chemical methods from a starting agent that contains basic and acidic groups. Typically, such salts can be obtained by

- 91 012429 reactions of these agents in the form of a free acid or free base with a stoichiometric amount of a suitable base or a suitable acid in water or in an organic solvent or a mixture thereof.

All acidic, saline, basic or other ionic and nonionic forms of the described compounds are included as compounds of this invention. For example, if a compound in this compound is presented as an acid, salt forms of the compound are also encompassed. Similarly, if the compound is shown as a salt, the acidic and / or base forms are also encompassed.

Specialists in the art will know or will be able to determine, using only ordinary experiments, the numerous equivalents of specific techniques, variants of the invention, claims and examples herein. It is believed that such equivalents are included in the scope of this invention and are covered by the attached claims. The contents of all references issued by patents and published patent applications cited in this publication are hereby incorporated by reference into this description. The invention is further illustrated by the following examples, which should not be construed as an additional limitation.

Examples

Binding Assay and Antifibrillogenic Assay

Test compounds are synthesized and screened by mass spectrometry (Μδ), with the exception of selected compounds that are obtained industrially. Μδ analysis gives data on the ability of compounds to bind to proteins, in this case, β-amyloid and ΙΑΡΡ.

In the Μδ analysis for Aβ40, samples are prepared in aqueous solutions (adding 20% ethanol if necessary to solubilize in water), 200 μM of the test compound and 20 μM of the solubilized Aβ40, or 400 μM of the test compound and 40 μM of solubilized Ar40. The pH of each sample was adjusted to 7.4 (± 0.2) by adding a 0.1% aqueous solution of sodium hydroxide. Then, the solutions were analyzed by electrospray ionization mass spectrometry on a Na1e5 ΖΡ 4000 mass spectrometer. Samples were directly injected (poured) at a flow rate of 25 μl / min for 2 hours after sample preparation. The temperature in the sensor is maintained at 70 ° C, and the voltage of the cone is 20 V in all analyzes. Data is obtained using the program Ma551unkh 3.5. Mass spectrometry provides data on the ability of compounds to bind to soluble Aβ, while analyzes of TNT, ΕΜ, and SI allow data on the inhibition of fibrillogenesis. The results of the analysis of binding to Aβ are summarized in table. 3. In the table. 3 empty cell means that in this analysis the value for the compound was not determined.

Analysis for ΙΑΡΡ was carried out under the same conditions, except that 200 μM of the test compound and 20 μM of solubilized используют were used.

Index to the table. 3

Αβί- 40 The code 400 μM 200 μm Strong binding +++ 90-100% 60-100% Moderate binding ++ 70-89% 30-69% Weak binding + 45-59% 20-44% Small / non-detectable binding 20- 39% 20-39% ΙΑΡΡ 200 μM (20% UNL) 100 μM (20% UNL) Strong binding +++ > 75% > 50% Moderate binding ++ 40-75% 30-50% Weak binding + 20-40% 15-30% Mapoe / not detectable binding 0-20% 0-15%

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Table 3 Relative binding affinity of the compounds of the invention

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OE + - ABOUT? +++ - os - + it + ++ ϋΐ - - oe +++ - OK ++ +++ ϋί - + om + ++ ΟΝ + ++ 00 ++ +++ ΟΡ - + ΟΡ - + ϋκ + + 05 + + ϋΤ + + ου +++ +++ ον +++ +++ ϋ \ Ν +++ ++ οχ +++ +++ ΟΥ ++ +++ ϋΖ +++ +++ ΕΑ + ++ ΕΒ +++ +++ The EU +++ Εϋ ++ +++ HER ++ +++ ΕΡ - + The EU +++ +++ EN +++ +++ ΕΙ - - EE + ++ ΕΚ +++ +++ Εί + ++ ΕΝ + + ΕΟ - + ΕΡ ++ + Ε <2 - + ΕΚ ++ Ε5 +++ +++ ΕΤ +++ ΓΠ < +++ EUU +++ ΕΥ +++ +++ ΕΖ +++ +++ ΡΑ ++ +++ ΡΗ - - Ρί +++ ++ ΡΚ +++ ++ ΡΟ - -

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The effect of short-term treatment in adult transgenic SIKE 8, overexpressing bAPP

Transgenic mice, TgSKIP8 expressing human amyloid protein precursor (CARP), develop a pathology resembling Alzheimer's disease. In particular, high levels of Av40 and Av42 were obtained in the plasma and brain of these 8-9-week-old animals, followed by an early accumulation of amyloid plaques similar to senile plaques observed in patients with AO. These animals also exhibit progressive cognitive impairment corresponding to the manifestation of degenerative changes. See, for example, Szym, e! A1., I. Βΐο1. Sket. 276, 21562-70 (2001).

The short-term therapeutic effect of 19 compounds of the invention was studied. These compounds are administered over a 14- or 28-day period; at the end of each of them, the levels of Av peptides in the plasma and brain of the TDCCO8 animals are determined.

Ways.

In this example, females and males of 3rd and 4th generation B6C311 transgenic mice are used, they are injected subcutaneously daily or given orally one of three series of compounds for 14-28 days. The following abbreviations are used in this protocol to refer to these animals of the 3rd and 4th generation of backcrossing: T§SKIV8-2.V6S3G1 (I3); T§SKIV8-2.V6S3G1 (I4).

The group of control animals (group 1) consists of native TDsGI) 8-2. B6C31-’1 (M3) at the age of 11 ± 1 weeks. These mice are used to determine Av levels in plasma and brain.

- 95 012429 rearing animals at the beginning of treatment.

Starting from 11 weeks of age (± 1 week), animals receive daily appropriate treatment for 14 or 18 days (groups 2-21) at a dose of 250 mg / kg at 10 ml / kg, or only vehicle (water; group 2), or only 1% methylcellulose (group 21). The route of administration is subcutaneous for water-soluble compounds and oral for compounds solubilized in 1% methylcellulose (MS 1%). At the end of the treatment period, plasma and brain after perfusion are collected to quantify Av levels.

Table 4

Test system

View: Mouse Strain T _g SKCHO8- 2.V6SZR1 (N ₃₎ & (Ν ₄₎ Genotype: 11ARP +/- Floor Male and female Age on Day 1: 11 ± 1 weeks Body weight per day 1: 10-30 g Number of groups: 21 Number of animals / group per day 1 Original: 8 Carrier and processing: 12-15 Additions: The original mice Τ ^ ί'ΚΝΟΒ- 2 are obtained from Sep £ ge Gog Kezeag ίη ΝειιΐΌάοβεηε-ιαΙϊνε E) 15сa5С5. υηίνββίΐγ оГТогогХо. Inbred B6C3P1 mice are obtained from Chabez Κινεί (Descp. Sapa <1a).

The mice used in the study were taken from a colony bred in 1pcSi1 Agtapy erygarr, and before the start of the study they are acclimatized in the environment. Animals, depending on age and gender, are divided into the following experimental groups.

Table 5

Groups of mice

Group N Treatment If dose (mg / kg) Duration of treatment (days) one The control Not approx. Not approx. 2 Water Not approx. 14 and 28 4 ΒΥ 250 14 and 28 6 SU 250 14 and 28 12 SU Not approx. 14 and 28 fifteen V5U 250 14 and 28 sixteen ΒΖ 250 14 and 28 eighteen VX 250 14 and 28 twenty Bc 250 14 and 28 21 Microcellulose 1% one hundred 14 and 28

Animal health monitoring.

All animals are checked daily for signs of pain when a daily dose is given in the morning, and death control is checked twice a day (once a day for weekends and holidays). A detailed examination is carried out at the beginning of treatment, daily during the course of the study and once before the last procedures. If necessary, the examination is carried out more often. Separately, death and all individual clinical signs are recorded. Individual body weight is recorded with randomization, once a week during the study and once before the last procedures.

Sampling.

In the control group, age 11 ± 1 weeks, and at the end of the treatment period (14 or 28 days) in groups 2-21, 24 hours after the last administration of the compound, the animals were sacrificed and samples were collected. Approximately 500 μl of blood is collected from the orbital sinus and stored on ice until centrifuged, centrifuged at 4 ° C at a minimum speed of 3000 rpm for 10 minutes. Plasma samples are immediately frozen and stored at -80 ° C until analysis. The brain is removed, frozen and stored at -80 ° C until analysis.

Level measurement Av.

The brain was weighed in a frozen state and homogenized with 4 volumes of ice-cold buffer 50 mM Tpc-C1 pH 8.0 with a protease-inhibitory cocktail (4 ml of buffer per 1 g of wet brain). Samples were centrifuged at 15,000 d for 20 minutes and supernatants were transferred to new tubes. One hundred fifty (150) μl of each supernatant is mixed with 250 μl of 8 M guanidine-HC1 / 50 mM Tpk-C1 pH 8.0 (in the ratio of 0.6 volumes of supernatant: 1 volume of 8 M guanidine / 50 mM Tpk-C1 pH 8, 0) and add

- 96 012429

400 μl of 5 M guanidine / 50 mM TG18-C1 pH 8.0. The tubes are shaken for 30 s and frozen at -80 ° C. In parallel, the precipitate (pellets) is treated with 7 volumes of 5 M guanidine / 50 mM Tp8-C1 pH 8.0 (7 ml guanidine per 1 g of wet brain), shaken for 30 s and frozen at -80 ° C. Samples are thawed at room temperature, destroyed by ultrasound at 80 ° C for 15 minutes, and frozen again. This cycle is repeated 3 times to ensure homogeneity, and the samples are again cooled to -80 ° C and stored at this temperature until analysis.

Levels of Aβ in plasma and brain samples are determined using the ESA method, using sets of human Aβ40 and Aβ42 Ε1иο ^ οίίί ^^ with ЕЫ8А from Вю ^ itce (Ca1. No. 89-344 and 89-348) in accordance with the manufacturer's recommendations. In short, samples are thawed at room temperature, sonicated for 5 minutes at 80 ° C (sonic homogenates, but not plasma samples, are destroyed by ultrasound) and stored on ice. The β peptides are applied to the plate using 100 μl of the diluted sample and incubated without shaking, incubated at 4 ° C. overnight. Samples (liquid) are suctioned off (aspiration) and the wells are washed 4 times with an aqueous buffer from a Vyushse EY8A kit. A rabbit polyclonal antiserum was added to Aβ40 or Aβ42 (specific for the Aβ40- or Aβ42 peptide) (100 μl) and the plate was incubated at room temperature for 2 hours with shaking. The liquid from the wells is aspirated and the wells washed 4 times, 100 μl of an antibody to rabbit immunoglobulin labeled with alkaline phosphatase is added and incubated at room temperature for 2 hours with shaking. Then the plates are washed 5 times and a fluorescent substrate (100 μl) is added to the plate. The plate was incubated for 35 minutes at room temperature and the plate was read on a photometer for microtiter plates (reader) at an excitation wavelength of 460 nm and an emission of 560 nm.

Compounds are evaluated based on their ability to modulate plasma levels of Aβ peptides and cerebral soluble / insoluble Aβ levels in the brain. The levels of Aβ observed in the plasma and brain of treated animals are normalized according to the values obtained in the control groups treated with vehicle (water) or methyl cellulose, and ranked according to the intensity of the pharmacological action (effect). The results are shown in table. 3-11.

An increase in the levels of Aβ peptides is indicated by + symbols, while a decrease in levels of Aβ peptides is shown by symbols. The strongest effect is shown as +++ or '' -, while the weakest is shown as + or

Specifically, an increase in Aβ levels (relative to the control level in the absence of treatment) by 20-39% is estimated as +; an increase of 40-69% is estimated as ++; and an increase of 70% or more is estimated as +++. A 5-19% decrease in Aβ levels is estimated as -; a decrease of 20-38% is estimated as -; and a decrease of 39% or more is rated as -.

The data are presented in table. 6-11. Treatment with the compounds of this invention after 14 and / or 28 days causes a significant change in cerebral levels of Aβ40 and / or Aβ42 (Table 8-11). In addition, treatment using these compounds, for example Compound BX (3- (tert-butyl) amino-1-propanesulfonic acid) after 14 and 28 days leads to a significant increase in plasma levels of Aβ peptides (Tables 6-7). This suggests that some of these compounds can act by the effect of penetration from the periphery, isolating Aβ in plasma and thereby facilitating its clearance from ΟΝ8, as was previously assumed with respect to treatment with passive immunization using monoclonal antibody against Aβ t266 (OeMa1U5 eί A1., 8c1ense 295 (5563): 2264-7).

The tables show the levels of Aβ peptides in the plasma and brain of the mice of TDCBYE8 treated for 14 and 28 days with the compounds of the invention.

In the table. 6A and 6C show plasma data on day 14 and day 28, respectively, for the vehicle group. In the table. 6B and 7 show the plasma data for the methyl cellulose group on day 14 and day 28, respectively. In the table. Figures 8 and 10 show data for brain homogenate on day 14 and day 28, respectively, for the group receiving the vehicle. In the table. Figures 9 and 11 show the data for brain homogenate in the methyl cellulose group on day 14 and day 28, respectively.

Table 6A

Plasma in vehicle group, day 14

Drug substance Change Αβ40 Change Αβ42 ΒΥ + + ον + ++ OS +++ ++ VX +++ ++

- 97 012429

Table 6B

Plasma in the group receiving methylcellulose, day 14

Drug substance Change Αβ40 Change Αβ42 ΒΖ + Βνν SU

Table 6C

Plasma in vehicle group, day 28

Drug substance Change Αβ40 Change Αβ42 ΒΥ SU ++ +++ OS +++ in +++

Table 7

Plasma in the group receiving methylcellulose, day 28

Table 8

Brain homogenate in vehicle group, day 14

Change Αβ40 Change Αβ42 Drug substance Soluble Insoluble Soluble Insoluble ΒΥ +++ +++ +++ SU ** - OS - - + - - in - - - - -

** The effect of this compound in the brain is more likely to be tested only on its ability to modulate total levels of Άβ40 and Άβ42 peptides rather than independently measuring the levels of soluble and insoluble peptide.

Table 9

Brain homogenate in the group receiving methylcellulose, day 14

Change Αβ40 Change Αβ42 Drug substance Soluble Insoluble Soluble Insoluble ΒΖ - - - Βνν - - - - SU - +++ ++

Table 10

Brain homogenate in vehicle group, day 28

Change Αβ40 Change Αβ42 Drug substance Soluble Insoluble mogo Soluble Insoluble mogo ΒΥ + +++ +++ SU ** ++ +++ OS - + ++ ++ + in - - - - -

** The effect of this compound in the brain is rather tested only on its ability to modulate

- 98 012429 total levels of Av40 and Av42 peptides, rather than independently measuring the levels of soluble and insoluble peptide.

Table 11

Brain homogenate in methylcellulose-receiving group, day 28

Change Αβ40 Change Αβ42 Drug substance Soluble Insoluble Soluble Insoluble ΒΖ - - - - - lice - - - - - SU +++ +++ +++ +

The effect of long-term treatment on adult transgenic mice ΟΒΝΌ8, overexpressing bAPP

Transgenic mice, TDCN ^ 8. those used for short-term treatment overexpress a human APP gene with a Swedish or Indiana mutation, which leads to the formation of high levels of amyloid peptides and the development of early actively progressing brain amyloidosis. It is believed that high levels of Av peptides and a relative excess of Av ₄₂ compared to Av ₄₀ are associated with the observed severe and early degenerative pathology. The nature of amyloid deposition, the presence of dystrophic neurites, and cognitive deficiency in this line of transgenic mice are well understood and described. The levels of Av peptides in the brain of these mice increase dramatically with age. During the study, total levels of amyloid peptides increase from ~ 1.6 x 10 ⁵ pg / g of the brain to ~ 3.8 x 10 ⁶ over a period of 9 to 17 weeks.

While early deposition of amyloid in this model allows you to quickly test compounds in a relatively short time frame, the activity (aggressiveness) of this model and high levels of the Av peptide make therapeutic evaluation in a longer experiment a more difficult task.

The long-term therapeutic effect of the compounds of the present invention on cerebral amyloid deposition and levels of β-amyloid (Av) in the plasma and brain of transgenic mice, TDSCI8 expressing human amyloid precursor protein (yAPP) was studied. These compounds are administered over an 8 or 16 week period, at the end of which the levels of Av peptides in the plasma and brain of TdSCNO8 animals are determined. The aim of this study is to evaluate the effectiveness of compounds in modulating the progression of the amyloidogenic process in the brain and plasma of a transgenic mouse model of Alzheimer's disease (AE).

Ways.

The mice used in the study consist of animals carrying one copy of the yAPP gene (+/-) from the 2nd and 3rd generations from ancestors (Ν ₂ and Ν ₃ ), obtained by backcrossing from TDSCIV 8.EUB (^) A1 ^ h) with B6AP / 1 hybrid animals.

Ν = TdSK \ 1) 8.EkB (\ _; ) A.1 (\ _; ) B6AB / .1

Ν ₂ = T'dSK \ B8.EkB (\ _; ) A.1 (\ _; ) .B6AE / .1 (\ ₁ ) B6AV / .1

Ν ₃ = T'dSK \ B8.EkB (\;) A.1 (\ _; ) .B6AE / .1 (\ _; ) B6AB / .1

TdSKYP8.V6AR / 1 (K _2): To designate these animals following abbreviations are used in this study TDKSKHO8.V6AV / 1 (X ₃ ). Male and female transgenic mice are injected subcutaneously daily (compound BX) or given orally (compounds B \ Y and B2) corresponding compounds for 8 or 16 weeks.

The initial (base) animals are 9 ± 1-week untreated TdSKYP8. B6AP / 1 animals of the 2nd and 3rd generations. These mice are used to determine the degree (magnitude) of cerebral amyloid deposits and Av levels in plasma and brain of previously untreated transgenic animals at the beginning of treatment.

Starting at 9 weeks of age (± 1 week), animals receive daily appropriate treatment for 8 or 16 weeks at a dose of 30 or 100 mg / kg at 10 ml / kg. The route of administration is subcutaneous for water-soluble compounds (compound BX) and oral for compounds solubilized in 1% methylcellulose (MS 1%) (compounds B1 and B2). At the end of the treatment period, plasma and brain after perfusion are collected to quantify Av levels.

The health status of animals is monitored, samples are collected and Ab levels are determined as described above when describing a short-term treatment study. Compounds are evaluated based on their ability to modulate plasma Av-peptide levels and cerebral soluble / insoluble Av levels in the brain. Av levels observed in the plasma and brain of treated animals are compared with levels obtained in the control groups treated with vehicle (water) or methyl cellulose and ranked according to the intensity of the pharmacological action (effect).

- 99 012429

The results are shown in table. 12. An increase in the levels of Λβ peptides is indicated by + symbols, while a decrease in the levels of Av peptides is shown by symbols. The strongest effect is shown as +++ or -, while the weakest is shown as + or

Specifically, an increase in Av levels (relative to the control level in the absence of treatment) by 514% is estimated as +; an increase of 15-29% is estimated as ++; and an increase of 30% or more is estimated as +++. A 5-14% decrease in Av levels is estimated as -; a decrease of 15-29% is estimated as -; and a decrease of 30% or more is rated as -. In addition, a change of 4% or less in one direction or another is evaluated as 0.

In the table. 12 shows the levels of Av peptides in the plasma and brain of mice TdSChO8 treated for 8 and 16 weeks with the compounds of the invention. Treatment with these compounds after 8 and / or 16 weeks in many cases causes a change in Av ₄₀ and / or Av ₄₂ levels in plasma and / or in the brain. For example, administration of compound BX usually causes a sharp decrease in the amount of AB in the brain after 8 and 16 weeks. Compound Β \ ν also causes a sharp decrease in Av levels in the brain and in plasma after 8 weeks and Av levels in plasma after 16 weeks, in addition, preliminary histochemical studies with staining of brain sections using THo8 show that both the number of plaques and the area occupied by plaques in mice receiving a dose of 30 mg / kg of compound BX is reduced.

Table 12

The effect of compounds BX, Βν and ΒΖ on Av levels in plasma and brain

Swede- Dose Time Plasma Brain not (mg / kg) (weeks) Abeta40 Abeta42 Abeta40 Abeta42 Rome solution Romance Rome solution Romance VX thirty 8 + + - - - - - VX one hundred 8 ++ +++ + ++ + 0 VX thirty sixteen - - - - - 0 - VX one hundred sixteen - 0 - - 0 - - Βνν thirty 8 - - - - - - 0 Βνν one hundred 8 - - - - - - - - Είνν thirty sixteen - - - + ++ - + Βνν one hundred sixteen - - ++ + + ++ ΒΖ thirty 8 0 0 0 - 0 - ΒΖ one hundred 8 ++ +++ ++ 0 0 - ΒΖ thirty sixteen 0 + 0 + + 0 ΒΖ one hundred sixteen ++ ++ - - 0 +

Example 11. Evaluation of the binding of compounds with NΑC peptide by mass spectrometry.

Recent discoveries have shown that a high percentage of patients with Alzheimer's disease (AO) is different in that they form Levi bodies, most of all in the amygdala (Iat111op. 2000. Vgash Pa1o1, 10: 378; Mikae1oua-Baishka, e (a1. 2000 1 It is interesting to note that the region of the highly hydrophobic non-amyloid component (HR) of α-synuclein was later described as the second most common component of amyloid plaques in the brains of AO patients. It was shown that α-synuclein forms fibrils ίη νίΙΐΌ. binds to Av and stimulates aggregation (UokYto! o, e (a1. 1995 Proc. Νη11. Asai. 8sk I8A 91: 9141). In reality, it was first identified as a precursor of the non-amyloid component (HO) of AO plaques (Ieya, e (a1. 1993 Proc. Νη11. Acai. 8sk I8A 90: 11282; 1 ^ a1, 2000. Wuset Würük Ac1a 1502: 95; MacLaB, e1 a1. 1996. At 1 Pa1Lo1 148: 201) HOUR is a 35 amino acid peptide with highly hydrophobic sections (segments) that are capable of self-aggregation and the formation of fibrils ίη yugo, in addition, these fibrils can be the nuclei of actively formed Av fibrils (General (a1. 1995. Siet Vue1. 2: 163-169; 1 ^ a1, e (a1. 1995. Tips 34: 10139). In fact, thanks to this HOUR domain, α-synuclein retains its fibrillogenic properties. Therefore, modulating the properties of QAS or targeting QAS compounds of the invention can be an effective means of inhibiting the formation of protein aggregates and inclusions due to α-synucleopathies, as well as aggregation between the β-amyloid peptide and QAS of α-synuclein.

The ability of the compounds of the present invention to bind to the QA peptide in aqueous solution was studied. Binding ability correlates with peak intensity of the peptide complex

- 100 012429 compound observed in the mass spectrum obtained by electrospray mass spectrometry (electrospray ionization). To prepare all aqueous solutions, distilled deionized water obtained using the millipore system is used. To determine the pH, a Vesktap F36 pH meter is used, equipped with Sotshpd combined half-micro pH electrode.

NAC (M.w. 3260.6 Da) (20 μM) was first analyzed at pH 7.40 and ordinary sodium clusters were obtained at +2, +3 and +4 with t / ζ 1335.5, 1116.7 and 843.4, respectively. Determine the optimal voltage of the cone, equal to 20 V.

Mass spectrometric study.

The analysis by mass spectrometry is carried out on an Aa1et8 2O 4000 mass spectrometer equipped with a program that controls the sampling of Aa1ega 2975. For the data processing and analysis, the McKyph 4.0 program (formerly McKyph 3.5) is used. The test compound is mixed with non-aggregated peptides in aqueous media (6.6% E1OH) in a 5: 1 ratio (20 μM NAC: 100 μM test compound or 40 μM NAC: 200 μM test compound). The pH of the mixture was adjusted to 7.4 (± 0.2) by adding 0.1% No. 1OH (3-5 μl). A solution of NAC peptide (20 or 40 μM) is also periodically prepared and used as a control solution. Spectra are obtained by introducing solutions into the electrospray source by direct infusion (infusion) using a syringe pump at a flow rate of 25 μl / min and scanning from 100 to 2100 Da in positive mode. The scan time is 0.9 s per run (scan) with a delay between scans of 0.1 s, and the analysis time of each sample is 5 minutes. All mass spectra are the sum of 300 (runs) scans. The temperature of desolvation and the source is 70 ° C, and the voltage of the cone and capillaries is maintained at 20 V and 3.2 kV, respectively.

For each test compound, the total peak area for the complex associated NAC compound divided by the total peak area is determined. The results are shown below in table. thirteen.

Table 13

NAC peptide binding data

Structure

Binding Strength

ΝαΟ _:( 8αΐΐ2 (€ ΤΡ) 2ίΉ ₂ 8Ο ₃ Ν3 - NaO ₃ 8OCH ₂ CH ₂ CH ₂ O8OsIa - EUN ₂ CH ₂ CH ₂ O8O ₃ N - H ₂ MSN ₂ CH ₂ CH ₂ O8O ₃ Ka +++ Н ₂ КСН ₂ СН ₂ 80зН + ^η · ' _Ν · ^ -χ ^ · 30 ₁ η +++ +++ H ₂ And, - '3O ₃ N + n he +++ n AND

+++ Strong; when the total binding is 120% and higher; ++ Moderate; when the total binding is 120-70%;

+ Weak; when the total binding is 70-30%;

- Missing; when the total binding is 30-0%.

- 101 012429

The present invention also relates to new compounds and their synthesis. Therefore, the following examples are presented below to illustrate the preparation of some of these compounds.

Synthesis of Compounds of the Invention

Preparation of 3-isopropylamino-1-propanesulfonic acid (compound CO)

V

Isopropylamine (2.5 ml, 29 mmol) was added to a solution of 1,3-propanesulfone (3.05 g, 25 mmol) in a mixture of methylene chloride / ether (40 ml, 1: 1). The mixture was boiled for 3 hours. It was cooled to room temperature and hexane (10 ml) was added. The precipitate was filtered off, washed with ether (10 ml) and dried in vacuo. The compound of SP is obtained in the form of a fine white powder (yield 2.98 g, 65.6%).

T. pl. 240-43 ° C.

^! H NMR (500 MHz, Ό ₂ Θ) δ 1.06 (d, 1 = 6.3 Hz, 6H), 1.86 (qt, 1 = 7.6 Hz, 2H), 2.76 (t, 1 = 7.6 Hz, 2H), 3.14 (t, 1 = 7.8 Hz, 2H); 3.13-3.21 (m, 1 = 6.6 Hz, 1H).

¹³ C NMR (125 MHz, Ό ₂ Θ) δ 18.2, 21.5, 25.8, 43.4, 47.9, 50.8.

Preparation of 3-cyclopropylamino-1-propanesulfonic acid (compound O)

To a solution of 1,3-propanesulfone (6.9 g, 55.3 mmol) in THF (60 ml) cyclopropylamine (3.7 ml, 52 mmol) is added. The mixture is heated in an oil bath at 42 ° C for 2 hours. Stirring is difficult and part of the solid forms a crust on the surface of the stirred mixture. The mixture is boiled for 1 h, cooled to room temperature. The precipitate was filtered off, dried in a vacuum oven for 2 hours at 60 ° C (4.95 g). Recrystallized from methanol / water (35 ml / 5 ml, v / v). The mixture was cooled in the refrigerator, filtered, washed with methanol (15 ml), air dried for 15 minutes and then in a vacuum oven at 60 ° C overnight. Compound O was obtained in the form of long thin white needles (yield 3.74 d, 40%).

T. pl. 234-236 ° C.

^! H NMR (500 MHz, Ό ₂ Θ) δ 0.62-0.71 (m, 4H), 1.92 (qt, 1 = 7.6 Hz, 2H), 2.51-2.55 (m, 1 = 3.7 Hz, 1H), 2.78 (d, 1 = 7.3 Hz, 2H), 3.09 (t, 1 = 7.8 Hz, 2H).

¹³ C NMR (125 MHz, Ό ₂ Θ) δ 3.0, 21.2. 30.0.46.8.47.9.

Fourier NK (KBg) ν 3051, 1570, 1465, 1039.

Preparation of 3-cyclopentylamino-1-propanesulfonic acid (compound C1)

Cyclopentylamine (3.95 ml, 40 mmol) is added to a solution of 1,3-propanesulfone (5.5 g, 45 mmol) in THF (80 ml). The mixture is boiled in an oil bath for 4 hours. Stirring is difficult, so a little acetone and ethanol are added to continue mixing. The mixture was cooled to room temperature. The precipitate was filtered off, dried in a vacuum oven for 1 h at 60 ° С (5.47 g). Dissolve while boiling in a mixture of methanol / water (35 ml / 2.5 ml, vol./about.). The mixture was slowly cooled to room temperature overnight, and then in the refrigerator. The product is filtered off, washed with methanol (15 ml), dried in air for 15 minutes and then in a vacuum oven at 60 ° C overnight. The product, compound C1, was obtained as long, thin white needles (4.79 g). A second portion is obtained from the combined filtrates after filtering the crude product and filtering after the first recrystallization (mother liquor) (0.84 g). In both portions the product is pure, the portions are combined, the total yield of 5.63 g, 68%.

T. pl. 280-82 ° C.

^! H NMR (500 MHz, Ό ₂ Θ) δ 1.34-1.43 (m, 4H), 1.46-1.54 (m, 2H), 1.82-1.90 (m, 4H), 2.76 (7, 1 = 7.6 Hz, 2H), 2.95 (t, 1 = 7.8 Hz, 2H), 3.35 (qt, 1 = 7.2 Hz, 1H).

¹³ C NMR (125 MHz, Ό ₂ Θ) δ 21.5, 23.6, 29.3, 45.1, 47.9, 59.5.

Fourier IR (KBr) ν 3558, 3501, 2972, 1647, 1587, 1466.

Obtaining 3-cycloheptylamino-1-propanesulfonic acid (compound SC)

To a solution of 1,3-propanesulfone (4.1 g, 33 mmol) in THF (65 ml) was added cycloheptylamine (3.9 ml, 30 mmol). The mixture is boiled in a mantle for 5 hours. The mixture is cooled to room temperature, the precipitate is filtered off, dried in a vacuum oven for 1 hour at 60 ° C (6.21 g). Dissolve in methanol / water (30 ml / 3 ml, v / v). The mixture was slowly cooled to room temperature overnight, and then in an ice bath. The product is filtered off, washed with methanol, air dried for 15 minutes and then in a vacuum oven at 60 ° C. Compound SC is obtained as small white flakes

- 102 012429 eV (yield 5.08 g, 72%).

T. pl. 341-43 ° C.

Ή NMR (500 MHz, 1) ₂ O) δ 1.21-1.42 (m, 8H), 1.45-1.51 (m, 2H), 1.79-1.89 (m, 4H), 2.7b (7, 1 = 7.3 Hz, 2H ), 2.9b (t, 1 = 7.8 Hz, 2H), 3.35 (m, 1 = 4.b Hz, 1H).

¹³ C NMR (125 MHz, 1) ₂ O) δ 21.b, 23.3, 27.3, 30.5, 43.b, 48.0, 59.b.

Fourier IR (KBr) ν 2924, 1b15, 14b4, 1243.

Preparation of 3-benzyloxycarbonylamino-2-hydroxy-1-propanesulfonic acid (compound AC)

3-amino-2-hydroxy-1-propanesulfonic acid (15.51 g, 100 mmol) was dissolved in water (150 ml) by adding 1 equiv. Naon (4.08 g). A solution of CB2-O8is (27.4 g, 110 mmol) in MeCSA (300 ml) was added. Stirred for 4 hours at room temperature, the solvent was evaporated in vacuo. The crude product (one weight equivalent of water) is suspended in acetone (400 ml) and boiled for 20 minutes. The mixture was cooled to room temperature and the precipitate was filtered off, washed with acetone and dried overnight, and then in a vacuum oven at 40 ° C. Compound AS was obtained as a white fine solid (28.85 g, 87.b mmol, 88%). Spectra ¹ H and ¹³ C NMR correspond to the structure.

Obtaining the sodium salt of 4-benzoyloxycarbonylamino-1-butanesulfonic acid (compound ΑΏ)

The sodium salt of 4-amino-1-butanesulfonic acid (0.51b g, 2.95 mmol) is dissolved in water to a final concentration of 0.5 M (light yellow solution). A solution of CB2-O8is in MeCS (2 M, 1.55 ml, 3.1 mmol, 1.05 equiv.) Was added. Reagent drops out. A mixture of 1,4-dioxane and ethanol was added until almost all of the precipitate had dissolved. After 3.75 hours, the solvent was evaporated in vacuo. The residue was dried in vacuo on Saturday and Sunday. Then they are suspended in acetone and boiled for 30 minutes. Cooled to room temperature and filtered off, washed with acetone and dried in vacuo overnight. Compound ΑΏ was obtained in the form of a finely divided white solid (0.7 × 10 g, 2.32 mmol, 78%). The ¹ H NMR spectrum is consistent with structure.

Obtaining the sodium salt of 3-benzoyloxycarbonylamino-1-propanesulfonic acid (compound AE)

The sodium salt of 3-amino-1-propanesulfonic acid (1.09 g, b.7b mmol) is dissolved in water to a final concentration of 0.5 M. A solution of CB2-O8is in MeCSA (2 M, 3.55 ml, 7.1 mmol, 1.05 equiv.) Is added. Reagent drops out. A mixture of 1,4-dioxane and ethanol was added until almost all of the precipitate had dissolved. After 3.75 hours, the solvent was evaporated in vacuo. The residue was dried in vacuo on Saturday and Sunday. Then they are suspended in acetone and boiled for 30 minutes. Cooled to room temperature and filtered off, washed with acetone and dried in vacuo overnight. Compound AE was obtained in the form of a finely divided white solid (1.58 g, 5.0b mmol, 75%). The ¹ H NMR spectrum is consistent with structure. Purity 90% (10 mol.% Homotaurin).

Obtaining isobutyl ether ^ - (N-Boc) -Be - ^ - Bb-homotaurin

- 103 012429

Component 1: b- (No. Boc) Rye-b-Rye

A solution of (Boc) ₂ O (800) is added to a cooled (0 ° C) solution of di-Li-Rye-Rye (1 g, 3.20 mmol) in 1,4-dioxane (6 ml) and 1 N No.OH (3.3 ml) mg, 3.5 mmol) in 1,4-dioxane (5 ml). The mixture was stirred at 0-5 ° C for 2 hours. A new portion of (Boc) 2O (100 mg) was added and the mixture was stirred for another 60 minutes at 0-5 ° C, and then for 30 minutes at room temperature. Then the mixture is evaporated to dryness. Dissolve the residue in a mixture of water / E! OAc and add 2Ν HCl to adjust the pH to 2. The aqueous layer is extracted 3 times with E! OAc. The combined organic extracts were dried with brine and the solvent was evaporated. A portion of the solid that does not dissolve in the E! OAc / CHC1 ₃ mixture is filtered. The desired Ε- (ΝBoc) -P11e-L-P11e 1 was obtained as a white foam (yield 913.7 mg, 2.215 mmol, 71%).

Component 2: 3-amino-1-propanesulfonic acid isobutyl ester o P

OH 5, K = Na C ₃ NBM ₃ No. Oz5 187.14

+ №N3

1) RS%, H = C1

2) LviON, 2,6-£ пе пе, ^{= =} f-Vi

3) H ₂ . Ρά / S, LVION

0τΗ ₁₇ ΝΟ ₃ 3

195.27

Stage 1. Sodium salt of 3-azido-1-propanesulfonic acid (5).

To a mixture of sodium azide (3.22 g, 49.1 mmol) in a water / acetone solvent (70 ml, 20 to 50), a solution of 1,3-propanesultone 4 (6.12 g, 49.1 mmol) in acetone (30 ml) is added. The clear solution was stirred at room temperature. The reaction ends in 1 hour. The solvent is evaporated in vacuo. The solid residue was washed with hot ether (50 ml) and then with ether at room temperature (150 ml). Dry in a vacuum oven at 40 ° C. overnight. Title compound 5 was obtained as a white solid (yield 8.69 g, 46.4 mmol, 95%).

Stage 2. 3-Azido-1-propanesulfonyl chloride.

The sodium salt of 3-azido-1-propanesulfonic acid 5 (1.87 g, 10.0 mmol) was suspended in dry benzene (20 ml) and PC15 (2.3 g, 10.5 mmol) was added to the suspension. The mixture was stirred at room temperature for 30 minutes, then heated for 1 hour under gentle boiling. Benzene and P (O) C13 are evaporated in vacuo. Benzene was added to the crude mixture and the solvent was again distilled off in vacuo. The residue was dried in vacuo. The dried residue was dissolved in methylene chloride (anhydrous, 15 ml) and cooled to -10 ° C in an ice / acetone bath.

Stage 3. 3-Azido-1-propanesulfonic acid.

To a cooled solution of sulfonyl chloride, a solution of isobutanol (1.00 ml, 10.8 mmol) and 2,6-lutidine (1.3 ml, 11.2 mmol) in methylene chloride (10 ml) is slowly added. The mixture was stirred at -10 ° C for 5 minutes, then at room temperature for 2 hours. Water was added to the reaction mixture (to terminate the reaction) and then methylene chloride to extract the product. The organic layer was washed once with water, a saturated aqueous NaHC- ₃ solution, brine, and then dried with magnesium sulfate. The solvent was evaporated in a weak vacuum, and the residue was dried in vacuo. The remaining 2,6-lutidine hydrochloride is removed by washing the residue with ether. The resulting oil (1.78 g) was transferred to a flash chromatography column (silica gel, E! OAc in a mixture of hexanes from 15 to 20%), and the desired ester was obtained in the form of an oil (790 mg, 35%).

Stage 4. Isobutyl ester of 3-amino-1-propanesulfonic acid.

To a suspension of Pd / C (10%, 200 mg) in isobutanol (4 ml) was saturated with H ₂ in N ₂ atmosphere through the hollow needle is introduced a solution of 3-isobutyl-azidopropansulfonata (1.13 g, 5.11 mmol). Then the mixture was stirred in an atmosphere of H ₂ (40 RK1, 275.79 kPa) at room temperature overnight. The precipitate is filtered off. The filtrate was evaporated to dryness. The residue was dried in vacuo. The title compound 2, isobutyl ether of homotaurin, was obtained as a brown oil (808.7 mg, 81%).

The reaction of component 1 with component 2.

To a cooled (0-5 ° C) solution of S-Boc-L-Rye-L-Rye 1 (913.7, 2.215 mmol) and homobaurin isobutyl ether 2 (423 mg, 2.21 mmol) in methylene chloride (anhydrous, 30 ml) NOVT (340 mg, 2.215 mmol). After 5 minutes, a solution of 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide metopatoluene sulfonate (982 mg, 2.215 mmol) in methylene chloride (10 ml) was added dropwise. The solution was stirred overnight at room temperature. Methylene chloride is added to the mixture.

- 104 012429 (50 ml) and the organic layer was washed successively with 1 N NaH8O ₄ , a saturated aqueous NaHCO3 solution and brine, and dried with sodium sulfate. The solvent was evaporated in vacuo. TLC shows the presence of three substances. Since impurities are less soluble in methanol, re-treatment with methanol, followed by filtration, removes most of the impurities. Column chromatography on silica gel (2% MeOH in CHC1 ₃ ) gives tripeptide 3 as an amber glassy solid (156.1 mg, 12%).

Obtaining isobutyl ester of L-Rye-L-Rye-homotaurin.

Concentrated HCl (0.7 mmol) was added to a cooled (0 ° С) solution of isobutyl ether N-Ooc - ^ - Hye - ^ - Hye-homotaurin (202 mg, 0.343 mmol) in methanol. The mixture was stirred at room temperature for 2 hours and then left in the refrigerator overnight. The solvent was evaporated in vacuo, the solid residue was dried in vacuo to give isobutyl ester of L-Rye-L-Rye-homotaurin as a white solid (171.8 mg, 95%).

Obtaining L-Rye-Lye-homotaurin (compound X).

To a solution of L-Rye-homotaurin (273 mg, 1.0 mmol) in 1Ν No. 1OH (1.05 ml), water (3 ml) and ethanol (4 ml), a solution of BOC-L-phenylalanine-G-hydroxysuccinimido ester (400 mg, 1.1 mmol) was added. in a mixture of ethanol (6 ml) and 1,4-dioxane (4 ml). The mixture was stirred at room temperature overnight. The solvent was distilled off in vacuo and the solid residue (601.9 mg) was suspended in a mixture of acetone (8 ml) and isopropanol (0.2 ml) and stirred overnight at room temperature. The mixture is boiled for 30 minutes and then cooled to room temperature. The white precipitate was filtered off, washed with ether, and then dried in a vacuum oven for 45 minutes. The resulting solid (423.1 mg) was dissolved in water / tert-butanol (7: 3, 5 ml) and treated with Atbé1e [K-120 p1ik (washed, dry weight 15 g) at room temperature for 2 minutes. The resin is filtered off and washed 3 times with a mixture of solvents of water and tert-butanol (10 ml). Concentrated HC1 (4 ml) was added. The solvents were distilled off in vacuo, and the resulting solid residue was dried in vacuo. The compound is purified by recrystallization from a mixture of THF and MeOH solvents. The resulting solid was heated in boiling methanol (about 3 ml) until the yellow color disappeared. The solid is dried in vacuo. Compound X was obtained as a white solid (84.4 mg, 20%).

¹ H and ¹³ C NMR spectra correspond to the structure.

Obtaining ethyl ether No. (3-aminopropan-1-sulfonyl) phenylalanine (compound CI)

To a chilled (-10 ° C) solution of ethyl b-phenylalanine ethyl ester (10 mmol, 2.3 g) and 4 methylmorpholine (20 mmol, 2.2 ml) in methylene chloride (30 ml), 3-chloropropane-1-sulfonyl chloride (10 mmol, 1.21) was added dropwise. ml). The mixture was stirred for 30 minutes at −10 ° C. and for 2 hours at room temperature. Methylene chloride (40 ml) was added and washed twice with water, once with brine, dried with sodium sulfate. Evaporation of the solvent in vacuo afforded almost pure 3-chloropropylsulfonamide as a yellow oil in quantitative yield. ¹ H and ¹³ C NMR spectra correspond to the structure.

A mixture of 3-chloropropylsulfonamide (10 ml), sodium azide (20 mmol) and a catalytic amount of HMM in DMF (40 ml) was heated at 60 ° C for 24 hours. Ethyl acetate was added to the mixture, washed three times with water and once with brine, dried with sulfate sodium. After evaporation, azide in vie is obtained.

105 012429 de brown oil (3.0489 g, 8.96 mmol, 90%). 'H and ¹³ C NMR spectra correspond to the structure.

Azide (2.70 g, 7.94 mmol) was stirred in an atmosphere of H ₂ (40 RA, 275.79 kPa) with 10% GB / C (348 mg) in ethanol (16 ml) at room temperature overnight. Filter the mixture through celite. TΜδC1 / ΕίOH was added to the filtrate in order to obtain a product salt-crystalline hydrochloride. The solvent was evaporated to give a viscous residue (2.2 g, 6.27 mmol, 79%), which could not be crystallized under any conditions. The crude hydrochloride is dissolved in methylene chloride and washed once with saturated aqueous sodium bicarbonate. The organic layer was separated and dried with sodium sulfate. The solvent was evaporated in vacuo. The residue was dissolved in methanol and treated with activated carbon. It is filtered through celite and the filtrate is evaporated to dryness. The residue was dried in vacuo to give a yellow-brown oil (1.3969 g, 56% based on azide).

¹ H and ¹³ C NMR spectra corresponded to the structure of compound Cb.

Obtaining ethyl ester N-Boc - ^ - Ρye- (3-aminopropane-1-sulfonyl) - ^ - Ρye (compound Υ)

To a cooled (0 ° C) solution of 3-aminopropane-1-sulfonyl - ^ - Ρye-ОΕί (2.66 mmol, 839 mg) in methylene chloride (10 ml), a solution of N-tert-ΒОС '- ^ - Ρ11е Ν-hydroxysuccinimido ester is added (280 mmol, 1.01 g) in methylene chloride (12 ml). The mixture was stirred at room temperature overnight. Methylene chloride was added and washed with 2Ν HC1, saturated aqueous solution No. 1 HCO3 and brine.

The organic layer was dried with magnesium sulfate and the solvent was removed in vacuo. The residue was applied to a column for flash chromatography over silica gel (2% in CHC1 ₃ ΜeON). A portion of the pure desired substance (600 mg) is isolated. The remaining product is mixed with 40% succinimide. A little 3-aminopropanol (70 μl) was added to the mixture dissolved in methylene chloride (8 ml) and cooled to 0 ° C. The mixture was stirred for 1 h at room temperature. Methylene chloride was added and washed with 2Ν HCl, saturated aqueous NaHCO3 solution and brine. The organic layer was dried with magnesium sulfate and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica gel (2% in CHC1 ₃ ΜeON). Another portion of the pure desired substance (432.4 mg) was isolated along with the adduct of succinimide and 3-aminopropanol (220.6 mg, 0.684 mmol). Compound Υ was obtained as a white crystalline foam (1030 mg, 1.83 mmol, 65%).

¹ H and ¹³ C NMR spectra correspond to the structure.

Obtaining ethyl ester ^ -Ρye- (3-aminopropane-1-sulfonyl) - ^ - Ρйе (compound Ζ)

To a cooled (0 ° C) solution of N-Boc - ^ - Ρye- (3-aminopropane-1-sulfonyl) - ^ - Ρye ethyl ether (197 mg, 0.350 mmol) in ethanol (8 ml) was added concentrated НС1 (0.8 ml) ) The mixture was cooled in an ice / water bath and stirred for 45 minutes and then for 3 hours at room temperature. During the weekend (Sat, Sun) the mixture is stored in the freezer (-20 ° C). The solvent was distilled off in vacuo. The ethanol residue is removed by three co-evaporation in vacuo with chloroform. The residue was dried in vacuo to give crystals not a pure white color (175.3 mg) in quantitative yield.

¹ H and ¹³ C NMR spectra correspond to the structure of compound Ζ.

Obtaining the sodium salt of ^ - (N-Boc) -Ρye- (3-aminopropane-1-sulfonyl) - ^ - Ρye (compound AA)

To a solution of ethyl ether ^ - (N-Boc) -Ρye- (3-aminopropane-1-sulfonyl) - ^ - Ρye (110 mg,

0.197 mmol) in methanol (2 ml) add one equivalent of 1Ν No. OH (202 μl). The mixture was stirred at room temperature overnight. A white suspension forms. Add GeOH (1 ml), water (1 ml) and 1Ν No. JUN (10 μl). The mixture was stirred in a warm water bath for about 2 hours. Methanol was distilled off in vacuo. The wet residue was lyophilized to give compound AA as a white powder in quantitative yield (110.2 g).

¹ H and ¹³ C NMR spectra correspond to the structure.

- 106 012429

Preparation of L-Rye - (3-aminopropane-1-sulfonyl) -L-Rye methyl ester (compound AB)

Hydrolysis is carried out by the usual method using OH / MeOH. The product is purified by recrystallization from EJAc and a mixture of hexanes.

E-Pye- (3-aminopropane-1-sulfonyl) -E-PEE-OH (203 mg, 0.382 mmol) was dissolved in methanol (4 ml) and the solution was cooled to 0 ° C. Concentrated HCl (0.35 ml) was added and the mixture was stirred for 2 hours at 0 ° C and for 2.5 hours at room temperature. Volatiles are distilled off in vacuo. The aqueous residue was lyophilized to give the product as a white solid (171.4 mg). The NMR and MOH spectra show that the product is a mixture of free acid and methyl ester. The mass spectrum also shows a strong association of the peptide. The peak of the dimer in the mass spectrum is the main one. The solid was dissolved in methanol and incubated with HCl at room temperature overnight. The solvent was evaporated and the residue was dried in vacuo. The product was obtained as a white foamy solid (180.4 mg, 97%).

¹ H and ¹³ C NMR spectra correspond to the structure of compound AB.

Preparation of 4-iodo-Y- (3-sulfopropyl) -E-phenylalanamide (compound CO)

Thionyl chloride (8.2 ml, 112.5 mmol) was added to chilled (ice / water bath) MeOH (60 ml). The ice bath was set aside and 4-iodo-L-phenylalanine (6.55 g, 22.4 mmol) was added to the mixture. The solution was boiled for 2 hours. The solvent was distilled off in vacuo. The solid residue was dissolved in MeOH (40 ml) and the solution was poured into Eb (300 ml). The precipitate was filtered off, washed with EO (2x50 ml) and dried in vacuum.

The solid compound (1.96 g, 5.8 mmol) is dissolved in a minimum amount of water. Раство / OH aqueous solution (28-30%, 15 ml) was added to the solution. The reaction mixture was stirred at room temperature for Saturday and Sunday. The solvent was distilled off in vacuo and EyAc (15 ml) was added. The mixture is boiled. The hot solution is filtered. The filtrate was cooled to room temperature and left in the refrigerator. The precipitate formed is filtered off, washed with ЕУАс, 4iodophenylalaninamide is obtained.

Amide (1.3 g, 4.4 mmol) was dissolved in 15 ml of 2-butanone with a few drops of DMF and 1,3-propanesultone (560 mg, 4.9 mmol) was added. The reaction mixture is boiled for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x20 ml) and dried in vacuo. The dry residue was suspended in MeOH (25 ml) with a small amount of water (1 ml). The suspension is boiled. The precipitate is filtered off hot. Washed with hot MeOH (2x10 ml). Compound CO was obtained as a white solid (320 g).

Preparation of 3 - [4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] -1-propanesulfonic acid (compound E)

To 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (2.58 g, 14.5 mmol) was added 1Ν OH (20 ml). The aqueous mixture was extracted with CH ₂ Cl ₂ (20 ml). The organic layer was separated and dried with MgSO ₄ . The solvents are evaporated in vacuo.

To a solution of 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine (1.96 g, 13.7 mmol) in acetone (30 ml) was added 1,3-propanesultone (1.74 g, 14.5 mmol). The mixture is boiled with stirring overnight. Only a small amount of the substance falls out. The resulting suspension with stirring is cooled to room temperature, the amount of precipitate increases. The suspension is heated with the addition of a small amount of MeOH until the precipitate is completely dissolved. The resulting solution was boiled with stirring for several minutes and cooled to room temperature. The precipitate was filtered off, washed with MeOH and dried in vacuo. Thus, compound E, 1.33 g (32%), was isolated.

Preparation of 3- [4- (4-bromophenyl) -4-hydroxypiperidin-1-yl] -1-propanesulfonic acid (compound C)

To a solution of 4- (4-bromophenyl) -4-piperidinol (2.51 g, 9.8 mmol) in MeOH (25 ml) was added 1,3propanesulton (1.28 g, 10.7 mmol). The mixture is stirred while boiling for 2 hours. Drops out slightly

- 107 012429 th substance. The resulting suspension was cooled to room temperature with stirring, and a 50% solution of MeOH in acetone was added to precipitate the maximum amount of compound. The precipitate was filtered off, washed with a 50% solution of MeOH in acetone (2x25 ml) and dried in vacuo. Thus, compound C, 2.11 g (57%), was isolated.

Preparation of 3- [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl] -1-propanesulfonic acid (compound H) but

To a solution of 4- (4-chlorophenyl) -4-piperidinol (2.5 g, 11.8 mmol) in acetone (25 ml) was added 1,3propanesultone (1.56 g, 13.0 mmol). The mixture was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with acetone (2x20 ml) and dried in vacuo. Thus, compound H, 2.83 g (72%), was isolated.

Preparation of 3- (4-acetyl-4-phenylpiperidin-1-yl) -1-propanesulfonic acid (compound I)

1Ν NaOH (20 ml) was added to 4-acetyl-4-phenylpiperidine hydrochloride (3.32 g, 12.5 mmol). The aqueous mixture was extracted with CH ₂ Cl ₂ (20 ml). The organic layer was separated and dried No. ₂ 8O ₄ , filtered and the solvent was evaporated in vacuo.

To a solution of 4-acetylphenylpiperidine (1.83 g, 9.0 mmol) in acetone (22 ml), 1.3propanesultone (1.20 g, 10.0 mmol) was added. The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x20 ml) and dried in vacuo. Thus, compound I, 2.65 g (90%) was isolated.

Preparation of 3- [4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] -1-propanesulfonic acid (compound 1)

To 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (2.52 g, 10.5 mmol) was added 1ΝOH (10 ml) and the aqueous mixture was extracted with CH ₂ Cl ₂ (20 ml). The organic layer was separated and dried No. 8O ₄ and filtered. The solvents are evaporated in vacuo.

To a solution of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine (2.07 g, 10.7 mmol) in acetone (25 ml) was added 1,3-propansultone (1.41 g, 11.8 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x20 ml) and dried in vacuo. The product is suspended in a 50% solution of MeOH in acetone (75 ml). The suspension is boiled with stirring for 5 minutes, 25 ml of cold acetone are added. The precipitate was filtered off and washed with acetone (2x25 ml). Thus, compound 1, 1.48 g (44%) was isolated.

Preparation of 3- (4-phenylpiperazin-1-yl) -1-propanesulfonic acid (compound K)

To a solution of 1-phenylpiperazine (2.0 g, 1.9 ml, 12.3 mmol) in acetone (20 ml) was added 1,3 propansultone (1.53 g, 12.9 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Thus, compound K, 3.04 g (87%) was isolated.

Preparation of 3- [4- (4-chlorophenyl) piperazin-1-yl] -1-propanesulfonic acid (compound b)

C1

To dihydrochloride of 1- (4-chlorophenyl) piperazine (2.5 g, 9.3 mmol) was added 1Ν NJ (40 ml); and the aqueous mixture was extracted with CH ₂ Cl ₂ (40 ml). The organic layer was separated and dried No. 8O ₄ and filtered. The solvents are evaporated in vacuo.

To a solution of 1- (4-chlorophenyl) piperazine (1.62 g, 8.2 mmol) in acetone (20 ml) was added 1,3 propansultone (1.06 g, 8.6 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Compound L, 2.11 g (81%) was thus isolated.

Preparation of 3- [4- (2-fluorophenyl) piperazin-1-yl] -1-propanesulfonic acid (compound M)

- 108 012429

To a solution of 1- (2-fluorophenyl) piperazine (2.5 g, 2.2 ml, 13.9 mmol) in acetone (25 ml) was added 1,3propanesulton (1.73 g, 14.6 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Thus, compound M, 3.56 g (85%), is isolated.

Preparation of 3- [4- (4-nitrophenyl) piperazin-1-yl] -1-propanesulfonic acid (compound Ν)

To a solution of 1- (4-nitrophenyl) piperazine (2.58 g, 12.1 mmol) in acetone (25 ml) was added 1,3 propansultone (1.06 g, 8.6 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Thus, compound Ν, 2.85 g (71%) was isolated.

Preparation of 3- [4- (4-fluorophenyl) piperazin-1-yl] -1-propanesulfonic acid (compound P)

To a solution of 1- (4-fluorophenyl) piperazine (2.0 g, 11.1 mmol) in acetone (20 ml) was added 1,3 propansultone (1.46 g, 11.7 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Thus, compound P, 2.62 g (78%), was isolated.

Preparation of 3- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) propanoic acid (compound O)

4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.5 g, 7.8 mmol) was suspended in 16 ml of CH ₂ Cl ₂ . Triethylamine (2.1 ml, 15.3 mmol) was added to this suspension, followed by 3-bromopropionate (1.0 ml, 9.2 mmol). The reaction mixture was stirred at room temperature for 4 hours and then boiled for 2 hours. Washed with water, 1Ν HCl (2x20 ml), 1Ν No. 1OH (2x20 ml) and brine. The organic layer was separated, dried No. ₂ 8 O ₄ , filtered. The solvent was evaporated in vacuo.

2Ν No. 1OH (15 ml) was added to the crude product. The mixture is boiled with stirring for 1 hour. It is washed with CH ₂ Cl ₂ (3x20 ml) and neutralized with concentrated HCl. The aqueous solution was evaporated to dryness in vacuo to give a solid residue. Sodium chloride is removed from the residue as follows (the procedure is repeated three times): the residue is dissolved in a minimum amount of water, acetone is added to the aqueous solution, the precipitate formed is filtered off and the filtrate is evaporated to dryness in vacuo. Compound O (159.4 mg) was thus isolated.

Obtaining 3-dibenzylamino-1-propanesulfonic acid (compound Αν)

To a solution of dibenzylamine (9.8 ml, 50.8 mmol) in toluene (50 ml) was added 1,3-propansultone (6.50 g, 53.3 mmol). The mixture is stirred while boiling for 3 hours. A sticky mass (paste) forms at the bottom of the flask. Cool to room temperature. The upper layer is decanted, and the paste (mass) is partially dissolved by heating in ΕΐΌΑο. The mixture was poured into 10% Ε! OΑc / hexanes (200 ml). Heated and paste (mass) is distributed on the walls of the conical flask. The solvent is removed. The process is repeated twice. MeOH (75 ml) was added. The mixture is heated until a white precipitate appears. The precipitate was filtered off, washed with cold MeOH and dried in vacuo to give compound Αν, 7.03 7 (43%).

Preparation of 3- (4-cyano-4-phenylpiperidin-1-yl) -1-propanesulfonic acid (compound E)

To 4-cyano-4-phenylpiperidine hydrochloride (2.0 g, 9.0 mmol) was added 1Ν OH (20 ml) and the aqueous mixture was extracted with CH ₂ Cl ₂ (20 ml). The organic layer was separated, dried Md8O ₄ and filtered. The solvent was evaporated in vacuo.

To a suspension of piperidine (1.43 g, 7.7 mmol) in acetone (20 ml), 1,3-propanesultone (1.02 g, 8.5 mmol) was added. The mixture is boiled with stirring for 2 hours. The resulting suspension is cooled to room temperature. The precipitate was filtered off, washed with acetone and dried in vacuo. The product was recrystallized from MeOH (with traces of water) to give compound E, 800 mg (34%).

- 109 012429

Preparation of 3- (4-phenyl-1,2,3,6-tetratidropyridin-1-yl) butanoic acid hydrochloride (compound K)

To 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (2.01 g, 10.2 mmol), 1Ν No. 1OH (20 ml) was added and the aqueous mixture was extracted with CH ₂ Cl ₂ (20 ml). The organic layer was separated and dried with MgSO ₄ , filtered and the solvent was evaporated in vacuo.

The resulting 4-phenyl-1,2,3,6-tetrahydropyridine (1.55 g, 9.7 mmol) was dissolved in 20 ml of 2-butanone. Potassium carbonate (2.02 g, 14.6 mmol) was added to this solution. The mixture was stirred for 30 minutes at room temperature; ethyl 4-bromobutyrate (1.46 ml, 10.1 mmol) was added. The reaction mixture is boiled with stirring for 5 hours. After cooling to room temperature, the precipitated inorganic salts are filtered off. The solvent was evaporated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (20 ml). The organic layer was washed with water (2x30 ml), 2Ν HC1 (2x30 ml) and brine. The organic layer was dried No. ₂ 8O ₄ , filtered, evaporated and dried in vacuo. Obtain 1.55 g (58%) of the desired ester.

The ester (5.7 mmol) was dissolved in 6Ν HCl (40 ml). The reaction mixture was stirred at room temperature for 5 hours and, while boiling for 1 hour, cooled to room temperature. The reaction mixture was extracted with CH ₂ Cl ₂ (3x30 ml). The aqueous layer was evaporated in vacuo. The residue was dissolved in water (20 ml); the aqueous solution was evaporated to dryness in vacuo. The resulting product was further dried in vacuo to give compound K, 973 mg (61%).

Preparation of 3-piperonylamino-1-propanesulfonic acid (compound ΆV)

To a solution of piperonylamine (2.5 ml, 19.8 mmol) in acetone (30 ml), 1,3-propanesultone (2.52 g, 20.8 mmol) was added. The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. The product was suspended in 90% acetone / MeOH (75 ml). The suspension is stirred at boiling for 30 s, the precipitate is filtered off and dried in vacuo. Thus, compound Άν, 2.56 g (45%) is isolated.

Preparation of 3- (3,4,5-trimethoxybenzyl) amino-1-propanesulfonic acid (compound AC)

To a solution of 3,4,5-trimethoxybenzylamine (2.2 ml, 12.7 mmol) in 2-butanone (20 ml) was added 1,3-propanesultone (1.66 g, 13.3 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. The product was suspended in 90% acetone / MeOH (75 ml). The suspension is stirred at boiling for 30 s, the precipitate is filtered off and dried in vacuo, compound AC, 2.61 g (64%) is isolated.

Preparation of 3- (2,3-Dimethoxybenzyl) amino-1-propanesulfonic acid (compound A2)

To a solution of 2,3-dimethoxybenzylamine (2.2 ml, 15.0 mmol) in 2-butanone (20 ml), 1,3propanesultone (1.97 g, 15.8 mmol) was added. The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. The crude product is suspended in 90% acetone / MeOH (75 ml). The suspension was stirred at boiling for 30 s, the precipitate was filtered off and dried in vacuo, compound A2, 1.95 g (45%) was isolated.

Preparation of 3- (No. benzhydrylcarbamyl) amino-1-propanesulfonic acid (compound AE)

3-amino-1-propanesulfonic acid (1.0 g, 7.2 mmol) was dissolved in 3Ν NaOH (370 mg, 9.4 mmol in 3 ml of water). The solution was cooled to 0 ° C, diphenylmethyl isocyanate (1.4 ml, 7.2 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 8 hours (room temperature), and 3Ν No. 1OH (3 ml) was added. The reaction mixture was stirred for 18 hours. PH

- 110 012429 mixture was adjusted to 3 by adding 5Ν HCl. The solvent was evaporated in vacuo. 25 ml of E! OH are added and the mixture is stirred at the boil for 30 s. The hot mixture is filtered. The filtrate was evaporated to dryness. This procedure is repeated twice more. The final product was dried in vacuo to give compound AP, 837 mg (34%).

Preparation of 3- (3,5-dimethoxybenzyl) amino-1-propanesulfonic acid (compound BΆ)

To a solution of 3,5-dimethoxybenzylamine (2.5 g, 15.0 mmol) in 2-butanone (22 ml) was added 1,3propanesulton (1.95 g, 15.8 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Thus, compound ΕΆ, 2.89 g (67%) was isolated.

Preparation of 3- (2,4-Dimethoxybenzyl) amino-1-propanesulfonic acid (Compound BB)

1Ν NaOH (20 ml) was added to 2,4-dimethoxybenzylamine hydrochloride (2.51 g, 12.3 mmol) and the aqueous mixture was extracted with CH ₂ Cl ₂ (20 ml). The organic layer was separated and dried with MgSO ₄ and filtered. The solvent was evaporated in vacuo to give the amine (in the form of a free base).

To a solution of 2,4-dimethoxybenzylamine (1.71 g, 10.3 mmol) in 2-butanone (15 ml), 1.3propanesultone (1.31 g, 10.7 mmol) is added. The mixture is boiled with stirring for 2.5 hours. It is cooled to room temperature. The supernatant is decanted; the paste is washed with acetone (2x30 ml) and dissolved in MeOH with heating. The addition of acetone to the methanol solution causes precipitation. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo; Compound BB, 1.14 g (38%), is obtained.

Obtaining the sodium salt of 3- (phenylacetamido) -1-propanesulfonic acid (compound AC) n

3-Άmino-1-propanesulfonic acid (1.0 g, 7.2 mmol) was dissolved in 3Ν NaOH (7.2 ml). The solution was cooled to 0 ° C, phenylacetyl chloride (1.4 ml, 10.8 mmol) was added. The reaction mixture was brought to room temperature, stirred for 22 hours. The solvent was evaporated in vacuo. The residue was suspended in 50% E! OH / Ά acetone. The mixture is stirred at the boil for 30 s. The precipitate was filtered off and dried in vacuo. The product was recrystallized from 95% E! OH / H ₂ O and dried in vacuo. Thus, compound AC, 880 mg (44%) was isolated.

Obtaining the sodium salt of 3- (Y-benzylcarbamyl) amino-1-propanesulfonic acid (compound Ά4)

3-M-1-propanesulfonic acid (1.06 g, 7.7 mmol) was dissolved in 1.5 N NaOH (5.3 ml). Benzyl isocyanate (927 μl, 7.7 mmol) was added to this solution. The reaction mixture was heated at 70 ° C for 30 minutes, and then one equivalent of benzyl isocyanate (927 μl, 7.7 mmol) was added. The reaction mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure. The residue was suspended in hot acetone. The precipitate was filtered off, washed with hot acetone and dried in vacuo; give compound ΆΚ 2.07 g (92%).

Obtaining the sodium salt of 3- (N-n-dodecylcarbamyl) amino-1-propanesulfonic acid (compound A1)

3-M-1-propanesulfonic acid (1.06 g, 7.7 mmol) was dissolved in 1.5 N NaOH (5.3 ml). To this solution, n-dodecyl isocyanate (1.7 ml, 7.7 mmol) was added. The reaction mixture was heated at 70 ° C for 30 minutes, and then one equivalent of n-dodecyl isocyanate (1.7 ml, 7.7 mmol) was added. The reaction mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure. The residue was suspended in hot acetone. The precipitate was filtered off, washed with hot acetone and dried in vacuo; Compound A1, 2.47 g (86%), is obtained.

- 111 012429

Obtaining the sodium salt of 3- (Y-1-adamantylcarbamyl) amino-1-propanesulfonic acid (compound ΑΚ)

3-amino-1-propanesulfonic acid (1.0 bg, 7.7 mmol) was dissolved in 1.5 N NaOH (5.3 ml). To this solution was added 1-adamantyl isocyanate (1.3 bg, 7.7 mmol) in hot Ε! OΑs (5 ml). The reaction mixture is heated at 70 ° C for 30 minutes, and then one equivalent of 1 adamantyl isocyanate (1.37 g, 7.7 mmol) in hot Ε! OΑs (5 ml) is added. The reaction mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure. The residue was suspended in hot acetone. The precipitate was filtered off, washed with hot acetone and dried in vacuo. The product was recrystallized from E! OH to give compound ΑΚ, 519.4 mg (20%).

Obtaining the sodium salt of 3- [2- (4-isobutylphenyl) propanoyl] amino-1-propanesulfonic acid (compound ΑΣ)

Thionyl chloride (1.b ml, 21.1. Mmol) is added to ibuprofen (1.02 g, 4.9 mmol). The reaction mixture was boiled for 4 hours. The solvent was evaporated, the residue was dried in vacuo, and the corresponding acid chloride was obtained.

3-amino-1-propanesulfonic acid (308 mg, 2.2 mmol) was dissolved in 1.5 N NaOH (3 ml). The acid chloride obtained above (500.8 mg, 4.4 mmol) is added dropwise to this solution. The reaction mixture was heated at 70 ° C. overnight. The solvent was evaporated under reduced pressure. The residue is suspended in acetone.

The suspension is boiled with stirring for 30 s. The precipitate is filtered off. The filtrate was evaporated to dryness in vacuo. The residue was separated by flash chromatography (80% CH2C12 / MeOH). Compound ΑΣ, 237 mg (14%) was obtained.

Obtaining the sodium salt of 3 - [(benzylamino) thiocarbonyl] amino-1-propanesulfonic acid (compound No.)

3-amino-1-propanesulfonic acid (1.07 g, 7.7 mmol) was dissolved in 1.5 N NO. (5.3 ml). Benzyl isothiocyanate (1.02 ml, 7.7 mmol) is added to this solution. The reaction mixture was stirred at 70 ° C for 0.5 h; add the second equivalent of benzylisothiocyanate (1.02 ml, 7.7 mmol) in hot E! OΑc (5 ml). The reaction mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure. The residue was suspended in hot acetone. The precipitate was filtered off, washed with hot acetone and dried in vacuo. The product was recrystallized from MeOH (with traces of water) to give a compound of Α ^ 1.00 g (42%).

Preparation of 3- (3,4-dihydrobenzyl) amino-1-propanesulfonic acid (compound 8)

To a solution of 3,4-dimethoxybenzylamine (2.2 ml, 15.0 mmol) in 2-butanone (20 ml) was added 1,3propanesulton (1.98 g, 15.8 mmol). The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. The crude product is suspended in 75% acetone / MeOH (75 ml). The suspension is stirred while boiling with, the precipitate is filtered off, washed with acetone (2x25 ml) and dried in vacuum. The solid product (1.94 g, b.7 mmol) was dissolved in hydrobromic acid (48%, 27 ml). The solution was stirred at 100 ° C. for 4 hours. The solvent was distilled off in vacuo. The residue was dissolved in water (20 ml). The aqueous solution was washed with CH ₂ Cl ₂ (3x20 ml) and evaporated in vacuo. The dry residue was suspended in hot MeOH (75 ml). The suspension is boiled for 30 s; the precipitate is filtered off, washed with 50% MeOH / acetone and dried in vacuum. Compound 8, 1.22 g (70%) was isolated.

Obtaining an internal salt of 4- (3-phenylpropyl) -1-sulfopropylpyridinium hydroxide (compound

FROM)

- 112 012429

To a solution of 4- (3-phenylpropyl) pyridine (14.5 ml, 76 mmol) in 2-butanone (150 ml), 1.3propanesultone (10.0 g, 83.6 mmol) was added. The mixture is boiled with stirring for 1.5 hours. After cooling the mixture to room temperature, a precipitate precipitates, the precipitate is filtered off, washed with acetone. The precipitate was recrystallized from EUN (traces Εΐ ₂ Ο) to give compound C, 15.8 g (66%).

Preparation of 4- (3-phenylpropyl) -1-sulfopropyl-1,2,3,6-tetrahydropyridine (compound Ό)

4- (3-Phenylpropyl) -1-sulfopropylpyridine (10.7 g, 33.5 mmol) was dissolved in 60 ml of HeΟH. The solution was cooled to 0 ° C and sodium borohydride (2.55 g, 67.0 mmol) was added portionwise. The reaction mixture was stirred for 0.5 h at room temperature. Water (10 ml) and concentrated HCl (5 ml) were successively added to the mixture. Inorganic substances are filtered off. The filtrate was evaporated to dryness under reduced pressure and dried in vacuo. The resulting viscous residue was dissolved in HeΟH (60 ml). The solution was mixed with an ion-exchange resin AmBlHe ^ -120 (8.3 g) for 15 minutes. The resin is filtered off and washed with HeΟN. The filtrate and washings were evaporated to dryness in vacuo. The residue was recrystallized from water to give compound Ό (8.05 g, 75%) as white crystals.

Obtaining 3-ethylamino-1-propanesulfonic acid (compound SU)

N

In a three-necked 2 L flask (equipped with a reflux condenser), tetrahydrofuran (THF, 800 ml) was placed and cooled to 5 ° C in an ice bath. An aqueous solution of ethylamine (70 wt.% Solution in water, 85 ml, 1.07 mol) is added to cold THF, and then a cold solution of 1,3-propanesultone (25.08 g, 201 mmol) in THF (100 ml) is added over 24 minutes. . The mixture was stirred for 1 h, cooling with an ice bath. The cooling bath was set aside and the mixture was stirred at room temperature overnight. Then, while boiling for 1 h, ethylamine is distilled off. The hot mixture is biphasic. Upon cooling, crystals appear at the bottom of the flask. Ether (400 ml) was added and the mixture was cooled to -20 ° C. The liquid is decanted. Methanol (about 120 ml) was added to the residue. The mixture is boiled until the precipitate is completely dissolved. Upon cooling the solution to room temperature, a precipitate forms. The mixture is cooled in an ice bath; the precipitate is filtered off, washed with cold methanol and dried in vacuo (20.66 g, NMR spectrum shows the pure compound). Recrystallized from methanol (100 ml). After cooling in an ice bath, the precipitate is filtered off, washed with cold methanol and dried in a vacuum oven at 40 ° C. Compound CV was obtained in the form of white long needles (19.12 g,

57%).

¹ H and ¹³ C NMR spectra correspond to the structure.

Obtaining 3- (1-adamantyl) amino-1-propanesulfonic acid (compound B \ U)

To 1-adamantylamine hydrochloride (80 g, 0.426 mol), IAOH (10%, 400 ml) in water was added. Extracted with methylene chloride (1x400 ml, 2x100 ml). The combined organic extracts were washed with brine (50 ml) and dried with sodium sulfate (10 g). The solvent was distilled off in vacuo. The resulting white waxy mass was evaporated with acetonitrile (50 ml). The wet solid residue is suspended in acetonitrile (200 ml). The suspended mixture is added dropwise over a period of 20 minutes to a solution of 1,3-propanesultone (53 g, 0.426 mol) in acetonitrile (300 ml) and THF (200 ml). Then the suspension is cooled to 13 ° C. The precipitate was filtered off with suction, washed with acetonitrile (2x100 ml) and ether (1x100 ml), dried in air for 30 minutes, and then dried in vacuum at 60 ° C overnight (1 portion, 104.17 g). A second portion was obtained from the filtrate and dried in vacuo in the same manner (2 portions, 3.39 g). Both portions have the same NMR spectrum. Two batches are combined for subsequent purification.

The solid is suspended in methanol (720 ml) and the mixture is boiled. Dropwise, over 45 minutes, water (490 ml) is added at the boil. After complete dissolution of the precipitate, the solution is boiled for another 30 minutes. The mixture is left on the mantle off for slow cooling. After 90 minutes, the temperature reaches 40 ° C. The mantle is replaced with a thermostatic water bath. The mixture was cooled to 5 ° C and stirred overnight at this temperature. The white flocculent precipitate was filtered off, washed with cold (0 ° С) methanol (2x125 ml), dried in air for 60 min, and then overnight in a vacuum oven at 60 ° С. Compound Βν was obtained as a white flocculent substance (white plates, 88.48 g, first portion yield 76%).

¹ H and ¹³ C NMR spectra correspond to the structure.

The second portion (8.62 g) of compound Βν is obtained from the mother liquor.

- 113 012429 ¹ H NMR spectrum identical to the spectrum of the first portion. The total yield of hydrochloride is 83%. Preparation of 3- (2-norbornyl) amino-1-propanesulfonic acid (compound ΒΥ)

To a solution of 2-aminonorbornane (7.3 g, 65.7 mmol) in 2-butanone (50 ml) was added dropwise a solution of 1,3-propansultone (8.1 g, 65.7 mmol) in 2-butanone (10 ml). The mixture was stirred at 60 ° C for 1 h. The suspension was cooled to room temperature. The precipitate was filtered off and washed with ethanol (2x20 ml). The crude product was recrystallized from 95% UNN to give compound ΒΥ in the form of white crystals (yield 8.2 g, 53%).

Preparation of 3- (2-adamantyl) amino-1-propanesulfonic acid (compound ΒΖ)

No. 2OH in water was added to 2-aminoadamantane hydrochloride (2x5 g). Extracted with methylene chloride. The organic extracts are dried with magnesium sulfate. The solvent was distilled off in vacuo. The solid white residue was dried for 30 minutes at room temperature in vacuo. To a solution of free amine (7.98 g, 52 mmol) in THF (70 ml, total) is added a solution of 1,3-propansultone (7.4 g, 60 mol). The mixture is boiled for 4 hours, cooled in an ice bath. The precipitate was filtered off, dried in air for 15 minutes and further dried in vacuo (11.2 g). Recrystallized from methanol / water (60 ml / 35 ml). The filtrate is cooled in the refrigerator, the precipitate is filtered off, dried in a vacuum oven at 60 ° C overnight. A white crystalline precipitate is obtained (small plates, yield 10.45 g, 74%).

¹ H and ¹³ C NMR spectra correspond to the structure of compound ΒΖ.

Preparation of 3- (3,4-dimethoxybenzyl) amino-1-propanesulfonic acid (compound 8)

To a solution of 3,4-dimethoxybenzylamine (2.2 ml, 15 mmol) in acetone (20 ml), 1.3propanesultone (1.97 g, 15.8 mmol) was added. The mixture was stirred at the boil for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. The crude product is suspended in 90% acetone / MeOH (75 ml). The suspension is boiled with stirring for 30 s, the precipitate is filtered off and dried in vacuo. Compound 8 (1.84 g, 43%) was isolated as a white solid.

¹ H NMR (1) .0, 500 MHz) δ ppm, 6.96 (m, 3H), 4.06 (s, 2H), 3.74 (s, 6H), 3.07 (t, 1H, 1 = 7.8 Hz), 2.86 (t, 1H, 1 = 7.8 Hz), 2.01 (m, 2H).

¹³ C NMR (1) 0, 125 MHz) δ ppm 149.23, 148.50, 123.63, 123.37, 55.90, 55.86, 50.96, 48.06, 45.62, 21.39.

E8-M8 290 (M + 1).

Preparation of 3- (2,2-diphenylethyl) amino-1-propanesulfonic acid (compound ET)

To a solution of 1,2-diphenylethylamine (2.49 ml, 12.7 mmol) in 2-butanone (15 ml), 1.3propanesultone (1.67 g, 13.3 mmol) was added. The mixture is refluxed with stirring for 2 hours. Cool to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo. Compound ET was obtained: 3.02 g (74%).

¹ H NMR (DMSO- ₆ , 500 MHz) δ ppm 8.58 (s (broad), 1H), 7.34 (m, 8H), 7.23 (t, 2H, 1 = 7.3 Hz), 4.32 (t, 1H, 1 = 7.8 Hz), 3.68 (d, 2H, 1 = 7.3 Hz), 3.08 (t, 2H, 1 = 6.1 Hz), 2.57 (t, 2H, 1 = 7.3 Hz), 1.92 (m, 2H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 141.63, 129.46, 128.47. 127.76, 50.85, 49.91, 48.53, 22.07.

E8-M8 318 (M-1).

Preparation of 4- (tert-butylamino) -2-butanesulfonic acid (compound E8)

- 114 012429

To a solution of tert-butylamine (1.0 ml, 9.5 mmol) in tetrahydrofuran (15 ml) was added 2,4butanesultone (1.33 g, 10.0 mmol). The mixture is boiled with stirring for 2 hours. The mixture is cooled to room temperature. The precipitate was filtered off, washed with THF (2x20 ml) and dried in vacuo to give compound Εδ.

^! H NMR (DMSO-b ₆ , 500 MHz) δ ppm 2.97 (t, 2H, 1 = 6.6 Hz), 2.62 (m, 1H), 1.95 (m, 0.5H), 1.750 (m, 0.5H), 1.22 (s, 9H), 1.12 (d, 3H, 1 = 6.8 Hz).

¹³ C NMR (DMSO, 125 MHz) δ ppm 56.17.53.15, 29.87, 25.87, 17.05.

Εδ-Μδ 207 (M-1).

Preparation of 4- (tert-butylamino) -1-butanesulfonic acid (compound EB)

To a solution of tert-butylamine (1.0 ml, 9.5 mmol) in tetrahydrofuran (4 ml) was added 1,4 butansultone (1.36 g, 10.0 mmol). The mixture is boiled with stirring for 2 hours. The mixture is cooled to room temperature. The precipitate was filtered off, washed with acetone (2x20 ml) and dried in vacuo: compound EB 690 mg, (34%) was obtained.

^! H NMR (I ₂ O, 500 MHz) δ ppm 2.92 (t, 2H, 1 = 7.1 Hz), 2.82 (t, 2H, 1 = 7.1 Hz), 1.68 (m, 4H), 1.22 (s, 9H).

¹³ C NMR (I ₂ O, 125 MHz) δ ppm 57.07, 50.30, 40.95, 25.28, 24.96, 21.62.

Εδ-Μδ 210 (Μ-1).

Preparation of 3- (3-pentyl) amino-1-propanesulfonic acid (compound ΌΌ)

To a solution of 1-ethylpropylamine (10.0 ml, 115 mmol) in tetrahydrofuran (80 ml), 1.3propanesultone (13.7 g, 110.0 mmol) in 20 ml of THF was added. The mixture is boiled with stirring for 2 hours. The mixture is cooled to room temperature. The precipitate was filtered off, washed with acetone (2x50 ml) and dried in vacuo: compound получают (18.1 g, 80%) was obtained.

^! H NMR (I ₂ O, 500 MHz) δ ppm 3.08 (t, 2H, 1 = 7.3 Hz), 3.01 (m, 1H), 2.87 (t, 2H, 1 = 7.3 Hz), 2.00 (m, 2H), 1.59 (m, 4H), 0.82 (t, 6H) , 1 = 7.3 Hz).

¹³ C NMR (I ₂ O, 125 MHz) δ ppm 60.87, 48.14, 43.68, 21.81. 21.60, 8.25.

Εδ-Μδ 208 (M-1).

Preparation of 3- (tert-amyl) amino-1-propanesulfonic acid (compound IP)

To a solution of tert-amylamine (2.0 g, 23.3 mmol) in tetrahydrofuran (15 ml), 1.3propanesultone (2.76 g, 22.2 mmol) was added. The mixture is boiled with stirring for 2 hours. The mixture is cooled to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in vacuo: an IS compound (3.3 g, 73%) was obtained.

^! H NMR (I ₂ O, 500 MHz) δ ppm 3.04 (t, 2H, 1 = 7.8 Hz), 2.89 (t, 2H, 1 = 7.8 Hz), 2.87 (t, 2H, 1 = 7.3 Hz), 1.97 (m, 2H), 1.55 (m, 2H), 1.18 (s, 6H), 0.82 (t, 6H, 1 = 7.3 Hz).

¹³ NMR (I ₂ O, 125 MHz) δ ppm 60.42, 48.17, 39.88, 30.81, 22.23, 21.98, 7.25.

Εδ-Μδ 208 (M-1).

Preparation of 3- (1,1-dimethyl-2-hydroxyethyl) amino-1-propanesulfonic acid (compound IN)

To a solution of 2-amino-2-methyl-1-propanol (2.0 g, 21.4 mmol) in tetrahydrofuran (15 ml) was added 1,3-propanesultone (2.66 g, 21.4 mmol). The mixture is boiled with stirring for 2 hours. The mixture is cooled to room temperature. The crude product is filtered off, washed with acetone (2x25 ml). Suspend in HOH (50 ml). The suspension is boiled with stirring for 5 minutes. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to obtain IN compound (2.5 g, 58%).

^! H NMR (I ₂ O, 500 MHz) δ ppm 3.48 (s, 2H), 3.04 (t, 2H, 1 = 7.8 Hz), 2.90 (t, 2H, 1 = 7.3 Hz), 2.00 (m, 2H),

1.18 (s, 6H).

¹³ C NMR (I ₂ O, 125 MHz) δ ppm 64.88, 60.27, 48.19, 40.10, 21.92, 20.02. Εδ-Μδ 210 (M-1).

- 115 012429

Preparation of 3- (1-carboxy-1-methylethylamino) -1-propanesulfonic acid (Compound Op

To a cooled (5 ° C) mixture of 2-aminoisobutyric acid (2.0 g, 19.4 mmol), No. 1OH (776 mg, 19.4 mmol) in 1,4-dioxane (10 ml) and water (4 ml) was added using a syringe pump (within 4 hours) a solution of 1,3-propanesultone (2.02 g, 16.2 mmol) in 1.4-dioxane (total 4 ml). The solution was stirred at this temperature for 2 hours, and then brought to room temperature. Stir under these conditions overnight. The solvent was evaporated in vacuo. The solid residue is recrystallized from 5% water / E! OH. The product is dissolved in water and the aqueous solution is passed through an ion exchange column (Όο \\ όχ 50 \ CX 8, 100 g, solvent water). The solvent was evaporated in vacuo. The product is lyophilized to give compound □ I (880 mg, 28%).

Ή NMR (P ₂ O, 500 MHz) δ ppm 3.00 (t, 2H, 1 = 7.6 Hz), 2.91 (t, 2H, 1 = 7.3 Hz), 2.01 (m, 2H), 1.34 (s, 6H).

¹³ C NMR (P ₂ O, 125 MHz) δ ppm 176.93, 63.89, 48.13, 42.04, 22.15, 21.86.

E8-M8 224 (M-1).

Preparation of 3 - [(1K, 28) -2-methylcyclohexyl] amino-1-propanesulfonic acid (compound Ό1)

To a solution of 2-methylcyclohexylamine (98% cis and trans isomers, 10.0 g, 88.3 mmol) in tetrahydrofuran (60 ml), a solution of 1,3-propanesultone (10.5 g, 84.1 mmol) in THF (20 ml) is slowly added. Stirred at the boil for 2 hours. Cool to room temperature. The precipitate is filtered off, washed with acetone (2x50 ml). The solid product is dissolved in a mixture of E! OH / water (200 ml); and the solution is treated with resin Ωο \\ όχ 50 \ CX 8 (15 g). The suspension is stirred at room temperature for 15 minutes. The resin is filtered off. The filtrate is evaporated on a rotary evaporator to half the original volume. The solid product slowly crystallizes. The product was filtered off, washed with acetone (2x50 ml) and dried in a vacuum oven (50 ° С) to give compound No. 1 (10.4 g, 53%).

Ή NMR (P ₂ O, 500 MHz) δ ppm 3.15 (m, 1H), 3.03 (m, 1H), 2.88 (t, 2H, 1 = 7.3 Hz), 2.76 (m, 1H), 1.98 (m, 3H), 1.68 (m, 2H), 1.51 (m , 2H), 1.18 (m, 3H), 1.01 (m, 1H), 0.92 (m, 3H).

¹³ C NMR (P ₂ O, 125 MHz) δ ppm 62.97, 48.16. 42.72, 34.77, 33.50, 27.57, 24.51, 24.23, 21.51, 17.80.

E8-M8 234 (M-1).

Preparation of 3- (2,3-dimethylcyclohexyl) amino-1-propanesulfonic acid (compound ΌΚ)

To a solution of 2,3-dimethylcyclohexylamine (10.0 g, 79.0 mmol) in tetrahydrofuran (60 ml), a solution of 1,3-propanesultone (9.3 g, 75.0 mmol) in THF (20 ml) is slowly added. The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with THF (50 ml) and acetone (50 ml). The solid product is dissolved in 25% E! OH / water (150 ml) and treated with resin Ωο \\ όχ 50 \ CX 8 (15 g). The suspension is stirred at room temperature for 5 minutes. The resin is filtered off. The filtrate was evaporated to dryness in vacuo; the solid residue is suspended in acetone (100 ml). The precipitate was filtered off and dried in vacuo to give compound ΌΚ (7.4 g, 43%).

Ή NMR (P ₂ O, 500 MHz) δ ppm 3.29 (m, 0.5H), 3.09 (m, 2H), 2.88 (t, 2H, 1 = 7.3 Hz), 2.80 (m, 0.5H), 1.99 (m, 3H), 1.40 (m, 7H), 0.81 (m, 6H).

¹³ C NMR (P ₂ O, 125 MHz) δ ppm 62.85, 61.56, 59.88, 58.22, 48.26, 48.15, 44.29, 43.84, 43.59, 42.65, 42.01, 41.03, 37.34, 36.12, 34.73, 34.45, 33.88, 33.64, 29.39, 28.00, 26.50, 24.25, 24.02, 23.64, 22.42, 21.55,

21.45, 21.35, 19.38, 19.13, 18.82, 18.40, 14.38, 13.39, 4.59.

E8-M8 248 (M-1).

Obtaining 3-neopentylamino-1-propanesulfonic acid (compound ΌΚ)

To a solution of neopentylamine (8.5 g, 98 mmol) in tetrahydrofuran (75 ml), a solution of 1,3-propanesultone (11.5 g, 93 mmol) in THF (20 ml) is slowly added. The solution was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x50 ml). The solid product is suspended in E! OH (150 ml). The suspension is boiled with stirring for 15 minutes. The precipitate is filtered off, washed with acetone (2x50 ml) and dried in vacuo, according to

- 116 012429 radiate compound E (13.3 g, 69%).

Ή NMR (E ₂ O, 500 MHz) δ ppm 3.09 (t, 2H, 1 = 7.3 Hz), 2.89 (t, 2H, 1 = 7.3 Hz), 2.78 (s, 2H), 2.04 (m, 2H), 0.901 (s, 9H).

¹³ C NMR (E ₂ O, 125 MHz) δ ppm 50.44, 48.31, 47.84, 29.91, 26.42, 21.06.

E8-M8 208 (M-1).

Preparation of 3-cumylamino-1-propanesulfonic acid (EM compound)

5O, N

To a solution of cumylamine (10.5 g, 78 mmol) in tetrahydrofuran (75 ml), a solution of 1,3-propanesultone (9.2 g, 74 mmol) in THF (20 ml) is slowly added. The solution was stirred at the boil for 4 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with THF (2x35 ml). The solid product is suspended in E! OH (80 ml). The suspension is boiled with stirring.

Compound EM (5.6 g, 30%).

Ή NMR (E ₂ O, 500 MHz) δ ppm 7.41 (m, 5H), 2.74 (s, 4H), 1.88 (m, 2H), 1.66 (s, 6H).

¹³ C NMR (E ₂ O, 125 MHz) δ ppm 138.36, 129.44, 129.41, 126.52, 61.56, 48.04, 41.21, 24.80, 21.81. E8-M8 256 (M-1).

Preparation of 3 - [(1K) -1- (4-methylphenyl) ethyl] amino-1-propanesulfonic acid (compound ΕΝ)

To a solution of (K) - (+) - 1- (4-methoxyphenyl) ethylamine (5.83 g, 38.6 mmol) in tetrahydrofuran (25 ml), 1,3-propanesultone (4.56 g, 36.8 mmol) was slowly added. The solution was stirred at the boil for 4 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with THF (25 ml) and acetone (25 ml). The solid product is suspended in E! OH (200 ml). The suspension is boiled with stirring for 15 minutes. The precipitate was filtered off, washed with cold E! OH (50 ml) and dried in a vacuum oven (50 ° C) to give compound ΕΝ (5.6 g, 56%).

Ή NMR (E ₂ O, 500 MHz) δ ppm 7.26 (d, 2H, 1 = 8.3 Hz), 6.90 (d, 2H, 1 = 8.3 Hz), 4.22 (m, 1H), 3.68 (s, 3H), 2.92 (m, 1H), 2.76 (m, 3H ), 1.90 (m, 2H), 1.49 (d, 3H, 1 = 6.8 Hz).

¹³ C NMR (E ₂ O, 125 MHz) δ ppm 159.87, 129.34, 128.18, 114.85, 57.99, 55.58, 48.05, 44.21, 21.45, 18.21. E8-M8 272 (M-1).

Preparation of 3 - [(1K) -1-indanamino] -1-propanesulfonic acid (EO compound)

Wed

To a solution of (K) - (-) - 1-aminoindane (1.0 g, 7.5 mmol) in tetrahydrofuran (10 ml), 1,3-propanesultone (890 mg, 7.1 mmol) is slowly added. Stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with THF (20 ml) and acetone (20 ml). The solid product is suspended in 80% acetone / E! OH (40 ml). The suspension is boiled with stirring for 30 s. The precipitate was filtered off, washed with acetone (2x20 ml) and dried in vacuo to give EO compound (1.1 g, 61%).

Ή NMR (E ₂ O, 500 MHz) δ ppm 7.41 (d, 1H, 1 = 7.3 Hz), 7.30 (m, 2H), 7.24 (m, 1H), 4.72 (m, 1H), 3.14 (t, 2H, 1 = 7.8 Hz), 3.02 (m, 1H ), 2.88 (m, 3H), 2.43 (m, 1H), 2.12 (m, 1H), 2.01 (m, 2H).

¹³ C NMR (E ₂ O, 125 MHz) δ ppm 145.38, 136.39, 130.31, 127.20, 125.72, 125.54, 62.98, 48.10, 43.93, 29.84, 28.62, 21.64. [α] _ο = -1.3 ° (c = 0.00515 in water).

E8-M8 254 (M-1).

Obtaining the sodium salt of 3- (No. tert-butylcarbamyl) amino-1-propanesulfonic acid (sodium salt of the compound ER)

3-amino-1-propanesulfonic acid (2.0 g, 14.3 mmol) was dissolved in 1.6 M No. OH (10 ml). Tert-butyl isocyanate (1.1 g, 14.3 mmol) was added to this solution. The reaction mixture was stirred at 70 ° C. for 1 h, and then another equivalent of tert-butyl isocyanate (1.1 g, 14.3 mmol) was added. The reaction mixture was stirred for 1 hour. The solvent was evaporated in vacuo. The rest of the sauce

- 117 012429 pendiruyut in E1OH (30 ml). The precipitate was filtered off, washed with E1OH (20 ml) and acetone (20 ml). The product was dried in vacuo to give the sodium salt of compound ER (2.1 g, 66%).

Ή NMR (1 + O. 500 MHz) δ ppm 3.03 (t, 2H, 1 = 6.6 Hz), 2.76 (t, 2H, 1 = 7.6 Hz), 1.72 (m, 2H), 1.12 (s, 9H).

¹³ C NMR (1 + O. 125 MHz) δ ppm 160.35, 50.26, 48.74, 38.31, 28.86, 25.24.

EZ-MZ 280 (M + No.).

Preparation of 3- (1,2-dimethyl-1-propyl) amino-1-propanesulfonic acid (compound ΌΟ)

To a solution of 1,2-dimethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 ml), a solution of 1,3-propanesultone (13.7 g, 110 mmol) in THF (20 ml) is slowly added. The solution was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with THF (50 ml) and E1OH (50 ml). The precipitate was dried in vacuo to give compound ΌΟ (17.5 g, 76%).

Ή NMR (1 + O. 500 MHz) δ ppm 3.07 (m, 3H), 2.88 (t. 2H, 1 = 7.3 Hz), 1.97 (m, 3H), 1.10 (d, 3H, 1 = 6.8 Hz), 0.85 (d, 3H, 1 = 6.8 Hz), 0.81 (d, 3H, 1 = 6.8 Hz).

¹³ C NMR (1 + O. 125 MHz) δ ppm 59.79, 48.19, 44.18, 29.72, 21.51, 18.44, 15.02, 10.71.

EZ-MZ 232 (M + No.).

Preparation of 3- (4-methylcyclohexyl) amino-1-propanesulfonic acid (compound ΌΚ)

To a solution of 4-methylcyclohexylamine (97% cis and trans isomers, 11.0 g, 97.4 mmol) in tetrahydrofuran (70 ml), a solution of 1,3-propanesultone (11.5 g, 92.8 mmol) in THF (20 ml) is slowly added. The solution was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with THF (50 ml) and acetone (50 ml). Suspended in E1OH. The suspension is stirred at room temperature for 5 minutes. The precipitate was filtered off, washed with E1OH (50 ml) and dried in a vacuum oven (50 ° C) to give compound ΌΚ (16.1 g, 75%).

Ή NMR (1 + O. 500 MHz) δ ppm 3.08 (m, 2.5H), 2.93 (m, 0.5H), 2.87 (m, 2H), 1.99 (m, 4H), 1.64 (m, 3H), 1.47 (m, 1H), 1.24 (m, 2H) 0.88 (m, 1H); 0.78 (m, 3H).

¹³ C NMR (1 + O. 125 MHz) δ ppm 57.35, 56.52, 48.16, 18.05, 43.73, 43.30, 32.45, 31.13, 28.92, 28.69, 27.77, 24.55, 21.65, 21.53, 21.20, 18.38.

EZ-MZ 236 (M + 1).

Preparation of 3- (2-methyl-1-butyl) amino-1-propanesulfonic acid (compound OZ)

To a solution of (+/-) - 2-methylbutylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 ml), a solution of 1,3-propanesultone (13.5 g, 109 mmol) in THF (20 ml) is slowly added. The solution was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x30 ml). Suspended in 95% acetone / E1OH. The suspension is stirred at room temperature for 5 minutes. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to obtain the OZ compound (17.6 g, 78%).

Ή NMR (1 + O. 500 MHz) δ ppm 3.07 (t, 2H, 1 = 7.8 Hz), 2.93 (m, 3H), 2.76 (m, 1H), 2.01 (m, 2H), 1.67 (m, 1H), 1.30 (m, 1H), 1.09 (m , 1H), 0.81 (d, 3H, 1 = 6.8 Hz), 0.77 (t, 3H, 1 = 6.8 Hz).

¹³ C NMR (1 + O. 125 MHz) δ ppm 53.48, 48.13, 46.92, 31.96, 26.38, 21.29, 16.11, 10.19.

EZ-MZ 210 (M + 1).

Preparation of 3-pivaloylamino-1-propanesulfonic acid (compound ΌΚ)

3-aminopropanesulfonic acid (2.0 g, 14.4 mmol) was dissolved in a solution of No. YOU (1.2 g, 30.2 mmol) in a mixture of 1,4-dioxane (5 ml) and water (15 ml). The mixture was cooled to 0 ° C. and a solution of pivaloyl chloride (2.8 ml, 21.6 mmol) in 1,4-dioxane (5 ml) was added dropwise. The reaction mixture was brought to room temperature and stirred for 4 hours at 65 ° C. The solvent was evaporated in vacuo. The solid residue is dissolved in water (30 ml) and Όο \\ όχ 50 \ νΧ8 resin is added. The suspension is stirred for 5 minutes and the resin is filtered. The filtrate was evaporated in vacuo. The residue was suspended in 20% E1OH / acetone. The mixture is stirred at the boil for 30 s. The precipitate was filtered off and dried in vacuo to give compound ΌΤ (1.3 g, 41%).

- 118 012429

Ίί NMR (ΙΜλ 500 MHz) δ ppm 3.16 (t 2H, 1 = 6.8 Hz), 2.75 (t, 2H, 1 = 7.8 Hz), 1.78 (m, 2H), 1.1 (s, 9H). ¹³ C NMR (ΙΜλ 125 MHz) δ ppm 182.75, 48.70, 38.57, 38.18, 26.65, 24.27.

Ε8-Χ18 222 (M-1).

Preparation of 3- (3,3,5-trimethylcyclohexyl) amino-1-propanesulfonic acid (compound ΕΌ)

To a solution of 3,3,5-trimethylcyclohexylamine (5.0 g, 35.4 mmol) in tetrahydrofuran (35 ml), a solution of 1,3-propanesultone (4.17 g, 33.7 mmol) in THF is slowly added. The solution was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x25 ml). Suspended in 90% acetone / E! OH (100 ml). The suspension is stirred at room temperature for 5 minutes. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to give compound ΕΌ (5.9 g, 67%).

'|| NMR Ш ₂ О, 500 MHz) δ ppm 3.20 (m, 1H), 3.08 (m, 2H), 2.87 (t, 2H, 1 = 6.8 Hz), 1.96 (m, 3H), 1.60 (m, 2H). 1.29 (m, 1H), 1.01 (m, 1H), 0.84 (s, 3H), 0.73 (m, 8H).

¹³ C NMR (ΙΜλ 125 MHz) δ ppm 54.98, 48.06, 46.51, 43.28, 40.96, 37.02, 32.07, 31.23, 26.68, 24.28, 21.67, 21.52.

Ε8-Χ18 262 (M-1).

Preparation of 3- (2-indanamino) -1-propanesulfonic acid (compound EE)

To a solution of 2-aminoindan (2.50 g, 18.8 mmol) in tetrahydrofuran (25 ml) is slowly added

1,3-propanesultone (2.24 g, 17.9 mmol). The solution was stirred at the boil for 2.5 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x25 ml). The crude product is suspended in 90% a ^ ton ^ OH (100 ml). The suspension is stirred at room temperature for 5 minutes. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to obtain EE compound (3.1 g, 67%).

'H NMR (DMSO, 500 MHz) δ ppm 7.25 (m, 2H), 7.20 (m, 2H), 4.00 (m, 1H), 3.30 (m, 2H), 3.13 (m 2H), 3.02 (m, 2H), 2.64 (m, 2H). 1.96 (m, 2H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 130.98, 127.80, 125.25, 57.70, 49.24, 45.87, 36.32, 22.66.

Ε8-Χ18 254 (M-1).

Preparation of 3- (4-biphenylamino) -1-propanesulfonic acid (compound ΕΕ)

To a solution of 4-aminobiphenyl (3.0 g, 17.8 mmol) in tetrahydrofuran (25 ml) is slowly added

1,3-propanesultone (2.11 g, 16.9 mmol). The solution was stirred at the boil for 3 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x25 ml). The crude product is dissolved in a hot solution of 80% MeOH / H ₂ O (120 ml). To this warm solution is added an ion-exchange resin Eo ^ ex 50kX8 (10 g). The hot suspension is stirred for 5 minutes and the resin is filtered. The filtrate was evaporated to dryness in vacuo. The solid residue was dried in a vacuum oven (50 ° C) to give compound ΕΕ (283 mg, 6%).

'H NMR (DMSO, 500 MHz) δ ppm 7.77 (d, 2H, 1 = 7.8 Hz), 7.66 (d, 2H, 1 = 7.8 Hz), 7.46 (m, 3H), 7.37 (m, 1H), 3.44 (m, 2H), 2.68 (m, 2H ), 1.98 (m, 2H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 139.74, 129.69, 128.74, 128.33, 127.31, 122.23, 49.70, 22.93.

Ε8-Χ18 290 (M-1).

Preparation of 3 - [(1B, 28) -2-hydroxy-1 - (methoxymethyl) -2-phenylethyl] amino-1-propanesulfonic acid (compound ΕΟ)

To a solution of (18.28) -2-amino-3-methoxy-1-phenyl-1-propanol (1.0 g, 5.5 mmol) in tetrahydrofuran (10 ml), 1,3-propanesultone (662 mg, 5.3 mmol) was slowly added. . The mixture was stirred at the boil for 2.5 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x25 ml). Suspended in 80% acetone JUNE. The suspension is stirred while boiling for 30 s. The precipitate is filtered off and dried in a vacuum oven (50 ° C) to give a compound.

- 119 012429

E6 (1.0 g, 63%).

Ή NMR (1CO. 500 MHz) δ ppm 7.32 (m, 5H), 4.77 (d, 1H, 1 = 9.8 Hz), 3.53 (m, 1H), 3.37 (m, 1), 3.26 (m, 1H), 3.17 (m, 6H), 2.91 (t , 2H, 1 = 7.3 Hz), 2.07 (m, 2H).

¹³ C NMR (1CO. 125 MHz) δ ppm 139.09, 129.33, 129.27, 127.11, 70.85, 66.29, 62.62, 58.76, 48.14, 44.24, 21.47. [α] _ο = + 42.6 ° (c = 0.00091 in water).

E8-M8 302 (M-1).

Preparation of 3 - [(1B, 2B, 3B, 58) -1,2,6,6-tetramethylbicyclo [3.1.1] hept-3-yl] amino-1-propanesulfonic acid (ЕН compound)

To a solution of (1B, 2B, 3B, 58) - (-) - isopinocampheylamine (2.0 g, 13.0 mmol) in tetrahydrofuran (20 ml), 1,3-propanesultone (1.56 g, 12.5 mmol) is slowly added. The mixture was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in a vacuum oven (50 ° C) to obtain the compound ЕН (2.7 g, 80%).

Ή NMR (DMSO, 500 MHz) δ ppm 3.32 (m, 2H), 3.09 (d, 2H), 2.67 (m, 2H), 2.30 (m, 2H), 1.96 (m, 4H), 1.75 (m, 2H), 1.18 (s, 3H), 1.11 (m, 4H), 0.90 (s, 3H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 55.97, 50.11, 47.55, 45.86, 41.15, 40.91, 38.94, 32.81, 31.61, 27.96,

23.85, 22.59, 21.21, [α] _ο = -17.2 ° (c = 0.00083 in water). E8-M8 274 (M-1).

Preparation of 3- (2-methoxy-1-methylethyl) amino-1-propanesulfonic acid (compound E1)

To a solution of 2-amino-1-methoxypropane (5.0 g, 17.8 mmol) in tetrahydrofuran (25 ml), 1,3-propanesultone (2.12 g, 17 mmol) was slowly added. The mixture was stirred at the boil for 4 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in a vacuum oven (50 ° С) to give compound Е1 (3.1 g, 86%).

Ή NMR (1CO. 500 MHz) δ ppm 3.53 (m, 1H), 3.41 (m, 2H), 3.27 (s, 3H), 3.11 (m, 2H), 2.89 (t, 2H, 1 = 7.3 Hz), 2.00 (m, 2H). 1.18 (d, 3H, 1 = 5.9 Hz).

¹³ C NMR (1CO. 125 MHz) δ ppm 71.73, 58.80, 53.79, 48.08, 43.55, 21.52, 12.79.

E8-M8 210 (M-1).

Preparation of 3 - [(1B) -2-benzyl-1-hydroxyethyl] amino-1-propanesulfonic acid (compound E1)

N

To a solution of (B) - (+) - 2-amino-3-phenyl-1-propanol (1.0 g, 6.6 mmol) in tetrahydrofuran (10 ml), 1,3-propanesultone (785 mg, 6.3 mmol) was slowly added. The mixture was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x25 ml). Suspended in 80% acetone / EUN (100 ml). The suspension is stirred while boiling for 30 s. The precipitate was filtered off, washed with acetone (2x25 ml) and dried in a vacuum oven (50 ° C) to give compound E1 (890 mg, 52%).

Ή NMR (DMSO, 500 MHz) δ ppm 8.58 (s (br), 1H), 7.26 (m, 5H), 5.30 (s), 1H), 3.53 (m, 1H), 3.31 (m, 2H), 3.14 (t, 2H), 2.98 ( m, 1H), 2.80 (m, 1H), 2.62 (t, 2H), 1.98 (m, 2H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 137.31, 130.00, 129.26, 127.49, 60.16, 57.78, 49.90, 45.34, 33.78,

22.49. [α] _ο = + 9.7 ° (c = 0.00118 in water).

E8-M8 272 (M-1).

Preparation of 3 - [(18) -2-benzyl-1-hydroxyethyl] amino-1-propanesulfonic acid (compound EC)

N

To a solution of (8) - (-) - 2-amino-3-phenyl-1-propanol (2.0 g, 13.2 mmol) in tetrahydrofuran (20 ml), 1,3-propanesultone (1.57 g, 12.6 mmol) was slowly added. The mixture was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off, washed with acetone (2x25 ml). Suspended in 80% acetone / JUN. The suspension is stirred while boiling for 30 s. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to give EC compound (1.9 g, 56%).

- 120 012429

Ή NMR (DMSO, 500 MHz) δ ppm 8.63 (s (broad), 1 H), 7.27 (m, 5H), 5.31 (s (broad), 1H), 3.53 (m, 1H), 3.25 (m, 2H), 3.15 (t, 2H), 2.98 (m, 1H), 2.80 (m, 1H), 2.61 (t, 2H), 1.99 (m, 2H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 137.31, 130.01, 129.27, 127.49, 60.18, 57.77, 49.88, 45.32, 33.78,

22.49. [α] _ο = -7.5 ° (c = 0.00118, H ₂ O).

E8-M8 272 (M-1).

Preparation of 3- (No. methyl-I-tert-butylamino) -1-propanesulfonic acid (compound ΞΝ)

To a solution of Ν-methyl-tert-butylamine (2.0 g, 22.9 mmol) in acetone (25 ml) was slowly added

1,3-propanesultone (2.72 g, 21.8 mmol). The mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2 25 ml). The crude product is suspended in 80% acetone / EUN. The suspension is stirred while boiling for 30 s. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to give the compound EN (2.9 g, 65%).

Ή NMR (DMSO, 500 MHz) δ ppm 9.40 (s (broad), 1H), 3.45 (m, 1H), 2.85 (m, 1H), 2.59 (m, 5H), 1.99 (m, 2H), 1.28 (s, 9H).

¹³ C NMR (DMSO, 125 MHz) δ ppm 63.23, 51.12, 49.73, 34.79, 25.50, 21.72.

E8-M8 208 (M-1).

Preparation of 3 - [(1K, 28) -2-hydroxyindan-1-amino] -1-propanesulfonic acid (EO compound)

To a solution of (1K, 28) -1-amino-2-indanol (2.37 g, 15.9 mmol) in tetrahydrofuran (25 ml), 1,3-propanesultone (1.89 g, 15.1 mmol) was slowly added. The mixture was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2 25 ml). The crude product is suspended in 80% acetone / ethanol (75 ml). The suspension is stirred while boiling for 30 s. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to give EO compound (2.7 g, 65%).

Ή NMR (O.-O, 500 MHz) δ ppm 7.36 (d, 1H, 1 = 7.4 Hz), 7.24 (m, 3H), 4.70 (q, 1H, 1 = 5.5 Hz), 4.53 (d, 1H, 1 = 5.4 Hz), 3.23 (t, 2H, 1 = 7.8 Hz), 3.10 (m, 1H), 2.89 (m, 3H), (m, 1H), 2.08 (m, 2H).

¹³ C NMR (O.-O, 125 MHz) δ ppm 141.60, 134.30, 130.53, 127.61, 126.10, 125.69, 70.42, 64.08, 48.25,

44.73, 38.33, 21.50. [α] _ο = + 3.0 ° (c = 0.0018, water).

E8-M8 272 (M + 1).

Preparation of 3 - [(18) -1- (hydroxymethyl) -2-methylpropyl] amino-1-propanesulfonic acid (compound EP)

sn _r he

To a solution of (8) - (-) - 2-amino-3-methyl-1-butanol (2.50 g, 24.2 mmol) in tetrahydrofuran (35 ml), 1,3-propanesultone (2.89 g, 23.0 mmol) was slowly added.

The mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2 25 ml). The crude product is suspended in 80% acetone / ethanol (75 ml). The suspension is stirred while boiling for 30 s. The precipitate was filtered off and dried in a vacuum oven (50 ° C) to give EP compound (2.9 g, 56%).

Ή NMR (O.-O, 500 MHz) δ ppm 3.78 (dd, 1H), 3.62 (dd, 1H), 3.13 (m, 2H), 2.90 (m, 1H), 2.88 (t, 3H),

1.90 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H).

¹³ C NMR (O.-O, 125 MHz) δ ppm 64.74, 57.24, 48.20, 44.44.26.98, 21.49, 18.53, 17.00. [α] _ο = + 4.1 ° (c = 0.0017, in water).

E8-M8 224 (M-1).

Preparation of 3 - [(18) -1-carbamoyl-2-methylpropyl] amino-1-propanesulfonic acid (compound

Yer)

A saturated solution of K ₂ CO ₃ (75 ml) was added to L-valinamide hydrochloride (2.50 g, 16.4 mmol). The mixture was extracted with EuAc (3x75 ml). The combined organic extracts dried No. ₂ 8O4. Solution

- 121 012429 was filtered and the filtrate was evaporated to dryness in vacuo and dried in vacuo.

To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 ml) is slowly added

1,3-propanesultone (1.61 g. 12.9 mmol). The mixture was stirred at the boil for 2 hours. The reaction mixture was cooled to room temperature. The precipitate is filtered off, washed with acetone (2x25 ml). The crude product is dissolved in water (60 ml) and the ion exchange resin Eo ^ ex MagaShop C (strong acid, 15 g) is added. The mixture is stirred for 15 minutes. The resin is filtered off. The filtrate was poured into E! OH (250 ml). At the end of the precipitation, the precipitate was filtered off and dried in vacuo to give compound Ep (1.6 g, 51%).

Ή NMR Yu ₂ O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H).

¹³ C NMR (1) .0, 125 MHz) δ 170.24, 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α] _ο = + 10.5 ° (c = 0.0027, in water).

E8-M8 237 (M-1).

Preparation of 3-isobutylamino-1-propanesulfonic acid (Compound CE)

Isobutylamine (2.4 ml, 24 mmol) is added to a solution of 1,3-propansultone (3.04 g, 24.5 mmol) in 2-butanone (20 ml). The mixture is boiled for 10 minutes, by which time the mixture turns into a clot. Cool to room temperature. Acetone is added and the clot (lump) is destroyed. The precipitate was filtered off and dried in vacuo (2.2 g). A white precipitate was suspended in ethanol (10 ml) and the mixture was brought to a boil. A significant amount of sediment is dissolved. Slowly add water until a clear pink solution forms. The solution is left overnight at room temperature. The flask was refrigerated for 2 hours. The precipitate was filtered off, washed with ethanol (5 ml), ether (10 ml) and dried in vacuo. The compound CE is obtained in the form of long, thin, white needles (yield 1.87 g, 40%). T. pl. 255-257 ° C.

Ή NMR (1) 0, 500 MHz) δ ppm 0.88 (d, 1 = 6.8 Hz, 6H), 1.85-1.93 (m, 1 = 6.8 Hz, 1H), 2.03 (kW, 1 = 7.6 Hz, 2H), 2.80 (d, 1 = 7.3 Hz, 2H), 2.90 (t, 1 = 7.3 Hz, 2H), 3.08 (t, 1 = 8.1 Hz, 2H).

¹³ C NMR (1) 0, 125 MHz) δ 19.2, 21.2, 25.8, 46.9, 48.1, 54.9. E8-M8 196 (M + 1).

Fourier IR (KBr) at _max 3566, 2973, 2021, 1719.

Preparation of 3-isoamylamino-1-propanesulfonic acid (Compound CH)

Isoamylamine (4 ml, 34.5 mmol) is added to a solution of 1,3-propansultone (4.7 g, 38 mmol) in 2 butanone (70 ml). The mixture is brought to a boil. After 30 minutes, the mixture becomes too viscous and difficult to mix. Acetone (15 ml) was added. Boiling is continued for another 4 hours. The suspension is cooled to room temperature. The precipitate was filtered off, washed with acetone (10 ml), then with ether (10 ml). Compound CH was obtained as a light bulk white solid (yield 4.48 g, 62%).

T. pl. 220 ° C (decomp.).

Ή NMR (1) 0, 500 MHz) δ ppm 0.65 (d, 1 = 6.3 Hz, 6H), 1.29 (q, 1 = 7.7 Hz, 2H), 1.35-1.42 (m, 1 = 6.6 Hz, 1H), 1.86 (qt, 1 = 7.6 Hz, 2H), 2.74 (t, 1 = 7.3 Hz, 2H), 2.81 (t, 1 = 8.1 Hz, 2H), 2.93 (t, 1 = 7.8 Hz, 2H).

¹³ C NMR (1) 0, 125 MHz) δ 21.3, 21.4, 25.2, 34.2, 46.1, 46.2, 47.9.

Preparation of 2- (tert-butyl) amino-1-ethanesulfonic acid (compound Όυ)

A solution of sodium salt of 2-bromoethanesulfonic acid (4.2 g, 20 mmol) in water (total 12 ml) is added to a solution of butylamine (10 ml, 94 mmol) heated to 42 ° C in a mixture of water (10 ml) and 1 over 6 hours 4-dioxane (10 ml). The mixture was stirred at 42 ° C. for 18 hours. Then the mixture was heated at 60 ° C. for 24 hours. 30% of the elimination product (vinyl sulfonic acid) was observed in the NMR spectrum. The mixture was evaporated to dryness and treated with ethanol at the boiling point. The first portion of the substance is collected (solid precipitate). The mother liquor is evaporated to dryness and the solid residue is again treated with ethanol at the boiling point, a second portion of the solid is collected. Both portions of the solid are dissolved in water and the resulting aqueous solution is passed sequentially through an ion exchange column Eo ^ ex 50 8 (100 g of resin). The fractions containing the title compound are combined and evaporated to dryness. The resulting solid residue was recrystallized from a mixture of ethanol (20 ml) and water (2 ml). The crystals are filtered off, dried in a vacuum oven (60 ° C) for 18 hours. Compound получаютυ is obtained in the form of white thin needles (yield 860 mg, 24%).

H NMR (500 MHz, O. O) δ ppm 1.16 (s, 9H), 3.02 (t, 1 = 6.8 Hz, 2H), 3.19 (t, 1 = 6.8 Hz; 2H).

- 122 012429 ¹³ C NMR (125 MHz, B ₂ O) δ 24.8, 37.3, 47.0, 57.8.

E8-M8 182 (M + 1).

Obtaining 2- (cyclohexanomethyl) amino-1-propanesulfonic acid (compound BU)

A mixture of cyclohexanomethylamine (11.12 ml, 0.085 mol) and 1,3-propanesultone (11.00 g, 0.090 mol) in acetonitrile (120 ml) is boiled for 2 hours. It is cooled to room temperature. The precipitate was filtered off, dried in air for 20 minutes (19 g). Suspend in methanol (100 ml) and the suspension is heated to boiling. Water (4 ml) is added dropwise at the boil until a clear solution forms. Then, with stirring, the mixture is cooled to 5 ° C. The precipitate is suctioned off, dried in air for 45 minutes and further dried in a vacuum oven (b0 ° C) for 3 days. The BU compound is obtained in the form of white flakes (yield 1b.23 g, 81%).

Ή NMR (500 MHz, B ₂ O) δ ppm 0.82 (br.sq., 1 = 11 Hz, 2H), 0.91-1.09 (m, 3H), 1.43-1.53 (m, bN), 1.93 (sq. , 1 = b.3 Hz, 2H), 2.80 (t, 1 = 7.3 Hz, 2H), 2.71 (t, 1 = 7.8 Hz, 2H).

¹³ C NMR (125 MHz, B ₂ O) δ 21.2, 25.0, 25.5, 29.9, 34.7, 4b.8, 48.1, 53.7.

E8-M8 23b (M + 1).

Preparation of 3- (1,1-diethylpropargyl) amino-1-propanesulfonic acid (BCH compound)

A mixture of 1,1-diethylpropargylamine (5 g, 45 mmol) and 1,3-propanesultone (b.05 g, 49.5 mmol) in THF (25 ml) is boiled for 5 hours. It is cooled to room temperature. The precipitate was filtered off, washed with diisopropyl ether (2x10 ml), then dried in a vacuum oven (7.1b g). Suspend in ethanol (30 ml) and the suspension is boiled for 1 h. Then the mixture is cooled to room temperature and the precipitate is suctioned off, dried in air for 5 min and additionally dried in a vacuum oven at b ° C overnight (5.8 g). The substance contains a significant amount of ethanol. It is additionally dried in a vacuum oven for 40 hours. The BChU compound is obtained in the form of a finely divided white solid (yield 5.bb g, 81%).

Ή NMR (500 MHz, B ₂ O) δ 0.92 (t, 1 = 7.b Hz, 2H), 1.71 (q, 1 = 7.3 Hz, 3H), 1.93 (q, 1 = 7.3 Hz, 2H ), 2.81 (t, 1 = 7.3 Hz, 2H), 2.94 (s, 1H), 3.13 (t, 1 = 7.b Hz, 2H).

¹³ C NMR (125 MHz, B ₂ O) δ 7.2, 21.b, 27.8, 41.4, 48.1, b.2.2, 78.b, 78.9.

E8-M8 234 (M + 1)

Preparation of 3- (1-ethynylcyclohexyl) amino-1-propanesulfonic acid (compound BX)

A mixture of 1-ethynylcyclohexylamine (bg, 48.7 mmol) and 1,3-propanesultone (b.55 g, 53.b mmol) in THF (35 ml) is boiled for 2 hours (viscous mass). Cool to room temperature. The precipitate was filtered off, washed with THF (3x5 ml), dried in air for 15 minutes (7.3 g). Suspend in ethanol (30 ml) and the suspension is boiled for 1 hour. Then the mixture is cooled to room temperature, the precipitate is suctioned off, washed with ethanol (2x5 ml), air dried for 10 minutes, then in a vacuum oven at b0 ° С overnight (batch) 1, 7.10 g). The combined mother liquors were stirred overnight at room temperature. A large amount of precipitate is formed. The precipitate was filtered off, washed with acetone (3x5 ml), dried in air for 30 minutes, and then suspended in ethanol (12 ml). The suspension is boiled for 1 hour. Then the mixture is cooled to room temperature, the precipitate is suctioned off, washed with ethanol (2x5 ml), air dried for 2 minutes, then in a vacuum oven at b ° C overnight (batch 2, 1.85 g). Compound BH is obtained in the form of a finely divided white substance (in only two batches of 8.95 g, yield 75%).

Ή NMR (500 MHz, B ₂ O) δ 0.95-1.05 (m, 1H), 1.38-1.54 (m, 5H), 1.b0-1.b4 (m, 2H), 1.94 (q, 1 = 7.8 Hz, 2H), 2.85 (t, 1 = 7.3 Hz, 2H), 3.01 (s, 1H), 3.22 (t, 1 = 7.8 Hz, 2H).

¹³ C NMR (125 MHz, B ₂ O) δ 21.8, 22.3, 24.2, 34.4, 40.9, 48.0, 59.2, 78.b, 79.3.

E8-M8 243.0 (M-1).

Obtaining 3- (2-hydroxy-2-phenyl) amino-1-propanesulfonic acid (compound BU)

A mixture of (±) -2-amino-1-phenylethanol (9.9 g, 72 mmol) and 1,3-propanesultone (9.3 g, 7b mmol) in acetone

- 123 012429 nitrile (70 ml) and ethanol (2 ml) are boiled for 1.5 hours (viscous mass). Cool to room temperature. The precipitate was filtered off, washed with acetonitrile (2x25 ml), dried in air for 20 minutes (21.3 g). Suspend in methanol (110 ml) and the suspension is boiled. Water (4 ml) was added dropwise until a clear solution appeared. Then the mixture was cooled to room temperature. The precipitate is suctioned off, dried in air for 30 minutes, then in a vacuum oven at 60 ° C for 40 hours (lot 1, 4.47 g). The combined mother liquors are left for 40 hours at -20 ° C. A second portion of the solid is filtered off, washed with acetone (2x15 ml), dried in air (1 h), then in a vacuum oven at 60 ° C for 24 hours. Compound ΌΥ is obtained in two portions (7.82 g in total, 42% yield) )

Ή NMR (500 MHz. B ₂ O) δ, 2.03-2.06 (m, 2H), 2.90 (t, 1 = 7.3 Hz, 2H), 3.16 (t, 1 = 7.3 Hz, 2H), 3.20-3.24 (m , 2H), 4.92-4.95 (m, 1H), 7.30-7.37 (m, 5H).

¹³ C NMR (125 MHz, B ₂ O) δ 21.3, 46.6, 78.1, 53.2, 69.0, 126.1, 129.0, 129.2, 139.6.

E8-M8 260 (M + 1).

Preparation of 3 - [(8) -1- (4-methoxyphenyl) ethyl] amino-1-propanesulfonic acid (compound ΌΖ)

A mixture of (8) - (-) - (4-methoxyphenyl) ethylamine (1.83 g, 12.1 mmol) and 1,3-propanesultone (1.6 g, 13 mmol) in acetonitrile (25 ml) is boiled for 2.5 hours.

The mixture was cooled to room temperature. The precipitate was filtered off, washed with acetonitrile (2x5 ml), dried in air for 15 minutes (3.07 g). Suspend in methanol (15 ml) and the suspension is boiled for 1 h. Then the mixture is cooled to room temperature. The precipitate was suctioned off, washed with ethanol (2x10 ml), dried in air for 15 minutes, then in a vacuum oven at 60 ° C for 18 hours. Compound ΌΖ was obtained as a white solid (2.95 g, 10.8 mmol, 89% yield) .

Ή NMR (500 MHz, B ₂ O) δ 1.52 (d, 1 = 6.8 Hz, 3H), 1.88-1.98 (m, 2H), 2.76-2.79 (m, 3H), 2.80-2.98 (m, 1H), 3.71 (s, 3H), 4.25 (q, 1 = 6.7 Hz, 2H), 6.93 (d, 1 = 8.3 Hz, 2H), 7.29 (d, 1 = 8.3 Hz, 2H).

¹³ C NMR (125 MHz, B ₂ O) δ 18.3, 21.5, 44.2, 48.1, 55.6, 58.0, 114.9, 128.2, 129.4, 159.9.

E8-M8 274. (M + 1). [α] _ο = -28.8 ° (c = 0.0038, in water).

Preparation of 3- (4-bromophenethyl) amino-1-propanesulfonic acid (compound EA)

A mixture of 4-bromophenethylamine (4 g, 20 mmol) and 1,3-propanesultone (2.56 g, 21 mmol) in acetonitrile (30 ml) is boiled for 2.5 hours. Cool to room temperature. The precipitate was filtered off, washed with acetonitrile (2x5 ml), dried in air for 15 minutes (9.57 g) and further dried for 15 minutes in vacuum (8.02 g). Suspend in ethanol (40 ml) and the suspension is boiled for 1 hour. Then the mixture is cooled to room temperature. The precipitate was suctioned off, washed with ethanol (2x5 ml), dried in air for 15 minutes, then in a vacuum oven at 60 ° C for 18 hours. Compound EA was obtained as a white solid (6.04 g, 18.8 mmol, 94% yield) .

Ή NMR (500 MHz, DMSO) δ, 1.95 (t, 1 = 6.3 Hz, 3Н), 2.63 (t, 1 = 6.1 Hz, 2Н), 2.88 (t, 1 = 7.6 Hz, 2Н), 3.09 (t, 1 = 6.3 Hz, 2Н), 3.15 (t, 1 = 7.8 Hz, 2Н), 7.25 (2, 1 = 7.8 Hz, 2Н), 7.53 (2, 1 = 7.8 Hz, 2Н), 8.63 (br.s, 2H).

¹³ C NMR (125 MHz, DMSO) δ 21.8, 31.0, 46.7, 47.2, 48.8, 119.9, 131.0, 131.4, 136.5.

E8-M8 324 (M + 1).

Preparation of 3 - [(8) -1-indanamino] -1-propanesulfonic acid (compound EB)

A mixture of (8) - (-) - 1-aminoindan (0.92 g, 6.9 mmol) and 1,3-propanesultone (0.93 g, 7.6 mmol) in acetonitrile (15 ml) is boiled for 2.5 hours. It is cooled to room temperature. The precipitate is filtered off, washed with acetonitrile (2x4 ml), dried in air for 15 minutes. Suspend in ethanol (12 ml) and the suspension is boiled for 1 hour. Then the mixture is cooled to room temperature. The precipitate is suctioned off, washed with ethanol (2x4 ml), dried in air for 15 minutes, then in a vacuum oven at 60 ° C for a Saturday Sunday (weekend). Compound EB was obtained as a pale pink solid (1.54 g, 87% yield).

Ή NMR (500 MHz, B ₂ O) δ 2.00 (sq.t, 1 = 7.3 Hz, 2H), 2.09-2.13 (m, 1H), 2.40-2.45 (m, 1H), 2.84-2.87 (m, 3H ), 2.98-3.04 (m, 1H), 3.12 (t, 1 = 7.8 Hz, 2H), 4.67-4.70 (m, 1H), 7.22 (m, 2H), 7.29-7.32 (m, 2H), 7.40 ( d, 1 = 7.8 Hz, 1H).

¹³ C NMR (125 MHz, B ₂ O) δ 21.6, 28.6, 29.8, 43.9, 48.1, 63.0, 1255, 125.7, 127.2, 130.3, 136.3, 145.4.

E8-M8 256 (M + 1). [a] _c = -1.0 ° (c = 0.003095 in water).

- 124 012429

Preparation of 3-cyclobutylamino-1-propanesulfonic acid (EC compound)

A mixture of cyclobutylamine (1.11 g, 15.6 mmol) and 1,3-propanesultone (2 g, 17 mmol) in acetonitrile (18 ml) is heated at the boil. After 15 minutes, the mixture forms a clot (lump). THF (10 ml) was added. Boiling is continued for another 1 hour. The mixture is cooled to room temperature. The precipitate is filtered off, washed with acetonitrile (2x4 ml), dried in air for 60 minutes (2.41 g). Suspend in methanol (20 ml) and the suspension is boiled until the precipitate is completely dissolved. Then the mixture was cooled to room temperature. The precipitate falling out is suctioned off, washed with methanol (2x4 ml), dried in air for 20 minutes, then in a vacuum oven at 40 ° С for 18 hours (lot 1, 4.47 g). The EC compound was obtained as a white solid (1.81 g, 60% yield).

Ή NMR (500 MHz, 1UO) δ 1.70-1.77 (m, 2H), 1.94-2.03 (m, 4H), 2.18 (br.s, 2H), 2.85 (t, 1 = 6.8 Hz, 1H), 2.95 ( t, 1 = 7.3 Hz, 1H), 3.63-3.66 (m, 1H).

¹³ C NMR (125 MHz, 1 VO) δ 14.5, 21.5, 26.1, 43.6, 48.0, 51.8.

E8-M8 194 (M + 1).

Preparation of 3- (4-mexiletino) -1-propanesulfonic acid (EU compound)

Mexiletine hydrochloride (2.45 g, 11.3 mmol) is converted to the free amine by adding 1Ν NaOH (50 ml), extracted with ethyl acetate (2x50 ml). The combined extracts are dried with sodium sulfate. The solvent was evaporated. A solution of 1,3-propansultone (1.46 g, 11.9 mmol) in THF (35 ml) was added to the free amine. The mixture is boiled for 4 hours. Cool to room temperature; the precipitate is filtered off, washed with THF (5 ml). The precipitate was dried overnight at 40 ° C. The filtrate was dried overnight to give a brownish solid (1.45 g), less pure than the filtered first portion. The EU compound was obtained as a white solid (1.19 g, yield 56% (99% crude)).

Ή NMR (500 MHz, DMSO) δ, 1.39 (d, 1 = 6.3 Hz, 3H), 2.02 (t, 1 = 5.9 Hz, 2H), 2.26 (s, 6H), 2.67 (t, 1 = 5.9 Hz, 2H). 3.21 (br.s.d, 1 = 19.5 Hz, 2H), 3.61 (br.s, 1H), 3.83-3.91 (m, 2H), 6.95 (t, 1 = 7.3 Hz, 1H), 7.04 (m, 2H) 8.91 (br s, 2H).

¹³ C NMR (125 MHz, DMSO) δ 13.3, 16.0, 21.8, 44.6, 49.2, 52.9, 70.8, 124.3, 128.9, 130.4, 154.2.

E8-M8 302 (M + 1).

Preparation of 3- (1-benzyl-2-methoxyethyl) amino-1-propanesulfonic acid (compound E \ Y)

8 - (+) - 2-amino-1-methoxy-3-phenylpropane hydrochloride (2.06 g, 10.0 mmol) was converted to the free amine by adding a saturated solution of potassium carbonate (20 ml). The aqueous mixture was extracted with ethyl acetate (3x15 ml) and the combined extracts were dried with sodium sulfate. The solvent was evaporated. A solution of 1,3-propanesultone (1.29 g, 10.5 mmol) in THF (15 ml) was added to the free amine. The mixture is boiled for 4 hours. It is cooled to room temperature and stirred for 1 hour. The precipitate is filtered off, washed with acetone (5 ml). The precipitate was dried overnight at 40 ° C. Compound E \ U was obtained as a white solid (2.48 g, 83% yield).

Ή NMR (500 MHz, DMSO) δ 1.99 (m, 2H), 2.65 (t, 1 = 6.1 Hz, 2H), 2.80 (t, 1 = 12.0 Hz, 1H), 3.05 (m, 2H), 3.17 (m , 3H), 3.22 (dd, 1 = 3.4 Hz, 10.7 Hz, 2H), 3.33 (m, 1H), 3.43 (d, 1 = 10.7 Hz, 2H), 3.50 (m, 1H), 7.27 (m, 3H ), 7.35 (t, 1 = 7.1 Hz, 2H), 8.86 (br.s.d, 1H).

¹³ C NMR (125 MHz, DMSO) δ 21.8, 33.4, 45.0, 49.2, 57.8, 58.5, 68.1, 126.9, 128.7, 129.2, 136.3.

E8-M8 310 (M + 1). [α] _ο = -0.8 ° (c = 0.0025 in water).

Preparation of 3- [1- (Y-hydroxycarbamoyl) -2-phenylethyl] amino-1-propanesulfonic acid (PO compound)

To a solution of ethyl ester of L-L- (3-sulfopropyl) phenylalanine (1.00 g, 3.17 mmol in water (5 ml)) was added a 50% solution of hydroxylamine in water (w / w, 7 ml). The mixture was stirred at room temperature for 24 hours. The mixture was evaporated to dryness. The solid residue is dissolved in a mixture of burning

- 125 012429 of which methanol (10 ml) and water; the mixture is left for 3 days at 5 ° C. Only a small amount of sediment is formed. After the addition of acetone (3 ml), a large amount of precipitate forms. The precipitate was filtered off in vacuo, washed with acetone (2x5 ml) and dried in a vacuum oven at 40 ° C. overnight. The compound was obtained as a white solid (700 mg, 73%).

¹ H NMR (500 MHz, 1) ₃ O) δ 2.03-2.07 (m, 2H), 2.88-2.90 (m, 2H), 2.99-3.03 (m, 1H), 3.07-3.12 (m, 1H), 3.18 -3.23 (m, 1H), 3.82-3.85 (m, 1H), 7.15 (d, 1 = 6.8 Hz, 2H), 7.26-7.31 (m, 3H).

¹³ C NMR (125 MHz, 1) ₃ O) δ 19.3, 33.8, 43.2, 45.8, 57.9, 126.0, 127.1, 127.3, 131.4, 162.2.

E8-M8 303 (M + No.). [α] _Β = 40 ° (c = 0.001983 in water).

Claims (48)

CLAIM 1. The use of the compounds of formula (I) where In ¹ denotes a substituted or unsubstituted 3-10-membered containing from 1 to 4 heteroatoms selected from, O and 8, heterocyclyl, 6-10-membered aryl, 8-15-membered arylcycloalkyl or substituted or unsubstituted C ₂ -C _{1 0} -alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate or fused rings; In ² denotes hydrogen or C1-Su-alkyl; Υ stands for 8O ₃ N; L ¹ denotes a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent; L ² denotes a substituted or unsubstituted C ₂ -C ₅ -alkyl group, provided that when B ¹ is alkyl, L ^{1 is} absent; provided that when B ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X ⁺ ; B ¹ does not denote phenyl, 1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when B ² is hydrogen, B ² is - (CH2) 3; L ^{1 is} absent and Υ means 8O3 ^- X ', B ¹ does not denote n-pentyl, n-hexyl, n-heptyl, noctil, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy -2-Butyl, 2-hydroxy-1-propyl, 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1 -butyl, 5-hydroxy-1-pentyl, 6-hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy-2-pentyl, 3-methylbutyric acid, 4-methylpentanoic acid methyl ester or 2,2-diphenylethyl, or its pharmaceutically with a soluble salt, ester, or prodrug for treating or preventing an amyloid-related disease or condition. 2. The use according to claim 1, characterized in that the disease or condition is characterized by the deposition of β-amyloid. 3. The use of the compounds of formula (I) where B ¹ denotes a substituted or unsubstituted 3-10 membered containing from 1 to 4 heteroatoms selected from, O and 8, heterocyclyl, 6-10 membered aryl, 8-15 membered arylcycloalkyl or substituted or unsubstituted C ₂ -C _{1 0} -alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate or fused rings; In ² denotes hydrogen or C1-Su-alkyl; Υ stands for 8O ₃ N; L ¹ denotes a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent; L ² denotes a substituted or unsubstituted C ₂ -C ₅ -alkyl group, provided that when B ¹ is alkyl, L ^{1 is} absent; provided that when B ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X ⁺ ; B ¹ does not denote phenyl, 1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when B ² is hydrogen, B ² means - (CH2) 3-, L ^{1 is} absent and Υ means 8O3 ^- X ', B ¹ does not denote n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl , 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6 -hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy- 2-pentyl, 3rd tilmaslyanuyu acid, methyl 4-methylpentanoic acid or 2,2-diphenylethyl, or a pharmaceutically acceptable salt, ester or prodrug thereof for the treatment or prevention of amyloid deposition. - 126 012429 4. The use of the compounds of formula (I) K ² where K ¹ denotes a substituted or unsubstituted 3-10 membered containing from 1 to 4 heteroatoms selected from, O and 8, heterocyclyl, 6-10 membered aryl, 8-15 membered arylcycloalkyl or substituted or unsubstituted C ₂ -C1 _{0 is an} alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate or fused rings; K ² is hydrogen or C 1 -Cyu-alkyl; Υ stands for 8O ₃ N; L ¹ denotes a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent; L ² denotes a substituted or unsubstituted C ₂ -C ₅ -alkyl group, provided that when K ¹ is alkyl, L ^{1 is} absent; provided that when K ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X '; K ¹ does not denote phenyl, 1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when K ² is hydrogen, B ² is - (CH2) 3-, L ^{1 is} absent and Υ is 8O3 ^- X ^, K ¹ does not denote n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl , 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6 -hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy- 2-pentyl, 3rd tilmaslyanoic acid, 4-methylpentanoic acid methyl ester or 2,2-diphenylethyl, or its pharmaceutically acceptable salt, ester or prodrug for treating or preventing a disease selected from the group including Alzheimer's disease, cerebral amyloid angiopathy, incision myositis, yellow degeneration spots, ΜΟ or down syndrome. 5. The use according to claim 4, wherein the disease is Alzheimer's disease. 6. The use of the compounds of formula (I) where K ¹ denotes a substituted or unsubstituted 3-10-membered containing from 1 to 4 heteroatoms selected from, O and 8, heterocyclyl, 6-10-membered aryl, 8-15-membered arylcycloalkyl or substituted or unsubstituted C ₂ -C _{1 0} -alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate or fused rings; K ² is hydrogen or C 1 -Cyu-alkyl; Υ stands for 8O ₃ N; L ¹ denotes a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent; L ² denotes a substituted or unsubstituted C ₂ -C ₅ -alkyl group, provided that when K ¹ is alkyl, L ^{1 is} absent; provided that when K ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X ⁺ ; K ¹ does not denote phenyl, 1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when K ² is hydrogen, B ² is - (CH2) 3-, L ^{1 is} absent and Υ is 8O3 ^- X ^, K ¹ does not denote n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl , 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6 -hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy- 2-pentyl, 3rd tilmaslyanuyu acid, methyl 4-methylpentanoic acid or 2,2-diphenylethyl, or a pharmaceutically acceptable salt, ester or prodrug thereof for the manufacture of a medicament for treating or preventing amyloid-related diseases and conditions. 7. The use according to claim 6, characterized in that the disease or condition is characterized by deposition of β-amyloid. 8. The use of the compounds of formula (I) where K ¹ denotes a substituted or unsubstituted 3-10-membered containing from 1 to 4 heteroatoms selected from, O and 8, heterocyclyl, 6-10-membered aryl, 8-15-membered arylcycloalkyl or substituted - 127 012429 an unsubstituted or unsubstituted C ₂ -C _{1 0} -alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate or fused rings; K ² is hydrogen or C 1 -Cyu-alkyl; Υ stands for 8O ₃ N; L ¹ denotes a substituted or unsubstituted C ₁ -C ₅ -alkyl group or is absent; L ² denotes a substituted or unsubstituted C ₂ -C ₅ -alkyl group, provided that when K ¹ is alkyl, L ^{1 is} absent; provided that when K ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X '; K ¹ does not denote phenyl, 1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when K ² is hydrogen, B ² is - (CH2) 3-, L ^{1 is} absent and Υ is 8O3 ^- X ^, K ¹ does not denote n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl , 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6 -hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl or 4-pyridyl, 1-hydroxy- 2-pentyl, 3rd tylbutyric acid, 4-methylpentanoic acid methyl ester or 2,2-diphenylethyl, or a pharmaceutically acceptable salt, ester or prodrug thereof for the manufacture of a medicament for treating or preventing a disease selected from the group including Alzheimer's disease, cerebral amyloid angiopathy, myositis inclusions, macular degeneration, MC1 or Down syndrome. 9. The use of claim 8, wherein the disease is Alzheimer's disease ^. _one 10. The use according to claims 1-9, characterized in that K ¹ denotes hydrogen. 11. The use according to claim 1, characterized in that K ¹ denotes a linear C ₂ -C _{1 0} -alkyl. 12. The use according to claim 11, wherein K ¹ is ethyl, n-pentyl, n-heptyl, n-octyl or n-nonyl. 13. The use according to claims 1-9, characterized in that K ¹ denotes tert-butyl. 14. The use according to claim 13, characterized in that the compound is a 3- (tert-butyl) amino-1-propane sulfonic acid or its pharmaceutically acceptable salt, ester or prodrug. 15. The use according to claims 1-9, wherein K ¹ is C4-C10 cycloalkyl. 16. The application of clause 15, wherein K ¹ denotes cycloalkyl containing 2 or 3 condensed rings. 17. The use according to claim 16, wherein K ¹ is C7-C10 cycloalkyl containing 2 condensed rings. 18. The use according to claim 16, wherein K ¹ is cycloalkyl containing 2 condensed rings. 19. The application of claim 17, wherein K ¹ denotes tricyclo [3.3.1.0 ^3.7 ] decyl or adamantyl. 20. The use according to claim 19, wherein K ¹ is bicyclo [2.1.2] heptyl. 21. The use according to claim 19, wherein the compound is 3- (1-adamantyl) amino-1-propanesulfonic acid or its pharmaceutically acceptable salt, ester or prodrug. 22. The use according to any one of claims 1 to 21, characterized in that b ² means (CH ₂ ) ₃ . 23. The use according to any one of claims 1 to 22, characterized in that b ² is substituted C ₂ -C ₅ alkyl. 24. The use according to claim 23, characterized in that b ^{2 is} selected from -CH ₂ CH ₂ CH (CH ₃ ) - and-CH ₂ CH (OH) CH ₂ -. 25. The use according to claims 1-9, characterized in that the compound is selected from - 128 012429 χζ - 129 012429 - 130 012429 - 131 012429 - 132 012429 - 133 012429 - 134 012429 - 135 012429 - 136 012429 - 137 012429 - 138 012429 - 139 012429 - 140 012429 - 141 012429 or its pharmaceutically acceptable salt, ester or prodrug. 26. A method of treating or preventing an amyloid-related disease, comprising administering to the subject an effective amount of a compound of formula (I) wherein K ¹ is a substituted or unsubstituted 3-10-membered containing from 1 to 4 heteroatoms selected from, O and 8, heterocyclyl 6-10 membered aryl, 8-15 membered arylcycloalkyl or substituted or unsubstituted C ₂ -C _{1 0} alkyl group; moreover, substituted or unsubstituted heterocyclyl, aryl or arylcycloalkyl contain from 1 to 3 separate rings; K ² is hydrogen or C 1 -Cyu-alkyl; Υ stands for 8O ₃ N; L ¹ denotes a substituted or unsubstituted C 1 -C ₅ alkyl group or is absent; L ² denotes a substituted or unsubstituted C ₂ -C ₅ -alkyl group, provided that when K ¹ is alkyl, L ^{1 is} absent; provided that when K ² is hydrogen, L ¹ is methylene, L ² is - (CH ₂ ) ₃ - and Υ is 8O ₃ ^- X ⁺ ; K ¹ does not denote phenyl, 1,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl, and provided that when K ² denotes hydrogen, L ² means - (CH2) 3-, L ^{1 is} absent and Υ means 8O3 ^- X ⁺ , K ¹ does not mean n-pentyl, n-hexyl, n-heptyl, noctil, n-nonyl, n-decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2 -hydroxy-1-propyl, 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, 5-hydroxy -1-pentyl, 6-hydroxy-1-hexyl, 3,5-dimethyl-1-adamantyl, 1-hydroxymethyl-1-cyclopentyl, 2 (2-deoxy-E-glucose), phenyl, 4-hydroxyphenyl, or 4- pyrid l, 1-hydroxy-2-pentyl, 3-methylbutyric acid, methyl 4-methylpentanoic acid or 2,2-diphenylethyl, or a pharmaceutically acceptable salt, ester or prodrug thereof. 27. The method according to p. 26, characterized in that the disease associated with amyloid is characterized by the deposition of β-amyloid. 28. The method according to p. 26 or 27, characterized in that K ¹ denotes hydrogen. 29. The method according to p. 26 or 27, characterized in that K ¹ denotes a linear C ₂ -C _{1 0} -alkyl. 30. The method according to clause 29, wherein K ¹ is ethyl, n-pentyl, n-heptyl, n-octyl or nonyl. 31. The method according to p. 26 or 27, characterized in that K ¹ denotes tert-butyl. - 142 012429 32. The method according to p. 31, characterized in that the compound is a 3- (tert-butyl) amino-1 propane sulfonic acid or its pharmaceutically acceptable salt, ester or prodrug. 33. The method according to p. 26 or 27, characterized in that K ¹ denotes C ₄ -Cy-cycloalkyl. 34. The method according to p. 33, wherein K ¹ denotes cycloalkyl containing 2 or 3 condensed rings. 35. The method according to clause 34, wherein K ¹ denotes a C7-C1 ₀ cycloalkyl containing 2 condensed rings. 36. The method according to clause 34, wherein K ¹ denotes cycloalkyl containing 2 condensed rings. 37. The method of claim 36, wherein K ¹ denotes tricyclo [3.3.1.0 ^3.7 ] decyl or adamantyl. 38. The method according to p. 35, wherein K ¹ denotes bicyclo [2.1.2] heptyl. 39. The method according to claim 37, wherein the compound is 3- (1-adamantyl) amino 1 -propanesulfonic acid or its pharmaceutically acceptable salt, ester or prodrug. 40. The method according to any of paragraphs.26-39, characterized in that b ² means (CH ₂ ) ₃ . 41. The method according to any of paragraphs.26-39, wherein B ² represents substituted C ₂ -C ₅ -alkyl. 42. The method according to claim 41, wherein b ^{2 is} selected from —CH ₂ CH ₂ CH (CH ₃ ) - and CH ₂ CH (OH) CH ₂ -. 43. The method according to p. 26 or 27, characterized in that the compound is selected from - 143 012429 - 144 012429 - 145 012429 - 146 012429 - 147 012429 - 148 012429 - 149 012429 - 150 012429 - 151 012429 - 152 012429 - 153 012429 - 154 012429 - 155 012429 - 156 012429 or its pharmaceutically acceptable salt, ester or prodrug. 44. The compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof, selected from the group consisting of - 157 012429 - 158 012429 - 159 012429 - 160 012429 - 1b1 012429 - 162 012429 - 163 012429 - 164 012429 - 165 012429 - 166 012429 - 167 012429 - 168 012429 where I ¹ means a substituted or unsubstituted bicyclo [2.1.2] heptyl or a substituted or unsubstituted adamantyl; I ² denotes hydrogen or C1-Syu-alkyl; Υ stands for 8O ₃ N; L ¹ is substituted or unsubstituted C ₂ -C ₅ -alkyl or is absent; L ² represents substituted or unsubstituted C2-C5 alkyl group or absent; with the proviso that I ² is hydrogen, L ² is - (CH 2) ₃ -, L ^{1 is} absent, and that I ^{1 is} not 3,4-dimethyl-1 adamantyl or 3,5-dimethyl-1-adamantyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 46. The compound according to claim 44, selected from the group - 169 012429 or its pharmaceutically acceptable salt, ester or prodrug. 47. The compound according to claim 46, which is or its pharmaceutically acceptable salt, ester or prodrug. 48. A compound selected from or a pharmaceutically acceptable salt, ester or prodrug thereof. 49. A pharmaceutical composition for treating or preventing an amyloid disease, comprising a compound according to any one of claims 44 to 48 with a pharmaceutically acceptable carrier.